App overload is a challenge for both providers and patients. As of September 2015, the number of health apps in the US Apple iTunes and Google Play stores exceeded 165,000, with approximately 7% focused on women's health and pregnancy.¹ Clinicians express interest in promoting the use of health apps with their patients and seek guidance about making app recommendations.² In my prior articles in this "App review" series, I have recommended due date calculator and drug reference apps.

One area in which an app may enhance your patient care is in menstrual cycle tracking. Patients may be more honest with their phones than with their health care professionals, and the results are more accurate than paper questionnaires and calendars.³ Of note, menstrual cycle tracking apps are the fourth most popular health app among adults and likely even more popular if limited to adult women.⁴

Dr. Paula Castano and her team systematically identified and evaluated free menstrual cycle tracking apps.⁵ The accuracy of each app was determined by menstrual cycle predictions based on average cycle lengths of at least 3 previous cycles, ovulation predicted at 13 to 15 days prior to the start of the next cycle, and qualification that the application contained no misinformation.⁵

The top 3 recommended menstrual cycle tracking apps from Dr. Castano and colleagues' study are listed in the TABLE alphabetically and are detailed with a shortened version of the APPLICATIONS scoring system, APPLI (app comprehensiveness, price, platform, literature use, and important special features).⁶ I hope this column will allow you to feel more comfortable recommending these "vetted" apps to your patients.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

App overload is a challenge for both providers and patients. As of September 2015, the number of health apps in the US Apple iTunes and Google Play stores exceeded 165,000, with approximately 7% focused on women's health and pregnancy.¹ Clinicians express interest in promoting the use of health apps with their patients and seek guidance about making app recommendations.² In my prior articles in this "App review" series, I have recommended due date calculator and drug reference apps.

One area in which an app may enhance your patient care is in menstrual cycle tracking. Patients may be more honest with their phones than with their health care professionals, and the results are more accurate than paper questionnaires and calendars.³ Of note, menstrual cycle tracking apps are the fourth most popular health app among adults and likely even more popular if limited to adult women.⁴

Dr. Paula Castano and her team systematically identified and evaluated free menstrual cycle tracking apps.⁵ The accuracy of each app was determined by menstrual cycle predictions based on average cycle lengths of at least 3 previous cycles, ovulation predicted at 13 to 15 days prior to the start of the next cycle, and qualification that the application contained no misinformation.⁵

The top 3 recommended menstrual cycle tracking apps from Dr. Castano and colleagues' study are listed in the TABLE alphabetically and are detailed with a shortened version of the APPLICATIONS scoring system, APPLI (app comprehensiveness, price, platform, literature use, and important special features).⁶ I hope this column will allow you to feel more comfortable recommending these "vetted" apps to your patients.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

App overload is a challenge for both providers and patients. As of September 2015, the number of health apps in the US Apple iTunes and Google Play stores exceeded 165,000, with approximately 7% focused on women's health and pregnancy.¹ Clinicians express interest in promoting the use of health apps with their patients and seek guidance about making app recommendations.² In my prior articles in this "App review" series, I have recommended due date calculator and drug reference apps.

One area in which an app may enhance your patient care is in menstrual cycle tracking. Patients may be more honest with their phones than with their health care professionals, and the results are more accurate than paper questionnaires and calendars.³ Of note, menstrual cycle tracking apps are the fourth most popular health app among adults and likely even more popular if limited to adult women.⁴

Dr. Paula Castano and her team systematically identified and evaluated free menstrual cycle tracking apps.⁵ The accuracy of each app was determined by menstrual cycle predictions based on average cycle lengths of at least 3 previous cycles, ovulation predicted at 13 to 15 days prior to the start of the next cycle, and qualification that the application contained no misinformation.⁵

The top 3 recommended menstrual cycle tracking apps from Dr. Castano and colleagues' study are listed in the TABLE alphabetically and are detailed with a shortened version of the APPLICATIONS scoring system, APPLI (app comprehensiveness, price, platform, literature use, and important special features).⁶ I hope this column will allow you to feel more comfortable recommending these "vetted" apps to your patients.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

From the Nationwide Children’s Hospital, Columbus, OH (Dr. Patel) and Cook Children’s Medical Center, Fort Worth, TX (Dr. Perry).

Abstract

• Objective: To review the current understanding and management of febrile seizures.
• Methods: Review of the literature.
• Results: Febrile seizures are a common manifestation in early childhood and very often a benign occurrence. For simple febrile seizures, minimal evaluation is necessary and treatment typically not warranted beyond reassurance and education of caregivers. For complex febrile seizures, additional evaluation in rare cases may suggest an underlying seizure tendency, though most follow a typical benign course of febrile seizures. In some cases, as-needed benzodiazepines used for prolonged or recurrent febrile seizures may be of value. There are well described epilepsy syndromes for which febrile seizures may be the initial manifestation and it is paramount that providers recognize the signs and symptoms of these syndromes in order to appropriately counsel families and initiate treatment or referral when warranted.
• Conclusion: Providers caring for pediatric patients should be aware of the clinical considerations in managing patients with febrile seizures.

Key words: febrile seizure; Dravat syndrome; GEFS+; PCDH19; FIRES; complex febrile seizure.

A febrile seizure is defined as a seizure in association with a febrile illness in the absence of a central nervous system infection or acute electrolyte imbalance in children older than 1 month of age without prior afebrile seizures [1]. The mechanism by which fever provokes a febrile seizure is unclear [2]. Febrile seizures are the most common type of childhood seizures, affecting 2% to 5% of children [1]. The age of onset is between 6 months and 5 years [3]; peak incidence occurs at about 18 months of age. Simple febrile seizures are the most common type of febrile seizure. By definition, they are generalized, last less than 10 minutes and only occur once in a 24-hour time-period. A complex febrile seizure is one with focal onset or one that occurs more than once during a febrile illness, or lasts more than 10 minutes. Febrile status epilepticus, a subtype of complex febrile seizures, represents about 25% of all episodes of childhood status epilepticus. They account for more than two-thirds of cases during the first 2 years of life.

The risk of reoccurrence after presenting with one febrile seizure is approximately 30%, with the risk being 60% after 2 febrile seizures and 90% after 3 [4–6]. Some families have an autosomal dominant inheritance pattern with polygenic inheritance suspected for the majority of patients presenting with febrile seizures.

Multiple chromosomes have been postulated to be associated with genetic susceptibility for febrile seizures, with siblings having a 25% increased risk and high concordance noted in monozygotic twins [7]. The pathophysiology for febrile seizures has been associated with a genetic risk associated with the rate of temperature rise with animal studies suggesting temperature regulation of c-aminobutyric acid (GABA) a receptors [2]. Other studies propose a link between genetic and environmental factors resulting in an inflammatory process which influences neuronal excitement predisposing one to a febrile seizure [8].

Debate exists between the relation of febrile seizures and childhood vaccinations. Seizures are rare following administration of childhood vaccines. Most seizures following administration of vaccines are simple febrile seizures [9]. Febrile seizures associated with vaccines are more associated with underlying epilepsy. In a study of patients with vaccine-related encephalopathy and febrile status epilepticus, the majority of patients were found to have Dravet syndrome; it was determined that the vaccine may have triggered an earlier onset of the presentation for Dravet in those predestined to develop this disease but did not adversely impact ultimate outcome [10].

In this article, we review simple and complex febrile seizures with a focus on clinical management. Epilepsy syndromes associated with febrile seizures are also discussed. Cases are provided to highlight important clinical considerations.

Case 1: Simple Febrile Seizure

A 9-month-old infant and his mother present to the pediatrician. The mother notes that the infant had an event of concern. She notes the infant had stiffness in all 4 extremities followed by jerking that lasted 30 to 60 seconds. The infant was not responsive during the event. He was sleepy afterward, but returned to normal soon after the event ended. After, she noted that the infant felt warm and she checked his temperature. He had a fever of 101°F. The infant has normal development and no other medical problems.

• What are management considerations for simple febrile seizure?

A simple febrile seizure is the most common type of febrile seizure. They are generalized, lasting less than 10 minutes and only occur once in a 24-hour period. There is no increased risk of developing epilepsy or developmental delay for patients after the first simple febrile seizures when compared to other children [5,6]. The diagnosis is based on history provided and a physical examination including evaluation of body temperature [11,12].

No routine laboratory tests are needed as a result of a simple febrile seizure unless obtained to assist in identifying the fever source [3,11]. Routine EEG testing is not recommended for these patients [3,11]. Routine imaging of the brain is also not needed [3,11]. Only if a patient has signs of meningitis should a lumbar puncture be performed [11]. The American Academy of Pediatrics states that a lumbar puncture is strongly considered for those younger than 12 months if they present with their first complex febrile seizure as signs of meningitis may be absent in young children. For infants 6 to 12 months of age, a lumbar puncture can be considered when immunization status is deficient or unknown [13,14]. Also, a lumbar puncture is an option for children who are pretreated with antibiotics [11]. For patients younger than 6 months, data is lacking on the percentage of patients with bacterial meningitis following a simple febrile seizure.

Daily preventative therapy with an anti-epilepsy medication is not necessary [3,11]. A review of several treatment studies shows that some anti-epileptic medications are effective in preventing recurrent simple febrile seizures. Studies have demonstrated the effectiveness of phenobarbital, primidone, and valproic acid in preventing the recurrence of simple febrile seizures; however, the side effects of each medication outweighed the benefit [3]. Carbamazepine and phenytoin have not been shown to be effective in preventing recurrent febrile seizures [3].

For anxious caregivers with children having recurrent febrile seizures, a daily medication or treating with an abortive seizure medication at the time of a febrile illness can be considered [3,5,6,15]. Treating with an abortive medication may mask signs and symptoms of meningitis making evaluation more challenging [16]. Evidence does not support that using antipyretic medications such as acetaminophen or ibuprofen will reduce the recurrence of febrile seizures. The seizure usually is the first noticed symptom due to the rise of temperature being the cause of the febrile seizure in an otherwise well child prior to the seizure [11,17]. Damage to the brain and associated structures is not found with patients presenting with simple febrile seizures [5,6]. Education on all of these principles is strongly recommended for caregiver reassurance.

Case 2: Complex Febrile Seizure

A 1-year-old child presents to the emergency department. Mother was with the child and she noticed stiffness followed by jerking of the left arm and leg, which quickly became noted in both arms and legs. The episode appeared to last for 15 minutes before EMS arrived to the house. A medication was given to the child by EMS that stopped the event. EMS noted the child had a temperature of 101.5°F. The child was previously healthy and has had normal development thus far.

• What is the epidemiology of complex febrile seizure?

A complex febrile seizure is one with focal onset, or one that occurs more than once during a febrile illness or lasts more than 10 minutes. They are less common, representing only 20% to 30% of all febrile seizures [18–20]. In The National Collaborative Perinatal Project (NCPP), 1706 children with febrile seizures were identified from 54,000 and were followed from birth until 7 years of age. The initial febrile seizure was defined as complex in about 28%. For all febrile seizures, focal features were present in 4%, prolonged duration (> 10 minutes) in 7.6%, and recurrent episodes within 24 hours in 16.2% [21]. Similar observations have been reported by Berg and Shinnar [5,6]. Of 136 children who had recurrences, 41.2% had one or more complex features and the strongest correlate of having recurrent complex febrile seizure was the number of recurrent seizures. They also found that children with complex recurrences had other recurrences that were not complex; however, complex features had a tendency to recur. Further, a strong association between focal onset and prolonged duration was found [5,6]. Previous studies established a correlation between complex attacks, particularly prolonged ones and young age (age < 1 year) [5,6]. Additionally, children with seizures with a relatively low fever (< 102°F) were slightly more likely to have a complex febrile seizure as the initial episode [5,6].

Children with febrile seizures are already at 4- to 5-fold increased risk for subsequent unprovoked seizures. A history of febrile seizures has been found in 13% to 18% of children with new-onset epilepsy. In the NCPP study, the predictors identified for the development of epilepsy following febrile seizures were an abnormal neurological and developmental status of the child before the seizure, a history of afebrile seizures in a parent or prior-born sibling, or complex features [21]. Ten percent of children with 2 or more of the previously mentioned risk factors (including complex features) developed epilepsy and 13% of them had seizures without fever [20,22]. Further, intractable epilepsy and neurological impair-ment have been found to be more common in children with prior prolonged febrile seizure, with no association to any specific seizure type [18,23–25]. The association between febrile seizures and mesial temporal sclerosis (MTS) is a commonly debated topic. Retrospective studies have reported an association between prolonged or atypical febrile seizures and intractable temporal lobe epilepsy. Epidemiological studies fail to show a causal relationship between febrile seizures and temporal lobe epilepsy [26]. This suggests that febrile seizures are a marker of susceptibility to seizures and future epilepsy (in some cases) rather than a direct cause. It is clear that a minority of cases of MTS or complex partial seizures are associated with prior febrile seizures [20,22].

• What is the risk of intracranial pathology in complex febrile seizure?

Patients with complex febrile seizures usually seek medical attention [27]. However, the risk of acute pathology necessitating treatment changes based on neuroimaging was found to be very low and likely not necessary in the evaluation of complex febrile seizures during the acute presentation [27]. Imaging with a high-resolution brain MRI could be considered later on a routine basis for prolonged febrile seizures due to the possible association between prolonged febrile seizures and mesial temporal sclerosis [19,28,29].

Neuroimaging has provided evidence that hippocampal injury can occasionally occur during prolonged and focal febrile seizures in infants who otherwise appear normal. It has been speculated that a pre-existing abnormality increases the propensity to focal prolonged seizures and further hippocampal damage. Hesdorffer and colleagues [30] found definite abnormalities on MRI in 14.8% of children with complex febrile seizures and 11.4 % of simple febrile seizures among 159 children with a first febrile seizure. However, MRI abnormalities were related to a specific subtype of complex seizures: focal and prolonged. The most common abnormalities observed were subcortical focal hyperintensity, an abnormal white matter signal, and focal cortical dysplasia.

• What are important aspects of the clinical evaluation?

The evaluation and management of the child with complex febrile seizures is debated as well. The most important part in the history and examination is to look for the source of the fever and rule out the presence of a CNS infection, since complex febrile seizures are much more frequently associated with meningitis than simple febrile seizures [16]. The American Academy of Pediatrics recommended that a lumbar puncture be strongly considered in infants younger than 12 months after a first febrile seizure and should be considered in children between 12 and 18 months of age, since signs of meningitis may be absent in young children [13]. If the threshold for a lumbar puncture is low in infants with febrile seizures in general, it should be even lower for children with complex febrile episodes for all the factors mentioned above. The guidelines developed in 1990 by the Royal College of Physicians and the British Paediatric Association concluded that indications for performing an lumbar puncture were complex febrile seizure, signs of meningismus, or a child who is unduly drowsy and irritable or systematically ill [21].

Obtaining an EEG within 24 hours of presentation may show generalized background slowing, which could make identifying possible epileptiform abnormalities difficult [22]. Therefore, a routine sleep deprived EEG when the child is back to baseline can be more useful in identifying if epileptiform abnormalities are present. If epileptiform abnormalities are present on a routine sleep deprived EEG, this may suggest the patient is at higher risk for developing future epilepsy and the febrile illness lowered the seizure threshold; however, it is unclear whether clinical management would change as a result [31].

• What treatment options are available?

Complications with prolonged and/or recurrent seizures can occur. Treatments options can be stratified into 3 possible categories: emergency rescue treatment for prolonged or a cluster of febrile seizures, intermittent treatment at the time of illness, and chronic use of medication. Treatment options for complex febrile seizures may include the use of a rescue seizure medication when the febrile seizure is prolonged. Rectal preparations of diazepam gel can be effective in stopping an ongoing seizure and can be provided for home use in patients with known recurrence of febrile status epilepticus [3]. For children and adolescents where a rectal administration is not ideal, intranasal versed can be utilized instead of rectal diazepam. In addition, the use of an intermittent benzodiazepine at the onset of febrile illness can also be considered a treatment option. Using oral diazepam at the time of a febrile illness has been demonstrated in reducing the recurrence of febrile seizures [3]. Other studies have shown similar results when using buccal midazolam [32]. No adequate studies have been performed using second- or third-generation anti-epilepsy medications in the treatment of recurrent of complex febrile seizures [3].

It is unclear whether benefit is present to using intermittent benzodiazepine doses prior or during a febrile illness for those prone for recurrent febrile seizures [33]. Physicians may consider this option in patients with frequent recurrent seizures, when caregivers can identify the fever before the seizure occurs.

Overall, parental education of efficacy and side effect profiles should be discussed in detail when considering any treatment options for complex febrile seizures [34]. It is important to remember that the long-term prognosis in terms of developing epilepsy or neurological and cognitive problems is not influenced by the use of antiepileptic medications for recurrent febrile seizures [17]. Even in the case of prolonged febrile seizures in otherwise neurodevelopmentally normal children, antiepileptics have not been shown to cause damage to the brain [19].

Febrile Status Epilepticus

Febrile status epilepticus is a subtype of complex febrile seizures and is defined as a febrile seizure lasting greater than 30 minutes. Overall, febrile status epilepticus accounts for approximately 5% of all presentations of febrile seizures [35]. It represents about 25% of all episodes of childhood status epilepticus and more than two-thirds of cases during the first 2 years of life. Literature suggests that an increased risk for focal epilepsy exists [36]. Children presenting with febrile status epilepticus are more likely to have a family history of epilepsy and a history of a previous neurological abnormality [22]. It is likely to reoccur if the first presentation was febrile status epilepticus. However, increased risk for death or developmental disability as a result of the seizure is not seen [37].

The prospective multicenter study of the consequences of prolonged febrile seizures in childhood (FEBSTAT) has been conducted. The study reported that febrile status epilepticus is usually focal (67% of episodes), occurs in very young children (median age 1.3 years), and is frequently the first febrile seizure [22]. In this study, the median duration of the seizure was about 68 minutes and 24% of children had an episode lasting more than 2 hours. In 87% of the events, seizures did not stop spontaneously and benzodiazepines were needed. Focal features observed were eye and head deviation, staring, and impaired consciousness prior to the seizure and an asymmetric convulsion or Todd’s paresis.

Case 3: Epilepsy Syndromes Associated With Febrile Seizures

A 1-year-old female presents for evaluation of seizures that began at age 8 months. Seizures are described as occurring in the setting of fever with bilateral symmetric tonic clonic activity lasting durations of less than 10 minutes on average, but at least 2 instances of seizure lasting 20 minutes or more. The family notes that seizures have occurred almost every time the child has had a febrile illness and often cluster over several days. They report at least 1 seizure that occurred in the absence of fever. Development has been normal to date and an EEG done by their primary provider was also normal.

• What epilepsy syndromes are associated with febrile seizures?

Genetic Epilepsy with Febrile Seizures Plus

GEFS+ was first described in 1997 following recognition of a pattern of febrile seizures followed later by the development of various epilepsy syndromes within the same family [38]. As such, the syndrome is defined based on the familial occurrence of febrile and afebrile seizures in at least 2 family members and can have a wide range of phenotypes. The most common presentation is of typical febrile seizures which can persist beyond the typical upper age limit of 6 years. Unprovoked generalized seizures of multiple types (ie, myoclonic, absence, atonic) occur at a later age, though focal seizures may also be present. The presence of focal onset seizures led to the naming change from “generalized” epilepsy with febrile seizures plus as it was previously referred. Seizure frequency and severity may vary between family members, as can response to treatment, making prognosis difficult to predict. As even in typical febrile seizures a family history of febrile seizure may be common, it may be difficult to diagnose the syndrome after the initial febrile seizure. However, if the family history is strong for a family member with a GEFS+ phenotype, one can appropriately counsel the family on the possibility that a similar course may evolve. While the majority of GEFS+ patients have milder phenotypes, some more severe phenotypes can have cognitive delays. Dravet syndrome falls within the spectrum of GEFS+ and is a prime example of the phenotypic continuum to more severe presentations in some patients.

The syndrome is believed to be inherited in an auto-somal dominant fashion with incomplete penetrance. Multiple genes have been implicated as a cause, though only 11.5% of families with clinical GEFS+ may have mutations [39]. SCN1A, encoding the α-subunit of the voltage-gated sodium channel is most frequently reported in GEFS+ families, yet is only found in 10% [38]. When associated with GEFS+, SCN1A mutations are more often missense type, whereas truncating and nonsense mutations are more commonly encountered in Dravet syndrome. Mutations in SCN1B encoding the β1 subunit of the voltage-gated sodium channel has also been reported [40]. Finally, the GABA(A) receptor gamma 2 subunit GABRG2 has been found in < 1% of GEFS+ families [39]. The variability in causative genes underscores the reasons for phenotype variability and it is likely that other modifier genes are responsible for the heterogeneity within GEFS+ families [41].

Dravet Syndrome

Dravet syndrome, often referred to as severe myoclonic epilepsy of infancy, was first described in 1978 and has since become one of the most recognized genetic epilepsy syndromes [42]. The clinical presentation often begins with seizures in the first year of life, frequently in the setting of febrile illness. The initial seizures are generalized or hemiclonic in the majority and are often prolonged evolving to status epilepticus. Unlike typical febrile seizures, one should suspect Dravet syndrome in children that present with repetitive bouts of complex febrile seizures or febrile status epilepticus, especially if the associated seizure semiology is of hemiclonic type. In addition, seizures in the setting of modest hyperthermia (ie, hot baths) should raise suspicion for this condition. Commonly EEG and MRI are normal in the first year of life and psychomotor development remains normal until typically the second year of life [43].

By the second year, other seizure types including myoclonic, atypical absence, clonic, and tonic seizures arise. The EEG frequently begins to show generalized spike wave and polyspike wave discharges. Seizures continue occurring frequently during early childhood, often resulting in status epilepticus. Cognitive development begins to stagnate between the ages of 1 and 4 years with emergence of autistic traits and hyperactivity [44]. Development may stabilize between the ages of 5 and 16 years, but fails to demonstrate much improvement [44]. Higher frequency of seizures may correlate with increase in cognitive impairment and behavior problems, supporting the need for rapid diagnosis and appropriate therapy [44].

Over the years, several cases of atypical or borderline Dravet syndrome have been described, most highlighting the absence of myoclonic seizures [45]. Others may present with primarily clonic or tonic-clonic type seizures only [46]. Despite these differences, all cases share a similar drug resistance and cognitive delay and are categorized as Dravet syndrome.

In 2001, Claus et al discovered the genetic alteration in SCN1A responsible for 70% of Dravet syndrome cases [47]. The disorder is inherited in an autosomal dominant fashion, though 40% to 80% of mutations resulting in Dravet syndrome are de novo [48]. Mutations can be present in other family members, as this syndrome is part of the spectrum of GEFS+, though parental phenotypes are often much less severe. Approximately 50% of mutations resulting in Dravet syndrome are truncating, while the other 50% are missense mutations involving splice site or pore forming regions leading to loss of function [49]. Finally, small and large chromosome rearrangements make up 2% to 3% of cases [50]. Other genes reported to result in Dravet syndrome include SCN1B and GABRG2 mutations. In addition, PCDH19 can produce a phenotype similar to Dravet syndrome in females and is discussed in more detail below.

With the emergence of more rapid and cheaper forms of genetic testing, molecular diagnosis can now be made earlier in life before all the typical clinical features of Dravet syndrome arise. As a result, one might hope to alter treatment strategy and gear therapy towards the most effective medications. While drug resistance is the norm for the condition, certain drugs such as benzodiazepines, valproate, and stiripentol may be most effective [43]. Topiramate and levetiracetam have been reported as effi-cacious in small series, as has the ketogenic diet [51–55]. Varieties of medications which target sodium channels are known to exacerbate seizures in Dravet syndrome and should be avoided, including lamotrigine, carbamazepine, oxcarbazepine, and phenytoin [56]. In addition to maintenance therapy, it is important to provide patients with a rescue plan for acute seizures in an effort to avoid status epilepticus. In addition, measures to avoid overheating may provide additional benefit.

Case 3 Continued

After a careful history, the physician discovers that the child also has frequent myoclonic seizures described as brief jerks of the extremities or sudden forward falls. The family notes they have seen these seizures more frequently since antiepileptic therapy was started. The physician recognize that this child may have Dravet syndrome and suspect her medication may be resulting in aggravation of seizures.

The physician decides to discontinue the medication suspected to aggravate the seizures and chooses to start the child on clobazam. The physician also begins evaluation for Dravet syndrome by sending directed SCN1A genetic testing. The testing comes back negative for mutations in the SCN1A gene.

• What other investigations would be warranted now?

PCDH19

PCDH19 was first recognized as a cause of epilepsy and mental retardation limited to females (EFMR), a syndrome characterized by onset of seizures in infancy or early childhood with predominantly generalized type seizures including tonic-clonic, absence, myoclonic, tonic, and atonic [57]. Since that initial description, the phenotype associated with PCDH19 mutations has expanded to include female patients with primarily focal epilepsy, variable cognitive impairment, and commonly onset with seizures in the setting of fever [58,59]. Typically seizures begin around age 10 months presenting as a cluster of focal seizures in the setting of fever, often followed by a second cluster 6 months later [59]. Generalized seizures occur in a small proportion of patients (9%) and this feature, along with relatively fewer bouts of status epilepticus and less frequent seizures (most monthly to yearly frequency) can differentiate PCDH19 associated epilepsy from Dravet syndrome [59]. Seizures tend to improve with age and no particular antiepileptic drug has been found especially efficacious in the syndrome. Unlike Dravet syndrome, up to a third of patients with this syndrome may ultimately become seizure-free [59].

Cognitive development is normal prior to seizure onset in the majority of patients and most but not all patients will develop some cognitive impairment ranging from mild to severe [59]. It is the more severe patients that most often have overlapping characteristics of Dravet syndrome, thus PCDH19 mutations should be investigated in female patients with Dravet phenotype yet negative SCN1A testing.

PCDH19 is a calcium-dependent adhesion protein involved in neuronal circuit formation during development and in the maintenance of normal synaptic circuits in adulthood [60,61]. Disease causing mutations in PCDH19 are primarily missense (48.5%) or frameshift, nonsense, and splice-site mutations resulting in premature termination codon [59]. Ninety percent of mutations are de novo. When inherited, the disorder is X-linked and may come from an unaffected father or a mother that is similarly affected or not, suggesting variable clinical severity in females and gender-related protections in males [59].

Case 3 Continued

Given the negative SCN1A testing, the physician chooses to pursue other genetic testing that may explain the patient’s phenotype. A more extensive “epilepsy gene panel” that includes 70 different genes associated with epilepsy syndromes is ordered.

Hemiconvulsion-Hemiplegia Epilepsy Syndrome

Hemiconvulsion-hemiplegia epilepsy syndrome (HHE) is characterized by the occurrence of unilateral convulsive status epilepticus followed by transient or permanent ipsilateral hemiplegia. The syndrome occurs in otherwise healthy children often in the setting of nonspecific febrile illness before the age of 4 years, with peak occurrence in the first 2 years of life [62]. Seizures are characterized by unilateral clonic activity with EEG demonstrating rhythmic 2–3 Hz slow wave activity and spikes in the hemisphere contralateral to the body involvement. MRI frequently demonstrates diffusion changes congruent with EEG findings, often in the perisylvian region. The hemiplegia that remains following status epilepticus is permanent in up to 80% of cases [63]. As hemiplegia can occur following complex febrile seizures, it is recommended a minimum duration of hemiplegia of 1 week be used to differentiate HHE [64]. Status epilepticus is persistent in this syndrome and can last for hours if untreated. Focal onset seizures will often continue to occur in the patient even after the status has been aborted.

The etiology of HHE is variable with many cases idiopathic. Some cases are reported as symptomatic, as the syndrome can present in the setting of other underlying brain disorders such as Sturge-Weber and tuberous sclerosis complex. While some viruses have been proposed as a cause, they are not found in the cerebral spinal fluid of patients [65]. Treatment consists of rapid treatment of status epilepticus with benzodiazepines as first-line therapy, often followed by other intravenous antiepileptic drugs as necessary.

Febrile Infection–Related Epilepsy Syndrome

Febrile infection–related epilepsy syndrome (FIRES) is presented under several names in the literature including idiopathic catastrophic epileptic encephalopathy [66], devastating encephalopathy in school-age children [67], new-onset refractory status epilepticus [68], as well as fever-induced refractory epileptic encephalopathy syndrome [69] and fever-induced refractory epileptic encephalopathy in school-age children [70]. All describe rare catastrophic epilepsy presenting in otherwise healthy children during or days following a febrile illness. While febrile illness precedes the epilepsy in 96% of cases, up to 50% of patients may not have fever at the time they present [41,65]. While age of onset is typically in early childhood, presentation in adulthood also occurs. Initial seizures are often focal, presenting as forced lateral head or eye deviation, oral or manual automatisms, and clonic movements of the face and extremities. Seizures will inevitably progress to status epilepticus with ictal onset often multifocal predominating in the perisylvian regions [41]. MRI is often normal at onset or shows only subtle swelling of the mesial temporal structures. Over months, MRI often shows T2-hyperintensity and atrophy of the mesial temporal structures, though as many as 50% of MRIs may remain normal [71].

The evaluation for cause in FIRES is often unrewarding. Inflammatory markers are typically absent from both serum and CSF. CSF may show minimal pleocytosis with negative oligoclonal bands and absence of common receptor antibodies. Treatment is equally unrewarding with patients typically failing conventional antiepileptic drugs and continuous infusions titrated to burst suppression. Immunomodulatory therapies are mostly ineffective as well. The most useful therapy reported has been the keto-genic diet with efficacy in up to 50% of patients [72]. Recently, therapeutic hypothermia has also been reported to be effective in 2 cases [73]. For the majority of patients, therapy will remain ineffective and seizures will continue for weeks to months with gradual resolution, though seizures often continue intermittently following the end of status epilepticus. Prognosis is poor for seizure control and neurocognitive recovery with mortality of 30% reported [41].

Case 3 Conclusion

The epilepsy gene panel ordered returns with the result of a disease-causing mutation in the PCDH19 gene. The child is diagnosed with PCDH19-associated epilepsy and is treated with phenobarbital. For the first years of life, she presents on average once per year with a cluster of seizures in the setting of febrile illness which is often managed with short durations of scheduled benzodiazepines. Seizures slow by age 6. She has mild delays in speech and receives some accommodations through her school system. By age 10, she has been seizure-free for several years. She is able to be weaned off medications without recurrence of seizures.

Summary

Febrile seizures are a common manifestation in early childhood and very often a benign occurrence. For simple febrile seizures, minimal evaluation is necessary and treatment typically not warranted beyond reassurance and education of caregivers. For complex febrile seizures, additional evaluation in rare cases may suggest an underlying seizure tendency, though most follow a typical benign course of febrile seizures. In some cases, as needed benzodiazepines used for prolonged or recurrent febrile seizures may be of value. There are well described epilepsy syndromes for which febrile seizures may be the initial manifestation and it is paramount that providers recognize the signs and symptoms of these syndromes in order to appropriately counsel families and initiate treatment or referral when warranted. Providers should have a high index of suspicion for these syndromes when they encounter children that repeatedly present with prolonged febrile seizures, clusters of febrile seizures, or febrile seizures in addition to afebrile seizure events. Early referral, diagnosis, and treatment has the potential to alter outcome in some of these syndromes, thus the importance of becoming familiar with these diagnoses.

Corresponding author: Anup D. Patel, MD, Nationwide Children's Hospital, Columbus, OH 43205, [email protected].

Financial disclosures: Dr. Patel disclosed that he has consulted for GW Pharmaceuticals and Supernus and is on the Scientific Advisory Board for UCB Pharma.

From the Nationwide Children’s Hospital, Columbus, OH (Dr. Patel) and Cook Children’s Medical Center, Fort Worth, TX (Dr. Perry).

Abstract

• Objective: To review the current understanding and management of febrile seizures.
• Methods: Review of the literature.
• Results: Febrile seizures are a common manifestation in early childhood and very often a benign occurrence. For simple febrile seizures, minimal evaluation is necessary and treatment typically not warranted beyond reassurance and education of caregivers. For complex febrile seizures, additional evaluation in rare cases may suggest an underlying seizure tendency, though most follow a typical benign course of febrile seizures. In some cases, as-needed benzodiazepines used for prolonged or recurrent febrile seizures may be of value. There are well described epilepsy syndromes for which febrile seizures may be the initial manifestation and it is paramount that providers recognize the signs and symptoms of these syndromes in order to appropriately counsel families and initiate treatment or referral when warranted.
• Conclusion: Providers caring for pediatric patients should be aware of the clinical considerations in managing patients with febrile seizures.

Key words: febrile seizure; Dravat syndrome; GEFS+; PCDH19; FIRES; complex febrile seizure.

A febrile seizure is defined as a seizure in association with a febrile illness in the absence of a central nervous system infection or acute electrolyte imbalance in children older than 1 month of age without prior afebrile seizures [1]. The mechanism by which fever provokes a febrile seizure is unclear [2]. Febrile seizures are the most common type of childhood seizures, affecting 2% to 5% of children [1]. The age of onset is between 6 months and 5 years [3]; peak incidence occurs at about 18 months of age. Simple febrile seizures are the most common type of febrile seizure. By definition, they are generalized, last less than 10 minutes and only occur once in a 24-hour time-period. A complex febrile seizure is one with focal onset or one that occurs more than once during a febrile illness, or lasts more than 10 minutes. Febrile status epilepticus, a subtype of complex febrile seizures, represents about 25% of all episodes of childhood status epilepticus. They account for more than two-thirds of cases during the first 2 years of life.

The risk of reoccurrence after presenting with one febrile seizure is approximately 30%, with the risk being 60% after 2 febrile seizures and 90% after 3 [4–6]. Some families have an autosomal dominant inheritance pattern with polygenic inheritance suspected for the majority of patients presenting with febrile seizures.

Multiple chromosomes have been postulated to be associated with genetic susceptibility for febrile seizures, with siblings having a 25% increased risk and high concordance noted in monozygotic twins [7]. The pathophysiology for febrile seizures has been associated with a genetic risk associated with the rate of temperature rise with animal studies suggesting temperature regulation of c-aminobutyric acid (GABA) a receptors [2]. Other studies propose a link between genetic and environmental factors resulting in an inflammatory process which influences neuronal excitement predisposing one to a febrile seizure [8].

Debate exists between the relation of febrile seizures and childhood vaccinations. Seizures are rare following administration of childhood vaccines. Most seizures following administration of vaccines are simple febrile seizures [9]. Febrile seizures associated with vaccines are more associated with underlying epilepsy. In a study of patients with vaccine-related encephalopathy and febrile status epilepticus, the majority of patients were found to have Dravet syndrome; it was determined that the vaccine may have triggered an earlier onset of the presentation for Dravet in those predestined to develop this disease but did not adversely impact ultimate outcome [10].

In this article, we review simple and complex febrile seizures with a focus on clinical management. Epilepsy syndromes associated with febrile seizures are also discussed. Cases are provided to highlight important clinical considerations.

Case 1: Simple Febrile Seizure

A 9-month-old infant and his mother present to the pediatrician. The mother notes that the infant had an event of concern. She notes the infant had stiffness in all 4 extremities followed by jerking that lasted 30 to 60 seconds. The infant was not responsive during the event. He was sleepy afterward, but returned to normal soon after the event ended. After, she noted that the infant felt warm and she checked his temperature. He had a fever of 101°F. The infant has normal development and no other medical problems.

• What are management considerations for simple febrile seizure?

A simple febrile seizure is the most common type of febrile seizure. They are generalized, lasting less than 10 minutes and only occur once in a 24-hour period. There is no increased risk of developing epilepsy or developmental delay for patients after the first simple febrile seizures when compared to other children [5,6]. The diagnosis is based on history provided and a physical examination including evaluation of body temperature [11,12].

No routine laboratory tests are needed as a result of a simple febrile seizure unless obtained to assist in identifying the fever source [3,11]. Routine EEG testing is not recommended for these patients [3,11]. Routine imaging of the brain is also not needed [3,11]. Only if a patient has signs of meningitis should a lumbar puncture be performed [11]. The American Academy of Pediatrics states that a lumbar puncture is strongly considered for those younger than 12 months if they present with their first complex febrile seizure as signs of meningitis may be absent in young children. For infants 6 to 12 months of age, a lumbar puncture can be considered when immunization status is deficient or unknown [13,14]. Also, a lumbar puncture is an option for children who are pretreated with antibiotics [11]. For patients younger than 6 months, data is lacking on the percentage of patients with bacterial meningitis following a simple febrile seizure.

Daily preventative therapy with an anti-epilepsy medication is not necessary [3,11]. A review of several treatment studies shows that some anti-epileptic medications are effective in preventing recurrent simple febrile seizures. Studies have demonstrated the effectiveness of phenobarbital, primidone, and valproic acid in preventing the recurrence of simple febrile seizures; however, the side effects of each medication outweighed the benefit [3]. Carbamazepine and phenytoin have not been shown to be effective in preventing recurrent febrile seizures [3].

For anxious caregivers with children having recurrent febrile seizures, a daily medication or treating with an abortive seizure medication at the time of a febrile illness can be considered [3,5,6,15]. Treating with an abortive medication may mask signs and symptoms of meningitis making evaluation more challenging [16]. Evidence does not support that using antipyretic medications such as acetaminophen or ibuprofen will reduce the recurrence of febrile seizures. The seizure usually is the first noticed symptom due to the rise of temperature being the cause of the febrile seizure in an otherwise well child prior to the seizure [11,17]. Damage to the brain and associated structures is not found with patients presenting with simple febrile seizures [5,6]. Education on all of these principles is strongly recommended for caregiver reassurance.

Case 2: Complex Febrile Seizure

A 1-year-old child presents to the emergency department. Mother was with the child and she noticed stiffness followed by jerking of the left arm and leg, which quickly became noted in both arms and legs. The episode appeared to last for 15 minutes before EMS arrived to the house. A medication was given to the child by EMS that stopped the event. EMS noted the child had a temperature of 101.5°F. The child was previously healthy and has had normal development thus far.

• What is the epidemiology of complex febrile seizure?

A complex febrile seizure is one with focal onset, or one that occurs more than once during a febrile illness or lasts more than 10 minutes. They are less common, representing only 20% to 30% of all febrile seizures [18–20]. In The National Collaborative Perinatal Project (NCPP), 1706 children with febrile seizures were identified from 54,000 and were followed from birth until 7 years of age. The initial febrile seizure was defined as complex in about 28%. For all febrile seizures, focal features were present in 4%, prolonged duration (> 10 minutes) in 7.6%, and recurrent episodes within 24 hours in 16.2% [21]. Similar observations have been reported by Berg and Shinnar [5,6]. Of 136 children who had recurrences, 41.2% had one or more complex features and the strongest correlate of having recurrent complex febrile seizure was the number of recurrent seizures. They also found that children with complex recurrences had other recurrences that were not complex; however, complex features had a tendency to recur. Further, a strong association between focal onset and prolonged duration was found [5,6]. Previous studies established a correlation between complex attacks, particularly prolonged ones and young age (age < 1 year) [5,6]. Additionally, children with seizures with a relatively low fever (< 102°F) were slightly more likely to have a complex febrile seizure as the initial episode [5,6].

Children with febrile seizures are already at 4- to 5-fold increased risk for subsequent unprovoked seizures. A history of febrile seizures has been found in 13% to 18% of children with new-onset epilepsy. In the NCPP study, the predictors identified for the development of epilepsy following febrile seizures were an abnormal neurological and developmental status of the child before the seizure, a history of afebrile seizures in a parent or prior-born sibling, or complex features [21]. Ten percent of children with 2 or more of the previously mentioned risk factors (including complex features) developed epilepsy and 13% of them had seizures without fever [20,22]. Further, intractable epilepsy and neurological impair-ment have been found to be more common in children with prior prolonged febrile seizure, with no association to any specific seizure type [18,23–25]. The association between febrile seizures and mesial temporal sclerosis (MTS) is a commonly debated topic. Retrospective studies have reported an association between prolonged or atypical febrile seizures and intractable temporal lobe epilepsy. Epidemiological studies fail to show a causal relationship between febrile seizures and temporal lobe epilepsy [26]. This suggests that febrile seizures are a marker of susceptibility to seizures and future epilepsy (in some cases) rather than a direct cause. It is clear that a minority of cases of MTS or complex partial seizures are associated with prior febrile seizures [20,22].

• What is the risk of intracranial pathology in complex febrile seizure?

Patients with complex febrile seizures usually seek medical attention [27]. However, the risk of acute pathology necessitating treatment changes based on neuroimaging was found to be very low and likely not necessary in the evaluation of complex febrile seizures during the acute presentation [27]. Imaging with a high-resolution brain MRI could be considered later on a routine basis for prolonged febrile seizures due to the possible association between prolonged febrile seizures and mesial temporal sclerosis [19,28,29].

Neuroimaging has provided evidence that hippocampal injury can occasionally occur during prolonged and focal febrile seizures in infants who otherwise appear normal. It has been speculated that a pre-existing abnormality increases the propensity to focal prolonged seizures and further hippocampal damage. Hesdorffer and colleagues [30] found definite abnormalities on MRI in 14.8% of children with complex febrile seizures and 11.4 % of simple febrile seizures among 159 children with a first febrile seizure. However, MRI abnormalities were related to a specific subtype of complex seizures: focal and prolonged. The most common abnormalities observed were subcortical focal hyperintensity, an abnormal white matter signal, and focal cortical dysplasia.

• What are important aspects of the clinical evaluation?

The evaluation and management of the child with complex febrile seizures is debated as well. The most important part in the history and examination is to look for the source of the fever and rule out the presence of a CNS infection, since complex febrile seizures are much more frequently associated with meningitis than simple febrile seizures [16]. The American Academy of Pediatrics recommended that a lumbar puncture be strongly considered in infants younger than 12 months after a first febrile seizure and should be considered in children between 12 and 18 months of age, since signs of meningitis may be absent in young children [13]. If the threshold for a lumbar puncture is low in infants with febrile seizures in general, it should be even lower for children with complex febrile episodes for all the factors mentioned above. The guidelines developed in 1990 by the Royal College of Physicians and the British Paediatric Association concluded that indications for performing an lumbar puncture were complex febrile seizure, signs of meningismus, or a child who is unduly drowsy and irritable or systematically ill [21].

Obtaining an EEG within 24 hours of presentation may show generalized background slowing, which could make identifying possible epileptiform abnormalities difficult [22]. Therefore, a routine sleep deprived EEG when the child is back to baseline can be more useful in identifying if epileptiform abnormalities are present. If epileptiform abnormalities are present on a routine sleep deprived EEG, this may suggest the patient is at higher risk for developing future epilepsy and the febrile illness lowered the seizure threshold; however, it is unclear whether clinical management would change as a result [31].

• What treatment options are available?

Complications with prolonged and/or recurrent seizures can occur. Treatments options can be stratified into 3 possible categories: emergency rescue treatment for prolonged or a cluster of febrile seizures, intermittent treatment at the time of illness, and chronic use of medication. Treatment options for complex febrile seizures may include the use of a rescue seizure medication when the febrile seizure is prolonged. Rectal preparations of diazepam gel can be effective in stopping an ongoing seizure and can be provided for home use in patients with known recurrence of febrile status epilepticus [3]. For children and adolescents where a rectal administration is not ideal, intranasal versed can be utilized instead of rectal diazepam. In addition, the use of an intermittent benzodiazepine at the onset of febrile illness can also be considered a treatment option. Using oral diazepam at the time of a febrile illness has been demonstrated in reducing the recurrence of febrile seizures [3]. Other studies have shown similar results when using buccal midazolam [32]. No adequate studies have been performed using second- or third-generation anti-epilepsy medications in the treatment of recurrent of complex febrile seizures [3].

It is unclear whether benefit is present to using intermittent benzodiazepine doses prior or during a febrile illness for those prone for recurrent febrile seizures [33]. Physicians may consider this option in patients with frequent recurrent seizures, when caregivers can identify the fever before the seizure occurs.

Overall, parental education of efficacy and side effect profiles should be discussed in detail when considering any treatment options for complex febrile seizures [34]. It is important to remember that the long-term prognosis in terms of developing epilepsy or neurological and cognitive problems is not influenced by the use of antiepileptic medications for recurrent febrile seizures [17]. Even in the case of prolonged febrile seizures in otherwise neurodevelopmentally normal children, antiepileptics have not been shown to cause damage to the brain [19].

Febrile Status Epilepticus

Febrile status epilepticus is a subtype of complex febrile seizures and is defined as a febrile seizure lasting greater than 30 minutes. Overall, febrile status epilepticus accounts for approximately 5% of all presentations of febrile seizures [35]. It represents about 25% of all episodes of childhood status epilepticus and more than two-thirds of cases during the first 2 years of life. Literature suggests that an increased risk for focal epilepsy exists [36]. Children presenting with febrile status epilepticus are more likely to have a family history of epilepsy and a history of a previous neurological abnormality [22]. It is likely to reoccur if the first presentation was febrile status epilepticus. However, increased risk for death or developmental disability as a result of the seizure is not seen [37].

The prospective multicenter study of the consequences of prolonged febrile seizures in childhood (FEBSTAT) has been conducted. The study reported that febrile status epilepticus is usually focal (67% of episodes), occurs in very young children (median age 1.3 years), and is frequently the first febrile seizure [22]. In this study, the median duration of the seizure was about 68 minutes and 24% of children had an episode lasting more than 2 hours. In 87% of the events, seizures did not stop spontaneously and benzodiazepines were needed. Focal features observed were eye and head deviation, staring, and impaired consciousness prior to the seizure and an asymmetric convulsion or Todd’s paresis.

Case 3: Epilepsy Syndromes Associated With Febrile Seizures

A 1-year-old female presents for evaluation of seizures that began at age 8 months. Seizures are described as occurring in the setting of fever with bilateral symmetric tonic clonic activity lasting durations of less than 10 minutes on average, but at least 2 instances of seizure lasting 20 minutes or more. The family notes that seizures have occurred almost every time the child has had a febrile illness and often cluster over several days. They report at least 1 seizure that occurred in the absence of fever. Development has been normal to date and an EEG done by their primary provider was also normal.

• What epilepsy syndromes are associated with febrile seizures?

Genetic Epilepsy with Febrile Seizures Plus

GEFS+ was first described in 1997 following recognition of a pattern of febrile seizures followed later by the development of various epilepsy syndromes within the same family [38]. As such, the syndrome is defined based on the familial occurrence of febrile and afebrile seizures in at least 2 family members and can have a wide range of phenotypes. The most common presentation is of typical febrile seizures which can persist beyond the typical upper age limit of 6 years. Unprovoked generalized seizures of multiple types (ie, myoclonic, absence, atonic) occur at a later age, though focal seizures may also be present. The presence of focal onset seizures led to the naming change from “generalized” epilepsy with febrile seizures plus as it was previously referred. Seizure frequency and severity may vary between family members, as can response to treatment, making prognosis difficult to predict. As even in typical febrile seizures a family history of febrile seizure may be common, it may be difficult to diagnose the syndrome after the initial febrile seizure. However, if the family history is strong for a family member with a GEFS+ phenotype, one can appropriately counsel the family on the possibility that a similar course may evolve. While the majority of GEFS+ patients have milder phenotypes, some more severe phenotypes can have cognitive delays. Dravet syndrome falls within the spectrum of GEFS+ and is a prime example of the phenotypic continuum to more severe presentations in some patients.

The syndrome is believed to be inherited in an auto-somal dominant fashion with incomplete penetrance. Multiple genes have been implicated as a cause, though only 11.5% of families with clinical GEFS+ may have mutations [39]. SCN1A, encoding the α-subunit of the voltage-gated sodium channel is most frequently reported in GEFS+ families, yet is only found in 10% [38]. When associated with GEFS+, SCN1A mutations are more often missense type, whereas truncating and nonsense mutations are more commonly encountered in Dravet syndrome. Mutations in SCN1B encoding the β1 subunit of the voltage-gated sodium channel has also been reported [40]. Finally, the GABA(A) receptor gamma 2 subunit GABRG2 has been found in < 1% of GEFS+ families [39]. The variability in causative genes underscores the reasons for phenotype variability and it is likely that other modifier genes are responsible for the heterogeneity within GEFS+ families [41].

Dravet Syndrome

Dravet syndrome, often referred to as severe myoclonic epilepsy of infancy, was first described in 1978 and has since become one of the most recognized genetic epilepsy syndromes [42]. The clinical presentation often begins with seizures in the first year of life, frequently in the setting of febrile illness. The initial seizures are generalized or hemiclonic in the majority and are often prolonged evolving to status epilepticus. Unlike typical febrile seizures, one should suspect Dravet syndrome in children that present with repetitive bouts of complex febrile seizures or febrile status epilepticus, especially if the associated seizure semiology is of hemiclonic type. In addition, seizures in the setting of modest hyperthermia (ie, hot baths) should raise suspicion for this condition. Commonly EEG and MRI are normal in the first year of life and psychomotor development remains normal until typically the second year of life [43].

By the second year, other seizure types including myoclonic, atypical absence, clonic, and tonic seizures arise. The EEG frequently begins to show generalized spike wave and polyspike wave discharges. Seizures continue occurring frequently during early childhood, often resulting in status epilepticus. Cognitive development begins to stagnate between the ages of 1 and 4 years with emergence of autistic traits and hyperactivity [44]. Development may stabilize between the ages of 5 and 16 years, but fails to demonstrate much improvement [44]. Higher frequency of seizures may correlate with increase in cognitive impairment and behavior problems, supporting the need for rapid diagnosis and appropriate therapy [44].

Over the years, several cases of atypical or borderline Dravet syndrome have been described, most highlighting the absence of myoclonic seizures [45]. Others may present with primarily clonic or tonic-clonic type seizures only [46]. Despite these differences, all cases share a similar drug resistance and cognitive delay and are categorized as Dravet syndrome.

In 2001, Claus et al discovered the genetic alteration in SCN1A responsible for 70% of Dravet syndrome cases [47]. The disorder is inherited in an autosomal dominant fashion, though 40% to 80% of mutations resulting in Dravet syndrome are de novo [48]. Mutations can be present in other family members, as this syndrome is part of the spectrum of GEFS+, though parental phenotypes are often much less severe. Approximately 50% of mutations resulting in Dravet syndrome are truncating, while the other 50% are missense mutations involving splice site or pore forming regions leading to loss of function [49]. Finally, small and large chromosome rearrangements make up 2% to 3% of cases [50]. Other genes reported to result in Dravet syndrome include SCN1B and GABRG2 mutations. In addition, PCDH19 can produce a phenotype similar to Dravet syndrome in females and is discussed in more detail below.

With the emergence of more rapid and cheaper forms of genetic testing, molecular diagnosis can now be made earlier in life before all the typical clinical features of Dravet syndrome arise. As a result, one might hope to alter treatment strategy and gear therapy towards the most effective medications. While drug resistance is the norm for the condition, certain drugs such as benzodiazepines, valproate, and stiripentol may be most effective [43]. Topiramate and levetiracetam have been reported as effi-cacious in small series, as has the ketogenic diet [51–55]. Varieties of medications which target sodium channels are known to exacerbate seizures in Dravet syndrome and should be avoided, including lamotrigine, carbamazepine, oxcarbazepine, and phenytoin [56]. In addition to maintenance therapy, it is important to provide patients with a rescue plan for acute seizures in an effort to avoid status epilepticus. In addition, measures to avoid overheating may provide additional benefit.

Case 3 Continued

After a careful history, the physician discovers that the child also has frequent myoclonic seizures described as brief jerks of the extremities or sudden forward falls. The family notes they have seen these seizures more frequently since antiepileptic therapy was started. The physician recognize that this child may have Dravet syndrome and suspect her medication may be resulting in aggravation of seizures.

The physician decides to discontinue the medication suspected to aggravate the seizures and chooses to start the child on clobazam. The physician also begins evaluation for Dravet syndrome by sending directed SCN1A genetic testing. The testing comes back negative for mutations in the SCN1A gene.

• What other investigations would be warranted now?

PCDH19

PCDH19 was first recognized as a cause of epilepsy and mental retardation limited to females (EFMR), a syndrome characterized by onset of seizures in infancy or early childhood with predominantly generalized type seizures including tonic-clonic, absence, myoclonic, tonic, and atonic [57]. Since that initial description, the phenotype associated with PCDH19 mutations has expanded to include female patients with primarily focal epilepsy, variable cognitive impairment, and commonly onset with seizures in the setting of fever [58,59]. Typically seizures begin around age 10 months presenting as a cluster of focal seizures in the setting of fever, often followed by a second cluster 6 months later [59]. Generalized seizures occur in a small proportion of patients (9%) and this feature, along with relatively fewer bouts of status epilepticus and less frequent seizures (most monthly to yearly frequency) can differentiate PCDH19 associated epilepsy from Dravet syndrome [59]. Seizures tend to improve with age and no particular antiepileptic drug has been found especially efficacious in the syndrome. Unlike Dravet syndrome, up to a third of patients with this syndrome may ultimately become seizure-free [59].

Cognitive development is normal prior to seizure onset in the majority of patients and most but not all patients will develop some cognitive impairment ranging from mild to severe [59]. It is the more severe patients that most often have overlapping characteristics of Dravet syndrome, thus PCDH19 mutations should be investigated in female patients with Dravet phenotype yet negative SCN1A testing.

PCDH19 is a calcium-dependent adhesion protein involved in neuronal circuit formation during development and in the maintenance of normal synaptic circuits in adulthood [60,61]. Disease causing mutations in PCDH19 are primarily missense (48.5%) or frameshift, nonsense, and splice-site mutations resulting in premature termination codon [59]. Ninety percent of mutations are de novo. When inherited, the disorder is X-linked and may come from an unaffected father or a mother that is similarly affected or not, suggesting variable clinical severity in females and gender-related protections in males [59].

Case 3 Continued

Given the negative SCN1A testing, the physician chooses to pursue other genetic testing that may explain the patient’s phenotype. A more extensive “epilepsy gene panel” that includes 70 different genes associated with epilepsy syndromes is ordered.

Hemiconvulsion-Hemiplegia Epilepsy Syndrome

Hemiconvulsion-hemiplegia epilepsy syndrome (HHE) is characterized by the occurrence of unilateral convulsive status epilepticus followed by transient or permanent ipsilateral hemiplegia. The syndrome occurs in otherwise healthy children often in the setting of nonspecific febrile illness before the age of 4 years, with peak occurrence in the first 2 years of life [62]. Seizures are characterized by unilateral clonic activity with EEG demonstrating rhythmic 2–3 Hz slow wave activity and spikes in the hemisphere contralateral to the body involvement. MRI frequently demonstrates diffusion changes congruent with EEG findings, often in the perisylvian region. The hemiplegia that remains following status epilepticus is permanent in up to 80% of cases [63]. As hemiplegia can occur following complex febrile seizures, it is recommended a minimum duration of hemiplegia of 1 week be used to differentiate HHE [64]. Status epilepticus is persistent in this syndrome and can last for hours if untreated. Focal onset seizures will often continue to occur in the patient even after the status has been aborted.

The etiology of HHE is variable with many cases idiopathic. Some cases are reported as symptomatic, as the syndrome can present in the setting of other underlying brain disorders such as Sturge-Weber and tuberous sclerosis complex. While some viruses have been proposed as a cause, they are not found in the cerebral spinal fluid of patients [65]. Treatment consists of rapid treatment of status epilepticus with benzodiazepines as first-line therapy, often followed by other intravenous antiepileptic drugs as necessary.

Febrile Infection–Related Epilepsy Syndrome

Febrile infection–related epilepsy syndrome (FIRES) is presented under several names in the literature including idiopathic catastrophic epileptic encephalopathy [66], devastating encephalopathy in school-age children [67], new-onset refractory status epilepticus [68], as well as fever-induced refractory epileptic encephalopathy syndrome [69] and fever-induced refractory epileptic encephalopathy in school-age children [70]. All describe rare catastrophic epilepsy presenting in otherwise healthy children during or days following a febrile illness. While febrile illness precedes the epilepsy in 96% of cases, up to 50% of patients may not have fever at the time they present [41,65]. While age of onset is typically in early childhood, presentation in adulthood also occurs. Initial seizures are often focal, presenting as forced lateral head or eye deviation, oral or manual automatisms, and clonic movements of the face and extremities. Seizures will inevitably progress to status epilepticus with ictal onset often multifocal predominating in the perisylvian regions [41]. MRI is often normal at onset or shows only subtle swelling of the mesial temporal structures. Over months, MRI often shows T2-hyperintensity and atrophy of the mesial temporal structures, though as many as 50% of MRIs may remain normal [71].

The evaluation for cause in FIRES is often unrewarding. Inflammatory markers are typically absent from both serum and CSF. CSF may show minimal pleocytosis with negative oligoclonal bands and absence of common receptor antibodies. Treatment is equally unrewarding with patients typically failing conventional antiepileptic drugs and continuous infusions titrated to burst suppression. Immunomodulatory therapies are mostly ineffective as well. The most useful therapy reported has been the keto-genic diet with efficacy in up to 50% of patients [72]. Recently, therapeutic hypothermia has also been reported to be effective in 2 cases [73]. For the majority of patients, therapy will remain ineffective and seizures will continue for weeks to months with gradual resolution, though seizures often continue intermittently following the end of status epilepticus. Prognosis is poor for seizure control and neurocognitive recovery with mortality of 30% reported [41].

Case 3 Conclusion

The epilepsy gene panel ordered returns with the result of a disease-causing mutation in the PCDH19 gene. The child is diagnosed with PCDH19-associated epilepsy and is treated with phenobarbital. For the first years of life, she presents on average once per year with a cluster of seizures in the setting of febrile illness which is often managed with short durations of scheduled benzodiazepines. Seizures slow by age 6. She has mild delays in speech and receives some accommodations through her school system. By age 10, she has been seizure-free for several years. She is able to be weaned off medications without recurrence of seizures.

Summary

Febrile seizures are a common manifestation in early childhood and very often a benign occurrence. For simple febrile seizures, minimal evaluation is necessary and treatment typically not warranted beyond reassurance and education of caregivers. For complex febrile seizures, additional evaluation in rare cases may suggest an underlying seizure tendency, though most follow a typical benign course of febrile seizures. In some cases, as needed benzodiazepines used for prolonged or recurrent febrile seizures may be of value. There are well described epilepsy syndromes for which febrile seizures may be the initial manifestation and it is paramount that providers recognize the signs and symptoms of these syndromes in order to appropriately counsel families and initiate treatment or referral when warranted. Providers should have a high index of suspicion for these syndromes when they encounter children that repeatedly present with prolonged febrile seizures, clusters of febrile seizures, or febrile seizures in addition to afebrile seizure events. Early referral, diagnosis, and treatment has the potential to alter outcome in some of these syndromes, thus the importance of becoming familiar with these diagnoses.

Corresponding author: Anup D. Patel, MD, Nationwide Children's Hospital, Columbus, OH 43205, [email protected].

Financial disclosures: Dr. Patel disclosed that he has consulted for GW Pharmaceuticals and Supernus and is on the Scientific Advisory Board for UCB Pharma.

From the Nationwide Children’s Hospital, Columbus, OH (Dr. Patel) and Cook Children’s Medical Center, Fort Worth, TX (Dr. Perry).

Abstract

• Objective: To review the current understanding and management of febrile seizures.
• Methods: Review of the literature.
• Results: Febrile seizures are a common manifestation in early childhood and very often a benign occurrence. For simple febrile seizures, minimal evaluation is necessary and treatment typically not warranted beyond reassurance and education of caregivers. For complex febrile seizures, additional evaluation in rare cases may suggest an underlying seizure tendency, though most follow a typical benign course of febrile seizures. In some cases, as-needed benzodiazepines used for prolonged or recurrent febrile seizures may be of value. There are well described epilepsy syndromes for which febrile seizures may be the initial manifestation and it is paramount that providers recognize the signs and symptoms of these syndromes in order to appropriately counsel families and initiate treatment or referral when warranted.
• Conclusion: Providers caring for pediatric patients should be aware of the clinical considerations in managing patients with febrile seizures.

Key words: febrile seizure; Dravat syndrome; GEFS+; PCDH19; FIRES; complex febrile seizure.

A febrile seizure is defined as a seizure in association with a febrile illness in the absence of a central nervous system infection or acute electrolyte imbalance in children older than 1 month of age without prior afebrile seizures [1]. The mechanism by which fever provokes a febrile seizure is unclear [2]. Febrile seizures are the most common type of childhood seizures, affecting 2% to 5% of children [1]. The age of onset is between 6 months and 5 years [3]; peak incidence occurs at about 18 months of age. Simple febrile seizures are the most common type of febrile seizure. By definition, they are generalized, last less than 10 minutes and only occur once in a 24-hour time-period. A complex febrile seizure is one with focal onset or one that occurs more than once during a febrile illness, or lasts more than 10 minutes. Febrile status epilepticus, a subtype of complex febrile seizures, represents about 25% of all episodes of childhood status epilepticus. They account for more than two-thirds of cases during the first 2 years of life.

The risk of reoccurrence after presenting with one febrile seizure is approximately 30%, with the risk being 60% after 2 febrile seizures and 90% after 3 [4–6]. Some families have an autosomal dominant inheritance pattern with polygenic inheritance suspected for the majority of patients presenting with febrile seizures.

Multiple chromosomes have been postulated to be associated with genetic susceptibility for febrile seizures, with siblings having a 25% increased risk and high concordance noted in monozygotic twins [7]. The pathophysiology for febrile seizures has been associated with a genetic risk associated with the rate of temperature rise with animal studies suggesting temperature regulation of c-aminobutyric acid (GABA) a receptors [2]. Other studies propose a link between genetic and environmental factors resulting in an inflammatory process which influences neuronal excitement predisposing one to a febrile seizure [8].

Debate exists between the relation of febrile seizures and childhood vaccinations. Seizures are rare following administration of childhood vaccines. Most seizures following administration of vaccines are simple febrile seizures [9]. Febrile seizures associated with vaccines are more associated with underlying epilepsy. In a study of patients with vaccine-related encephalopathy and febrile status epilepticus, the majority of patients were found to have Dravet syndrome; it was determined that the vaccine may have triggered an earlier onset of the presentation for Dravet in those predestined to develop this disease but did not adversely impact ultimate outcome [10].

In this article, we review simple and complex febrile seizures with a focus on clinical management. Epilepsy syndromes associated with febrile seizures are also discussed. Cases are provided to highlight important clinical considerations.

Case 1: Simple Febrile Seizure

A 9-month-old infant and his mother present to the pediatrician. The mother notes that the infant had an event of concern. She notes the infant had stiffness in all 4 extremities followed by jerking that lasted 30 to 60 seconds. The infant was not responsive during the event. He was sleepy afterward, but returned to normal soon after the event ended. After, she noted that the infant felt warm and she checked his temperature. He had a fever of 101°F. The infant has normal development and no other medical problems.

• What are management considerations for simple febrile seizure?

A simple febrile seizure is the most common type of febrile seizure. They are generalized, lasting less than 10 minutes and only occur once in a 24-hour period. There is no increased risk of developing epilepsy or developmental delay for patients after the first simple febrile seizures when compared to other children [5,6]. The diagnosis is based on history provided and a physical examination including evaluation of body temperature [11,12].

No routine laboratory tests are needed as a result of a simple febrile seizure unless obtained to assist in identifying the fever source [3,11]. Routine EEG testing is not recommended for these patients [3,11]. Routine imaging of the brain is also not needed [3,11]. Only if a patient has signs of meningitis should a lumbar puncture be performed [11]. The American Academy of Pediatrics states that a lumbar puncture is strongly considered for those younger than 12 months if they present with their first complex febrile seizure as signs of meningitis may be absent in young children. For infants 6 to 12 months of age, a lumbar puncture can be considered when immunization status is deficient or unknown [13,14]. Also, a lumbar puncture is an option for children who are pretreated with antibiotics [11]. For patients younger than 6 months, data is lacking on the percentage of patients with bacterial meningitis following a simple febrile seizure.

Daily preventative therapy with an anti-epilepsy medication is not necessary [3,11]. A review of several treatment studies shows that some anti-epileptic medications are effective in preventing recurrent simple febrile seizures. Studies have demonstrated the effectiveness of phenobarbital, primidone, and valproic acid in preventing the recurrence of simple febrile seizures; however, the side effects of each medication outweighed the benefit [3]. Carbamazepine and phenytoin have not been shown to be effective in preventing recurrent febrile seizures [3].

For anxious caregivers with children having recurrent febrile seizures, a daily medication or treating with an abortive seizure medication at the time of a febrile illness can be considered [3,5,6,15]. Treating with an abortive medication may mask signs and symptoms of meningitis making evaluation more challenging [16]. Evidence does not support that using antipyretic medications such as acetaminophen or ibuprofen will reduce the recurrence of febrile seizures. The seizure usually is the first noticed symptom due to the rise of temperature being the cause of the febrile seizure in an otherwise well child prior to the seizure [11,17]. Damage to the brain and associated structures is not found with patients presenting with simple febrile seizures [5,6]. Education on all of these principles is strongly recommended for caregiver reassurance.

Case 2: Complex Febrile Seizure

A 1-year-old child presents to the emergency department. Mother was with the child and she noticed stiffness followed by jerking of the left arm and leg, which quickly became noted in both arms and legs. The episode appeared to last for 15 minutes before EMS arrived to the house. A medication was given to the child by EMS that stopped the event. EMS noted the child had a temperature of 101.5°F. The child was previously healthy and has had normal development thus far.

• What is the epidemiology of complex febrile seizure?

A complex febrile seizure is one with focal onset, or one that occurs more than once during a febrile illness or lasts more than 10 minutes. They are less common, representing only 20% to 30% of all febrile seizures [18–20]. In The National Collaborative Perinatal Project (NCPP), 1706 children with febrile seizures were identified from 54,000 and were followed from birth until 7 years of age. The initial febrile seizure was defined as complex in about 28%. For all febrile seizures, focal features were present in 4%, prolonged duration (> 10 minutes) in 7.6%, and recurrent episodes within 24 hours in 16.2% [21]. Similar observations have been reported by Berg and Shinnar [5,6]. Of 136 children who had recurrences, 41.2% had one or more complex features and the strongest correlate of having recurrent complex febrile seizure was the number of recurrent seizures. They also found that children with complex recurrences had other recurrences that were not complex; however, complex features had a tendency to recur. Further, a strong association between focal onset and prolonged duration was found [5,6]. Previous studies established a correlation between complex attacks, particularly prolonged ones and young age (age < 1 year) [5,6]. Additionally, children with seizures with a relatively low fever (< 102°F) were slightly more likely to have a complex febrile seizure as the initial episode [5,6].

Children with febrile seizures are already at 4- to 5-fold increased risk for subsequent unprovoked seizures. A history of febrile seizures has been found in 13% to 18% of children with new-onset epilepsy. In the NCPP study, the predictors identified for the development of epilepsy following febrile seizures were an abnormal neurological and developmental status of the child before the seizure, a history of afebrile seizures in a parent or prior-born sibling, or complex features [21]. Ten percent of children with 2 or more of the previously mentioned risk factors (including complex features) developed epilepsy and 13% of them had seizures without fever [20,22]. Further, intractable epilepsy and neurological impair-ment have been found to be more common in children with prior prolonged febrile seizure, with no association to any specific seizure type [18,23–25]. The association between febrile seizures and mesial temporal sclerosis (MTS) is a commonly debated topic. Retrospective studies have reported an association between prolonged or atypical febrile seizures and intractable temporal lobe epilepsy. Epidemiological studies fail to show a causal relationship between febrile seizures and temporal lobe epilepsy [26]. This suggests that febrile seizures are a marker of susceptibility to seizures and future epilepsy (in some cases) rather than a direct cause. It is clear that a minority of cases of MTS or complex partial seizures are associated with prior febrile seizures [20,22].

• What is the risk of intracranial pathology in complex febrile seizure?

Patients with complex febrile seizures usually seek medical attention [27]. However, the risk of acute pathology necessitating treatment changes based on neuroimaging was found to be very low and likely not necessary in the evaluation of complex febrile seizures during the acute presentation [27]. Imaging with a high-resolution brain MRI could be considered later on a routine basis for prolonged febrile seizures due to the possible association between prolonged febrile seizures and mesial temporal sclerosis [19,28,29].

Neuroimaging has provided evidence that hippocampal injury can occasionally occur during prolonged and focal febrile seizures in infants who otherwise appear normal. It has been speculated that a pre-existing abnormality increases the propensity to focal prolonged seizures and further hippocampal damage. Hesdorffer and colleagues [30] found definite abnormalities on MRI in 14.8% of children with complex febrile seizures and 11.4 % of simple febrile seizures among 159 children with a first febrile seizure. However, MRI abnormalities were related to a specific subtype of complex seizures: focal and prolonged. The most common abnormalities observed were subcortical focal hyperintensity, an abnormal white matter signal, and focal cortical dysplasia.

• What are important aspects of the clinical evaluation?

The evaluation and management of the child with complex febrile seizures is debated as well. The most important part in the history and examination is to look for the source of the fever and rule out the presence of a CNS infection, since complex febrile seizures are much more frequently associated with meningitis than simple febrile seizures [16]. The American Academy of Pediatrics recommended that a lumbar puncture be strongly considered in infants younger than 12 months after a first febrile seizure and should be considered in children between 12 and 18 months of age, since signs of meningitis may be absent in young children [13]. If the threshold for a lumbar puncture is low in infants with febrile seizures in general, it should be even lower for children with complex febrile episodes for all the factors mentioned above. The guidelines developed in 1990 by the Royal College of Physicians and the British Paediatric Association concluded that indications for performing an lumbar puncture were complex febrile seizure, signs of meningismus, or a child who is unduly drowsy and irritable or systematically ill [21].

Obtaining an EEG within 24 hours of presentation may show generalized background slowing, which could make identifying possible epileptiform abnormalities difficult [22]. Therefore, a routine sleep deprived EEG when the child is back to baseline can be more useful in identifying if epileptiform abnormalities are present. If epileptiform abnormalities are present on a routine sleep deprived EEG, this may suggest the patient is at higher risk for developing future epilepsy and the febrile illness lowered the seizure threshold; however, it is unclear whether clinical management would change as a result [31].

• What treatment options are available?

Complications with prolonged and/or recurrent seizures can occur. Treatments options can be stratified into 3 possible categories: emergency rescue treatment for prolonged or a cluster of febrile seizures, intermittent treatment at the time of illness, and chronic use of medication. Treatment options for complex febrile seizures may include the use of a rescue seizure medication when the febrile seizure is prolonged. Rectal preparations of diazepam gel can be effective in stopping an ongoing seizure and can be provided for home use in patients with known recurrence of febrile status epilepticus [3]. For children and adolescents where a rectal administration is not ideal, intranasal versed can be utilized instead of rectal diazepam. In addition, the use of an intermittent benzodiazepine at the onset of febrile illness can also be considered a treatment option. Using oral diazepam at the time of a febrile illness has been demonstrated in reducing the recurrence of febrile seizures [3]. Other studies have shown similar results when using buccal midazolam [32]. No adequate studies have been performed using second- or third-generation anti-epilepsy medications in the treatment of recurrent of complex febrile seizures [3].

It is unclear whether benefit is present to using intermittent benzodiazepine doses prior or during a febrile illness for those prone for recurrent febrile seizures [33]. Physicians may consider this option in patients with frequent recurrent seizures, when caregivers can identify the fever before the seizure occurs.

Overall, parental education of efficacy and side effect profiles should be discussed in detail when considering any treatment options for complex febrile seizures [34]. It is important to remember that the long-term prognosis in terms of developing epilepsy or neurological and cognitive problems is not influenced by the use of antiepileptic medications for recurrent febrile seizures [17]. Even in the case of prolonged febrile seizures in otherwise neurodevelopmentally normal children, antiepileptics have not been shown to cause damage to the brain [19].

Febrile Status Epilepticus

Febrile status epilepticus is a subtype of complex febrile seizures and is defined as a febrile seizure lasting greater than 30 minutes. Overall, febrile status epilepticus accounts for approximately 5% of all presentations of febrile seizures [35]. It represents about 25% of all episodes of childhood status epilepticus and more than two-thirds of cases during the first 2 years of life. Literature suggests that an increased risk for focal epilepsy exists [36]. Children presenting with febrile status epilepticus are more likely to have a family history of epilepsy and a history of a previous neurological abnormality [22]. It is likely to reoccur if the first presentation was febrile status epilepticus. However, increased risk for death or developmental disability as a result of the seizure is not seen [37].

The prospective multicenter study of the consequences of prolonged febrile seizures in childhood (FEBSTAT) has been conducted. The study reported that febrile status epilepticus is usually focal (67% of episodes), occurs in very young children (median age 1.3 years), and is frequently the first febrile seizure [22]. In this study, the median duration of the seizure was about 68 minutes and 24% of children had an episode lasting more than 2 hours. In 87% of the events, seizures did not stop spontaneously and benzodiazepines were needed. Focal features observed were eye and head deviation, staring, and impaired consciousness prior to the seizure and an asymmetric convulsion or Todd’s paresis.

Case 3: Epilepsy Syndromes Associated With Febrile Seizures

A 1-year-old female presents for evaluation of seizures that began at age 8 months. Seizures are described as occurring in the setting of fever with bilateral symmetric tonic clonic activity lasting durations of less than 10 minutes on average, but at least 2 instances of seizure lasting 20 minutes or more. The family notes that seizures have occurred almost every time the child has had a febrile illness and often cluster over several days. They report at least 1 seizure that occurred in the absence of fever. Development has been normal to date and an EEG done by their primary provider was also normal.

• What epilepsy syndromes are associated with febrile seizures?

Genetic Epilepsy with Febrile Seizures Plus

GEFS+ was first described in 1997 following recognition of a pattern of febrile seizures followed later by the development of various epilepsy syndromes within the same family [38]. As such, the syndrome is defined based on the familial occurrence of febrile and afebrile seizures in at least 2 family members and can have a wide range of phenotypes. The most common presentation is of typical febrile seizures which can persist beyond the typical upper age limit of 6 years. Unprovoked generalized seizures of multiple types (ie, myoclonic, absence, atonic) occur at a later age, though focal seizures may also be present. The presence of focal onset seizures led to the naming change from “generalized” epilepsy with febrile seizures plus as it was previously referred. Seizure frequency and severity may vary between family members, as can response to treatment, making prognosis difficult to predict. As even in typical febrile seizures a family history of febrile seizure may be common, it may be difficult to diagnose the syndrome after the initial febrile seizure. However, if the family history is strong for a family member with a GEFS+ phenotype, one can appropriately counsel the family on the possibility that a similar course may evolve. While the majority of GEFS+ patients have milder phenotypes, some more severe phenotypes can have cognitive delays. Dravet syndrome falls within the spectrum of GEFS+ and is a prime example of the phenotypic continuum to more severe presentations in some patients.

The syndrome is believed to be inherited in an auto-somal dominant fashion with incomplete penetrance. Multiple genes have been implicated as a cause, though only 11.5% of families with clinical GEFS+ may have mutations [39]. SCN1A, encoding the α-subunit of the voltage-gated sodium channel is most frequently reported in GEFS+ families, yet is only found in 10% [38]. When associated with GEFS+, SCN1A mutations are more often missense type, whereas truncating and nonsense mutations are more commonly encountered in Dravet syndrome. Mutations in SCN1B encoding the β1 subunit of the voltage-gated sodium channel has also been reported [40]. Finally, the GABA(A) receptor gamma 2 subunit GABRG2 has been found in < 1% of GEFS+ families [39]. The variability in causative genes underscores the reasons for phenotype variability and it is likely that other modifier genes are responsible for the heterogeneity within GEFS+ families [41].

Dravet Syndrome

Dravet syndrome, often referred to as severe myoclonic epilepsy of infancy, was first described in 1978 and has since become one of the most recognized genetic epilepsy syndromes [42]. The clinical presentation often begins with seizures in the first year of life, frequently in the setting of febrile illness. The initial seizures are generalized or hemiclonic in the majority and are often prolonged evolving to status epilepticus. Unlike typical febrile seizures, one should suspect Dravet syndrome in children that present with repetitive bouts of complex febrile seizures or febrile status epilepticus, especially if the associated seizure semiology is of hemiclonic type. In addition, seizures in the setting of modest hyperthermia (ie, hot baths) should raise suspicion for this condition. Commonly EEG and MRI are normal in the first year of life and psychomotor development remains normal until typically the second year of life [43].

By the second year, other seizure types including myoclonic, atypical absence, clonic, and tonic seizures arise. The EEG frequently begins to show generalized spike wave and polyspike wave discharges. Seizures continue occurring frequently during early childhood, often resulting in status epilepticus. Cognitive development begins to stagnate between the ages of 1 and 4 years with emergence of autistic traits and hyperactivity [44]. Development may stabilize between the ages of 5 and 16 years, but fails to demonstrate much improvement [44]. Higher frequency of seizures may correlate with increase in cognitive impairment and behavior problems, supporting the need for rapid diagnosis and appropriate therapy [44].

Over the years, several cases of atypical or borderline Dravet syndrome have been described, most highlighting the absence of myoclonic seizures [45]. Others may present with primarily clonic or tonic-clonic type seizures only [46]. Despite these differences, all cases share a similar drug resistance and cognitive delay and are categorized as Dravet syndrome.

In 2001, Claus et al discovered the genetic alteration in SCN1A responsible for 70% of Dravet syndrome cases [47]. The disorder is inherited in an autosomal dominant fashion, though 40% to 80% of mutations resulting in Dravet syndrome are de novo [48]. Mutations can be present in other family members, as this syndrome is part of the spectrum of GEFS+, though parental phenotypes are often much less severe. Approximately 50% of mutations resulting in Dravet syndrome are truncating, while the other 50% are missense mutations involving splice site or pore forming regions leading to loss of function [49]. Finally, small and large chromosome rearrangements make up 2% to 3% of cases [50]. Other genes reported to result in Dravet syndrome include SCN1B and GABRG2 mutations. In addition, PCDH19 can produce a phenotype similar to Dravet syndrome in females and is discussed in more detail below.

With the emergence of more rapid and cheaper forms of genetic testing, molecular diagnosis can now be made earlier in life before all the typical clinical features of Dravet syndrome arise. As a result, one might hope to alter treatment strategy and gear therapy towards the most effective medications. While drug resistance is the norm for the condition, certain drugs such as benzodiazepines, valproate, and stiripentol may be most effective [43]. Topiramate and levetiracetam have been reported as effi-cacious in small series, as has the ketogenic diet [51–55]. Varieties of medications which target sodium channels are known to exacerbate seizures in Dravet syndrome and should be avoided, including lamotrigine, carbamazepine, oxcarbazepine, and phenytoin [56]. In addition to maintenance therapy, it is important to provide patients with a rescue plan for acute seizures in an effort to avoid status epilepticus. In addition, measures to avoid overheating may provide additional benefit.

Case 3 Continued

After a careful history, the physician discovers that the child also has frequent myoclonic seizures described as brief jerks of the extremities or sudden forward falls. The family notes they have seen these seizures more frequently since antiepileptic therapy was started. The physician recognize that this child may have Dravet syndrome and suspect her medication may be resulting in aggravation of seizures.

The physician decides to discontinue the medication suspected to aggravate the seizures and chooses to start the child on clobazam. The physician also begins evaluation for Dravet syndrome by sending directed SCN1A genetic testing. The testing comes back negative for mutations in the SCN1A gene.

• What other investigations would be warranted now?

PCDH19

PCDH19 was first recognized as a cause of epilepsy and mental retardation limited to females (EFMR), a syndrome characterized by onset of seizures in infancy or early childhood with predominantly generalized type seizures including tonic-clonic, absence, myoclonic, tonic, and atonic [57]. Since that initial description, the phenotype associated with PCDH19 mutations has expanded to include female patients with primarily focal epilepsy, variable cognitive impairment, and commonly onset with seizures in the setting of fever [58,59]. Typically seizures begin around age 10 months presenting as a cluster of focal seizures in the setting of fever, often followed by a second cluster 6 months later [59]. Generalized seizures occur in a small proportion of patients (9%) and this feature, along with relatively fewer bouts of status epilepticus and less frequent seizures (most monthly to yearly frequency) can differentiate PCDH19 associated epilepsy from Dravet syndrome [59]. Seizures tend to improve with age and no particular antiepileptic drug has been found especially efficacious in the syndrome. Unlike Dravet syndrome, up to a third of patients with this syndrome may ultimately become seizure-free [59].

Cognitive development is normal prior to seizure onset in the majority of patients and most but not all patients will develop some cognitive impairment ranging from mild to severe [59]. It is the more severe patients that most often have overlapping characteristics of Dravet syndrome, thus PCDH19 mutations should be investigated in female patients with Dravet phenotype yet negative SCN1A testing.

PCDH19 is a calcium-dependent adhesion protein involved in neuronal circuit formation during development and in the maintenance of normal synaptic circuits in adulthood [60,61]. Disease causing mutations in PCDH19 are primarily missense (48.5%) or frameshift, nonsense, and splice-site mutations resulting in premature termination codon [59]. Ninety percent of mutations are de novo. When inherited, the disorder is X-linked and may come from an unaffected father or a mother that is similarly affected or not, suggesting variable clinical severity in females and gender-related protections in males [59].

Case 3 Continued

Given the negative SCN1A testing, the physician chooses to pursue other genetic testing that may explain the patient’s phenotype. A more extensive “epilepsy gene panel” that includes 70 different genes associated with epilepsy syndromes is ordered.

Hemiconvulsion-Hemiplegia Epilepsy Syndrome

Hemiconvulsion-hemiplegia epilepsy syndrome (HHE) is characterized by the occurrence of unilateral convulsive status epilepticus followed by transient or permanent ipsilateral hemiplegia. The syndrome occurs in otherwise healthy children often in the setting of nonspecific febrile illness before the age of 4 years, with peak occurrence in the first 2 years of life [62]. Seizures are characterized by unilateral clonic activity with EEG demonstrating rhythmic 2–3 Hz slow wave activity and spikes in the hemisphere contralateral to the body involvement. MRI frequently demonstrates diffusion changes congruent with EEG findings, often in the perisylvian region. The hemiplegia that remains following status epilepticus is permanent in up to 80% of cases [63]. As hemiplegia can occur following complex febrile seizures, it is recommended a minimum duration of hemiplegia of 1 week be used to differentiate HHE [64]. Status epilepticus is persistent in this syndrome and can last for hours if untreated. Focal onset seizures will often continue to occur in the patient even after the status has been aborted.

The etiology of HHE is variable with many cases idiopathic. Some cases are reported as symptomatic, as the syndrome can present in the setting of other underlying brain disorders such as Sturge-Weber and tuberous sclerosis complex. While some viruses have been proposed as a cause, they are not found in the cerebral spinal fluid of patients [65]. Treatment consists of rapid treatment of status epilepticus with benzodiazepines as first-line therapy, often followed by other intravenous antiepileptic drugs as necessary.

Febrile Infection–Related Epilepsy Syndrome

Febrile infection–related epilepsy syndrome (FIRES) is presented under several names in the literature including idiopathic catastrophic epileptic encephalopathy [66], devastating encephalopathy in school-age children [67], new-onset refractory status epilepticus [68], as well as fever-induced refractory epileptic encephalopathy syndrome [69] and fever-induced refractory epileptic encephalopathy in school-age children [70]. All describe rare catastrophic epilepsy presenting in otherwise healthy children during or days following a febrile illness. While febrile illness precedes the epilepsy in 96% of cases, up to 50% of patients may not have fever at the time they present [41,65]. While age of onset is typically in early childhood, presentation in adulthood also occurs. Initial seizures are often focal, presenting as forced lateral head or eye deviation, oral or manual automatisms, and clonic movements of the face and extremities. Seizures will inevitably progress to status epilepticus with ictal onset often multifocal predominating in the perisylvian regions [41]. MRI is often normal at onset or shows only subtle swelling of the mesial temporal structures. Over months, MRI often shows T2-hyperintensity and atrophy of the mesial temporal structures, though as many as 50% of MRIs may remain normal [71].

The evaluation for cause in FIRES is often unrewarding. Inflammatory markers are typically absent from both serum and CSF. CSF may show minimal pleocytosis with negative oligoclonal bands and absence of common receptor antibodies. Treatment is equally unrewarding with patients typically failing conventional antiepileptic drugs and continuous infusions titrated to burst suppression. Immunomodulatory therapies are mostly ineffective as well. The most useful therapy reported has been the keto-genic diet with efficacy in up to 50% of patients [72]. Recently, therapeutic hypothermia has also been reported to be effective in 2 cases [73]. For the majority of patients, therapy will remain ineffective and seizures will continue for weeks to months with gradual resolution, though seizures often continue intermittently following the end of status epilepticus. Prognosis is poor for seizure control and neurocognitive recovery with mortality of 30% reported [41].

Case 3 Conclusion

The epilepsy gene panel ordered returns with the result of a disease-causing mutation in the PCDH19 gene. The child is diagnosed with PCDH19-associated epilepsy and is treated with phenobarbital. For the first years of life, she presents on average once per year with a cluster of seizures in the setting of febrile illness which is often managed with short durations of scheduled benzodiazepines. Seizures slow by age 6. She has mild delays in speech and receives some accommodations through her school system. By age 10, she has been seizure-free for several years. She is able to be weaned off medications without recurrence of seizures.

Summary

Febrile seizures are a common manifestation in early childhood and very often a benign occurrence. For simple febrile seizures, minimal evaluation is necessary and treatment typically not warranted beyond reassurance and education of caregivers. For complex febrile seizures, additional evaluation in rare cases may suggest an underlying seizure tendency, though most follow a typical benign course of febrile seizures. In some cases, as needed benzodiazepines used for prolonged or recurrent febrile seizures may be of value. There are well described epilepsy syndromes for which febrile seizures may be the initial manifestation and it is paramount that providers recognize the signs and symptoms of these syndromes in order to appropriately counsel families and initiate treatment or referral when warranted. Providers should have a high index of suspicion for these syndromes when they encounter children that repeatedly present with prolonged febrile seizures, clusters of febrile seizures, or febrile seizures in addition to afebrile seizure events. Early referral, diagnosis, and treatment has the potential to alter outcome in some of these syndromes, thus the importance of becoming familiar with these diagnoses.

Corresponding author: Anup D. Patel, MD, Nationwide Children's Hospital, Columbus, OH 43205, [email protected].

Financial disclosures: Dr. Patel disclosed that he has consulted for GW Pharmaceuticals and Supernus and is on the Scientific Advisory Board for UCB Pharma.

SAN DIEGO – The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide significantly reduced the risk of initial and recurrent major cardiovascular events in high-risk patients with type 2 diabetes, according to new posthoc analyses from the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial.

Liraglutide’s cardioprotective effect did not depend on baseline use of insulin or cardiovascular medications, nor whether patients started insulin, sulfonylureas, or thiazolidinediones, or developed severe hypoglycemia during the trial, Richard Pratley, MD, told a packed auditorium at the annual scientific sessions of the American Diabetes Association. “It appears unlikely that the cardiovascular risk reduction with liraglutide can be fully explained by the observed differences in hemoglobin A1c, body weight, systolic blood pressure, and lipids,” he said. Experts have proposed several pathways, “but the bottom line is, in humans, we don’t know the mechanism for liraglutide’s benefit.”

In LEADER, 9,340 older patients with suboptimally controlled type 2 diabetes and additional cardiovascular risk factors were randomly assigned to liraglutide or placebo once daily. Patients were typically male, obese, and hypertensive, and about 18% had prior heart failure. Topline results reported last year at ADA included a 13% reduction in the rate of initial cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke in the liraglutide group, compared with the placebo group (hazard ratio, 0.87; 95% confidence interval, 0.78 to 0.97).

The new posthoc analyses indicate that liraglutide also prevents both initial and recurrent cardiovascular events (HR, 0.86; 95% CI, 0.78 to 0.95) and that its cardioprotective effect spans subgroups of patients stratified according to whether they were on insulin, beta-blockers, ACE inhibitors, statins, and platelet aggregation inhibitors at baseline, said Dr. Pratley, senior investigator at the Translational Research Institute for Metabolism and Diabetes, and medical director of the Florida Hospital Diabetes Institute, Orlando.

SAN DIEGO – The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide significantly reduced the risk of initial and recurrent major cardiovascular events in high-risk patients with type 2 diabetes, according to new posthoc analyses from the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial.

Liraglutide’s cardioprotective effect did not depend on baseline use of insulin or cardiovascular medications, nor whether patients started insulin, sulfonylureas, or thiazolidinediones, or developed severe hypoglycemia during the trial, Richard Pratley, MD, told a packed auditorium at the annual scientific sessions of the American Diabetes Association. “It appears unlikely that the cardiovascular risk reduction with liraglutide can be fully explained by the observed differences in hemoglobin A1c, body weight, systolic blood pressure, and lipids,” he said. Experts have proposed several pathways, “but the bottom line is, in humans, we don’t know the mechanism for liraglutide’s benefit.”

In LEADER, 9,340 older patients with suboptimally controlled type 2 diabetes and additional cardiovascular risk factors were randomly assigned to liraglutide or placebo once daily. Patients were typically male, obese, and hypertensive, and about 18% had prior heart failure. Topline results reported last year at ADA included a 13% reduction in the rate of initial cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke in the liraglutide group, compared with the placebo group (hazard ratio, 0.87; 95% confidence interval, 0.78 to 0.97).

The new posthoc analyses indicate that liraglutide also prevents both initial and recurrent cardiovascular events (HR, 0.86; 95% CI, 0.78 to 0.95) and that its cardioprotective effect spans subgroups of patients stratified according to whether they were on insulin, beta-blockers, ACE inhibitors, statins, and platelet aggregation inhibitors at baseline, said Dr. Pratley, senior investigator at the Translational Research Institute for Metabolism and Diabetes, and medical director of the Florida Hospital Diabetes Institute, Orlando.

SAN DIEGO – The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide significantly reduced the risk of initial and recurrent major cardiovascular events in high-risk patients with type 2 diabetes, according to new posthoc analyses from the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial.

Liraglutide’s cardioprotective effect did not depend on baseline use of insulin or cardiovascular medications, nor whether patients started insulin, sulfonylureas, or thiazolidinediones, or developed severe hypoglycemia during the trial, Richard Pratley, MD, told a packed auditorium at the annual scientific sessions of the American Diabetes Association. “It appears unlikely that the cardiovascular risk reduction with liraglutide can be fully explained by the observed differences in hemoglobin A1c, body weight, systolic blood pressure, and lipids,” he said. Experts have proposed several pathways, “but the bottom line is, in humans, we don’t know the mechanism for liraglutide’s benefit.”

In LEADER, 9,340 older patients with suboptimally controlled type 2 diabetes and additional cardiovascular risk factors were randomly assigned to liraglutide or placebo once daily. Patients were typically male, obese, and hypertensive, and about 18% had prior heart failure. Topline results reported last year at ADA included a 13% reduction in the rate of initial cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke in the liraglutide group, compared with the placebo group (hazard ratio, 0.87; 95% confidence interval, 0.78 to 0.97).

The new posthoc analyses indicate that liraglutide also prevents both initial and recurrent cardiovascular events (HR, 0.86; 95% CI, 0.78 to 0.95) and that its cardioprotective effect spans subgroups of patients stratified according to whether they were on insulin, beta-blockers, ACE inhibitors, statins, and platelet aggregation inhibitors at baseline, said Dr. Pratley, senior investigator at the Translational Research Institute for Metabolism and Diabetes, and medical director of the Florida Hospital Diabetes Institute, Orlando.

By the time this column appears in print we will know whether the US Senate passed a version of the GOP health care bill. If so, millions of our patients will be at risk of losing insurance coverage in the name of tax and deficit reduction. I refer you to an article I wrote for the June issue of Clinical Gastroenterology and Hepatology about the potential transition from Obamacare to Trumpcare.

Our “Flashback” article this month concerns another long-running Congressional issue: repeal of the Sustainable Growth Rate and implementation of value-based reimbursement. We thank Dr. Larry Kosinski for his commentary and for successfully creating the first GI-specific alternative payment model to be endorsed by CMS.

John I. Allen, MD, MBA, AGAF, FACP

Editor in Chief

By the time this column appears in print we will know whether the US Senate passed a version of the GOP health care bill. If so, millions of our patients will be at risk of losing insurance coverage in the name of tax and deficit reduction. I refer you to an article I wrote for the June issue of Clinical Gastroenterology and Hepatology about the potential transition from Obamacare to Trumpcare.

Our “Flashback” article this month concerns another long-running Congressional issue: repeal of the Sustainable Growth Rate and implementation of value-based reimbursement. We thank Dr. Larry Kosinski for his commentary and for successfully creating the first GI-specific alternative payment model to be endorsed by CMS.

John I. Allen, MD, MBA, AGAF, FACP

Editor in Chief

By the time this column appears in print we will know whether the US Senate passed a version of the GOP health care bill. If so, millions of our patients will be at risk of losing insurance coverage in the name of tax and deficit reduction. I refer you to an article I wrote for the June issue of Clinical Gastroenterology and Hepatology about the potential transition from Obamacare to Trumpcare.

Our “Flashback” article this month concerns another long-running Congressional issue: repeal of the Sustainable Growth Rate and implementation of value-based reimbursement. We thank Dr. Larry Kosinski for his commentary and for successfully creating the first GI-specific alternative payment model to be endorsed by CMS.

John I. Allen, MD, MBA, AGAF, FACP

Editor in Chief

In this Update we review the results of 4 recent investigations that have important implications:

• the first analysis of the US Zika Virus Infection in Pregnancy Registry
• a study revealing an improved antibiotic regimen to prevent postcesarean infection
• an important new methodology for reducing the rate of perinatal transmission of hepatitis B virus (HBV) infection
• the risks and benefits of combination antiretroviral therapy (ART) in pregnancy.

Zika virus-associated birth defect rates similar regardless of symptom presence; first-trimester exposure has highest rate of anomalies

Honein MA, Dawson AL, Petersen EE, et al; US Zika Pregnancy Registry Collaboration. Birth defects among fetuses and infants of US women with evidence of possible Zika virus infection during pregnancy. JAMA. 2017;317(1):59-68.

Honein and colleagues provide a summary of the data from the US Zika Virus in Pregnancy Registry (a collaboration between the Centers for Disease Control and Prevention and state and local health departments), estimating the proportion of fetuses and infants with birth defects based on maternal symptoms of Zika virus infection and  trimester of possible infection.

Related article:
Zika virus: Counseling considerations for this emerging perinatal threat

Details of the study

The authors evaluated the outcomes of 442 women who had laboratory evidence of a possible Zika virus infection during pregnancy. Overall, 26 infants (6%; 95% confidence interval (CI), 4%-8%) had evidence of birth defects related to the Zika virus. Of note, abnormalities were detected in 16 of the 271 children (6%; 95% CI, 4%-9%) born to women who were asymptomatic and 10 of 167 (6%; 95% CI, 3%-11%) children delivered to women with symptomatic infections. 

The most common birth defect was microcephaly, although other serious central nervous system abnormalities were noted as well. Nine of 85 women (11%; 95% CI, 6%-19%) who had exposure only during the first trimester had infants with birth defects. There were no documented abnormalities in infants born to mothers who developed Zika virus infection only in the second or third trimester. 

Related article:
Zika virus update: A rapidly moving target

Key study findings

This article is important for several reasons. First, the authors describe the largest series of pregnant women in the United States with Zika virus infection. All of these patients developed Zika virus infection as a result of foreign travel or exposure to sexual partners who had traveled to Zika virus endemic areas. Second, the authors confirmed findings that previously had been based only on mathematical models rather than on actual case series. Specifically, they demonstrated that the risk of a serious birth defect following first-trimester exposure to Zika virus infection was approximately 11%, with a 95% CI that extended from 6% to 19%. Finally, Honein and colleagues highlighted the key fact that the risk of a serious birth defect was comparable in mothers who had either an asymptomatic or a symptomatic infection, a finding that seems somewhat counterintuitive.

Read about prophylaxis for postcesarean infection

Two antibiotics before cesarean delivery reduce infection rates further than one agent

Tita AT, Szychowski JM, Boggess K, et al; for the C/SOAP Trial Consortium. Adjunctive azithromycin prophylaxis for cesarean delivery. N Engl J Med. 2016;375(13):1231-1241.

Tita and colleagues reported the results of a multicenter trial that was designed to assess whether a combination of 2 antibiotics, including one that specifically targets ureaplasma species, provided more effective prophylaxis against postcesarean infection than single-agent prophylaxis.

Details of the study

The Cesarean Section Optimal Antibiotic Prophylaxis (C/SOAP) trial was conducted at 14 centers in the United States and included 2,013 women who were at least at 24 weeks' gestation and who had a cesarean delivery during labor or after membrane rupture.

The authors randomly assigned 1,019 women to receive 500 mg of intravenous azithromycin plus conventional single-agent prophylaxis (usually cefazolin) and 994 women to receive a placebo plus conventional prophylaxis. The primary outcome was the composite of endometritis, wound infection, or other infection occurring within 6 weeks.

The authors observed that the primary outcome occurred in 62 women (6.1%) who received azithromycin plus conventional prophylaxis and in 119 women (12%) who received only single-agent prophylaxis. The relative risk of developing a postoperative infection was 0.51 in women who received the combined therapy. There were significant differences between the 2 groups in both the rates of endometritis (3.8% vs 6.1%, P = .02) and wound infection (2.4% vs 6.6%, P<.001). There were no differences between the groups in the frequency of the secondary neonatal composite outcome, which included neonatal death and serious neonatal complications.

Related article:
Preventing infection after cesarean delivery: 5 more evidence-based measures to consider

Efficacy of dual-agent prophylaxis

At present, the standard of care is to administer prophylactic antibiotics to all women having cesarean delivery, including women having a scheduled cesarean in the absence of labor or ruptured membranes. Multiple studies have shown clearly that prophylaxis reduces the frequency of endometritis and, in high-risk patient populations, wound infection, and that prophylaxis is most beneficial when administered prior to the time the surgical incision is made. The most commonly used drug for prophylaxis is cefazolin, a first-generation cephalosporin. The usual recommended dose is 2 g, administered immediately prior to surgery.^3,4

Although most centers in the United States traditionally have used just a single antibiotic for prophylaxis, selected recent reports indicate that expanding the spectrum of activity of prophylactic antibiotics can result in additional beneficial effects. Specifically, Tita and colleagues evaluated an indigent patient population with an inherently high rate of postoperative infection.⁵ They showed that adding azithromycin 500 mg to cefazolin significantly reduced the rate of postcesarean endometritis. In a follow-up report from the same institution, Tita and colleagues demonstrated that adding azithromycin also significantly reduced the frequency of wound infection.⁶ Of note, in both these investigations, the antibiotics were administered after cord clamping. In a subsequent report, Ward and Duff showed that the combination of azithromycin plus cefazolin administered preoperatively resulted in a combined rate of endometritis and wound infection that was less than 3%.⁷

Related article:
Preventing infection after cesarean delivery: Evidence-based guidance

C/SOAP trial confirmed lower infection rates with combined regimen

Results of the present study confirm the findings of these 3 investigations. The trial included a large sample size. The study was carefully designed, and the end points were clearly defined. It included only patients at increased risk for postoperative infection by virtue of being in labor or having ruptured membranes at the time of cesarean delivery. Patients who received standard prophylaxis, usually cefazolin, plus azithromycin had a significantly lower risk of postcesarean endometritis and wound infection compared with patients who received a single antibiotic. The overall risk of infection was reduced by an impressive 50%.  
 

Read about reducing HBV transmission

Tenofovir treatment in pregnant women with HBV reduces vertical transmission

Pan CQ, Duan Z, Dai E, et al; China Study Group for the Mother-to-Child Transmission of Hepatitis B. Tenofovir to prevent hepatitis B transmission in mothers with high viral load. N Engl J Med. 2016;374(24):2324-2334.

A multicenter, open-label, randomized, parallel-group investigation was conducted from March 2012 to June 2013 at academic tertiary care centers in 5 geographic regions of China. Two hundred mothers, who were positive for both hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) and who had HBV DNA concentrations of 200,000 IU/mL or greater, were randomly assigned in a 1:1 ratio to either tenofovir or to usual treatment. Exclusion criteria were coexistent viral infections or medical conditions, renal failure, laboratory abnormalities, fetal deformities, and use of many medications.

Related article:
5 ways to reduce infection risk during pregnancy

Details of the study

Women in the active treatment group received tenofovir 300 mg by mouth daily from 30 to 32 weeks' gestation until postpartum week 4. Patients were monitored every 4 weeks in the antepartum period for adverse events and laboratory abnormalities. In the postpartum period, mother-infant dyads were evaluated at weeks 4, 12, 24, and 28.

Primary outcomes were the rates of mother-to-child transmission and birth defects with, or without, tenofovir exposure. Secondary outcomes were the percentage of mothers who had an HBV DNA serum concentration of less than 200,000 IU/mL at delivery and the percentage of mothers with HBeAg or HBsAg loss or seroconversion at postpartum week 28. Safety outcomes included the adverse event profile of tenofovir in mothers and safety events in the mother-infant dyads. These outcomes encompassed  all adverse events and drug discontinuations in patients who received at least one dose of tenofovir.

Sixty-eight percent of mothers in the tenofovir group, compared with 2% of mothers in the control group, had HBV levels less than 200,000 IU/mL at delivery (P<.001). The rate of mother-to-child HBV transmission at postpartum week 28 was lower in the tenofovir group. In the intention-to-treat analysis, the rate was 5% (95% CI, 1-10; 5 of 97 infants) in the tenofovir group versus 18% (95% CI, 10-26; 18 of 100 infants) in the control group (P = .007). In the per-protocol analysis, the rate was 0% (95% CI, 0-3; 0 of 92 infants) in the tenofovir group versus 7% (95% CI, 2-12; 6 of 88 infants) in the control group (P = .01). Maternal and infant safety profiles were similar between the 2 groups, with the exception of elevated creatinine kinase and alanine aminotransferase levels in mothers treated with tenofovir. Maternal HBV serologic titers did not differ significantly between the 2 groups.

Study strengths and limitations

This study's strengths include a multicenter, randomized controlled design, with strict inclusion and exclusion criteria. The results are clinically relevant and of global impact, with potential to decrease morbidity and  mortality from HBV infection in children born to infected mothers. 

A limitation, however, is that the study was probably underpowered to detect small differences in the rate of birth defects between the tenofovir and usual-care treatment groups. Additionally, some patients ceased taking tenofovir in the postpartum time period. Abrupt cessation may be associated with acute, severe HBV exacerbation.  

Benefits of ART for reducing mother-to-baby HIV transmission outweigh higher risk of adverse outcomes

Fowler MG, Qin M, Fiscus SA, et al; IMPAACT 1077BF/1077FF PROMISE Study Team. Benefits and risks of antiretroviral therapy for perinatal HIV prevention. N Engl J Med. 2016;375(18):1726-1737.

Part of the larger PROMISE (Promoting Maternal and Infant Survival Everywhere) trial, a study by Fowler and colleagues compared the relative efficacy and safety of various proven ART strategies for prevention of mother-to-child transmission of HIV infection in women with relatively high CD4 counts.

Details of the study

The trial was conducted at 14 sites in 7 countries. Patients were stratified according to HBV coinfection status and country of origin. The primary efficacy outcome was frequency of early infant HIV infection.

Women were randomly assigned to 1 of 3 treatment categories:

• zidovudine alone (zidovudine plus a single intrapartum dose of nevirapine, followed by 6 to 14 days of tenofovir plus emtricitabine postpartum)  
• zidovudine-based ART (zidovudine in combination with lamivudine and lopinavir-ritonavir)  
• tenofovir-based ART (tenofovir in combination with emtricitabine and lopinavir-ritonavir). 

All regimens were continued through 6 to 14 days postpartum. All infants received nevirapine at birth and in the immediate postpartum period.

Two trial periods. During period 1 (April 2011-September 2012), safety data on tenofovir in pregnancy were limited. Women without HBV coinfection were assigned only to zidovudine alone or zidovudine-based ART. During period 2 (October 2012-October 2014), since more information about tenofovir use in pregnancy was available, the study protocol was modified to allow women to be assigned to any of the 3 regimens, regardless of their HBV status.

Inclusion criteria were as follows: CD4 count of at least 350 cells/mm3 (or country-specific threshold for initiating triple-drug ART, if that threshold was higher), gestation of at least 14 weeks and not in labor, no previous use of triple-drug ART, no clinical or immune-related indication for triple-drug ART, hemoglobin level of at least 6.5 g/dL, an absolute neutrophil count of at least 750 cells/mm3, an alanine aminotransferase level of less than 2.5 times the upper limit of normal range, an estimated creatinine clearance of greater than 60 mL/min, and no serious pregnancy complications. Patients were excluded if they had active tuberculosis, HBV infection requiring treatment, a structural or conduction heart defect, or a fetus with a serious congenital malformation.

Primary outcomes. The primary efficacy outcome was early infant HIV infection, defined as a positive infant HIV nucleic acid test result at birth or at 1 week postpartum. The primary safety outcome was a composite of adverse events.

Adverse events in mothers were defined as hematologic abnormalities, abnormal blood chemical values, or abnormal signs/symptoms during pregnancy through 1 week postpartum. Severe pregnancy composite outcomes were low birth weight (<2,500 g), preterm delivery before 37 weeks' gestation, spontaneous abortion (<20 weeks), stillbirth (≥20 weeks), or congenital anomaly. Adverse events in infants were defined as death from any cause, hematologic abnormalities or abnormal blood chemical values, and abnormal signs/symptoms through 1 week postpartum.

A total of 3,490 mother-infant sets were included in the analysis (2,261 during trial period 1 and 1,229 during trial period 2). Baseline maternal characteristics were well balanced between groups. Most women were African, young (median age, 26 years), and asymptomatic.

Related article:
2016 Update on infectious disease

Study results

The combined maternal ART-treated groups had significantly lower rates of early transmission of HIV infection compared with the zidovudine-alone group (0.5% vs 1.8%, -1.3 percentage points; CI, -2.1 to -0.4). The zidovudine-based ART-treated group had a significantly higher rate of infant HIV-free survival through postpartum week 1 than did the zidovudine-alone group (P = .001) or the tenofovir-based ART group (P = .002).

When examining trial periods 1 and 2 combined, the zidovudine-based ART group experienced significantly higher rates of any adverse event than those receiving zidovudine alone (21.1% vs 17.3%, P = .008) and higher rates of abnormal blood chemical values (5.8% vs 1.3%, P<.001). During period 2 alone, the tenofovir-based ART group had significantly higher rates of abnormal blood chemical values than did the zidovudine-alone group (2.9% vs 0.8%, P = .03). There were no significant differences between the 2 ART treatment groups. No maternal deaths occurred during the study, and the trial-drug discontinuation rate was low (2%-5%) and did not vary among the 3 groups.

During trial periods 1 and 2, the zidovudine-based ART group had significantly higher rates of adverse pregnancy outcomes than did the zidovudine-alone group (40% vs 27.5%, P<.001). These included low birth weight less than 2,500 g (23% vs 12%) and preterm delivery before 37 weeks (20.5% vs 13.1%). During trial period 2, the tenofovir-based ART group had significantly higher rates of adverse pregnancy outcomes than did the zidovudine-alone group (34.7% vs 27.2%, P = .04). There were no significant differences for any outcome between the 2 ART-treated groups, and there were no significant differences in stillbirth or spontaneous abortion and congenital anomalies among the 3 groups.

Regarding severe pregnancy outcomes, there were no significant differences (composite or individual) between the zidovudine-based ART group and the zidovudine-alone group. The tenofovir-based ART group experienced significantly higher rates of composite severe adverse pregnancy outcomes compared with the zidovudine-based ART group (9.2% vs 4.3%, P = .02), and very preterm birth before 34 weeks (6.0% vs 2.6%, P = .04).

Infant safety outcomes were also examined. There were no significant differences for composite or individual adverse neonatal outcomes other than death. The tenofovir-based ART group experienced a significantly higher rate of infant death than did the zidovudine-based ART group (4.4% vs 0.6%, P<.001). However, a post hoc analysis suggested that extreme prematurity contributed to the infant mortality.

Limitations of the study

This study had minor limitations. It divided patients into only 2 major categories with respect to gestational age--more than or less than 34 weeks. Some maternal medical conditions, such as malaria, were not controlled for. In addition, breastfeeding and formula feeding were combined for analysis, and we know that breastfeeding would inherently confer a higher risk of HIV transmission. 

Nevertheless, this study was thoughtfully designed and carefully conducted, and the results are of significant global impact.  

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In this Update we review the results of 4 recent investigations that have important implications:

• the first analysis of the US Zika Virus Infection in Pregnancy Registry
• a study revealing an improved antibiotic regimen to prevent postcesarean infection
• an important new methodology for reducing the rate of perinatal transmission of hepatitis B virus (HBV) infection
• the risks and benefits of combination antiretroviral therapy (ART) in pregnancy.

Zika virus-associated birth defect rates similar regardless of symptom presence; first-trimester exposure has highest rate of anomalies

Honein MA, Dawson AL, Petersen EE, et al; US Zika Pregnancy Registry Collaboration. Birth defects among fetuses and infants of US women with evidence of possible Zika virus infection during pregnancy. JAMA. 2017;317(1):59-68.

Honein and colleagues provide a summary of the data from the US Zika Virus in Pregnancy Registry (a collaboration between the Centers for Disease Control and Prevention and state and local health departments), estimating the proportion of fetuses and infants with birth defects based on maternal symptoms of Zika virus infection and  trimester of possible infection.

Related article:
Zika virus: Counseling considerations for this emerging perinatal threat

Details of the study

The authors evaluated the outcomes of 442 women who had laboratory evidence of a possible Zika virus infection during pregnancy. Overall, 26 infants (6%; 95% confidence interval (CI), 4%-8%) had evidence of birth defects related to the Zika virus. Of note, abnormalities were detected in 16 of the 271 children (6%; 95% CI, 4%-9%) born to women who were asymptomatic and 10 of 167 (6%; 95% CI, 3%-11%) children delivered to women with symptomatic infections. 

The most common birth defect was microcephaly, although other serious central nervous system abnormalities were noted as well. Nine of 85 women (11%; 95% CI, 6%-19%) who had exposure only during the first trimester had infants with birth defects. There were no documented abnormalities in infants born to mothers who developed Zika virus infection only in the second or third trimester. 

Related article:
Zika virus update: A rapidly moving target

Key study findings

This article is important for several reasons. First, the authors describe the largest series of pregnant women in the United States with Zika virus infection. All of these patients developed Zika virus infection as a result of foreign travel or exposure to sexual partners who had traveled to Zika virus endemic areas. Second, the authors confirmed findings that previously had been based only on mathematical models rather than on actual case series. Specifically, they demonstrated that the risk of a serious birth defect following first-trimester exposure to Zika virus infection was approximately 11%, with a 95% CI that extended from 6% to 19%. Finally, Honein and colleagues highlighted the key fact that the risk of a serious birth defect was comparable in mothers who had either an asymptomatic or a symptomatic infection, a finding that seems somewhat counterintuitive.

Read about prophylaxis for postcesarean infection

Two antibiotics before cesarean delivery reduce infection rates further than one agent

Tita AT, Szychowski JM, Boggess K, et al; for the C/SOAP Trial Consortium. Adjunctive azithromycin prophylaxis for cesarean delivery. N Engl J Med. 2016;375(13):1231-1241.

Tita and colleagues reported the results of a multicenter trial that was designed to assess whether a combination of 2 antibiotics, including one that specifically targets ureaplasma species, provided more effective prophylaxis against postcesarean infection than single-agent prophylaxis.

Details of the study

The Cesarean Section Optimal Antibiotic Prophylaxis (C/SOAP) trial was conducted at 14 centers in the United States and included 2,013 women who were at least at 24 weeks' gestation and who had a cesarean delivery during labor or after membrane rupture.

The authors randomly assigned 1,019 women to receive 500 mg of intravenous azithromycin plus conventional single-agent prophylaxis (usually cefazolin) and 994 women to receive a placebo plus conventional prophylaxis. The primary outcome was the composite of endometritis, wound infection, or other infection occurring within 6 weeks.

The authors observed that the primary outcome occurred in 62 women (6.1%) who received azithromycin plus conventional prophylaxis and in 119 women (12%) who received only single-agent prophylaxis. The relative risk of developing a postoperative infection was 0.51 in women who received the combined therapy. There were significant differences between the 2 groups in both the rates of endometritis (3.8% vs 6.1%, P = .02) and wound infection (2.4% vs 6.6%, P<.001). There were no differences between the groups in the frequency of the secondary neonatal composite outcome, which included neonatal death and serious neonatal complications.

Related article:
Preventing infection after cesarean delivery: 5 more evidence-based measures to consider

Efficacy of dual-agent prophylaxis

At present, the standard of care is to administer prophylactic antibiotics to all women having cesarean delivery, including women having a scheduled cesarean in the absence of labor or ruptured membranes. Multiple studies have shown clearly that prophylaxis reduces the frequency of endometritis and, in high-risk patient populations, wound infection, and that prophylaxis is most beneficial when administered prior to the time the surgical incision is made. The most commonly used drug for prophylaxis is cefazolin, a first-generation cephalosporin. The usual recommended dose is 2 g, administered immediately prior to surgery.^3,4

Although most centers in the United States traditionally have used just a single antibiotic for prophylaxis, selected recent reports indicate that expanding the spectrum of activity of prophylactic antibiotics can result in additional beneficial effects. Specifically, Tita and colleagues evaluated an indigent patient population with an inherently high rate of postoperative infection.⁵ They showed that adding azithromycin 500 mg to cefazolin significantly reduced the rate of postcesarean endometritis. In a follow-up report from the same institution, Tita and colleagues demonstrated that adding azithromycin also significantly reduced the frequency of wound infection.⁶ Of note, in both these investigations, the antibiotics were administered after cord clamping. In a subsequent report, Ward and Duff showed that the combination of azithromycin plus cefazolin administered preoperatively resulted in a combined rate of endometritis and wound infection that was less than 3%.⁷

Related article:
Preventing infection after cesarean delivery: Evidence-based guidance

C/SOAP trial confirmed lower infection rates with combined regimen

Results of the present study confirm the findings of these 3 investigations. The trial included a large sample size. The study was carefully designed, and the end points were clearly defined. It included only patients at increased risk for postoperative infection by virtue of being in labor or having ruptured membranes at the time of cesarean delivery. Patients who received standard prophylaxis, usually cefazolin, plus azithromycin had a significantly lower risk of postcesarean endometritis and wound infection compared with patients who received a single antibiotic. The overall risk of infection was reduced by an impressive 50%.  
 

Read about reducing HBV transmission

Tenofovir treatment in pregnant women with HBV reduces vertical transmission

Pan CQ, Duan Z, Dai E, et al; China Study Group for the Mother-to-Child Transmission of Hepatitis B. Tenofovir to prevent hepatitis B transmission in mothers with high viral load. N Engl J Med. 2016;374(24):2324-2334.

A multicenter, open-label, randomized, parallel-group investigation was conducted from March 2012 to June 2013 at academic tertiary care centers in 5 geographic regions of China. Two hundred mothers, who were positive for both hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) and who had HBV DNA concentrations of 200,000 IU/mL or greater, were randomly assigned in a 1:1 ratio to either tenofovir or to usual treatment. Exclusion criteria were coexistent viral infections or medical conditions, renal failure, laboratory abnormalities, fetal deformities, and use of many medications.

Related article:
5 ways to reduce infection risk during pregnancy

Details of the study

Women in the active treatment group received tenofovir 300 mg by mouth daily from 30 to 32 weeks' gestation until postpartum week 4. Patients were monitored every 4 weeks in the antepartum period for adverse events and laboratory abnormalities. In the postpartum period, mother-infant dyads were evaluated at weeks 4, 12, 24, and 28.

Primary outcomes were the rates of mother-to-child transmission and birth defects with, or without, tenofovir exposure. Secondary outcomes were the percentage of mothers who had an HBV DNA serum concentration of less than 200,000 IU/mL at delivery and the percentage of mothers with HBeAg or HBsAg loss or seroconversion at postpartum week 28. Safety outcomes included the adverse event profile of tenofovir in mothers and safety events in the mother-infant dyads. These outcomes encompassed  all adverse events and drug discontinuations in patients who received at least one dose of tenofovir.

Sixty-eight percent of mothers in the tenofovir group, compared with 2% of mothers in the control group, had HBV levels less than 200,000 IU/mL at delivery (P<.001). The rate of mother-to-child HBV transmission at postpartum week 28 was lower in the tenofovir group. In the intention-to-treat analysis, the rate was 5% (95% CI, 1-10; 5 of 97 infants) in the tenofovir group versus 18% (95% CI, 10-26; 18 of 100 infants) in the control group (P = .007). In the per-protocol analysis, the rate was 0% (95% CI, 0-3; 0 of 92 infants) in the tenofovir group versus 7% (95% CI, 2-12; 6 of 88 infants) in the control group (P = .01). Maternal and infant safety profiles were similar between the 2 groups, with the exception of elevated creatinine kinase and alanine aminotransferase levels in mothers treated with tenofovir. Maternal HBV serologic titers did not differ significantly between the 2 groups.

Study strengths and limitations

This study's strengths include a multicenter, randomized controlled design, with strict inclusion and exclusion criteria. The results are clinically relevant and of global impact, with potential to decrease morbidity and  mortality from HBV infection in children born to infected mothers. 

A limitation, however, is that the study was probably underpowered to detect small differences in the rate of birth defects between the tenofovir and usual-care treatment groups. Additionally, some patients ceased taking tenofovir in the postpartum time period. Abrupt cessation may be associated with acute, severe HBV exacerbation.  

Benefits of ART for reducing mother-to-baby HIV transmission outweigh higher risk of adverse outcomes

Fowler MG, Qin M, Fiscus SA, et al; IMPAACT 1077BF/1077FF PROMISE Study Team. Benefits and risks of antiretroviral therapy for perinatal HIV prevention. N Engl J Med. 2016;375(18):1726-1737.

Part of the larger PROMISE (Promoting Maternal and Infant Survival Everywhere) trial, a study by Fowler and colleagues compared the relative efficacy and safety of various proven ART strategies for prevention of mother-to-child transmission of HIV infection in women with relatively high CD4 counts.

Details of the study

The trial was conducted at 14 sites in 7 countries. Patients were stratified according to HBV coinfection status and country of origin. The primary efficacy outcome was frequency of early infant HIV infection.

Women were randomly assigned to 1 of 3 treatment categories:

• zidovudine alone (zidovudine plus a single intrapartum dose of nevirapine, followed by 6 to 14 days of tenofovir plus emtricitabine postpartum)  
• zidovudine-based ART (zidovudine in combination with lamivudine and lopinavir-ritonavir)  
• tenofovir-based ART (tenofovir in combination with emtricitabine and lopinavir-ritonavir). 

All regimens were continued through 6 to 14 days postpartum. All infants received nevirapine at birth and in the immediate postpartum period.

Two trial periods. During period 1 (April 2011-September 2012), safety data on tenofovir in pregnancy were limited. Women without HBV coinfection were assigned only to zidovudine alone or zidovudine-based ART. During period 2 (October 2012-October 2014), since more information about tenofovir use in pregnancy was available, the study protocol was modified to allow women to be assigned to any of the 3 regimens, regardless of their HBV status.

Inclusion criteria were as follows: CD4 count of at least 350 cells/mm3 (or country-specific threshold for initiating triple-drug ART, if that threshold was higher), gestation of at least 14 weeks and not in labor, no previous use of triple-drug ART, no clinical or immune-related indication for triple-drug ART, hemoglobin level of at least 6.5 g/dL, an absolute neutrophil count of at least 750 cells/mm3, an alanine aminotransferase level of less than 2.5 times the upper limit of normal range, an estimated creatinine clearance of greater than 60 mL/min, and no serious pregnancy complications. Patients were excluded if they had active tuberculosis, HBV infection requiring treatment, a structural or conduction heart defect, or a fetus with a serious congenital malformation.

Primary outcomes. The primary efficacy outcome was early infant HIV infection, defined as a positive infant HIV nucleic acid test result at birth or at 1 week postpartum. The primary safety outcome was a composite of adverse events.

Adverse events in mothers were defined as hematologic abnormalities, abnormal blood chemical values, or abnormal signs/symptoms during pregnancy through 1 week postpartum. Severe pregnancy composite outcomes were low birth weight (<2,500 g), preterm delivery before 37 weeks' gestation, spontaneous abortion (<20 weeks), stillbirth (≥20 weeks), or congenital anomaly. Adverse events in infants were defined as death from any cause, hematologic abnormalities or abnormal blood chemical values, and abnormal signs/symptoms through 1 week postpartum.

A total of 3,490 mother-infant sets were included in the analysis (2,261 during trial period 1 and 1,229 during trial period 2). Baseline maternal characteristics were well balanced between groups. Most women were African, young (median age, 26 years), and asymptomatic.

Related article:
2016 Update on infectious disease

Study results

The combined maternal ART-treated groups had significantly lower rates of early transmission of HIV infection compared with the zidovudine-alone group (0.5% vs 1.8%, -1.3 percentage points; CI, -2.1 to -0.4). The zidovudine-based ART-treated group had a significantly higher rate of infant HIV-free survival through postpartum week 1 than did the zidovudine-alone group (P = .001) or the tenofovir-based ART group (P = .002).

When examining trial periods 1 and 2 combined, the zidovudine-based ART group experienced significantly higher rates of any adverse event than those receiving zidovudine alone (21.1% vs 17.3%, P = .008) and higher rates of abnormal blood chemical values (5.8% vs 1.3%, P<.001). During period 2 alone, the tenofovir-based ART group had significantly higher rates of abnormal blood chemical values than did the zidovudine-alone group (2.9% vs 0.8%, P = .03). There were no significant differences between the 2 ART treatment groups. No maternal deaths occurred during the study, and the trial-drug discontinuation rate was low (2%-5%) and did not vary among the 3 groups.

During trial periods 1 and 2, the zidovudine-based ART group had significantly higher rates of adverse pregnancy outcomes than did the zidovudine-alone group (40% vs 27.5%, P<.001). These included low birth weight less than 2,500 g (23% vs 12%) and preterm delivery before 37 weeks (20.5% vs 13.1%). During trial period 2, the tenofovir-based ART group had significantly higher rates of adverse pregnancy outcomes than did the zidovudine-alone group (34.7% vs 27.2%, P = .04). There were no significant differences for any outcome between the 2 ART-treated groups, and there were no significant differences in stillbirth or spontaneous abortion and congenital anomalies among the 3 groups.

Regarding severe pregnancy outcomes, there were no significant differences (composite or individual) between the zidovudine-based ART group and the zidovudine-alone group. The tenofovir-based ART group experienced significantly higher rates of composite severe adverse pregnancy outcomes compared with the zidovudine-based ART group (9.2% vs 4.3%, P = .02), and very preterm birth before 34 weeks (6.0% vs 2.6%, P = .04).

Infant safety outcomes were also examined. There were no significant differences for composite or individual adverse neonatal outcomes other than death. The tenofovir-based ART group experienced a significantly higher rate of infant death than did the zidovudine-based ART group (4.4% vs 0.6%, P<.001). However, a post hoc analysis suggested that extreme prematurity contributed to the infant mortality.

Limitations of the study

This study had minor limitations. It divided patients into only 2 major categories with respect to gestational age--more than or less than 34 weeks. Some maternal medical conditions, such as malaria, were not controlled for. In addition, breastfeeding and formula feeding were combined for analysis, and we know that breastfeeding would inherently confer a higher risk of HIV transmission. 

Nevertheless, this study was thoughtfully designed and carefully conducted, and the results are of significant global impact.  

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In this Update we review the results of 4 recent investigations that have important implications:

• the first analysis of the US Zika Virus Infection in Pregnancy Registry
• a study revealing an improved antibiotic regimen to prevent postcesarean infection
• an important new methodology for reducing the rate of perinatal transmission of hepatitis B virus (HBV) infection
• the risks and benefits of combination antiretroviral therapy (ART) in pregnancy.

Zika virus-associated birth defect rates similar regardless of symptom presence; first-trimester exposure has highest rate of anomalies

Honein MA, Dawson AL, Petersen EE, et al; US Zika Pregnancy Registry Collaboration. Birth defects among fetuses and infants of US women with evidence of possible Zika virus infection during pregnancy. JAMA. 2017;317(1):59-68.

Honein and colleagues provide a summary of the data from the US Zika Virus in Pregnancy Registry (a collaboration between the Centers for Disease Control and Prevention and state and local health departments), estimating the proportion of fetuses and infants with birth defects based on maternal symptoms of Zika virus infection and  trimester of possible infection.

Related article:
Zika virus: Counseling considerations for this emerging perinatal threat

Details of the study

The authors evaluated the outcomes of 442 women who had laboratory evidence of a possible Zika virus infection during pregnancy. Overall, 26 infants (6%; 95% confidence interval (CI), 4%-8%) had evidence of birth defects related to the Zika virus. Of note, abnormalities were detected in 16 of the 271 children (6%; 95% CI, 4%-9%) born to women who were asymptomatic and 10 of 167 (6%; 95% CI, 3%-11%) children delivered to women with symptomatic infections. 

The most common birth defect was microcephaly, although other serious central nervous system abnormalities were noted as well. Nine of 85 women (11%; 95% CI, 6%-19%) who had exposure only during the first trimester had infants with birth defects. There were no documented abnormalities in infants born to mothers who developed Zika virus infection only in the second or third trimester. 

Related article:
Zika virus update: A rapidly moving target

Key study findings

This article is important for several reasons. First, the authors describe the largest series of pregnant women in the United States with Zika virus infection. All of these patients developed Zika virus infection as a result of foreign travel or exposure to sexual partners who had traveled to Zika virus endemic areas. Second, the authors confirmed findings that previously had been based only on mathematical models rather than on actual case series. Specifically, they demonstrated that the risk of a serious birth defect following first-trimester exposure to Zika virus infection was approximately 11%, with a 95% CI that extended from 6% to 19%. Finally, Honein and colleagues highlighted the key fact that the risk of a serious birth defect was comparable in mothers who had either an asymptomatic or a symptomatic infection, a finding that seems somewhat counterintuitive.

Read about prophylaxis for postcesarean infection

Two antibiotics before cesarean delivery reduce infection rates further than one agent

Tita AT, Szychowski JM, Boggess K, et al; for the C/SOAP Trial Consortium. Adjunctive azithromycin prophylaxis for cesarean delivery. N Engl J Med. 2016;375(13):1231-1241.

Tita and colleagues reported the results of a multicenter trial that was designed to assess whether a combination of 2 antibiotics, including one that specifically targets ureaplasma species, provided more effective prophylaxis against postcesarean infection than single-agent prophylaxis.

Details of the study

The Cesarean Section Optimal Antibiotic Prophylaxis (C/SOAP) trial was conducted at 14 centers in the United States and included 2,013 women who were at least at 24 weeks' gestation and who had a cesarean delivery during labor or after membrane rupture.

The authors randomly assigned 1,019 women to receive 500 mg of intravenous azithromycin plus conventional single-agent prophylaxis (usually cefazolin) and 994 women to receive a placebo plus conventional prophylaxis. The primary outcome was the composite of endometritis, wound infection, or other infection occurring within 6 weeks.

The authors observed that the primary outcome occurred in 62 women (6.1%) who received azithromycin plus conventional prophylaxis and in 119 women (12%) who received only single-agent prophylaxis. The relative risk of developing a postoperative infection was 0.51 in women who received the combined therapy. There were significant differences between the 2 groups in both the rates of endometritis (3.8% vs 6.1%, P = .02) and wound infection (2.4% vs 6.6%, P<.001). There were no differences between the groups in the frequency of the secondary neonatal composite outcome, which included neonatal death and serious neonatal complications.

Related article:
Preventing infection after cesarean delivery: 5 more evidence-based measures to consider

Efficacy of dual-agent prophylaxis

At present, the standard of care is to administer prophylactic antibiotics to all women having cesarean delivery, including women having a scheduled cesarean in the absence of labor or ruptured membranes. Multiple studies have shown clearly that prophylaxis reduces the frequency of endometritis and, in high-risk patient populations, wound infection, and that prophylaxis is most beneficial when administered prior to the time the surgical incision is made. The most commonly used drug for prophylaxis is cefazolin, a first-generation cephalosporin. The usual recommended dose is 2 g, administered immediately prior to surgery.^3,4

Although most centers in the United States traditionally have used just a single antibiotic for prophylaxis, selected recent reports indicate that expanding the spectrum of activity of prophylactic antibiotics can result in additional beneficial effects. Specifically, Tita and colleagues evaluated an indigent patient population with an inherently high rate of postoperative infection.⁵ They showed that adding azithromycin 500 mg to cefazolin significantly reduced the rate of postcesarean endometritis. In a follow-up report from the same institution, Tita and colleagues demonstrated that adding azithromycin also significantly reduced the frequency of wound infection.⁶ Of note, in both these investigations, the antibiotics were administered after cord clamping. In a subsequent report, Ward and Duff showed that the combination of azithromycin plus cefazolin administered preoperatively resulted in a combined rate of endometritis and wound infection that was less than 3%.⁷

Related article:
Preventing infection after cesarean delivery: Evidence-based guidance

C/SOAP trial confirmed lower infection rates with combined regimen

Results of the present study confirm the findings of these 3 investigations. The trial included a large sample size. The study was carefully designed, and the end points were clearly defined. It included only patients at increased risk for postoperative infection by virtue of being in labor or having ruptured membranes at the time of cesarean delivery. Patients who received standard prophylaxis, usually cefazolin, plus azithromycin had a significantly lower risk of postcesarean endometritis and wound infection compared with patients who received a single antibiotic. The overall risk of infection was reduced by an impressive 50%.  
 

Read about reducing HBV transmission

Tenofovir treatment in pregnant women with HBV reduces vertical transmission

Pan CQ, Duan Z, Dai E, et al; China Study Group for the Mother-to-Child Transmission of Hepatitis B. Tenofovir to prevent hepatitis B transmission in mothers with high viral load. N Engl J Med. 2016;374(24):2324-2334.

A multicenter, open-label, randomized, parallel-group investigation was conducted from March 2012 to June 2013 at academic tertiary care centers in 5 geographic regions of China. Two hundred mothers, who were positive for both hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) and who had HBV DNA concentrations of 200,000 IU/mL or greater, were randomly assigned in a 1:1 ratio to either tenofovir or to usual treatment. Exclusion criteria were coexistent viral infections or medical conditions, renal failure, laboratory abnormalities, fetal deformities, and use of many medications.

Related article:
5 ways to reduce infection risk during pregnancy

Details of the study

Women in the active treatment group received tenofovir 300 mg by mouth daily from 30 to 32 weeks' gestation until postpartum week 4. Patients were monitored every 4 weeks in the antepartum period for adverse events and laboratory abnormalities. In the postpartum period, mother-infant dyads were evaluated at weeks 4, 12, 24, and 28.

Primary outcomes were the rates of mother-to-child transmission and birth defects with, or without, tenofovir exposure. Secondary outcomes were the percentage of mothers who had an HBV DNA serum concentration of less than 200,000 IU/mL at delivery and the percentage of mothers with HBeAg or HBsAg loss or seroconversion at postpartum week 28. Safety outcomes included the adverse event profile of tenofovir in mothers and safety events in the mother-infant dyads. These outcomes encompassed  all adverse events and drug discontinuations in patients who received at least one dose of tenofovir.

Sixty-eight percent of mothers in the tenofovir group, compared with 2% of mothers in the control group, had HBV levels less than 200,000 IU/mL at delivery (P<.001). The rate of mother-to-child HBV transmission at postpartum week 28 was lower in the tenofovir group. In the intention-to-treat analysis, the rate was 5% (95% CI, 1-10; 5 of 97 infants) in the tenofovir group versus 18% (95% CI, 10-26; 18 of 100 infants) in the control group (P = .007). In the per-protocol analysis, the rate was 0% (95% CI, 0-3; 0 of 92 infants) in the tenofovir group versus 7% (95% CI, 2-12; 6 of 88 infants) in the control group (P = .01). Maternal and infant safety profiles were similar between the 2 groups, with the exception of elevated creatinine kinase and alanine aminotransferase levels in mothers treated with tenofovir. Maternal HBV serologic titers did not differ significantly between the 2 groups.

Study strengths and limitations

This study's strengths include a multicenter, randomized controlled design, with strict inclusion and exclusion criteria. The results are clinically relevant and of global impact, with potential to decrease morbidity and  mortality from HBV infection in children born to infected mothers. 

A limitation, however, is that the study was probably underpowered to detect small differences in the rate of birth defects between the tenofovir and usual-care treatment groups. Additionally, some patients ceased taking tenofovir in the postpartum time period. Abrupt cessation may be associated with acute, severe HBV exacerbation.  

Benefits of ART for reducing mother-to-baby HIV transmission outweigh higher risk of adverse outcomes

Fowler MG, Qin M, Fiscus SA, et al; IMPAACT 1077BF/1077FF PROMISE Study Team. Benefits and risks of antiretroviral therapy for perinatal HIV prevention. N Engl J Med. 2016;375(18):1726-1737.

Part of the larger PROMISE (Promoting Maternal and Infant Survival Everywhere) trial, a study by Fowler and colleagues compared the relative efficacy and safety of various proven ART strategies for prevention of mother-to-child transmission of HIV infection in women with relatively high CD4 counts.

Details of the study

The trial was conducted at 14 sites in 7 countries. Patients were stratified according to HBV coinfection status and country of origin. The primary efficacy outcome was frequency of early infant HIV infection.

Women were randomly assigned to 1 of 3 treatment categories:

• zidovudine alone (zidovudine plus a single intrapartum dose of nevirapine, followed by 6 to 14 days of tenofovir plus emtricitabine postpartum)  
• zidovudine-based ART (zidovudine in combination with lamivudine and lopinavir-ritonavir)  
• tenofovir-based ART (tenofovir in combination with emtricitabine and lopinavir-ritonavir). 

All regimens were continued through 6 to 14 days postpartum. All infants received nevirapine at birth and in the immediate postpartum period.

Two trial periods. During period 1 (April 2011-September 2012), safety data on tenofovir in pregnancy were limited. Women without HBV coinfection were assigned only to zidovudine alone or zidovudine-based ART. During period 2 (October 2012-October 2014), since more information about tenofovir use in pregnancy was available, the study protocol was modified to allow women to be assigned to any of the 3 regimens, regardless of their HBV status.

Inclusion criteria were as follows: CD4 count of at least 350 cells/mm3 (or country-specific threshold for initiating triple-drug ART, if that threshold was higher), gestation of at least 14 weeks and not in labor, no previous use of triple-drug ART, no clinical or immune-related indication for triple-drug ART, hemoglobin level of at least 6.5 g/dL, an absolute neutrophil count of at least 750 cells/mm3, an alanine aminotransferase level of less than 2.5 times the upper limit of normal range, an estimated creatinine clearance of greater than 60 mL/min, and no serious pregnancy complications. Patients were excluded if they had active tuberculosis, HBV infection requiring treatment, a structural or conduction heart defect, or a fetus with a serious congenital malformation.

Primary outcomes. The primary efficacy outcome was early infant HIV infection, defined as a positive infant HIV nucleic acid test result at birth or at 1 week postpartum. The primary safety outcome was a composite of adverse events.

Adverse events in mothers were defined as hematologic abnormalities, abnormal blood chemical values, or abnormal signs/symptoms during pregnancy through 1 week postpartum. Severe pregnancy composite outcomes were low birth weight (<2,500 g), preterm delivery before 37 weeks' gestation, spontaneous abortion (<20 weeks), stillbirth (≥20 weeks), or congenital anomaly. Adverse events in infants were defined as death from any cause, hematologic abnormalities or abnormal blood chemical values, and abnormal signs/symptoms through 1 week postpartum.

A total of 3,490 mother-infant sets were included in the analysis (2,261 during trial period 1 and 1,229 during trial period 2). Baseline maternal characteristics were well balanced between groups. Most women were African, young (median age, 26 years), and asymptomatic.

Related article:
2016 Update on infectious disease

Study results

The combined maternal ART-treated groups had significantly lower rates of early transmission of HIV infection compared with the zidovudine-alone group (0.5% vs 1.8%, -1.3 percentage points; CI, -2.1 to -0.4). The zidovudine-based ART-treated group had a significantly higher rate of infant HIV-free survival through postpartum week 1 than did the zidovudine-alone group (P = .001) or the tenofovir-based ART group (P = .002).

When examining trial periods 1 and 2 combined, the zidovudine-based ART group experienced significantly higher rates of any adverse event than those receiving zidovudine alone (21.1% vs 17.3%, P = .008) and higher rates of abnormal blood chemical values (5.8% vs 1.3%, P<.001). During period 2 alone, the tenofovir-based ART group had significantly higher rates of abnormal blood chemical values than did the zidovudine-alone group (2.9% vs 0.8%, P = .03). There were no significant differences between the 2 ART treatment groups. No maternal deaths occurred during the study, and the trial-drug discontinuation rate was low (2%-5%) and did not vary among the 3 groups.

During trial periods 1 and 2, the zidovudine-based ART group had significantly higher rates of adverse pregnancy outcomes than did the zidovudine-alone group (40% vs 27.5%, P<.001). These included low birth weight less than 2,500 g (23% vs 12%) and preterm delivery before 37 weeks (20.5% vs 13.1%). During trial period 2, the tenofovir-based ART group had significantly higher rates of adverse pregnancy outcomes than did the zidovudine-alone group (34.7% vs 27.2%, P = .04). There were no significant differences for any outcome between the 2 ART-treated groups, and there were no significant differences in stillbirth or spontaneous abortion and congenital anomalies among the 3 groups.

Regarding severe pregnancy outcomes, there were no significant differences (composite or individual) between the zidovudine-based ART group and the zidovudine-alone group. The tenofovir-based ART group experienced significantly higher rates of composite severe adverse pregnancy outcomes compared with the zidovudine-based ART group (9.2% vs 4.3%, P = .02), and very preterm birth before 34 weeks (6.0% vs 2.6%, P = .04).

Infant safety outcomes were also examined. There were no significant differences for composite or individual adverse neonatal outcomes other than death. The tenofovir-based ART group experienced a significantly higher rate of infant death than did the zidovudine-based ART group (4.4% vs 0.6%, P<.001). However, a post hoc analysis suggested that extreme prematurity contributed to the infant mortality.

Limitations of the study

This study had minor limitations. It divided patients into only 2 major categories with respect to gestational age--more than or less than 34 weeks. Some maternal medical conditions, such as malaria, were not controlled for. In addition, breastfeeding and formula feeding were combined for analysis, and we know that breastfeeding would inherently confer a higher risk of HIV transmission. 

Nevertheless, this study was thoughtfully designed and carefully conducted, and the results are of significant global impact.  

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

LAS VEGAS – One of the most intriguing clues that suggest the metabolic syndrome or one of its components might cause hand osteoarthritis comes from a recent study of middle-aged HIV-positive patients, David T. Felson, MD, asserted at the World Congress on Osteoarthritis.

“This is an important study. The identification of an unusual cohort, which otherwise wasn’t supposed to get a particular disease, has really helped us to determine the cause of diseases in other circumstances,” said Dr. Felson, a rheumatologist who is professor of medicine and epidemiology and director of the clinical epidemiology research and training unit at Boston University. He cited an example that also happens to have been related to HIV: Kaposi’s sarcoma in gay men “that alerted us initially to the existence of HIV infection,” he commented.

Other evidence to suggest that metabolic factors are causally related to hand OA comes from animal models, as well as from large population-based cohort studies, including the Netherlands Epidemiology of Obesity (NEO) study. NEO involved 6,673 middle-aged Dutch men and women. Metabolic syndrome was associated with increased rates of both hand OA and knee OA in analyses unadjusted for body weight. However, when the Leiden University investigators adjusted for body weight, the association between metabolic syndrome and knee OA went away, whereas the association between metabolic syndrome and hand OA remained strong (Ann Rheum Dis. 2015 Oct;74[10]:1842-7).

This has uniformly been the case in other cohort studies reporting an association between metabolic syndrome and knee OA: upon adjusting for body mass index (BMI), there is no longer a residual relationship between metabolic syndrome and knee OA.

“One of the challenges in studying metabolic syndrome and knee osteoarthritis is that all the components of the metabolic syndrome are strongly correlated with obesity, and obesity is a major risk factor for knee osteoarthritis through its effects on joint loading. So obesity – at least for knee osteoarthritis – is an enormous confounder,” Dr. Felson said.

The findings from NEO and other large cohort studies underscore a key point: “Metabolic syndrome is not a risk factor for knee osteoarthritis, despite a lot of hullabaloo to the contrary. It doesn’t emerge in cohort studies as an important factor,” according to the rheum

Thinkstock/ LarsNeumann

[email protected]
 

LAS VEGAS – One of the most intriguing clues that suggest the metabolic syndrome or one of its components might cause hand osteoarthritis comes from a recent study of middle-aged HIV-positive patients, David T. Felson, MD, asserted at the World Congress on Osteoarthritis.

“This is an important study. The identification of an unusual cohort, which otherwise wasn’t supposed to get a particular disease, has really helped us to determine the cause of diseases in other circumstances,” said Dr. Felson, a rheumatologist who is professor of medicine and epidemiology and director of the clinical epidemiology research and training unit at Boston University. He cited an example that also happens to have been related to HIV: Kaposi’s sarcoma in gay men “that alerted us initially to the existence of HIV infection,” he commented.

Other evidence to suggest that metabolic factors are causally related to hand OA comes from animal models, as well as from large population-based cohort studies, including the Netherlands Epidemiology of Obesity (NEO) study. NEO involved 6,673 middle-aged Dutch men and women. Metabolic syndrome was associated with increased rates of both hand OA and knee OA in analyses unadjusted for body weight. However, when the Leiden University investigators adjusted for body weight, the association between metabolic syndrome and knee OA went away, whereas the association between metabolic syndrome and hand OA remained strong (Ann Rheum Dis. 2015 Oct;74[10]:1842-7).

This has uniformly been the case in other cohort studies reporting an association between metabolic syndrome and knee OA: upon adjusting for body mass index (BMI), there is no longer a residual relationship between metabolic syndrome and knee OA.

“One of the challenges in studying metabolic syndrome and knee osteoarthritis is that all the components of the metabolic syndrome are strongly correlated with obesity, and obesity is a major risk factor for knee osteoarthritis through its effects on joint loading. So obesity – at least for knee osteoarthritis – is an enormous confounder,” Dr. Felson said.

The findings from NEO and other large cohort studies underscore a key point: “Metabolic syndrome is not a risk factor for knee osteoarthritis, despite a lot of hullabaloo to the contrary. It doesn’t emerge in cohort studies as an important factor,” according to the rheum

Thinkstock/ LarsNeumann

[email protected]
 

LAS VEGAS – One of the most intriguing clues that suggest the metabolic syndrome or one of its components might cause hand osteoarthritis comes from a recent study of middle-aged HIV-positive patients, David T. Felson, MD, asserted at the World Congress on Osteoarthritis.

“This is an important study. The identification of an unusual cohort, which otherwise wasn’t supposed to get a particular disease, has really helped us to determine the cause of diseases in other circumstances,” said Dr. Felson, a rheumatologist who is professor of medicine and epidemiology and director of the clinical epidemiology research and training unit at Boston University. He cited an example that also happens to have been related to HIV: Kaposi’s sarcoma in gay men “that alerted us initially to the existence of HIV infection,” he commented.

Other evidence to suggest that metabolic factors are causally related to hand OA comes from animal models, as well as from large population-based cohort studies, including the Netherlands Epidemiology of Obesity (NEO) study. NEO involved 6,673 middle-aged Dutch men and women. Metabolic syndrome was associated with increased rates of both hand OA and knee OA in analyses unadjusted for body weight. However, when the Leiden University investigators adjusted for body weight, the association between metabolic syndrome and knee OA went away, whereas the association between metabolic syndrome and hand OA remained strong (Ann Rheum Dis. 2015 Oct;74[10]:1842-7).

This has uniformly been the case in other cohort studies reporting an association between metabolic syndrome and knee OA: upon adjusting for body mass index (BMI), there is no longer a residual relationship between metabolic syndrome and knee OA.

“One of the challenges in studying metabolic syndrome and knee osteoarthritis is that all the components of the metabolic syndrome are strongly correlated with obesity, and obesity is a major risk factor for knee osteoarthritis through its effects on joint loading. So obesity – at least for knee osteoarthritis – is an enormous confounder,” Dr. Felson said.

The findings from NEO and other large cohort studies underscore a key point: “Metabolic syndrome is not a risk factor for knee osteoarthritis, despite a lot of hullabaloo to the contrary. It doesn’t emerge in cohort studies as an important factor,” according to the rheum

Thinkstock/ LarsNeumann

[email protected]
 

CASE Patient wants minimally invasive surgery for her fibroids, and no hysterectomy

A 44-year-old G1P1 woman comes to the office to discuss her uterine fibroids, heavy menstrual bleeding, and urinary frequency. Treatment with oral contraceptives has not been effective in reducing the bleeding. She now wants surgical treatment without a hysterectomy (the hysterectomy was recommended by her previous gynecologist). On examination, a 14-week-size irregular uterus is felt. Myomectomy is discussed, and the patient asks if minimally invasive surgery (MIS) is possible. Complete blood cell count testing shows a hemoglobin level of 9.4 g/dL. Pelvic magnetic resonance imaging (MRI) shows a 6-cm type 2 posterior fundal fibroid and a 6-cm type 5 posterior lower-uterine-segment fibroid (FIGURE 1). These 2 fibroids have regular contours, and enhancement is not increased with contrast, consistent with benign fibroids.

Determining that laparoscopic myomectomy is a good option

Fibroids may affect quality of life—they may cause heavy menstrual bleeding, pelvic pain or pressure, or urinary frequency or incontinence. For many women who want large or numerous fibroids removed but the uterus preserved, abdominal myomectomy is required. Smaller and less numerous fibroids usually can be managed laparoscopically or with robotic assistance.

A systematic review of 6 randomized, controlled trials comparing laparoscopic and open myomectomy in 576 patients found that, although laparoscopic myomectomy was associated with longer operative time (approximately 13 minutes), it was also linked to less operative blood loss, fewer overall complications, reduced postoperative pain, and faster recovery.¹ However, wide application of the laparoscopic approach may be limited by the size and number of fibroids that can be reasonably removed and by the surgical skill needed for fibroid excision and laparoscopic suturing.

Four imaging modalities can be used for fibroids: transvaginal sonography (TVS), saline-infusion sonography (SIS), hysteroscopy, and MRI. TVS is the most readily available and least costly modality used to differentiate fibroids from other pelvic pathology; SIS provides contrast for the endometrial cavity and better defines submucous fibroids; and hysteroscopy detects visually apparent distortion of the cavity. MRI, however, provides the most complete evaluation of size, position, and number of fibroids.

A study comparing TVS, SIS, hysteroscopy, and MRI found that number and position of fibroids were best identified with MRI.² In addition, with MRI, the proximity of the fibroids and uterus to the bladder, rectum, and iliac bones can be evaluated. As tactility in laparoscopic and robot-assisted surgery is very limited, surgeons who use MRI to accurately assess fibroids preoperatively may be able to avoid missing them during the procedure.³ MRI also can be used reliably to diagnose adenomyosis and may be able to help identify uterine sarcoma.

Tip. For all women considering laparoscopic or robot-assisted myomectomy, I order pelvic MRI with and without contrast. Having the radiologist limit the number of MRI sequences may reduce the cost and make it comparable to that of other imaging modalities. I request T2-weighted MRI scans in the coronal, sagittal, and axial planes; in addition, to determine distortion of the uterine cavity by submucous fibroids, I request scans in the planes parallel with and perpendicular to the uterine axis. One gadolinium-enhanced T1-weighted MRI scan is needed to evaluate perfusion.

Although radiologists are experts in image interpretation, they are unfamiliar with the treatments and surgical issues that gynecologists must consider. Reading MRI scans for fibroids is straightforward, and gynecologists who regularly treat women with fibroids should consider viewing images with a radiologist until they become proficient.

Related article:
Surgical management of broad ligament fibroids

Surgeons who have the experience and skill and know the size, number, and position of fibroids are able to select the appropriate candidates for laparoscopic myomectomy. Authors of a study of 2,050 laparoscopic myomectomies found that fibroids larger than 5 cm, removal of more than 3 fibroids, and broad ligament fibroids were more likely to be associated with major complications, including visceral injury, conversion to laparotomy, and bleeding requiring blood transfusion.⁴

In laparoscopic myomectomy, uterus reconstruction requires laparoscopic suturing. Although robot-assisted myomectomy may make laparoscopic suturing easier, the added cost, longer operative time, and unimproved outcomes must be considered too.

Read about trocar placement and managing blood loss

Trocar placement

Place the patient in the dorsal lithotomy position.

Tip. For most women, I do not use a uterine manipulator, as my assistant can manipulate the uterus with laparoscopic graspers.

Port placement should be based on the position and size of the fibroids to be removed. Laparoscopic suturing is more ergonomic with 2 ports placed on one side of the patient (FIGURE 2). For suture access, a 12-mm port is placed about 2 cm medial to the iliac crest and a 5-mm port is placed medial to the 12-mm port, near the level of the umbilicus. Lateral trocars should be placed high, above the superior aspect of the uterus, to make it easier to access the fibroids, and lateral to the inferior epigastric vessels, to avoid injuring those vessels. If the uterus is near or above the umbilicus, a left upper quadrant approach may be used, with the access ports placed above the umbilicus.

Related article:
How to avoid major vessel injury during gynecologic laparoscopy

Managing intraoperative blood loss

I use a combination of 3 agents to reduce intraoperative blood loss during laparoscopic myomectomy: preoperative misoprostol and tranexamic acid and intraoperative vasopressin. Although there are no data showing an advantage in using these drugs together, the agents have different mechanisms of action and no negative interactions.

Injected below the vascular pseudocapsule, 20 units of vasopressin in 100 mL of normal saline causes vasoconstriction of capillaries, small arterioles, and venules. Avoid intravascular injection given that bradycardia and cardiovascular collapse have been reported (rare cases). Loss of peripheral pulses, bradycardia, unmeasurable blood pressure, and cardiac complications have been reported after myometrial injection of ≥5 units of vasopressin.⁵

Although vasopressin is a powerful vasoconstrictor, these clinical findings are often interpreted as severe hypotension. However, evaluation of peripheral arterial blood flow by Doppler ultrasonography has revealed severe vasospasm and increased proximal blood pressure.⁵ Keep this potential reaction in mind to avoid misinterpreting findings and treating a patient with vasopressors. Presence of palpable carotid pulses and maintenance of normal partial pressure of end-tidal carbon dioxide can help differentiate peripheral vasospasm from global hypotension.

Use of vasopressin to reduce blood loss during myomectomy is off-label. On occasion, I apply a tourniquet around the lower uterine segment, including the infundibular pelvic ligaments. I use a red Robinson catheter, throw 1 tie in front of the uterus, pull with graspers on both ends until it is tight, and then clamp the half-knot with a locking grasper.

Tip. Although a salvage-type autologous blood transfusion device may be used during laparoscopic or robot-assisted myomectomy, cases in which this device is considered for very large or multiple fibroids might be better managed with abdominal myomectomy.

Read about surgical technique

Surgical technique

After injecting vasopressin, I use a high-frequency mechanical vibration scalpel to incise the myometrium directly over a prominent fibroid and carry the incision deeply until fibroid tissue is definite. Alternatively, a monopolar laparoscopic needle can be used in cut mode—which also limits damage to the myometrium.

Tip. The course of vessels over a fibroid is unpredictable, and we cannot be certain that any uterine incision will avoid bleeding. Therefore, I make transverse incisions, which allow more ergonomic laparoscopic suturing.

It is important to incise completely through the myometrium and through the pink-red pseudocapsule containing the vascular network surrounding the fibroid. This plane is often deeper than usually recognized and can be identified just over the white fibroid.

The fibroid is grasped with a tenaculum for traction, and countertraction is applied with a grasper on the myometrial edges. Once the fibroid is reached, graspers and the mechanical vibration scalpel are used to tease the pseudocapsule away from the fibroid (VIDEO).

Watch the video that accompanies this article:

---

Laparoscopic myomectomy technique

 

 

 

Tip. Staying under the pseudocapsule reduces bleeding and may preserve the tissue’s growth factors and neurotransmitters, which are thought to promote wound healing.⁶

Dissection with the mechanical vibration scalpel (or monopolar needle) should be performed under visual control to identify the tissue adhering to the fibroid, which is desiccated and then divided. The fibroid is dissected until free of the myometrium and is placed in the right lower abdomen. Small fibroids can be strung together on a long suture so none will be lost. Using bipolar paddles, desiccate large bleeding vessels in the myometrial defect sparingly, with care taken to avoid devascularizing the myometrium, which might compromise wound healing. Myometrial repair should be performed in accordance with the accepted surgical technique used in laparotomy.

Place delayed absorbable sutures in 2 or 3 layers, as needed, to reapproximate the myometrium and secure hemostasis.

Tip: I use 0 polydioxanone interrupted figure-of-8 sutures, but continuous running sutures with or without barbs also can be used. For the serosa, I use a continuous barbed suture in a baseball stitch, which buries both the raw edges of the serosa and the barbs for smooth closure (FIGURE 3). These closure methods have not been compared to see which provides superior wound healing or subsequent wound strength.

The fibroid can be morcellated with an electromechanical morcellator or a scalpel (hand morcellation). Either instrument can be used in contained or uncontained fashion. I insert an electromechanical morcellator through the right lower quadrant incision and morcellate tissue in the anterior midpelvis. Safety requires careful control of the rotating blade and scrutiny of the bowel, bladder, and major vessels. Our operating room has 4 rules for morcellator use:

1. The blade is activated only under direct visualization.
2. Both the surgeon and the assistant must say “ready” before the blade is activated.
3. The hand holding the morcellator must remain still while tissue is being drawn into the device.
4. Any undue resistance from the tissue is cause to stop the blade. This precaution is taken because there is a tendency to drop the blade in an attempt to overcome the resistance.

Tip: I limit rotational forces and scattering of tissue by “pulsing” the blade on and off when morcellating softer tissue.

Various methods of contained morcellation (morcellation in a containment bag) have been described.⁷ In one method, tissue is placed in a bag, the neck of the bag is brought through an enlarged umbilical incision, and the tissue is cut into small pieces until it is entirely removed. Another method is to use an electromechanical morcellator with a specially designed containment bag inside the abdomen. The bag is introduced through a 12-mm port and unfurled inside the abdomen; the specimen is placed in the bag; the neck of the bag is brought out through the port; the bag is insufflated with carbon dioxide; the laparoscope, a 5-mm grasper, and the morcellator tip are passed into the bag; and morcellation is performed. Early studies of contained morcellation reported longer operating times, leaking bags, and visceral injuries. In 2016, the US Food and Drug Administration (FDA) cleared the PneumoLiner containment system but required that its manufacturer (Advanced Surgical Concepts) warn patients and health care providers that its bag has not been proved to reduce the risk of spreading cancer during morcellation procedures.⁸

During laparoscopic myomectomy, fibroid removal by myometrial dissection disperses tissue fragments, and the unprotected fibroid is usually stored in the abdomen until hemostasis is secured and suturing completed. Limiting the rotational forces that lead to further dispersement and irrigating copiously to remove tissue fragments help eliminate residual tissue.

The pelvis and the abdomen are irrigated with normal saline (approximately 3 L) and suctioned multiple times.

Tip. Alternating between the Trendelenburg and reverse Trendelenburg positions allows fluid to wash tissue down to the pelvis, where it is more easily seen and removed.

Careful inspection for tissue fragments and copious irrigation and suctioning are important in reducing the risk that tissue fragments will remain in the peritoneal cavity and parasitic fibroids will develop. In cases of occult leiomyosarcoma (LMS), this step may be particularly important.

I place a knitted fabric of modified cellulose over the hysterotomy suture lines to reduce the incidence of adhesion formation. Once the procedure is complete, the local anesthetic bupivicaine is injected deep into the incision sites. Injecting anesthetic before making the incisions does not provide better pain relief; injecting after the procedure provides pain relief for 6 hours.⁹

Related article:
Robot-assisted laparoscopic myomectomy

Morcellation and risk of leiomyosarcoma

Given the need to prevent laparoscopic morcellators from inadvertently spreading tissue within the peritoneal cavity of women with occult LMS, the FDA issued a safety communication in 2014 warning against their use in the majority of women who undergo myomectomy or hysterectomy for fibroids.¹⁰ However, Pritts and colleagues estimated the prevalence of LMS in women who had surgery for presumed uterine fibroids at about 1 in 2,000 (0.05%), significantly lower than the FDA’s estimate of 1 in 350.^10,11 In 2015, a large population-based prospective registry study found 2 cases of occult LMS in 8,720 fibroid surgery patients (0.02%).¹²

Related article:
The FDA’s review of the data on open power morcellation was “inadequate, irresponsible” and a “disservice to women”

Since LMS metastasizes through the bloodstream, there is no reliable evidence that morcellation influences survival or that electromechanical morcellation is inferior to vaginal or mini-laparotomy morcellation with a scalpel. According to recent publications, compared with MIS, open abdominal surgery is associated with more morbidity and mortality in women.¹³ Since the FDA advisory was issued, the number of abdominal surgeries has increased, as has the number of related complications.¹³

I use electromechanical morcellation techniques for women who want MIS. All surgical procedures have potential risks, and patients’ and physicians’ understanding of risks forms the foundation of medical decision making. The possibility of occult LMS should be considered by women and their gynecologists, and proper informed consent, noting both the LMS risk and the increased risks of abdominal surgery, should be obtained.

Related article:
Tissue extraction: Can the pendulum change direction?

Risk of uterine rupture after laparoscopic myomectomy

After abdominal myomectomy, uterine rupture during pregnancy or delivery is rare, according to reviews of delivery records of many thousands of women.¹⁴ Operative techniques, instruments, and energy sources used during laparoscopic or robot-assisted myomectomy may differ from those used during laparotomy, and anecdotal communications suggest that uterine rupture may be more common after laparoscopic or robot-assisted myomectomy. A meta-analysis of 56 articles (3,685 pregnancies) published between 1970 and 2013 found 29 cases of uterine rupture after myomectomy, with no statistical difference in rupture risk between laparoscopic and abdominal myomectomy.¹⁵ As most reports are case studies or small case series, the incidence of rupture cannot be reliably calculated.

There is no consensus regarding the factors that may increase the risk of uterine rupture after laparoscopic myomectomy. Three factors are postulated to interfere with myometrial wound healing and increase uterine rupture risk: failure to adequately suture myometrial defects, excessive use of monopolar or bipolar electrosurgery with devascularization of the myometrium, and lack of hemostasis with subsequent hematoma formation.¹⁶ It seems prudent that surgeons should adhere to time-tested techniques for abdominal myomectomy. Even with use of ideal surgical techniques, however, individual wound-healing characteristics may predispose to uterine rupture.

CASE Resolved

After giving proper informed consent, the patient underwent laparoscopic myomectomy and electromechanical morcellation. Her 2 fibroids were removed, with a blood loss of 200 mL, and that afternoon she was discharged from the surgery center with written postoperative instructions and oral pain medication. A telephone call the next day found her comfortable, with no nausea or vomiting, and happy to be fibroid free. Pathologic inspection of the morcellated tissue confirmed that the fibroids were benign. At 2-week follow-up, the patient was no longer taking pain medication and was ready to return to work and normal activity. Her fatigue persisted, though, and she arranged to take time to rest during the day.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

CASE Patient wants minimally invasive surgery for her fibroids, and no hysterectomy

A 44-year-old G1P1 woman comes to the office to discuss her uterine fibroids, heavy menstrual bleeding, and urinary frequency. Treatment with oral contraceptives has not been effective in reducing the bleeding. She now wants surgical treatment without a hysterectomy (the hysterectomy was recommended by her previous gynecologist). On examination, a 14-week-size irregular uterus is felt. Myomectomy is discussed, and the patient asks if minimally invasive surgery (MIS) is possible. Complete blood cell count testing shows a hemoglobin level of 9.4 g/dL. Pelvic magnetic resonance imaging (MRI) shows a 6-cm type 2 posterior fundal fibroid and a 6-cm type 5 posterior lower-uterine-segment fibroid (FIGURE 1). These 2 fibroids have regular contours, and enhancement is not increased with contrast, consistent with benign fibroids.

Determining that laparoscopic myomectomy is a good option

Fibroids may affect quality of life—they may cause heavy menstrual bleeding, pelvic pain or pressure, or urinary frequency or incontinence. For many women who want large or numerous fibroids removed but the uterus preserved, abdominal myomectomy is required. Smaller and less numerous fibroids usually can be managed laparoscopically or with robotic assistance.

A systematic review of 6 randomized, controlled trials comparing laparoscopic and open myomectomy in 576 patients found that, although laparoscopic myomectomy was associated with longer operative time (approximately 13 minutes), it was also linked to less operative blood loss, fewer overall complications, reduced postoperative pain, and faster recovery.¹ However, wide application of the laparoscopic approach may be limited by the size and number of fibroids that can be reasonably removed and by the surgical skill needed for fibroid excision and laparoscopic suturing.

Four imaging modalities can be used for fibroids: transvaginal sonography (TVS), saline-infusion sonography (SIS), hysteroscopy, and MRI. TVS is the most readily available and least costly modality used to differentiate fibroids from other pelvic pathology; SIS provides contrast for the endometrial cavity and better defines submucous fibroids; and hysteroscopy detects visually apparent distortion of the cavity. MRI, however, provides the most complete evaluation of size, position, and number of fibroids.

A study comparing TVS, SIS, hysteroscopy, and MRI found that number and position of fibroids were best identified with MRI.² In addition, with MRI, the proximity of the fibroids and uterus to the bladder, rectum, and iliac bones can be evaluated. As tactility in laparoscopic and robot-assisted surgery is very limited, surgeons who use MRI to accurately assess fibroids preoperatively may be able to avoid missing them during the procedure.³ MRI also can be used reliably to diagnose adenomyosis and may be able to help identify uterine sarcoma.

Tip. For all women considering laparoscopic or robot-assisted myomectomy, I order pelvic MRI with and without contrast. Having the radiologist limit the number of MRI sequences may reduce the cost and make it comparable to that of other imaging modalities. I request T2-weighted MRI scans in the coronal, sagittal, and axial planes; in addition, to determine distortion of the uterine cavity by submucous fibroids, I request scans in the planes parallel with and perpendicular to the uterine axis. One gadolinium-enhanced T1-weighted MRI scan is needed to evaluate perfusion.

Although radiologists are experts in image interpretation, they are unfamiliar with the treatments and surgical issues that gynecologists must consider. Reading MRI scans for fibroids is straightforward, and gynecologists who regularly treat women with fibroids should consider viewing images with a radiologist until they become proficient.

Related article:
Surgical management of broad ligament fibroids

Surgeons who have the experience and skill and know the size, number, and position of fibroids are able to select the appropriate candidates for laparoscopic myomectomy. Authors of a study of 2,050 laparoscopic myomectomies found that fibroids larger than 5 cm, removal of more than 3 fibroids, and broad ligament fibroids were more likely to be associated with major complications, including visceral injury, conversion to laparotomy, and bleeding requiring blood transfusion.⁴

In laparoscopic myomectomy, uterus reconstruction requires laparoscopic suturing. Although robot-assisted myomectomy may make laparoscopic suturing easier, the added cost, longer operative time, and unimproved outcomes must be considered too.

Read about trocar placement and managing blood loss

Trocar placement

Place the patient in the dorsal lithotomy position.

Tip. For most women, I do not use a uterine manipulator, as my assistant can manipulate the uterus with laparoscopic graspers.

Port placement should be based on the position and size of the fibroids to be removed. Laparoscopic suturing is more ergonomic with 2 ports placed on one side of the patient (FIGURE 2). For suture access, a 12-mm port is placed about 2 cm medial to the iliac crest and a 5-mm port is placed medial to the 12-mm port, near the level of the umbilicus. Lateral trocars should be placed high, above the superior aspect of the uterus, to make it easier to access the fibroids, and lateral to the inferior epigastric vessels, to avoid injuring those vessels. If the uterus is near or above the umbilicus, a left upper quadrant approach may be used, with the access ports placed above the umbilicus.

Related article:
How to avoid major vessel injury during gynecologic laparoscopy

Managing intraoperative blood loss

I use a combination of 3 agents to reduce intraoperative blood loss during laparoscopic myomectomy: preoperative misoprostol and tranexamic acid and intraoperative vasopressin. Although there are no data showing an advantage in using these drugs together, the agents have different mechanisms of action and no negative interactions.

Injected below the vascular pseudocapsule, 20 units of vasopressin in 100 mL of normal saline causes vasoconstriction of capillaries, small arterioles, and venules. Avoid intravascular injection given that bradycardia and cardiovascular collapse have been reported (rare cases). Loss of peripheral pulses, bradycardia, unmeasurable blood pressure, and cardiac complications have been reported after myometrial injection of ≥5 units of vasopressin.⁵

Although vasopressin is a powerful vasoconstrictor, these clinical findings are often interpreted as severe hypotension. However, evaluation of peripheral arterial blood flow by Doppler ultrasonography has revealed severe vasospasm and increased proximal blood pressure.⁵ Keep this potential reaction in mind to avoid misinterpreting findings and treating a patient with vasopressors. Presence of palpable carotid pulses and maintenance of normal partial pressure of end-tidal carbon dioxide can help differentiate peripheral vasospasm from global hypotension.

Use of vasopressin to reduce blood loss during myomectomy is off-label. On occasion, I apply a tourniquet around the lower uterine segment, including the infundibular pelvic ligaments. I use a red Robinson catheter, throw 1 tie in front of the uterus, pull with graspers on both ends until it is tight, and then clamp the half-knot with a locking grasper.

Tip. Although a salvage-type autologous blood transfusion device may be used during laparoscopic or robot-assisted myomectomy, cases in which this device is considered for very large or multiple fibroids might be better managed with abdominal myomectomy.

Read about surgical technique

Surgical technique

After injecting vasopressin, I use a high-frequency mechanical vibration scalpel to incise the myometrium directly over a prominent fibroid and carry the incision deeply until fibroid tissue is definite. Alternatively, a monopolar laparoscopic needle can be used in cut mode—which also limits damage to the myometrium.

Tip. The course of vessels over a fibroid is unpredictable, and we cannot be certain that any uterine incision will avoid bleeding. Therefore, I make transverse incisions, which allow more ergonomic laparoscopic suturing.

It is important to incise completely through the myometrium and through the pink-red pseudocapsule containing the vascular network surrounding the fibroid. This plane is often deeper than usually recognized and can be identified just over the white fibroid.

The fibroid is grasped with a tenaculum for traction, and countertraction is applied with a grasper on the myometrial edges. Once the fibroid is reached, graspers and the mechanical vibration scalpel are used to tease the pseudocapsule away from the fibroid (VIDEO).

Watch the video that accompanies this article:

---

Laparoscopic myomectomy technique

 

 

 

Tip. Staying under the pseudocapsule reduces bleeding and may preserve the tissue’s growth factors and neurotransmitters, which are thought to promote wound healing.⁶

Dissection with the mechanical vibration scalpel (or monopolar needle) should be performed under visual control to identify the tissue adhering to the fibroid, which is desiccated and then divided. The fibroid is dissected until free of the myometrium and is placed in the right lower abdomen. Small fibroids can be strung together on a long suture so none will be lost. Using bipolar paddles, desiccate large bleeding vessels in the myometrial defect sparingly, with care taken to avoid devascularizing the myometrium, which might compromise wound healing. Myometrial repair should be performed in accordance with the accepted surgical technique used in laparotomy.

Place delayed absorbable sutures in 2 or 3 layers, as needed, to reapproximate the myometrium and secure hemostasis.

Tip: I use 0 polydioxanone interrupted figure-of-8 sutures, but continuous running sutures with or without barbs also can be used. For the serosa, I use a continuous barbed suture in a baseball stitch, which buries both the raw edges of the serosa and the barbs for smooth closure (FIGURE 3). These closure methods have not been compared to see which provides superior wound healing or subsequent wound strength.

The fibroid can be morcellated with an electromechanical morcellator or a scalpel (hand morcellation). Either instrument can be used in contained or uncontained fashion. I insert an electromechanical morcellator through the right lower quadrant incision and morcellate tissue in the anterior midpelvis. Safety requires careful control of the rotating blade and scrutiny of the bowel, bladder, and major vessels. Our operating room has 4 rules for morcellator use:

1. The blade is activated only under direct visualization.
2. Both the surgeon and the assistant must say “ready” before the blade is activated.
3. The hand holding the morcellator must remain still while tissue is being drawn into the device.
4. Any undue resistance from the tissue is cause to stop the blade. This precaution is taken because there is a tendency to drop the blade in an attempt to overcome the resistance.

Tip: I limit rotational forces and scattering of tissue by “pulsing” the blade on and off when morcellating softer tissue.

Various methods of contained morcellation (morcellation in a containment bag) have been described.⁷ In one method, tissue is placed in a bag, the neck of the bag is brought through an enlarged umbilical incision, and the tissue is cut into small pieces until it is entirely removed. Another method is to use an electromechanical morcellator with a specially designed containment bag inside the abdomen. The bag is introduced through a 12-mm port and unfurled inside the abdomen; the specimen is placed in the bag; the neck of the bag is brought out through the port; the bag is insufflated with carbon dioxide; the laparoscope, a 5-mm grasper, and the morcellator tip are passed into the bag; and morcellation is performed. Early studies of contained morcellation reported longer operating times, leaking bags, and visceral injuries. In 2016, the US Food and Drug Administration (FDA) cleared the PneumoLiner containment system but required that its manufacturer (Advanced Surgical Concepts) warn patients and health care providers that its bag has not been proved to reduce the risk of spreading cancer during morcellation procedures.⁸

During laparoscopic myomectomy, fibroid removal by myometrial dissection disperses tissue fragments, and the unprotected fibroid is usually stored in the abdomen until hemostasis is secured and suturing completed. Limiting the rotational forces that lead to further dispersement and irrigating copiously to remove tissue fragments help eliminate residual tissue.

The pelvis and the abdomen are irrigated with normal saline (approximately 3 L) and suctioned multiple times.

Tip. Alternating between the Trendelenburg and reverse Trendelenburg positions allows fluid to wash tissue down to the pelvis, where it is more easily seen and removed.

Careful inspection for tissue fragments and copious irrigation and suctioning are important in reducing the risk that tissue fragments will remain in the peritoneal cavity and parasitic fibroids will develop. In cases of occult leiomyosarcoma (LMS), this step may be particularly important.

I place a knitted fabric of modified cellulose over the hysterotomy suture lines to reduce the incidence of adhesion formation. Once the procedure is complete, the local anesthetic bupivicaine is injected deep into the incision sites. Injecting anesthetic before making the incisions does not provide better pain relief; injecting after the procedure provides pain relief for 6 hours.⁹

Related article:
Robot-assisted laparoscopic myomectomy

Morcellation and risk of leiomyosarcoma

Given the need to prevent laparoscopic morcellators from inadvertently spreading tissue within the peritoneal cavity of women with occult LMS, the FDA issued a safety communication in 2014 warning against their use in the majority of women who undergo myomectomy or hysterectomy for fibroids.¹⁰ However, Pritts and colleagues estimated the prevalence of LMS in women who had surgery for presumed uterine fibroids at about 1 in 2,000 (0.05%), significantly lower than the FDA’s estimate of 1 in 350.^10,11 In 2015, a large population-based prospective registry study found 2 cases of occult LMS in 8,720 fibroid surgery patients (0.02%).¹²

Related article:
The FDA’s review of the data on open power morcellation was “inadequate, irresponsible” and a “disservice to women”

Since LMS metastasizes through the bloodstream, there is no reliable evidence that morcellation influences survival or that electromechanical morcellation is inferior to vaginal or mini-laparotomy morcellation with a scalpel. According to recent publications, compared with MIS, open abdominal surgery is associated with more morbidity and mortality in women.¹³ Since the FDA advisory was issued, the number of abdominal surgeries has increased, as has the number of related complications.¹³

I use electromechanical morcellation techniques for women who want MIS. All surgical procedures have potential risks, and patients’ and physicians’ understanding of risks forms the foundation of medical decision making. The possibility of occult LMS should be considered by women and their gynecologists, and proper informed consent, noting both the LMS risk and the increased risks of abdominal surgery, should be obtained.

Related article:
Tissue extraction: Can the pendulum change direction?

Risk of uterine rupture after laparoscopic myomectomy

After abdominal myomectomy, uterine rupture during pregnancy or delivery is rare, according to reviews of delivery records of many thousands of women.¹⁴ Operative techniques, instruments, and energy sources used during laparoscopic or robot-assisted myomectomy may differ from those used during laparotomy, and anecdotal communications suggest that uterine rupture may be more common after laparoscopic or robot-assisted myomectomy. A meta-analysis of 56 articles (3,685 pregnancies) published between 1970 and 2013 found 29 cases of uterine rupture after myomectomy, with no statistical difference in rupture risk between laparoscopic and abdominal myomectomy.¹⁵ As most reports are case studies or small case series, the incidence of rupture cannot be reliably calculated.

There is no consensus regarding the factors that may increase the risk of uterine rupture after laparoscopic myomectomy. Three factors are postulated to interfere with myometrial wound healing and increase uterine rupture risk: failure to adequately suture myometrial defects, excessive use of monopolar or bipolar electrosurgery with devascularization of the myometrium, and lack of hemostasis with subsequent hematoma formation.¹⁶ It seems prudent that surgeons should adhere to time-tested techniques for abdominal myomectomy. Even with use of ideal surgical techniques, however, individual wound-healing characteristics may predispose to uterine rupture.

CASE Resolved

After giving proper informed consent, the patient underwent laparoscopic myomectomy and electromechanical morcellation. Her 2 fibroids were removed, with a blood loss of 200 mL, and that afternoon she was discharged from the surgery center with written postoperative instructions and oral pain medication. A telephone call the next day found her comfortable, with no nausea or vomiting, and happy to be fibroid free. Pathologic inspection of the morcellated tissue confirmed that the fibroids were benign. At 2-week follow-up, the patient was no longer taking pain medication and was ready to return to work and normal activity. Her fatigue persisted, though, and she arranged to take time to rest during the day.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

CASE Patient wants minimally invasive surgery for her fibroids, and no hysterectomy

A 44-year-old G1P1 woman comes to the office to discuss her uterine fibroids, heavy menstrual bleeding, and urinary frequency. Treatment with oral contraceptives has not been effective in reducing the bleeding. She now wants surgical treatment without a hysterectomy (the hysterectomy was recommended by her previous gynecologist). On examination, a 14-week-size irregular uterus is felt. Myomectomy is discussed, and the patient asks if minimally invasive surgery (MIS) is possible. Complete blood cell count testing shows a hemoglobin level of 9.4 g/dL. Pelvic magnetic resonance imaging (MRI) shows a 6-cm type 2 posterior fundal fibroid and a 6-cm type 5 posterior lower-uterine-segment fibroid (FIGURE 1). These 2 fibroids have regular contours, and enhancement is not increased with contrast, consistent with benign fibroids.

Determining that laparoscopic myomectomy is a good option

Fibroids may affect quality of life—they may cause heavy menstrual bleeding, pelvic pain or pressure, or urinary frequency or incontinence. For many women who want large or numerous fibroids removed but the uterus preserved, abdominal myomectomy is required. Smaller and less numerous fibroids usually can be managed laparoscopically or with robotic assistance.

A systematic review of 6 randomized, controlled trials comparing laparoscopic and open myomectomy in 576 patients found that, although laparoscopic myomectomy was associated with longer operative time (approximately 13 minutes), it was also linked to less operative blood loss, fewer overall complications, reduced postoperative pain, and faster recovery.¹ However, wide application of the laparoscopic approach may be limited by the size and number of fibroids that can be reasonably removed and by the surgical skill needed for fibroid excision and laparoscopic suturing.

Four imaging modalities can be used for fibroids: transvaginal sonography (TVS), saline-infusion sonography (SIS), hysteroscopy, and MRI. TVS is the most readily available and least costly modality used to differentiate fibroids from other pelvic pathology; SIS provides contrast for the endometrial cavity and better defines submucous fibroids; and hysteroscopy detects visually apparent distortion of the cavity. MRI, however, provides the most complete evaluation of size, position, and number of fibroids.

A study comparing TVS, SIS, hysteroscopy, and MRI found that number and position of fibroids were best identified with MRI.² In addition, with MRI, the proximity of the fibroids and uterus to the bladder, rectum, and iliac bones can be evaluated. As tactility in laparoscopic and robot-assisted surgery is very limited, surgeons who use MRI to accurately assess fibroids preoperatively may be able to avoid missing them during the procedure.³ MRI also can be used reliably to diagnose adenomyosis and may be able to help identify uterine sarcoma.

Tip. For all women considering laparoscopic or robot-assisted myomectomy, I order pelvic MRI with and without contrast. Having the radiologist limit the number of MRI sequences may reduce the cost and make it comparable to that of other imaging modalities. I request T2-weighted MRI scans in the coronal, sagittal, and axial planes; in addition, to determine distortion of the uterine cavity by submucous fibroids, I request scans in the planes parallel with and perpendicular to the uterine axis. One gadolinium-enhanced T1-weighted MRI scan is needed to evaluate perfusion.

Although radiologists are experts in image interpretation, they are unfamiliar with the treatments and surgical issues that gynecologists must consider. Reading MRI scans for fibroids is straightforward, and gynecologists who regularly treat women with fibroids should consider viewing images with a radiologist until they become proficient.

Related article:
Surgical management of broad ligament fibroids

Surgeons who have the experience and skill and know the size, number, and position of fibroids are able to select the appropriate candidates for laparoscopic myomectomy. Authors of a study of 2,050 laparoscopic myomectomies found that fibroids larger than 5 cm, removal of more than 3 fibroids, and broad ligament fibroids were more likely to be associated with major complications, including visceral injury, conversion to laparotomy, and bleeding requiring blood transfusion.⁴

In laparoscopic myomectomy, uterus reconstruction requires laparoscopic suturing. Although robot-assisted myomectomy may make laparoscopic suturing easier, the added cost, longer operative time, and unimproved outcomes must be considered too.

Read about trocar placement and managing blood loss

Trocar placement

Place the patient in the dorsal lithotomy position.

Tip. For most women, I do not use a uterine manipulator, as my assistant can manipulate the uterus with laparoscopic graspers.

Port placement should be based on the position and size of the fibroids to be removed. Laparoscopic suturing is more ergonomic with 2 ports placed on one side of the patient (FIGURE 2). For suture access, a 12-mm port is placed about 2 cm medial to the iliac crest and a 5-mm port is placed medial to the 12-mm port, near the level of the umbilicus. Lateral trocars should be placed high, above the superior aspect of the uterus, to make it easier to access the fibroids, and lateral to the inferior epigastric vessels, to avoid injuring those vessels. If the uterus is near or above the umbilicus, a left upper quadrant approach may be used, with the access ports placed above the umbilicus.

Related article:
How to avoid major vessel injury during gynecologic laparoscopy

Managing intraoperative blood loss

I use a combination of 3 agents to reduce intraoperative blood loss during laparoscopic myomectomy: preoperative misoprostol and tranexamic acid and intraoperative vasopressin. Although there are no data showing an advantage in using these drugs together, the agents have different mechanisms of action and no negative interactions.

Injected below the vascular pseudocapsule, 20 units of vasopressin in 100 mL of normal saline causes vasoconstriction of capillaries, small arterioles, and venules. Avoid intravascular injection given that bradycardia and cardiovascular collapse have been reported (rare cases). Loss of peripheral pulses, bradycardia, unmeasurable blood pressure, and cardiac complications have been reported after myometrial injection of ≥5 units of vasopressin.⁵

Although vasopressin is a powerful vasoconstrictor, these clinical findings are often interpreted as severe hypotension. However, evaluation of peripheral arterial blood flow by Doppler ultrasonography has revealed severe vasospasm and increased proximal blood pressure.⁵ Keep this potential reaction in mind to avoid misinterpreting findings and treating a patient with vasopressors. Presence of palpable carotid pulses and maintenance of normal partial pressure of end-tidal carbon dioxide can help differentiate peripheral vasospasm from global hypotension.

Use of vasopressin to reduce blood loss during myomectomy is off-label. On occasion, I apply a tourniquet around the lower uterine segment, including the infundibular pelvic ligaments. I use a red Robinson catheter, throw 1 tie in front of the uterus, pull with graspers on both ends until it is tight, and then clamp the half-knot with a locking grasper.

Tip. Although a salvage-type autologous blood transfusion device may be used during laparoscopic or robot-assisted myomectomy, cases in which this device is considered for very large or multiple fibroids might be better managed with abdominal myomectomy.

Read about surgical technique

Surgical technique

After injecting vasopressin, I use a high-frequency mechanical vibration scalpel to incise the myometrium directly over a prominent fibroid and carry the incision deeply until fibroid tissue is definite. Alternatively, a monopolar laparoscopic needle can be used in cut mode—which also limits damage to the myometrium.

Tip. The course of vessels over a fibroid is unpredictable, and we cannot be certain that any uterine incision will avoid bleeding. Therefore, I make transverse incisions, which allow more ergonomic laparoscopic suturing.

It is important to incise completely through the myometrium and through the pink-red pseudocapsule containing the vascular network surrounding the fibroid. This plane is often deeper than usually recognized and can be identified just over the white fibroid.

The fibroid is grasped with a tenaculum for traction, and countertraction is applied with a grasper on the myometrial edges. Once the fibroid is reached, graspers and the mechanical vibration scalpel are used to tease the pseudocapsule away from the fibroid (VIDEO).

Watch the video that accompanies this article:

---

Laparoscopic myomectomy technique

 

 

 

Tip. Staying under the pseudocapsule reduces bleeding and may preserve the tissue’s growth factors and neurotransmitters, which are thought to promote wound healing.⁶

Dissection with the mechanical vibration scalpel (or monopolar needle) should be performed under visual control to identify the tissue adhering to the fibroid, which is desiccated and then divided. The fibroid is dissected until free of the myometrium and is placed in the right lower abdomen. Small fibroids can be strung together on a long suture so none will be lost. Using bipolar paddles, desiccate large bleeding vessels in the myometrial defect sparingly, with care taken to avoid devascularizing the myometrium, which might compromise wound healing. Myometrial repair should be performed in accordance with the accepted surgical technique used in laparotomy.

Place delayed absorbable sutures in 2 or 3 layers, as needed, to reapproximate the myometrium and secure hemostasis.

Tip: I use 0 polydioxanone interrupted figure-of-8 sutures, but continuous running sutures with or without barbs also can be used. For the serosa, I use a continuous barbed suture in a baseball stitch, which buries both the raw edges of the serosa and the barbs for smooth closure (FIGURE 3). These closure methods have not been compared to see which provides superior wound healing or subsequent wound strength.

The fibroid can be morcellated with an electromechanical morcellator or a scalpel (hand morcellation). Either instrument can be used in contained or uncontained fashion. I insert an electromechanical morcellator through the right lower quadrant incision and morcellate tissue in the anterior midpelvis. Safety requires careful control of the rotating blade and scrutiny of the bowel, bladder, and major vessels. Our operating room has 4 rules for morcellator use:

1. The blade is activated only under direct visualization.
2. Both the surgeon and the assistant must say “ready” before the blade is activated.
3. The hand holding the morcellator must remain still while tissue is being drawn into the device.
4. Any undue resistance from the tissue is cause to stop the blade. This precaution is taken because there is a tendency to drop the blade in an attempt to overcome the resistance.

Tip: I limit rotational forces and scattering of tissue by “pulsing” the blade on and off when morcellating softer tissue.

Various methods of contained morcellation (morcellation in a containment bag) have been described.⁷ In one method, tissue is placed in a bag, the neck of the bag is brought through an enlarged umbilical incision, and the tissue is cut into small pieces until it is entirely removed. Another method is to use an electromechanical morcellator with a specially designed containment bag inside the abdomen. The bag is introduced through a 12-mm port and unfurled inside the abdomen; the specimen is placed in the bag; the neck of the bag is brought out through the port; the bag is insufflated with carbon dioxide; the laparoscope, a 5-mm grasper, and the morcellator tip are passed into the bag; and morcellation is performed. Early studies of contained morcellation reported longer operating times, leaking bags, and visceral injuries. In 2016, the US Food and Drug Administration (FDA) cleared the PneumoLiner containment system but required that its manufacturer (Advanced Surgical Concepts) warn patients and health care providers that its bag has not been proved to reduce the risk of spreading cancer during morcellation procedures.⁸

During laparoscopic myomectomy, fibroid removal by myometrial dissection disperses tissue fragments, and the unprotected fibroid is usually stored in the abdomen until hemostasis is secured and suturing completed. Limiting the rotational forces that lead to further dispersement and irrigating copiously to remove tissue fragments help eliminate residual tissue.

The pelvis and the abdomen are irrigated with normal saline (approximately 3 L) and suctioned multiple times.

Tip. Alternating between the Trendelenburg and reverse Trendelenburg positions allows fluid to wash tissue down to the pelvis, where it is more easily seen and removed.

Careful inspection for tissue fragments and copious irrigation and suctioning are important in reducing the risk that tissue fragments will remain in the peritoneal cavity and parasitic fibroids will develop. In cases of occult leiomyosarcoma (LMS), this step may be particularly important.

I place a knitted fabric of modified cellulose over the hysterotomy suture lines to reduce the incidence of adhesion formation. Once the procedure is complete, the local anesthetic bupivicaine is injected deep into the incision sites. Injecting anesthetic before making the incisions does not provide better pain relief; injecting after the procedure provides pain relief for 6 hours.⁹

Related article:
Robot-assisted laparoscopic myomectomy

Morcellation and risk of leiomyosarcoma

Given the need to prevent laparoscopic morcellators from inadvertently spreading tissue within the peritoneal cavity of women with occult LMS, the FDA issued a safety communication in 2014 warning against their use in the majority of women who undergo myomectomy or hysterectomy for fibroids.¹⁰ However, Pritts and colleagues estimated the prevalence of LMS in women who had surgery for presumed uterine fibroids at about 1 in 2,000 (0.05%), significantly lower than the FDA’s estimate of 1 in 350.^10,11 In 2015, a large population-based prospective registry study found 2 cases of occult LMS in 8,720 fibroid surgery patients (0.02%).¹²

Related article:
The FDA’s review of the data on open power morcellation was “inadequate, irresponsible” and a “disservice to women”

Since LMS metastasizes through the bloodstream, there is no reliable evidence that morcellation influences survival or that electromechanical morcellation is inferior to vaginal or mini-laparotomy morcellation with a scalpel. According to recent publications, compared with MIS, open abdominal surgery is associated with more morbidity and mortality in women.¹³ Since the FDA advisory was issued, the number of abdominal surgeries has increased, as has the number of related complications.¹³

I use electromechanical morcellation techniques for women who want MIS. All surgical procedures have potential risks, and patients’ and physicians’ understanding of risks forms the foundation of medical decision making. The possibility of occult LMS should be considered by women and their gynecologists, and proper informed consent, noting both the LMS risk and the increased risks of abdominal surgery, should be obtained.

Related article:
Tissue extraction: Can the pendulum change direction?

Risk of uterine rupture after laparoscopic myomectomy

After abdominal myomectomy, uterine rupture during pregnancy or delivery is rare, according to reviews of delivery records of many thousands of women.¹⁴ Operative techniques, instruments, and energy sources used during laparoscopic or robot-assisted myomectomy may differ from those used during laparotomy, and anecdotal communications suggest that uterine rupture may be more common after laparoscopic or robot-assisted myomectomy. A meta-analysis of 56 articles (3,685 pregnancies) published between 1970 and 2013 found 29 cases of uterine rupture after myomectomy, with no statistical difference in rupture risk between laparoscopic and abdominal myomectomy.¹⁵ As most reports are case studies or small case series, the incidence of rupture cannot be reliably calculated.

There is no consensus regarding the factors that may increase the risk of uterine rupture after laparoscopic myomectomy. Three factors are postulated to interfere with myometrial wound healing and increase uterine rupture risk: failure to adequately suture myometrial defects, excessive use of monopolar or bipolar electrosurgery with devascularization of the myometrium, and lack of hemostasis with subsequent hematoma formation.¹⁶ It seems prudent that surgeons should adhere to time-tested techniques for abdominal myomectomy. Even with use of ideal surgical techniques, however, individual wound-healing characteristics may predispose to uterine rupture.

CASE Resolved

After giving proper informed consent, the patient underwent laparoscopic myomectomy and electromechanical morcellation. Her 2 fibroids were removed, with a blood loss of 200 mL, and that afternoon she was discharged from the surgery center with written postoperative instructions and oral pain medication. A telephone call the next day found her comfortable, with no nausea or vomiting, and happy to be fibroid free. Pathologic inspection of the morcellated tissue confirmed that the fibroids were benign. At 2-week follow-up, the patient was no longer taking pain medication and was ready to return to work and normal activity. Her fatigue persisted, though, and she arranged to take time to rest during the day.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

As it does annually, the Centers for Medicare & Medicaid Services (CMS) has announced changes to the resource-based relative value scale (RBRVS) physician payment system. This system is not static, and each year the CMS identifies codes to review that appear to be either overvalued or undervalued. While the CMS leads this process, the American Medical Association (AMA), working in conjunction with national medical specialty societies, provides annual recommended updates and changes to the CMS via its AMA/Specialty Society RVS Update Committee (RUC).

RVUs defined

Relative value units (RVUs), assigned to most codes found in the AMA’s Current Procedural Terminology (CPT) book, are calculated based on 3 elements: physician work, practice expense, and malpractice cost. For Medicare reimbursement purposes, these elements are adjusted by the current geographic index, and this adjusted RVU is then multiplied by the Medicare calculated annual conversion factor (in fiscal year 2017, that amount is $35.8887) to determine the final allowable for any given provider.

Commercial payers who use the RBRVS system for reimbursement usually calculate their own conversion factors, which they may or may not publish. Such calculation can be based on a percentage increase over the Medicare rate or other factors.

In-office hysteroscopy procedure reimbursement increases

This year, some notable increases and decreases in the practice expense element will impact payment to ObGyn practices. The best news is that for practices in which clinicians have been removing polyps or performing endometrial sampling or a full dilation and curettage (D & C) using a hysteroscope in the office, practice expense reimbursement now will improve dramatically. The practice expense RVU for CPT code 58558, Hysteroscopy, surgical; with sampling (biopsy) of endometrium and/or polypectomy, with or without D & C, has been increased more than 450% in this setting, with an increase from 6.11 in 2016 to 33.82 as of January 2, 2017, which reduces to a 237% increase when the change to the total RVU is calculated.

More new-found income. The only other procedure showing at least a 10% increase in reimbursement in the office setting is the professional component for the ultrasonic guidance for aspiration of ova.

When your reimbursements will decrease

Unfortunately, reimbursement has also been decreased for some CPT code procedures. The urodynamic study code 51784, Electromyography studies (EMG) of anal or urethral sphincter, other than needle, any technique, has decreased in RVU value by about 64%. This is due to cutting by half the physician work, practice expense, and malpractice cost RVU elements. Although hit with a somewhat smaller decrease, code 58562, Hysteroscopy, surgical; with removal of impacted foreign body, also suffered a decrease in all 3 RVU elements in the office setting, amounting to about a 19% decrease.

In the facility setting, the RVU for the code for vaginoplasty has been increased by 10%, but 11 procedures have lost between 11% and 19% of their previous RVU levels in this setting, and more than half are for hysteroscopic procedures. The complete list of codes that have incurred at least a 10% RVU change in 2017 are listed in TABLES 1 and 2 according to place of service.

Related article:
GYN coding changes to note for your maximized reimbursement

What’s up next for review and possible adjustment

Finally, as a reminder to all providers, the CMS has identified 3 procedure codes that are potentially misvalued due to their being reported more than 50% of the time with an evaluation and management (E/M) service. These codes represent 0-day procedures and will be evaluated during 2017:

• 57150, Irrigation of vagina and/or application of medicament for treatment of bacterial, parasitic, or fungoid disease
• 57160, Fitting and insertion of pessary or other intravaginal support device
• 58100, Endometrial sampling (biopsy) with or without endocervical sampling (biopsy), without cervical dilation, any method (separate procedure).

The CMS has made it clear that all 0-day procedure codes include evaluation services on the date of service, including the decision to do the procedure. If the CMS examination of data finds that the documentation does not support a separate and significant E/M service at the time of the procedure, the agency will consider adjusting the physician work component. All providers should therefore examine their reporting of an E/M service with 0-day procedures to ensure that the documentation clearly supports doing so.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

As it does annually, the Centers for Medicare & Medicaid Services (CMS) has announced changes to the resource-based relative value scale (RBRVS) physician payment system. This system is not static, and each year the CMS identifies codes to review that appear to be either overvalued or undervalued. While the CMS leads this process, the American Medical Association (AMA), working in conjunction with national medical specialty societies, provides annual recommended updates and changes to the CMS via its AMA/Specialty Society RVS Update Committee (RUC).

RVUs defined

Relative value units (RVUs), assigned to most codes found in the AMA’s Current Procedural Terminology (CPT) book, are calculated based on 3 elements: physician work, practice expense, and malpractice cost. For Medicare reimbursement purposes, these elements are adjusted by the current geographic index, and this adjusted RVU is then multiplied by the Medicare calculated annual conversion factor (in fiscal year 2017, that amount is $35.8887) to determine the final allowable for any given provider.

Commercial payers who use the RBRVS system for reimbursement usually calculate their own conversion factors, which they may or may not publish. Such calculation can be based on a percentage increase over the Medicare rate or other factors.

In-office hysteroscopy procedure reimbursement increases

This year, some notable increases and decreases in the practice expense element will impact payment to ObGyn practices. The best news is that for practices in which clinicians have been removing polyps or performing endometrial sampling or a full dilation and curettage (D & C) using a hysteroscope in the office, practice expense reimbursement now will improve dramatically. The practice expense RVU for CPT code 58558, Hysteroscopy, surgical; with sampling (biopsy) of endometrium and/or polypectomy, with or without D & C, has been increased more than 450% in this setting, with an increase from 6.11 in 2016 to 33.82 as of January 2, 2017, which reduces to a 237% increase when the change to the total RVU is calculated.

More new-found income. The only other procedure showing at least a 10% increase in reimbursement in the office setting is the professional component for the ultrasonic guidance for aspiration of ova.

When your reimbursements will decrease

Unfortunately, reimbursement has also been decreased for some CPT code procedures. The urodynamic study code 51784, Electromyography studies (EMG) of anal or urethral sphincter, other than needle, any technique, has decreased in RVU value by about 64%. This is due to cutting by half the physician work, practice expense, and malpractice cost RVU elements. Although hit with a somewhat smaller decrease, code 58562, Hysteroscopy, surgical; with removal of impacted foreign body, also suffered a decrease in all 3 RVU elements in the office setting, amounting to about a 19% decrease.

In the facility setting, the RVU for the code for vaginoplasty has been increased by 10%, but 11 procedures have lost between 11% and 19% of their previous RVU levels in this setting, and more than half are for hysteroscopic procedures. The complete list of codes that have incurred at least a 10% RVU change in 2017 are listed in TABLES 1 and 2 according to place of service.

Related article:
GYN coding changes to note for your maximized reimbursement

What’s up next for review and possible adjustment

Finally, as a reminder to all providers, the CMS has identified 3 procedure codes that are potentially misvalued due to their being reported more than 50% of the time with an evaluation and management (E/M) service. These codes represent 0-day procedures and will be evaluated during 2017:

• 57150, Irrigation of vagina and/or application of medicament for treatment of bacterial, parasitic, or fungoid disease
• 57160, Fitting and insertion of pessary or other intravaginal support device
• 58100, Endometrial sampling (biopsy) with or without endocervical sampling (biopsy), without cervical dilation, any method (separate procedure).

The CMS has made it clear that all 0-day procedure codes include evaluation services on the date of service, including the decision to do the procedure. If the CMS examination of data finds that the documentation does not support a separate and significant E/M service at the time of the procedure, the agency will consider adjusting the physician work component. All providers should therefore examine their reporting of an E/M service with 0-day procedures to ensure that the documentation clearly supports doing so.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

As it does annually, the Centers for Medicare & Medicaid Services (CMS) has announced changes to the resource-based relative value scale (RBRVS) physician payment system. This system is not static, and each year the CMS identifies codes to review that appear to be either overvalued or undervalued. While the CMS leads this process, the American Medical Association (AMA), working in conjunction with national medical specialty societies, provides annual recommended updates and changes to the CMS via its AMA/Specialty Society RVS Update Committee (RUC).

RVUs defined

Relative value units (RVUs), assigned to most codes found in the AMA’s Current Procedural Terminology (CPT) book, are calculated based on 3 elements: physician work, practice expense, and malpractice cost. For Medicare reimbursement purposes, these elements are adjusted by the current geographic index, and this adjusted RVU is then multiplied by the Medicare calculated annual conversion factor (in fiscal year 2017, that amount is $35.8887) to determine the final allowable for any given provider.

Commercial payers who use the RBRVS system for reimbursement usually calculate their own conversion factors, which they may or may not publish. Such calculation can be based on a percentage increase over the Medicare rate or other factors.

In-office hysteroscopy procedure reimbursement increases

This year, some notable increases and decreases in the practice expense element will impact payment to ObGyn practices. The best news is that for practices in which clinicians have been removing polyps or performing endometrial sampling or a full dilation and curettage (D & C) using a hysteroscope in the office, practice expense reimbursement now will improve dramatically. The practice expense RVU for CPT code 58558, Hysteroscopy, surgical; with sampling (biopsy) of endometrium and/or polypectomy, with or without D & C, has been increased more than 450% in this setting, with an increase from 6.11 in 2016 to 33.82 as of January 2, 2017, which reduces to a 237% increase when the change to the total RVU is calculated.

More new-found income. The only other procedure showing at least a 10% increase in reimbursement in the office setting is the professional component for the ultrasonic guidance for aspiration of ova.

When your reimbursements will decrease

Unfortunately, reimbursement has also been decreased for some CPT code procedures. The urodynamic study code 51784, Electromyography studies (EMG) of anal or urethral sphincter, other than needle, any technique, has decreased in RVU value by about 64%. This is due to cutting by half the physician work, practice expense, and malpractice cost RVU elements. Although hit with a somewhat smaller decrease, code 58562, Hysteroscopy, surgical; with removal of impacted foreign body, also suffered a decrease in all 3 RVU elements in the office setting, amounting to about a 19% decrease.

In the facility setting, the RVU for the code for vaginoplasty has been increased by 10%, but 11 procedures have lost between 11% and 19% of their previous RVU levels in this setting, and more than half are for hysteroscopic procedures. The complete list of codes that have incurred at least a 10% RVU change in 2017 are listed in TABLES 1 and 2 according to place of service.

Related article:
GYN coding changes to note for your maximized reimbursement

What’s up next for review and possible adjustment

Finally, as a reminder to all providers, the CMS has identified 3 procedure codes that are potentially misvalued due to their being reported more than 50% of the time with an evaluation and management (E/M) service. These codes represent 0-day procedures and will be evaluated during 2017:

• 57150, Irrigation of vagina and/or application of medicament for treatment of bacterial, parasitic, or fungoid disease
• 57160, Fitting and insertion of pessary or other intravaginal support device
• 58100, Endometrial sampling (biopsy) with or without endocervical sampling (biopsy), without cervical dilation, any method (separate procedure).

The CMS has made it clear that all 0-day procedure codes include evaluation services on the date of service, including the decision to do the procedure. If the CMS examination of data finds that the documentation does not support a separate and significant E/M service at the time of the procedure, the agency will consider adjusting the physician work component. All providers should therefore examine their reporting of an E/M service with 0-day procedures to ensure that the documentation clearly supports doing so.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Clinician educators face numerous obstacles to their joint mission of facilitating learning while also ensuring high-quality and patient-centered care. Time constraints, including the institution of house officer duty hour limitations,¹ shorter lengths of stay for hospitalized patients,² and competing career responsibilities, combine to create a dynamic learning environment. Additionally, clinician educators must balance the autonomy of their learners with the safety of their patients. They must teach to multiple learning levels and work collaboratively with multiple disciplines to foster an effective team-based approach to patient care. Yet, many clinician educators have no formal training in pedagogical methods.³ Such challenges necessitate increased attention to the work of excellent clinician educators and their respective teaching approaches.

Many studies of clinical teaching rely primarily on survey data of attributes of good clinical teachers.^3-7 While some studies have incorporated direct observations of teaching^8,9 or interviews with clinician educators or learners,^10,11 few have incorporated multiple perspectives from the current team and from former learners in order to provide a comprehensive picture of team-based learning.¹²

The goal of this study was to gain a thorough understanding, through multiple perspectives, of the techniques and behaviors used by exemplary educators within actual clinical environments. We studied attitudes, behaviors, and approaches of 12 such inpatient clinician educators.

Study Design and Sampling

This was a multisite study using an exploratory qualitative approach to inquiry. This approach was used to study the techniques and behaviors of excellent attendings during inpatient general medicine rounds. A modified snowball sampling approach¹³ was used, meaning individuals known to one member of the research team (SS) were initially contacted and asked to identify clinician educators (also referred to as attendings) for potential inclusion in the study. In an effort to identify attendings from a broad range of medical schools, the “2015 U.S. News and World Report Top Medical Schools: Research” rankings¹⁴ were also reviewed, with priority given to the top 25, as these are widely used to represent the best US hospitals. In an attempt to invite attendings from diverse institutions, additional medical schools not in the top 25 as well as historically black medical schools were also included. Division chiefs and chairs of internal medicine and/or directors of internal medicine residency programs at these schools were contacted and asked for recommendations of attendings, both within and outside their institutions, who they considered to be great inpatient teachers. In addition, key experts who have won teaching awards or were known to be specialists in the field of medical education were asked to nominate one or two other outstanding attendings.

By using this sampling method, 59 potential participants were identified. An internet search was conducted to obtain information about the potential participants and their institutions. Organizational characteristics such as geographic location, hospital size and affiliation, and patient population, as well as individual characteristics such as gender, medical education and training, and educational awards received were considered so that a diversity of organizations and backgrounds was represented. The list was narrowed down to 16 attendings who were contacted via e-mail and asked to participate. Interested participants were asked for a list of their current team members and 6 to 10 former learners to contact for interviews and focus groups. Former learners were included in an effort to better understand lasting effects on learners from their exemplary teaching attendings. A total of 12 attending physicians agreed to participate (Table 1). Literature on field methods has shown that 12 interviews are found to be adequate in accomplishing data saturation.¹⁵ Although 2 attendings were located at the same institution, we decided to include them given that both are recognized as master clinician educators and were each recommended by several individuals from various institutions. Hospitals were located throughout the US and included both university-affiliated hospitals and Veterans Affairs medical centers. Despite efforts to include physicians from historically black colleges and universities, only one attending was identified, and they declined the request to participate.

Data Collection

Observations. The one-day site visits were mainly conducted by two research team members, a physician (SS) and a medical anthropologist (MH), both of whom have extensive experience in qualitative methods. Teams were not uniform but were generally comprised of 1 attending, 1 senior medical resident, 1 to 2 interns, and approximately 2 medical students. Occasionally, a pharmacist, clinical assistant, or other health professional accompanied the team on rounds. Not infrequently, the bedside nurse would explicitly be included in the discussion regarding his or her specific patient. Each site visit began with observing attendings (N = 12) and current learners (N = 57) during rounds. Each research team member recorded their own observations via handwritten field notes, paying particular attention to group interactions, teaching approach, conversations occurring within and peripheral to the team, patient-team interactions, and the physical environment. By standing outside of the medical team circle and remaining silent during rounds, research team members remained unobtrusive to the discussion and process of rounds. Materials the attendings used during their teaching rounds were also documented and collected. Rounds generally lasted 2 to 3 hours. After each site visit, the research team met to compare and combine field notes.

Interviews and Focus Groups. The research team then conducted individual, semi-structured interviews with the attendings, focus groups with their current team (N = 46), and interviews or focus groups with their former learners (N = 26; Supplement 1). Eleven of the current team members observed during rounds were unable to participate in the focus groups due to clinical duties. Because the current learners who participated in the focus groups were also observed during rounds, the research team was able to ask them open-ended questions regarding teaching rounds and their roles as learners within this environment. Former learners who were still at the hospital participated in separate focus groups or interviews. Former learners who were no longer present at the hospital were contacted by telephone and individually interviewed by one research team member (MH). All interviews and focus groups were audio-recorded and transcribed.

This study was determined to be exempt by the University of Michigan Institutional Review Board. All participants were informed that their participation was completely voluntary and that they could terminate their involvement at any time.

Data Analysis

Data were analyzed using a thematic analysis approach.¹⁶ Thematic analysis entails reading through the data to identify patterns (and create codes) that relate to behaviors, experiences, meanings, and activities. Once patterns have been identified, they are grouped according to similarity into themes, which help to further explain the findings.¹⁷

After the first site visit was completed, the research team members that participated (SS and MH) met to develop initial ideas about meanings and possible patterns. All transcripts were read by one team member (MH) and, based on review of the data, codes were developed, defined, and documented in a codebook. This process was repeated after every site visit using the codebook to expand or combine codes and refine definitions as necessary. If a new code was added, the previously coded data were reviewed to apply the new code. NVivo® 10 software (QSR International; Melbourne, Australia) was used to manage the data.

Once all field notes and transcripts were coded (MH), the code reports, which list all data described within a specific code, were run to ensure consistency and identify relationships between codes. Once coding was verified, codes were grouped based on similarities and relationships into salient themes by 3 members of the research team (NH, MH, and SM). Themes, along with their supporting codes, were then further defined to understand how these attendings worked to facilitate excellent teaching in clinical settings.

The coded interview data and field notes were categorized into broad, overlapping themes. Three of these major themes include (1) fostering positive relationships, (2) patient-centered teaching, and (3) collaboration and coaching. Table 2 lists each theme, salient behaviors, examples, and selected quotes that further elucidate its meaning.

Fostering Positive Relationships

Attending physicians took observable steps to develop positive relationships with their team members, which in turn created a safe learning environment. For instance, attendings used learners’ first names, demonstrated interest in their well-being, deployed humor, and generally displayed informal actions—uncrossed arms, “fist bump” when recognizing learners’ success, standing outside the circle of team members and leaning in to listen—during learner interactions. Attendings also made it a priority to get to know individuals on a personal level. As one current learner put it, “He asks about where we are from. He will try to find some kind of connection that he can establish with not only each of the team members but also with each of the patients.”

Additionally, attendings built positive relationships with their learners by responding thoughtfully to their input, even when learners’ evaluations of patients required modification. In turn, learners reported feeling safe to ask questions, admit uncertainty, and respectfully disagree with their attendings. As one attending reflected, “If I can get them into a place where they feel like the learning environment is someplace where they can make a mistake and know that that mistake does not necessarily mean that it’s going to cost them in their evaluation part, then I feel like that’s why it’s important.”

To build rapport and create a safe learning environment, attendings used a number of strategies to position themselves as learners alongside their team members. For instance, attendings indicated that they wanted their ideas questioned because they saw it as an opportunity to learn. Moreover, in conversations with learners, attendings demonstrated humility, admitting when they did not know something. One former learner noted, “There have been times when he has asked [a] question…nobody knows and then he admits that he doesn’t know either. So everybody goes and looks it up…The whole thing turns out to be a fun learning experience.”

Attendings demonstrated respect for their team members’ time by reading about patients before rounds, identifying learning opportunities during rounds, and integrating teaching points into the daily work of patient care. Teaching was not relegated exclusively to the conference room or confined to the traditional “chalk talk” before or after rounds but rather was assimilated into daily workflow. They appeared to be responsive to the needs of individual patients and the team, which allowed attendings to both directly oversee their patients’ care and overcome the challenges of multiple competing demands for time. The importance of this approach was made clear by one current learner who stated “…she does prepare before, especially you know on call days, she does prepare for the new patients before coming in to staff, which is really appreciated… it saves a lot of time on rounds.”

Attendings also included other health professionals in team discussions. Attendings used many of the same relationship-building techniques with these professionals as they did with learners and patients. They consistently asked these professionals to provide insight and direction in patients’ plans of care. A former learner commented, “He always asks the [nurse] what is her impression of the patient...he truly values the [nurse’s] opinion of the patient.” One attending reiterated this approach, stating “I don’t want them to think that anything I have to say is more valuable than our pharmacist or the [nurse].”

Patient-Centered Teaching

Attending physicians modeled numerous teaching techniques that focused learning around the patient. Attendings knew their patients well through review of the medical records, discussion with the patient, and personal examination. This preparation allowed attendings to focus on key teaching points in the context of the patient. One former learner noted, “He tended to bring up a variety of things that really fit well into the clinical scenario. So whether that is talking about what is the differential for a new symptom that just came up for this patient or kind of here is a new paper talking about this condition or maybe some other pearl of physical exam for a patient that has a certain physical condition.”

Attendings served as effective role models by being directly involved in examining and talking with patients as well as demonstrating excellent physical examination and communication techniques. One current learner articulated the importance of learning these skills by observing them done well: “I think he teaches by example and by doing, again, those little things: being attentive to the patients and being very careful during exams…I think those are things that you teach people by doing them, not by saying you need to do this better during the patient encounter.”

Collaboration and Coaching

Attending physicians used varied collaboration and coaching techniques to facilitate learning across the entire care team. During rounds, attendings utilized visual aids to reinforce key concepts and simplify complex topics. They also collaborated by using discussion rather than lecture to engage with team members. For instance, attendings used Socratic questioning, asking questions that lead learners through critical thinking and allow them to solve problems themselves, to guide learners’ decision-making. One former learner reported, “He never gives you the answer, and he always asks your opinion; ‘So what are your thoughts on this?’”

Coaching for success, rather than directing the various team members, was emphasized. Attendings did not wish to be seen as the “leaders” of the team. During rounds, one attending was noted to explain his role in ensuring that the team was building connections with others: “When we have a bad outcome, if it feels like your soul has been ripped out, then you’ve done something right. You’ve made that connection with the patient. My job, as your coach, was to build communication between all of us so we feel vested in each other and our patients.”

Attendings also fostered clinical reasoning skills in their learners by encouraging them to verbalize their thought processes aloud in order to clarify and check for understanding. Attendings also placed emphasis not simply on memorizing content but rather prioritization of the patient’s problems and thinking step by step through individual medical problems. One current learner applauded an attending who could “come up with schematics of how to approach problems rather than feeding us factual information of this paper or this trial.”

Additionally, attendings facilitated learning across the entire care team by differentiating their teaching to meet the needs of multiple learning levels. While the entire team was explicitly included in the learning process, attendings encouraged learners to play various roles, execute tasks, and answer questions depending on their educational level. Attendings positioned learners as leaders of the team by allowing them to talk without interruption and by encouraging them to take ownership of their patients’ care. One former learner stated, “She set expectations…we would be the ones who would be running the team, that you know it would very much be our team and that she is there to advise us and provide supervision but also safety for the patients as well.”

This study reveals the complex ways effective attendings build rapport, create a safe learning environment, utilize patient-centered teaching strategies, and engage in collaboration and coaching with all members of the team. These findings provide a framework of shared themes and their salient behaviors that may influence the success of inpatient general medicine clinician educators (Table 3).

There is a broad and voluminous literature on the subject of outstanding clinical teaching characteristics, much of which has shaped various faculty development curricula for decades. This study sought not to identify novel approaches of inpatient teaching necessarily but rather to closely examine the techniques and behaviors of clinician educators identified as exemplary. The findings affirm and reinforce the numerous, well-documented lists of personal attributes, techniques, and behaviors that resonate with learners, including creating a positive environment, demonstrating enthusiasm and interest in the learner, reading facial expressions, being student-centered, maintaining a high level of clinical knowledge, and utilizing effective communication skills.^18-24 The strengths of this study lie within the nuanced and rich observations and discussions that move beyond learners’ Likert scale evaluations and responses.^3-7,12 Input was sought from multiple perspectives on the care team, which provided detail from key stakeholders. Out of these comprehensive data arose several conclusions that extend the research literature on medical education.

In their seminal review, Sutkin et al.¹⁸ demonstrate that two thirds of characteristics of outstanding clinical teachers are “noncognitive” and that, “Perhaps what makes a clinical educator truly great depends less on the acquisition of cognitive skills such as medical knowledge and formulating learning objectives, and more on inherent, relationship-based, noncognitive attributes. Whereas cognitive abilities generally involve skills that may be taught and learned, albeit with difficulty, noncognitive abilities represent personal attributes, such as relationship skills, personality types, and emotional states, which are more difficult to develop and teach.”¹⁸ Our study, thus, adds to the literature by (1) highlighting examples of techniques and behaviors that encompass the crucial “noncognitive” arena and (2) informing best practices in teaching clinical medicine, especially those that resonate with learners, for future faculty development.

The findings highlight the role that relationships play in the teaching and learning of team-based medicine. Building rapport and sustaining successful relationships are cornerstones of effective teaching.¹⁸ For the attendings in this study, this manifested in observable, tangible behaviors such as greeting others by name, joking, using physical touch, and actively involving all team members, regardless of role or level of education. Previous literature has highlighted the importance of showing interest in learners.^7,19,25-27 This study provides multiple and varied examples of ways in which interest might be displayed.

For patients, the critical role of relationships was evidenced through rapport building and attention to patients as people outside their acute hospitalization. For instance, attendings regularly put patients’ medical issues into context and anticipated future outpatient challenges. To the authors’ knowledge, previous scholarship has not significantly emphasized this form of contextualized medicine, which involves the mindful consideration of the ongoing needs patients may experience upon transitions of care.

Several participants highlighted humility as an important characteristic of effective clinician educators. Attendings recognized that the field produces more new knowledge than can possibly be assimilated and that uncertainty is a mainstay of modern medical care. Attendings frequently utilized self-deprecation to acknowledge doubt, a technique that created a collaborative environment in which learners also felt safe to ask questions. These findings support the viewpoints by Reilly and Beckman that humility and an appreciation for questions and push-back from learners encourage lifelong learning through role modeling.^19,23 In responding to the interviewer’s question “And what happens when [the attending] is wrong?” one learner simply stated, “He makes fun of himself.”

This study has several limitations. First, it was conducted in a limited number of US based healthcare systems. The majority of institutions represented were larger, research intensive hospitals. While these hospitals were purposefully selected to provide a range in geography, size, type, and access to resources, the findings may differ in other settings. Second, it was conducted with a limited number of attendings and learners, which may limit the study’s generalizability. However, enough interviews were conducted to reach data saturation.¹⁵ Because evidence for a causal relationship between quality teaching and student and patient outcomes is lacking,¹⁸ we must rely on imperfect proxies for teaching excellence, including awards and recognition. This study attempted to identify exemplary educators through various means, but it is recognized that bias is likely. Third, because attendings provided lists of former learners, selection and recall biases may have been introduced, as attendings may have more readily identified former learners with whom they formed strong relationships. Fourth, focus was placed exclusively on teaching and learning within general medicine rounds. This was because there would be ample opportunity for teaching on this service, the structure of the teams and the types of patients would be comparable across sites, and the principal investigator was also a general medicine attending and would have a frame of reference for these types of rounds. Due to this narrow focus, the findings may not be generalizable to other subspecialties. Fifth, attendings were selected through a nonexhaustive method. However, the multisite design, the modified snowball sampling, and the inclusion of several types of institutions in the final participant pool introduced diversity to the final list. Finally, although we cannot discount the potential role of a Hawthorne effect on our data collection, the research team did attempt to mitigate this by standing apart from the care teams and remaining unobtrusive during observations.

Using a combination of interviews, focus group discussions, and direct observation, we identified consistent techniques and behaviors of excellent teaching attendings during inpatient general medicine rounds. We hope that all levels of clinician educators may use them to elevate their own teaching.

Disclosure

Dr. Saint is on a medical advisory board of Doximity, a new social networking site for physicians, and receives an honorarium. He is also on the scientific advisory board of Jvion, a healthcare technology company. Drs. Houchens, Harrod, Moody, and Ms. Fowler have no conflicts of interest.

Clinician educators face numerous obstacles to their joint mission of facilitating learning while also ensuring high-quality and patient-centered care. Time constraints, including the institution of house officer duty hour limitations,¹ shorter lengths of stay for hospitalized patients,² and competing career responsibilities, combine to create a dynamic learning environment. Additionally, clinician educators must balance the autonomy of their learners with the safety of their patients. They must teach to multiple learning levels and work collaboratively with multiple disciplines to foster an effective team-based approach to patient care. Yet, many clinician educators have no formal training in pedagogical methods.³ Such challenges necessitate increased attention to the work of excellent clinician educators and their respective teaching approaches.

Many studies of clinical teaching rely primarily on survey data of attributes of good clinical teachers.^3-7 While some studies have incorporated direct observations of teaching^8,9 or interviews with clinician educators or learners,^10,11 few have incorporated multiple perspectives from the current team and from former learners in order to provide a comprehensive picture of team-based learning.¹²

The goal of this study was to gain a thorough understanding, through multiple perspectives, of the techniques and behaviors used by exemplary educators within actual clinical environments. We studied attitudes, behaviors, and approaches of 12 such inpatient clinician educators.

Study Design and Sampling

This was a multisite study using an exploratory qualitative approach to inquiry. This approach was used to study the techniques and behaviors of excellent attendings during inpatient general medicine rounds. A modified snowball sampling approach¹³ was used, meaning individuals known to one member of the research team (SS) were initially contacted and asked to identify clinician educators (also referred to as attendings) for potential inclusion in the study. In an effort to identify attendings from a broad range of medical schools, the “2015 U.S. News and World Report Top Medical Schools: Research” rankings¹⁴ were also reviewed, with priority given to the top 25, as these are widely used to represent the best US hospitals. In an attempt to invite attendings from diverse institutions, additional medical schools not in the top 25 as well as historically black medical schools were also included. Division chiefs and chairs of internal medicine and/or directors of internal medicine residency programs at these schools were contacted and asked for recommendations of attendings, both within and outside their institutions, who they considered to be great inpatient teachers. In addition, key experts who have won teaching awards or were known to be specialists in the field of medical education were asked to nominate one or two other outstanding attendings.

By using this sampling method, 59 potential participants were identified. An internet search was conducted to obtain information about the potential participants and their institutions. Organizational characteristics such as geographic location, hospital size and affiliation, and patient population, as well as individual characteristics such as gender, medical education and training, and educational awards received were considered so that a diversity of organizations and backgrounds was represented. The list was narrowed down to 16 attendings who were contacted via e-mail and asked to participate. Interested participants were asked for a list of their current team members and 6 to 10 former learners to contact for interviews and focus groups. Former learners were included in an effort to better understand lasting effects on learners from their exemplary teaching attendings. A total of 12 attending physicians agreed to participate (Table 1). Literature on field methods has shown that 12 interviews are found to be adequate in accomplishing data saturation.¹⁵ Although 2 attendings were located at the same institution, we decided to include them given that both are recognized as master clinician educators and were each recommended by several individuals from various institutions. Hospitals were located throughout the US and included both university-affiliated hospitals and Veterans Affairs medical centers. Despite efforts to include physicians from historically black colleges and universities, only one attending was identified, and they declined the request to participate.

Data Collection

Observations. The one-day site visits were mainly conducted by two research team members, a physician (SS) and a medical anthropologist (MH), both of whom have extensive experience in qualitative methods. Teams were not uniform but were generally comprised of 1 attending, 1 senior medical resident, 1 to 2 interns, and approximately 2 medical students. Occasionally, a pharmacist, clinical assistant, or other health professional accompanied the team on rounds. Not infrequently, the bedside nurse would explicitly be included in the discussion regarding his or her specific patient. Each site visit began with observing attendings (N = 12) and current learners (N = 57) during rounds. Each research team member recorded their own observations via handwritten field notes, paying particular attention to group interactions, teaching approach, conversations occurring within and peripheral to the team, patient-team interactions, and the physical environment. By standing outside of the medical team circle and remaining silent during rounds, research team members remained unobtrusive to the discussion and process of rounds. Materials the attendings used during their teaching rounds were also documented and collected. Rounds generally lasted 2 to 3 hours. After each site visit, the research team met to compare and combine field notes.

Interviews and Focus Groups. The research team then conducted individual, semi-structured interviews with the attendings, focus groups with their current team (N = 46), and interviews or focus groups with their former learners (N = 26; Supplement 1). Eleven of the current team members observed during rounds were unable to participate in the focus groups due to clinical duties. Because the current learners who participated in the focus groups were also observed during rounds, the research team was able to ask them open-ended questions regarding teaching rounds and their roles as learners within this environment. Former learners who were still at the hospital participated in separate focus groups or interviews. Former learners who were no longer present at the hospital were contacted by telephone and individually interviewed by one research team member (MH). All interviews and focus groups were audio-recorded and transcribed.

This study was determined to be exempt by the University of Michigan Institutional Review Board. All participants were informed that their participation was completely voluntary and that they could terminate their involvement at any time.

Data Analysis

Data were analyzed using a thematic analysis approach.¹⁶ Thematic analysis entails reading through the data to identify patterns (and create codes) that relate to behaviors, experiences, meanings, and activities. Once patterns have been identified, they are grouped according to similarity into themes, which help to further explain the findings.¹⁷

After the first site visit was completed, the research team members that participated (SS and MH) met to develop initial ideas about meanings and possible patterns. All transcripts were read by one team member (MH) and, based on review of the data, codes were developed, defined, and documented in a codebook. This process was repeated after every site visit using the codebook to expand or combine codes and refine definitions as necessary. If a new code was added, the previously coded data were reviewed to apply the new code. NVivo® 10 software (QSR International; Melbourne, Australia) was used to manage the data.

Once all field notes and transcripts were coded (MH), the code reports, which list all data described within a specific code, were run to ensure consistency and identify relationships between codes. Once coding was verified, codes were grouped based on similarities and relationships into salient themes by 3 members of the research team (NH, MH, and SM). Themes, along with their supporting codes, were then further defined to understand how these attendings worked to facilitate excellent teaching in clinical settings.

The coded interview data and field notes were categorized into broad, overlapping themes. Three of these major themes include (1) fostering positive relationships, (2) patient-centered teaching, and (3) collaboration and coaching. Table 2 lists each theme, salient behaviors, examples, and selected quotes that further elucidate its meaning.

Fostering Positive Relationships

Attending physicians took observable steps to develop positive relationships with their team members, which in turn created a safe learning environment. For instance, attendings used learners’ first names, demonstrated interest in their well-being, deployed humor, and generally displayed informal actions—uncrossed arms, “fist bump” when recognizing learners’ success, standing outside the circle of team members and leaning in to listen—during learner interactions. Attendings also made it a priority to get to know individuals on a personal level. As one current learner put it, “He asks about where we are from. He will try to find some kind of connection that he can establish with not only each of the team members but also with each of the patients.”

Additionally, attendings built positive relationships with their learners by responding thoughtfully to their input, even when learners’ evaluations of patients required modification. In turn, learners reported feeling safe to ask questions, admit uncertainty, and respectfully disagree with their attendings. As one attending reflected, “If I can get them into a place where they feel like the learning environment is someplace where they can make a mistake and know that that mistake does not necessarily mean that it’s going to cost them in their evaluation part, then I feel like that’s why it’s important.”

To build rapport and create a safe learning environment, attendings used a number of strategies to position themselves as learners alongside their team members. For instance, attendings indicated that they wanted their ideas questioned because they saw it as an opportunity to learn. Moreover, in conversations with learners, attendings demonstrated humility, admitting when they did not know something. One former learner noted, “There have been times when he has asked [a] question…nobody knows and then he admits that he doesn’t know either. So everybody goes and looks it up…The whole thing turns out to be a fun learning experience.”

Attendings demonstrated respect for their team members’ time by reading about patients before rounds, identifying learning opportunities during rounds, and integrating teaching points into the daily work of patient care. Teaching was not relegated exclusively to the conference room or confined to the traditional “chalk talk” before or after rounds but rather was assimilated into daily workflow. They appeared to be responsive to the needs of individual patients and the team, which allowed attendings to both directly oversee their patients’ care and overcome the challenges of multiple competing demands for time. The importance of this approach was made clear by one current learner who stated “…she does prepare before, especially you know on call days, she does prepare for the new patients before coming in to staff, which is really appreciated… it saves a lot of time on rounds.”

Attendings also included other health professionals in team discussions. Attendings used many of the same relationship-building techniques with these professionals as they did with learners and patients. They consistently asked these professionals to provide insight and direction in patients’ plans of care. A former learner commented, “He always asks the [nurse] what is her impression of the patient...he truly values the [nurse’s] opinion of the patient.” One attending reiterated this approach, stating “I don’t want them to think that anything I have to say is more valuable than our pharmacist or the [nurse].”

Patient-Centered Teaching

Attending physicians modeled numerous teaching techniques that focused learning around the patient. Attendings knew their patients well through review of the medical records, discussion with the patient, and personal examination. This preparation allowed attendings to focus on key teaching points in the context of the patient. One former learner noted, “He tended to bring up a variety of things that really fit well into the clinical scenario. So whether that is talking about what is the differential for a new symptom that just came up for this patient or kind of here is a new paper talking about this condition or maybe some other pearl of physical exam for a patient that has a certain physical condition.”

Attendings served as effective role models by being directly involved in examining and talking with patients as well as demonstrating excellent physical examination and communication techniques. One current learner articulated the importance of learning these skills by observing them done well: “I think he teaches by example and by doing, again, those little things: being attentive to the patients and being very careful during exams…I think those are things that you teach people by doing them, not by saying you need to do this better during the patient encounter.”

Collaboration and Coaching

Attending physicians used varied collaboration and coaching techniques to facilitate learning across the entire care team. During rounds, attendings utilized visual aids to reinforce key concepts and simplify complex topics. They also collaborated by using discussion rather than lecture to engage with team members. For instance, attendings used Socratic questioning, asking questions that lead learners through critical thinking and allow them to solve problems themselves, to guide learners’ decision-making. One former learner reported, “He never gives you the answer, and he always asks your opinion; ‘So what are your thoughts on this?’”

Coaching for success, rather than directing the various team members, was emphasized. Attendings did not wish to be seen as the “leaders” of the team. During rounds, one attending was noted to explain his role in ensuring that the team was building connections with others: “When we have a bad outcome, if it feels like your soul has been ripped out, then you’ve done something right. You’ve made that connection with the patient. My job, as your coach, was to build communication between all of us so we feel vested in each other and our patients.”

Attendings also fostered clinical reasoning skills in their learners by encouraging them to verbalize their thought processes aloud in order to clarify and check for understanding. Attendings also placed emphasis not simply on memorizing content but rather prioritization of the patient’s problems and thinking step by step through individual medical problems. One current learner applauded an attending who could “come up with schematics of how to approach problems rather than feeding us factual information of this paper or this trial.”

Additionally, attendings facilitated learning across the entire care team by differentiating their teaching to meet the needs of multiple learning levels. While the entire team was explicitly included in the learning process, attendings encouraged learners to play various roles, execute tasks, and answer questions depending on their educational level. Attendings positioned learners as leaders of the team by allowing them to talk without interruption and by encouraging them to take ownership of their patients’ care. One former learner stated, “She set expectations…we would be the ones who would be running the team, that you know it would very much be our team and that she is there to advise us and provide supervision but also safety for the patients as well.”

This study reveals the complex ways effective attendings build rapport, create a safe learning environment, utilize patient-centered teaching strategies, and engage in collaboration and coaching with all members of the team. These findings provide a framework of shared themes and their salient behaviors that may influence the success of inpatient general medicine clinician educators (Table 3).

There is a broad and voluminous literature on the subject of outstanding clinical teaching characteristics, much of which has shaped various faculty development curricula for decades. This study sought not to identify novel approaches of inpatient teaching necessarily but rather to closely examine the techniques and behaviors of clinician educators identified as exemplary. The findings affirm and reinforce the numerous, well-documented lists of personal attributes, techniques, and behaviors that resonate with learners, including creating a positive environment, demonstrating enthusiasm and interest in the learner, reading facial expressions, being student-centered, maintaining a high level of clinical knowledge, and utilizing effective communication skills.^18-24 The strengths of this study lie within the nuanced and rich observations and discussions that move beyond learners’ Likert scale evaluations and responses.^3-7,12 Input was sought from multiple perspectives on the care team, which provided detail from key stakeholders. Out of these comprehensive data arose several conclusions that extend the research literature on medical education.

In their seminal review, Sutkin et al.¹⁸ demonstrate that two thirds of characteristics of outstanding clinical teachers are “noncognitive” and that, “Perhaps what makes a clinical educator truly great depends less on the acquisition of cognitive skills such as medical knowledge and formulating learning objectives, and more on inherent, relationship-based, noncognitive attributes. Whereas cognitive abilities generally involve skills that may be taught and learned, albeit with difficulty, noncognitive abilities represent personal attributes, such as relationship skills, personality types, and emotional states, which are more difficult to develop and teach.”¹⁸ Our study, thus, adds to the literature by (1) highlighting examples of techniques and behaviors that encompass the crucial “noncognitive” arena and (2) informing best practices in teaching clinical medicine, especially those that resonate with learners, for future faculty development.

The findings highlight the role that relationships play in the teaching and learning of team-based medicine. Building rapport and sustaining successful relationships are cornerstones of effective teaching.¹⁸ For the attendings in this study, this manifested in observable, tangible behaviors such as greeting others by name, joking, using physical touch, and actively involving all team members, regardless of role or level of education. Previous literature has highlighted the importance of showing interest in learners.^7,19,25-27 This study provides multiple and varied examples of ways in which interest might be displayed.

For patients, the critical role of relationships was evidenced through rapport building and attention to patients as people outside their acute hospitalization. For instance, attendings regularly put patients’ medical issues into context and anticipated future outpatient challenges. To the authors’ knowledge, previous scholarship has not significantly emphasized this form of contextualized medicine, which involves the mindful consideration of the ongoing needs patients may experience upon transitions of care.

Several participants highlighted humility as an important characteristic of effective clinician educators. Attendings recognized that the field produces more new knowledge than can possibly be assimilated and that uncertainty is a mainstay of modern medical care. Attendings frequently utilized self-deprecation to acknowledge doubt, a technique that created a collaborative environment in which learners also felt safe to ask questions. These findings support the viewpoints by Reilly and Beckman that humility and an appreciation for questions and push-back from learners encourage lifelong learning through role modeling.^19,23 In responding to the interviewer’s question “And what happens when [the attending] is wrong?” one learner simply stated, “He makes fun of himself.”

This study has several limitations. First, it was conducted in a limited number of US based healthcare systems. The majority of institutions represented were larger, research intensive hospitals. While these hospitals were purposefully selected to provide a range in geography, size, type, and access to resources, the findings may differ in other settings. Second, it was conducted with a limited number of attendings and learners, which may limit the study’s generalizability. However, enough interviews were conducted to reach data saturation.¹⁵ Because evidence for a causal relationship between quality teaching and student and patient outcomes is lacking,¹⁸ we must rely on imperfect proxies for teaching excellence, including awards and recognition. This study attempted to identify exemplary educators through various means, but it is recognized that bias is likely. Third, because attendings provided lists of former learners, selection and recall biases may have been introduced, as attendings may have more readily identified former learners with whom they formed strong relationships. Fourth, focus was placed exclusively on teaching and learning within general medicine rounds. This was because there would be ample opportunity for teaching on this service, the structure of the teams and the types of patients would be comparable across sites, and the principal investigator was also a general medicine attending and would have a frame of reference for these types of rounds. Due to this narrow focus, the findings may not be generalizable to other subspecialties. Fifth, attendings were selected through a nonexhaustive method. However, the multisite design, the modified snowball sampling, and the inclusion of several types of institutions in the final participant pool introduced diversity to the final list. Finally, although we cannot discount the potential role of a Hawthorne effect on our data collection, the research team did attempt to mitigate this by standing apart from the care teams and remaining unobtrusive during observations.

Using a combination of interviews, focus group discussions, and direct observation, we identified consistent techniques and behaviors of excellent teaching attendings during inpatient general medicine rounds. We hope that all levels of clinician educators may use them to elevate their own teaching.

Disclosure

Dr. Saint is on a medical advisory board of Doximity, a new social networking site for physicians, and receives an honorarium. He is also on the scientific advisory board of Jvion, a healthcare technology company. Drs. Houchens, Harrod, Moody, and Ms. Fowler have no conflicts of interest.

Clinician educators face numerous obstacles to their joint mission of facilitating learning while also ensuring high-quality and patient-centered care. Time constraints, including the institution of house officer duty hour limitations,¹ shorter lengths of stay for hospitalized patients,² and competing career responsibilities, combine to create a dynamic learning environment. Additionally, clinician educators must balance the autonomy of their learners with the safety of their patients. They must teach to multiple learning levels and work collaboratively with multiple disciplines to foster an effective team-based approach to patient care. Yet, many clinician educators have no formal training in pedagogical methods.³ Such challenges necessitate increased attention to the work of excellent clinician educators and their respective teaching approaches.

Many studies of clinical teaching rely primarily on survey data of attributes of good clinical teachers.^3-7 While some studies have incorporated direct observations of teaching^8,9 or interviews with clinician educators or learners,^10,11 few have incorporated multiple perspectives from the current team and from former learners in order to provide a comprehensive picture of team-based learning.¹²

The goal of this study was to gain a thorough understanding, through multiple perspectives, of the techniques and behaviors used by exemplary educators within actual clinical environments. We studied attitudes, behaviors, and approaches of 12 such inpatient clinician educators.

Study Design and Sampling

This was a multisite study using an exploratory qualitative approach to inquiry. This approach was used to study the techniques and behaviors of excellent attendings during inpatient general medicine rounds. A modified snowball sampling approach¹³ was used, meaning individuals known to one member of the research team (SS) were initially contacted and asked to identify clinician educators (also referred to as attendings) for potential inclusion in the study. In an effort to identify attendings from a broad range of medical schools, the “2015 U.S. News and World Report Top Medical Schools: Research” rankings¹⁴ were also reviewed, with priority given to the top 25, as these are widely used to represent the best US hospitals. In an attempt to invite attendings from diverse institutions, additional medical schools not in the top 25 as well as historically black medical schools were also included. Division chiefs and chairs of internal medicine and/or directors of internal medicine residency programs at these schools were contacted and asked for recommendations of attendings, both within and outside their institutions, who they considered to be great inpatient teachers. In addition, key experts who have won teaching awards or were known to be specialists in the field of medical education were asked to nominate one or two other outstanding attendings.

By using this sampling method, 59 potential participants were identified. An internet search was conducted to obtain information about the potential participants and their institutions. Organizational characteristics such as geographic location, hospital size and affiliation, and patient population, as well as individual characteristics such as gender, medical education and training, and educational awards received were considered so that a diversity of organizations and backgrounds was represented. The list was narrowed down to 16 attendings who were contacted via e-mail and asked to participate. Interested participants were asked for a list of their current team members and 6 to 10 former learners to contact for interviews and focus groups. Former learners were included in an effort to better understand lasting effects on learners from their exemplary teaching attendings. A total of 12 attending physicians agreed to participate (Table 1). Literature on field methods has shown that 12 interviews are found to be adequate in accomplishing data saturation.¹⁵ Although 2 attendings were located at the same institution, we decided to include them given that both are recognized as master clinician educators and were each recommended by several individuals from various institutions. Hospitals were located throughout the US and included both university-affiliated hospitals and Veterans Affairs medical centers. Despite efforts to include physicians from historically black colleges and universities, only one attending was identified, and they declined the request to participate.

Data Collection

Observations. The one-day site visits were mainly conducted by two research team members, a physician (SS) and a medical anthropologist (MH), both of whom have extensive experience in qualitative methods. Teams were not uniform but were generally comprised of 1 attending, 1 senior medical resident, 1 to 2 interns, and approximately 2 medical students. Occasionally, a pharmacist, clinical assistant, or other health professional accompanied the team on rounds. Not infrequently, the bedside nurse would explicitly be included in the discussion regarding his or her specific patient. Each site visit began with observing attendings (N = 12) and current learners (N = 57) during rounds. Each research team member recorded their own observations via handwritten field notes, paying particular attention to group interactions, teaching approach, conversations occurring within and peripheral to the team, patient-team interactions, and the physical environment. By standing outside of the medical team circle and remaining silent during rounds, research team members remained unobtrusive to the discussion and process of rounds. Materials the attendings used during their teaching rounds were also documented and collected. Rounds generally lasted 2 to 3 hours. After each site visit, the research team met to compare and combine field notes.

Interviews and Focus Groups. The research team then conducted individual, semi-structured interviews with the attendings, focus groups with their current team (N = 46), and interviews or focus groups with their former learners (N = 26; Supplement 1). Eleven of the current team members observed during rounds were unable to participate in the focus groups due to clinical duties. Because the current learners who participated in the focus groups were also observed during rounds, the research team was able to ask them open-ended questions regarding teaching rounds and their roles as learners within this environment. Former learners who were still at the hospital participated in separate focus groups or interviews. Former learners who were no longer present at the hospital were contacted by telephone and individually interviewed by one research team member (MH). All interviews and focus groups were audio-recorded and transcribed.

This study was determined to be exempt by the University of Michigan Institutional Review Board. All participants were informed that their participation was completely voluntary and that they could terminate their involvement at any time.

Data Analysis

Data were analyzed using a thematic analysis approach.¹⁶ Thematic analysis entails reading through the data to identify patterns (and create codes) that relate to behaviors, experiences, meanings, and activities. Once patterns have been identified, they are grouped according to similarity into themes, which help to further explain the findings.¹⁷

After the first site visit was completed, the research team members that participated (SS and MH) met to develop initial ideas about meanings and possible patterns. All transcripts were read by one team member (MH) and, based on review of the data, codes were developed, defined, and documented in a codebook. This process was repeated after every site visit using the codebook to expand or combine codes and refine definitions as necessary. If a new code was added, the previously coded data were reviewed to apply the new code. NVivo® 10 software (QSR International; Melbourne, Australia) was used to manage the data.

Once all field notes and transcripts were coded (MH), the code reports, which list all data described within a specific code, were run to ensure consistency and identify relationships between codes. Once coding was verified, codes were grouped based on similarities and relationships into salient themes by 3 members of the research team (NH, MH, and SM). Themes, along with their supporting codes, were then further defined to understand how these attendings worked to facilitate excellent teaching in clinical settings.

The coded interview data and field notes were categorized into broad, overlapping themes. Three of these major themes include (1) fostering positive relationships, (2) patient-centered teaching, and (3) collaboration and coaching. Table 2 lists each theme, salient behaviors, examples, and selected quotes that further elucidate its meaning.

Fostering Positive Relationships

Attending physicians took observable steps to develop positive relationships with their team members, which in turn created a safe learning environment. For instance, attendings used learners’ first names, demonstrated interest in their well-being, deployed humor, and generally displayed informal actions—uncrossed arms, “fist bump” when recognizing learners’ success, standing outside the circle of team members and leaning in to listen—during learner interactions. Attendings also made it a priority to get to know individuals on a personal level. As one current learner put it, “He asks about where we are from. He will try to find some kind of connection that he can establish with not only each of the team members but also with each of the patients.”

Additionally, attendings built positive relationships with their learners by responding thoughtfully to their input, even when learners’ evaluations of patients required modification. In turn, learners reported feeling safe to ask questions, admit uncertainty, and respectfully disagree with their attendings. As one attending reflected, “If I can get them into a place where they feel like the learning environment is someplace where they can make a mistake and know that that mistake does not necessarily mean that it’s going to cost them in their evaluation part, then I feel like that’s why it’s important.”

To build rapport and create a safe learning environment, attendings used a number of strategies to position themselves as learners alongside their team members. For instance, attendings indicated that they wanted their ideas questioned because they saw it as an opportunity to learn. Moreover, in conversations with learners, attendings demonstrated humility, admitting when they did not know something. One former learner noted, “There have been times when he has asked [a] question…nobody knows and then he admits that he doesn’t know either. So everybody goes and looks it up…The whole thing turns out to be a fun learning experience.”

Attendings demonstrated respect for their team members’ time by reading about patients before rounds, identifying learning opportunities during rounds, and integrating teaching points into the daily work of patient care. Teaching was not relegated exclusively to the conference room or confined to the traditional “chalk talk” before or after rounds but rather was assimilated into daily workflow. They appeared to be responsive to the needs of individual patients and the team, which allowed attendings to both directly oversee their patients’ care and overcome the challenges of multiple competing demands for time. The importance of this approach was made clear by one current learner who stated “…she does prepare before, especially you know on call days, she does prepare for the new patients before coming in to staff, which is really appreciated… it saves a lot of time on rounds.”

Attendings also included other health professionals in team discussions. Attendings used many of the same relationship-building techniques with these professionals as they did with learners and patients. They consistently asked these professionals to provide insight and direction in patients’ plans of care. A former learner commented, “He always asks the [nurse] what is her impression of the patient...he truly values the [nurse’s] opinion of the patient.” One attending reiterated this approach, stating “I don’t want them to think that anything I have to say is more valuable than our pharmacist or the [nurse].”

Patient-Centered Teaching

Attending physicians modeled numerous teaching techniques that focused learning around the patient. Attendings knew their patients well through review of the medical records, discussion with the patient, and personal examination. This preparation allowed attendings to focus on key teaching points in the context of the patient. One former learner noted, “He tended to bring up a variety of things that really fit well into the clinical scenario. So whether that is talking about what is the differential for a new symptom that just came up for this patient or kind of here is a new paper talking about this condition or maybe some other pearl of physical exam for a patient that has a certain physical condition.”

Attendings served as effective role models by being directly involved in examining and talking with patients as well as demonstrating excellent physical examination and communication techniques. One current learner articulated the importance of learning these skills by observing them done well: “I think he teaches by example and by doing, again, those little things: being attentive to the patients and being very careful during exams…I think those are things that you teach people by doing them, not by saying you need to do this better during the patient encounter.”

Collaboration and Coaching

Attending physicians used varied collaboration and coaching techniques to facilitate learning across the entire care team. During rounds, attendings utilized visual aids to reinforce key concepts and simplify complex topics. They also collaborated by using discussion rather than lecture to engage with team members. For instance, attendings used Socratic questioning, asking questions that lead learners through critical thinking and allow them to solve problems themselves, to guide learners’ decision-making. One former learner reported, “He never gives you the answer, and he always asks your opinion; ‘So what are your thoughts on this?’”

Coaching for success, rather than directing the various team members, was emphasized. Attendings did not wish to be seen as the “leaders” of the team. During rounds, one attending was noted to explain his role in ensuring that the team was building connections with others: “When we have a bad outcome, if it feels like your soul has been ripped out, then you’ve done something right. You’ve made that connection with the patient. My job, as your coach, was to build communication between all of us so we feel vested in each other and our patients.”

Attendings also fostered clinical reasoning skills in their learners by encouraging them to verbalize their thought processes aloud in order to clarify and check for understanding. Attendings also placed emphasis not simply on memorizing content but rather prioritization of the patient’s problems and thinking step by step through individual medical problems. One current learner applauded an attending who could “come up with schematics of how to approach problems rather than feeding us factual information of this paper or this trial.”

Additionally, attendings facilitated learning across the entire care team by differentiating their teaching to meet the needs of multiple learning levels. While the entire team was explicitly included in the learning process, attendings encouraged learners to play various roles, execute tasks, and answer questions depending on their educational level. Attendings positioned learners as leaders of the team by allowing them to talk without interruption and by encouraging them to take ownership of their patients’ care. One former learner stated, “She set expectations…we would be the ones who would be running the team, that you know it would very much be our team and that she is there to advise us and provide supervision but also safety for the patients as well.”

This study reveals the complex ways effective attendings build rapport, create a safe learning environment, utilize patient-centered teaching strategies, and engage in collaboration and coaching with all members of the team. These findings provide a framework of shared themes and their salient behaviors that may influence the success of inpatient general medicine clinician educators (Table 3).

There is a broad and voluminous literature on the subject of outstanding clinical teaching characteristics, much of which has shaped various faculty development curricula for decades. This study sought not to identify novel approaches of inpatient teaching necessarily but rather to closely examine the techniques and behaviors of clinician educators identified as exemplary. The findings affirm and reinforce the numerous, well-documented lists of personal attributes, techniques, and behaviors that resonate with learners, including creating a positive environment, demonstrating enthusiasm and interest in the learner, reading facial expressions, being student-centered, maintaining a high level of clinical knowledge, and utilizing effective communication skills.^18-24 The strengths of this study lie within the nuanced and rich observations and discussions that move beyond learners’ Likert scale evaluations and responses.^3-7,12 Input was sought from multiple perspectives on the care team, which provided detail from key stakeholders. Out of these comprehensive data arose several conclusions that extend the research literature on medical education.

In their seminal review, Sutkin et al.¹⁸ demonstrate that two thirds of characteristics of outstanding clinical teachers are “noncognitive” and that, “Perhaps what makes a clinical educator truly great depends less on the acquisition of cognitive skills such as medical knowledge and formulating learning objectives, and more on inherent, relationship-based, noncognitive attributes. Whereas cognitive abilities generally involve skills that may be taught and learned, albeit with difficulty, noncognitive abilities represent personal attributes, such as relationship skills, personality types, and emotional states, which are more difficult to develop and teach.”¹⁸ Our study, thus, adds to the literature by (1) highlighting examples of techniques and behaviors that encompass the crucial “noncognitive” arena and (2) informing best practices in teaching clinical medicine, especially those that resonate with learners, for future faculty development.

The findings highlight the role that relationships play in the teaching and learning of team-based medicine. Building rapport and sustaining successful relationships are cornerstones of effective teaching.¹⁸ For the attendings in this study, this manifested in observable, tangible behaviors such as greeting others by name, joking, using physical touch, and actively involving all team members, regardless of role or level of education. Previous literature has highlighted the importance of showing interest in learners.^7,19,25-27 This study provides multiple and varied examples of ways in which interest might be displayed.

For patients, the critical role of relationships was evidenced through rapport building and attention to patients as people outside their acute hospitalization. For instance, attendings regularly put patients’ medical issues into context and anticipated future outpatient challenges. To the authors’ knowledge, previous scholarship has not significantly emphasized this form of contextualized medicine, which involves the mindful consideration of the ongoing needs patients may experience upon transitions of care.

Several participants highlighted humility as an important characteristic of effective clinician educators. Attendings recognized that the field produces more new knowledge than can possibly be assimilated and that uncertainty is a mainstay of modern medical care. Attendings frequently utilized self-deprecation to acknowledge doubt, a technique that created a collaborative environment in which learners also felt safe to ask questions. These findings support the viewpoints by Reilly and Beckman that humility and an appreciation for questions and push-back from learners encourage lifelong learning through role modeling.^19,23 In responding to the interviewer’s question “And what happens when [the attending] is wrong?” one learner simply stated, “He makes fun of himself.”

This study has several limitations. First, it was conducted in a limited number of US based healthcare systems. The majority of institutions represented were larger, research intensive hospitals. While these hospitals were purposefully selected to provide a range in geography, size, type, and access to resources, the findings may differ in other settings. Second, it was conducted with a limited number of attendings and learners, which may limit the study’s generalizability. However, enough interviews were conducted to reach data saturation.¹⁵ Because evidence for a causal relationship between quality teaching and student and patient outcomes is lacking,¹⁸ we must rely on imperfect proxies for teaching excellence, including awards and recognition. This study attempted to identify exemplary educators through various means, but it is recognized that bias is likely. Third, because attendings provided lists of former learners, selection and recall biases may have been introduced, as attendings may have more readily identified former learners with whom they formed strong relationships. Fourth, focus was placed exclusively on teaching and learning within general medicine rounds. This was because there would be ample opportunity for teaching on this service, the structure of the teams and the types of patients would be comparable across sites, and the principal investigator was also a general medicine attending and would have a frame of reference for these types of rounds. Due to this narrow focus, the findings may not be generalizable to other subspecialties. Fifth, attendings were selected through a nonexhaustive method. However, the multisite design, the modified snowball sampling, and the inclusion of several types of institutions in the final participant pool introduced diversity to the final list. Finally, although we cannot discount the potential role of a Hawthorne effect on our data collection, the research team did attempt to mitigate this by standing apart from the care teams and remaining unobtrusive during observations.

Using a combination of interviews, focus group discussions, and direct observation, we identified consistent techniques and behaviors of excellent teaching attendings during inpatient general medicine rounds. We hope that all levels of clinician educators may use them to elevate their own teaching.

Disclosure

Dr. Saint is on a medical advisory board of Doximity, a new social networking site for physicians, and receives an honorarium. He is also on the scientific advisory board of Jvion, a healthcare technology company. Drs. Houchens, Harrod, Moody, and Ms. Fowler have no conflicts of interest.

EXPERT COMMENTARY

The role of lymphadenectomy for endometrial cancer has evolved considerably over the last 30 years. While pathologic assessment of the nodes provides important information to tailor adjuvant therapy, 2 randomized trials both reported no survival benefit in women who underwent lymphadenectomy compared with hysterectomy alone.^1,2 Further, these trials revealed that lymphadenectomy was associated with significant short- and long-term sequelae.

SLN biopsy, a procedure in which a small number of nodes that represent the first drainage basins of a primary tumor are removed, has been proposed as an alternative to traditional lymphadenectomy. Although SLN biopsy is commonly used for other solid tumors, few large, multicenter studies have been conducted to evaluate the technique’s safety in endometrial cancer.

Related article:
2016 Update on cancer

Details of the study

The Fluorescence Imaging for Robotic Endometrial Sentinel lymph node biopsy (FIRES) trial was a prospective trial evaluating the performance characteristics of SLN biopsy in women with clinical stage 1 endometrial cancer at 10 sites in the United States. After cervical injection of indocyanine green, patients underwent robot-assisted hysterectomy with SLN biopsy followed by pelvic lymphadenectomy. Para-aortic lymphadenectomy was performed at the discretion of the attending surgeon. The study’s primary end point was sensitivity of SLN biopsy for detecting metastatic disease in women who had mapping.

Over approximately 3 years, 385 patients were enrolled. Overall, 86% of patients had mapping of at least 1 SLN and 52% had bilateral mapping. Positive nodes were found in 12% of the study population. Among women who had SLNs identified, 35 of 36 nodal metastases were identified (97% sensitivity). Negative SLNs correctly predicted the absence of metastases (negative predictive value) in 99.6% of patients.

Overall, the procedure was well tolerated. Adverse events were noted in 9% of patients, and approximately two-thirds were considered serious adverse events. The most common adverse events were neurologic complications, respiratory distress, nausea and vomiting, and bowel injury in 3 patients. One ureteral injury occurred during SLN biopsy.

Related article:
Does laparoscopic versus open abdominal surgery for stage I endometrial cancer affect oncologic outcomes?

Study strengths and weaknesses

The FIRES study provides strong evidence for the effectiveness of SLN biopsy in women with apparent early stage endometrial cancer. The procedure not only was highly accurate in identifying nodal disease but it also had acceptable adverse events. Further, many of the benefits of SLN biopsy, such as a reduction in lymphedema, will require long-term follow-up.

Consider study results in context. As oncologists consider the role of SLN biopsy in practice, this work should be interpreted in the context of the study design. The study was performed by only 18 surgeons at 10 centers. Prior to study initiation, each site and surgeon underwent formal training and observation to ensure that the technique for SLN biopsy was adequate. Clearly, there will be a learning curve for SLN biopsy, and this study’s results may not immediately be generalizable.

Despite rigorous quality control procedures, there was no nodal mapping in 48% of the hemi-pelvises. In practice, these patients require lymph node dissection. The authors estimated that 50% of patients would still require lymphadenectomy (40% unilateral, 10% bilateral) if SLN mapping was used in routine practice. In addition, while the FIRES trial included women with high-risk histologies, the majority of patients had low-risk, endometrioid tumors. Further study will help to define performance of SLN biopsy in populations at higher risk for nodal metastases.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

The role of lymphadenectomy for endometrial cancer has evolved considerably over the last 30 years. While pathologic assessment of the nodes provides important information to tailor adjuvant therapy, 2 randomized trials both reported no survival benefit in women who underwent lymphadenectomy compared with hysterectomy alone.^1,2 Further, these trials revealed that lymphadenectomy was associated with significant short- and long-term sequelae.

SLN biopsy, a procedure in which a small number of nodes that represent the first drainage basins of a primary tumor are removed, has been proposed as an alternative to traditional lymphadenectomy. Although SLN biopsy is commonly used for other solid tumors, few large, multicenter studies have been conducted to evaluate the technique’s safety in endometrial cancer.

Related article:
2016 Update on cancer

Details of the study

The Fluorescence Imaging for Robotic Endometrial Sentinel lymph node biopsy (FIRES) trial was a prospective trial evaluating the performance characteristics of SLN biopsy in women with clinical stage 1 endometrial cancer at 10 sites in the United States. After cervical injection of indocyanine green, patients underwent robot-assisted hysterectomy with SLN biopsy followed by pelvic lymphadenectomy. Para-aortic lymphadenectomy was performed at the discretion of the attending surgeon. The study’s primary end point was sensitivity of SLN biopsy for detecting metastatic disease in women who had mapping.

Over approximately 3 years, 385 patients were enrolled. Overall, 86% of patients had mapping of at least 1 SLN and 52% had bilateral mapping. Positive nodes were found in 12% of the study population. Among women who had SLNs identified, 35 of 36 nodal metastases were identified (97% sensitivity). Negative SLNs correctly predicted the absence of metastases (negative predictive value) in 99.6% of patients.

Overall, the procedure was well tolerated. Adverse events were noted in 9% of patients, and approximately two-thirds were considered serious adverse events. The most common adverse events were neurologic complications, respiratory distress, nausea and vomiting, and bowel injury in 3 patients. One ureteral injury occurred during SLN biopsy.

Related article:
Does laparoscopic versus open abdominal surgery for stage I endometrial cancer affect oncologic outcomes?

Study strengths and weaknesses

The FIRES study provides strong evidence for the effectiveness of SLN biopsy in women with apparent early stage endometrial cancer. The procedure not only was highly accurate in identifying nodal disease but it also had acceptable adverse events. Further, many of the benefits of SLN biopsy, such as a reduction in lymphedema, will require long-term follow-up.

Consider study results in context. As oncologists consider the role of SLN biopsy in practice, this work should be interpreted in the context of the study design. The study was performed by only 18 surgeons at 10 centers. Prior to study initiation, each site and surgeon underwent formal training and observation to ensure that the technique for SLN biopsy was adequate. Clearly, there will be a learning curve for SLN biopsy, and this study’s results may not immediately be generalizable.

Despite rigorous quality control procedures, there was no nodal mapping in 48% of the hemi-pelvises. In practice, these patients require lymph node dissection. The authors estimated that 50% of patients would still require lymphadenectomy (40% unilateral, 10% bilateral) if SLN mapping was used in routine practice. In addition, while the FIRES trial included women with high-risk histologies, the majority of patients had low-risk, endometrioid tumors. Further study will help to define performance of SLN biopsy in populations at higher risk for nodal metastases.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

The role of lymphadenectomy for endometrial cancer has evolved considerably over the last 30 years. While pathologic assessment of the nodes provides important information to tailor adjuvant therapy, 2 randomized trials both reported no survival benefit in women who underwent lymphadenectomy compared with hysterectomy alone.^1,2 Further, these trials revealed that lymphadenectomy was associated with significant short- and long-term sequelae.

SLN biopsy, a procedure in which a small number of nodes that represent the first drainage basins of a primary tumor are removed, has been proposed as an alternative to traditional lymphadenectomy. Although SLN biopsy is commonly used for other solid tumors, few large, multicenter studies have been conducted to evaluate the technique’s safety in endometrial cancer.

Related article:
2016 Update on cancer

Details of the study

The Fluorescence Imaging for Robotic Endometrial Sentinel lymph node biopsy (FIRES) trial was a prospective trial evaluating the performance characteristics of SLN biopsy in women with clinical stage 1 endometrial cancer at 10 sites in the United States. After cervical injection of indocyanine green, patients underwent robot-assisted hysterectomy with SLN biopsy followed by pelvic lymphadenectomy. Para-aortic lymphadenectomy was performed at the discretion of the attending surgeon. The study’s primary end point was sensitivity of SLN biopsy for detecting metastatic disease in women who had mapping.

Over approximately 3 years, 385 patients were enrolled. Overall, 86% of patients had mapping of at least 1 SLN and 52% had bilateral mapping. Positive nodes were found in 12% of the study population. Among women who had SLNs identified, 35 of 36 nodal metastases were identified (97% sensitivity). Negative SLNs correctly predicted the absence of metastases (negative predictive value) in 99.6% of patients.

Overall, the procedure was well tolerated. Adverse events were noted in 9% of patients, and approximately two-thirds were considered serious adverse events. The most common adverse events were neurologic complications, respiratory distress, nausea and vomiting, and bowel injury in 3 patients. One ureteral injury occurred during SLN biopsy.

Related article:
Does laparoscopic versus open abdominal surgery for stage I endometrial cancer affect oncologic outcomes?

Study strengths and weaknesses

The FIRES study provides strong evidence for the effectiveness of SLN biopsy in women with apparent early stage endometrial cancer. The procedure not only was highly accurate in identifying nodal disease but it also had acceptable adverse events. Further, many of the benefits of SLN biopsy, such as a reduction in lymphedema, will require long-term follow-up.

Consider study results in context. As oncologists consider the role of SLN biopsy in practice, this work should be interpreted in the context of the study design. The study was performed by only 18 surgeons at 10 centers. Prior to study initiation, each site and surgeon underwent formal training and observation to ensure that the technique for SLN biopsy was adequate. Clearly, there will be a learning curve for SLN biopsy, and this study’s results may not immediately be generalizable.

Despite rigorous quality control procedures, there was no nodal mapping in 48% of the hemi-pelvises. In practice, these patients require lymph node dissection. The authors estimated that 50% of patients would still require lymphadenectomy (40% unilateral, 10% bilateral) if SLN mapping was used in routine practice. In addition, while the FIRES trial included women with high-risk histologies, the majority of patients had low-risk, endometrioid tumors. Further study will help to define performance of SLN biopsy in populations at higher risk for nodal metastases.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.