ANSWER

The correct interpretation includes normal sinus rhythm, evidence of a previous inferior MI, an anterior MI, and lateral ischemia (evidenced by ST- and T-wave abnormalities in the lateral chest leads).

Normal sinus rhythm is demonstrated by the presence of a P wave for every QRS complex and a QRS complex for every P wave, with a consistent PR interval of 72 beats/min. The Q waves in leads II, III, and aVF indicate an old inferior MI.

Progression of proximal LAD stenosis and an anterior MI is evidenced by the ST segment elevations in leads V₁ to V₃, and lateral ischemia is represented by ST- and T-wave abnormalities in leads V₄ to V₆. Note that there are also Q waves in leads V₄ to V₆, which suggest a previously undiagnosed lateral MI.

ANSWER

The correct interpretation includes normal sinus rhythm, evidence of a previous inferior MI, an anterior MI, and lateral ischemia (evidenced by ST- and T-wave abnormalities in the lateral chest leads).

Normal sinus rhythm is demonstrated by the presence of a P wave for every QRS complex and a QRS complex for every P wave, with a consistent PR interval of 72 beats/min. The Q waves in leads II, III, and aVF indicate an old inferior MI.

Progression of proximal LAD stenosis and an anterior MI is evidenced by the ST segment elevations in leads V₁ to V₃, and lateral ischemia is represented by ST- and T-wave abnormalities in leads V₄ to V₆. Note that there are also Q waves in leads V₄ to V₆, which suggest a previously undiagnosed lateral MI.

ANSWER

The correct interpretation includes normal sinus rhythm, evidence of a previous inferior MI, an anterior MI, and lateral ischemia (evidenced by ST- and T-wave abnormalities in the lateral chest leads).

Normal sinus rhythm is demonstrated by the presence of a P wave for every QRS complex and a QRS complex for every P wave, with a consistent PR interval of 72 beats/min. The Q waves in leads II, III, and aVF indicate an old inferior MI.

Progression of proximal LAD stenosis and an anterior MI is evidenced by the ST segment elevations in leads V₁ to V₃, and lateral ischemia is represented by ST- and T-wave abnormalities in leads V₄ to V₆. Note that there are also Q waves in leads V₄ to V₆, which suggest a previously undiagnosed lateral MI.

From the Johns Hopkins Hospital, Baltimore, MD (Dr. Ramadan), and the Henry Ford Hospital, Detroit, MI (Dr. Varelas).

Abstract

• Objective: To review the management of status epilepticus (SE).
• Methods: Review of the literature.
• Results: SE is a relatively common condition that accounts for 3% to 5% of all emergency department evaluations for seizure disorders and occurs in 2% to 16% of all epilepsy patients. The 3 most common etiologies are low levels of antiepileptic drugs, remote symptomatic etiologies, and cerebrovascular accidents. The majority of SEs are convulsant, but there is growing awareness of non-convulsive SEs, which can be diagnosed only via electroencephalogram. Management, which must be initiated at the earliest possible time, has evolved to incorporate pre-hospital measures and 4 treatment stages, with supportive measures and benzodiazepine administration remaining the mainstay initially and followed by older and newer antiepileptic drugs and anesthetics for resistant cases.
• Conclusion: SE is a neurological emergency that still carries significant mortality and morbidity if not treated immediately and properly.

Key words: status epilepticus; seizures; convulsive status epilepticus; nonconvulsive status epilepticus.

Status epilepticus (SE) is a relatively common condition that accounts for 3% to 5% of all emergency department (ED) evaluations for seizure disorders and occurs in 2% to 16% of all epilepsy patients [1]. It remains a major neurological emergency that, if not properly and timely treated, leads to death or permanent neurological injury. Since most of patients with convulsive SE are admitted to the hospital via the ED and are then transferred to the intensive care unit (ICU), our focus in this review will be on the latter.

Although only a handful prospective, randomized studies have been reported, guidelines on SE have been published in Europe [2] and the US [3,4]. In this paper, we review the evolving definition and types of SE, its incidence, etiology, and pathophysiology, its diagnosis and treatment algorithms, and its outcome. Our goal is to provide the reader with a concise but thorough review of this still lethal neurological emergency.

Definitions

The International Classification of Epileptic Seizures had previously defined SE as any seizure lasting ≥ 30 minutes or intermittent seizures lasting for > 30 min without recovery of consciousness interictally [5,6]. More recently, a duration of 5 or more minutes of (a) continuous seizures or (b) 2 or more discrete seizures with incomplete recovery of consciousness in-between, proposed by Lowenstein [3,7], offers the advantage of incorporating new knowledge. The shortening of the convulsive period to 5 minutes was based on the fact that the majority of tonic-clonic seizures last for only 1 to 2 minutes, that those lasting > 5 minutes do not stop spontaneously [8], that permanent neuronal injury occurs before 30 minutes, and that refractoriness to treatment increases with longer seizure duration [9].

Refractory SE (RSE) has been defined as SE not controlled after adequate doses of an initial benzodiazepine followed by a second acceptable antiepileptic drug (AED) or SE not controlled after the initial parenteral therapy with a minimum number of standard “front-line” AEDs (either 2 or 3) or SE with a minimum duration of seizures that persist despite treatment (eg, at least or 2 hours) [3,10]. Super-refractory SE (SRSE) is defined as SE that continues or recurs 24 hours or more after the onset of anesthetic therapy or recurs on the reduction or withdrawal of anesthesia [11].

Non-convulsive SE (NCSE) is defined as the presence of altered consciousness or behavior for ≥ 30 minutes, the absence of overt clinical signs of convulsive activity during that period, and the electroencephalographic (EEG) confirmation of seizures or activity that responds to treatment together with improvement of consciousness [12–15]. Two major types of NCSE can be encountered: the one in patients with epileptic encephalopathy/coma and the one in patients with absence or complex partial seizures, who are not usually admitted to ICU and are functional yet impaired. Because of the confusion between these 2 extremes in the NCSE spectrum, working criteria for standardization of reporting, utilizing the frequency of electroencephalographic epileptiform discharges or delta/theta waveforms have been proposed [15]. A recent compendium of 123 cases of NCSE with clinical descriptions and EEG patterns following a syndromic classification approach has also been published [16].

Types of SE

Three major categories of SE have been described: generalized convulsive SE (GCSE), focal motor SE (FMSE or epilepsia partialis continua [EPC]) of Kojevnikov, and NCSE. GCSE and FMSE are easily recognized due to overt convulsions. NCSE, however, has a more obscure phenotype and can be subdivided into a spectrum encompassing typical absence and complex partial SE, atypical absence SE and tonic SE (usually in children with learning disabilities), epileptic behavioral disturbance and psychosis, including Balint–like syndrome [17], confusional states or delirium with epileptiform discharges) and SE in coma (after significant brain injuries, such as hypoxia-ischemia, most commonly encountered in ICUs) [13,18]. The 2 extremes in this NCSE spectrum have completely different prognoses, with absence SE the most benign and SE in coma the most dismal.

Lastly, SE presents either spontaneously or can be “semi-intentional” iatrogenic, encountered either in the neuro-ICU or epilepsy monitoring unit, when AEDs are withdrawn under continuous EEG recording in order for seizures to emerge and be recorded with surface or intracranial electrodes.

Incidence of SE

In a prospective population-based epidemiological study, the incidence of SE was estimated at 41–61/100,000 patients/year. For the US, this translates to 125,000 to 195,000 episodes per year [19].

The highest incidence of SE occurs during the first year of life and during the decades beyond 60 years, and is also dependent on the SE subtype. Partial SE occurs in 25% of cases of SE and NCSE accounts for another 4% to 26 % [19,20], but the incidence for the latter is considered an underestimate due to the need for continuous EEG monitoring (which is not widely available). For example, NCSE was discovered in no patient with acute stroke [21], 8% of comatose ICU patients [22], 7% of patients with intracerebral hemorrhage [23], 3% to 8% of patients with subarachnoid hemorrhage [24–26], 6% of patients with metastatic cancer [27], and 6% of patients with head trauma [28].

The incidence of RSE and SRSE is also unknown. In a recent retrospective study from a neuro-ICU in a West China hospital, the percentage of non-refractory SE, RSE, and SRSE were 67.3%, 20.4% and 12.2%, respectively [29]. Other retrospective studies have shown that 12% to 43% of SE cases become refractory [30–33] and that approximately 10% to 15% of all cases of hospital-admitted SE will become super-refractory at some point, but no prospective studies have been published.

Risk factors that have been identified for RSE are encephalitis as a cause, severe consciousness impairment, de novo episodes of SE, delay in initiation of treatment, NCSE, and focal motor seizures at onset [30,32,34,35]. In a more recent study from ICU patients in Switzerland and the US, acute SE etiology (traumatic brain injuries, cerebrovascular accidents, meningoencephalitis, brain tumors, surgical brain lesions, exposure to, or withdrawal from, recreational drugs, prescription drugs, alcohol, metabolic disturbances and fever), coma/stupor, and serum albumin < 35 g/L at SE onset were independent predictors for RSE [36].

Etiology of SE

The 3 most common etiologies for SE are low levels of antiepileptic drugs (AEDs) in 34% of the cases (usually due to noncompliance), remote symptomatic etiologies (history of neurological insults remote to the first unprovoked SE episode, 24%), and cerebrovascular accidents (ischemic and hemorrhagic strokes, 22%). These are followed by hypoxia (13%) and metabolic disturbances (15%). Because 82% of patients in the remote group have a history of cerebrovascular disease, almost 50% have either acute or remote cerebrovascular disease as etiology of SE [19].

In general ICUs, metabolic abnormalities can account for 33% of seizures, drug withdrawal for 33%, drug toxicity for 14.5%, and stroke for 9% to 39% [37,38]. In ICUs, sepsis remains a common etiology of electrographic seizures or periodic epileptiform discharges [39,40], and legal or illegal drugs, such as ciprofloxacin, levofloxacin, piperacillin/tazobactam, cefepime and carbapenems [41–43], lithium or theophylline intoxication, vigabatrin, tiagabine or crack/cocaine, are another [18] (especially when their metabolism is altered due to interactions with other drugs or when their excretion is impaired due to hepatic or renal failure).

Beyond these common causes of SE, a workup for rare etiologies should be entertained. In a systematic review of 513 papers on SE, 181 uncommon causes of SE were identified and subdivided into immunologically mediated disorders, mitochondrial diseases, rare infectious disorders, genetic disorders, and drugs or toxins [18,44].

The most recent knowledge in this category is the contribution of paraneoplastic or autoimmune conditions to a large percentage of previously cryptogenic pharmaco-resistant seizures or super-refractory SE, most in the context of limbic encephalitis. Many of these patients have never experienced seizures or SE before and a new acronym has been devised for them: new-onset refractory status epilepticus (NORSE), ie, a state of persistent seizures with no identifiable etiology in patients without preexisting epilepsy that lasts longer than 24 hour despite optimal therapy [45]. A growing array of autoantibodies against intracellular and surface or synaptic neuronal targets has been described in addition to the previous literature of Rassmussen’s encephalitis and Hashimoto’s encephalopathy [46]. The most common autoantibodies associated with seizures and SE include anti-Hu, anti-Ma2, anti-CV2/CRMP5, anti-Ri, ANNA3, anti-amphiphysin, anti-NMDA receptor, anti-LGI1 and CASPR2, anti-GABA-beta, anti-GluR3, anti-mGluR5 and alpha 3 ganglionic acetylcholine receptor [47,48]. The diagnosis frequently remains elusive due to lack of knowledge or absence of widespread availability of serologic testing (with sometimes weeks-long delay for the results to be available), but the response to treatment with removal of tumor, plasmapheresis, or immunomodulation and immunosuppression is often dramatic.

Pathophysiology of SE

Most seizures are self-terminating phenomena lasting from a few seconds to a few minutes [49]. One of the distinguishing characteristics of seizures evolving into SE, however, is the switch to a self-sustaining situation, which is time-dependent. Seizures lasting more than 30 minutes would rarely stop spontaneously compared to 47% of those lasting between 10 to 29 minutes, which are self-resolving [50]. Moreover, in one study no self-limited seizure lasted more than 11 minutes [8].

The self-limiting character of seizures is due to inhibitory circuitry that suppresses their duration and propagation in the brain. Under specific circumstances, however, the inhibitory mechanisms fail and seizures progress to SE, which leads to synaptic reorganization, blood-brain barrier disruption, inflammation, metabolic crisis, more tissue damage, and further seizures. Neuronal injury during SE is the result of increased excitotoxicity [51–53] but also stems from systemic derangements such as hypoxia, acidosis, hypotension, or multiorgan dysfunction [54]. The seminal animal studies by Meldrum have shed a light on the systemic effects: after prolonged bicuculine-induced convulsive SE in baboons, neuronal damage and cell loss was evident in the neocortex, cerebellum and hippocampus. When systemic factors were kept within normal physiological limits (paralyzed and artificially ventilated animals with adequate serum glucose levels), there was decreased but still present neocortical and hippocampal cell damage, but absent cerebellar cell injury [55,56]. These experiments showed more than 40 years ago that the seizure activity per se is responsible for the neuronal damage and the systemic derangements play an additional role.

The direct neuronal injury as a result of the ongoing seizures, the perpetuation of seizures into SE, the resistance to treatment and the refractoriness that ensues have also been elucidated at a molecular level during the last decades. Initially, the g-aminobutyric acid (GABA) inhibitory circuits may be deficient and this is the reason why benzodiazepines or barbiturates, which work through GABAergic receptor agonism, are very effective during this early period. As time passes however, GABA receptors undergo a significant shift in their ability to respond to benzodiazepines [57,58]. This is due to changes in receptor presence at the inhibitory synapse, a phenomenon that has been called “receptor trafficking” by Arancibia and Kittler in 2009 [59]. There are differences in the type of GABA_A receptors found synaptically and extrasynaptically. GABA_A receptors containing the γ subunit are located synaptically and mediate phasic inhibition. Conversely, the δ subunit-containing GABA_A receptors are located exclusively extrasynaptically and mediate tonic inhibition [60,61]. Smith and Kittler described the highly dynamic state of receptor presence on the surface of axons and explained how receptors move laterally from extrasynaptic sites to the synapse and then out of it to be internalized and either recycled to the surface or degraded [62]. This “receptor trafficking” intensifies during SE, and the overall effect becomes a reduction in the number of functional GABA_A receptors in the synapses. As GABA is the principle inhib-itory transmitter, this reduction in GABAergic activity may be an important reason for seizures to become persistent.

However, this is not all. Additional mechanisms leading to refractoriness include the following:

(a) Excessive relocation of N-methyl-D-aspartate (NMDA)type glutamate receptors to the cell surface after 1 hour of SE, leading to increase of miniature excitatory NMDA currents and NMDA neurotransmission, with potentiation of glutamate excitotoxicity [53,63]

(b) Increased brain expression of drug efflux transporters, such as P-glycoprotein at the blood-brain barrier, which may reduce concentrations of AEDs at their brain targets [64]

(c) Up- and down-regulation of specific ATP-gated ion channels (P2X receptors) inducing altered response to ATP release [65]

(d) Change in the extracellular ionic environment (for example, the normally inhibitory GABA_A receptor-mediated currents may become excitatory with changes in extracellular chloride concentrations) [66]

(e) Mitochondrial insufficiency or failure, which would lead to cell necrosis and apoptosis [67]

(f) Inflammatory processes, with opening of the blood-brain barrier (BBB) contributing to perpetuation of seizures [44]. The underlying mechanism is a maladaptive response of the astrocytes to the BBB damage, leading to activation of the innate immune system and disturbed homeostasis of the extracellular potassium and glutamate [68].

(g) Large-scale changes in gene expression within the affected brain regions; these are regulated by micro-RNAs, influencing protein levels playing a role in excitability, neuronal death and neuroinflammation [69].

All of these pathophysiologic derangements may become targets for future antiepileptic treatments.

Although the direct and indirect injury from ongoing convulsive SE is not in doubt, the significance of NCSE or the ictal-interictal continuum on inflicting additional injury has been more controversial. Recent data, however, do not support a benign process in these situations. It has been shown lately that nonconvulsive seizures lead to physiologic changes in the brain, including elevated intracranial pressure, changes in the brain metabolism, and delayed increase in cerebral blood flow [25]. In addition, using microdialysis, elevated lactate/puruvate ratio, indicating metabolic crisis, has been shown during periods of nonconvulsive seizures or periodic discharges [70]. Similarly, high-frequency periodic discharges lead to inadequate increase in cerebral blood flow and tissue hypoxia [71], and lateralized periodic discharges, lateralized rhythmic delta activity, and generalized periodic discharges are associated with seizures [72].

Diagnosis of SE

The diagnosis of SE is primarily clinical and encompasses motor phenomena and alteration of mental status. Focal-onset convulsions can remain focal, follow a Jacksonian march, or immediately generalize to involve the whole body with loss of consciousness. Most of the time, this secondary generalization can only be appreciated during EEG recording. In addition, mental status alteration can differentiate simple partial SE (no change in mental status) from complex partial SE (disturbed sensorium).

The presence or absence of motor phenomena and loss of consciousness do not necessarily correlate with the EEG activity during or after SE. For example, persistent electrographic seizures or NCSE after control of convulsive SE have been demonstrated with continuous EEG [73]. Conversely, altered mental status is also a poor clinical differentiator, since 87% of patients successfully treated for convulsive SE and 100% treated for NCSE remained comatose 12 hours following the initiation of therapy [20]. In addition, only 27% of motor, seizure-like phenomena in the ICU were proven to be seizures in a retrospective study [74]. Psychogenic nonepileptic attacks, occurring in between 3.8% and 9.5% of ICU patients presenting with seizures [74,75], is another situation that may lead to confusion, inappropriate intubation, and ICU admission. Strange phenomena, such as fasciobrachial seizures (brief facial grimacing and ipsilateral arm posturing) many times preceding the onset of amnesia, confusion, or temporal lobe seizures have been described in patients who have non-paraneoplastic limbic encephalitis associated with voltage-gated potassium channel (VGKC) antibodies, especially against the leucine-rich glioma inactivated-1 (LGI1) protein [76,77].Without a continuous video EEG, these phenomena may not be captured or appreciated. Therefore, EEG monitoring is an important tool for the evaluation of these patients and criteria for its use have been published [78]. The EEG criteria for convulsive SE have been clearly delineated, but for NCSE a mix of clinical and EEG criteria should be met [14,15,79].

In addition to clinical observation and EEG, there has been interest lately in multimodality monitoring of acutely brain-injured patients for seizures or SE using electrocorticography or mini depth electrode placement, partial brain tissue oxygen tension, cerebral blood flow, and microdialysis in addition to scalp EEG. Although preliminary and limited in few academic centers, this approach has produced interesting findings. For example, in a study from Columbia University, 38% of 48 patients with subarachnoid hemorrhage and multimodality monitoring had intracortical seizures, while only 8% of them had surface seizures, all nonconvulsive [25]. In another study, 68% of seizures and 23% of periodic discharges were only captured on the depth electrodes and were missed on the surface ones [71]. Therefore, detection of SE may change in the future with use of more sensitive techniques than scalp EEG.

Treatment

Significant practice variations exist in the management of SE even among academic centers in the US [80] despite the fact that the goals of treatment are concrete. These include (1) emergent medical management, (2) termination of seizures, (3) prevention of recurrence of seizures, and (4) prevention or treatment of complications.

Management of SE must begin in a prehospital setting by the emergency medical services, because the faster the treatment is offered, the better the response. Several studies have attempted to assess the possibility of aborting SE even prior to the hospital. In a randomized, double-blinded study, lorazepam was 4.8 times and diazepam 2.3 times more effective than placebo in terminating SE on arrival in the ED when given intravenously (IV) by paramedics [81]. The RAMPART study was a double-blind, randomized, non-inferiority trial comparing the efficacy of intramuscular (IM) midazolam (10 mg followed by placebo IV) with that of IM placebo followed by intravenous lorazepam (4 mg) for children and adults in SE treated by paramedics. At the time of arrival in the ED, seizures had ceased without rescue therapy in 73.4% and 63.4%, respectively, favoring midazolam [82].

Emergent Initial Phase

During the emergent initial phase, the goals are protection of the airway, oxygenation, maintenance of blood pressure, exclusion of easily 

Urgent Control

If seizures continue, stage 2 medications should be used for benzodiazepine-refractory SE as urgent control treatment. There are some data suggesting better response rate to valproate after failure to control seizures with phenytoin than to phenytoin after failure of valproate [88]. If available, IV fosphenytoin is preferable to IV phenytoin due to potentially lower risk of side effects. Levetiracetam and phenobarbital IV are also acceptable choices. Levetiracetam can be administered as an off-label loading dose of 20–60 mg/kg IV (although the initial manufacturer was not supporting a “loading” dose; dose of up to 60 mg/kg IV up to 4500 mg maximum has been supported by the latest American Epilepsy Society guidelines [4]). This AED at an initial dose of 2–3 g/day confers an estimated success rate around 70% [89]. In a systematic review of 27 studies (798 cases of convulsive SE) comparing 5 AEDs in the treatment of benzodiazepine-resistant convulsive SE, phenobarbital and valproate had the highest efficacy (73.6% and 75.7%, respectively), followed by levetiracetam (68.5%) and phenytoin (50.2%). Lacosamide studies were excluded from the meta-analysis due to insufficient data [90], but its efficacy has been reported for patients with convulsive and NCSE [91,92]. There is not enough evidence at this point, however, to recommend its routine use for benzodiazepine refractory SE [90].

Refractory SE

When seizures continue despite the use of benzodiazepines and 2nd stage AEDs, SE becomes refractory (stage 3). Treatment of these resistant cases is frequently initiated in the ED and continued in an ICU. Outcomes were not significantly better in patients with SE admitted and managed in a neuro-ICU compared to a general medical ICU in a retrospective study, but the numbers were small (only 27% of SE were admitted to the former) [93] and this may change in the future. Intubation and mechanical ventilation is the first step, if not already present (only 21% of patients in the RAMPART study received endotracheal intubation, with 6.4% in the prehospital setting and 93.6% after admission [87]). Hemodynamic support with pressors or inotropes may be required as most anesthetic agents may decrease the blood pressure. Because of the urgency of controlling the seizures during SE, the potential aspiration risk and the questionable enteral absorption per os administration of additional AEDs is problematic, and IV formulations should be used.

Currently in the US, phenytoin, valproic acid, phenobarbital, levetiracetam, lacosamide, diazepam, lorazepam are available in IV formulations. In February 2016, the FDA also approved brivaracetam (which also is available in an IV formulation) and in October of the same year IV carbamazepine. None of these AEDs has an FDA indication for SE, although they are widely used. Parenteral lacosamide has a success rate of 33% to 67.7% (200–400 mg over 3–5 min was the most common bolus dose) depending on its use as second or third AED [94–96]. In lacosamide-naive patients with RSE on continuous EEG monitoring, the success rate for cessation of SE was 15.7, 25.5, 58.8, and 82.4 % by 4, 12, 24, and 48 hours, respectively [97]. Alternatively, topiramate in doses 300–1600 mg/day per oro/nasogastric tube can be considered [98]. In a study of 35 patients with RSE treated with topiramate as an adjunct AED, the response rate was 86% (as the third AED), and remained stable at 67% after administration as the fourth to seventh AED. Overall, RSE was terminated in 71% of patients within 72 hours after first administration of topiramate [99]. Other studies, however, adjusting for co-variates, did not prove topiramate to be effective in RSE [100]. Clobazam, a unique oral 1,5-benzodiazepine with excellent absorption, has been also used in the treatment of RSE. Seventeen patients with RSE (11 with prior epilepsy) were successfully treated with clobazam, which was introduced after a median duration of 4 days and after a median of 3 failed AEDs. Termination of RSE within 24 hours of administration, without addition or modification of concurrent AED and with successful wean of anesthetic infusions, was seen in 13 patients, whereas indeterminate response was seen in another 3. Clobazam was deemed unsuccessful in 1 patient [101]. In another recent report of 70 episodes of RSE, clobazam was used in 24 (34.3%) of them. If clobazam was the last AED added to therapy before RSE termination, the success was attributed to this drug. Based on this definition, clobazam led to 6 episodes (25%) of successful RSE resolution [102]. If primary or metastatic brain tumor is the presumed cause of SE, a combination of IV phenytoin, IV levetiracetam (median dose 3 g/d) and enterically administered pregabalin (median dose 375 mg/day) led to 70% control of SE on average 24 hours after addition of the third AED [103]. However, the major treatment options, which should not be delayed in unresponsive RSE, are propofol or midazolam infusions at high rates and under continuous EEG monitoring. These infusions should be continued for at least 24 hours and then held to reassess the situation. By that time, cocurrent metabolic derangements and low AED levels from noncompliance should have been corrected. Prolonged and high-dose propofol should be avoided because of the risk for propofol infusion syndrome, especially if pressors/inotropes are co-infused [104].

Super-refractory SE

Should seizures continue or recur, stage 4 options for SRSE are considered [105]. Pentobarbital with shorter half-life is favored to phenobarbital. The main disadvantages of barbiturates are compromised neuro-exam (which has to be assessed frequently), cardiovascular depression and hypotension, respiratory depression with need for full ventilator support, cough suppression with increased risk for atelectasis and pneumonia, immunosuppression increasing the risk for infection or sepsis, immobility increasing the risk for thromboembolism and ileus mandating parenteral nutrition [106,107]. The depth and duration of the EEG suppression that must be achieved by barbiturates is unknown. Some experts recommend instead of burst-suppression pattern complete suppression or “flat record” because of better seizure control and fewer relapses [108]. Moreover, patients with more prolonged barbiturate treatment (> 96 hours) and those receiving phenobarbital at the time of pentobarbital taper are less likely to relapse [109]. European guidelines recommend titration of propofol and barbiturate to EEG burst-suppression, and midazolam to seizure suppression, maintained for at least 24 h [2]. In recent reviews, it was found that barbiturates control refractory and super-refractory SE in 64% of patients and are ineffective in only 5% [11,110].

If SE continues or recurs after emergence from barbiturate coma, ketamine may be an option [11,83]. Ketamine offers the advantage of NMDA receptor antagonism, which may be important in the late phase of SE and lacks cardiodepressant or hypotensive properties. Early [111] or late [112] use of ketamine has been reported in small case series with various success rates. In a recent multicenter retrospective study from North America and Europe, evaluating 58 patients with 60 RSE, ketamine was likely responsible for seizure control in 12% and possibly responsible in an additional 20%. No responses were observed when infusion rate was lower than 0.9 mg/kg/h or when ketamine was introduced 8 days or more after onset of SE or after failure of seven or more drugs [113].

If all these measures have failed, stage 4.2 treatment options are available (Table 2), but these are mostly based on small case series and expert opinions (except for the recent hypothermia study). Pyridoxine hydrochloride in an IV or enteral form at a dose of 100–300 mg/day for few days can be used in stage 4 or earlier stages, as it is a cofactor in the synthesis of the inhibitory neurotransmitter GABA [114]. There are no strong data for its effectiveness, but it can be used as a cheap and safe alternative [115]. Magnesium has been successfully used in 2 girls with juvenile Alper’s syndrome [116] and is the treatment of choice for eclamptic seizures. Ketogenic diet may also be an optionfor these patients [117]. Resection of the epileptic focus after mapping with intracranial EEG electrodes may be highly effective but cannot be used in many patients due to lack of focus or eloquence location [83,106,115]. Use of steroids, plasmapheresis or IVIG, followed by immunosuppression can be tried, but one should balance risks and benefits. These immunosuppressive or immunomodulating treatments should be especially considered in patients with NORSE or suspected autoimmune or paraneoplastic encephalitides, where AEDs usually have no effect [46]. These therapies though often precede the diagnosis, since it takes time for the autoantibody panel results to return and the treating physician has to make a decision to blindly start treatment for SRSE.

There were some promising data regarding hypothermia use in these desperate situations [118,119] until the HYBERNATUS study, conducted in France, was recently published. In this study, 270 patients with convulsive SE were randomized in to hypothermia (32° to 34°C for 24 hours) in addition to standard care or to standard care alone. A Glasgow Outcome Scale score of 5 (primary outcome) occurred in 49% of patients in the hypothermia group and in 43% in the control group (a nonstatistical difference). Secondary outcomes, including mortality at 90 days, RSE on day 1, SRSE and functional sequelae on day 90 were not different except for the rate of progression to EEG-confirmed SE on the first day, which was lower in the hypothermia group (11% vs. 22% in the controls). Adverse events were more frequent in the hypothermia group than in the control group [120].

Additional anecdotal treatments are presented in Table 2, but their efficacy is questionable.

This staged management approach may change in the future to a more physiologic and rational treatment with polytherapy based on synaptic receptor trafficking during SE [63]. For example, in an animal model of severe SE, combinations of a benzodiazepine with ketamine and valproate, or with ketamine and brivaracetam, were more effective and less toxic than benzodiazepine monotherapy [121]. Allopregnalonone, a metabolite of progesterone, is an endogenous, naturally occurring neuroactive steroid produced in the ovary, the adrenal cortex and the central nervous system. It is a potent positive allosteric modulator of synaptic and extrasynaptic GABA_A receptors with antiepileptic activity [122]. Neuroactive steroids, such as allopregnanolone, are currently evaluated in SE.

Outcomes

SE still carries significant mortality and morbidity. Distinct variants of SE carry different mortalities, and the range is quite broad: from zero mortality for absence or complex partial SE in ambulatory patients [12], to 19% to 27% 30-day mortality for generalized tonic-clonic SE [20,123] and to 64.7% 30-day mortality for subtle SE [20]. Variables playing an important role in the outcome are the underlying cause (regarded by most authorities the most important variable), the duration of SE (mortality 32% if persistent for > 1 hour vs 2.7% if < 1 hour), the type of SE, the treatment administered, and the age of the patient (children have better outcomes than adults) [123–125]. The etiology of SE still remains the most important prognostic factor, with alcohol and AED-withdrawal/noncompliance having the best outcomes; structural brain injuries, such as anoxia-ischemia, vascular lesions, or brain tumors, have the worst prognosis.

The most resistant cases pose significant dilemmas regarding the length of treatment using barbiturate coma and the potential for acceptable prognosis or the need to withdraw life support. For RSE, for example, in-hospital mortality is 31.7% and 76.2% of patients reach poor functional outcome. Long-term outcomes are also dismal: at 1 year post-discharge, 74% are dead or in a state of unresponsive wakefulness, 16% severely disabled, and only 10% have no or minimal disability [126]. Duration of drug-induced coma, arrhythmias requiring intervention, and pneumonia are associated with poor functional outcome, whereas prolonged mechanical ventilation with mortality and seizure control without burst-suppression or isoelectric EEG are associated with good functional outcome [127,128].

Treatment with barbiturates may contribute to these outcomes, although it is very challenging to prove causality in such a complex and prolonged ICU environment. Some data have shed light towards that direction: in a recent retrospective study of 171 patients with SE, of which 37% were treated with IV anesthetic drugs, there was a higher risk for infections and a 2.9-fold relative risk for death after adjustment for confounders in the group treated with IV anesthetics compared to the group without these agents [129].

The SE Severity Score (STESS, range 0–6) is a prognostic score for survival [130] and can be used as a scaffold for discussions with families and covariate adjustment tool for research. A favorable score of 0–2 has a negative predictive value of 0.97 for survival and likelihood to return to baseline clinical condition in survivors, although an unfavorable score (3–6) had a positive predictive value for death of only 0.39 [131].

The risk for recurrence of afebrile SE in a population-based study in Minnesota has been estimated at 31.7% over a 10-year follow-up period. The risk for recurrence was about 25% regardless of the underlying etiology, except in those patients with SE occurring in the setting of a progressive brain disorder (who had a 100% risk). Female gender, generalized (vs partial) SE and lack of response to the first AED after the initial episode of SE were independent factors for recurrence [132].

Conclusion

Despite the use of better diagnostic tools (continuous video EEG), advances in technology in the ICU, and availability of new AEDs, SE still carries significant mortality and morbidity, which depends mainly on age and etiology. The current treatment is still staged, with supportive measures and benzodiazepine administration remaining the mainstay initially and followed by older and newer AEDs and anesthetics for resistant cases. With the advance of pathophysiologic mechanisms elucidation at a molecular/receptor level, combinations of AEDs may become the foundation of future SE control.

Corresponding author: Panayiotis N. Varelas, MD, PhD, FNCS, Division Head, Neuro-Critical Care Service, Henry Ford Hospital, K-11, 2799 W. Grand Blvd., Detroit, MI 48202, [email protected].

Financial disclosures: Dr. Varelas was local principal investigator for a super-refractory status epilepticus study sponsored by Sage Therapeutics.

Author contributions: conception and design, ARR, PNV; analysis and interpretation of data, PNV; drafting of article, PNV; critical revision of the article, ARR, PNV; administrative or technical support, PNV; collection and assembly of data, ARR, PNV.

From the Johns Hopkins Hospital, Baltimore, MD (Dr. Ramadan), and the Henry Ford Hospital, Detroit, MI (Dr. Varelas).

Abstract

• Objective: To review the management of status epilepticus (SE).
• Methods: Review of the literature.
• Results: SE is a relatively common condition that accounts for 3% to 5% of all emergency department evaluations for seizure disorders and occurs in 2% to 16% of all epilepsy patients. The 3 most common etiologies are low levels of antiepileptic drugs, remote symptomatic etiologies, and cerebrovascular accidents. The majority of SEs are convulsant, but there is growing awareness of non-convulsive SEs, which can be diagnosed only via electroencephalogram. Management, which must be initiated at the earliest possible time, has evolved to incorporate pre-hospital measures and 4 treatment stages, with supportive measures and benzodiazepine administration remaining the mainstay initially and followed by older and newer antiepileptic drugs and anesthetics for resistant cases.
• Conclusion: SE is a neurological emergency that still carries significant mortality and morbidity if not treated immediately and properly.

Key words: status epilepticus; seizures; convulsive status epilepticus; nonconvulsive status epilepticus.

Status epilepticus (SE) is a relatively common condition that accounts for 3% to 5% of all emergency department (ED) evaluations for seizure disorders and occurs in 2% to 16% of all epilepsy patients [1]. It remains a major neurological emergency that, if not properly and timely treated, leads to death or permanent neurological injury. Since most of patients with convulsive SE are admitted to the hospital via the ED and are then transferred to the intensive care unit (ICU), our focus in this review will be on the latter.

Although only a handful prospective, randomized studies have been reported, guidelines on SE have been published in Europe [2] and the US [3,4]. In this paper, we review the evolving definition and types of SE, its incidence, etiology, and pathophysiology, its diagnosis and treatment algorithms, and its outcome. Our goal is to provide the reader with a concise but thorough review of this still lethal neurological emergency.

Definitions

The International Classification of Epileptic Seizures had previously defined SE as any seizure lasting ≥ 30 minutes or intermittent seizures lasting for > 30 min without recovery of consciousness interictally [5,6]. More recently, a duration of 5 or more minutes of (a) continuous seizures or (b) 2 or more discrete seizures with incomplete recovery of consciousness in-between, proposed by Lowenstein [3,7], offers the advantage of incorporating new knowledge. The shortening of the convulsive period to 5 minutes was based on the fact that the majority of tonic-clonic seizures last for only 1 to 2 minutes, that those lasting > 5 minutes do not stop spontaneously [8], that permanent neuronal injury occurs before 30 minutes, and that refractoriness to treatment increases with longer seizure duration [9].

Refractory SE (RSE) has been defined as SE not controlled after adequate doses of an initial benzodiazepine followed by a second acceptable antiepileptic drug (AED) or SE not controlled after the initial parenteral therapy with a minimum number of standard “front-line” AEDs (either 2 or 3) or SE with a minimum duration of seizures that persist despite treatment (eg, at least or 2 hours) [3,10]. Super-refractory SE (SRSE) is defined as SE that continues or recurs 24 hours or more after the onset of anesthetic therapy or recurs on the reduction or withdrawal of anesthesia [11].

Non-convulsive SE (NCSE) is defined as the presence of altered consciousness or behavior for ≥ 30 minutes, the absence of overt clinical signs of convulsive activity during that period, and the electroencephalographic (EEG) confirmation of seizures or activity that responds to treatment together with improvement of consciousness [12–15]. Two major types of NCSE can be encountered: the one in patients with epileptic encephalopathy/coma and the one in patients with absence or complex partial seizures, who are not usually admitted to ICU and are functional yet impaired. Because of the confusion between these 2 extremes in the NCSE spectrum, working criteria for standardization of reporting, utilizing the frequency of electroencephalographic epileptiform discharges or delta/theta waveforms have been proposed [15]. A recent compendium of 123 cases of NCSE with clinical descriptions and EEG patterns following a syndromic classification approach has also been published [16].

Types of SE

Three major categories of SE have been described: generalized convulsive SE (GCSE), focal motor SE (FMSE or epilepsia partialis continua [EPC]) of Kojevnikov, and NCSE. GCSE and FMSE are easily recognized due to overt convulsions. NCSE, however, has a more obscure phenotype and can be subdivided into a spectrum encompassing typical absence and complex partial SE, atypical absence SE and tonic SE (usually in children with learning disabilities), epileptic behavioral disturbance and psychosis, including Balint–like syndrome [17], confusional states or delirium with epileptiform discharges) and SE in coma (after significant brain injuries, such as hypoxia-ischemia, most commonly encountered in ICUs) [13,18]. The 2 extremes in this NCSE spectrum have completely different prognoses, with absence SE the most benign and SE in coma the most dismal.

Lastly, SE presents either spontaneously or can be “semi-intentional” iatrogenic, encountered either in the neuro-ICU or epilepsy monitoring unit, when AEDs are withdrawn under continuous EEG recording in order for seizures to emerge and be recorded with surface or intracranial electrodes.

Incidence of SE

In a prospective population-based epidemiological study, the incidence of SE was estimated at 41–61/100,000 patients/year. For the US, this translates to 125,000 to 195,000 episodes per year [19].

The highest incidence of SE occurs during the first year of life and during the decades beyond 60 years, and is also dependent on the SE subtype. Partial SE occurs in 25% of cases of SE and NCSE accounts for another 4% to 26 % [19,20], but the incidence for the latter is considered an underestimate due to the need for continuous EEG monitoring (which is not widely available). For example, NCSE was discovered in no patient with acute stroke [21], 8% of comatose ICU patients [22], 7% of patients with intracerebral hemorrhage [23], 3% to 8% of patients with subarachnoid hemorrhage [24–26], 6% of patients with metastatic cancer [27], and 6% of patients with head trauma [28].

The incidence of RSE and SRSE is also unknown. In a recent retrospective study from a neuro-ICU in a West China hospital, the percentage of non-refractory SE, RSE, and SRSE were 67.3%, 20.4% and 12.2%, respectively [29]. Other retrospective studies have shown that 12% to 43% of SE cases become refractory [30–33] and that approximately 10% to 15% of all cases of hospital-admitted SE will become super-refractory at some point, but no prospective studies have been published.

Risk factors that have been identified for RSE are encephalitis as a cause, severe consciousness impairment, de novo episodes of SE, delay in initiation of treatment, NCSE, and focal motor seizures at onset [30,32,34,35]. In a more recent study from ICU patients in Switzerland and the US, acute SE etiology (traumatic brain injuries, cerebrovascular accidents, meningoencephalitis, brain tumors, surgical brain lesions, exposure to, or withdrawal from, recreational drugs, prescription drugs, alcohol, metabolic disturbances and fever), coma/stupor, and serum albumin < 35 g/L at SE onset were independent predictors for RSE [36].

Etiology of SE

The 3 most common etiologies for SE are low levels of antiepileptic drugs (AEDs) in 34% of the cases (usually due to noncompliance), remote symptomatic etiologies (history of neurological insults remote to the first unprovoked SE episode, 24%), and cerebrovascular accidents (ischemic and hemorrhagic strokes, 22%). These are followed by hypoxia (13%) and metabolic disturbances (15%). Because 82% of patients in the remote group have a history of cerebrovascular disease, almost 50% have either acute or remote cerebrovascular disease as etiology of SE [19].

In general ICUs, metabolic abnormalities can account for 33% of seizures, drug withdrawal for 33%, drug toxicity for 14.5%, and stroke for 9% to 39% [37,38]. In ICUs, sepsis remains a common etiology of electrographic seizures or periodic epileptiform discharges [39,40], and legal or illegal drugs, such as ciprofloxacin, levofloxacin, piperacillin/tazobactam, cefepime and carbapenems [41–43], lithium or theophylline intoxication, vigabatrin, tiagabine or crack/cocaine, are another [18] (especially when their metabolism is altered due to interactions with other drugs or when their excretion is impaired due to hepatic or renal failure).

Beyond these common causes of SE, a workup for rare etiologies should be entertained. In a systematic review of 513 papers on SE, 181 uncommon causes of SE were identified and subdivided into immunologically mediated disorders, mitochondrial diseases, rare infectious disorders, genetic disorders, and drugs or toxins [18,44].

The most recent knowledge in this category is the contribution of paraneoplastic or autoimmune conditions to a large percentage of previously cryptogenic pharmaco-resistant seizures or super-refractory SE, most in the context of limbic encephalitis. Many of these patients have never experienced seizures or SE before and a new acronym has been devised for them: new-onset refractory status epilepticus (NORSE), ie, a state of persistent seizures with no identifiable etiology in patients without preexisting epilepsy that lasts longer than 24 hour despite optimal therapy [45]. A growing array of autoantibodies against intracellular and surface or synaptic neuronal targets has been described in addition to the previous literature of Rassmussen’s encephalitis and Hashimoto’s encephalopathy [46]. The most common autoantibodies associated with seizures and SE include anti-Hu, anti-Ma2, anti-CV2/CRMP5, anti-Ri, ANNA3, anti-amphiphysin, anti-NMDA receptor, anti-LGI1 and CASPR2, anti-GABA-beta, anti-GluR3, anti-mGluR5 and alpha 3 ganglionic acetylcholine receptor [47,48]. The diagnosis frequently remains elusive due to lack of knowledge or absence of widespread availability of serologic testing (with sometimes weeks-long delay for the results to be available), but the response to treatment with removal of tumor, plasmapheresis, or immunomodulation and immunosuppression is often dramatic.

Pathophysiology of SE

Most seizures are self-terminating phenomena lasting from a few seconds to a few minutes [49]. One of the distinguishing characteristics of seizures evolving into SE, however, is the switch to a self-sustaining situation, which is time-dependent. Seizures lasting more than 30 minutes would rarely stop spontaneously compared to 47% of those lasting between 10 to 29 minutes, which are self-resolving [50]. Moreover, in one study no self-limited seizure lasted more than 11 minutes [8].

The self-limiting character of seizures is due to inhibitory circuitry that suppresses their duration and propagation in the brain. Under specific circumstances, however, the inhibitory mechanisms fail and seizures progress to SE, which leads to synaptic reorganization, blood-brain barrier disruption, inflammation, metabolic crisis, more tissue damage, and further seizures. Neuronal injury during SE is the result of increased excitotoxicity [51–53] but also stems from systemic derangements such as hypoxia, acidosis, hypotension, or multiorgan dysfunction [54]. The seminal animal studies by Meldrum have shed a light on the systemic effects: after prolonged bicuculine-induced convulsive SE in baboons, neuronal damage and cell loss was evident in the neocortex, cerebellum and hippocampus. When systemic factors were kept within normal physiological limits (paralyzed and artificially ventilated animals with adequate serum glucose levels), there was decreased but still present neocortical and hippocampal cell damage, but absent cerebellar cell injury [55,56]. These experiments showed more than 40 years ago that the seizure activity per se is responsible for the neuronal damage and the systemic derangements play an additional role.

The direct neuronal injury as a result of the ongoing seizures, the perpetuation of seizures into SE, the resistance to treatment and the refractoriness that ensues have also been elucidated at a molecular level during the last decades. Initially, the g-aminobutyric acid (GABA) inhibitory circuits may be deficient and this is the reason why benzodiazepines or barbiturates, which work through GABAergic receptor agonism, are very effective during this early period. As time passes however, GABA receptors undergo a significant shift in their ability to respond to benzodiazepines [57,58]. This is due to changes in receptor presence at the inhibitory synapse, a phenomenon that has been called “receptor trafficking” by Arancibia and Kittler in 2009 [59]. There are differences in the type of GABA_A receptors found synaptically and extrasynaptically. GABA_A receptors containing the γ subunit are located synaptically and mediate phasic inhibition. Conversely, the δ subunit-containing GABA_A receptors are located exclusively extrasynaptically and mediate tonic inhibition [60,61]. Smith and Kittler described the highly dynamic state of receptor presence on the surface of axons and explained how receptors move laterally from extrasynaptic sites to the synapse and then out of it to be internalized and either recycled to the surface or degraded [62]. This “receptor trafficking” intensifies during SE, and the overall effect becomes a reduction in the number of functional GABA_A receptors in the synapses. As GABA is the principle inhib-itory transmitter, this reduction in GABAergic activity may be an important reason for seizures to become persistent.

However, this is not all. Additional mechanisms leading to refractoriness include the following:

(a) Excessive relocation of N-methyl-D-aspartate (NMDA)type glutamate receptors to the cell surface after 1 hour of SE, leading to increase of miniature excitatory NMDA currents and NMDA neurotransmission, with potentiation of glutamate excitotoxicity [53,63]

(b) Increased brain expression of drug efflux transporters, such as P-glycoprotein at the blood-brain barrier, which may reduce concentrations of AEDs at their brain targets [64]

(c) Up- and down-regulation of specific ATP-gated ion channels (P2X receptors) inducing altered response to ATP release [65]

(d) Change in the extracellular ionic environment (for example, the normally inhibitory GABA_A receptor-mediated currents may become excitatory with changes in extracellular chloride concentrations) [66]

(e) Mitochondrial insufficiency or failure, which would lead to cell necrosis and apoptosis [67]

(f) Inflammatory processes, with opening of the blood-brain barrier (BBB) contributing to perpetuation of seizures [44]. The underlying mechanism is a maladaptive response of the astrocytes to the BBB damage, leading to activation of the innate immune system and disturbed homeostasis of the extracellular potassium and glutamate [68].

(g) Large-scale changes in gene expression within the affected brain regions; these are regulated by micro-RNAs, influencing protein levels playing a role in excitability, neuronal death and neuroinflammation [69].

All of these pathophysiologic derangements may become targets for future antiepileptic treatments.

Although the direct and indirect injury from ongoing convulsive SE is not in doubt, the significance of NCSE or the ictal-interictal continuum on inflicting additional injury has been more controversial. Recent data, however, do not support a benign process in these situations. It has been shown lately that nonconvulsive seizures lead to physiologic changes in the brain, including elevated intracranial pressure, changes in the brain metabolism, and delayed increase in cerebral blood flow [25]. In addition, using microdialysis, elevated lactate/puruvate ratio, indicating metabolic crisis, has been shown during periods of nonconvulsive seizures or periodic discharges [70]. Similarly, high-frequency periodic discharges lead to inadequate increase in cerebral blood flow and tissue hypoxia [71], and lateralized periodic discharges, lateralized rhythmic delta activity, and generalized periodic discharges are associated with seizures [72].

Diagnosis of SE

The diagnosis of SE is primarily clinical and encompasses motor phenomena and alteration of mental status. Focal-onset convulsions can remain focal, follow a Jacksonian march, or immediately generalize to involve the whole body with loss of consciousness. Most of the time, this secondary generalization can only be appreciated during EEG recording. In addition, mental status alteration can differentiate simple partial SE (no change in mental status) from complex partial SE (disturbed sensorium).

The presence or absence of motor phenomena and loss of consciousness do not necessarily correlate with the EEG activity during or after SE. For example, persistent electrographic seizures or NCSE after control of convulsive SE have been demonstrated with continuous EEG [73]. Conversely, altered mental status is also a poor clinical differentiator, since 87% of patients successfully treated for convulsive SE and 100% treated for NCSE remained comatose 12 hours following the initiation of therapy [20]. In addition, only 27% of motor, seizure-like phenomena in the ICU were proven to be seizures in a retrospective study [74]. Psychogenic nonepileptic attacks, occurring in between 3.8% and 9.5% of ICU patients presenting with seizures [74,75], is another situation that may lead to confusion, inappropriate intubation, and ICU admission. Strange phenomena, such as fasciobrachial seizures (brief facial grimacing and ipsilateral arm posturing) many times preceding the onset of amnesia, confusion, or temporal lobe seizures have been described in patients who have non-paraneoplastic limbic encephalitis associated with voltage-gated potassium channel (VGKC) antibodies, especially against the leucine-rich glioma inactivated-1 (LGI1) protein [76,77].Without a continuous video EEG, these phenomena may not be captured or appreciated. Therefore, EEG monitoring is an important tool for the evaluation of these patients and criteria for its use have been published [78]. The EEG criteria for convulsive SE have been clearly delineated, but for NCSE a mix of clinical and EEG criteria should be met [14,15,79].

In addition to clinical observation and EEG, there has been interest lately in multimodality monitoring of acutely brain-injured patients for seizures or SE using electrocorticography or mini depth electrode placement, partial brain tissue oxygen tension, cerebral blood flow, and microdialysis in addition to scalp EEG. Although preliminary and limited in few academic centers, this approach has produced interesting findings. For example, in a study from Columbia University, 38% of 48 patients with subarachnoid hemorrhage and multimodality monitoring had intracortical seizures, while only 8% of them had surface seizures, all nonconvulsive [25]. In another study, 68% of seizures and 23% of periodic discharges were only captured on the depth electrodes and were missed on the surface ones [71]. Therefore, detection of SE may change in the future with use of more sensitive techniques than scalp EEG.

Treatment

Significant practice variations exist in the management of SE even among academic centers in the US [80] despite the fact that the goals of treatment are concrete. These include (1) emergent medical management, (2) termination of seizures, (3) prevention of recurrence of seizures, and (4) prevention or treatment of complications.

Management of SE must begin in a prehospital setting by the emergency medical services, because the faster the treatment is offered, the better the response. Several studies have attempted to assess the possibility of aborting SE even prior to the hospital. In a randomized, double-blinded study, lorazepam was 4.8 times and diazepam 2.3 times more effective than placebo in terminating SE on arrival in the ED when given intravenously (IV) by paramedics [81]. The RAMPART study was a double-blind, randomized, non-inferiority trial comparing the efficacy of intramuscular (IM) midazolam (10 mg followed by placebo IV) with that of IM placebo followed by intravenous lorazepam (4 mg) for children and adults in SE treated by paramedics. At the time of arrival in the ED, seizures had ceased without rescue therapy in 73.4% and 63.4%, respectively, favoring midazolam [82].

Emergent Initial Phase

During the emergent initial phase, the goals are protection of the airway, oxygenation, maintenance of blood pressure, exclusion of easily 

Urgent Control

If seizures continue, stage 2 medications should be used for benzodiazepine-refractory SE as urgent control treatment. There are some data suggesting better response rate to valproate after failure to control seizures with phenytoin than to phenytoin after failure of valproate [88]. If available, IV fosphenytoin is preferable to IV phenytoin due to potentially lower risk of side effects. Levetiracetam and phenobarbital IV are also acceptable choices. Levetiracetam can be administered as an off-label loading dose of 20–60 mg/kg IV (although the initial manufacturer was not supporting a “loading” dose; dose of up to 60 mg/kg IV up to 4500 mg maximum has been supported by the latest American Epilepsy Society guidelines [4]). This AED at an initial dose of 2–3 g/day confers an estimated success rate around 70% [89]. In a systematic review of 27 studies (798 cases of convulsive SE) comparing 5 AEDs in the treatment of benzodiazepine-resistant convulsive SE, phenobarbital and valproate had the highest efficacy (73.6% and 75.7%, respectively), followed by levetiracetam (68.5%) and phenytoin (50.2%). Lacosamide studies were excluded from the meta-analysis due to insufficient data [90], but its efficacy has been reported for patients with convulsive and NCSE [91,92]. There is not enough evidence at this point, however, to recommend its routine use for benzodiazepine refractory SE [90].

Refractory SE

When seizures continue despite the use of benzodiazepines and 2nd stage AEDs, SE becomes refractory (stage 3). Treatment of these resistant cases is frequently initiated in the ED and continued in an ICU. Outcomes were not significantly better in patients with SE admitted and managed in a neuro-ICU compared to a general medical ICU in a retrospective study, but the numbers were small (only 27% of SE were admitted to the former) [93] and this may change in the future. Intubation and mechanical ventilation is the first step, if not already present (only 21% of patients in the RAMPART study received endotracheal intubation, with 6.4% in the prehospital setting and 93.6% after admission [87]). Hemodynamic support with pressors or inotropes may be required as most anesthetic agents may decrease the blood pressure. Because of the urgency of controlling the seizures during SE, the potential aspiration risk and the questionable enteral absorption per os administration of additional AEDs is problematic, and IV formulations should be used.

Currently in the US, phenytoin, valproic acid, phenobarbital, levetiracetam, lacosamide, diazepam, lorazepam are available in IV formulations. In February 2016, the FDA also approved brivaracetam (which also is available in an IV formulation) and in October of the same year IV carbamazepine. None of these AEDs has an FDA indication for SE, although they are widely used. Parenteral lacosamide has a success rate of 33% to 67.7% (200–400 mg over 3–5 min was the most common bolus dose) depending on its use as second or third AED [94–96]. In lacosamide-naive patients with RSE on continuous EEG monitoring, the success rate for cessation of SE was 15.7, 25.5, 58.8, and 82.4 % by 4, 12, 24, and 48 hours, respectively [97]. Alternatively, topiramate in doses 300–1600 mg/day per oro/nasogastric tube can be considered [98]. In a study of 35 patients with RSE treated with topiramate as an adjunct AED, the response rate was 86% (as the third AED), and remained stable at 67% after administration as the fourth to seventh AED. Overall, RSE was terminated in 71% of patients within 72 hours after first administration of topiramate [99]. Other studies, however, adjusting for co-variates, did not prove topiramate to be effective in RSE [100]. Clobazam, a unique oral 1,5-benzodiazepine with excellent absorption, has been also used in the treatment of RSE. Seventeen patients with RSE (11 with prior epilepsy) were successfully treated with clobazam, which was introduced after a median duration of 4 days and after a median of 3 failed AEDs. Termination of RSE within 24 hours of administration, without addition or modification of concurrent AED and with successful wean of anesthetic infusions, was seen in 13 patients, whereas indeterminate response was seen in another 3. Clobazam was deemed unsuccessful in 1 patient [101]. In another recent report of 70 episodes of RSE, clobazam was used in 24 (34.3%) of them. If clobazam was the last AED added to therapy before RSE termination, the success was attributed to this drug. Based on this definition, clobazam led to 6 episodes (25%) of successful RSE resolution [102]. If primary or metastatic brain tumor is the presumed cause of SE, a combination of IV phenytoin, IV levetiracetam (median dose 3 g/d) and enterically administered pregabalin (median dose 375 mg/day) led to 70% control of SE on average 24 hours after addition of the third AED [103]. However, the major treatment options, which should not be delayed in unresponsive RSE, are propofol or midazolam infusions at high rates and under continuous EEG monitoring. These infusions should be continued for at least 24 hours and then held to reassess the situation. By that time, cocurrent metabolic derangements and low AED levels from noncompliance should have been corrected. Prolonged and high-dose propofol should be avoided because of the risk for propofol infusion syndrome, especially if pressors/inotropes are co-infused [104].

Super-refractory SE

Should seizures continue or recur, stage 4 options for SRSE are considered [105]. Pentobarbital with shorter half-life is favored to phenobarbital. The main disadvantages of barbiturates are compromised neuro-exam (which has to be assessed frequently), cardiovascular depression and hypotension, respiratory depression with need for full ventilator support, cough suppression with increased risk for atelectasis and pneumonia, immunosuppression increasing the risk for infection or sepsis, immobility increasing the risk for thromboembolism and ileus mandating parenteral nutrition [106,107]. The depth and duration of the EEG suppression that must be achieved by barbiturates is unknown. Some experts recommend instead of burst-suppression pattern complete suppression or “flat record” because of better seizure control and fewer relapses [108]. Moreover, patients with more prolonged barbiturate treatment (> 96 hours) and those receiving phenobarbital at the time of pentobarbital taper are less likely to relapse [109]. European guidelines recommend titration of propofol and barbiturate to EEG burst-suppression, and midazolam to seizure suppression, maintained for at least 24 h [2]. In recent reviews, it was found that barbiturates control refractory and super-refractory SE in 64% of patients and are ineffective in only 5% [11,110].

If SE continues or recurs after emergence from barbiturate coma, ketamine may be an option [11,83]. Ketamine offers the advantage of NMDA receptor antagonism, which may be important in the late phase of SE and lacks cardiodepressant or hypotensive properties. Early [111] or late [112] use of ketamine has been reported in small case series with various success rates. In a recent multicenter retrospective study from North America and Europe, evaluating 58 patients with 60 RSE, ketamine was likely responsible for seizure control in 12% and possibly responsible in an additional 20%. No responses were observed when infusion rate was lower than 0.9 mg/kg/h or when ketamine was introduced 8 days or more after onset of SE or after failure of seven or more drugs [113].

If all these measures have failed, stage 4.2 treatment options are available (Table 2), but these are mostly based on small case series and expert opinions (except for the recent hypothermia study). Pyridoxine hydrochloride in an IV or enteral form at a dose of 100–300 mg/day for few days can be used in stage 4 or earlier stages, as it is a cofactor in the synthesis of the inhibitory neurotransmitter GABA [114]. There are no strong data for its effectiveness, but it can be used as a cheap and safe alternative [115]. Magnesium has been successfully used in 2 girls with juvenile Alper’s syndrome [116] and is the treatment of choice for eclamptic seizures. Ketogenic diet may also be an optionfor these patients [117]. Resection of the epileptic focus after mapping with intracranial EEG electrodes may be highly effective but cannot be used in many patients due to lack of focus or eloquence location [83,106,115]. Use of steroids, plasmapheresis or IVIG, followed by immunosuppression can be tried, but one should balance risks and benefits. These immunosuppressive or immunomodulating treatments should be especially considered in patients with NORSE or suspected autoimmune or paraneoplastic encephalitides, where AEDs usually have no effect [46]. These therapies though often precede the diagnosis, since it takes time for the autoantibody panel results to return and the treating physician has to make a decision to blindly start treatment for SRSE.

There were some promising data regarding hypothermia use in these desperate situations [118,119] until the HYBERNATUS study, conducted in France, was recently published. In this study, 270 patients with convulsive SE were randomized in to hypothermia (32° to 34°C for 24 hours) in addition to standard care or to standard care alone. A Glasgow Outcome Scale score of 5 (primary outcome) occurred in 49% of patients in the hypothermia group and in 43% in the control group (a nonstatistical difference). Secondary outcomes, including mortality at 90 days, RSE on day 1, SRSE and functional sequelae on day 90 were not different except for the rate of progression to EEG-confirmed SE on the first day, which was lower in the hypothermia group (11% vs. 22% in the controls). Adverse events were more frequent in the hypothermia group than in the control group [120].

Additional anecdotal treatments are presented in Table 2, but their efficacy is questionable.

This staged management approach may change in the future to a more physiologic and rational treatment with polytherapy based on synaptic receptor trafficking during SE [63]. For example, in an animal model of severe SE, combinations of a benzodiazepine with ketamine and valproate, or with ketamine and brivaracetam, were more effective and less toxic than benzodiazepine monotherapy [121]. Allopregnalonone, a metabolite of progesterone, is an endogenous, naturally occurring neuroactive steroid produced in the ovary, the adrenal cortex and the central nervous system. It is a potent positive allosteric modulator of synaptic and extrasynaptic GABA_A receptors with antiepileptic activity [122]. Neuroactive steroids, such as allopregnanolone, are currently evaluated in SE.

Outcomes

SE still carries significant mortality and morbidity. Distinct variants of SE carry different mortalities, and the range is quite broad: from zero mortality for absence or complex partial SE in ambulatory patients [12], to 19% to 27% 30-day mortality for generalized tonic-clonic SE [20,123] and to 64.7% 30-day mortality for subtle SE [20]. Variables playing an important role in the outcome are the underlying cause (regarded by most authorities the most important variable), the duration of SE (mortality 32% if persistent for > 1 hour vs 2.7% if < 1 hour), the type of SE, the treatment administered, and the age of the patient (children have better outcomes than adults) [123–125]. The etiology of SE still remains the most important prognostic factor, with alcohol and AED-withdrawal/noncompliance having the best outcomes; structural brain injuries, such as anoxia-ischemia, vascular lesions, or brain tumors, have the worst prognosis.

The most resistant cases pose significant dilemmas regarding the length of treatment using barbiturate coma and the potential for acceptable prognosis or the need to withdraw life support. For RSE, for example, in-hospital mortality is 31.7% and 76.2% of patients reach poor functional outcome. Long-term outcomes are also dismal: at 1 year post-discharge, 74% are dead or in a state of unresponsive wakefulness, 16% severely disabled, and only 10% have no or minimal disability [126]. Duration of drug-induced coma, arrhythmias requiring intervention, and pneumonia are associated with poor functional outcome, whereas prolonged mechanical ventilation with mortality and seizure control without burst-suppression or isoelectric EEG are associated with good functional outcome [127,128].

Treatment with barbiturates may contribute to these outcomes, although it is very challenging to prove causality in such a complex and prolonged ICU environment. Some data have shed light towards that direction: in a recent retrospective study of 171 patients with SE, of which 37% were treated with IV anesthetic drugs, there was a higher risk for infections and a 2.9-fold relative risk for death after adjustment for confounders in the group treated with IV anesthetics compared to the group without these agents [129].

The SE Severity Score (STESS, range 0–6) is a prognostic score for survival [130] and can be used as a scaffold for discussions with families and covariate adjustment tool for research. A favorable score of 0–2 has a negative predictive value of 0.97 for survival and likelihood to return to baseline clinical condition in survivors, although an unfavorable score (3–6) had a positive predictive value for death of only 0.39 [131].

The risk for recurrence of afebrile SE in a population-based study in Minnesota has been estimated at 31.7% over a 10-year follow-up period. The risk for recurrence was about 25% regardless of the underlying etiology, except in those patients with SE occurring in the setting of a progressive brain disorder (who had a 100% risk). Female gender, generalized (vs partial) SE and lack of response to the first AED after the initial episode of SE were independent factors for recurrence [132].

Conclusion

Despite the use of better diagnostic tools (continuous video EEG), advances in technology in the ICU, and availability of new AEDs, SE still carries significant mortality and morbidity, which depends mainly on age and etiology. The current treatment is still staged, with supportive measures and benzodiazepine administration remaining the mainstay initially and followed by older and newer AEDs and anesthetics for resistant cases. With the advance of pathophysiologic mechanisms elucidation at a molecular/receptor level, combinations of AEDs may become the foundation of future SE control.

Corresponding author: Panayiotis N. Varelas, MD, PhD, FNCS, Division Head, Neuro-Critical Care Service, Henry Ford Hospital, K-11, 2799 W. Grand Blvd., Detroit, MI 48202, [email protected].

Financial disclosures: Dr. Varelas was local principal investigator for a super-refractory status epilepticus study sponsored by Sage Therapeutics.

Author contributions: conception and design, ARR, PNV; analysis and interpretation of data, PNV; drafting of article, PNV; critical revision of the article, ARR, PNV; administrative or technical support, PNV; collection and assembly of data, ARR, PNV.

From the Johns Hopkins Hospital, Baltimore, MD (Dr. Ramadan), and the Henry Ford Hospital, Detroit, MI (Dr. Varelas).

Abstract

• Objective: To review the management of status epilepticus (SE).
• Methods: Review of the literature.
• Results: SE is a relatively common condition that accounts for 3% to 5% of all emergency department evaluations for seizure disorders and occurs in 2% to 16% of all epilepsy patients. The 3 most common etiologies are low levels of antiepileptic drugs, remote symptomatic etiologies, and cerebrovascular accidents. The majority of SEs are convulsant, but there is growing awareness of non-convulsive SEs, which can be diagnosed only via electroencephalogram. Management, which must be initiated at the earliest possible time, has evolved to incorporate pre-hospital measures and 4 treatment stages, with supportive measures and benzodiazepine administration remaining the mainstay initially and followed by older and newer antiepileptic drugs and anesthetics for resistant cases.
• Conclusion: SE is a neurological emergency that still carries significant mortality and morbidity if not treated immediately and properly.

Key words: status epilepticus; seizures; convulsive status epilepticus; nonconvulsive status epilepticus.

Status epilepticus (SE) is a relatively common condition that accounts for 3% to 5% of all emergency department (ED) evaluations for seizure disorders and occurs in 2% to 16% of all epilepsy patients [1]. It remains a major neurological emergency that, if not properly and timely treated, leads to death or permanent neurological injury. Since most of patients with convulsive SE are admitted to the hospital via the ED and are then transferred to the intensive care unit (ICU), our focus in this review will be on the latter.

Although only a handful prospective, randomized studies have been reported, guidelines on SE have been published in Europe [2] and the US [3,4]. In this paper, we review the evolving definition and types of SE, its incidence, etiology, and pathophysiology, its diagnosis and treatment algorithms, and its outcome. Our goal is to provide the reader with a concise but thorough review of this still lethal neurological emergency.

Definitions

The International Classification of Epileptic Seizures had previously defined SE as any seizure lasting ≥ 30 minutes or intermittent seizures lasting for > 30 min without recovery of consciousness interictally [5,6]. More recently, a duration of 5 or more minutes of (a) continuous seizures or (b) 2 or more discrete seizures with incomplete recovery of consciousness in-between, proposed by Lowenstein [3,7], offers the advantage of incorporating new knowledge. The shortening of the convulsive period to 5 minutes was based on the fact that the majority of tonic-clonic seizures last for only 1 to 2 minutes, that those lasting > 5 minutes do not stop spontaneously [8], that permanent neuronal injury occurs before 30 minutes, and that refractoriness to treatment increases with longer seizure duration [9].

Refractory SE (RSE) has been defined as SE not controlled after adequate doses of an initial benzodiazepine followed by a second acceptable antiepileptic drug (AED) or SE not controlled after the initial parenteral therapy with a minimum number of standard “front-line” AEDs (either 2 or 3) or SE with a minimum duration of seizures that persist despite treatment (eg, at least or 2 hours) [3,10]. Super-refractory SE (SRSE) is defined as SE that continues or recurs 24 hours or more after the onset of anesthetic therapy or recurs on the reduction or withdrawal of anesthesia [11].

Non-convulsive SE (NCSE) is defined as the presence of altered consciousness or behavior for ≥ 30 minutes, the absence of overt clinical signs of convulsive activity during that period, and the electroencephalographic (EEG) confirmation of seizures or activity that responds to treatment together with improvement of consciousness [12–15]. Two major types of NCSE can be encountered: the one in patients with epileptic encephalopathy/coma and the one in patients with absence or complex partial seizures, who are not usually admitted to ICU and are functional yet impaired. Because of the confusion between these 2 extremes in the NCSE spectrum, working criteria for standardization of reporting, utilizing the frequency of electroencephalographic epileptiform discharges or delta/theta waveforms have been proposed [15]. A recent compendium of 123 cases of NCSE with clinical descriptions and EEG patterns following a syndromic classification approach has also been published [16].

Types of SE

Three major categories of SE have been described: generalized convulsive SE (GCSE), focal motor SE (FMSE or epilepsia partialis continua [EPC]) of Kojevnikov, and NCSE. GCSE and FMSE are easily recognized due to overt convulsions. NCSE, however, has a more obscure phenotype and can be subdivided into a spectrum encompassing typical absence and complex partial SE, atypical absence SE and tonic SE (usually in children with learning disabilities), epileptic behavioral disturbance and psychosis, including Balint–like syndrome [17], confusional states or delirium with epileptiform discharges) and SE in coma (after significant brain injuries, such as hypoxia-ischemia, most commonly encountered in ICUs) [13,18]. The 2 extremes in this NCSE spectrum have completely different prognoses, with absence SE the most benign and SE in coma the most dismal.

Lastly, SE presents either spontaneously or can be “semi-intentional” iatrogenic, encountered either in the neuro-ICU or epilepsy monitoring unit, when AEDs are withdrawn under continuous EEG recording in order for seizures to emerge and be recorded with surface or intracranial electrodes.

Incidence of SE

In a prospective population-based epidemiological study, the incidence of SE was estimated at 41–61/100,000 patients/year. For the US, this translates to 125,000 to 195,000 episodes per year [19].

The highest incidence of SE occurs during the first year of life and during the decades beyond 60 years, and is also dependent on the SE subtype. Partial SE occurs in 25% of cases of SE and NCSE accounts for another 4% to 26 % [19,20], but the incidence for the latter is considered an underestimate due to the need for continuous EEG monitoring (which is not widely available). For example, NCSE was discovered in no patient with acute stroke [21], 8% of comatose ICU patients [22], 7% of patients with intracerebral hemorrhage [23], 3% to 8% of patients with subarachnoid hemorrhage [24–26], 6% of patients with metastatic cancer [27], and 6% of patients with head trauma [28].

The incidence of RSE and SRSE is also unknown. In a recent retrospective study from a neuro-ICU in a West China hospital, the percentage of non-refractory SE, RSE, and SRSE were 67.3%, 20.4% and 12.2%, respectively [29]. Other retrospective studies have shown that 12% to 43% of SE cases become refractory [30–33] and that approximately 10% to 15% of all cases of hospital-admitted SE will become super-refractory at some point, but no prospective studies have been published.

Risk factors that have been identified for RSE are encephalitis as a cause, severe consciousness impairment, de novo episodes of SE, delay in initiation of treatment, NCSE, and focal motor seizures at onset [30,32,34,35]. In a more recent study from ICU patients in Switzerland and the US, acute SE etiology (traumatic brain injuries, cerebrovascular accidents, meningoencephalitis, brain tumors, surgical brain lesions, exposure to, or withdrawal from, recreational drugs, prescription drugs, alcohol, metabolic disturbances and fever), coma/stupor, and serum albumin < 35 g/L at SE onset were independent predictors for RSE [36].

Etiology of SE

The 3 most common etiologies for SE are low levels of antiepileptic drugs (AEDs) in 34% of the cases (usually due to noncompliance), remote symptomatic etiologies (history of neurological insults remote to the first unprovoked SE episode, 24%), and cerebrovascular accidents (ischemic and hemorrhagic strokes, 22%). These are followed by hypoxia (13%) and metabolic disturbances (15%). Because 82% of patients in the remote group have a history of cerebrovascular disease, almost 50% have either acute or remote cerebrovascular disease as etiology of SE [19].

In general ICUs, metabolic abnormalities can account for 33% of seizures, drug withdrawal for 33%, drug toxicity for 14.5%, and stroke for 9% to 39% [37,38]. In ICUs, sepsis remains a common etiology of electrographic seizures or periodic epileptiform discharges [39,40], and legal or illegal drugs, such as ciprofloxacin, levofloxacin, piperacillin/tazobactam, cefepime and carbapenems [41–43], lithium or theophylline intoxication, vigabatrin, tiagabine or crack/cocaine, are another [18] (especially when their metabolism is altered due to interactions with other drugs or when their excretion is impaired due to hepatic or renal failure).

Beyond these common causes of SE, a workup for rare etiologies should be entertained. In a systematic review of 513 papers on SE, 181 uncommon causes of SE were identified and subdivided into immunologically mediated disorders, mitochondrial diseases, rare infectious disorders, genetic disorders, and drugs or toxins [18,44].

The most recent knowledge in this category is the contribution of paraneoplastic or autoimmune conditions to a large percentage of previously cryptogenic pharmaco-resistant seizures or super-refractory SE, most in the context of limbic encephalitis. Many of these patients have never experienced seizures or SE before and a new acronym has been devised for them: new-onset refractory status epilepticus (NORSE), ie, a state of persistent seizures with no identifiable etiology in patients without preexisting epilepsy that lasts longer than 24 hour despite optimal therapy [45]. A growing array of autoantibodies against intracellular and surface or synaptic neuronal targets has been described in addition to the previous literature of Rassmussen’s encephalitis and Hashimoto’s encephalopathy [46]. The most common autoantibodies associated with seizures and SE include anti-Hu, anti-Ma2, anti-CV2/CRMP5, anti-Ri, ANNA3, anti-amphiphysin, anti-NMDA receptor, anti-LGI1 and CASPR2, anti-GABA-beta, anti-GluR3, anti-mGluR5 and alpha 3 ganglionic acetylcholine receptor [47,48]. The diagnosis frequently remains elusive due to lack of knowledge or absence of widespread availability of serologic testing (with sometimes weeks-long delay for the results to be available), but the response to treatment with removal of tumor, plasmapheresis, or immunomodulation and immunosuppression is often dramatic.

Pathophysiology of SE

Most seizures are self-terminating phenomena lasting from a few seconds to a few minutes [49]. One of the distinguishing characteristics of seizures evolving into SE, however, is the switch to a self-sustaining situation, which is time-dependent. Seizures lasting more than 30 minutes would rarely stop spontaneously compared to 47% of those lasting between 10 to 29 minutes, which are self-resolving [50]. Moreover, in one study no self-limited seizure lasted more than 11 minutes [8].

The self-limiting character of seizures is due to inhibitory circuitry that suppresses their duration and propagation in the brain. Under specific circumstances, however, the inhibitory mechanisms fail and seizures progress to SE, which leads to synaptic reorganization, blood-brain barrier disruption, inflammation, metabolic crisis, more tissue damage, and further seizures. Neuronal injury during SE is the result of increased excitotoxicity [51–53] but also stems from systemic derangements such as hypoxia, acidosis, hypotension, or multiorgan dysfunction [54]. The seminal animal studies by Meldrum have shed a light on the systemic effects: after prolonged bicuculine-induced convulsive SE in baboons, neuronal damage and cell loss was evident in the neocortex, cerebellum and hippocampus. When systemic factors were kept within normal physiological limits (paralyzed and artificially ventilated animals with adequate serum glucose levels), there was decreased but still present neocortical and hippocampal cell damage, but absent cerebellar cell injury [55,56]. These experiments showed more than 40 years ago that the seizure activity per se is responsible for the neuronal damage and the systemic derangements play an additional role.

The direct neuronal injury as a result of the ongoing seizures, the perpetuation of seizures into SE, the resistance to treatment and the refractoriness that ensues have also been elucidated at a molecular level during the last decades. Initially, the g-aminobutyric acid (GABA) inhibitory circuits may be deficient and this is the reason why benzodiazepines or barbiturates, which work through GABAergic receptor agonism, are very effective during this early period. As time passes however, GABA receptors undergo a significant shift in their ability to respond to benzodiazepines [57,58]. This is due to changes in receptor presence at the inhibitory synapse, a phenomenon that has been called “receptor trafficking” by Arancibia and Kittler in 2009 [59]. There are differences in the type of GABA_A receptors found synaptically and extrasynaptically. GABA_A receptors containing the γ subunit are located synaptically and mediate phasic inhibition. Conversely, the δ subunit-containing GABA_A receptors are located exclusively extrasynaptically and mediate tonic inhibition [60,61]. Smith and Kittler described the highly dynamic state of receptor presence on the surface of axons and explained how receptors move laterally from extrasynaptic sites to the synapse and then out of it to be internalized and either recycled to the surface or degraded [62]. This “receptor trafficking” intensifies during SE, and the overall effect becomes a reduction in the number of functional GABA_A receptors in the synapses. As GABA is the principle inhib-itory transmitter, this reduction in GABAergic activity may be an important reason for seizures to become persistent.

However, this is not all. Additional mechanisms leading to refractoriness include the following:

(a) Excessive relocation of N-methyl-D-aspartate (NMDA)type glutamate receptors to the cell surface after 1 hour of SE, leading to increase of miniature excitatory NMDA currents and NMDA neurotransmission, with potentiation of glutamate excitotoxicity [53,63]

(b) Increased brain expression of drug efflux transporters, such as P-glycoprotein at the blood-brain barrier, which may reduce concentrations of AEDs at their brain targets [64]

(c) Up- and down-regulation of specific ATP-gated ion channels (P2X receptors) inducing altered response to ATP release [65]

(d) Change in the extracellular ionic environment (for example, the normally inhibitory GABA_A receptor-mediated currents may become excitatory with changes in extracellular chloride concentrations) [66]

(e) Mitochondrial insufficiency or failure, which would lead to cell necrosis and apoptosis [67]

(f) Inflammatory processes, with opening of the blood-brain barrier (BBB) contributing to perpetuation of seizures [44]. The underlying mechanism is a maladaptive response of the astrocytes to the BBB damage, leading to activation of the innate immune system and disturbed homeostasis of the extracellular potassium and glutamate [68].

(g) Large-scale changes in gene expression within the affected brain regions; these are regulated by micro-RNAs, influencing protein levels playing a role in excitability, neuronal death and neuroinflammation [69].

All of these pathophysiologic derangements may become targets for future antiepileptic treatments.

Although the direct and indirect injury from ongoing convulsive SE is not in doubt, the significance of NCSE or the ictal-interictal continuum on inflicting additional injury has been more controversial. Recent data, however, do not support a benign process in these situations. It has been shown lately that nonconvulsive seizures lead to physiologic changes in the brain, including elevated intracranial pressure, changes in the brain metabolism, and delayed increase in cerebral blood flow [25]. In addition, using microdialysis, elevated lactate/puruvate ratio, indicating metabolic crisis, has been shown during periods of nonconvulsive seizures or periodic discharges [70]. Similarly, high-frequency periodic discharges lead to inadequate increase in cerebral blood flow and tissue hypoxia [71], and lateralized periodic discharges, lateralized rhythmic delta activity, and generalized periodic discharges are associated with seizures [72].

Diagnosis of SE

The diagnosis of SE is primarily clinical and encompasses motor phenomena and alteration of mental status. Focal-onset convulsions can remain focal, follow a Jacksonian march, or immediately generalize to involve the whole body with loss of consciousness. Most of the time, this secondary generalization can only be appreciated during EEG recording. In addition, mental status alteration can differentiate simple partial SE (no change in mental status) from complex partial SE (disturbed sensorium).

The presence or absence of motor phenomena and loss of consciousness do not necessarily correlate with the EEG activity during or after SE. For example, persistent electrographic seizures or NCSE after control of convulsive SE have been demonstrated with continuous EEG [73]. Conversely, altered mental status is also a poor clinical differentiator, since 87% of patients successfully treated for convulsive SE and 100% treated for NCSE remained comatose 12 hours following the initiation of therapy [20]. In addition, only 27% of motor, seizure-like phenomena in the ICU were proven to be seizures in a retrospective study [74]. Psychogenic nonepileptic attacks, occurring in between 3.8% and 9.5% of ICU patients presenting with seizures [74,75], is another situation that may lead to confusion, inappropriate intubation, and ICU admission. Strange phenomena, such as fasciobrachial seizures (brief facial grimacing and ipsilateral arm posturing) many times preceding the onset of amnesia, confusion, or temporal lobe seizures have been described in patients who have non-paraneoplastic limbic encephalitis associated with voltage-gated potassium channel (VGKC) antibodies, especially against the leucine-rich glioma inactivated-1 (LGI1) protein [76,77].Without a continuous video EEG, these phenomena may not be captured or appreciated. Therefore, EEG monitoring is an important tool for the evaluation of these patients and criteria for its use have been published [78]. The EEG criteria for convulsive SE have been clearly delineated, but for NCSE a mix of clinical and EEG criteria should be met [14,15,79].

In addition to clinical observation and EEG, there has been interest lately in multimodality monitoring of acutely brain-injured patients for seizures or SE using electrocorticography or mini depth electrode placement, partial brain tissue oxygen tension, cerebral blood flow, and microdialysis in addition to scalp EEG. Although preliminary and limited in few academic centers, this approach has produced interesting findings. For example, in a study from Columbia University, 38% of 48 patients with subarachnoid hemorrhage and multimodality monitoring had intracortical seizures, while only 8% of them had surface seizures, all nonconvulsive [25]. In another study, 68% of seizures and 23% of periodic discharges were only captured on the depth electrodes and were missed on the surface ones [71]. Therefore, detection of SE may change in the future with use of more sensitive techniques than scalp EEG.

Treatment

Significant practice variations exist in the management of SE even among academic centers in the US [80] despite the fact that the goals of treatment are concrete. These include (1) emergent medical management, (2) termination of seizures, (3) prevention of recurrence of seizures, and (4) prevention or treatment of complications.

Management of SE must begin in a prehospital setting by the emergency medical services, because the faster the treatment is offered, the better the response. Several studies have attempted to assess the possibility of aborting SE even prior to the hospital. In a randomized, double-blinded study, lorazepam was 4.8 times and diazepam 2.3 times more effective than placebo in terminating SE on arrival in the ED when given intravenously (IV) by paramedics [81]. The RAMPART study was a double-blind, randomized, non-inferiority trial comparing the efficacy of intramuscular (IM) midazolam (10 mg followed by placebo IV) with that of IM placebo followed by intravenous lorazepam (4 mg) for children and adults in SE treated by paramedics. At the time of arrival in the ED, seizures had ceased without rescue therapy in 73.4% and 63.4%, respectively, favoring midazolam [82].

Emergent Initial Phase

During the emergent initial phase, the goals are protection of the airway, oxygenation, maintenance of blood pressure, exclusion of easily 

Urgent Control

If seizures continue, stage 2 medications should be used for benzodiazepine-refractory SE as urgent control treatment. There are some data suggesting better response rate to valproate after failure to control seizures with phenytoin than to phenytoin after failure of valproate [88]. If available, IV fosphenytoin is preferable to IV phenytoin due to potentially lower risk of side effects. Levetiracetam and phenobarbital IV are also acceptable choices. Levetiracetam can be administered as an off-label loading dose of 20–60 mg/kg IV (although the initial manufacturer was not supporting a “loading” dose; dose of up to 60 mg/kg IV up to 4500 mg maximum has been supported by the latest American Epilepsy Society guidelines [4]). This AED at an initial dose of 2–3 g/day confers an estimated success rate around 70% [89]. In a systematic review of 27 studies (798 cases of convulsive SE) comparing 5 AEDs in the treatment of benzodiazepine-resistant convulsive SE, phenobarbital and valproate had the highest efficacy (73.6% and 75.7%, respectively), followed by levetiracetam (68.5%) and phenytoin (50.2%). Lacosamide studies were excluded from the meta-analysis due to insufficient data [90], but its efficacy has been reported for patients with convulsive and NCSE [91,92]. There is not enough evidence at this point, however, to recommend its routine use for benzodiazepine refractory SE [90].

Refractory SE

When seizures continue despite the use of benzodiazepines and 2nd stage AEDs, SE becomes refractory (stage 3). Treatment of these resistant cases is frequently initiated in the ED and continued in an ICU. Outcomes were not significantly better in patients with SE admitted and managed in a neuro-ICU compared to a general medical ICU in a retrospective study, but the numbers were small (only 27% of SE were admitted to the former) [93] and this may change in the future. Intubation and mechanical ventilation is the first step, if not already present (only 21% of patients in the RAMPART study received endotracheal intubation, with 6.4% in the prehospital setting and 93.6% after admission [87]). Hemodynamic support with pressors or inotropes may be required as most anesthetic agents may decrease the blood pressure. Because of the urgency of controlling the seizures during SE, the potential aspiration risk and the questionable enteral absorption per os administration of additional AEDs is problematic, and IV formulations should be used.

Currently in the US, phenytoin, valproic acid, phenobarbital, levetiracetam, lacosamide, diazepam, lorazepam are available in IV formulations. In February 2016, the FDA also approved brivaracetam (which also is available in an IV formulation) and in October of the same year IV carbamazepine. None of these AEDs has an FDA indication for SE, although they are widely used. Parenteral lacosamide has a success rate of 33% to 67.7% (200–400 mg over 3–5 min was the most common bolus dose) depending on its use as second or third AED [94–96]. In lacosamide-naive patients with RSE on continuous EEG monitoring, the success rate for cessation of SE was 15.7, 25.5, 58.8, and 82.4 % by 4, 12, 24, and 48 hours, respectively [97]. Alternatively, topiramate in doses 300–1600 mg/day per oro/nasogastric tube can be considered [98]. In a study of 35 patients with RSE treated with topiramate as an adjunct AED, the response rate was 86% (as the third AED), and remained stable at 67% after administration as the fourth to seventh AED. Overall, RSE was terminated in 71% of patients within 72 hours after first administration of topiramate [99]. Other studies, however, adjusting for co-variates, did not prove topiramate to be effective in RSE [100]. Clobazam, a unique oral 1,5-benzodiazepine with excellent absorption, has been also used in the treatment of RSE. Seventeen patients with RSE (11 with prior epilepsy) were successfully treated with clobazam, which was introduced after a median duration of 4 days and after a median of 3 failed AEDs. Termination of RSE within 24 hours of administration, without addition or modification of concurrent AED and with successful wean of anesthetic infusions, was seen in 13 patients, whereas indeterminate response was seen in another 3. Clobazam was deemed unsuccessful in 1 patient [101]. In another recent report of 70 episodes of RSE, clobazam was used in 24 (34.3%) of them. If clobazam was the last AED added to therapy before RSE termination, the success was attributed to this drug. Based on this definition, clobazam led to 6 episodes (25%) of successful RSE resolution [102]. If primary or metastatic brain tumor is the presumed cause of SE, a combination of IV phenytoin, IV levetiracetam (median dose 3 g/d) and enterically administered pregabalin (median dose 375 mg/day) led to 70% control of SE on average 24 hours after addition of the third AED [103]. However, the major treatment options, which should not be delayed in unresponsive RSE, are propofol or midazolam infusions at high rates and under continuous EEG monitoring. These infusions should be continued for at least 24 hours and then held to reassess the situation. By that time, cocurrent metabolic derangements and low AED levels from noncompliance should have been corrected. Prolonged and high-dose propofol should be avoided because of the risk for propofol infusion syndrome, especially if pressors/inotropes are co-infused [104].

Super-refractory SE

Should seizures continue or recur, stage 4 options for SRSE are considered [105]. Pentobarbital with shorter half-life is favored to phenobarbital. The main disadvantages of barbiturates are compromised neuro-exam (which has to be assessed frequently), cardiovascular depression and hypotension, respiratory depression with need for full ventilator support, cough suppression with increased risk for atelectasis and pneumonia, immunosuppression increasing the risk for infection or sepsis, immobility increasing the risk for thromboembolism and ileus mandating parenteral nutrition [106,107]. The depth and duration of the EEG suppression that must be achieved by barbiturates is unknown. Some experts recommend instead of burst-suppression pattern complete suppression or “flat record” because of better seizure control and fewer relapses [108]. Moreover, patients with more prolonged barbiturate treatment (> 96 hours) and those receiving phenobarbital at the time of pentobarbital taper are less likely to relapse [109]. European guidelines recommend titration of propofol and barbiturate to EEG burst-suppression, and midazolam to seizure suppression, maintained for at least 24 h [2]. In recent reviews, it was found that barbiturates control refractory and super-refractory SE in 64% of patients and are ineffective in only 5% [11,110].

If SE continues or recurs after emergence from barbiturate coma, ketamine may be an option [11,83]. Ketamine offers the advantage of NMDA receptor antagonism, which may be important in the late phase of SE and lacks cardiodepressant or hypotensive properties. Early [111] or late [112] use of ketamine has been reported in small case series with various success rates. In a recent multicenter retrospective study from North America and Europe, evaluating 58 patients with 60 RSE, ketamine was likely responsible for seizure control in 12% and possibly responsible in an additional 20%. No responses were observed when infusion rate was lower than 0.9 mg/kg/h or when ketamine was introduced 8 days or more after onset of SE or after failure of seven or more drugs [113].

If all these measures have failed, stage 4.2 treatment options are available (Table 2), but these are mostly based on small case series and expert opinions (except for the recent hypothermia study). Pyridoxine hydrochloride in an IV or enteral form at a dose of 100–300 mg/day for few days can be used in stage 4 or earlier stages, as it is a cofactor in the synthesis of the inhibitory neurotransmitter GABA [114]. There are no strong data for its effectiveness, but it can be used as a cheap and safe alternative [115]. Magnesium has been successfully used in 2 girls with juvenile Alper’s syndrome [116] and is the treatment of choice for eclamptic seizures. Ketogenic diet may also be an optionfor these patients [117]. Resection of the epileptic focus after mapping with intracranial EEG electrodes may be highly effective but cannot be used in many patients due to lack of focus or eloquence location [83,106,115]. Use of steroids, plasmapheresis or IVIG, followed by immunosuppression can be tried, but one should balance risks and benefits. These immunosuppressive or immunomodulating treatments should be especially considered in patients with NORSE or suspected autoimmune or paraneoplastic encephalitides, where AEDs usually have no effect [46]. These therapies though often precede the diagnosis, since it takes time for the autoantibody panel results to return and the treating physician has to make a decision to blindly start treatment for SRSE.

There were some promising data regarding hypothermia use in these desperate situations [118,119] until the HYBERNATUS study, conducted in France, was recently published. In this study, 270 patients with convulsive SE were randomized in to hypothermia (32° to 34°C for 24 hours) in addition to standard care or to standard care alone. A Glasgow Outcome Scale score of 5 (primary outcome) occurred in 49% of patients in the hypothermia group and in 43% in the control group (a nonstatistical difference). Secondary outcomes, including mortality at 90 days, RSE on day 1, SRSE and functional sequelae on day 90 were not different except for the rate of progression to EEG-confirmed SE on the first day, which was lower in the hypothermia group (11% vs. 22% in the controls). Adverse events were more frequent in the hypothermia group than in the control group [120].

Additional anecdotal treatments are presented in Table 2, but their efficacy is questionable.

This staged management approach may change in the future to a more physiologic and rational treatment with polytherapy based on synaptic receptor trafficking during SE [63]. For example, in an animal model of severe SE, combinations of a benzodiazepine with ketamine and valproate, or with ketamine and brivaracetam, were more effective and less toxic than benzodiazepine monotherapy [121]. Allopregnalonone, a metabolite of progesterone, is an endogenous, naturally occurring neuroactive steroid produced in the ovary, the adrenal cortex and the central nervous system. It is a potent positive allosteric modulator of synaptic and extrasynaptic GABA_A receptors with antiepileptic activity [122]. Neuroactive steroids, such as allopregnanolone, are currently evaluated in SE.

Outcomes

SE still carries significant mortality and morbidity. Distinct variants of SE carry different mortalities, and the range is quite broad: from zero mortality for absence or complex partial SE in ambulatory patients [12], to 19% to 27% 30-day mortality for generalized tonic-clonic SE [20,123] and to 64.7% 30-day mortality for subtle SE [20]. Variables playing an important role in the outcome are the underlying cause (regarded by most authorities the most important variable), the duration of SE (mortality 32% if persistent for > 1 hour vs 2.7% if < 1 hour), the type of SE, the treatment administered, and the age of the patient (children have better outcomes than adults) [123–125]. The etiology of SE still remains the most important prognostic factor, with alcohol and AED-withdrawal/noncompliance having the best outcomes; structural brain injuries, such as anoxia-ischemia, vascular lesions, or brain tumors, have the worst prognosis.

The most resistant cases pose significant dilemmas regarding the length of treatment using barbiturate coma and the potential for acceptable prognosis or the need to withdraw life support. For RSE, for example, in-hospital mortality is 31.7% and 76.2% of patients reach poor functional outcome. Long-term outcomes are also dismal: at 1 year post-discharge, 74% are dead or in a state of unresponsive wakefulness, 16% severely disabled, and only 10% have no or minimal disability [126]. Duration of drug-induced coma, arrhythmias requiring intervention, and pneumonia are associated with poor functional outcome, whereas prolonged mechanical ventilation with mortality and seizure control without burst-suppression or isoelectric EEG are associated with good functional outcome [127,128].

Treatment with barbiturates may contribute to these outcomes, although it is very challenging to prove causality in such a complex and prolonged ICU environment. Some data have shed light towards that direction: in a recent retrospective study of 171 patients with SE, of which 37% were treated with IV anesthetic drugs, there was a higher risk for infections and a 2.9-fold relative risk for death after adjustment for confounders in the group treated with IV anesthetics compared to the group without these agents [129].

The SE Severity Score (STESS, range 0–6) is a prognostic score for survival [130] and can be used as a scaffold for discussions with families and covariate adjustment tool for research. A favorable score of 0–2 has a negative predictive value of 0.97 for survival and likelihood to return to baseline clinical condition in survivors, although an unfavorable score (3–6) had a positive predictive value for death of only 0.39 [131].

The risk for recurrence of afebrile SE in a population-based study in Minnesota has been estimated at 31.7% over a 10-year follow-up period. The risk for recurrence was about 25% regardless of the underlying etiology, except in those patients with SE occurring in the setting of a progressive brain disorder (who had a 100% risk). Female gender, generalized (vs partial) SE and lack of response to the first AED after the initial episode of SE were independent factors for recurrence [132].

Conclusion

Despite the use of better diagnostic tools (continuous video EEG), advances in technology in the ICU, and availability of new AEDs, SE still carries significant mortality and morbidity, which depends mainly on age and etiology. The current treatment is still staged, with supportive measures and benzodiazepine administration remaining the mainstay initially and followed by older and newer AEDs and anesthetics for resistant cases. With the advance of pathophysiologic mechanisms elucidation at a molecular/receptor level, combinations of AEDs may become the foundation of future SE control.

Corresponding author: Panayiotis N. Varelas, MD, PhD, FNCS, Division Head, Neuro-Critical Care Service, Henry Ford Hospital, K-11, 2799 W. Grand Blvd., Detroit, MI 48202, [email protected].

Financial disclosures: Dr. Varelas was local principal investigator for a super-refractory status epilepticus study sponsored by Sage Therapeutics.

Author contributions: conception and design, ARR, PNV; analysis and interpretation of data, PNV; drafting of article, PNV; critical revision of the article, ARR, PNV; administrative or technical support, PNV; collection and assembly of data, ARR, PNV.

BOSTON—In an attempt to be supportive, bed partners of patients with insomnia may engage in behaviors that unintentionally perpetuate insomnia, according to preliminary results presented at the 31st Annual Meeting of the Associated Professional Sleep Societies. Bed partners also may make accommodations that affect their own sleep and life outside of work.

“It is possible that partners are unwittingly perpetuating insomnia symptoms in the patient with insomnia,” said Alix Mellor, PhD, a postdoctoral research fellow and coordinator of the Researching Effective Sleep Treatments (REST) project in the School of Psychological Sciences at Monash University in Victoria, Australia. “It is therefore important for more data to be collected to determine whether insomnia treatments may better benefit patients and their partners by proactively assessing and addressing bed partner behaviors in treatment programs.”

Relationship problems and mismatched bedtimes and wake times within couples have been linked to insomnia. Research in disorders such as obsessive–compulsive disorder (OCD) and depression indicates that partners can reinforce maladaptive behaviors inadvertently. No data have documented the specific behaviors engaged in by partners of individuals with insomnia, however, and these behaviors might perpetuate the disorder.

Partners Encouraged Early Bedtimes

In a randomized controlled trial investigating partner-assisted interventions for insomnia, Dr. Mellor and colleagues studied 31 bed partners (14 women) of patients seeking treatment for insomnia. At baseline, partners completed the Family Accommodation Scale for OCD, Beck Anxiety Inventory, and Dyadic Adjustment Scale. Patients with insomnia completed the Insomnia Severity Index and other questionnaires at baseline and kept a sleep diary for one week prior to treatment initiation.

Approximately 74% of bed partners encouraged an early bedtime or late wake time, which directly contradicts the principles of cognitive behavioral therapy for insomnia (CBT-I). In addition, 42% of bed partners encouraged doing other things in bed, such as reading or watching TV, and 35% encouraged naps, caffeine, or reduced daytime activities. About 11% encouraged their partners to take sleep medication or alcohol to improve sleep. About 56% of bed partners reported that their partner becomes distressed when they do not provide assistance with their insomnia.

Half of bed partners adjusted their own sleep. Furthermore, 39% of bed partners adjusted their family routine, and half modified their leisure activities in response to their partners’ insomnia. Approximately 17% modified their work schedule. The bed partners who attempted to be helpful experienced more anxiety, even though the patients with insomnia perceived the relationship to be more satisfying.

Neurologists Could Explain Principles Behind Treatment

“If neurologists are using behavioral interventions like CBT-I, our findings suggest they should ask their patients about a few specific things their partner might do to unintentionally undermine the treatment,” said Sean P.A. Drummond, PhD, Professor of Clinical Neuroscience at Monash University and lead investigator of this study. “The neurologist should take the time to make sure the patient knows why those things are incompatible with treatment and encourage the patient to explain those ideas to the partner. An extra bonus would be if the patient could ask the partner for help in making sure they follow the treatment guidelines.”

Dr. Drummond and colleagues are studying a form of CBT-I that incorporates assistance from a partner. “We are explicitly incorporating the partner into the intervention in an effort to improve outcomes,” said Dr. Drummond.

—Erik Greb

Suggested Reading

Ellis JG, Deary V, Troxel WM. The role of perceived partner alliance on the efficacy of CBT-I: preliminary findings from the Partner Alliance in Insomnia Research Study (PAIRS). Behav Sleep Med. 2015;13(1):64-72.

McCall WV. Cognitive behavioral therapy for insomnia (CBT-I): What is known, and advancing the science by avoiding the pitfalls of the placebo effect. Sleep Med Rev. 2017 May 5 [Epub ahead of print].

Rogojanski J, Carney CE, Monson CM. Interpersonal factors in insomnia: a model for integrating bed partners into cognitive behavioral therapy for insomnia. Sleep Med Rev. 2013;17(1):55-64.

van Straten A, van der Zweerde T, Kleiboer A, et al. Cognitive and behavioral therapies in the treatment of insomnia: A meta-analysis. Sleep Med Rev. 2017 Feb 9 [Epub ahead of print].

BOSTON—In an attempt to be supportive, bed partners of patients with insomnia may engage in behaviors that unintentionally perpetuate insomnia, according to preliminary results presented at the 31st Annual Meeting of the Associated Professional Sleep Societies. Bed partners also may make accommodations that affect their own sleep and life outside of work.

“It is possible that partners are unwittingly perpetuating insomnia symptoms in the patient with insomnia,” said Alix Mellor, PhD, a postdoctoral research fellow and coordinator of the Researching Effective Sleep Treatments (REST) project in the School of Psychological Sciences at Monash University in Victoria, Australia. “It is therefore important for more data to be collected to determine whether insomnia treatments may better benefit patients and their partners by proactively assessing and addressing bed partner behaviors in treatment programs.”

Relationship problems and mismatched bedtimes and wake times within couples have been linked to insomnia. Research in disorders such as obsessive–compulsive disorder (OCD) and depression indicates that partners can reinforce maladaptive behaviors inadvertently. No data have documented the specific behaviors engaged in by partners of individuals with insomnia, however, and these behaviors might perpetuate the disorder.

Partners Encouraged Early Bedtimes

In a randomized controlled trial investigating partner-assisted interventions for insomnia, Dr. Mellor and colleagues studied 31 bed partners (14 women) of patients seeking treatment for insomnia. At baseline, partners completed the Family Accommodation Scale for OCD, Beck Anxiety Inventory, and Dyadic Adjustment Scale. Patients with insomnia completed the Insomnia Severity Index and other questionnaires at baseline and kept a sleep diary for one week prior to treatment initiation.

Approximately 74% of bed partners encouraged an early bedtime or late wake time, which directly contradicts the principles of cognitive behavioral therapy for insomnia (CBT-I). In addition, 42% of bed partners encouraged doing other things in bed, such as reading or watching TV, and 35% encouraged naps, caffeine, or reduced daytime activities. About 11% encouraged their partners to take sleep medication or alcohol to improve sleep. About 56% of bed partners reported that their partner becomes distressed when they do not provide assistance with their insomnia.

Half of bed partners adjusted their own sleep. Furthermore, 39% of bed partners adjusted their family routine, and half modified their leisure activities in response to their partners’ insomnia. Approximately 17% modified their work schedule. The bed partners who attempted to be helpful experienced more anxiety, even though the patients with insomnia perceived the relationship to be more satisfying.

Neurologists Could Explain Principles Behind Treatment

“If neurologists are using behavioral interventions like CBT-I, our findings suggest they should ask their patients about a few specific things their partner might do to unintentionally undermine the treatment,” said Sean P.A. Drummond, PhD, Professor of Clinical Neuroscience at Monash University and lead investigator of this study. “The neurologist should take the time to make sure the patient knows why those things are incompatible with treatment and encourage the patient to explain those ideas to the partner. An extra bonus would be if the patient could ask the partner for help in making sure they follow the treatment guidelines.”

Dr. Drummond and colleagues are studying a form of CBT-I that incorporates assistance from a partner. “We are explicitly incorporating the partner into the intervention in an effort to improve outcomes,” said Dr. Drummond.

—Erik Greb

Suggested Reading

Ellis JG, Deary V, Troxel WM. The role of perceived partner alliance on the efficacy of CBT-I: preliminary findings from the Partner Alliance in Insomnia Research Study (PAIRS). Behav Sleep Med. 2015;13(1):64-72.

McCall WV. Cognitive behavioral therapy for insomnia (CBT-I): What is known, and advancing the science by avoiding the pitfalls of the placebo effect. Sleep Med Rev. 2017 May 5 [Epub ahead of print].

Rogojanski J, Carney CE, Monson CM. Interpersonal factors in insomnia: a model for integrating bed partners into cognitive behavioral therapy for insomnia. Sleep Med Rev. 2013;17(1):55-64.

van Straten A, van der Zweerde T, Kleiboer A, et al. Cognitive and behavioral therapies in the treatment of insomnia: A meta-analysis. Sleep Med Rev. 2017 Feb 9 [Epub ahead of print].

BOSTON—In an attempt to be supportive, bed partners of patients with insomnia may engage in behaviors that unintentionally perpetuate insomnia, according to preliminary results presented at the 31st Annual Meeting of the Associated Professional Sleep Societies. Bed partners also may make accommodations that affect their own sleep and life outside of work.

“It is possible that partners are unwittingly perpetuating insomnia symptoms in the patient with insomnia,” said Alix Mellor, PhD, a postdoctoral research fellow and coordinator of the Researching Effective Sleep Treatments (REST) project in the School of Psychological Sciences at Monash University in Victoria, Australia. “It is therefore important for more data to be collected to determine whether insomnia treatments may better benefit patients and their partners by proactively assessing and addressing bed partner behaviors in treatment programs.”

Relationship problems and mismatched bedtimes and wake times within couples have been linked to insomnia. Research in disorders such as obsessive–compulsive disorder (OCD) and depression indicates that partners can reinforce maladaptive behaviors inadvertently. No data have documented the specific behaviors engaged in by partners of individuals with insomnia, however, and these behaviors might perpetuate the disorder.

Partners Encouraged Early Bedtimes

In a randomized controlled trial investigating partner-assisted interventions for insomnia, Dr. Mellor and colleagues studied 31 bed partners (14 women) of patients seeking treatment for insomnia. At baseline, partners completed the Family Accommodation Scale for OCD, Beck Anxiety Inventory, and Dyadic Adjustment Scale. Patients with insomnia completed the Insomnia Severity Index and other questionnaires at baseline and kept a sleep diary for one week prior to treatment initiation.

Approximately 74% of bed partners encouraged an early bedtime or late wake time, which directly contradicts the principles of cognitive behavioral therapy for insomnia (CBT-I). In addition, 42% of bed partners encouraged doing other things in bed, such as reading or watching TV, and 35% encouraged naps, caffeine, or reduced daytime activities. About 11% encouraged their partners to take sleep medication or alcohol to improve sleep. About 56% of bed partners reported that their partner becomes distressed when they do not provide assistance with their insomnia.

Half of bed partners adjusted their own sleep. Furthermore, 39% of bed partners adjusted their family routine, and half modified their leisure activities in response to their partners’ insomnia. Approximately 17% modified their work schedule. The bed partners who attempted to be helpful experienced more anxiety, even though the patients with insomnia perceived the relationship to be more satisfying.

Neurologists Could Explain Principles Behind Treatment

“If neurologists are using behavioral interventions like CBT-I, our findings suggest they should ask their patients about a few specific things their partner might do to unintentionally undermine the treatment,” said Sean P.A. Drummond, PhD, Professor of Clinical Neuroscience at Monash University and lead investigator of this study. “The neurologist should take the time to make sure the patient knows why those things are incompatible with treatment and encourage the patient to explain those ideas to the partner. An extra bonus would be if the patient could ask the partner for help in making sure they follow the treatment guidelines.”

Dr. Drummond and colleagues are studying a form of CBT-I that incorporates assistance from a partner. “We are explicitly incorporating the partner into the intervention in an effort to improve outcomes,” said Dr. Drummond.

—Erik Greb

Suggested Reading

Ellis JG, Deary V, Troxel WM. The role of perceived partner alliance on the efficacy of CBT-I: preliminary findings from the Partner Alliance in Insomnia Research Study (PAIRS). Behav Sleep Med. 2015;13(1):64-72.

McCall WV. Cognitive behavioral therapy for insomnia (CBT-I): What is known, and advancing the science by avoiding the pitfalls of the placebo effect. Sleep Med Rev. 2017 May 5 [Epub ahead of print].

Rogojanski J, Carney CE, Monson CM. Interpersonal factors in insomnia: a model for integrating bed partners into cognitive behavioral therapy for insomnia. Sleep Med Rev. 2013;17(1):55-64.

van Straten A, van der Zweerde T, Kleiboer A, et al. Cognitive and behavioral therapies in the treatment of insomnia: A meta-analysis. Sleep Med Rev. 2017 Feb 9 [Epub ahead of print].

BOSTON—Midlife shift work is associated with an increased risk of incident dementia in later life, according to research presented at the 31st Annual Meeting of the Associated Professional Sleep Societies. The association is stronger with longer duration of shift work, said Kathleen Bokenberger, a doctoral student in the Department of Medical Epidemiology and Biostatistics at the Karolinska Institutet in Stockholm.

“To the best of our knowledge, this is the first study to find a connection between shift work and greater dementia incidence,” said Ms. Bokenberger. “As such, we will need confirmation from other studies, especially if they have more nuanced measures of shift work, and perhaps repeated measures of shift work.”

An Analysis of Two Population-Based Cohorts

Shift work interferes with the circadian and homeostatic regulation of sleep and can lead to insomnia and excessive sleepiness. A prospective Danish study found that rotating and evening shift work were associated with increased dementia mortality, but the link between shift work and dementia is still relatively unexplored, said Ms. Bokenberger.

She and her colleagues followed two population-based cohorts from the Swedish Twin Registry. The first cohort, which the researchers called STR-1973, included 13,283 people who were age 30 or older when they received a mailed questionnaire in 1973 that elicited information about shift work status and duration. The Screening Across the Lifespan Twin (SALT) sample included 41,199 participants who participated in a telephone interview between 1998 and 2002 that asked about status and duration of night work history.

The primary outcome was all-cause dementia, and dementia diagnoses were obtained from Swedish national health registers. Investigators followed participants until the date of dementia diagnosis, death, or the end of follow-up in 2015.

A Dose-Response Relationship

The mean age at baseline was 38 in the STR-1973 cohort and 58 in the SALT cohort. Median follow-up time was 41 years in the STR-73 cohort and 14 years in the SALT cohort. The proportion of participants with shift work history was 17% in the STR-1973 cohort. The proportion of people who worked nights was 30% in the SALT cohort. Dementia incidence was 7.4% in the STR-1973 cohort and 5.0% in the SALT cohort.

The researchers used Cox proportional hazard models to analyze the data and adjust for age, sex, education, cardiovascular disease, stroke, and type 2 diabetes. Having shift work versus day work was associated with an increased hazard of dementia (hazard ratio [HR], 1.40), as was having night work versus day work (HR, 1.13). Spline models indicated modest dose-response relationships in which longer duration of shift work and night work predicted greater dementia risk.

Information about APOE e4 genotype was available for subsamples of both cohorts. APOE e4 seemed to be an effect modifier for the association of night work and dementia, but not for that of shift work and dementia. APOE e4 carriers with 20 or more years of shift work had a fourfold increased risk of dementia. APOE e4 carriers with 20 or more years of night work had a twofold increased risk of dementia. The sample sizes were small, however, and “it is possible that these findings are spurious,” said Ms. Bokenberger.

“Individuals in the labor force might consider minimizing shift work exposure or managing work scheduling practices, but this is dependent on individual differences and tolerances to certain types of shift work,” she concluded.

—Erik Greb

Suggested Reading

Bokenberger K, Ström P, Dahl Aslan AK, et al. Shift work and cognitive aging: a longitudinal study. Scand J Work Environ Health. 2017 Mar 31 [Epub ahead of print].

Jørgensen JT, Karlsen S, Stayner L, et al. Shift work and overall and cause-specific mortality in the Danish nurse cohort. Scand J Work Environ Health. 2017;43(2):117-126.

BOSTON—Midlife shift work is associated with an increased risk of incident dementia in later life, according to research presented at the 31st Annual Meeting of the Associated Professional Sleep Societies. The association is stronger with longer duration of shift work, said Kathleen Bokenberger, a doctoral student in the Department of Medical Epidemiology and Biostatistics at the Karolinska Institutet in Stockholm.

“To the best of our knowledge, this is the first study to find a connection between shift work and greater dementia incidence,” said Ms. Bokenberger. “As such, we will need confirmation from other studies, especially if they have more nuanced measures of shift work, and perhaps repeated measures of shift work.”

An Analysis of Two Population-Based Cohorts

Shift work interferes with the circadian and homeostatic regulation of sleep and can lead to insomnia and excessive sleepiness. A prospective Danish study found that rotating and evening shift work were associated with increased dementia mortality, but the link between shift work and dementia is still relatively unexplored, said Ms. Bokenberger.

She and her colleagues followed two population-based cohorts from the Swedish Twin Registry. The first cohort, which the researchers called STR-1973, included 13,283 people who were age 30 or older when they received a mailed questionnaire in 1973 that elicited information about shift work status and duration. The Screening Across the Lifespan Twin (SALT) sample included 41,199 participants who participated in a telephone interview between 1998 and 2002 that asked about status and duration of night work history.

The primary outcome was all-cause dementia, and dementia diagnoses were obtained from Swedish national health registers. Investigators followed participants until the date of dementia diagnosis, death, or the end of follow-up in 2015.

A Dose-Response Relationship

The mean age at baseline was 38 in the STR-1973 cohort and 58 in the SALT cohort. Median follow-up time was 41 years in the STR-73 cohort and 14 years in the SALT cohort. The proportion of participants with shift work history was 17% in the STR-1973 cohort. The proportion of people who worked nights was 30% in the SALT cohort. Dementia incidence was 7.4% in the STR-1973 cohort and 5.0% in the SALT cohort.

The researchers used Cox proportional hazard models to analyze the data and adjust for age, sex, education, cardiovascular disease, stroke, and type 2 diabetes. Having shift work versus day work was associated with an increased hazard of dementia (hazard ratio [HR], 1.40), as was having night work versus day work (HR, 1.13). Spline models indicated modest dose-response relationships in which longer duration of shift work and night work predicted greater dementia risk.

Information about APOE e4 genotype was available for subsamples of both cohorts. APOE e4 seemed to be an effect modifier for the association of night work and dementia, but not for that of shift work and dementia. APOE e4 carriers with 20 or more years of shift work had a fourfold increased risk of dementia. APOE e4 carriers with 20 or more years of night work had a twofold increased risk of dementia. The sample sizes were small, however, and “it is possible that these findings are spurious,” said Ms. Bokenberger.

“Individuals in the labor force might consider minimizing shift work exposure or managing work scheduling practices, but this is dependent on individual differences and tolerances to certain types of shift work,” she concluded.

—Erik Greb

Suggested Reading

Bokenberger K, Ström P, Dahl Aslan AK, et al. Shift work and cognitive aging: a longitudinal study. Scand J Work Environ Health. 2017 Mar 31 [Epub ahead of print].

Jørgensen JT, Karlsen S, Stayner L, et al. Shift work and overall and cause-specific mortality in the Danish nurse cohort. Scand J Work Environ Health. 2017;43(2):117-126.

BOSTON—Midlife shift work is associated with an increased risk of incident dementia in later life, according to research presented at the 31st Annual Meeting of the Associated Professional Sleep Societies. The association is stronger with longer duration of shift work, said Kathleen Bokenberger, a doctoral student in the Department of Medical Epidemiology and Biostatistics at the Karolinska Institutet in Stockholm.

“To the best of our knowledge, this is the first study to find a connection between shift work and greater dementia incidence,” said Ms. Bokenberger. “As such, we will need confirmation from other studies, especially if they have more nuanced measures of shift work, and perhaps repeated measures of shift work.”

An Analysis of Two Population-Based Cohorts

Shift work interferes with the circadian and homeostatic regulation of sleep and can lead to insomnia and excessive sleepiness. A prospective Danish study found that rotating and evening shift work were associated with increased dementia mortality, but the link between shift work and dementia is still relatively unexplored, said Ms. Bokenberger.

She and her colleagues followed two population-based cohorts from the Swedish Twin Registry. The first cohort, which the researchers called STR-1973, included 13,283 people who were age 30 or older when they received a mailed questionnaire in 1973 that elicited information about shift work status and duration. The Screening Across the Lifespan Twin (SALT) sample included 41,199 participants who participated in a telephone interview between 1998 and 2002 that asked about status and duration of night work history.

The primary outcome was all-cause dementia, and dementia diagnoses were obtained from Swedish national health registers. Investigators followed participants until the date of dementia diagnosis, death, or the end of follow-up in 2015.

A Dose-Response Relationship

The mean age at baseline was 38 in the STR-1973 cohort and 58 in the SALT cohort. Median follow-up time was 41 years in the STR-73 cohort and 14 years in the SALT cohort. The proportion of participants with shift work history was 17% in the STR-1973 cohort. The proportion of people who worked nights was 30% in the SALT cohort. Dementia incidence was 7.4% in the STR-1973 cohort and 5.0% in the SALT cohort.

The researchers used Cox proportional hazard models to analyze the data and adjust for age, sex, education, cardiovascular disease, stroke, and type 2 diabetes. Having shift work versus day work was associated with an increased hazard of dementia (hazard ratio [HR], 1.40), as was having night work versus day work (HR, 1.13). Spline models indicated modest dose-response relationships in which longer duration of shift work and night work predicted greater dementia risk.

Information about APOE e4 genotype was available for subsamples of both cohorts. APOE e4 seemed to be an effect modifier for the association of night work and dementia, but not for that of shift work and dementia. APOE e4 carriers with 20 or more years of shift work had a fourfold increased risk of dementia. APOE e4 carriers with 20 or more years of night work had a twofold increased risk of dementia. The sample sizes were small, however, and “it is possible that these findings are spurious,” said Ms. Bokenberger.

“Individuals in the labor force might consider minimizing shift work exposure or managing work scheduling practices, but this is dependent on individual differences and tolerances to certain types of shift work,” she concluded.

—Erik Greb

Suggested Reading

Bokenberger K, Ström P, Dahl Aslan AK, et al. Shift work and cognitive aging: a longitudinal study. Scand J Work Environ Health. 2017 Mar 31 [Epub ahead of print].

Jørgensen JT, Karlsen S, Stayner L, et al. Shift work and overall and cause-specific mortality in the Danish nurse cohort. Scand J Work Environ Health. 2017;43(2):117-126.

The high costs of endoscopy make screening patients with gastroesophageal reflux disease (GERD) for Barrett’s esophagus a costly endeavor. But using a minimally invasive test followed by endoscopy only if results are positive could cut costs by up to 41%, according to investigators.

The report is in the September issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.02.017).

The findings mirror those from a prior study (Gastroenterology. 2013 Jan;144[1]:62-73.e60) of the new cytosponge device, which tests surface esophageal tissue for trefoil factor 3, a biomarker for Barrett’s esophagus, said Curtis R. Heberle, of Massachusetts General Hospital in Boston, and his associates. In addition, two separate models found the cytosponge strategy cost effective compared with no screening (incremental cost-effectiveness ratios [ICERs], about $26,000-$33,000). However, using the cytosponge instead of screening all GERD patients with endoscopy would reduce quality-adjusted life-years (QALYs) by about 1.8-5.5 years for every 1,000 patients.

Rates of esophageal adenocarcinoma have climbed more than sixfold in the United States in 4 decades, and 5-year survival rates remain below 20%. Nonetheless, the high cost of endoscopy and 10%-20% prevalence of GERD makes screening all patients for Barrett’s esophagus infeasible. To evaluate the cytosponge strategy, the researchers fit data from the multicenter BEST2 study (PLoS Med. 2015 Jan; 12[1]: e1001780) into two validated models calibrated to high-quality Surveillance, Epidemiology and End Results (SEER) data on esophageal cancer. Both models compared no screening with a one-time screen by either endoscopy alone or cytosponge with follow-up endoscopy in the event of a positive test. The models assumed patients were male, were 60 years old, and had GERD but not esophageal adenocarcinoma.

Without screening, there were about 14-16 cancer cases and about 15,077 quality-adjusted life years (QALYs) for every 1,000 patients. The cytosponge strategy was associated with about 8-13 cancer cases and about 15,105 QALYs. Endoscopic screening produced the most benefit overall – only about 7-12 cancer cases, with more than 15,100 QALYs. “However, greater benefits were accompanied by higher total costs,” the researchers said. For every 1,000 patients, no screening cost about $704,000 to $762,000, the cytosponge strategy cost about $1.5 to $1.6 million, and population-wide endoscopy cost about $2.1 to $2.2 million. Thus, the cytosponge method would lower the cost of screening by 37%-41% compared with endoscopically screening all men with GERD. The cytosponge was also cost effective in a model of 60-year-old women with GERD.

Using only endoscopic screening was not cost effective in either model, exceeding a $100,000 threshold of willingness to pay by anywhere from $107,000 to $330,000. The cytosponge is not yet available commercially, but the investigators assumed it cost $182 based on information from the manufacturer (Medtronic) and Medicare payments for similar devices. Although the findings withstood variations in indirect costs and age at initial screening, they were “somewhat sensitive” to variations in costs of the cytosponge and its presumed sensitivity and specificity in clinical settings. However, endoscopic screening only became cost effective when the cytosponge test cost at least $225.

The models assumed perfect adherence to screening, which probably exaggerated the effectiveness of the cytosponge and endoscopic screening, the investigators said. They noted that cytosponge screening can be performed without sedation during a short outpatient visit.

The National Institutes of Health provided funding. The investigators had no relevant disclosures.

The high costs of endoscopy make screening patients with gastroesophageal reflux disease (GERD) for Barrett’s esophagus a costly endeavor. But using a minimally invasive test followed by endoscopy only if results are positive could cut costs by up to 41%, according to investigators.

The report is in the September issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.02.017).

The findings mirror those from a prior study (Gastroenterology. 2013 Jan;144[1]:62-73.e60) of the new cytosponge device, which tests surface esophageal tissue for trefoil factor 3, a biomarker for Barrett’s esophagus, said Curtis R. Heberle, of Massachusetts General Hospital in Boston, and his associates. In addition, two separate models found the cytosponge strategy cost effective compared with no screening (incremental cost-effectiveness ratios [ICERs], about $26,000-$33,000). However, using the cytosponge instead of screening all GERD patients with endoscopy would reduce quality-adjusted life-years (QALYs) by about 1.8-5.5 years for every 1,000 patients.

Rates of esophageal adenocarcinoma have climbed more than sixfold in the United States in 4 decades, and 5-year survival rates remain below 20%. Nonetheless, the high cost of endoscopy and 10%-20% prevalence of GERD makes screening all patients for Barrett’s esophagus infeasible. To evaluate the cytosponge strategy, the researchers fit data from the multicenter BEST2 study (PLoS Med. 2015 Jan; 12[1]: e1001780) into two validated models calibrated to high-quality Surveillance, Epidemiology and End Results (SEER) data on esophageal cancer. Both models compared no screening with a one-time screen by either endoscopy alone or cytosponge with follow-up endoscopy in the event of a positive test. The models assumed patients were male, were 60 years old, and had GERD but not esophageal adenocarcinoma.

Without screening, there were about 14-16 cancer cases and about 15,077 quality-adjusted life years (QALYs) for every 1,000 patients. The cytosponge strategy was associated with about 8-13 cancer cases and about 15,105 QALYs. Endoscopic screening produced the most benefit overall – only about 7-12 cancer cases, with more than 15,100 QALYs. “However, greater benefits were accompanied by higher total costs,” the researchers said. For every 1,000 patients, no screening cost about $704,000 to $762,000, the cytosponge strategy cost about $1.5 to $1.6 million, and population-wide endoscopy cost about $2.1 to $2.2 million. Thus, the cytosponge method would lower the cost of screening by 37%-41% compared with endoscopically screening all men with GERD. The cytosponge was also cost effective in a model of 60-year-old women with GERD.

Using only endoscopic screening was not cost effective in either model, exceeding a $100,000 threshold of willingness to pay by anywhere from $107,000 to $330,000. The cytosponge is not yet available commercially, but the investigators assumed it cost $182 based on information from the manufacturer (Medtronic) and Medicare payments for similar devices. Although the findings withstood variations in indirect costs and age at initial screening, they were “somewhat sensitive” to variations in costs of the cytosponge and its presumed sensitivity and specificity in clinical settings. However, endoscopic screening only became cost effective when the cytosponge test cost at least $225.

The models assumed perfect adherence to screening, which probably exaggerated the effectiveness of the cytosponge and endoscopic screening, the investigators said. They noted that cytosponge screening can be performed without sedation during a short outpatient visit.

The National Institutes of Health provided funding. The investigators had no relevant disclosures.

The high costs of endoscopy make screening patients with gastroesophageal reflux disease (GERD) for Barrett’s esophagus a costly endeavor. But using a minimally invasive test followed by endoscopy only if results are positive could cut costs by up to 41%, according to investigators.

The report is in the September issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.02.017).

The findings mirror those from a prior study (Gastroenterology. 2013 Jan;144[1]:62-73.e60) of the new cytosponge device, which tests surface esophageal tissue for trefoil factor 3, a biomarker for Barrett’s esophagus, said Curtis R. Heberle, of Massachusetts General Hospital in Boston, and his associates. In addition, two separate models found the cytosponge strategy cost effective compared with no screening (incremental cost-effectiveness ratios [ICERs], about $26,000-$33,000). However, using the cytosponge instead of screening all GERD patients with endoscopy would reduce quality-adjusted life-years (QALYs) by about 1.8-5.5 years for every 1,000 patients.

Rates of esophageal adenocarcinoma have climbed more than sixfold in the United States in 4 decades, and 5-year survival rates remain below 20%. Nonetheless, the high cost of endoscopy and 10%-20% prevalence of GERD makes screening all patients for Barrett’s esophagus infeasible. To evaluate the cytosponge strategy, the researchers fit data from the multicenter BEST2 study (PLoS Med. 2015 Jan; 12[1]: e1001780) into two validated models calibrated to high-quality Surveillance, Epidemiology and End Results (SEER) data on esophageal cancer. Both models compared no screening with a one-time screen by either endoscopy alone or cytosponge with follow-up endoscopy in the event of a positive test. The models assumed patients were male, were 60 years old, and had GERD but not esophageal adenocarcinoma.

Without screening, there were about 14-16 cancer cases and about 15,077 quality-adjusted life years (QALYs) for every 1,000 patients. The cytosponge strategy was associated with about 8-13 cancer cases and about 15,105 QALYs. Endoscopic screening produced the most benefit overall – only about 7-12 cancer cases, with more than 15,100 QALYs. “However, greater benefits were accompanied by higher total costs,” the researchers said. For every 1,000 patients, no screening cost about $704,000 to $762,000, the cytosponge strategy cost about $1.5 to $1.6 million, and population-wide endoscopy cost about $2.1 to $2.2 million. Thus, the cytosponge method would lower the cost of screening by 37%-41% compared with endoscopically screening all men with GERD. The cytosponge was also cost effective in a model of 60-year-old women with GERD.

Using only endoscopic screening was not cost effective in either model, exceeding a $100,000 threshold of willingness to pay by anywhere from $107,000 to $330,000. The cytosponge is not yet available commercially, but the investigators assumed it cost $182 based on information from the manufacturer (Medtronic) and Medicare payments for similar devices. Although the findings withstood variations in indirect costs and age at initial screening, they were “somewhat sensitive” to variations in costs of the cytosponge and its presumed sensitivity and specificity in clinical settings. However, endoscopic screening only became cost effective when the cytosponge test cost at least $225.

The models assumed perfect adherence to screening, which probably exaggerated the effectiveness of the cytosponge and endoscopic screening, the investigators said. They noted that cytosponge screening can be performed without sedation during a short outpatient visit.

The National Institutes of Health provided funding. The investigators had no relevant disclosures.

Skin cancer is diagnosed in approximately 5.4 million individuals annually in the United States, more than the total number of breast, lung, colon, and prostate cancers diagnosed per year.¹ It is estimated that 1 in 5 Americans will develop skin cancer during their lifetime.² The 2 most common forms of skin cancer are basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), accounting for 4 million and 1 million cases diagnosed each year, respectively.³ With the increasing incidence of these skin cancers, the use of noninvasive imaging tools for detection and diagnosis has grown.

Ex vivo confocal microscopy is a diagnostic imaging tool that can be used in real-time at the bedside to assess freshly excised tissue for malignancies. It images tissue samples with cellular resolution and within minutes of biopsy or excision. Ex vivo confocal microscopy is a versatile tool that can assist in the diagnosis and management of skin malignancies such as melanoma, BCC, and SCC.

Reflectance vs Fluorescence Mode

Excised lesions can be examined in reflectance or fluorescence mode in great detail but with slightly varying nuclear-to-dermis contrasts depending on the chromophore that is targeted. In reflectance mode (reflectance confocal microscopy [RCM]), melanin and keratin act as endogenous chromophores because of their high refractive index relative to water,^4,5 which allows for the visualization of cellular structures of the skin at low power, as well as microscopic substructures such as melanosomes, cytoplasmic granules, and other cellular organelles at high power. Although an exogenous contrast agent is not required, acetic acid has the capability to highlight nuclei, enhancing the tumor cell-to-dermis contrast in RCM.⁶ Acetic acid is clinically used as a predictor for certain skin and mucosal membrane neoplasms that blanch when exposed to the solution. In the case of RCM, acetic acid increases the visibility of nuclei by inducing the compaction of chromatin. For the acetowhitening to be effective, the sample must be soaked in the solution for a specific amount of time, depending on the concentration.⁷ A concentration between 1% and 10% can be used, but the less concentrated the solution, the longer the time of soaking that is required to achieve sufficiently bright nuclei.⁶

The contrast with acetic acid, however, is quite weak when the tissue is imaged en face, or along the horizontal surface of the sample, due to the collagen in the dermal layer, which has a high reflectance index. This issue is rectified when using the confocal microscope in the fluorescence mode with an exogenous fluorescent dye as a nuclear stain. Fluorescence confocal microscopy (FCM), results in a stronger nuclear-to-dermal contrast because of the role of contrast agents.⁸ The 1000-fold increase in contrast between nuclei and dermis is the result of dye agents that preferentially bind to nuclear DNA, of which acridine orange is the most commonly used.^5,8 Basal cell carcinoma and SCC tumor cells can be visualized with FCM because they appear hyperfluorescent when stained with acridine orange.⁹ The acridine orange–stained cells display bright nuclei, while the cytoplasm and collagen remains dark. A positive feature of acridine orange is that it does not alter the tissue sample during freezing or formalin fixation and thus has no effect on subsequent histopathology that may need to be performed on the sample.¹⁰

High-Resolution Images Aid in Diagnosis

After it is harvested, the tissue sample is soaked in a contrast agent or dye, if needed, depending on the confocal mode to be used. The confocal microscope is then used to take a series of high-resolution individual en face images that are then stitched together to create a final mosaic image that can be up to 12×12 mm.^6,11 With a 200-µm depth visibility, confocal microscopy can capture the cellular structures in the epidermis, dermis, and (if compressed enough) subcutaneous fat in just under 3 minutes.¹²

The images produced through confocal microscopy have an excellent correlation to frozen histological sections and can aid in the diagnosis of many epidermal and dermal malignancies including melanoma, BCC, and SCC. New criteria have been established to aid in the interpretation of the confocal images and identify some of the more common skin cancers.^5,12,13 Basal cell carcinoma samples imaged through fluorescence and reflectance in low-power mode display the distinct nodular patterns with well-demarcated edges, as seen on classical histopathology. In the case of FCM, the cells that make up the tumor display hyperfluorescent areas consistent with nucleated cells that are stained with acridine orange. The main features that identify BCC on FCM images include nuclear pleomorphism and crowding, peripheral palisading, clefting of the basaloid islands, increased nucleus-to-cytoplasm ratio, and the presence of a modified dermis surrounding the mass known as the tumoral stroma^5,12 (Figure).

In addition to fluorescence and a well-defined tumor silhouette, SCC under FCM displays keratin pearls composed of keratinized squames, nuclear pleomorphism, and fluorescent scales in the stratum corneum that are a result of keratin formation.^5,13 The extent of differentiation of the SCC lesion also can be determined by assessing if the silhouette is well defined. A well-defined tumor silhouette is consistent with the diagnosis of a well-differentiated SCC, and vice versa.¹³ Ex vivo RCM also has been shown to be useful in diagnosing malignant melanomas, with melanin acting as an endogenous chromophore. Some of the features seen on imaging include a disarranged epithelium, hyperreflective roundish and dendritic pagetoid cells, and large hyperreflective polymorphic cells in the superficial chorion.¹⁴

Comparison to Conventional Histopathology

Ex vivo confocal microscopy in both the reflectance and fluorescence mode has been shown to perform well compared to conventional histopathology in the diagnosis of biopsy specimens. Ex vivo FCM has been shown to have an overall sensitivity of 88% and specificity of 99% in detecting residual BCC at the margins of excised tissue samples and in the fraction of the time it takes to attain similar results with frozen histopathology.⁹ Ex vivo RCM has been shown to have a higher prognostic capability, with 100% sensitivity and specificity in identifying BCC when scanning the tissue samples en face.¹⁵

Qualitatively, the images produced by RCM and FCM are similar to histopathology in overall architecture. Both techniques enhance the contrast between the epithelium and stroma and create images that can be examined in low as well as high resolution. A substantial difference between confocal microscopy and conventional hematoxylin and eosin–stained histopathology is that the confocal microscope produces images in gray scale. One way to alter the black-and-white images to resemble hematoxylin and eosin–stained slides is through the use of digital staining,¹⁶ which could boost clinical acceptance by physicians who are accustomed to the classical pink-purple appearance of pathology slides and could potentially limit the learning curve needed to read the confocal images.

Application in Mohs Micrographic Surgery

An important clinical application of ex vivo FCM imaging that has emerged is the detection of malignant cells at the excision margins during Mohs micrographic surgery. The use of confocal microscopy has the potential to save time by eliminating the need for tissue fixation while still providing good diagnostic accuracy. Implementing FCM as an imaging tool to guide surgical excisions could provide rapid diagnosis of the tissue, expediting excisions and reconstruction or the Mohs procedure while eliminating patient wait time and the need for frozen histopathology. Ex vivo RCM also has been used to establish laser parameters for CO₂ laser ablation of superficial and early nodular BCC lesions.¹⁷ Other potential uses for ex vivo RCM/FCM could include rapid evaluation of tissue during operating room procedures where rapid frozen sections are currently utilized.

Combining In Vivo and Ex Vivo Confocal Microscopy

Many of the diagnostic guidelines created with the use of ex vivo confocal microscopy have been applied to in vivo use, and therefore the use of both modalities is appealing. In vivo confocal microscopy is a noninvasive technique that has been used to map margins of skin tumors such as BCC and lentigo maligna at the bedside.⁵ It also has been shown to help plan both surgical and nonsurgical treatment modalities and reconstruction before the tumor is excised.¹⁸ This technique also can help the patient understand the extent of the excision and any subsequent reconstruction that may be needed.

Limitations

Ex vivo confocal microscopy used as a diagnostic tool does have some limitations. Its novelty may require surgeons and pathologists to be trained to interpret the images properly and correlate them to conventional diagnostic guidelines. The imaging also is limited to a depth of approximately 200 µm; however, the sample may be flipped so that the underside can be imaged as well, which increases the depth to approximately 400 µm. The tissue being imaged must be fixed flat, which may alter its shape. Complex tissue samples may be difficult to flatten out completely and therefore may be difficult to image. A special mount may be required for the sample to be fixed in a proper position for imaging.⁶

Final Thoughts

Despite some of these limitations, the need for rapid bedside tissue diagnosis makes ex vivo confocal microscopy an attractive device that can be used as an additional diagnostic tool to histopathology and also has been tested in other disciplines, such as breast cancer pathology. In the future, both in vivo and ex vivo confocal microscopy may be utilized to diagnose cutaneous malignancies, guide surgical excisions, and detect lesion progression, and it may become a basis for rapid diagnosis and detection.¹⁹

Skin cancer is diagnosed in approximately 5.4 million individuals annually in the United States, more than the total number of breast, lung, colon, and prostate cancers diagnosed per year.¹ It is estimated that 1 in 5 Americans will develop skin cancer during their lifetime.² The 2 most common forms of skin cancer are basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), accounting for 4 million and 1 million cases diagnosed each year, respectively.³ With the increasing incidence of these skin cancers, the use of noninvasive imaging tools for detection and diagnosis has grown.

Ex vivo confocal microscopy is a diagnostic imaging tool that can be used in real-time at the bedside to assess freshly excised tissue for malignancies. It images tissue samples with cellular resolution and within minutes of biopsy or excision. Ex vivo confocal microscopy is a versatile tool that can assist in the diagnosis and management of skin malignancies such as melanoma, BCC, and SCC.

Reflectance vs Fluorescence Mode

Excised lesions can be examined in reflectance or fluorescence mode in great detail but with slightly varying nuclear-to-dermis contrasts depending on the chromophore that is targeted. In reflectance mode (reflectance confocal microscopy [RCM]), melanin and keratin act as endogenous chromophores because of their high refractive index relative to water,^4,5 which allows for the visualization of cellular structures of the skin at low power, as well as microscopic substructures such as melanosomes, cytoplasmic granules, and other cellular organelles at high power. Although an exogenous contrast agent is not required, acetic acid has the capability to highlight nuclei, enhancing the tumor cell-to-dermis contrast in RCM.⁶ Acetic acid is clinically used as a predictor for certain skin and mucosal membrane neoplasms that blanch when exposed to the solution. In the case of RCM, acetic acid increases the visibility of nuclei by inducing the compaction of chromatin. For the acetowhitening to be effective, the sample must be soaked in the solution for a specific amount of time, depending on the concentration.⁷ A concentration between 1% and 10% can be used, but the less concentrated the solution, the longer the time of soaking that is required to achieve sufficiently bright nuclei.⁶

The contrast with acetic acid, however, is quite weak when the tissue is imaged en face, or along the horizontal surface of the sample, due to the collagen in the dermal layer, which has a high reflectance index. This issue is rectified when using the confocal microscope in the fluorescence mode with an exogenous fluorescent dye as a nuclear stain. Fluorescence confocal microscopy (FCM), results in a stronger nuclear-to-dermal contrast because of the role of contrast agents.⁸ The 1000-fold increase in contrast between nuclei and dermis is the result of dye agents that preferentially bind to nuclear DNA, of which acridine orange is the most commonly used.^5,8 Basal cell carcinoma and SCC tumor cells can be visualized with FCM because they appear hyperfluorescent when stained with acridine orange.⁹ The acridine orange–stained cells display bright nuclei, while the cytoplasm and collagen remains dark. A positive feature of acridine orange is that it does not alter the tissue sample during freezing or formalin fixation and thus has no effect on subsequent histopathology that may need to be performed on the sample.¹⁰

High-Resolution Images Aid in Diagnosis

After it is harvested, the tissue sample is soaked in a contrast agent or dye, if needed, depending on the confocal mode to be used. The confocal microscope is then used to take a series of high-resolution individual en face images that are then stitched together to create a final mosaic image that can be up to 12×12 mm.^6,11 With a 200-µm depth visibility, confocal microscopy can capture the cellular structures in the epidermis, dermis, and (if compressed enough) subcutaneous fat in just under 3 minutes.¹²

The images produced through confocal microscopy have an excellent correlation to frozen histological sections and can aid in the diagnosis of many epidermal and dermal malignancies including melanoma, BCC, and SCC. New criteria have been established to aid in the interpretation of the confocal images and identify some of the more common skin cancers.^5,12,13 Basal cell carcinoma samples imaged through fluorescence and reflectance in low-power mode display the distinct nodular patterns with well-demarcated edges, as seen on classical histopathology. In the case of FCM, the cells that make up the tumor display hyperfluorescent areas consistent with nucleated cells that are stained with acridine orange. The main features that identify BCC on FCM images include nuclear pleomorphism and crowding, peripheral palisading, clefting of the basaloid islands, increased nucleus-to-cytoplasm ratio, and the presence of a modified dermis surrounding the mass known as the tumoral stroma^5,12 (Figure).

In addition to fluorescence and a well-defined tumor silhouette, SCC under FCM displays keratin pearls composed of keratinized squames, nuclear pleomorphism, and fluorescent scales in the stratum corneum that are a result of keratin formation.^5,13 The extent of differentiation of the SCC lesion also can be determined by assessing if the silhouette is well defined. A well-defined tumor silhouette is consistent with the diagnosis of a well-differentiated SCC, and vice versa.¹³ Ex vivo RCM also has been shown to be useful in diagnosing malignant melanomas, with melanin acting as an endogenous chromophore. Some of the features seen on imaging include a disarranged epithelium, hyperreflective roundish and dendritic pagetoid cells, and large hyperreflective polymorphic cells in the superficial chorion.¹⁴

Comparison to Conventional Histopathology

Ex vivo confocal microscopy in both the reflectance and fluorescence mode has been shown to perform well compared to conventional histopathology in the diagnosis of biopsy specimens. Ex vivo FCM has been shown to have an overall sensitivity of 88% and specificity of 99% in detecting residual BCC at the margins of excised tissue samples and in the fraction of the time it takes to attain similar results with frozen histopathology.⁹ Ex vivo RCM has been shown to have a higher prognostic capability, with 100% sensitivity and specificity in identifying BCC when scanning the tissue samples en face.¹⁵

Qualitatively, the images produced by RCM and FCM are similar to histopathology in overall architecture. Both techniques enhance the contrast between the epithelium and stroma and create images that can be examined in low as well as high resolution. A substantial difference between confocal microscopy and conventional hematoxylin and eosin–stained histopathology is that the confocal microscope produces images in gray scale. One way to alter the black-and-white images to resemble hematoxylin and eosin–stained slides is through the use of digital staining,¹⁶ which could boost clinical acceptance by physicians who are accustomed to the classical pink-purple appearance of pathology slides and could potentially limit the learning curve needed to read the confocal images.

Application in Mohs Micrographic Surgery

An important clinical application of ex vivo FCM imaging that has emerged is the detection of malignant cells at the excision margins during Mohs micrographic surgery. The use of confocal microscopy has the potential to save time by eliminating the need for tissue fixation while still providing good diagnostic accuracy. Implementing FCM as an imaging tool to guide surgical excisions could provide rapid diagnosis of the tissue, expediting excisions and reconstruction or the Mohs procedure while eliminating patient wait time and the need for frozen histopathology. Ex vivo RCM also has been used to establish laser parameters for CO₂ laser ablation of superficial and early nodular BCC lesions.¹⁷ Other potential uses for ex vivo RCM/FCM could include rapid evaluation of tissue during operating room procedures where rapid frozen sections are currently utilized.

Combining In Vivo and Ex Vivo Confocal Microscopy

Many of the diagnostic guidelines created with the use of ex vivo confocal microscopy have been applied to in vivo use, and therefore the use of both modalities is appealing. In vivo confocal microscopy is a noninvasive technique that has been used to map margins of skin tumors such as BCC and lentigo maligna at the bedside.⁵ It also has been shown to help plan both surgical and nonsurgical treatment modalities and reconstruction before the tumor is excised.¹⁸ This technique also can help the patient understand the extent of the excision and any subsequent reconstruction that may be needed.

Limitations

Ex vivo confocal microscopy used as a diagnostic tool does have some limitations. Its novelty may require surgeons and pathologists to be trained to interpret the images properly and correlate them to conventional diagnostic guidelines. The imaging also is limited to a depth of approximately 200 µm; however, the sample may be flipped so that the underside can be imaged as well, which increases the depth to approximately 400 µm. The tissue being imaged must be fixed flat, which may alter its shape. Complex tissue samples may be difficult to flatten out completely and therefore may be difficult to image. A special mount may be required for the sample to be fixed in a proper position for imaging.⁶

Final Thoughts

Despite some of these limitations, the need for rapid bedside tissue diagnosis makes ex vivo confocal microscopy an attractive device that can be used as an additional diagnostic tool to histopathology and also has been tested in other disciplines, such as breast cancer pathology. In the future, both in vivo and ex vivo confocal microscopy may be utilized to diagnose cutaneous malignancies, guide surgical excisions, and detect lesion progression, and it may become a basis for rapid diagnosis and detection.¹⁹

Skin cancer is diagnosed in approximately 5.4 million individuals annually in the United States, more than the total number of breast, lung, colon, and prostate cancers diagnosed per year.¹ It is estimated that 1 in 5 Americans will develop skin cancer during their lifetime.² The 2 most common forms of skin cancer are basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), accounting for 4 million and 1 million cases diagnosed each year, respectively.³ With the increasing incidence of these skin cancers, the use of noninvasive imaging tools for detection and diagnosis has grown.

Ex vivo confocal microscopy is a diagnostic imaging tool that can be used in real-time at the bedside to assess freshly excised tissue for malignancies. It images tissue samples with cellular resolution and within minutes of biopsy or excision. Ex vivo confocal microscopy is a versatile tool that can assist in the diagnosis and management of skin malignancies such as melanoma, BCC, and SCC.

Reflectance vs Fluorescence Mode

Excised lesions can be examined in reflectance or fluorescence mode in great detail but with slightly varying nuclear-to-dermis contrasts depending on the chromophore that is targeted. In reflectance mode (reflectance confocal microscopy [RCM]), melanin and keratin act as endogenous chromophores because of their high refractive index relative to water,^4,5 which allows for the visualization of cellular structures of the skin at low power, as well as microscopic substructures such as melanosomes, cytoplasmic granules, and other cellular organelles at high power. Although an exogenous contrast agent is not required, acetic acid has the capability to highlight nuclei, enhancing the tumor cell-to-dermis contrast in RCM.⁶ Acetic acid is clinically used as a predictor for certain skin and mucosal membrane neoplasms that blanch when exposed to the solution. In the case of RCM, acetic acid increases the visibility of nuclei by inducing the compaction of chromatin. For the acetowhitening to be effective, the sample must be soaked in the solution for a specific amount of time, depending on the concentration.⁷ A concentration between 1% and 10% can be used, but the less concentrated the solution, the longer the time of soaking that is required to achieve sufficiently bright nuclei.⁶

The contrast with acetic acid, however, is quite weak when the tissue is imaged en face, or along the horizontal surface of the sample, due to the collagen in the dermal layer, which has a high reflectance index. This issue is rectified when using the confocal microscope in the fluorescence mode with an exogenous fluorescent dye as a nuclear stain. Fluorescence confocal microscopy (FCM), results in a stronger nuclear-to-dermal contrast because of the role of contrast agents.⁸ The 1000-fold increase in contrast between nuclei and dermis is the result of dye agents that preferentially bind to nuclear DNA, of which acridine orange is the most commonly used.^5,8 Basal cell carcinoma and SCC tumor cells can be visualized with FCM because they appear hyperfluorescent when stained with acridine orange.⁹ The acridine orange–stained cells display bright nuclei, while the cytoplasm and collagen remains dark. A positive feature of acridine orange is that it does not alter the tissue sample during freezing or formalin fixation and thus has no effect on subsequent histopathology that may need to be performed on the sample.¹⁰

High-Resolution Images Aid in Diagnosis

After it is harvested, the tissue sample is soaked in a contrast agent or dye, if needed, depending on the confocal mode to be used. The confocal microscope is then used to take a series of high-resolution individual en face images that are then stitched together to create a final mosaic image that can be up to 12×12 mm.^6,11 With a 200-µm depth visibility, confocal microscopy can capture the cellular structures in the epidermis, dermis, and (if compressed enough) subcutaneous fat in just under 3 minutes.¹²

The images produced through confocal microscopy have an excellent correlation to frozen histological sections and can aid in the diagnosis of many epidermal and dermal malignancies including melanoma, BCC, and SCC. New criteria have been established to aid in the interpretation of the confocal images and identify some of the more common skin cancers.^5,12,13 Basal cell carcinoma samples imaged through fluorescence and reflectance in low-power mode display the distinct nodular patterns with well-demarcated edges, as seen on classical histopathology. In the case of FCM, the cells that make up the tumor display hyperfluorescent areas consistent with nucleated cells that are stained with acridine orange. The main features that identify BCC on FCM images include nuclear pleomorphism and crowding, peripheral palisading, clefting of the basaloid islands, increased nucleus-to-cytoplasm ratio, and the presence of a modified dermis surrounding the mass known as the tumoral stroma^5,12 (Figure).

In addition to fluorescence and a well-defined tumor silhouette, SCC under FCM displays keratin pearls composed of keratinized squames, nuclear pleomorphism, and fluorescent scales in the stratum corneum that are a result of keratin formation.^5,13 The extent of differentiation of the SCC lesion also can be determined by assessing if the silhouette is well defined. A well-defined tumor silhouette is consistent with the diagnosis of a well-differentiated SCC, and vice versa.¹³ Ex vivo RCM also has been shown to be useful in diagnosing malignant melanomas, with melanin acting as an endogenous chromophore. Some of the features seen on imaging include a disarranged epithelium, hyperreflective roundish and dendritic pagetoid cells, and large hyperreflective polymorphic cells in the superficial chorion.¹⁴

Comparison to Conventional Histopathology

Ex vivo confocal microscopy in both the reflectance and fluorescence mode has been shown to perform well compared to conventional histopathology in the diagnosis of biopsy specimens. Ex vivo FCM has been shown to have an overall sensitivity of 88% and specificity of 99% in detecting residual BCC at the margins of excised tissue samples and in the fraction of the time it takes to attain similar results with frozen histopathology.⁹ Ex vivo RCM has been shown to have a higher prognostic capability, with 100% sensitivity and specificity in identifying BCC when scanning the tissue samples en face.¹⁵

Qualitatively, the images produced by RCM and FCM are similar to histopathology in overall architecture. Both techniques enhance the contrast between the epithelium and stroma and create images that can be examined in low as well as high resolution. A substantial difference between confocal microscopy and conventional hematoxylin and eosin–stained histopathology is that the confocal microscope produces images in gray scale. One way to alter the black-and-white images to resemble hematoxylin and eosin–stained slides is through the use of digital staining,¹⁶ which could boost clinical acceptance by physicians who are accustomed to the classical pink-purple appearance of pathology slides and could potentially limit the learning curve needed to read the confocal images.

Application in Mohs Micrographic Surgery

An important clinical application of ex vivo FCM imaging that has emerged is the detection of malignant cells at the excision margins during Mohs micrographic surgery. The use of confocal microscopy has the potential to save time by eliminating the need for tissue fixation while still providing good diagnostic accuracy. Implementing FCM as an imaging tool to guide surgical excisions could provide rapid diagnosis of the tissue, expediting excisions and reconstruction or the Mohs procedure while eliminating patient wait time and the need for frozen histopathology. Ex vivo RCM also has been used to establish laser parameters for CO₂ laser ablation of superficial and early nodular BCC lesions.¹⁷ Other potential uses for ex vivo RCM/FCM could include rapid evaluation of tissue during operating room procedures where rapid frozen sections are currently utilized.

Combining In Vivo and Ex Vivo Confocal Microscopy

Many of the diagnostic guidelines created with the use of ex vivo confocal microscopy have been applied to in vivo use, and therefore the use of both modalities is appealing. In vivo confocal microscopy is a noninvasive technique that has been used to map margins of skin tumors such as BCC and lentigo maligna at the bedside.⁵ It also has been shown to help plan both surgical and nonsurgical treatment modalities and reconstruction before the tumor is excised.¹⁸ This technique also can help the patient understand the extent of the excision and any subsequent reconstruction that may be needed.

Limitations

Ex vivo confocal microscopy used as a diagnostic tool does have some limitations. Its novelty may require surgeons and pathologists to be trained to interpret the images properly and correlate them to conventional diagnostic guidelines. The imaging also is limited to a depth of approximately 200 µm; however, the sample may be flipped so that the underside can be imaged as well, which increases the depth to approximately 400 µm. The tissue being imaged must be fixed flat, which may alter its shape. Complex tissue samples may be difficult to flatten out completely and therefore may be difficult to image. A special mount may be required for the sample to be fixed in a proper position for imaging.⁶

Final Thoughts

Despite some of these limitations, the need for rapid bedside tissue diagnosis makes ex vivo confocal microscopy an attractive device that can be used as an additional diagnostic tool to histopathology and also has been tested in other disciplines, such as breast cancer pathology. In the future, both in vivo and ex vivo confocal microscopy may be utilized to diagnose cutaneous malignancies, guide surgical excisions, and detect lesion progression, and it may become a basis for rapid diagnosis and detection.¹⁹

Study Overview

Objective. To examine the heterogeneity in colorectal cancer (CRC) incidence in intermediate-risk patients and the effect of surveillance on CRC incidence.

Design. Retrospective, multicenter cohort study.

Setting and participants. Study patients underwent colonoscopy between 1 January 1990 and 21 December 2010 at 17 hospitals in the United Kingdom. Patients  were eligible for the study if they had a baseline colonoscopy with a newly diagnosed intermediate-risk adenoma. Intermediate-risk adenomas (as defined by the UK guidelines) included 1 to 2 large adenomas ≥ 10 mm or 3 to 4 small adenomas < 10 mm in size. Patients with a history of prior resections, colorectal cancer, inflammatory bowel disease or a family history of CRC were excluded from the study. Patient, procedural, and polyp characteristics were assessed at baseline.

Main outcome measures. The primary outcome was inci-dence of CRC. Additional factors assessed included age at first polyp detection, sex, completeness of colonoscopy, preparation quality, number of adenomas, size of largest adenoma, histology, and location. Proximal polyps were defined as those proximal to the descending colon. Information regarding social history (eg, smoking status) was not available.

Results. The authors identified 253,798 patients who underwent colonoscopy between 1 January 1990 and 21 December 2010. Of those, 223,539 were excluded based on not meeting the pre-specified inclusion criteria, resulting in 30,259 eligible patients for analysis. Review of histological data confirmed intermediate-risk adenomas in 11,995 (40%) of the patients. The median age in this study was 66 years and 55% were men. Fifty-eight percent attended 1 or more follow-up surveillance visits while 42% had no follow-up surveillance colonoscopy. Those who attended more than 1 follow-up surveillance visits were younger, had a greater proportion of large adenomas (> 20 mm), or had an adenoma with high-grade dysplasia. Both groups had similar rates of villous histology (9% vs. 10%).

After a median follow-up of 7.9 years, 210 CRCs were diagnosed and 32% of patients died. In the group with no follow-up surveillance, 46% died and 2% were diagnosed with cancer. In the group who had 1 or more follow-up colonoscopies, 21% died and 1% were diagnosed with cancer. One or 2 surveillance visits were associated with a significant reduction in CRC incidence (HR 0.57 [95% confidence interval {CI} 0.4–0.8) and 0.51 [95% CI 0.31–0.84], respectively). Three or more surveillance exams were also associated with a similar reduction in CRC incidence (HR 0.54; CI 0.29–0.99). Characteristics associated with increased CRC incidence were older age, adenomas > 20 mm, high-grade dysplasia, proximal polyps, and colonoscopies that were either incomplete or with poor preparation. The number of adenomas was not independently associated with CRC incidence.

The authors divided the cohort into higher-risk (74%) and lower-risk (26%)  subgroups based on polyp and procedural characteristics. The higher-risk group included patients with baseline adenomas ≥ 20 mm, high-grade dysplasia, proximal polyps, or suboptimal evaluation. The lower-risk group included all others. CRC incidence was higher in the “higher-risk” subgroup (247 CRC per 100,000 vs. 93 CRC per 100,000). In the higher-risk group, risk of CRC decreased with more surveillance visits, a finding that was not observed in the lower-risk group. The 10-year incidence of CRC in the cohort overall was 2.7%, in the higher-risk group was 3.3% and in the lower risk group was 1.1%. CRC incidence was significantly higher in the higher-risk subgroup compared with the general population.

Conclusion. Colonoscopy surveillance significantly reducedthe incidence of CRC in intermediate-risk patients (1 to 3 large adenomas ≥ 10 mm or 3 to 4 small adenomas < 10 mm in size) who were offered surveillance at 3-year intervals. Moreover, the benefit of surveillance was particularly noted in a sub-group of patients who had large adenomas (≥ 20 mm), high-grade dysplasia, proximal polyps or poor endoscopic evaluation at the time of initial screening.

Commentary

Screening colonoscopy with removal of adenomatous polyps prevents many CRCs and has been shown to reduce mortality [1]. The results of this retrospective study suggest that patients with intermediate-risk adenomas who underwent at least 1 surveillance colonoscopy at 3-year intervals had a significant reduction in the incidence of CRC. The authors have identified a subgroup of patients at higher risk for CRC, which included those who had a suboptimal initial colonoscopy including poor bowel preparation, adenomas ≥ 20 mm, adenomas with high-grade dysplasia, or proximal adenomas. In particular, ongoing surveillance in this high-risk cohort was associated with significant reductions in CRC incidence. Conversely, those in the lower-risk group had a CRC incidence lower than that of the general population,  raising some questions as to whether this group benefits from ongoing surveillance. However, definitive conclusions are difficult to make given the relatively low incidence of CRC in this group.

The risk of neoplasia in patients with colorectal ade-nomas has been evaluated in multiple studies. A pooled analysis by Martinez and colleagues examined over 9000 patients and noted advanced adenomas were found during follow up in 11.2% of the population, with 0.6% of the population developing invasive CRC [2]. Compared with adenomas < 5 mm, those with baseline adenomas 10–19 mm had a higher risk of advanced neoplasia (15.9% vs 7.7%; OR 2.2). Moreover, those with a baseline polyp ≥ 20 mm had a risk of advanced neoplasia at follow-up of 19.3% (OR 2.99). The results of the current investigation also suggest an increased risk of neoplasia with increased polyp size. Interestingly, the polyp size that conferred a higher risk in this study was ≥ 20 mm. The authors of this study suggest that polyps ≥ 20 mm along with the previously mentioned high-risk features may identify a subgroup within the intermediate-risk population who may benefit from close surveillance. One particularly interesting finding in this study was the identification of proximal colon polyps as a risk factor. While less well defined, previous investigations have noted a similar finding suggesting a risk of advanced neoplasia of up to 80% in patients with proximal polyps [3]. Given such, intensive surveillance may not be appropriate for all intermediate-risk patients and a more refined risk-adapted approach may be preferred.

There are some important limitations of the current study that warrant discussion. First, it should be emphasized that this study is observational in nature and therefore, definitive conclusions cannot be made despite the significant effect of surveillance colonoscopy in patients with high-risk features. In addition, the median follow-up in this study was 7.9 years and one could argue that longer-follow up is needed in order to validate the findings of this study, particularly in patients in the lower-risk cohort. Nevertheless, this study does suggest that there may be a population of patients that harbor higher-risk features and close surveillance limited to this group may be more appropriate. Furthermore, the duration of surveillance remains an important clinical question that requires further research.

Applications for Clinical Practice

In 2012, the United States Multi-Society Task Force (MSTF) on CRC issued updated guidelines defining adenoma risk and postpolypectomy surveillance. Low-risk adenomas (1 to 2 tubular adenomas ≤ 10 mm at baseline) should have repeat surveillance colonoscopy in 5 to 10 years. Advanced adenomas (≥ 10 mm, villous histology, or high-grade dysplasia) or those with 3 to 10 adenomas at baseline should undergo first surveillance in 3 years [4]. The authors of the current study suggest that surveillance colonoscopy at 3-year intervals for patients with particularly high-risk features including those with poor bowel preparation, adenomas ≥ 20 mm, adenomas with high-grade dysplasia or proximal adenomas benefit the greatest from at least 1 surveillance colonoscopy. Those with lower- risk features may not require such rigorous follow-up; however, further work to define which high-risk cohorts should undergo close surveillance is warranted. It is vital that the primary care provider understand such guidelines in order to facilitate the appropriate follow-up.

—Daniel Isaac, DO, MS, Michigan State University, East Lansing, MI

Study Overview

Objective. To examine the heterogeneity in colorectal cancer (CRC) incidence in intermediate-risk patients and the effect of surveillance on CRC incidence.

Design. Retrospective, multicenter cohort study.

Setting and participants. Study patients underwent colonoscopy between 1 January 1990 and 21 December 2010 at 17 hospitals in the United Kingdom. Patients  were eligible for the study if they had a baseline colonoscopy with a newly diagnosed intermediate-risk adenoma. Intermediate-risk adenomas (as defined by the UK guidelines) included 1 to 2 large adenomas ≥ 10 mm or 3 to 4 small adenomas < 10 mm in size. Patients with a history of prior resections, colorectal cancer, inflammatory bowel disease or a family history of CRC were excluded from the study. Patient, procedural, and polyp characteristics were assessed at baseline.

Main outcome measures. The primary outcome was inci-dence of CRC. Additional factors assessed included age at first polyp detection, sex, completeness of colonoscopy, preparation quality, number of adenomas, size of largest adenoma, histology, and location. Proximal polyps were defined as those proximal to the descending colon. Information regarding social history (eg, smoking status) was not available.

Results. The authors identified 253,798 patients who underwent colonoscopy between 1 January 1990 and 21 December 2010. Of those, 223,539 were excluded based on not meeting the pre-specified inclusion criteria, resulting in 30,259 eligible patients for analysis. Review of histological data confirmed intermediate-risk adenomas in 11,995 (40%) of the patients. The median age in this study was 66 years and 55% were men. Fifty-eight percent attended 1 or more follow-up surveillance visits while 42% had no follow-up surveillance colonoscopy. Those who attended more than 1 follow-up surveillance visits were younger, had a greater proportion of large adenomas (> 20 mm), or had an adenoma with high-grade dysplasia. Both groups had similar rates of villous histology (9% vs. 10%).

After a median follow-up of 7.9 years, 210 CRCs were diagnosed and 32% of patients died. In the group with no follow-up surveillance, 46% died and 2% were diagnosed with cancer. In the group who had 1 or more follow-up colonoscopies, 21% died and 1% were diagnosed with cancer. One or 2 surveillance visits were associated with a significant reduction in CRC incidence (HR 0.57 [95% confidence interval {CI} 0.4–0.8) and 0.51 [95% CI 0.31–0.84], respectively). Three or more surveillance exams were also associated with a similar reduction in CRC incidence (HR 0.54; CI 0.29–0.99). Characteristics associated with increased CRC incidence were older age, adenomas > 20 mm, high-grade dysplasia, proximal polyps, and colonoscopies that were either incomplete or with poor preparation. The number of adenomas was not independently associated with CRC incidence.

The authors divided the cohort into higher-risk (74%) and lower-risk (26%)  subgroups based on polyp and procedural characteristics. The higher-risk group included patients with baseline adenomas ≥ 20 mm, high-grade dysplasia, proximal polyps, or suboptimal evaluation. The lower-risk group included all others. CRC incidence was higher in the “higher-risk” subgroup (247 CRC per 100,000 vs. 93 CRC per 100,000). In the higher-risk group, risk of CRC decreased with more surveillance visits, a finding that was not observed in the lower-risk group. The 10-year incidence of CRC in the cohort overall was 2.7%, in the higher-risk group was 3.3% and in the lower risk group was 1.1%. CRC incidence was significantly higher in the higher-risk subgroup compared with the general population.

Conclusion. Colonoscopy surveillance significantly reducedthe incidence of CRC in intermediate-risk patients (1 to 3 large adenomas ≥ 10 mm or 3 to 4 small adenomas < 10 mm in size) who were offered surveillance at 3-year intervals. Moreover, the benefit of surveillance was particularly noted in a sub-group of patients who had large adenomas (≥ 20 mm), high-grade dysplasia, proximal polyps or poor endoscopic evaluation at the time of initial screening.

Commentary

Screening colonoscopy with removal of adenomatous polyps prevents many CRCs and has been shown to reduce mortality [1]. The results of this retrospective study suggest that patients with intermediate-risk adenomas who underwent at least 1 surveillance colonoscopy at 3-year intervals had a significant reduction in the incidence of CRC. The authors have identified a subgroup of patients at higher risk for CRC, which included those who had a suboptimal initial colonoscopy including poor bowel preparation, adenomas ≥ 20 mm, adenomas with high-grade dysplasia, or proximal adenomas. In particular, ongoing surveillance in this high-risk cohort was associated with significant reductions in CRC incidence. Conversely, those in the lower-risk group had a CRC incidence lower than that of the general population,  raising some questions as to whether this group benefits from ongoing surveillance. However, definitive conclusions are difficult to make given the relatively low incidence of CRC in this group.

The risk of neoplasia in patients with colorectal ade-nomas has been evaluated in multiple studies. A pooled analysis by Martinez and colleagues examined over 9000 patients and noted advanced adenomas were found during follow up in 11.2% of the population, with 0.6% of the population developing invasive CRC [2]. Compared with adenomas < 5 mm, those with baseline adenomas 10–19 mm had a higher risk of advanced neoplasia (15.9% vs 7.7%; OR 2.2). Moreover, those with a baseline polyp ≥ 20 mm had a risk of advanced neoplasia at follow-up of 19.3% (OR 2.99). The results of the current investigation also suggest an increased risk of neoplasia with increased polyp size. Interestingly, the polyp size that conferred a higher risk in this study was ≥ 20 mm. The authors of this study suggest that polyps ≥ 20 mm along with the previously mentioned high-risk features may identify a subgroup within the intermediate-risk population who may benefit from close surveillance. One particularly interesting finding in this study was the identification of proximal colon polyps as a risk factor. While less well defined, previous investigations have noted a similar finding suggesting a risk of advanced neoplasia of up to 80% in patients with proximal polyps [3]. Given such, intensive surveillance may not be appropriate for all intermediate-risk patients and a more refined risk-adapted approach may be preferred.

There are some important limitations of the current study that warrant discussion. First, it should be emphasized that this study is observational in nature and therefore, definitive conclusions cannot be made despite the significant effect of surveillance colonoscopy in patients with high-risk features. In addition, the median follow-up in this study was 7.9 years and one could argue that longer-follow up is needed in order to validate the findings of this study, particularly in patients in the lower-risk cohort. Nevertheless, this study does suggest that there may be a population of patients that harbor higher-risk features and close surveillance limited to this group may be more appropriate. Furthermore, the duration of surveillance remains an important clinical question that requires further research.

Applications for Clinical Practice

In 2012, the United States Multi-Society Task Force (MSTF) on CRC issued updated guidelines defining adenoma risk and postpolypectomy surveillance. Low-risk adenomas (1 to 2 tubular adenomas ≤ 10 mm at baseline) should have repeat surveillance colonoscopy in 5 to 10 years. Advanced adenomas (≥ 10 mm, villous histology, or high-grade dysplasia) or those with 3 to 10 adenomas at baseline should undergo first surveillance in 3 years [4]. The authors of the current study suggest that surveillance colonoscopy at 3-year intervals for patients with particularly high-risk features including those with poor bowel preparation, adenomas ≥ 20 mm, adenomas with high-grade dysplasia or proximal adenomas benefit the greatest from at least 1 surveillance colonoscopy. Those with lower- risk features may not require such rigorous follow-up; however, further work to define which high-risk cohorts should undergo close surveillance is warranted. It is vital that the primary care provider understand such guidelines in order to facilitate the appropriate follow-up.

—Daniel Isaac, DO, MS, Michigan State University, East Lansing, MI

Study Overview

Objective. To examine the heterogeneity in colorectal cancer (CRC) incidence in intermediate-risk patients and the effect of surveillance on CRC incidence.

Design. Retrospective, multicenter cohort study.

Setting and participants. Study patients underwent colonoscopy between 1 January 1990 and 21 December 2010 at 17 hospitals in the United Kingdom. Patients  were eligible for the study if they had a baseline colonoscopy with a newly diagnosed intermediate-risk adenoma. Intermediate-risk adenomas (as defined by the UK guidelines) included 1 to 2 large adenomas ≥ 10 mm or 3 to 4 small adenomas < 10 mm in size. Patients with a history of prior resections, colorectal cancer, inflammatory bowel disease or a family history of CRC were excluded from the study. Patient, procedural, and polyp characteristics were assessed at baseline.

Main outcome measures. The primary outcome was inci-dence of CRC. Additional factors assessed included age at first polyp detection, sex, completeness of colonoscopy, preparation quality, number of adenomas, size of largest adenoma, histology, and location. Proximal polyps were defined as those proximal to the descending colon. Information regarding social history (eg, smoking status) was not available.

Results. The authors identified 253,798 patients who underwent colonoscopy between 1 January 1990 and 21 December 2010. Of those, 223,539 were excluded based on not meeting the pre-specified inclusion criteria, resulting in 30,259 eligible patients for analysis. Review of histological data confirmed intermediate-risk adenomas in 11,995 (40%) of the patients. The median age in this study was 66 years and 55% were men. Fifty-eight percent attended 1 or more follow-up surveillance visits while 42% had no follow-up surveillance colonoscopy. Those who attended more than 1 follow-up surveillance visits were younger, had a greater proportion of large adenomas (> 20 mm), or had an adenoma with high-grade dysplasia. Both groups had similar rates of villous histology (9% vs. 10%).

After a median follow-up of 7.9 years, 210 CRCs were diagnosed and 32% of patients died. In the group with no follow-up surveillance, 46% died and 2% were diagnosed with cancer. In the group who had 1 or more follow-up colonoscopies, 21% died and 1% were diagnosed with cancer. One or 2 surveillance visits were associated with a significant reduction in CRC incidence (HR 0.57 [95% confidence interval {CI} 0.4–0.8) and 0.51 [95% CI 0.31–0.84], respectively). Three or more surveillance exams were also associated with a similar reduction in CRC incidence (HR 0.54; CI 0.29–0.99). Characteristics associated with increased CRC incidence were older age, adenomas > 20 mm, high-grade dysplasia, proximal polyps, and colonoscopies that were either incomplete or with poor preparation. The number of adenomas was not independently associated with CRC incidence.

The authors divided the cohort into higher-risk (74%) and lower-risk (26%)  subgroups based on polyp and procedural characteristics. The higher-risk group included patients with baseline adenomas ≥ 20 mm, high-grade dysplasia, proximal polyps, or suboptimal evaluation. The lower-risk group included all others. CRC incidence was higher in the “higher-risk” subgroup (247 CRC per 100,000 vs. 93 CRC per 100,000). In the higher-risk group, risk of CRC decreased with more surveillance visits, a finding that was not observed in the lower-risk group. The 10-year incidence of CRC in the cohort overall was 2.7%, in the higher-risk group was 3.3% and in the lower risk group was 1.1%. CRC incidence was significantly higher in the higher-risk subgroup compared with the general population.

Conclusion. Colonoscopy surveillance significantly reducedthe incidence of CRC in intermediate-risk patients (1 to 3 large adenomas ≥ 10 mm or 3 to 4 small adenomas < 10 mm in size) who were offered surveillance at 3-year intervals. Moreover, the benefit of surveillance was particularly noted in a sub-group of patients who had large adenomas (≥ 20 mm), high-grade dysplasia, proximal polyps or poor endoscopic evaluation at the time of initial screening.

Commentary

Screening colonoscopy with removal of adenomatous polyps prevents many CRCs and has been shown to reduce mortality [1]. The results of this retrospective study suggest that patients with intermediate-risk adenomas who underwent at least 1 surveillance colonoscopy at 3-year intervals had a significant reduction in the incidence of CRC. The authors have identified a subgroup of patients at higher risk for CRC, which included those who had a suboptimal initial colonoscopy including poor bowel preparation, adenomas ≥ 20 mm, adenomas with high-grade dysplasia, or proximal adenomas. In particular, ongoing surveillance in this high-risk cohort was associated with significant reductions in CRC incidence. Conversely, those in the lower-risk group had a CRC incidence lower than that of the general population,  raising some questions as to whether this group benefits from ongoing surveillance. However, definitive conclusions are difficult to make given the relatively low incidence of CRC in this group.

The risk of neoplasia in patients with colorectal ade-nomas has been evaluated in multiple studies. A pooled analysis by Martinez and colleagues examined over 9000 patients and noted advanced adenomas were found during follow up in 11.2% of the population, with 0.6% of the population developing invasive CRC [2]. Compared with adenomas < 5 mm, those with baseline adenomas 10–19 mm had a higher risk of advanced neoplasia (15.9% vs 7.7%; OR 2.2). Moreover, those with a baseline polyp ≥ 20 mm had a risk of advanced neoplasia at follow-up of 19.3% (OR 2.99). The results of the current investigation also suggest an increased risk of neoplasia with increased polyp size. Interestingly, the polyp size that conferred a higher risk in this study was ≥ 20 mm. The authors of this study suggest that polyps ≥ 20 mm along with the previously mentioned high-risk features may identify a subgroup within the intermediate-risk population who may benefit from close surveillance. One particularly interesting finding in this study was the identification of proximal colon polyps as a risk factor. While less well defined, previous investigations have noted a similar finding suggesting a risk of advanced neoplasia of up to 80% in patients with proximal polyps [3]. Given such, intensive surveillance may not be appropriate for all intermediate-risk patients and a more refined risk-adapted approach may be preferred.

There are some important limitations of the current study that warrant discussion. First, it should be emphasized that this study is observational in nature and therefore, definitive conclusions cannot be made despite the significant effect of surveillance colonoscopy in patients with high-risk features. In addition, the median follow-up in this study was 7.9 years and one could argue that longer-follow up is needed in order to validate the findings of this study, particularly in patients in the lower-risk cohort. Nevertheless, this study does suggest that there may be a population of patients that harbor higher-risk features and close surveillance limited to this group may be more appropriate. Furthermore, the duration of surveillance remains an important clinical question that requires further research.

Applications for Clinical Practice

In 2012, the United States Multi-Society Task Force (MSTF) on CRC issued updated guidelines defining adenoma risk and postpolypectomy surveillance. Low-risk adenomas (1 to 2 tubular adenomas ≤ 10 mm at baseline) should have repeat surveillance colonoscopy in 5 to 10 years. Advanced adenomas (≥ 10 mm, villous histology, or high-grade dysplasia) or those with 3 to 10 adenomas at baseline should undergo first surveillance in 3 years [4]. The authors of the current study suggest that surveillance colonoscopy at 3-year intervals for patients with particularly high-risk features including those with poor bowel preparation, adenomas ≥ 20 mm, adenomas with high-grade dysplasia or proximal adenomas benefit the greatest from at least 1 surveillance colonoscopy. Those with lower- risk features may not require such rigorous follow-up; however, further work to define which high-risk cohorts should undergo close surveillance is warranted. It is vital that the primary care provider understand such guidelines in order to facilitate the appropriate follow-up.

—Daniel Isaac, DO, MS, Michigan State University, East Lansing, MI

NEW YORK – If dermatopathologists had a wish list they could give their dermatologist colleagues, what might it include? High up on the list for many, said Robert Phelps, MD, might be to have them share the clinical picture, treat the specimen gently, and give the best landmarks possible.

Speaking at the summer meeting of the American Academy of Dermatology, Dr. Phelps, director of the dermatopathology service at Mount Sinai Medical Center in New York, led off the dermatopathologist-run session – appropriately titled “Help Me Help You” – by asking, “How can the clinician provide the optimal biopsy?”

It’s always helpful to have as much clinical information as possible, said Dr. Phelps, whose discussion focused on tips for neoplastic lesions. This might include prior history of malignancy, autoimmune disease, pathergy, or other relevant medical history, but clinical pictures can also be a big help, although there can be technical and patient privacy issues to overcome, he noted. If, for example, a larger lesion or rash is being biopsied rather than excised, it can be very helpful to see the larger field and full area of distribution of the lesion in question. Submitting multiple specimens for rashes and larger lesions is always a good idea too, he added.

Although curettage can be a great way to biopsy – and perhaps even definitively treat some lesions – problems can arise on the dermatopathologist’s side when melanocytic lesions are curetted for biopsy, according to Dr. Phelps, a practicing dermatologist and a dermatopathologist. “By virtue of the force of the biopsy, the specimen is often fragmented, and histology can be distorted,” he said. One element of that distortion can be that melanocytes can appear to be free floating, which is a problem. “Dyshesion of melanocytes is usually an indication of atypia … It is an important histologic clue as to the possibility of a malignancy supervening.”

These factors can make it tough for a dermatopathologist to make an accurate call. “If there are free-floating melanocytes from a curetted specimen, I can’t rule out invasive melanoma,” explained Dr. Phelps, since he can’t tell if he is seeing true atypia or disruption that’s an artifact of the collection technique.

In this instance, he said, a dermatopathologist would be “obligated to overcall, because one couldn’t really determine the pathology.” The bottom line? “Don’t curette biopsies of melanocytic lesions.”

Another technique that can interfere with the ability to read a tissue specimen accurately is electrodesiccation. Although it’s often performed in conjunction with curettage, electrodesiccation can cause changes in tissue consistent with thermal injury. “Essentially, the tissue has been burned,” Dr. Phelps pointed out. This can result in a characteristic streaming pattern of nuclei, and the dermis can acquire a “peculiar homogenized appearance,” he said.

Although electrodesiccation can be a useful technique to make sure margins are controlled, “when you do this, just be aware that the interpretation is difficult,” he noted. “It’s difficult to tell where the margins are and if they are the appropriate and correct margins,” he said.

When possible, try to avoid squeezing the tumor, Dr. Phelps advised. Excessive pressure on the specimen can distort cell architecture and make pathological diagnosis really challenging, particularly in lymphoid tumors, he said.

“Often, the tumor is not recognizable,” he added. Crush artifact can result in an appearance of small bluish clumps and smearing of collagen fibers. The effect, he said, can be particularly pronounced with small cell carcinoma and lymphoma, and with rapidly proliferating tumors.

Dr. Phelps said that during his training, he was taught not to use forceps to extract a stubborn punch biopsy specimen; rather, he was trained to use a needle to tease out the specimen. Fear of a self-inflicted needle stick with this technique may be a deterrent, he acknowledged. If forceps are used, he suggested being as gentle as possible and using the finest forceps available.

When pathologists receive an intact excised lesion – one not obtained using a Mohs technique, “delineation of the margin is essential,” Dr. Phelps said. Further, accurate mapping is critical to helping the examiner understand the anatomic orientation of the specimen, a key prerequisite that enables accurate communication from the dermatopathologist back to the clinician if there’s a question regarding the need for retreatment, he added.

For an elliptical excision, ideally, both poles of the ellipse would be suture-tagged, and at least one tag is essential, he said. Then superior and inferior borders can be inked with contrasting colors, and the epidermal borders of the lesion should be marked as well. When the specimen is submitted, it should be accompanied by an accurate map that clearly indicates the coding for medial, lateral, inferior, and superior aspects of the specimen. “Always prepare a specimen diagram for oriented specimens,” Dr. Phelps noted.

Don’t forget to make sure that the left-right orientation on the diagram corresponds to the specimen’s orientation on the patient, he added. Some facilities use a clock face system to indicate orientation and positioning, which may be the clearest method of all.

Sometimes, it’s difficult for the dermatopathologist to visualize whether the specimen is aligned in true medial-lateral fashion, or along skin tension lines, which tend to run diagonally, so “the more clinical information, the better,” he said. “With good mapping, precise retreatment can be optimal,” he said.

Dr. Phelps reported that he had no relevant conflicts of interest.
 

[email protected]

On Twitter @karioakes

NEW YORK – If dermatopathologists had a wish list they could give their dermatologist colleagues, what might it include? High up on the list for many, said Robert Phelps, MD, might be to have them share the clinical picture, treat the specimen gently, and give the best landmarks possible.

Speaking at the summer meeting of the American Academy of Dermatology, Dr. Phelps, director of the dermatopathology service at Mount Sinai Medical Center in New York, led off the dermatopathologist-run session – appropriately titled “Help Me Help You” – by asking, “How can the clinician provide the optimal biopsy?”

It’s always helpful to have as much clinical information as possible, said Dr. Phelps, whose discussion focused on tips for neoplastic lesions. This might include prior history of malignancy, autoimmune disease, pathergy, or other relevant medical history, but clinical pictures can also be a big help, although there can be technical and patient privacy issues to overcome, he noted. If, for example, a larger lesion or rash is being biopsied rather than excised, it can be very helpful to see the larger field and full area of distribution of the lesion in question. Submitting multiple specimens for rashes and larger lesions is always a good idea too, he added.

Although curettage can be a great way to biopsy – and perhaps even definitively treat some lesions – problems can arise on the dermatopathologist’s side when melanocytic lesions are curetted for biopsy, according to Dr. Phelps, a practicing dermatologist and a dermatopathologist. “By virtue of the force of the biopsy, the specimen is often fragmented, and histology can be distorted,” he said. One element of that distortion can be that melanocytes can appear to be free floating, which is a problem. “Dyshesion of melanocytes is usually an indication of atypia … It is an important histologic clue as to the possibility of a malignancy supervening.”

These factors can make it tough for a dermatopathologist to make an accurate call. “If there are free-floating melanocytes from a curetted specimen, I can’t rule out invasive melanoma,” explained Dr. Phelps, since he can’t tell if he is seeing true atypia or disruption that’s an artifact of the collection technique.

In this instance, he said, a dermatopathologist would be “obligated to overcall, because one couldn’t really determine the pathology.” The bottom line? “Don’t curette biopsies of melanocytic lesions.”

Another technique that can interfere with the ability to read a tissue specimen accurately is electrodesiccation. Although it’s often performed in conjunction with curettage, electrodesiccation can cause changes in tissue consistent with thermal injury. “Essentially, the tissue has been burned,” Dr. Phelps pointed out. This can result in a characteristic streaming pattern of nuclei, and the dermis can acquire a “peculiar homogenized appearance,” he said.

Although electrodesiccation can be a useful technique to make sure margins are controlled, “when you do this, just be aware that the interpretation is difficult,” he noted. “It’s difficult to tell where the margins are and if they are the appropriate and correct margins,” he said.

When possible, try to avoid squeezing the tumor, Dr. Phelps advised. Excessive pressure on the specimen can distort cell architecture and make pathological diagnosis really challenging, particularly in lymphoid tumors, he said.

“Often, the tumor is not recognizable,” he added. Crush artifact can result in an appearance of small bluish clumps and smearing of collagen fibers. The effect, he said, can be particularly pronounced with small cell carcinoma and lymphoma, and with rapidly proliferating tumors.

Dr. Phelps said that during his training, he was taught not to use forceps to extract a stubborn punch biopsy specimen; rather, he was trained to use a needle to tease out the specimen. Fear of a self-inflicted needle stick with this technique may be a deterrent, he acknowledged. If forceps are used, he suggested being as gentle as possible and using the finest forceps available.

When pathologists receive an intact excised lesion – one not obtained using a Mohs technique, “delineation of the margin is essential,” Dr. Phelps said. Further, accurate mapping is critical to helping the examiner understand the anatomic orientation of the specimen, a key prerequisite that enables accurate communication from the dermatopathologist back to the clinician if there’s a question regarding the need for retreatment, he added.

For an elliptical excision, ideally, both poles of the ellipse would be suture-tagged, and at least one tag is essential, he said. Then superior and inferior borders can be inked with contrasting colors, and the epidermal borders of the lesion should be marked as well. When the specimen is submitted, it should be accompanied by an accurate map that clearly indicates the coding for medial, lateral, inferior, and superior aspects of the specimen. “Always prepare a specimen diagram for oriented specimens,” Dr. Phelps noted.

Don’t forget to make sure that the left-right orientation on the diagram corresponds to the specimen’s orientation on the patient, he added. Some facilities use a clock face system to indicate orientation and positioning, which may be the clearest method of all.

Sometimes, it’s difficult for the dermatopathologist to visualize whether the specimen is aligned in true medial-lateral fashion, or along skin tension lines, which tend to run diagonally, so “the more clinical information, the better,” he said. “With good mapping, precise retreatment can be optimal,” he said.

Dr. Phelps reported that he had no relevant conflicts of interest.
 

[email protected]

On Twitter @karioakes

NEW YORK – If dermatopathologists had a wish list they could give their dermatologist colleagues, what might it include? High up on the list for many, said Robert Phelps, MD, might be to have them share the clinical picture, treat the specimen gently, and give the best landmarks possible.

Speaking at the summer meeting of the American Academy of Dermatology, Dr. Phelps, director of the dermatopathology service at Mount Sinai Medical Center in New York, led off the dermatopathologist-run session – appropriately titled “Help Me Help You” – by asking, “How can the clinician provide the optimal biopsy?”

It’s always helpful to have as much clinical information as possible, said Dr. Phelps, whose discussion focused on tips for neoplastic lesions. This might include prior history of malignancy, autoimmune disease, pathergy, or other relevant medical history, but clinical pictures can also be a big help, although there can be technical and patient privacy issues to overcome, he noted. If, for example, a larger lesion or rash is being biopsied rather than excised, it can be very helpful to see the larger field and full area of distribution of the lesion in question. Submitting multiple specimens for rashes and larger lesions is always a good idea too, he added.

Although curettage can be a great way to biopsy – and perhaps even definitively treat some lesions – problems can arise on the dermatopathologist’s side when melanocytic lesions are curetted for biopsy, according to Dr. Phelps, a practicing dermatologist and a dermatopathologist. “By virtue of the force of the biopsy, the specimen is often fragmented, and histology can be distorted,” he said. One element of that distortion can be that melanocytes can appear to be free floating, which is a problem. “Dyshesion of melanocytes is usually an indication of atypia … It is an important histologic clue as to the possibility of a malignancy supervening.”

These factors can make it tough for a dermatopathologist to make an accurate call. “If there are free-floating melanocytes from a curetted specimen, I can’t rule out invasive melanoma,” explained Dr. Phelps, since he can’t tell if he is seeing true atypia or disruption that’s an artifact of the collection technique.

In this instance, he said, a dermatopathologist would be “obligated to overcall, because one couldn’t really determine the pathology.” The bottom line? “Don’t curette biopsies of melanocytic lesions.”

Another technique that can interfere with the ability to read a tissue specimen accurately is electrodesiccation. Although it’s often performed in conjunction with curettage, electrodesiccation can cause changes in tissue consistent with thermal injury. “Essentially, the tissue has been burned,” Dr. Phelps pointed out. This can result in a characteristic streaming pattern of nuclei, and the dermis can acquire a “peculiar homogenized appearance,” he said.

Although electrodesiccation can be a useful technique to make sure margins are controlled, “when you do this, just be aware that the interpretation is difficult,” he noted. “It’s difficult to tell where the margins are and if they are the appropriate and correct margins,” he said.

When possible, try to avoid squeezing the tumor, Dr. Phelps advised. Excessive pressure on the specimen can distort cell architecture and make pathological diagnosis really challenging, particularly in lymphoid tumors, he said.

“Often, the tumor is not recognizable,” he added. Crush artifact can result in an appearance of small bluish clumps and smearing of collagen fibers. The effect, he said, can be particularly pronounced with small cell carcinoma and lymphoma, and with rapidly proliferating tumors.

Dr. Phelps said that during his training, he was taught not to use forceps to extract a stubborn punch biopsy specimen; rather, he was trained to use a needle to tease out the specimen. Fear of a self-inflicted needle stick with this technique may be a deterrent, he acknowledged. If forceps are used, he suggested being as gentle as possible and using the finest forceps available.

When pathologists receive an intact excised lesion – one not obtained using a Mohs technique, “delineation of the margin is essential,” Dr. Phelps said. Further, accurate mapping is critical to helping the examiner understand the anatomic orientation of the specimen, a key prerequisite that enables accurate communication from the dermatopathologist back to the clinician if there’s a question regarding the need for retreatment, he added.

For an elliptical excision, ideally, both poles of the ellipse would be suture-tagged, and at least one tag is essential, he said. Then superior and inferior borders can be inked with contrasting colors, and the epidermal borders of the lesion should be marked as well. When the specimen is submitted, it should be accompanied by an accurate map that clearly indicates the coding for medial, lateral, inferior, and superior aspects of the specimen. “Always prepare a specimen diagram for oriented specimens,” Dr. Phelps noted.

Don’t forget to make sure that the left-right orientation on the diagram corresponds to the specimen’s orientation on the patient, he added. Some facilities use a clock face system to indicate orientation and positioning, which may be the clearest method of all.

Sometimes, it’s difficult for the dermatopathologist to visualize whether the specimen is aligned in true medial-lateral fashion, or along skin tension lines, which tend to run diagonally, so “the more clinical information, the better,” he said. “With good mapping, precise retreatment can be optimal,” he said.

Dr. Phelps reported that he had no relevant conflicts of interest.
 

[email protected]

On Twitter @karioakes

Woman dies after robotic hysterectomy: $5M verdict

When a 36-year-old woman underwent robotic hysterectomy, the gynecologist inserted a plastic trocar and sleeve through the patient's umbilicus to access the abdominal cavity at 7:30 am.

The certified registered nurse anesthetist (CRNA) noted a significant abnormality in the patient's vital signs at 8:07 am and administered medication and fluids to treat a suspected blood loss. When the patient's heart rate became extremely elevated at 8:25 am, the CRNA administered another drug, which failed to bring the patient's heart rate down. At 8:37 am, the monitoring machine could not record the patient's blood pressure. The CRNA informed the surgeon of the patient's condition. The supervising anesthesiologist was called; he arrived at 8:45 am and determined that the patient was bleeding internally. He asked the surgeon if he could visualize any bleeding; the surgeon could not.

The patient's condition continued to deteriorate. At 9:05 am, her blood pressure was still undetectable on the monitor. A Code Blue was called at 9:30 am. Exploratory surgery and blood transfusions begun at  9:43 am were not able to counteract the patient's massive blood loss. After cardiac arrest, she was pronounced dead at 11:18 am.

ESTATE'S CLAIM:

The surgeon was negligent in lacerating the left common iliac artery when inserting the trocar, and in not detecting the injury intraoperatively.

The anesthesia staff was  negligent. The CRNA did not inform the surgeon until the situation was dire. A simple procedure could have been performed at any time to check the patient's hematocrit and hemoglobin levels, but that was not done until 9:30 am. If the severity of the patient's condition had been determined earlier, blood transfusions and further treatment could have saved her life.

DEFENDANTS' DEFENSE:

There was no negligence on the part of the surgeon or anesthesia team. The standard of care was met. Arterial laceration is a known risk of the surgery.

VERDICT:

A $5,008,922 Illinois verdict was returned against all defendants except the CRNA.

A woman with MS becomes incontinent after surgery

A 43-year-old woman with multiple sclerosis (MS) underwent a hysterectomy performed by a gynecologic surgeon. During surgery, the patient's ureter was injured, requiring additional surgery. The patient is now permanently incontinent.

PATIENT'S CLAIM:

During surgery, the surgeon constricted the ureter with stitches. A second surgery was needed to remove the stitches and reimplant the ureter. The second surgery left her permanently incontinent. Although incontinence is a known complication of the second surgery, the second surgery would not have been necessary if the surgeon had not injured the ureter during the first surgery. Incontinence was not a result of her MS as she was not incontinent before the second surgery.

DEFENDANTS' DEFENSE:

There was no deviation from the standard of care. There was no stitching around the ureter. The ureter was damaged by kinking, which was addressed during the second surgery. Incontinence was a result of her MS.

VERDICT:

A $700,000 South Carolina verdict was returned.

Bowel injury during robotic procedure: $6.25M settlement

A woman in her late 60s reported minor urinary incontinence to her gynecologist. She underwent robot-assisted laparoscopic hysterectomy with a sling procedure for pelvic prolapse. During the sling procedure, the transverse colon was injured. The patient developed sepsis, requiring multiple attempts at surgical repair, including colostomy. The patient requires a permanent colostomy. She has a malabsorption disorder and needs frequent intravenous treatment for dehydration.

PATIENT'S CLAIM:

The surgeon failed to properly control the robotic device, causing injury to the patient's bowel. The surgeon deviated from the standard of care by failing to convert from the robot-assisted laparoscopic procedure to an open procedure when complications arose. The injury was not properly treated before the surgeon closed the initial surgery, causing the patient to develop sepsis.

PHYSICIAN'S DEFENSE:

The surgeon claimed that the injuries and resulting sepsis were the fault of other physicians and hospital staff. The case settled during trial.

VERDICT:

A $6.25 million New Jersey settlement was reached.

Hydrothermal ablation led to genital burns

A woman SAW AN OBGYN on October 2 to report menorrhagia. She had been treated for uterine fibroids with a Mirena intrauterine device and hydrothermal ablation. Another physician had suggested hysterectomy, which she declined.

When the ObGyn found that the patient had an enlarged uterus, he ordered ultrasonography and an endometrial biopsy. On follow-up, the ObGyn provided options of robotic hysterectomy or operative hysteroscopy with hydrothermal ablation. The patient chose hysteroscopy and the procedure was scheduled for December 28.

During surgery, an improper seal to the cervix around the hydrothermal ablation sheath was detected before heating the fluid. A tenaculum and 2 sponges were placed on the cervix to help form a seal and the fluid was heated for 4 minutes. The procedure was aborted when fluid was seen to be leaking again. Instruments were removed after a cooling period. The patient was discharged from the surgery center the same day with a prescription for oral hydrocodone bitartrate and acetaminophen for pain.

On January 4, the patient reported severe vulvar pain. The ObGyn found thermal burns on both labia with possible cellulitis. He prescribed silver sulfadiazine cream twice daily, levofloxacin 500 mg for 7 days, and warm-water soaks. When the patient called to report continued pain on January 7, the hydrocodone and acetaminophen prescription was renewed. On January 8, the ObGyn found continued evidence of labia and introitus burns with no signs of infection. The patient was told to continue taking the oral pain medication and to apply topical lidocaine gel and silver sulfadiazine cream.

Examinations on January 11, 17, 24, and 31 showed continued evidence of active healing. When new evidence of vulvar ulceration with inflammation and infection appeared, supportive care and antibiotics were given. On February 7, granulation tissue had developed at the introitus with continued healing.

On March 27, she saw a gynecologist for dyspareunia. The skin was healed but a tender band of scar tissue was noted at the burn site. She was referred for physical therapy and given estradiol vaginal cream.

On December 11, the patient reported dyspareunia and depression to the gynecologist, who prescribed medication for depression and referred her to counseling.

PATIENT'S CLAIM:

The ObGyn was negligent in failing to maintain a proper seal around the hydrothermal ablation shield. The patient sustained second-degree burns to her genital area from the hot saline solution that leaked from the uterus. The injury caused lasting dyspareunia and depression.

PHYSICIAN'S DEFENSE:

There was no negligence. Once the ObGyn realized that the seal was incomplete, the procedure was stopped and the fluid cooled before being released. Burns were treated within the standard of care.

VERDICT:

A Texas defense verdict was returned based on a no- evidence partial summary judgment: neither the patient nor the expert witness supplied evidence to support the claims of gross negligence or exemplary damages against the ObGyn.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

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.

Woman dies after robotic hysterectomy: $5M verdict

When a 36-year-old woman underwent robotic hysterectomy, the gynecologist inserted a plastic trocar and sleeve through the patient's umbilicus to access the abdominal cavity at 7:30 am.

The certified registered nurse anesthetist (CRNA) noted a significant abnormality in the patient's vital signs at 8:07 am and administered medication and fluids to treat a suspected blood loss. When the patient's heart rate became extremely elevated at 8:25 am, the CRNA administered another drug, which failed to bring the patient's heart rate down. At 8:37 am, the monitoring machine could not record the patient's blood pressure. The CRNA informed the surgeon of the patient's condition. The supervising anesthesiologist was called; he arrived at 8:45 am and determined that the patient was bleeding internally. He asked the surgeon if he could visualize any bleeding; the surgeon could not.

The patient's condition continued to deteriorate. At 9:05 am, her blood pressure was still undetectable on the monitor. A Code Blue was called at 9:30 am. Exploratory surgery and blood transfusions begun at  9:43 am were not able to counteract the patient's massive blood loss. After cardiac arrest, she was pronounced dead at 11:18 am.

ESTATE'S CLAIM:

The surgeon was negligent in lacerating the left common iliac artery when inserting the trocar, and in not detecting the injury intraoperatively.

The anesthesia staff was  negligent. The CRNA did not inform the surgeon until the situation was dire. A simple procedure could have been performed at any time to check the patient's hematocrit and hemoglobin levels, but that was not done until 9:30 am. If the severity of the patient's condition had been determined earlier, blood transfusions and further treatment could have saved her life.

DEFENDANTS' DEFENSE:

There was no negligence on the part of the surgeon or anesthesia team. The standard of care was met. Arterial laceration is a known risk of the surgery.

VERDICT:

A $5,008,922 Illinois verdict was returned against all defendants except the CRNA.

A woman with MS becomes incontinent after surgery

A 43-year-old woman with multiple sclerosis (MS) underwent a hysterectomy performed by a gynecologic surgeon. During surgery, the patient's ureter was injured, requiring additional surgery. The patient is now permanently incontinent.

PATIENT'S CLAIM:

During surgery, the surgeon constricted the ureter with stitches. A second surgery was needed to remove the stitches and reimplant the ureter. The second surgery left her permanently incontinent. Although incontinence is a known complication of the second surgery, the second surgery would not have been necessary if the surgeon had not injured the ureter during the first surgery. Incontinence was not a result of her MS as she was not incontinent before the second surgery.

DEFENDANTS' DEFENSE:

There was no deviation from the standard of care. There was no stitching around the ureter. The ureter was damaged by kinking, which was addressed during the second surgery. Incontinence was a result of her MS.

VERDICT:

A $700,000 South Carolina verdict was returned.

Bowel injury during robotic procedure: $6.25M settlement

A woman in her late 60s reported minor urinary incontinence to her gynecologist. She underwent robot-assisted laparoscopic hysterectomy with a sling procedure for pelvic prolapse. During the sling procedure, the transverse colon was injured. The patient developed sepsis, requiring multiple attempts at surgical repair, including colostomy. The patient requires a permanent colostomy. She has a malabsorption disorder and needs frequent intravenous treatment for dehydration.

PATIENT'S CLAIM:

The surgeon failed to properly control the robotic device, causing injury to the patient's bowel. The surgeon deviated from the standard of care by failing to convert from the robot-assisted laparoscopic procedure to an open procedure when complications arose. The injury was not properly treated before the surgeon closed the initial surgery, causing the patient to develop sepsis.

PHYSICIAN'S DEFENSE:

The surgeon claimed that the injuries and resulting sepsis were the fault of other physicians and hospital staff. The case settled during trial.

VERDICT:

A $6.25 million New Jersey settlement was reached.

Hydrothermal ablation led to genital burns

A woman SAW AN OBGYN on October 2 to report menorrhagia. She had been treated for uterine fibroids with a Mirena intrauterine device and hydrothermal ablation. Another physician had suggested hysterectomy, which she declined.

When the ObGyn found that the patient had an enlarged uterus, he ordered ultrasonography and an endometrial biopsy. On follow-up, the ObGyn provided options of robotic hysterectomy or operative hysteroscopy with hydrothermal ablation. The patient chose hysteroscopy and the procedure was scheduled for December 28.

During surgery, an improper seal to the cervix around the hydrothermal ablation sheath was detected before heating the fluid. A tenaculum and 2 sponges were placed on the cervix to help form a seal and the fluid was heated for 4 minutes. The procedure was aborted when fluid was seen to be leaking again. Instruments were removed after a cooling period. The patient was discharged from the surgery center the same day with a prescription for oral hydrocodone bitartrate and acetaminophen for pain.

On January 4, the patient reported severe vulvar pain. The ObGyn found thermal burns on both labia with possible cellulitis. He prescribed silver sulfadiazine cream twice daily, levofloxacin 500 mg for 7 days, and warm-water soaks. When the patient called to report continued pain on January 7, the hydrocodone and acetaminophen prescription was renewed. On January 8, the ObGyn found continued evidence of labia and introitus burns with no signs of infection. The patient was told to continue taking the oral pain medication and to apply topical lidocaine gel and silver sulfadiazine cream.

Examinations on January 11, 17, 24, and 31 showed continued evidence of active healing. When new evidence of vulvar ulceration with inflammation and infection appeared, supportive care and antibiotics were given. On February 7, granulation tissue had developed at the introitus with continued healing.

On March 27, she saw a gynecologist for dyspareunia. The skin was healed but a tender band of scar tissue was noted at the burn site. She was referred for physical therapy and given estradiol vaginal cream.

On December 11, the patient reported dyspareunia and depression to the gynecologist, who prescribed medication for depression and referred her to counseling.

PATIENT'S CLAIM:

The ObGyn was negligent in failing to maintain a proper seal around the hydrothermal ablation shield. The patient sustained second-degree burns to her genital area from the hot saline solution that leaked from the uterus. The injury caused lasting dyspareunia and depression.

PHYSICIAN'S DEFENSE:

There was no negligence. Once the ObGyn realized that the seal was incomplete, the procedure was stopped and the fluid cooled before being released. Burns were treated within the standard of care.

VERDICT:

A Texas defense verdict was returned based on a no- evidence partial summary judgment: neither the patient nor the expert witness supplied evidence to support the claims of gross negligence or exemplary damages against the ObGyn.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

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.

Woman dies after robotic hysterectomy: $5M verdict

When a 36-year-old woman underwent robotic hysterectomy, the gynecologist inserted a plastic trocar and sleeve through the patient's umbilicus to access the abdominal cavity at 7:30 am.

The certified registered nurse anesthetist (CRNA) noted a significant abnormality in the patient's vital signs at 8:07 am and administered medication and fluids to treat a suspected blood loss. When the patient's heart rate became extremely elevated at 8:25 am, the CRNA administered another drug, which failed to bring the patient's heart rate down. At 8:37 am, the monitoring machine could not record the patient's blood pressure. The CRNA informed the surgeon of the patient's condition. The supervising anesthesiologist was called; he arrived at 8:45 am and determined that the patient was bleeding internally. He asked the surgeon if he could visualize any bleeding; the surgeon could not.

The patient's condition continued to deteriorate. At 9:05 am, her blood pressure was still undetectable on the monitor. A Code Blue was called at 9:30 am. Exploratory surgery and blood transfusions begun at  9:43 am were not able to counteract the patient's massive blood loss. After cardiac arrest, she was pronounced dead at 11:18 am.

ESTATE'S CLAIM:

The surgeon was negligent in lacerating the left common iliac artery when inserting the trocar, and in not detecting the injury intraoperatively.

The anesthesia staff was  negligent. The CRNA did not inform the surgeon until the situation was dire. A simple procedure could have been performed at any time to check the patient's hematocrit and hemoglobin levels, but that was not done until 9:30 am. If the severity of the patient's condition had been determined earlier, blood transfusions and further treatment could have saved her life.

DEFENDANTS' DEFENSE:

There was no negligence on the part of the surgeon or anesthesia team. The standard of care was met. Arterial laceration is a known risk of the surgery.

VERDICT:

A $5,008,922 Illinois verdict was returned against all defendants except the CRNA.

A woman with MS becomes incontinent after surgery

A 43-year-old woman with multiple sclerosis (MS) underwent a hysterectomy performed by a gynecologic surgeon. During surgery, the patient's ureter was injured, requiring additional surgery. The patient is now permanently incontinent.

PATIENT'S CLAIM:

During surgery, the surgeon constricted the ureter with stitches. A second surgery was needed to remove the stitches and reimplant the ureter. The second surgery left her permanently incontinent. Although incontinence is a known complication of the second surgery, the second surgery would not have been necessary if the surgeon had not injured the ureter during the first surgery. Incontinence was not a result of her MS as she was not incontinent before the second surgery.

DEFENDANTS' DEFENSE:

There was no deviation from the standard of care. There was no stitching around the ureter. The ureter was damaged by kinking, which was addressed during the second surgery. Incontinence was a result of her MS.

VERDICT:

A $700,000 South Carolina verdict was returned.

Bowel injury during robotic procedure: $6.25M settlement

A woman in her late 60s reported minor urinary incontinence to her gynecologist. She underwent robot-assisted laparoscopic hysterectomy with a sling procedure for pelvic prolapse. During the sling procedure, the transverse colon was injured. The patient developed sepsis, requiring multiple attempts at surgical repair, including colostomy. The patient requires a permanent colostomy. She has a malabsorption disorder and needs frequent intravenous treatment for dehydration.

PATIENT'S CLAIM:

The surgeon failed to properly control the robotic device, causing injury to the patient's bowel. The surgeon deviated from the standard of care by failing to convert from the robot-assisted laparoscopic procedure to an open procedure when complications arose. The injury was not properly treated before the surgeon closed the initial surgery, causing the patient to develop sepsis.

PHYSICIAN'S DEFENSE:

The surgeon claimed that the injuries and resulting sepsis were the fault of other physicians and hospital staff. The case settled during trial.

VERDICT:

A $6.25 million New Jersey settlement was reached.

Hydrothermal ablation led to genital burns

A woman SAW AN OBGYN on October 2 to report menorrhagia. She had been treated for uterine fibroids with a Mirena intrauterine device and hydrothermal ablation. Another physician had suggested hysterectomy, which she declined.

When the ObGyn found that the patient had an enlarged uterus, he ordered ultrasonography and an endometrial biopsy. On follow-up, the ObGyn provided options of robotic hysterectomy or operative hysteroscopy with hydrothermal ablation. The patient chose hysteroscopy and the procedure was scheduled for December 28.

During surgery, an improper seal to the cervix around the hydrothermal ablation sheath was detected before heating the fluid. A tenaculum and 2 sponges were placed on the cervix to help form a seal and the fluid was heated for 4 minutes. The procedure was aborted when fluid was seen to be leaking again. Instruments were removed after a cooling period. The patient was discharged from the surgery center the same day with a prescription for oral hydrocodone bitartrate and acetaminophen for pain.

On January 4, the patient reported severe vulvar pain. The ObGyn found thermal burns on both labia with possible cellulitis. He prescribed silver sulfadiazine cream twice daily, levofloxacin 500 mg for 7 days, and warm-water soaks. When the patient called to report continued pain on January 7, the hydrocodone and acetaminophen prescription was renewed. On January 8, the ObGyn found continued evidence of labia and introitus burns with no signs of infection. The patient was told to continue taking the oral pain medication and to apply topical lidocaine gel and silver sulfadiazine cream.

Examinations on January 11, 17, 24, and 31 showed continued evidence of active healing. When new evidence of vulvar ulceration with inflammation and infection appeared, supportive care and antibiotics were given. On February 7, granulation tissue had developed at the introitus with continued healing.

On March 27, she saw a gynecologist for dyspareunia. The skin was healed but a tender band of scar tissue was noted at the burn site. She was referred for physical therapy and given estradiol vaginal cream.

On December 11, the patient reported dyspareunia and depression to the gynecologist, who prescribed medication for depression and referred her to counseling.

PATIENT'S CLAIM:

The ObGyn was negligent in failing to maintain a proper seal around the hydrothermal ablation shield. The patient sustained second-degree burns to her genital area from the hot saline solution that leaked from the uterus. The injury caused lasting dyspareunia and depression.

PHYSICIAN'S DEFENSE:

There was no negligence. Once the ObGyn realized that the seal was incomplete, the procedure was stopped and the fluid cooled before being released. Burns were treated within the standard of care.

VERDICT:

A Texas defense verdict was returned based on a no- evidence partial summary judgment: neither the patient nor the expert witness supplied evidence to support the claims of gross negligence or exemplary damages against the ObGyn.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

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.

Large sessile or flat colorectal polyps or laterally spreading lesions were most likely to contain covert malignancies when their location was rectosigmoid, their Paris classification was 0-Is or 0-IIa+Is, and they were nongranular, according to the results of a multicenter prospective cohort study of 2,106 consecutive patients reported in the September issue of Gastroenterology (doi: 10.1053/j.gastro.2017.05.047).

“Distal nongranular lesions have a high risk of occult SMIC [submucosal invasive cancer], whereas proximal, granular 0-IIa lesions, after a careful assessment for features associated with SMIC, have a very low risk,” wrote Nicholas G. Burgess, MD, of Westmead Hospital, Sydney, with his associates. “These findings can be used to inform decisions [about] which patients should undergo endoscopic submucosal dissection, endoscopic mucosal resection, or surgery.”

Source: American Gastroenterological Association

Many studies of colonic lesions have examined predictors of SMIC. Nonetheless, clinicians need more information on factors that improve clinical decision making, especially as colonic endoscopic submucosal dissection becomes more accessible, the researchers said. Large colonic lesions can contain submucosal invasive SMICs that are not visible on endoscopy, and characterizing predictors of this occurrence could help patients and clinicians decide between endoscopic submucosal dissection and endoscopic mucosal resection. To do so, the researchers analyzed histologic specimens from 2,277 colonic lesions above 20 mm (average size, 37 mm) that lacked overt endoscopic high-risk features. The study ran from 2008 through 2016, study participants averaged 68 years of age, and 53% were male. A total of 171 lesions (8%) had evidence of SMIC on pathologic review, and 138 lesions had covert SMIC. Predictors of overt and occult SMIC included Kudo pit pattern V, a depressed component (0-IIc), rectosigmoid location, 0-Is or 0-IIa+Is Paris classification, nongranular surface morphology, and larger size. After excluding lesions with obvious SMIC features – including serrated lesions and those with depressed components (Kudo pit pattern of V and Paris 0-IIc) – the strongest predictors of occult SMIC included Paris classification, surface morphology, size, and location.

“Proximal 0-IIa G or 0-Is granular lesions had the lowest risk of SMIC (0.7% and 2.3%), whereas distal 0-Is nongranular lesions had the highest risk (21.4%),” the investigators added. Lesion location, size, and combined Paris classification and surface topography showed the best fit in a multivariable model. Notably, rectosigmoid lesions had nearly twice the odds of containing covert SMIC, compared with proximal lesions (odds ratio, 1.9; 95% confidence interval, 1.2-3.0; P = .01). Other significant predictors of covert SMIC in the multivariable model included combined Paris classification, surface morphology (OR, 4.0; 95% CI, 1.2-12.7; P = .02), and increasing size (OR, 1.2 per 10-mm increase; 95% CI, 1.04-1.3; P = .01). Increased size showed an even greater effect in lesions exceeding 50 mm.
 

Clinicians can use these factors to help evaluate risk of invasive cancer in lesions without overt SMIC, the researchers said. “One lesion type that differs from the pattern is 0-IIa nongranular lesions,” they noted. “Once lesions with overt evidence of SMIC are excluded, these lesions have a low risk (4.2%) of harboring underlying cancer.” Although 42% of lesions with covert SMIC were SM1 (potentially curable by endoscopic resection), no predictor of covert SMIC also predicted SMI status.

Funders included Cancer Institute of New South Wales and Gallipoli Medical Research Foundation. The investigators had no conflicts of interest.

Large sessile or flat colorectal polyps or laterally spreading lesions were most likely to contain covert malignancies when their location was rectosigmoid, their Paris classification was 0-Is or 0-IIa+Is, and they were nongranular, according to the results of a multicenter prospective cohort study of 2,106 consecutive patients reported in the September issue of Gastroenterology (doi: 10.1053/j.gastro.2017.05.047).

“Distal nongranular lesions have a high risk of occult SMIC [submucosal invasive cancer], whereas proximal, granular 0-IIa lesions, after a careful assessment for features associated with SMIC, have a very low risk,” wrote Nicholas G. Burgess, MD, of Westmead Hospital, Sydney, with his associates. “These findings can be used to inform decisions [about] which patients should undergo endoscopic submucosal dissection, endoscopic mucosal resection, or surgery.”

Source: American Gastroenterological Association

Many studies of colonic lesions have examined predictors of SMIC. Nonetheless, clinicians need more information on factors that improve clinical decision making, especially as colonic endoscopic submucosal dissection becomes more accessible, the researchers said. Large colonic lesions can contain submucosal invasive SMICs that are not visible on endoscopy, and characterizing predictors of this occurrence could help patients and clinicians decide between endoscopic submucosal dissection and endoscopic mucosal resection. To do so, the researchers analyzed histologic specimens from 2,277 colonic lesions above 20 mm (average size, 37 mm) that lacked overt endoscopic high-risk features. The study ran from 2008 through 2016, study participants averaged 68 years of age, and 53% were male. A total of 171 lesions (8%) had evidence of SMIC on pathologic review, and 138 lesions had covert SMIC. Predictors of overt and occult SMIC included Kudo pit pattern V, a depressed component (0-IIc), rectosigmoid location, 0-Is or 0-IIa+Is Paris classification, nongranular surface morphology, and larger size. After excluding lesions with obvious SMIC features – including serrated lesions and those with depressed components (Kudo pit pattern of V and Paris 0-IIc) – the strongest predictors of occult SMIC included Paris classification, surface morphology, size, and location.

“Proximal 0-IIa G or 0-Is granular lesions had the lowest risk of SMIC (0.7% and 2.3%), whereas distal 0-Is nongranular lesions had the highest risk (21.4%),” the investigators added. Lesion location, size, and combined Paris classification and surface topography showed the best fit in a multivariable model. Notably, rectosigmoid lesions had nearly twice the odds of containing covert SMIC, compared with proximal lesions (odds ratio, 1.9; 95% confidence interval, 1.2-3.0; P = .01). Other significant predictors of covert SMIC in the multivariable model included combined Paris classification, surface morphology (OR, 4.0; 95% CI, 1.2-12.7; P = .02), and increasing size (OR, 1.2 per 10-mm increase; 95% CI, 1.04-1.3; P = .01). Increased size showed an even greater effect in lesions exceeding 50 mm.
 

Clinicians can use these factors to help evaluate risk of invasive cancer in lesions without overt SMIC, the researchers said. “One lesion type that differs from the pattern is 0-IIa nongranular lesions,” they noted. “Once lesions with overt evidence of SMIC are excluded, these lesions have a low risk (4.2%) of harboring underlying cancer.” Although 42% of lesions with covert SMIC were SM1 (potentially curable by endoscopic resection), no predictor of covert SMIC also predicted SMI status.

Funders included Cancer Institute of New South Wales and Gallipoli Medical Research Foundation. The investigators had no conflicts of interest.

Large sessile or flat colorectal polyps or laterally spreading lesions were most likely to contain covert malignancies when their location was rectosigmoid, their Paris classification was 0-Is or 0-IIa+Is, and they were nongranular, according to the results of a multicenter prospective cohort study of 2,106 consecutive patients reported in the September issue of Gastroenterology (doi: 10.1053/j.gastro.2017.05.047).

“Distal nongranular lesions have a high risk of occult SMIC [submucosal invasive cancer], whereas proximal, granular 0-IIa lesions, after a careful assessment for features associated with SMIC, have a very low risk,” wrote Nicholas G. Burgess, MD, of Westmead Hospital, Sydney, with his associates. “These findings can be used to inform decisions [about] which patients should undergo endoscopic submucosal dissection, endoscopic mucosal resection, or surgery.”

Source: American Gastroenterological Association

Many studies of colonic lesions have examined predictors of SMIC. Nonetheless, clinicians need more information on factors that improve clinical decision making, especially as colonic endoscopic submucosal dissection becomes more accessible, the researchers said. Large colonic lesions can contain submucosal invasive SMICs that are not visible on endoscopy, and characterizing predictors of this occurrence could help patients and clinicians decide between endoscopic submucosal dissection and endoscopic mucosal resection. To do so, the researchers analyzed histologic specimens from 2,277 colonic lesions above 20 mm (average size, 37 mm) that lacked overt endoscopic high-risk features. The study ran from 2008 through 2016, study participants averaged 68 years of age, and 53% were male. A total of 171 lesions (8%) had evidence of SMIC on pathologic review, and 138 lesions had covert SMIC. Predictors of overt and occult SMIC included Kudo pit pattern V, a depressed component (0-IIc), rectosigmoid location, 0-Is or 0-IIa+Is Paris classification, nongranular surface morphology, and larger size. After excluding lesions with obvious SMIC features – including serrated lesions and those with depressed components (Kudo pit pattern of V and Paris 0-IIc) – the strongest predictors of occult SMIC included Paris classification, surface morphology, size, and location.

“Proximal 0-IIa G or 0-Is granular lesions had the lowest risk of SMIC (0.7% and 2.3%), whereas distal 0-Is nongranular lesions had the highest risk (21.4%),” the investigators added. Lesion location, size, and combined Paris classification and surface topography showed the best fit in a multivariable model. Notably, rectosigmoid lesions had nearly twice the odds of containing covert SMIC, compared with proximal lesions (odds ratio, 1.9; 95% confidence interval, 1.2-3.0; P = .01). Other significant predictors of covert SMIC in the multivariable model included combined Paris classification, surface morphology (OR, 4.0; 95% CI, 1.2-12.7; P = .02), and increasing size (OR, 1.2 per 10-mm increase; 95% CI, 1.04-1.3; P = .01). Increased size showed an even greater effect in lesions exceeding 50 mm.
 

Clinicians can use these factors to help evaluate risk of invasive cancer in lesions without overt SMIC, the researchers said. “One lesion type that differs from the pattern is 0-IIa nongranular lesions,” they noted. “Once lesions with overt evidence of SMIC are excluded, these lesions have a low risk (4.2%) of harboring underlying cancer.” Although 42% of lesions with covert SMIC were SM1 (potentially curable by endoscopic resection), no predictor of covert SMIC also predicted SMI status.

Funders included Cancer Institute of New South Wales and Gallipoli Medical Research Foundation. The investigators had no conflicts of interest.