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Evolving Treatment of Nonradiographic Axial Spondyloarthritis
Nonradiographic axial spondyloarthritis (nr-axSpA) shares many characteristics with radiographic disease and responds to the same treatments, yet it has fewer FDA-approved options.
As Dr Marina Magrey, from Case Western Reserve University School of Medicine, in Cleveland, Ohio, explains, the TNF inhibitor certolizumab has been approved on the basis of results from the C-axSpAnd study.
Similarly, the IL-17 inhibitors secukinumab and ixekizumab are also options, and the results of the COAST-X and PREVENT studies show them to be safe and efficacious.
In closing, Dr Magrey outlines the SELECT-AXIS 2 study showing benefit from the JAK inhibitor upadacitinib for nr-axSpA, with no additional safety signals.
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Professor of Rheumatology, Case Western Reserve University School of Medicine; Chief, Division of Rheumatology, University Hospitals, Cleveland, Ohio
Marina N. Magrey, MD, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Novartis; AbbVie; UCB Pharma; Pfizer; Eli Lilly; Janssen; Bristol Myers Squibb
Received research grant from: AbbVie; Bristol Myers Squibb; Amgen
Nonradiographic axial spondyloarthritis (nr-axSpA) shares many characteristics with radiographic disease and responds to the same treatments, yet it has fewer FDA-approved options.
As Dr Marina Magrey, from Case Western Reserve University School of Medicine, in Cleveland, Ohio, explains, the TNF inhibitor certolizumab has been approved on the basis of results from the C-axSpAnd study.
Similarly, the IL-17 inhibitors secukinumab and ixekizumab are also options, and the results of the COAST-X and PREVENT studies show them to be safe and efficacious.
In closing, Dr Magrey outlines the SELECT-AXIS 2 study showing benefit from the JAK inhibitor upadacitinib for nr-axSpA, with no additional safety signals.
--
Professor of Rheumatology, Case Western Reserve University School of Medicine; Chief, Division of Rheumatology, University Hospitals, Cleveland, Ohio
Marina N. Magrey, MD, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Novartis; AbbVie; UCB Pharma; Pfizer; Eli Lilly; Janssen; Bristol Myers Squibb
Received research grant from: AbbVie; Bristol Myers Squibb; Amgen
Nonradiographic axial spondyloarthritis (nr-axSpA) shares many characteristics with radiographic disease and responds to the same treatments, yet it has fewer FDA-approved options.
As Dr Marina Magrey, from Case Western Reserve University School of Medicine, in Cleveland, Ohio, explains, the TNF inhibitor certolizumab has been approved on the basis of results from the C-axSpAnd study.
Similarly, the IL-17 inhibitors secukinumab and ixekizumab are also options, and the results of the COAST-X and PREVENT studies show them to be safe and efficacious.
In closing, Dr Magrey outlines the SELECT-AXIS 2 study showing benefit from the JAK inhibitor upadacitinib for nr-axSpA, with no additional safety signals.
--
Professor of Rheumatology, Case Western Reserve University School of Medicine; Chief, Division of Rheumatology, University Hospitals, Cleveland, Ohio
Marina N. Magrey, MD, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Novartis; AbbVie; UCB Pharma; Pfizer; Eli Lilly; Janssen; Bristol Myers Squibb
Received research grant from: AbbVie; Bristol Myers Squibb; Amgen
Knee pain on walking
Overall, persons with schizophrenia are more likely than the general population to be overweight and have cardiovascular risk factors before starting treatment with antipsychotics, and such treatment generally worsens these measures. Weight gain and associated morbidity and mortality are common side effects of antipsychotic medications. Olanzapine is associated with significant weight gain of 7% or more, higher than other second-generation antipsychotics. Olanzapine treatment is the major contributor to this patient's additional weight gain over the past 2 years. This added weight has translated to excess wear and tear on her joints, leading to evidence of osteoarthritis. Treatment with olanzapine is also independently associated with detrimental changes in cardiometabolic parameters.
Interventions to prevent or mitigate weight gain with antipsychotics are limited. In general, the American Psychiatric Association does not recommend switching antipsychotics for patients whose schizophrenia is well managed. However, there is increasing evidence that metformin may have a role in mitigating weight gain as well as beneficially modifying cardiometabolic factors in patients with schizophrenia being treated with olanzapine. A systematic review of emerging evidence with metformin in patients with schizophrenia suggests that metformin may also improve some cognitive symptoms of the illness, although further research is needed. The randomized, double-blind MELIA trial of metformin plus lifestyle intervention in antipsychotic-induced weight gain is ongoing. Starting metformin as a preventive measure at the same time as antipsychotic therapy may help to limit excess weight gain.
Research continues on the potential benefit of adding weight loss medications, including glucagon-like peptide-1 (GLP-1) receptor agonists, to antipsychotics. Daily liraglutide is most widely studied, but a published case series with weekly semaglutide also demonstrated weight loss in this setting. Liraglutide also has shown beneficial cardiometabolic effects in patients using antipsychotic medications. More studies of these drugs and of GLP-1/glucose-dependent insulinotropic polypeptide agonists are needed to elucidate the optimal use of these therapies for patients with schizophrenia.
There are few other effective ways to mitigate weight gain with olanzapine. Patients should be counseled on nutrition and lifestyle modifications. Evidence supports improvement with structured lifestyle modifications across a range of patients with less severe mental health issues, and structured programs combined with motivational interviewing were associated with reductions in antipsychotic-induced weight gain in patients with severe mental illness. As with any patient with obesity, however, the success of lifestyle modifications is heavily dependent on the individual's ability and motivation to comply with recommended interventions.
Nonpharmacologic interventions to address joint pain include heat or cold compresses, physical therapy, and strength and resistance training to improve the strength of muscles supporting the joints. If these measures are ineffective, nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, naproxen, meloxicam, diclofenac, or celecoxib may be used with regular follow-up to assess cardiovascular and gastrointestinal health. Topical NSAIDs also may be useful. For more intractable joint pain, options include injecting a corticosteroid or sodium hyaluronate into the affected joints or joint replacement.
Carolyn Newberry, MD, Assistant Professor of Medicine, Director of GI Nutrition, Innovative Center for Health and Nutrition in Gastroenterology (ICHANGE), Division of Gastroenterology, Weill Cornell Medical Center, New York, NY.
Disclosure: Carolyn Newberry, MD, has disclosed the following relevant financial relationships:
Serve(d) as a speaker or a member of a speakers bureau for: Baster International; InBody.
Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.
Overall, persons with schizophrenia are more likely than the general population to be overweight and have cardiovascular risk factors before starting treatment with antipsychotics, and such treatment generally worsens these measures. Weight gain and associated morbidity and mortality are common side effects of antipsychotic medications. Olanzapine is associated with significant weight gain of 7% or more, higher than other second-generation antipsychotics. Olanzapine treatment is the major contributor to this patient's additional weight gain over the past 2 years. This added weight has translated to excess wear and tear on her joints, leading to evidence of osteoarthritis. Treatment with olanzapine is also independently associated with detrimental changes in cardiometabolic parameters.
Interventions to prevent or mitigate weight gain with antipsychotics are limited. In general, the American Psychiatric Association does not recommend switching antipsychotics for patients whose schizophrenia is well managed. However, there is increasing evidence that metformin may have a role in mitigating weight gain as well as beneficially modifying cardiometabolic factors in patients with schizophrenia being treated with olanzapine. A systematic review of emerging evidence with metformin in patients with schizophrenia suggests that metformin may also improve some cognitive symptoms of the illness, although further research is needed. The randomized, double-blind MELIA trial of metformin plus lifestyle intervention in antipsychotic-induced weight gain is ongoing. Starting metformin as a preventive measure at the same time as antipsychotic therapy may help to limit excess weight gain.
Research continues on the potential benefit of adding weight loss medications, including glucagon-like peptide-1 (GLP-1) receptor agonists, to antipsychotics. Daily liraglutide is most widely studied, but a published case series with weekly semaglutide also demonstrated weight loss in this setting. Liraglutide also has shown beneficial cardiometabolic effects in patients using antipsychotic medications. More studies of these drugs and of GLP-1/glucose-dependent insulinotropic polypeptide agonists are needed to elucidate the optimal use of these therapies for patients with schizophrenia.
There are few other effective ways to mitigate weight gain with olanzapine. Patients should be counseled on nutrition and lifestyle modifications. Evidence supports improvement with structured lifestyle modifications across a range of patients with less severe mental health issues, and structured programs combined with motivational interviewing were associated with reductions in antipsychotic-induced weight gain in patients with severe mental illness. As with any patient with obesity, however, the success of lifestyle modifications is heavily dependent on the individual's ability and motivation to comply with recommended interventions.
Nonpharmacologic interventions to address joint pain include heat or cold compresses, physical therapy, and strength and resistance training to improve the strength of muscles supporting the joints. If these measures are ineffective, nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, naproxen, meloxicam, diclofenac, or celecoxib may be used with regular follow-up to assess cardiovascular and gastrointestinal health. Topical NSAIDs also may be useful. For more intractable joint pain, options include injecting a corticosteroid or sodium hyaluronate into the affected joints or joint replacement.
Carolyn Newberry, MD, Assistant Professor of Medicine, Director of GI Nutrition, Innovative Center for Health and Nutrition in Gastroenterology (ICHANGE), Division of Gastroenterology, Weill Cornell Medical Center, New York, NY.
Disclosure: Carolyn Newberry, MD, has disclosed the following relevant financial relationships:
Serve(d) as a speaker or a member of a speakers bureau for: Baster International; InBody.
Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.
Overall, persons with schizophrenia are more likely than the general population to be overweight and have cardiovascular risk factors before starting treatment with antipsychotics, and such treatment generally worsens these measures. Weight gain and associated morbidity and mortality are common side effects of antipsychotic medications. Olanzapine is associated with significant weight gain of 7% or more, higher than other second-generation antipsychotics. Olanzapine treatment is the major contributor to this patient's additional weight gain over the past 2 years. This added weight has translated to excess wear and tear on her joints, leading to evidence of osteoarthritis. Treatment with olanzapine is also independently associated with detrimental changes in cardiometabolic parameters.
Interventions to prevent or mitigate weight gain with antipsychotics are limited. In general, the American Psychiatric Association does not recommend switching antipsychotics for patients whose schizophrenia is well managed. However, there is increasing evidence that metformin may have a role in mitigating weight gain as well as beneficially modifying cardiometabolic factors in patients with schizophrenia being treated with olanzapine. A systematic review of emerging evidence with metformin in patients with schizophrenia suggests that metformin may also improve some cognitive symptoms of the illness, although further research is needed. The randomized, double-blind MELIA trial of metformin plus lifestyle intervention in antipsychotic-induced weight gain is ongoing. Starting metformin as a preventive measure at the same time as antipsychotic therapy may help to limit excess weight gain.
Research continues on the potential benefit of adding weight loss medications, including glucagon-like peptide-1 (GLP-1) receptor agonists, to antipsychotics. Daily liraglutide is most widely studied, but a published case series with weekly semaglutide also demonstrated weight loss in this setting. Liraglutide also has shown beneficial cardiometabolic effects in patients using antipsychotic medications. More studies of these drugs and of GLP-1/glucose-dependent insulinotropic polypeptide agonists are needed to elucidate the optimal use of these therapies for patients with schizophrenia.
There are few other effective ways to mitigate weight gain with olanzapine. Patients should be counseled on nutrition and lifestyle modifications. Evidence supports improvement with structured lifestyle modifications across a range of patients with less severe mental health issues, and structured programs combined with motivational interviewing were associated with reductions in antipsychotic-induced weight gain in patients with severe mental illness. As with any patient with obesity, however, the success of lifestyle modifications is heavily dependent on the individual's ability and motivation to comply with recommended interventions.
Nonpharmacologic interventions to address joint pain include heat or cold compresses, physical therapy, and strength and resistance training to improve the strength of muscles supporting the joints. If these measures are ineffective, nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, naproxen, meloxicam, diclofenac, or celecoxib may be used with regular follow-up to assess cardiovascular and gastrointestinal health. Topical NSAIDs also may be useful. For more intractable joint pain, options include injecting a corticosteroid or sodium hyaluronate into the affected joints or joint replacement.
Carolyn Newberry, MD, Assistant Professor of Medicine, Director of GI Nutrition, Innovative Center for Health and Nutrition in Gastroenterology (ICHANGE), Division of Gastroenterology, Weill Cornell Medical Center, New York, NY.
Disclosure: Carolyn Newberry, MD, has disclosed the following relevant financial relationships:
Serve(d) as a speaker or a member of a speakers bureau for: Baster International; InBody.
Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.
A 32-year-old woman presents with knee pain on walking and elbow pain. She is 5 ft 6 in tall and weighs 187 lb (BMI 30.2). She was diagnosed with schizophrenia 2 years ago and began treatment with olanzapine at diagnosis; her symptoms currently are controlled, and she has tolerated the medication well.
The patient says that she has been overweight since her teenage years and weighed 170 lb (BMI ~27) at age 30. However, she remained physically active until development of painful joints over the past 18 months. She works remotely full time and lives alone. She describes her long-standing diet as heavy on meat protein and light on vegetables and snacks and says it hasn't changed; she denies binge eating or other disordered eating.
Physical exam reveals tender joints at knees and elbows and central obesity (waist circumference, 42 in). Blood pressure is 135/90 mm Hg. Lab results indicate a fasting glucose level of 115 mg/dL and a triglyceride level of 170 mg/dL. She is negative for rheumatoid factor. Radiography shows premature joint erosion at the knees and elbows.
Obesity and Pregnancy
Migraine Differential Diagnosis
Uncommon Locations for Brain Herniations Into Arachnoid Granulations: 5 Cases and Literature Review
The circulation of cerebrospinal fluid (CSF) is crucial for maintaining homeostasis for the optimal functioning of the multiple complex activities of the brain and spinal cord, including the disposal of metabolic waste products of brain and spinal cord activity into the cerebral venous drainage. Throughout the brain, the arachnoid mater forms small outpouchings or diverticula that penetrate the dura mater and communicate with the dural venous sinuses. These outpuchings are called arachnoid granulations or arachnoid villi, and most are found within the dural sinuses, primarily in the transverse sinuses and superior sagittal sinus, but can occasionally be seen extending into the inner table of the calvarium.1,2
The amount of arachnoid granulations seen in bone, particularly around the superior sagittal sinus, may increase with age.2 Arachnoid granulations are generally small but the largest ones can be seen on gross examination during intracranial procedures or autopsy.3 Magnetic resonance imaging (MRI) can detect arachnoid granulations, which are characterized as T1 hypointense and T2 hyperintense (CSF isointense), well-circumscribed, small, nonenhancing masses within the dural sinuses or in the diploic space (Figure 1). Even small arachnoid granulations < 1 mm in length can be detected.2
Smaller arachnoid granulations have been described histologically as entirely covered by a dural membrane, thus creating a subdural space that separates the body of the arachnoid granulation from the lumen of the accompanying venous sinus.4 However, larger arachnoid granulations may not be completely covered by a dural membrane, thus creating a point of contact between the arachnoid granulation and the venous sinus.4 Larger arachnoid granulations are normally filled with CSF, and their signal characteristics are similar to CSF on imaging.5,6 Arachnoid granulations also often contain vessels draining into the adjacent venous sinus.5,6
When larger arachnoid granulations are present, they may permit the protrusion of herniated brain tissue. There has been an increasing number of reports of these brain herniations into arachnoid granulations (BHAGs) in the literature.7-10 While these herniations have been associated with nonspecific neurologic symptoms like tinnitus and idiopathic intracranial hypertension, their true clinical significance remains undetermined.10,11 This article presents 5 cases of BHAG, discusses their clinical presentations and image findings, and reviews the current literature.
Case 1
A 30-year-old male with a history of multiple traumatic brain injuries presented for evaluation of seizures. The patient described the semiology of the seizures as a bright, colorful light in his right visual field, followed by loss of vision, then loss of awareness and full body convulsion. The semiology of this patient’s seizures was consistent with left temporo-occipital lobe seizure. The only abnormality seen in the brain MRI was the herniation of brain parenchyma originating from the occipital lobe into the transverse sinus, presumably through an arachnoid granulation (Figure 1). An electroencephalogram (EEG) was unremarkable, though the semiology of the seizure historically described by the patient was localized to the area of BHAG. The patient is currently taking antiseizure medications and has experienced no additional seizures.
Case 2
A male aged 53 years with a history of peripheral artery disease presented with a 6-month history of headaches and dizziness. The patient reported the onset of visual aura to his right visual field, starting as a fingernail-sized scintillating kaleidoscope light that would gradually increase in size to a round shape with fading kaleidoscope colors. This episode would last for a few minutes and was immediately followed by a headache. There was no alteration of consciousness during visual aura, although sometimes the patient would have right-sided scalp tingling. These episodes were often unprovoked, but occasionally triggered by bright lights. A single routine EEG was unremarkable. The patient reported headaches without aura, but not aura without headaches, which made occipital lobe seizure less likely. MRI demonstrated a small herniation of brain parenchyma into the inner table of the left occipital bone (Figure 2). The patient was diagnosed with migraine with aura, and the semiology of the visual aura corresponded to the location of the herniation in the left occipital region.
Case 3
A 77-year-old male with a history of left ear diving injury presented with left-sided asymmetric hearing loss and word recognition difficulty for several years. MRI obtained as part of his work-up to evaluate for possible schwannoma of the eighth left cranial nerve instead demonstrated an incidental right cerebellar herniation within an arachnoid granulation into the diploic space of the occipital bone (Figure 3). The BHAG for this patient appeared to be an incidental finding unrelated to his asymmetric hearing loss.
Case 4
A male aged 62 years with a history of metastatic esophageal cancer, substance abuse, and a prior presumed alcohol withdrawal seizure underwent an MRI for evaluation of brain metastasis after presenting to the hospital with confusion 1 day after starting chemotherapy (Figure 4). Nine years prior, the patient had an isolated generalized tonic-clonic seizure approximately 72 hours following a period of alcohol cessation. The MRI demonstrated an incidental left parasagittal herniation of left parietal lobe tissue through an arachnoid granulation into the superior sagittal sinus, in addition to metastatic brain lesions. An EEG showed mild encephalopathy without evidence of seizures. It was determined that the patient's confusion was most likely due to toxic-metabolic encephalopathy from chemotherapy.
Case 5
A 51-year-old male presented with worsening headache severity and frequency. He had a history of chronic headaches for about 20 years that occurred annually, but were now occurring twice weekly. The headaches often started with a left eye visual aura followed by pressure in the left eye, left frontal region, and left ear, with at times a cervicogenic component. No cervical spine imaging was available. An MRI revealed 2 small adjacent areas of cerebellar herniation into arachnoid granulations in the left occipital bone (Figure 5).
Discussion
Arachnoid granulations appear very early in life, although they are uncommon before age 2 years.2 Classically, they have been understood to act as 1-way valves permitting the outflow of CSF from the subarachnoid space to the dural venous sinuses. However, increasing evidence shows they may only play a minor role in that process.12 The structure of arachnoid granulations is being reexamined. A recent microscopy study demonstrated structural heterogeneity with a fine, porous lining that permits flow.13 Additionally, associated immune components in the microenvironment suggests that arachnoid granulations may function similarly to lymph nodes as part of a central nervous system lymphatic network.13 Evidence is lacking for arachnoid granulations being the primary route of CSF outflow, and newer models include CSF exit pathways along the cranial nerves and drainage through lymphatics within the dura mater.12
New MRI systems have demonstrated that the prevalence of arachnoid granulations increases with age. One study found that all subjects in the aged 40 years cohort had detectable arachnoid granulations on images obtained with a 3T MRI system, with the main site being the superior sagittal sinus.2 The prevalence increased until age 40 years and then noticeably decreased. Not only did the prevalence increase in this pattern, but the total number of detectable arachnoid granulations followed a similar pattern.2 In addition, the detectable arachnoid granulations tend to be larger in older patients. Arachnoid granulations are very common in adults, but little is known about when and why brain tissue herniates through these structures.
This case series illustrates how a small amount of adult cerebral or cerebellar matter in large arachnoid granulations can herniate into the dural sinuses and diploic space. Although arachnoid granulations extending into the dural sinuses and diploic space are a relatively common finding on MRI,BHAGs are rare in these locations.1,2,8 Improved spatial resolution afforded by newer high-field scanners with thinner sections, such as very thin (1 mm) T1- and heavily T2-weighted 3 dimensional sequences may lead to increased detection of BHAG. Some of these herniations are small and may be easily missed or confused for normal arachnoid granulations on 3 to 5 mm thickness MRIs.
Despite increased recognition, it is still uncertain to what degree these herniations contribute to the clinical presentations. Associated neurologic symptoms may include seizures, headaches, tinnitus, syncope, and increased intracranial pressure.7-10
Three cases presented in this article demonstrated abnormal signals adjacent to the herniated brain, presumably due to dysplasia of gliotic tissue. In 1 study, parenchymal signal and structural changes occurred in about one-half of the reported BHAG, all of which were cerebellar herniations.7 In Case 1, the herniation and adjacent abnormal MRI signal corresponded to localization of the seizure semiology as obtained from patient history, strongly suggesting the BHAG played a role in the presentation. Signal abnormality accompanying an adjacent BHAG may suggest a higher likelihood that the BHAG has clinical relevance. However, the patient in Case 2 had a visual aura that corresponded to the BHAG location, so a signal abnormality may not be necessary for a patient to develop symptoms. Case 1 also included a history of documented traumatic brain injuries, suggesting that perhaps head trauma may facilitate BHAG development. Regardless, there is likely also a congenital component to their formation, as BHAG has been observed in the pediatric population.14
The patient's asymmetric left-sided hearing loss in Case 3 appeared unrelated to the BHAG as its location was in the contralateral cerebellar region and did not correspond to the patient’s clinical findings. The patient in Case 4 had a limited history regarding localization details of their prior presumed alcohol withdrawal seizure, such as head movements, eye deviation, or lateralized onset of convulsions. Given this limited data, it is unclear whether their prior seizure could have been related to BHAG or not. The patient in case 5 reported worsening headaches on the left side of his head, which corresponded to BHAG occurring on the left side. However, given that the increased T2 signal occurred in the left cerebellar hemisphere with BHAG in the left occipital bone, the occipital cortex was not involved. In this case, the BHAG would not explain the patient’s visual aura as such a lesion would have been expected in the right occipital cortex rather than its actual location in this patient’s left cerebellar hemisphere.
CONCLUSIONS
Understanding the clinical impact of brain herniations is important because they are probably more common than previously thought. Improved MRI capabilities suggest that more BHAG will be detected moving forward as radiologists interpret images with higher resolution and thinner slices. Until its significance is fully understood, BHAG will continue to complicate the diagnosis of patients with neurologic complaints whose brain MRIs and EEGs are otherwise unremarkable.
There have been no cases of surgical BHAG intervention and pathology analysis that would help determine their clinical significance. A related entity, temporal lobe encephalocele, has been linked to focal temporal lobe epilepsy, which has demonstrated significant symptom improvement following surgical correction.15 However, encephaloceles have been distinguished from BHAG in part because they do not necessarily herniate through an arachnoid granulation.8 BHAG has only begun to be characterized in detail over the last decade, so more research is needed to understand how it develops and what clinical significance it truly holds.
1. Ikushima I, Korogi Y, Makita O, et al. MRI of arachnoid granulations within the dural sinuses using a FLAIR pulse sequence. Br J Radiol. 1999;72(863):1046-1051. doi:10.1259/bjr.72.863.10700819
2. Rados M, Zivko M, Perisa A, Oreskovic D, Klarica M. No arachnoid granulations-no problems: number, size, and distribution of arachnoid granulations from birth to 80 years of age. Front Aging Neurosci. 2021;13:698865. doi:10.3389/fnagi.2021.698865
3. Grossman CB, Potts DG. Arachnoid granulations: radiology and anatomy. Radiology. 1974;113(1):95-100. doi:10.1148/113.1.95
4. Wolpow ER, Schaumburg HH. Structure of the human arachnoid granulation. J Neurosurg. 1972;37(6):724-727. doi:10.3171/jns.1972.37.6.0724
5. Leach JL, Jones BV, Tomsick TA, Stewart CA, Balko MG. Normal appearance of arachnoid granulations on contrast-enhanced CT and MR of the brain: differentiation from dural sinus disease. AJNR Am J Neuroradiol. 1996;17(8):1523-1532.
6. Roche J, Warner D. Arachnoid granulations in the transverse and sigmoid sinuses: CT, MR, and MR angiographic appearance of a normal anatomic variation. AJNR Am J Neuroradiol. 1996;17(4):677-683.
7. Malekzadehlashkariani S, Wanke I, Rufenacht DA, San Millan D. Brain herniations into arachnoid granulations: about 68 cases in 38 patients and review of the literature. Neuroradiology. 2016;58(5):443-457. doi:10.1007/s00234-016-1662-5
8. Battal B, Castillo M. Brain herniations into the dural venous sinuses or calvarium: MRI of a recently recognized entity. Neuroradiol J. 2014;27(1):55-62. doi:10.15274/NRJ-2014-10006
9. Liebo GB, Lane JJ, Van Gompel JJ, Eckel LJ, Schwartz KM, Lehman VT. Brain herniation into arachnoid granulations: clinical and neuroimaging features. J Neuroimaging. 2016;26(6):592-598. doi:10.1111/jon.12366
10. Smith ER, Caton MT, Villanueva-Meyer JE, et al. Brain herniation (encephalocele) into arachnoid granulations: Prevalence and association with pulsatile tinnitus and idiopathic intracranial hypertension. Neuroradiology. 2022;64(9):1747-1754.
11. Battal B, Hamcan S, Akgun V, et al. Brain herniations into the dural venous sinus or calvarium: MRI findings, possible causes and clinical significance. Eur Radiol. 2016;26(6):1723-1731.
12. Proulx ST. Cerebrospinal fluid outflow: A review of the historical and contemporary evidence for arachnoid villi, perineural routes, and dural lymphatics. Cell Mol Life Sci. 2021;78(6):2429-2457.
13. Shah T, Leurgans SE, Mehta RI, et al. Arachnoid granulations are lymphatic conduits that communicate with bone marrow and dura-arachnoid stroma. J Exp Med. 2023;220(2).
14. Sade R, Ogul H, Polat G, Pirimoglu B, Kantarci M. Brain herniation into the transverse sinuses’ arachnoid granulations in the pediatric population investigated with 3 T MRI. Acta Neurol Belg. 2019;119(2):225-231.
15. Saavalainen T, Jutila L, Mervaala E, Kalviainen R, Vanninen R, Immonen A. Temporal anteroinferior encephalocele: An underrecognized etiology of temporal lobe epilepsy? Neurology. 2015;85(17):1467-1474.
The circulation of cerebrospinal fluid (CSF) is crucial for maintaining homeostasis for the optimal functioning of the multiple complex activities of the brain and spinal cord, including the disposal of metabolic waste products of brain and spinal cord activity into the cerebral venous drainage. Throughout the brain, the arachnoid mater forms small outpouchings or diverticula that penetrate the dura mater and communicate with the dural venous sinuses. These outpuchings are called arachnoid granulations or arachnoid villi, and most are found within the dural sinuses, primarily in the transverse sinuses and superior sagittal sinus, but can occasionally be seen extending into the inner table of the calvarium.1,2
The amount of arachnoid granulations seen in bone, particularly around the superior sagittal sinus, may increase with age.2 Arachnoid granulations are generally small but the largest ones can be seen on gross examination during intracranial procedures or autopsy.3 Magnetic resonance imaging (MRI) can detect arachnoid granulations, which are characterized as T1 hypointense and T2 hyperintense (CSF isointense), well-circumscribed, small, nonenhancing masses within the dural sinuses or in the diploic space (Figure 1). Even small arachnoid granulations < 1 mm in length can be detected.2
Smaller arachnoid granulations have been described histologically as entirely covered by a dural membrane, thus creating a subdural space that separates the body of the arachnoid granulation from the lumen of the accompanying venous sinus.4 However, larger arachnoid granulations may not be completely covered by a dural membrane, thus creating a point of contact between the arachnoid granulation and the venous sinus.4 Larger arachnoid granulations are normally filled with CSF, and their signal characteristics are similar to CSF on imaging.5,6 Arachnoid granulations also often contain vessels draining into the adjacent venous sinus.5,6
When larger arachnoid granulations are present, they may permit the protrusion of herniated brain tissue. There has been an increasing number of reports of these brain herniations into arachnoid granulations (BHAGs) in the literature.7-10 While these herniations have been associated with nonspecific neurologic symptoms like tinnitus and idiopathic intracranial hypertension, their true clinical significance remains undetermined.10,11 This article presents 5 cases of BHAG, discusses their clinical presentations and image findings, and reviews the current literature.
Case 1
A 30-year-old male with a history of multiple traumatic brain injuries presented for evaluation of seizures. The patient described the semiology of the seizures as a bright, colorful light in his right visual field, followed by loss of vision, then loss of awareness and full body convulsion. The semiology of this patient’s seizures was consistent with left temporo-occipital lobe seizure. The only abnormality seen in the brain MRI was the herniation of brain parenchyma originating from the occipital lobe into the transverse sinus, presumably through an arachnoid granulation (Figure 1). An electroencephalogram (EEG) was unremarkable, though the semiology of the seizure historically described by the patient was localized to the area of BHAG. The patient is currently taking antiseizure medications and has experienced no additional seizures.
Case 2
A male aged 53 years with a history of peripheral artery disease presented with a 6-month history of headaches and dizziness. The patient reported the onset of visual aura to his right visual field, starting as a fingernail-sized scintillating kaleidoscope light that would gradually increase in size to a round shape with fading kaleidoscope colors. This episode would last for a few minutes and was immediately followed by a headache. There was no alteration of consciousness during visual aura, although sometimes the patient would have right-sided scalp tingling. These episodes were often unprovoked, but occasionally triggered by bright lights. A single routine EEG was unremarkable. The patient reported headaches without aura, but not aura without headaches, which made occipital lobe seizure less likely. MRI demonstrated a small herniation of brain parenchyma into the inner table of the left occipital bone (Figure 2). The patient was diagnosed with migraine with aura, and the semiology of the visual aura corresponded to the location of the herniation in the left occipital region.
Case 3
A 77-year-old male with a history of left ear diving injury presented with left-sided asymmetric hearing loss and word recognition difficulty for several years. MRI obtained as part of his work-up to evaluate for possible schwannoma of the eighth left cranial nerve instead demonstrated an incidental right cerebellar herniation within an arachnoid granulation into the diploic space of the occipital bone (Figure 3). The BHAG for this patient appeared to be an incidental finding unrelated to his asymmetric hearing loss.
Case 4
A male aged 62 years with a history of metastatic esophageal cancer, substance abuse, and a prior presumed alcohol withdrawal seizure underwent an MRI for evaluation of brain metastasis after presenting to the hospital with confusion 1 day after starting chemotherapy (Figure 4). Nine years prior, the patient had an isolated generalized tonic-clonic seizure approximately 72 hours following a period of alcohol cessation. The MRI demonstrated an incidental left parasagittal herniation of left parietal lobe tissue through an arachnoid granulation into the superior sagittal sinus, in addition to metastatic brain lesions. An EEG showed mild encephalopathy without evidence of seizures. It was determined that the patient's confusion was most likely due to toxic-metabolic encephalopathy from chemotherapy.
Case 5
A 51-year-old male presented with worsening headache severity and frequency. He had a history of chronic headaches for about 20 years that occurred annually, but were now occurring twice weekly. The headaches often started with a left eye visual aura followed by pressure in the left eye, left frontal region, and left ear, with at times a cervicogenic component. No cervical spine imaging was available. An MRI revealed 2 small adjacent areas of cerebellar herniation into arachnoid granulations in the left occipital bone (Figure 5).
Discussion
Arachnoid granulations appear very early in life, although they are uncommon before age 2 years.2 Classically, they have been understood to act as 1-way valves permitting the outflow of CSF from the subarachnoid space to the dural venous sinuses. However, increasing evidence shows they may only play a minor role in that process.12 The structure of arachnoid granulations is being reexamined. A recent microscopy study demonstrated structural heterogeneity with a fine, porous lining that permits flow.13 Additionally, associated immune components in the microenvironment suggests that arachnoid granulations may function similarly to lymph nodes as part of a central nervous system lymphatic network.13 Evidence is lacking for arachnoid granulations being the primary route of CSF outflow, and newer models include CSF exit pathways along the cranial nerves and drainage through lymphatics within the dura mater.12
New MRI systems have demonstrated that the prevalence of arachnoid granulations increases with age. One study found that all subjects in the aged 40 years cohort had detectable arachnoid granulations on images obtained with a 3T MRI system, with the main site being the superior sagittal sinus.2 The prevalence increased until age 40 years and then noticeably decreased. Not only did the prevalence increase in this pattern, but the total number of detectable arachnoid granulations followed a similar pattern.2 In addition, the detectable arachnoid granulations tend to be larger in older patients. Arachnoid granulations are very common in adults, but little is known about when and why brain tissue herniates through these structures.
This case series illustrates how a small amount of adult cerebral or cerebellar matter in large arachnoid granulations can herniate into the dural sinuses and diploic space. Although arachnoid granulations extending into the dural sinuses and diploic space are a relatively common finding on MRI,BHAGs are rare in these locations.1,2,8 Improved spatial resolution afforded by newer high-field scanners with thinner sections, such as very thin (1 mm) T1- and heavily T2-weighted 3 dimensional sequences may lead to increased detection of BHAG. Some of these herniations are small and may be easily missed or confused for normal arachnoid granulations on 3 to 5 mm thickness MRIs.
Despite increased recognition, it is still uncertain to what degree these herniations contribute to the clinical presentations. Associated neurologic symptoms may include seizures, headaches, tinnitus, syncope, and increased intracranial pressure.7-10
Three cases presented in this article demonstrated abnormal signals adjacent to the herniated brain, presumably due to dysplasia of gliotic tissue. In 1 study, parenchymal signal and structural changes occurred in about one-half of the reported BHAG, all of which were cerebellar herniations.7 In Case 1, the herniation and adjacent abnormal MRI signal corresponded to localization of the seizure semiology as obtained from patient history, strongly suggesting the BHAG played a role in the presentation. Signal abnormality accompanying an adjacent BHAG may suggest a higher likelihood that the BHAG has clinical relevance. However, the patient in Case 2 had a visual aura that corresponded to the BHAG location, so a signal abnormality may not be necessary for a patient to develop symptoms. Case 1 also included a history of documented traumatic brain injuries, suggesting that perhaps head trauma may facilitate BHAG development. Regardless, there is likely also a congenital component to their formation, as BHAG has been observed in the pediatric population.14
The patient's asymmetric left-sided hearing loss in Case 3 appeared unrelated to the BHAG as its location was in the contralateral cerebellar region and did not correspond to the patient’s clinical findings. The patient in Case 4 had a limited history regarding localization details of their prior presumed alcohol withdrawal seizure, such as head movements, eye deviation, or lateralized onset of convulsions. Given this limited data, it is unclear whether their prior seizure could have been related to BHAG or not. The patient in case 5 reported worsening headaches on the left side of his head, which corresponded to BHAG occurring on the left side. However, given that the increased T2 signal occurred in the left cerebellar hemisphere with BHAG in the left occipital bone, the occipital cortex was not involved. In this case, the BHAG would not explain the patient’s visual aura as such a lesion would have been expected in the right occipital cortex rather than its actual location in this patient’s left cerebellar hemisphere.
CONCLUSIONS
Understanding the clinical impact of brain herniations is important because they are probably more common than previously thought. Improved MRI capabilities suggest that more BHAG will be detected moving forward as radiologists interpret images with higher resolution and thinner slices. Until its significance is fully understood, BHAG will continue to complicate the diagnosis of patients with neurologic complaints whose brain MRIs and EEGs are otherwise unremarkable.
There have been no cases of surgical BHAG intervention and pathology analysis that would help determine their clinical significance. A related entity, temporal lobe encephalocele, has been linked to focal temporal lobe epilepsy, which has demonstrated significant symptom improvement following surgical correction.15 However, encephaloceles have been distinguished from BHAG in part because they do not necessarily herniate through an arachnoid granulation.8 BHAG has only begun to be characterized in detail over the last decade, so more research is needed to understand how it develops and what clinical significance it truly holds.
The circulation of cerebrospinal fluid (CSF) is crucial for maintaining homeostasis for the optimal functioning of the multiple complex activities of the brain and spinal cord, including the disposal of metabolic waste products of brain and spinal cord activity into the cerebral venous drainage. Throughout the brain, the arachnoid mater forms small outpouchings or diverticula that penetrate the dura mater and communicate with the dural venous sinuses. These outpuchings are called arachnoid granulations or arachnoid villi, and most are found within the dural sinuses, primarily in the transverse sinuses and superior sagittal sinus, but can occasionally be seen extending into the inner table of the calvarium.1,2
The amount of arachnoid granulations seen in bone, particularly around the superior sagittal sinus, may increase with age.2 Arachnoid granulations are generally small but the largest ones can be seen on gross examination during intracranial procedures or autopsy.3 Magnetic resonance imaging (MRI) can detect arachnoid granulations, which are characterized as T1 hypointense and T2 hyperintense (CSF isointense), well-circumscribed, small, nonenhancing masses within the dural sinuses or in the diploic space (Figure 1). Even small arachnoid granulations < 1 mm in length can be detected.2
Smaller arachnoid granulations have been described histologically as entirely covered by a dural membrane, thus creating a subdural space that separates the body of the arachnoid granulation from the lumen of the accompanying venous sinus.4 However, larger arachnoid granulations may not be completely covered by a dural membrane, thus creating a point of contact between the arachnoid granulation and the venous sinus.4 Larger arachnoid granulations are normally filled with CSF, and their signal characteristics are similar to CSF on imaging.5,6 Arachnoid granulations also often contain vessels draining into the adjacent venous sinus.5,6
When larger arachnoid granulations are present, they may permit the protrusion of herniated brain tissue. There has been an increasing number of reports of these brain herniations into arachnoid granulations (BHAGs) in the literature.7-10 While these herniations have been associated with nonspecific neurologic symptoms like tinnitus and idiopathic intracranial hypertension, their true clinical significance remains undetermined.10,11 This article presents 5 cases of BHAG, discusses their clinical presentations and image findings, and reviews the current literature.
Case 1
A 30-year-old male with a history of multiple traumatic brain injuries presented for evaluation of seizures. The patient described the semiology of the seizures as a bright, colorful light in his right visual field, followed by loss of vision, then loss of awareness and full body convulsion. The semiology of this patient’s seizures was consistent with left temporo-occipital lobe seizure. The only abnormality seen in the brain MRI was the herniation of brain parenchyma originating from the occipital lobe into the transverse sinus, presumably through an arachnoid granulation (Figure 1). An electroencephalogram (EEG) was unremarkable, though the semiology of the seizure historically described by the patient was localized to the area of BHAG. The patient is currently taking antiseizure medications and has experienced no additional seizures.
Case 2
A male aged 53 years with a history of peripheral artery disease presented with a 6-month history of headaches and dizziness. The patient reported the onset of visual aura to his right visual field, starting as a fingernail-sized scintillating kaleidoscope light that would gradually increase in size to a round shape with fading kaleidoscope colors. This episode would last for a few minutes and was immediately followed by a headache. There was no alteration of consciousness during visual aura, although sometimes the patient would have right-sided scalp tingling. These episodes were often unprovoked, but occasionally triggered by bright lights. A single routine EEG was unremarkable. The patient reported headaches without aura, but not aura without headaches, which made occipital lobe seizure less likely. MRI demonstrated a small herniation of brain parenchyma into the inner table of the left occipital bone (Figure 2). The patient was diagnosed with migraine with aura, and the semiology of the visual aura corresponded to the location of the herniation in the left occipital region.
Case 3
A 77-year-old male with a history of left ear diving injury presented with left-sided asymmetric hearing loss and word recognition difficulty for several years. MRI obtained as part of his work-up to evaluate for possible schwannoma of the eighth left cranial nerve instead demonstrated an incidental right cerebellar herniation within an arachnoid granulation into the diploic space of the occipital bone (Figure 3). The BHAG for this patient appeared to be an incidental finding unrelated to his asymmetric hearing loss.
Case 4
A male aged 62 years with a history of metastatic esophageal cancer, substance abuse, and a prior presumed alcohol withdrawal seizure underwent an MRI for evaluation of brain metastasis after presenting to the hospital with confusion 1 day after starting chemotherapy (Figure 4). Nine years prior, the patient had an isolated generalized tonic-clonic seizure approximately 72 hours following a period of alcohol cessation. The MRI demonstrated an incidental left parasagittal herniation of left parietal lobe tissue through an arachnoid granulation into the superior sagittal sinus, in addition to metastatic brain lesions. An EEG showed mild encephalopathy without evidence of seizures. It was determined that the patient's confusion was most likely due to toxic-metabolic encephalopathy from chemotherapy.
Case 5
A 51-year-old male presented with worsening headache severity and frequency. He had a history of chronic headaches for about 20 years that occurred annually, but were now occurring twice weekly. The headaches often started with a left eye visual aura followed by pressure in the left eye, left frontal region, and left ear, with at times a cervicogenic component. No cervical spine imaging was available. An MRI revealed 2 small adjacent areas of cerebellar herniation into arachnoid granulations in the left occipital bone (Figure 5).
Discussion
Arachnoid granulations appear very early in life, although they are uncommon before age 2 years.2 Classically, they have been understood to act as 1-way valves permitting the outflow of CSF from the subarachnoid space to the dural venous sinuses. However, increasing evidence shows they may only play a minor role in that process.12 The structure of arachnoid granulations is being reexamined. A recent microscopy study demonstrated structural heterogeneity with a fine, porous lining that permits flow.13 Additionally, associated immune components in the microenvironment suggests that arachnoid granulations may function similarly to lymph nodes as part of a central nervous system lymphatic network.13 Evidence is lacking for arachnoid granulations being the primary route of CSF outflow, and newer models include CSF exit pathways along the cranial nerves and drainage through lymphatics within the dura mater.12
New MRI systems have demonstrated that the prevalence of arachnoid granulations increases with age. One study found that all subjects in the aged 40 years cohort had detectable arachnoid granulations on images obtained with a 3T MRI system, with the main site being the superior sagittal sinus.2 The prevalence increased until age 40 years and then noticeably decreased. Not only did the prevalence increase in this pattern, but the total number of detectable arachnoid granulations followed a similar pattern.2 In addition, the detectable arachnoid granulations tend to be larger in older patients. Arachnoid granulations are very common in adults, but little is known about when and why brain tissue herniates through these structures.
This case series illustrates how a small amount of adult cerebral or cerebellar matter in large arachnoid granulations can herniate into the dural sinuses and diploic space. Although arachnoid granulations extending into the dural sinuses and diploic space are a relatively common finding on MRI,BHAGs are rare in these locations.1,2,8 Improved spatial resolution afforded by newer high-field scanners with thinner sections, such as very thin (1 mm) T1- and heavily T2-weighted 3 dimensional sequences may lead to increased detection of BHAG. Some of these herniations are small and may be easily missed or confused for normal arachnoid granulations on 3 to 5 mm thickness MRIs.
Despite increased recognition, it is still uncertain to what degree these herniations contribute to the clinical presentations. Associated neurologic symptoms may include seizures, headaches, tinnitus, syncope, and increased intracranial pressure.7-10
Three cases presented in this article demonstrated abnormal signals adjacent to the herniated brain, presumably due to dysplasia of gliotic tissue. In 1 study, parenchymal signal and structural changes occurred in about one-half of the reported BHAG, all of which were cerebellar herniations.7 In Case 1, the herniation and adjacent abnormal MRI signal corresponded to localization of the seizure semiology as obtained from patient history, strongly suggesting the BHAG played a role in the presentation. Signal abnormality accompanying an adjacent BHAG may suggest a higher likelihood that the BHAG has clinical relevance. However, the patient in Case 2 had a visual aura that corresponded to the BHAG location, so a signal abnormality may not be necessary for a patient to develop symptoms. Case 1 also included a history of documented traumatic brain injuries, suggesting that perhaps head trauma may facilitate BHAG development. Regardless, there is likely also a congenital component to their formation, as BHAG has been observed in the pediatric population.14
The patient's asymmetric left-sided hearing loss in Case 3 appeared unrelated to the BHAG as its location was in the contralateral cerebellar region and did not correspond to the patient’s clinical findings. The patient in Case 4 had a limited history regarding localization details of their prior presumed alcohol withdrawal seizure, such as head movements, eye deviation, or lateralized onset of convulsions. Given this limited data, it is unclear whether their prior seizure could have been related to BHAG or not. The patient in case 5 reported worsening headaches on the left side of his head, which corresponded to BHAG occurring on the left side. However, given that the increased T2 signal occurred in the left cerebellar hemisphere with BHAG in the left occipital bone, the occipital cortex was not involved. In this case, the BHAG would not explain the patient’s visual aura as such a lesion would have been expected in the right occipital cortex rather than its actual location in this patient’s left cerebellar hemisphere.
CONCLUSIONS
Understanding the clinical impact of brain herniations is important because they are probably more common than previously thought. Improved MRI capabilities suggest that more BHAG will be detected moving forward as radiologists interpret images with higher resolution and thinner slices. Until its significance is fully understood, BHAG will continue to complicate the diagnosis of patients with neurologic complaints whose brain MRIs and EEGs are otherwise unremarkable.
There have been no cases of surgical BHAG intervention and pathology analysis that would help determine their clinical significance. A related entity, temporal lobe encephalocele, has been linked to focal temporal lobe epilepsy, which has demonstrated significant symptom improvement following surgical correction.15 However, encephaloceles have been distinguished from BHAG in part because they do not necessarily herniate through an arachnoid granulation.8 BHAG has only begun to be characterized in detail over the last decade, so more research is needed to understand how it develops and what clinical significance it truly holds.
1. Ikushima I, Korogi Y, Makita O, et al. MRI of arachnoid granulations within the dural sinuses using a FLAIR pulse sequence. Br J Radiol. 1999;72(863):1046-1051. doi:10.1259/bjr.72.863.10700819
2. Rados M, Zivko M, Perisa A, Oreskovic D, Klarica M. No arachnoid granulations-no problems: number, size, and distribution of arachnoid granulations from birth to 80 years of age. Front Aging Neurosci. 2021;13:698865. doi:10.3389/fnagi.2021.698865
3. Grossman CB, Potts DG. Arachnoid granulations: radiology and anatomy. Radiology. 1974;113(1):95-100. doi:10.1148/113.1.95
4. Wolpow ER, Schaumburg HH. Structure of the human arachnoid granulation. J Neurosurg. 1972;37(6):724-727. doi:10.3171/jns.1972.37.6.0724
5. Leach JL, Jones BV, Tomsick TA, Stewart CA, Balko MG. Normal appearance of arachnoid granulations on contrast-enhanced CT and MR of the brain: differentiation from dural sinus disease. AJNR Am J Neuroradiol. 1996;17(8):1523-1532.
6. Roche J, Warner D. Arachnoid granulations in the transverse and sigmoid sinuses: CT, MR, and MR angiographic appearance of a normal anatomic variation. AJNR Am J Neuroradiol. 1996;17(4):677-683.
7. Malekzadehlashkariani S, Wanke I, Rufenacht DA, San Millan D. Brain herniations into arachnoid granulations: about 68 cases in 38 patients and review of the literature. Neuroradiology. 2016;58(5):443-457. doi:10.1007/s00234-016-1662-5
8. Battal B, Castillo M. Brain herniations into the dural venous sinuses or calvarium: MRI of a recently recognized entity. Neuroradiol J. 2014;27(1):55-62. doi:10.15274/NRJ-2014-10006
9. Liebo GB, Lane JJ, Van Gompel JJ, Eckel LJ, Schwartz KM, Lehman VT. Brain herniation into arachnoid granulations: clinical and neuroimaging features. J Neuroimaging. 2016;26(6):592-598. doi:10.1111/jon.12366
10. Smith ER, Caton MT, Villanueva-Meyer JE, et al. Brain herniation (encephalocele) into arachnoid granulations: Prevalence and association with pulsatile tinnitus and idiopathic intracranial hypertension. Neuroradiology. 2022;64(9):1747-1754.
11. Battal B, Hamcan S, Akgun V, et al. Brain herniations into the dural venous sinus or calvarium: MRI findings, possible causes and clinical significance. Eur Radiol. 2016;26(6):1723-1731.
12. Proulx ST. Cerebrospinal fluid outflow: A review of the historical and contemporary evidence for arachnoid villi, perineural routes, and dural lymphatics. Cell Mol Life Sci. 2021;78(6):2429-2457.
13. Shah T, Leurgans SE, Mehta RI, et al. Arachnoid granulations are lymphatic conduits that communicate with bone marrow and dura-arachnoid stroma. J Exp Med. 2023;220(2).
14. Sade R, Ogul H, Polat G, Pirimoglu B, Kantarci M. Brain herniation into the transverse sinuses’ arachnoid granulations in the pediatric population investigated with 3 T MRI. Acta Neurol Belg. 2019;119(2):225-231.
15. Saavalainen T, Jutila L, Mervaala E, Kalviainen R, Vanninen R, Immonen A. Temporal anteroinferior encephalocele: An underrecognized etiology of temporal lobe epilepsy? Neurology. 2015;85(17):1467-1474.
1. Ikushima I, Korogi Y, Makita O, et al. MRI of arachnoid granulations within the dural sinuses using a FLAIR pulse sequence. Br J Radiol. 1999;72(863):1046-1051. doi:10.1259/bjr.72.863.10700819
2. Rados M, Zivko M, Perisa A, Oreskovic D, Klarica M. No arachnoid granulations-no problems: number, size, and distribution of arachnoid granulations from birth to 80 years of age. Front Aging Neurosci. 2021;13:698865. doi:10.3389/fnagi.2021.698865
3. Grossman CB, Potts DG. Arachnoid granulations: radiology and anatomy. Radiology. 1974;113(1):95-100. doi:10.1148/113.1.95
4. Wolpow ER, Schaumburg HH. Structure of the human arachnoid granulation. J Neurosurg. 1972;37(6):724-727. doi:10.3171/jns.1972.37.6.0724
5. Leach JL, Jones BV, Tomsick TA, Stewart CA, Balko MG. Normal appearance of arachnoid granulations on contrast-enhanced CT and MR of the brain: differentiation from dural sinus disease. AJNR Am J Neuroradiol. 1996;17(8):1523-1532.
6. Roche J, Warner D. Arachnoid granulations in the transverse and sigmoid sinuses: CT, MR, and MR angiographic appearance of a normal anatomic variation. AJNR Am J Neuroradiol. 1996;17(4):677-683.
7. Malekzadehlashkariani S, Wanke I, Rufenacht DA, San Millan D. Brain herniations into arachnoid granulations: about 68 cases in 38 patients and review of the literature. Neuroradiology. 2016;58(5):443-457. doi:10.1007/s00234-016-1662-5
8. Battal B, Castillo M. Brain herniations into the dural venous sinuses or calvarium: MRI of a recently recognized entity. Neuroradiol J. 2014;27(1):55-62. doi:10.15274/NRJ-2014-10006
9. Liebo GB, Lane JJ, Van Gompel JJ, Eckel LJ, Schwartz KM, Lehman VT. Brain herniation into arachnoid granulations: clinical and neuroimaging features. J Neuroimaging. 2016;26(6):592-598. doi:10.1111/jon.12366
10. Smith ER, Caton MT, Villanueva-Meyer JE, et al. Brain herniation (encephalocele) into arachnoid granulations: Prevalence and association with pulsatile tinnitus and idiopathic intracranial hypertension. Neuroradiology. 2022;64(9):1747-1754.
11. Battal B, Hamcan S, Akgun V, et al. Brain herniations into the dural venous sinus or calvarium: MRI findings, possible causes and clinical significance. Eur Radiol. 2016;26(6):1723-1731.
12. Proulx ST. Cerebrospinal fluid outflow: A review of the historical and contemporary evidence for arachnoid villi, perineural routes, and dural lymphatics. Cell Mol Life Sci. 2021;78(6):2429-2457.
13. Shah T, Leurgans SE, Mehta RI, et al. Arachnoid granulations are lymphatic conduits that communicate with bone marrow and dura-arachnoid stroma. J Exp Med. 2023;220(2).
14. Sade R, Ogul H, Polat G, Pirimoglu B, Kantarci M. Brain herniation into the transverse sinuses’ arachnoid granulations in the pediatric population investigated with 3 T MRI. Acta Neurol Belg. 2019;119(2):225-231.
15. Saavalainen T, Jutila L, Mervaala E, Kalviainen R, Vanninen R, Immonen A. Temporal anteroinferior encephalocele: An underrecognized etiology of temporal lobe epilepsy? Neurology. 2015;85(17):1467-1474.
Commentary: Predicting Migraine Treatment Outcomes, July 2024
Evidence is emerging to help identify predictors of migraine treatment outcomes. Additionally, research is beginning to pinpoint lifestyle factors that have a measurable effect on migraine frequency, severity, and duration. Guiding patients to select beneficial lifestyle interventions can influence their migraine-associated quality of life and reduce the need for medication and other interventions. Knowing which patients might or might not benefit from specific medication classes can help in selecting the right therapies, potentially shortening the "trial and error" process that many patients must actively participate in as they assess which migraine treatments are most effective and tolerable.
Medications classified as anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAb), a relatively new category of migraine therapy, have shown strong evidence of efficacy for migraine treatment and prevention. However, as these medications — which include Aimovig (erenumab), Emgality (galcanezumab), Ajovy (fremanezumab), and Vyepti (eptinezumab) — are new, their long-term outcomes are not known; in addition, they are expensive and they do not work for everyone. Patients who are doing relatively well on other medications might ask about switching to one of the anti-CGRP mAb so that they can experience the better outcomes and low side-effect profile that they've been hearing about. New research is showing some prognostic indicators that can help identify which patients might experience a better response to anti-CGRP mAb.
A prospective real-world study published in the May 2024 issue of Journal of Neurology, Neurosurgery, and Psychiatry included 5818 patients who had been treated with an anti-CGRP mAb for high-frequency episodic or chronic migraine. The researchers assessed responses after 6 months of use, defining a good response as ≥50% reduction in monthly headache days and excellent response as ≥75% reduction in monthly headache days. They found that several pretreatment baseline factors were predictors of a good or excellent 6-month response: older age, the presence of unilateral pain, the absence of depression, fewer monthly migraine days, and lower Migraine Disability Assessment (MIDAS) score. Notably, men and women experienced comparable outcomes. While it's not completely clear why these factors were associated with better responses to anti-CGRP mAb, the results could help in selecting patients who might or might not benefit from this new medication class.
Results of a prospective study published in the May 2024 in The Journal of Headache and Pain demonstrated that patients treated with eptinezumab for 3 months experienced a reduction of monthly headaches, migraines, and the use of acute medication. The patients who had previously had an inadequate response to or were unable to tolerate other anti-CGRP mAb (erenumab, galcanezumab, fremanezumab) were less likely to experience improvement with eptinezumab than patients who had not had previous unsuccessful attempts with anti-CGRP mAb. This suggests that it might not be beneficial for patents to try multiple medications in this category if they have had an inadequate response or intolerability to others in the same drug class.
Lifestyle factors can play a role in migraine outcomes and may reduce the need for medication. A study published in The Journal of Headache and Pain in May 2024 examined the relationship between migraine and the American Heart Association (AHA) Guidelines for Cardiovascular Health recommended lifestyle factors. The study included 332,895 participants, with a median follow-up of 13.58 years. Researchers found that maintaining targeted or recommended body mass index (BMI), physical activity, sleep duration, sleep pattern, and sedentary time were associated with substantial reductions in migraine risk.
Diet, another lifestyle factor, can also have an effect on migraine. Avoiding dietary triggers is a well-known adjustment that many patients are advised to make. Overall diet quality can play a role in migraine outcomes as well. According to a study published in the May 2024 issue of Nutritional Neuroscience, participants who followed a diet that qualified as having a high Carbohydrate Quality Index (CQI) had lower migraine severity and duration than participants whose diets did not qualify as high CQI. The study included 266 women (age 18-45 years), using a 147-item food frequency questionnaire to assess CQI. The CQI, a relatively new index for measuring carbohydrate quality, includes four components: glycemic index, dietary fiber intake, ratio of whole grain to total grain, ratio of solid carbohydrates to total (solid + liquid) carbohydrates.1 A low glycemic index and higher scores for the other three factors translates to a high CQI.
While the results of the AHA/migraine study and the CQI/migraine study are interesting, the physiologic reasons for the outcomes and validation of the results need further investigation. It's not clear whether the decrease in migraines that's associated with optimal carbohydrate intake is associated with outcomes such as low BMI or better sleep, or whether carbohydrate metabolism could be an independent factor.
Predictive factors can be beneficial in making migraine treatment decisions. While trial and error will always remain part of optimal migraine therapy, customizing treatment on the basis of an individual patient's characteristics can help in reaching an effective treatment and better quality of life sooner.
Additional References
1. Sawicki CM, Lichtenstein AH, Rogers GT, et al. Comparison of indices of carbohydrate quality and food sources of dietary fiber on longitudinal changes in waist circumference in the Framingham Offspring Cohort. Nutrients. 2021;13:997. Source
Evidence is emerging to help identify predictors of migraine treatment outcomes. Additionally, research is beginning to pinpoint lifestyle factors that have a measurable effect on migraine frequency, severity, and duration. Guiding patients to select beneficial lifestyle interventions can influence their migraine-associated quality of life and reduce the need for medication and other interventions. Knowing which patients might or might not benefit from specific medication classes can help in selecting the right therapies, potentially shortening the "trial and error" process that many patients must actively participate in as they assess which migraine treatments are most effective and tolerable.
Medications classified as anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAb), a relatively new category of migraine therapy, have shown strong evidence of efficacy for migraine treatment and prevention. However, as these medications — which include Aimovig (erenumab), Emgality (galcanezumab), Ajovy (fremanezumab), and Vyepti (eptinezumab) — are new, their long-term outcomes are not known; in addition, they are expensive and they do not work for everyone. Patients who are doing relatively well on other medications might ask about switching to one of the anti-CGRP mAb so that they can experience the better outcomes and low side-effect profile that they've been hearing about. New research is showing some prognostic indicators that can help identify which patients might experience a better response to anti-CGRP mAb.
A prospective real-world study published in the May 2024 issue of Journal of Neurology, Neurosurgery, and Psychiatry included 5818 patients who had been treated with an anti-CGRP mAb for high-frequency episodic or chronic migraine. The researchers assessed responses after 6 months of use, defining a good response as ≥50% reduction in monthly headache days and excellent response as ≥75% reduction in monthly headache days. They found that several pretreatment baseline factors were predictors of a good or excellent 6-month response: older age, the presence of unilateral pain, the absence of depression, fewer monthly migraine days, and lower Migraine Disability Assessment (MIDAS) score. Notably, men and women experienced comparable outcomes. While it's not completely clear why these factors were associated with better responses to anti-CGRP mAb, the results could help in selecting patients who might or might not benefit from this new medication class.
Results of a prospective study published in the May 2024 in The Journal of Headache and Pain demonstrated that patients treated with eptinezumab for 3 months experienced a reduction of monthly headaches, migraines, and the use of acute medication. The patients who had previously had an inadequate response to or were unable to tolerate other anti-CGRP mAb (erenumab, galcanezumab, fremanezumab) were less likely to experience improvement with eptinezumab than patients who had not had previous unsuccessful attempts with anti-CGRP mAb. This suggests that it might not be beneficial for patents to try multiple medications in this category if they have had an inadequate response or intolerability to others in the same drug class.
Lifestyle factors can play a role in migraine outcomes and may reduce the need for medication. A study published in The Journal of Headache and Pain in May 2024 examined the relationship between migraine and the American Heart Association (AHA) Guidelines for Cardiovascular Health recommended lifestyle factors. The study included 332,895 participants, with a median follow-up of 13.58 years. Researchers found that maintaining targeted or recommended body mass index (BMI), physical activity, sleep duration, sleep pattern, and sedentary time were associated with substantial reductions in migraine risk.
Diet, another lifestyle factor, can also have an effect on migraine. Avoiding dietary triggers is a well-known adjustment that many patients are advised to make. Overall diet quality can play a role in migraine outcomes as well. According to a study published in the May 2024 issue of Nutritional Neuroscience, participants who followed a diet that qualified as having a high Carbohydrate Quality Index (CQI) had lower migraine severity and duration than participants whose diets did not qualify as high CQI. The study included 266 women (age 18-45 years), using a 147-item food frequency questionnaire to assess CQI. The CQI, a relatively new index for measuring carbohydrate quality, includes four components: glycemic index, dietary fiber intake, ratio of whole grain to total grain, ratio of solid carbohydrates to total (solid + liquid) carbohydrates.1 A low glycemic index and higher scores for the other three factors translates to a high CQI.
While the results of the AHA/migraine study and the CQI/migraine study are interesting, the physiologic reasons for the outcomes and validation of the results need further investigation. It's not clear whether the decrease in migraines that's associated with optimal carbohydrate intake is associated with outcomes such as low BMI or better sleep, or whether carbohydrate metabolism could be an independent factor.
Predictive factors can be beneficial in making migraine treatment decisions. While trial and error will always remain part of optimal migraine therapy, customizing treatment on the basis of an individual patient's characteristics can help in reaching an effective treatment and better quality of life sooner.
Additional References
1. Sawicki CM, Lichtenstein AH, Rogers GT, et al. Comparison of indices of carbohydrate quality and food sources of dietary fiber on longitudinal changes in waist circumference in the Framingham Offspring Cohort. Nutrients. 2021;13:997. Source
Evidence is emerging to help identify predictors of migraine treatment outcomes. Additionally, research is beginning to pinpoint lifestyle factors that have a measurable effect on migraine frequency, severity, and duration. Guiding patients to select beneficial lifestyle interventions can influence their migraine-associated quality of life and reduce the need for medication and other interventions. Knowing which patients might or might not benefit from specific medication classes can help in selecting the right therapies, potentially shortening the "trial and error" process that many patients must actively participate in as they assess which migraine treatments are most effective and tolerable.
Medications classified as anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAb), a relatively new category of migraine therapy, have shown strong evidence of efficacy for migraine treatment and prevention. However, as these medications — which include Aimovig (erenumab), Emgality (galcanezumab), Ajovy (fremanezumab), and Vyepti (eptinezumab) — are new, their long-term outcomes are not known; in addition, they are expensive and they do not work for everyone. Patients who are doing relatively well on other medications might ask about switching to one of the anti-CGRP mAb so that they can experience the better outcomes and low side-effect profile that they've been hearing about. New research is showing some prognostic indicators that can help identify which patients might experience a better response to anti-CGRP mAb.
A prospective real-world study published in the May 2024 issue of Journal of Neurology, Neurosurgery, and Psychiatry included 5818 patients who had been treated with an anti-CGRP mAb for high-frequency episodic or chronic migraine. The researchers assessed responses after 6 months of use, defining a good response as ≥50% reduction in monthly headache days and excellent response as ≥75% reduction in monthly headache days. They found that several pretreatment baseline factors were predictors of a good or excellent 6-month response: older age, the presence of unilateral pain, the absence of depression, fewer monthly migraine days, and lower Migraine Disability Assessment (MIDAS) score. Notably, men and women experienced comparable outcomes. While it's not completely clear why these factors were associated with better responses to anti-CGRP mAb, the results could help in selecting patients who might or might not benefit from this new medication class.
Results of a prospective study published in the May 2024 in The Journal of Headache and Pain demonstrated that patients treated with eptinezumab for 3 months experienced a reduction of monthly headaches, migraines, and the use of acute medication. The patients who had previously had an inadequate response to or were unable to tolerate other anti-CGRP mAb (erenumab, galcanezumab, fremanezumab) were less likely to experience improvement with eptinezumab than patients who had not had previous unsuccessful attempts with anti-CGRP mAb. This suggests that it might not be beneficial for patents to try multiple medications in this category if they have had an inadequate response or intolerability to others in the same drug class.
Lifestyle factors can play a role in migraine outcomes and may reduce the need for medication. A study published in The Journal of Headache and Pain in May 2024 examined the relationship between migraine and the American Heart Association (AHA) Guidelines for Cardiovascular Health recommended lifestyle factors. The study included 332,895 participants, with a median follow-up of 13.58 years. Researchers found that maintaining targeted or recommended body mass index (BMI), physical activity, sleep duration, sleep pattern, and sedentary time were associated with substantial reductions in migraine risk.
Diet, another lifestyle factor, can also have an effect on migraine. Avoiding dietary triggers is a well-known adjustment that many patients are advised to make. Overall diet quality can play a role in migraine outcomes as well. According to a study published in the May 2024 issue of Nutritional Neuroscience, participants who followed a diet that qualified as having a high Carbohydrate Quality Index (CQI) had lower migraine severity and duration than participants whose diets did not qualify as high CQI. The study included 266 women (age 18-45 years), using a 147-item food frequency questionnaire to assess CQI. The CQI, a relatively new index for measuring carbohydrate quality, includes four components: glycemic index, dietary fiber intake, ratio of whole grain to total grain, ratio of solid carbohydrates to total (solid + liquid) carbohydrates.1 A low glycemic index and higher scores for the other three factors translates to a high CQI.
While the results of the AHA/migraine study and the CQI/migraine study are interesting, the physiologic reasons for the outcomes and validation of the results need further investigation. It's not clear whether the decrease in migraines that's associated with optimal carbohydrate intake is associated with outcomes such as low BMI or better sleep, or whether carbohydrate metabolism could be an independent factor.
Predictive factors can be beneficial in making migraine treatment decisions. While trial and error will always remain part of optimal migraine therapy, customizing treatment on the basis of an individual patient's characteristics can help in reaching an effective treatment and better quality of life sooner.
Additional References
1. Sawicki CM, Lichtenstein AH, Rogers GT, et al. Comparison of indices of carbohydrate quality and food sources of dietary fiber on longitudinal changes in waist circumference in the Framingham Offspring Cohort. Nutrients. 2021;13:997. Source
Flesh-Colored Pinpoint Papules With Fine White Spicules on the Upper Body
The Diagnosis: Trichodysplasia Spinulosa
A diagnosis of trichodysplasia spinulosa (TS) was rendered based on the clinical presentation— diffuse folliculocentric keratotic papules with spicules and leonine facies—coinciding with cyclosporine initiation. Biopsy was deferred given the classic presentation. The patient applied cidofovir cream 1% daily to lesions on the face. She was prescribed leflunomide 10 mg daily, which was later increased to 20 mg daily, for polyarthritis associated with systemic lupus erythematosus (SLE). Her transplant physician increased her cyclosporine dosage from 50 mg twice daily to 75 mg each morning and 50 mg each evening due to rising creatinine and donor-specific antibodies from the renal transplant. The patient’s TS eruption mildly improved 3 months after the cyclosporine dose was increased. To treat persistent lesions, oral valganciclovir was started at 450 mg once daily and later reduced to every other day due to leukopenia. After 3 months of taking valganciclovir 450 mg every other day, the patient’s TS rash resolved.
Trichodysplasia spinulosa is a rare condition caused by TS-associated polyomavirus1 that may arise in immunosuppressed patients, especially in solid organ transplant recipients.2 It is characterized by spiculated and folliculocentric papules, mainly on the face,1 and often is diagnosed clinically, but if the presentation is not classic, a skin biopsy can help to confirm the diagnosis. Because of its rarity, treatment options do not have well-established efficacy1 but include reducing immunosuppression and using the antivirals cidofovir1 or valganciclovir3 to treat the polyomavirus. Topical retinoids,3 photodynamic therapy, 4 and leflunomide5 also may be effective.
Although the typical approach to treating TS is to reduce immunosuppression, this was not an option for our patient, as she required increased immunosuppression for the treatment of active SLE. Leflunomide can be used for SLE, and in some reports it can be effective for BK viremia in kidney transplant recipients5 as well as for TS in solid organ transplant recipients.6 Our patient showed improvement of the TS, BK viremia, renal function, and SLE while taking leflunomide and valganciclovir.
The differential diagnosis includes keratosis pilaris, lichen nitidus, scleromyxedema, and trichostasis spinulosa. Keratosis pilaris is a benign skin disorder consisting of patches of keratotic papules with varying degrees of erythema and inflammation that are formed by dead keratinocytes plugging the hair follicles and often are seen on the extremities, face, and trunk.7 Our patient’s papules were flesh colored with no notable background erythema. Additionally, the presence of leonine facies was atypical for keratosis pilaris. Acids, steroids, and kinase inhibitors are the most frequently used treatments for keratosis pilaris.8
Lichen nitidus is a skin condition characterized by multiple shiny, dome-shaped, flesh-colored papules usually found on the flexor surfaces of the arms, anterior trunk, and genitalia. It is mostly asymptomatic, but patients may experience pruritus. Most cases occur in children and young adults, with no obvious racial or gender predilection. The diagnosis often is clinical, but biopsy shows downward enlargement of the epidermal rete ridges surrounding a focal inflammatory infiltrate, known as a ball-in-claw configuration.9-11 Lichen nitidus spontaneously resolves within a few years without treatment. Our patient did have flesh-colored papules on the arms and chest; however, major involvement of the face is not typical in lichen nitidus. Additionally, fine white spicules would not be seen in lichen nitidus. For severe generalized lichen nitidus, treatment options include topical corticosteroids, topical calcineurin inhibitors, oral antihistamines, or UV light to decrease inflammation.9-11
Scleromyxedema is a rare condition involving the deposition of mucinous material in the papillary dermis to cause the formation of infiltrative skin lesions.12 It is thought that immunoglobulins and cytokines secreted by inflammatory cells lead to the synthesis of glycosaminoglycans, which then causes deposition of mucin in the dermis.13 The classic cutaneous features of scleromyxedema include waxy indurated papules and plaques with skin thickening throughout the entire body.12 Our patient’s papules were not notably indurated and involved less than 50% of the total body surface area. An important diagnostic feature of scleromyxedema is monoclonal gammopathy, which our patient did not have. Intravenous immunoglobulin is the first-line treatment of scleromyxedema, and second-line treatments include systemic corticosteroids and thalidomide.14 Our patient also did not require treatment with intravenous immunoglobulin, as her rash improved with antiviral medication, which would not address the underlying inflammatory processes associated with scleromyxedema.
Trichostasis spinulosa is a rare hair follicle disorder consisting of dark, spiny, hyperkeratotic follicular papules that can be found on the extremities and face, especially the nose. The etiology is unknown, but risk factors include congenital dysplasia of hair follicles; exposure to UV light, dust, oil, or heat; chronic renal failure; Malassezia yeast; and Propionibacterium acnes. Adult women with darker skin types are most commonly affected by trichostasis spinulosa.15,16 Our patient fit the epidemiologic demographic of trichostasis spinulosa, including a history of chronic renal failure. Her rash covered the face, nose, and arms; however, the papules were flesh colored, whereas trichostasis spinulosa would appear as black papules. Furthermore, yeast and bacterial infections have been identified as potential agents associated with trichostasis spinulosa; therefore, antiviral agents would be ineffective. Viable treatments for trichostasis spinulosa include emollients, topical keratolytic agents, retinoic acids, and lasers to remove abnormal hair follicles.15,16
- Curman P, Näsman A, Brauner H. Trichodysplasia spinulosa: a comprehensive disease and its treatment. J Eur Acad Dermatol Venereol. 2021;35:1067-1076.
- Fischer MK, Kao GF, Nguyen HP, et al. Specific detection of trichodysplasia spinulosa-associated polyomavirus DNA in skin and renal allograft tissues in a patient with trichodysplasia spinulosa. Arch Dermatol. 2021;148:726-733.
- Shah PR, Esaa FS, Gupta P, et al. Trichodysplasia spinulosa successfully treated with adapalene 0.1% gel and oral valganciclovir in a renal transplant recipient. JAAD Case Rep. 2020;6:23-25.
- Liew YCC, Kee TYS, Kwek JL, et al. Photodynamic therapy for the treatment of trichodysplasia spinulosa in an Asian renal transplant recipient: a case report and review of the literature. JAAD Case Rep. 2021;7:74-83.
- Pierrotti LC, Urbano PRP, da Silva Nali LH, et al. Viremia and viuria of trichodysplasia spinulosa-associated polyomavirus before the development of clinical disease in a kidney transplant recipient. Transpl Infect Dis. 2019;21:E13133.
- Kassar R, Chang J, Chan AW, et al. Leflunomide for the treatment of trichodysplasia spinulosa in a liver transplant recipient. Transpl Infect Dis. 2017;19:E12702.
- Eckburg A, Kazemi T, Maguiness S. Keratosis pilaris rubra successfully treated with topical sirolimus: report of a case and review of the literature. Pediatr Dermatol. 2022;39:429-431.
- Reddy S, Brahmbhatt H. A narrative review on the role of acids, steroids, and kinase inhibitors in the treatment of keratosis pilaris. Cureus. 2021;13:E18917.
- Jordan AS, Green MC, Sulit DJ. Lichen nitidus. J Am Osteopath Assoc. 2019;119:704.
- Arizaga AT, Gaughan MD, Bang RH. Generalized lichen nitidus. Clin Exp Dermatol. 2002;27:115-117.
- Chu J, Lam JM. Lichen nitidus. CMAJ. 2014;186:E688.
- Haber R, Bachour J, El Gemayel M. Scleromyxedema treatment: a systematic review and update. Int J Dermatol. 2020;59:1191-1201.
- Christman MP, Sukhdeo K, Kim RH, et al. Papular mucinosis, or localized lichen myxedematosis (LM) (discrete papular type). Dermatol Online J. 2017;23:8.
- Hoffman JHO, Enk AH. Scleromyxedema. J Dtsch Dermatol Ges. 2020;18:1449-1467.
- Kositkuljorn C, Suchonwanit P. Trichostasis spinulosa: a case report with an unusual presentation. Case Rep Dermatol. 2020;12:178-185.
- Ramteke MN, Bhide AA. Trichostasis spinulosa at an unusual site. Int J Trichology. 2016;8:78-80.
The Diagnosis: Trichodysplasia Spinulosa
A diagnosis of trichodysplasia spinulosa (TS) was rendered based on the clinical presentation— diffuse folliculocentric keratotic papules with spicules and leonine facies—coinciding with cyclosporine initiation. Biopsy was deferred given the classic presentation. The patient applied cidofovir cream 1% daily to lesions on the face. She was prescribed leflunomide 10 mg daily, which was later increased to 20 mg daily, for polyarthritis associated with systemic lupus erythematosus (SLE). Her transplant physician increased her cyclosporine dosage from 50 mg twice daily to 75 mg each morning and 50 mg each evening due to rising creatinine and donor-specific antibodies from the renal transplant. The patient’s TS eruption mildly improved 3 months after the cyclosporine dose was increased. To treat persistent lesions, oral valganciclovir was started at 450 mg once daily and later reduced to every other day due to leukopenia. After 3 months of taking valganciclovir 450 mg every other day, the patient’s TS rash resolved.
Trichodysplasia spinulosa is a rare condition caused by TS-associated polyomavirus1 that may arise in immunosuppressed patients, especially in solid organ transplant recipients.2 It is characterized by spiculated and folliculocentric papules, mainly on the face,1 and often is diagnosed clinically, but if the presentation is not classic, a skin biopsy can help to confirm the diagnosis. Because of its rarity, treatment options do not have well-established efficacy1 but include reducing immunosuppression and using the antivirals cidofovir1 or valganciclovir3 to treat the polyomavirus. Topical retinoids,3 photodynamic therapy, 4 and leflunomide5 also may be effective.
Although the typical approach to treating TS is to reduce immunosuppression, this was not an option for our patient, as she required increased immunosuppression for the treatment of active SLE. Leflunomide can be used for SLE, and in some reports it can be effective for BK viremia in kidney transplant recipients5 as well as for TS in solid organ transplant recipients.6 Our patient showed improvement of the TS, BK viremia, renal function, and SLE while taking leflunomide and valganciclovir.
The differential diagnosis includes keratosis pilaris, lichen nitidus, scleromyxedema, and trichostasis spinulosa. Keratosis pilaris is a benign skin disorder consisting of patches of keratotic papules with varying degrees of erythema and inflammation that are formed by dead keratinocytes plugging the hair follicles and often are seen on the extremities, face, and trunk.7 Our patient’s papules were flesh colored with no notable background erythema. Additionally, the presence of leonine facies was atypical for keratosis pilaris. Acids, steroids, and kinase inhibitors are the most frequently used treatments for keratosis pilaris.8
Lichen nitidus is a skin condition characterized by multiple shiny, dome-shaped, flesh-colored papules usually found on the flexor surfaces of the arms, anterior trunk, and genitalia. It is mostly asymptomatic, but patients may experience pruritus. Most cases occur in children and young adults, with no obvious racial or gender predilection. The diagnosis often is clinical, but biopsy shows downward enlargement of the epidermal rete ridges surrounding a focal inflammatory infiltrate, known as a ball-in-claw configuration.9-11 Lichen nitidus spontaneously resolves within a few years without treatment. Our patient did have flesh-colored papules on the arms and chest; however, major involvement of the face is not typical in lichen nitidus. Additionally, fine white spicules would not be seen in lichen nitidus. For severe generalized lichen nitidus, treatment options include topical corticosteroids, topical calcineurin inhibitors, oral antihistamines, or UV light to decrease inflammation.9-11
Scleromyxedema is a rare condition involving the deposition of mucinous material in the papillary dermis to cause the formation of infiltrative skin lesions.12 It is thought that immunoglobulins and cytokines secreted by inflammatory cells lead to the synthesis of glycosaminoglycans, which then causes deposition of mucin in the dermis.13 The classic cutaneous features of scleromyxedema include waxy indurated papules and plaques with skin thickening throughout the entire body.12 Our patient’s papules were not notably indurated and involved less than 50% of the total body surface area. An important diagnostic feature of scleromyxedema is monoclonal gammopathy, which our patient did not have. Intravenous immunoglobulin is the first-line treatment of scleromyxedema, and second-line treatments include systemic corticosteroids and thalidomide.14 Our patient also did not require treatment with intravenous immunoglobulin, as her rash improved with antiviral medication, which would not address the underlying inflammatory processes associated with scleromyxedema.
Trichostasis spinulosa is a rare hair follicle disorder consisting of dark, spiny, hyperkeratotic follicular papules that can be found on the extremities and face, especially the nose. The etiology is unknown, but risk factors include congenital dysplasia of hair follicles; exposure to UV light, dust, oil, or heat; chronic renal failure; Malassezia yeast; and Propionibacterium acnes. Adult women with darker skin types are most commonly affected by trichostasis spinulosa.15,16 Our patient fit the epidemiologic demographic of trichostasis spinulosa, including a history of chronic renal failure. Her rash covered the face, nose, and arms; however, the papules were flesh colored, whereas trichostasis spinulosa would appear as black papules. Furthermore, yeast and bacterial infections have been identified as potential agents associated with trichostasis spinulosa; therefore, antiviral agents would be ineffective. Viable treatments for trichostasis spinulosa include emollients, topical keratolytic agents, retinoic acids, and lasers to remove abnormal hair follicles.15,16
The Diagnosis: Trichodysplasia Spinulosa
A diagnosis of trichodysplasia spinulosa (TS) was rendered based on the clinical presentation— diffuse folliculocentric keratotic papules with spicules and leonine facies—coinciding with cyclosporine initiation. Biopsy was deferred given the classic presentation. The patient applied cidofovir cream 1% daily to lesions on the face. She was prescribed leflunomide 10 mg daily, which was later increased to 20 mg daily, for polyarthritis associated with systemic lupus erythematosus (SLE). Her transplant physician increased her cyclosporine dosage from 50 mg twice daily to 75 mg each morning and 50 mg each evening due to rising creatinine and donor-specific antibodies from the renal transplant. The patient’s TS eruption mildly improved 3 months after the cyclosporine dose was increased. To treat persistent lesions, oral valganciclovir was started at 450 mg once daily and later reduced to every other day due to leukopenia. After 3 months of taking valganciclovir 450 mg every other day, the patient’s TS rash resolved.
Trichodysplasia spinulosa is a rare condition caused by TS-associated polyomavirus1 that may arise in immunosuppressed patients, especially in solid organ transplant recipients.2 It is characterized by spiculated and folliculocentric papules, mainly on the face,1 and often is diagnosed clinically, but if the presentation is not classic, a skin biopsy can help to confirm the diagnosis. Because of its rarity, treatment options do not have well-established efficacy1 but include reducing immunosuppression and using the antivirals cidofovir1 or valganciclovir3 to treat the polyomavirus. Topical retinoids,3 photodynamic therapy, 4 and leflunomide5 also may be effective.
Although the typical approach to treating TS is to reduce immunosuppression, this was not an option for our patient, as she required increased immunosuppression for the treatment of active SLE. Leflunomide can be used for SLE, and in some reports it can be effective for BK viremia in kidney transplant recipients5 as well as for TS in solid organ transplant recipients.6 Our patient showed improvement of the TS, BK viremia, renal function, and SLE while taking leflunomide and valganciclovir.
The differential diagnosis includes keratosis pilaris, lichen nitidus, scleromyxedema, and trichostasis spinulosa. Keratosis pilaris is a benign skin disorder consisting of patches of keratotic papules with varying degrees of erythema and inflammation that are formed by dead keratinocytes plugging the hair follicles and often are seen on the extremities, face, and trunk.7 Our patient’s papules were flesh colored with no notable background erythema. Additionally, the presence of leonine facies was atypical for keratosis pilaris. Acids, steroids, and kinase inhibitors are the most frequently used treatments for keratosis pilaris.8
Lichen nitidus is a skin condition characterized by multiple shiny, dome-shaped, flesh-colored papules usually found on the flexor surfaces of the arms, anterior trunk, and genitalia. It is mostly asymptomatic, but patients may experience pruritus. Most cases occur in children and young adults, with no obvious racial or gender predilection. The diagnosis often is clinical, but biopsy shows downward enlargement of the epidermal rete ridges surrounding a focal inflammatory infiltrate, known as a ball-in-claw configuration.9-11 Lichen nitidus spontaneously resolves within a few years without treatment. Our patient did have flesh-colored papules on the arms and chest; however, major involvement of the face is not typical in lichen nitidus. Additionally, fine white spicules would not be seen in lichen nitidus. For severe generalized lichen nitidus, treatment options include topical corticosteroids, topical calcineurin inhibitors, oral antihistamines, or UV light to decrease inflammation.9-11
Scleromyxedema is a rare condition involving the deposition of mucinous material in the papillary dermis to cause the formation of infiltrative skin lesions.12 It is thought that immunoglobulins and cytokines secreted by inflammatory cells lead to the synthesis of glycosaminoglycans, which then causes deposition of mucin in the dermis.13 The classic cutaneous features of scleromyxedema include waxy indurated papules and plaques with skin thickening throughout the entire body.12 Our patient’s papules were not notably indurated and involved less than 50% of the total body surface area. An important diagnostic feature of scleromyxedema is monoclonal gammopathy, which our patient did not have. Intravenous immunoglobulin is the first-line treatment of scleromyxedema, and second-line treatments include systemic corticosteroids and thalidomide.14 Our patient also did not require treatment with intravenous immunoglobulin, as her rash improved with antiviral medication, which would not address the underlying inflammatory processes associated with scleromyxedema.
Trichostasis spinulosa is a rare hair follicle disorder consisting of dark, spiny, hyperkeratotic follicular papules that can be found on the extremities and face, especially the nose. The etiology is unknown, but risk factors include congenital dysplasia of hair follicles; exposure to UV light, dust, oil, or heat; chronic renal failure; Malassezia yeast; and Propionibacterium acnes. Adult women with darker skin types are most commonly affected by trichostasis spinulosa.15,16 Our patient fit the epidemiologic demographic of trichostasis spinulosa, including a history of chronic renal failure. Her rash covered the face, nose, and arms; however, the papules were flesh colored, whereas trichostasis spinulosa would appear as black papules. Furthermore, yeast and bacterial infections have been identified as potential agents associated with trichostasis spinulosa; therefore, antiviral agents would be ineffective. Viable treatments for trichostasis spinulosa include emollients, topical keratolytic agents, retinoic acids, and lasers to remove abnormal hair follicles.15,16
- Curman P, Näsman A, Brauner H. Trichodysplasia spinulosa: a comprehensive disease and its treatment. J Eur Acad Dermatol Venereol. 2021;35:1067-1076.
- Fischer MK, Kao GF, Nguyen HP, et al. Specific detection of trichodysplasia spinulosa-associated polyomavirus DNA in skin and renal allograft tissues in a patient with trichodysplasia spinulosa. Arch Dermatol. 2021;148:726-733.
- Shah PR, Esaa FS, Gupta P, et al. Trichodysplasia spinulosa successfully treated with adapalene 0.1% gel and oral valganciclovir in a renal transplant recipient. JAAD Case Rep. 2020;6:23-25.
- Liew YCC, Kee TYS, Kwek JL, et al. Photodynamic therapy for the treatment of trichodysplasia spinulosa in an Asian renal transplant recipient: a case report and review of the literature. JAAD Case Rep. 2021;7:74-83.
- Pierrotti LC, Urbano PRP, da Silva Nali LH, et al. Viremia and viuria of trichodysplasia spinulosa-associated polyomavirus before the development of clinical disease in a kidney transplant recipient. Transpl Infect Dis. 2019;21:E13133.
- Kassar R, Chang J, Chan AW, et al. Leflunomide for the treatment of trichodysplasia spinulosa in a liver transplant recipient. Transpl Infect Dis. 2017;19:E12702.
- Eckburg A, Kazemi T, Maguiness S. Keratosis pilaris rubra successfully treated with topical sirolimus: report of a case and review of the literature. Pediatr Dermatol. 2022;39:429-431.
- Reddy S, Brahmbhatt H. A narrative review on the role of acids, steroids, and kinase inhibitors in the treatment of keratosis pilaris. Cureus. 2021;13:E18917.
- Jordan AS, Green MC, Sulit DJ. Lichen nitidus. J Am Osteopath Assoc. 2019;119:704.
- Arizaga AT, Gaughan MD, Bang RH. Generalized lichen nitidus. Clin Exp Dermatol. 2002;27:115-117.
- Chu J, Lam JM. Lichen nitidus. CMAJ. 2014;186:E688.
- Haber R, Bachour J, El Gemayel M. Scleromyxedema treatment: a systematic review and update. Int J Dermatol. 2020;59:1191-1201.
- Christman MP, Sukhdeo K, Kim RH, et al. Papular mucinosis, or localized lichen myxedematosis (LM) (discrete papular type). Dermatol Online J. 2017;23:8.
- Hoffman JHO, Enk AH. Scleromyxedema. J Dtsch Dermatol Ges. 2020;18:1449-1467.
- Kositkuljorn C, Suchonwanit P. Trichostasis spinulosa: a case report with an unusual presentation. Case Rep Dermatol. 2020;12:178-185.
- Ramteke MN, Bhide AA. Trichostasis spinulosa at an unusual site. Int J Trichology. 2016;8:78-80.
- Curman P, Näsman A, Brauner H. Trichodysplasia spinulosa: a comprehensive disease and its treatment. J Eur Acad Dermatol Venereol. 2021;35:1067-1076.
- Fischer MK, Kao GF, Nguyen HP, et al. Specific detection of trichodysplasia spinulosa-associated polyomavirus DNA in skin and renal allograft tissues in a patient with trichodysplasia spinulosa. Arch Dermatol. 2021;148:726-733.
- Shah PR, Esaa FS, Gupta P, et al. Trichodysplasia spinulosa successfully treated with adapalene 0.1% gel and oral valganciclovir in a renal transplant recipient. JAAD Case Rep. 2020;6:23-25.
- Liew YCC, Kee TYS, Kwek JL, et al. Photodynamic therapy for the treatment of trichodysplasia spinulosa in an Asian renal transplant recipient: a case report and review of the literature. JAAD Case Rep. 2021;7:74-83.
- Pierrotti LC, Urbano PRP, da Silva Nali LH, et al. Viremia and viuria of trichodysplasia spinulosa-associated polyomavirus before the development of clinical disease in a kidney transplant recipient. Transpl Infect Dis. 2019;21:E13133.
- Kassar R, Chang J, Chan AW, et al. Leflunomide for the treatment of trichodysplasia spinulosa in a liver transplant recipient. Transpl Infect Dis. 2017;19:E12702.
- Eckburg A, Kazemi T, Maguiness S. Keratosis pilaris rubra successfully treated with topical sirolimus: report of a case and review of the literature. Pediatr Dermatol. 2022;39:429-431.
- Reddy S, Brahmbhatt H. A narrative review on the role of acids, steroids, and kinase inhibitors in the treatment of keratosis pilaris. Cureus. 2021;13:E18917.
- Jordan AS, Green MC, Sulit DJ. Lichen nitidus. J Am Osteopath Assoc. 2019;119:704.
- Arizaga AT, Gaughan MD, Bang RH. Generalized lichen nitidus. Clin Exp Dermatol. 2002;27:115-117.
- Chu J, Lam JM. Lichen nitidus. CMAJ. 2014;186:E688.
- Haber R, Bachour J, El Gemayel M. Scleromyxedema treatment: a systematic review and update. Int J Dermatol. 2020;59:1191-1201.
- Christman MP, Sukhdeo K, Kim RH, et al. Papular mucinosis, or localized lichen myxedematosis (LM) (discrete papular type). Dermatol Online J. 2017;23:8.
- Hoffman JHO, Enk AH. Scleromyxedema. J Dtsch Dermatol Ges. 2020;18:1449-1467.
- Kositkuljorn C, Suchonwanit P. Trichostasis spinulosa: a case report with an unusual presentation. Case Rep Dermatol. 2020;12:178-185.
- Ramteke MN, Bhide AA. Trichostasis spinulosa at an unusual site. Int J Trichology. 2016;8:78-80.
A 54-year-old Black woman presented with a rash that developed 6 months after a renal transplant due to a history of systemic lupus erythematosus with lupus nephritis. She was started on mycophenolate mofetil and tacrolimus after the transplant but was switched to cyclosporine because of BK viremia. The rash developed 1 week after cyclosporine was initiated and consisted of pruritic papules that started on the face and spread to the trunk and arms. Physical examination revealed innumerable follicular-based, keratotic, flesh-colored, pinpoint papules with fine white spicules on the face (top), neck, chest, arms, and back. Leonine facies was seen along the glabella with madarosis of the lateral eyebrows (top) and ears (bottom).
Is Location a Risk Factor for Early-Onset Cancer?
Early-onset cancer—diagnosed in adults aged ≤ 50 years—is on the rise. Researchers have studied a variety of factors driving the trend, such as type of cancer. However, geographic locality might have as much, if not more, to do with it, according to a study by researchers at Fox Chase Cancer Center, a National Cancer Institute-designated Comprehensive Cancer Center research facility.
Using the US Cancer Statistics Public Use Research Database, the researchers collected data from adults aged 20 to 49 years with invasive cancer (excluding in situ cases) diagnosed from 2015 through 2020. They calculated the incidence for each state using the national rate as the reference. Then, they calculated a second set of rates, comparing each state to the US in terms of overall incidence and advanced-stage incidence for all early-onset cancers.
The resulting maps indicated that early-onset cancer cases are not evenly distributed. States with worse-than-national rates are frequently near each other geographically. For instance, the rate of early-onset female breast cancer was worse than the national rate in 17 states, 16 of which were located in the eastern half of the US (Hawaii was the 17th state). Similarly, most states with worse-than-national rates of digestive cancers were located in the eastern half of the US, with a concentration in the South. Rates of male genital cancers were worse than national rates in 18 states, primarily in the eastern half of the country (plus Montana, Nebraska, and Puerto Rico).
Three states in the Southeast, 7 in the Northeast, and Puerto Rico had the highest incidence of lymphohematopoietic cancers. Incidence rates of endocrine cancers were worse than national rates in 25 states, which the researchers found formed “a horizontal core of the country running from east to west,” plus Puerto Rico. Rates of urinary system cancers were worse than national rates in 17 contiguous states, from New Mexico to Pennsylvania.
Rates of female genital cancers were worse than national rates in 16 states, largely in the Midwest and South, plus California and Puerto Rico. Skin cancer, on the other hand, was a great leveler, with worse-than-national rates in 32 states, mostly in the northern portion of the country.
Kentucky and West Virginia had the highest overall and advanced-stage incidence rates of early-onset cancer for all cancer sites combined. They were followed by Arkansas, Connecticut, Florida, Georgia, Iowa, Louisiana, Maine, Missouri, New Jersey, New York, North Carolina, Ohio, and Pennsylvania.
According to the researchers, this study provides the first analysis of age-adjusted rates of early-onset cancer based on state-level population and case numbers. Geographic patterns in early-onset cancer, they suggest, indicate possible similarities that could relate to demographic, socioeconomic, behavioral, or environmental risks. “Focusing prevention efforts on the highest-incidence states for the most prevalent sites may reduce the rate of early-onset cancer nationally.”
Early-onset cancer—diagnosed in adults aged ≤ 50 years—is on the rise. Researchers have studied a variety of factors driving the trend, such as type of cancer. However, geographic locality might have as much, if not more, to do with it, according to a study by researchers at Fox Chase Cancer Center, a National Cancer Institute-designated Comprehensive Cancer Center research facility.
Using the US Cancer Statistics Public Use Research Database, the researchers collected data from adults aged 20 to 49 years with invasive cancer (excluding in situ cases) diagnosed from 2015 through 2020. They calculated the incidence for each state using the national rate as the reference. Then, they calculated a second set of rates, comparing each state to the US in terms of overall incidence and advanced-stage incidence for all early-onset cancers.
The resulting maps indicated that early-onset cancer cases are not evenly distributed. States with worse-than-national rates are frequently near each other geographically. For instance, the rate of early-onset female breast cancer was worse than the national rate in 17 states, 16 of which were located in the eastern half of the US (Hawaii was the 17th state). Similarly, most states with worse-than-national rates of digestive cancers were located in the eastern half of the US, with a concentration in the South. Rates of male genital cancers were worse than national rates in 18 states, primarily in the eastern half of the country (plus Montana, Nebraska, and Puerto Rico).
Three states in the Southeast, 7 in the Northeast, and Puerto Rico had the highest incidence of lymphohematopoietic cancers. Incidence rates of endocrine cancers were worse than national rates in 25 states, which the researchers found formed “a horizontal core of the country running from east to west,” plus Puerto Rico. Rates of urinary system cancers were worse than national rates in 17 contiguous states, from New Mexico to Pennsylvania.
Rates of female genital cancers were worse than national rates in 16 states, largely in the Midwest and South, plus California and Puerto Rico. Skin cancer, on the other hand, was a great leveler, with worse-than-national rates in 32 states, mostly in the northern portion of the country.
Kentucky and West Virginia had the highest overall and advanced-stage incidence rates of early-onset cancer for all cancer sites combined. They were followed by Arkansas, Connecticut, Florida, Georgia, Iowa, Louisiana, Maine, Missouri, New Jersey, New York, North Carolina, Ohio, and Pennsylvania.
According to the researchers, this study provides the first analysis of age-adjusted rates of early-onset cancer based on state-level population and case numbers. Geographic patterns in early-onset cancer, they suggest, indicate possible similarities that could relate to demographic, socioeconomic, behavioral, or environmental risks. “Focusing prevention efforts on the highest-incidence states for the most prevalent sites may reduce the rate of early-onset cancer nationally.”
Early-onset cancer—diagnosed in adults aged ≤ 50 years—is on the rise. Researchers have studied a variety of factors driving the trend, such as type of cancer. However, geographic locality might have as much, if not more, to do with it, according to a study by researchers at Fox Chase Cancer Center, a National Cancer Institute-designated Comprehensive Cancer Center research facility.
Using the US Cancer Statistics Public Use Research Database, the researchers collected data from adults aged 20 to 49 years with invasive cancer (excluding in situ cases) diagnosed from 2015 through 2020. They calculated the incidence for each state using the national rate as the reference. Then, they calculated a second set of rates, comparing each state to the US in terms of overall incidence and advanced-stage incidence for all early-onset cancers.
The resulting maps indicated that early-onset cancer cases are not evenly distributed. States with worse-than-national rates are frequently near each other geographically. For instance, the rate of early-onset female breast cancer was worse than the national rate in 17 states, 16 of which were located in the eastern half of the US (Hawaii was the 17th state). Similarly, most states with worse-than-national rates of digestive cancers were located in the eastern half of the US, with a concentration in the South. Rates of male genital cancers were worse than national rates in 18 states, primarily in the eastern half of the country (plus Montana, Nebraska, and Puerto Rico).
Three states in the Southeast, 7 in the Northeast, and Puerto Rico had the highest incidence of lymphohematopoietic cancers. Incidence rates of endocrine cancers were worse than national rates in 25 states, which the researchers found formed “a horizontal core of the country running from east to west,” plus Puerto Rico. Rates of urinary system cancers were worse than national rates in 17 contiguous states, from New Mexico to Pennsylvania.
Rates of female genital cancers were worse than national rates in 16 states, largely in the Midwest and South, plus California and Puerto Rico. Skin cancer, on the other hand, was a great leveler, with worse-than-national rates in 32 states, mostly in the northern portion of the country.
Kentucky and West Virginia had the highest overall and advanced-stage incidence rates of early-onset cancer for all cancer sites combined. They were followed by Arkansas, Connecticut, Florida, Georgia, Iowa, Louisiana, Maine, Missouri, New Jersey, New York, North Carolina, Ohio, and Pennsylvania.
According to the researchers, this study provides the first analysis of age-adjusted rates of early-onset cancer based on state-level population and case numbers. Geographic patterns in early-onset cancer, they suggest, indicate possible similarities that could relate to demographic, socioeconomic, behavioral, or environmental risks. “Focusing prevention efforts on the highest-incidence states for the most prevalent sites may reduce the rate of early-onset cancer nationally.”
Inpatient Management of Hidradenitis Suppurativa: A Delphi Consensus Study
Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that affects approximately 0.1% of the US population.1,2 Severe disease or HS flares can lead patients to seek care through the emergency department (ED), with some requiring inpatient admission. 3 Inpatient hospitalization of patients with HS has increased over the last 2 decades, and patients with HS utilize emergency and inpatient care more frequently than those with other dermatologic conditions.4,5 Minority patients and those of lower socioeconomic status are more likely to present to the ED for HS management due to limited access to care and other existing comorbid conditions. 4 In a 2022 study of the Nationwide Readmissions Database, the authors looked at hospital readmission rates of patients with HS compared with those with heart failure—both patient populations with chronic debilitating conditions. Results indicated that the hospital readmission rates for patients with HS surpassed those of patients with heart failure for that year, highlighting the need for improved inpatient management of HS.6
Patients with HS present to the ED with severe pain, fever, wound care, or the need for surgical intervention. The ED and inpatient hospital setting are locations in which physicians may not be as familiar with the diagnosis or treatment of HS, specifically flares or severe disease. 7 The inpatient care setting provides access to certain resources that can be challenging to obtain in the outpatient clinical setting, such as social workers and pain specialists, but also can prove challenging in obtaining other resources for HS management, such as advanced medical therapies. Given the increase in hospital- based care for HS and lack of widespread inpatient access to dermatology and HS experts, consensus recommendations for management of HS in the acute hospital setting would be beneficial. In our study, we sought to generate a collection of expert consensus statements providers can refer to when managing patients with HS in the inpatient setting.
Methods
The study team at the Wake Forest University School of Medicine (Winston-Salem, North Carolina)(M.N., R.P., L.C.S.) developed an initial set of consensus statements based on current published HS treatment guidelines,8,9 publications on management of inpatient HS,3 published supportive care guidelines for Stevens-Johnson syndrome, 10 and personal clinical experience in managing inpatient HS, which resulted in 50 statements organized into the following categories: overall care, wound care, genital care, pain management, infection control, medical management, surgical management, nutrition, and transitional care guidelines. This study was approved by the Wake Forest University institutional review board (IRB00084257).
Participant Recruitment—Dermatologists were identified for participation in the study based on membership in the Society of Dermatology Hospitalists and the Hidradenitis Suppurativa Foundation or authorship of publications relevant to HS or inpatient dermatology. Dermatologists from larger academic institutions with HS specialty clinics and inpatient dermatology services also were identified. Participants were invited via email and could suggest other experts for inclusion. A total of 31 dermatologists were invited to participate in the study, with 26 agreeing to participate. All participating dermatologists were practicing in the United States.
Delphi Study—In the first round of the Delphi study, the participants were sent an online survey via REDCap in which they were asked to rank the appropriateness of each of the proposed 50 guideline statements on a scale of 1 (very inappropriate) to 9 (very appropriate). Participants also were able to provide commentary and feedback on each of the statements. Survey results were analyzed using the RAND/ UCLA Appropriateness Method.11 For each statement, the median rating for appropriateness, interpercentile range (IPR), IPR adjusted for symmetry, and disagreement index (DI) were calculated (DI=IPR/IPR adjusted for symmetry). The 30th and 70th percentiles were used in the DI calculation as the upper and lower limits, respectively. A median rating for appropriateness of 1.0 to 3.9 was considered “inappropriate,” 4.0 to 6.9 was considered “uncertain appropriateness,” and 7.0 to 9.0 was “appropriate.” A DI value greater than or equal to 1 indicated a lack of consensus regarding the appropriateness of the statement. Following each round, participants received a copy of their responses along with the group median rank of each statement. Statements that did not reach consensus in the first Delphi round were revised based on feedback received by the participants, and a second survey with 14 statements was sent via REDCap 2 weeks later. The RAND/UCLA Appropriateness Method also was applied to this second Delphi round. After the second survey, participants received a copy of anonymized comments regarding the consensus statements and were allowed to provide additional final commentary to be included in the discussion of these recommendations.
Results
Twenty-six dermatologists completed the first-round survey, and 24 participants completed the second-round survey. All participants self-identified as having expertise in either HS (n=22 [85%]) or inpatient dermatology (n=17 [65%]), and 13 (50%) participants self-identified as experts in both HS and inpatient dermatology. All participants, except 1, were affiliated with an academic health system with inpatient dermatology services. The average length of time in practice as a dermatologist was 10 years (median, 9 years [range, 3–27 years]).
Of the 50 initial proposed consensus statements, 26 (52%) achieved consensus after the first round; 21 statements revealed DI calculations that did not achieve consensus. Two statements achieved consensus but received median ratings for appropriateness, indicating uncertain appropriateness; because of this, 1 statement was removed and 1 was revised based on participant feedback, resulting in 13 revised statements (eTable 1). Controversial topics in the consensus process included obtaining wound cultures and meaningful culture data interpretation, use of specific biologic medications in the inpatient setting, and use of intravenous ertapenem. Participant responses to these topics are discussed in detail below. Of these secondround statements, all achieved consensus. The final set of consensus statements can be found in eTable 2.
Comment
Our Delphi consensus study combined the expertise of both dermatologists who care for patients with HS and those with inpatient dermatology experience to produce a set of recommendations for the management of HS in the hospital care setting. A strength of this study is inclusion of many national leaders in both HS and inpatient dermatology, with some participants having developed the previously published HS treatment guidelines and others having participated in inpatient dermatology Delphi studies.8-10 The expertise is further strengthened by the geographically diverse institutional representation within the United States.
The final consensus recommendations included 40 statements covering a range of patient care issues, including use of appropriate inpatient subspecialists (care team), supportive care measures (wound care, pain control, genital care), disease-oriented treatment (medical management, surgical management), inpatient complications (infection control, nutrition), and successful transition back to outpatient management (transitional care). These recommendations are meant to serve as a resource for providers to consider when taking care of inpatient HS flares, recognizing that the complexity and individual circumstances of each patient are unique.
Delphi Consensus Recommendations Compared to Prior Guidelines—Several recommendations in the current study align with the previously published North American clinical management guidelines for HS.8,9 Our recommendations agree with prior guidelines on the importance of disease staging and pain assessment using validated assessment tools as well as screening for HS comorbidities. There also is agreement in the potential benefit of involving pain specialists in the development of a comprehensive pain management plan. The inpatient care setting provides a unique opportunity to engage multiple specialists and collaborate on patient care in a timely manner. Our recommendations regarding surgical care also align with established guidelines in recommending incision and drainage as an acute bedside procedure best utilized for symptom relief in inflamed abscesses and relegating most other surgical management to the outpatient setting. Wound care recommendations also are similar, with our expert participants agreeing on individualizing dressing choices based on wound characteristics. A benefit of inpatient wound care is access to skilled nursing for dressing changes and potentially improved access to more sophisticated dressing materials. Our recommendations differ from the prior guidelines in our focus on severe HS, HS flares, and HS complications, which constitute the majority of inpatient disease management. We provide additional guidance on management of secondary infections, perianal fistulous disease, and importantly transitional care to optimize discharge planning.
Differing Opinions in Our Analysis—Despite the success of our Delphi consensus process, there were some differing opinions regarding certain aspects of inpatient HS management, which is to be expected given the lack of strong evidence-based research to support some of the recommended practices. There were differing opinions on the utility of wound culture data, with some participants feeling culture data could help with antibiotic susceptibility and resistance patterns, while others felt wound cultures represent bacterial colonization or biofilm formation.
Initial consensus statements in the first Delphi round were created for individual biologic medications but did not achieve consensus, and feedback on the use of biologics in the inpatient environment was mixed, largely due to logistic and insurance issues. Many participants felt biologic medication cost, difficulty obtaining inpatient reimbursement, health care resource utilization, and availability of biologics in different hospital systems prevented recommending the use of specific biologics during hospitalization. The one exception was in the case of a hospitalized patient who was already receiving infliximab for HS: there was consensus on ensuring the patient dosing was maximized, if appropriate, to 10 mg/kg.12 Ertapenem use also was controversial, with some participants using it as a bridge therapy to either outpatient biologic use or surgery, while others felt it was onerous and difficult to establish reliable access to secure intravenous administration and regular dosing once the patient left the inpatient setting.13 Others said they have experienced objections from infectious disease colleagues on the use of intravenous antibiotics, citing antibiotic stewardship concerns.
Patient Care in the Inpatient Setting—Prior literature suggests patients admitted as inpatients for HS tend to be of lower socioeconomic status and are admitted to larger urban teaching hospitals.14,15 Patients with lower socioeconomic status have increased difficulty accessing health care resources; therefore, inpatient admission serves as an opportunity to provide a holistic HS assessment and coordinate resources for chronic outpatient management.
Study Limitations—This Delphi consensus study has some limitations. The existing literature on inpatient management of HS is limited, challenging our ability to assess the extent to which these published recommendations are already being implemented. Additionally, the study included HS and inpatient dermatology experts from the United States, which means the recommendations may not be generalizable to other countries. Most participants practiced dermatology at large tertiary care academic medical centers, which may limit the ability to implement recommendations in all US inpatient care settings such as small community-based hospitals; however, many of the supportive care guidelines such as pain control, wound care, nutritional support, and social work should be achievable in most inpatient care settings.
Conclusion
Given the increase in inpatient and ED health care utilization for HS, there is an urgent need for expert consensus recommendations on inpatient management of this unique patient population, which requires complex multidisciplinary care. Our recommendations are a resource for providers to utilize and potentially improve the standard of care we provide these patients.
Acknowledgment—We thank the Wake Forest University Clinical and Translational Science Institute (Winston- Salem, North Carolina) for providing statistical help.
- Garg A, Kirby JS, Lavian J, et al. Sex- and age-adjusted population analysis of prevalence estimates for hidradenitis suppurativa in the United States. JAMA Dermatol. 2017;153:760-764.
- Ingram JR. The epidemiology of hidradenitis suppurativa. Br J Dermatol. 2020;183:990-998. doi:10.1111/bjd.19435
- Charrow A, Savage KT, Flood K, et al. Hidradenitis suppurativa for the dermatologic hospitalist. Cutis. 2019;104:276-280.
- Anzaldi L, Perkins JA, Byrd AS, et al. Characterizing inpatient hospitalizations for hidradenitis suppurativa in the United States. J Am Acad Dermatol. 2020;82:510-513. doi:10.1016/j.jaad.2019.09.019
- Khalsa A, Liu G, Kirby JS. Increased utilization of emergency department and inpatient care by patients with hidradenitis suppurativa. J Am Acad Dermatol. 2015;73:609-614. doi:10.1016/j.jaad.2015.06.053
- Edigin E, Kaul S, Eseaton PO, et al. At 180 days hidradenitis suppurativa readmission rate is comparable to heart failure: analysis of the nationwide readmissions database. J Am Acad Dermatol. 2022;87:188-192. doi:10.1016/j.jaad.2021.06.894
- Kirby JS, Miller JJ, Adams DR, et al. Health care utilization patterns and costs for patients with hidradenitis suppurativa. JAMA Dermatol. 2014;150:937-944. doi:10.1001/jamadermatol.2014.691
- Alikhan A, Sayed C, Alavi A, et al. North American clinical management guidelines for hidradenitis suppurativa: a publication from the United States and Canadian Hidradenitis Suppurativa Foundations: part I: diagnosis, evaluation, and the use of complementary and procedural management. J Am Acad Dermatol. 2019;81:76-90. doi:10.1016/j .jaad.2019.02.067
- Alikhan A, Sayed C, Alavi A, et al. North American clinical management guidelines for hidradenitis suppurativa: a publication from the United States and Canadian Hidradenitis Suppurativa Foundations: part II: topical, intralesional, and systemic medical management. J Am Acad Dermatol. 2019;81:91-101. doi:10.1016/j.jaad.2019.02.068
- Seminario-Vidal L, Kroshinsky D, Malachowski SJ, et al. Society of Dermatology Hospitalists supportive care guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults. J Am Acad Dermatol. 2020;82:1553-1567. doi:10.1016/j .jaad.2020.02.066
- Fitch K, Bernstein SJ, Burnand B, et al. The RAND/UCLA Appropriateness Method: User’s Manual. Rand; 2001.
- Oskardmay AN, Miles JA, Sayed CJ. Determining the optimal dose of infliximab for treatment of hidradenitis suppurativa. J Am Acad Dermatol. 2019;81:702-708. doi:10.1016/j.jaad.2019.05.022
- Join-Lambert O, Coignard-Biehler H, Jais JP, et al. Efficacy of ertapenem in severe hidradenitis suppurativa: a pilot study in a cohort of 30 consecutive patients. J Antimicrob Chemother. 2016;71:513-520. doi:10.1093/jac/dkv361
- Khanna R, Whang KA, Huang AH, et al. Inpatient burden of hidradenitis suppurativa in the United States: analysis of the 2016 National Inpatient Sample. J Dermatolog Treat. 2022;33:1150-1152. doi:10.1080/09 546634.2020.1773380
- Patel A, Patel A, Solanki D, et al. Hidradenitis suppurativa in the United States: insights from the national inpatient sample (2008-2017) on contemporary trends in demographics, hospitalization rates, chronic comorbid conditions, and mortality. Cureus. 2022;14:E24755. doi:10.7759/cureus.24755
Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that affects approximately 0.1% of the US population.1,2 Severe disease or HS flares can lead patients to seek care through the emergency department (ED), with some requiring inpatient admission. 3 Inpatient hospitalization of patients with HS has increased over the last 2 decades, and patients with HS utilize emergency and inpatient care more frequently than those with other dermatologic conditions.4,5 Minority patients and those of lower socioeconomic status are more likely to present to the ED for HS management due to limited access to care and other existing comorbid conditions. 4 In a 2022 study of the Nationwide Readmissions Database, the authors looked at hospital readmission rates of patients with HS compared with those with heart failure—both patient populations with chronic debilitating conditions. Results indicated that the hospital readmission rates for patients with HS surpassed those of patients with heart failure for that year, highlighting the need for improved inpatient management of HS.6
Patients with HS present to the ED with severe pain, fever, wound care, or the need for surgical intervention. The ED and inpatient hospital setting are locations in which physicians may not be as familiar with the diagnosis or treatment of HS, specifically flares or severe disease. 7 The inpatient care setting provides access to certain resources that can be challenging to obtain in the outpatient clinical setting, such as social workers and pain specialists, but also can prove challenging in obtaining other resources for HS management, such as advanced medical therapies. Given the increase in hospital- based care for HS and lack of widespread inpatient access to dermatology and HS experts, consensus recommendations for management of HS in the acute hospital setting would be beneficial. In our study, we sought to generate a collection of expert consensus statements providers can refer to when managing patients with HS in the inpatient setting.
Methods
The study team at the Wake Forest University School of Medicine (Winston-Salem, North Carolina)(M.N., R.P., L.C.S.) developed an initial set of consensus statements based on current published HS treatment guidelines,8,9 publications on management of inpatient HS,3 published supportive care guidelines for Stevens-Johnson syndrome, 10 and personal clinical experience in managing inpatient HS, which resulted in 50 statements organized into the following categories: overall care, wound care, genital care, pain management, infection control, medical management, surgical management, nutrition, and transitional care guidelines. This study was approved by the Wake Forest University institutional review board (IRB00084257).
Participant Recruitment—Dermatologists were identified for participation in the study based on membership in the Society of Dermatology Hospitalists and the Hidradenitis Suppurativa Foundation or authorship of publications relevant to HS or inpatient dermatology. Dermatologists from larger academic institutions with HS specialty clinics and inpatient dermatology services also were identified. Participants were invited via email and could suggest other experts for inclusion. A total of 31 dermatologists were invited to participate in the study, with 26 agreeing to participate. All participating dermatologists were practicing in the United States.
Delphi Study—In the first round of the Delphi study, the participants were sent an online survey via REDCap in which they were asked to rank the appropriateness of each of the proposed 50 guideline statements on a scale of 1 (very inappropriate) to 9 (very appropriate). Participants also were able to provide commentary and feedback on each of the statements. Survey results were analyzed using the RAND/ UCLA Appropriateness Method.11 For each statement, the median rating for appropriateness, interpercentile range (IPR), IPR adjusted for symmetry, and disagreement index (DI) were calculated (DI=IPR/IPR adjusted for symmetry). The 30th and 70th percentiles were used in the DI calculation as the upper and lower limits, respectively. A median rating for appropriateness of 1.0 to 3.9 was considered “inappropriate,” 4.0 to 6.9 was considered “uncertain appropriateness,” and 7.0 to 9.0 was “appropriate.” A DI value greater than or equal to 1 indicated a lack of consensus regarding the appropriateness of the statement. Following each round, participants received a copy of their responses along with the group median rank of each statement. Statements that did not reach consensus in the first Delphi round were revised based on feedback received by the participants, and a second survey with 14 statements was sent via REDCap 2 weeks later. The RAND/UCLA Appropriateness Method also was applied to this second Delphi round. After the second survey, participants received a copy of anonymized comments regarding the consensus statements and were allowed to provide additional final commentary to be included in the discussion of these recommendations.
Results
Twenty-six dermatologists completed the first-round survey, and 24 participants completed the second-round survey. All participants self-identified as having expertise in either HS (n=22 [85%]) or inpatient dermatology (n=17 [65%]), and 13 (50%) participants self-identified as experts in both HS and inpatient dermatology. All participants, except 1, were affiliated with an academic health system with inpatient dermatology services. The average length of time in practice as a dermatologist was 10 years (median, 9 years [range, 3–27 years]).
Of the 50 initial proposed consensus statements, 26 (52%) achieved consensus after the first round; 21 statements revealed DI calculations that did not achieve consensus. Two statements achieved consensus but received median ratings for appropriateness, indicating uncertain appropriateness; because of this, 1 statement was removed and 1 was revised based on participant feedback, resulting in 13 revised statements (eTable 1). Controversial topics in the consensus process included obtaining wound cultures and meaningful culture data interpretation, use of specific biologic medications in the inpatient setting, and use of intravenous ertapenem. Participant responses to these topics are discussed in detail below. Of these secondround statements, all achieved consensus. The final set of consensus statements can be found in eTable 2.
Comment
Our Delphi consensus study combined the expertise of both dermatologists who care for patients with HS and those with inpatient dermatology experience to produce a set of recommendations for the management of HS in the hospital care setting. A strength of this study is inclusion of many national leaders in both HS and inpatient dermatology, with some participants having developed the previously published HS treatment guidelines and others having participated in inpatient dermatology Delphi studies.8-10 The expertise is further strengthened by the geographically diverse institutional representation within the United States.
The final consensus recommendations included 40 statements covering a range of patient care issues, including use of appropriate inpatient subspecialists (care team), supportive care measures (wound care, pain control, genital care), disease-oriented treatment (medical management, surgical management), inpatient complications (infection control, nutrition), and successful transition back to outpatient management (transitional care). These recommendations are meant to serve as a resource for providers to consider when taking care of inpatient HS flares, recognizing that the complexity and individual circumstances of each patient are unique.
Delphi Consensus Recommendations Compared to Prior Guidelines—Several recommendations in the current study align with the previously published North American clinical management guidelines for HS.8,9 Our recommendations agree with prior guidelines on the importance of disease staging and pain assessment using validated assessment tools as well as screening for HS comorbidities. There also is agreement in the potential benefit of involving pain specialists in the development of a comprehensive pain management plan. The inpatient care setting provides a unique opportunity to engage multiple specialists and collaborate on patient care in a timely manner. Our recommendations regarding surgical care also align with established guidelines in recommending incision and drainage as an acute bedside procedure best utilized for symptom relief in inflamed abscesses and relegating most other surgical management to the outpatient setting. Wound care recommendations also are similar, with our expert participants agreeing on individualizing dressing choices based on wound characteristics. A benefit of inpatient wound care is access to skilled nursing for dressing changes and potentially improved access to more sophisticated dressing materials. Our recommendations differ from the prior guidelines in our focus on severe HS, HS flares, and HS complications, which constitute the majority of inpatient disease management. We provide additional guidance on management of secondary infections, perianal fistulous disease, and importantly transitional care to optimize discharge planning.
Differing Opinions in Our Analysis—Despite the success of our Delphi consensus process, there were some differing opinions regarding certain aspects of inpatient HS management, which is to be expected given the lack of strong evidence-based research to support some of the recommended practices. There were differing opinions on the utility of wound culture data, with some participants feeling culture data could help with antibiotic susceptibility and resistance patterns, while others felt wound cultures represent bacterial colonization or biofilm formation.
Initial consensus statements in the first Delphi round were created for individual biologic medications but did not achieve consensus, and feedback on the use of biologics in the inpatient environment was mixed, largely due to logistic and insurance issues. Many participants felt biologic medication cost, difficulty obtaining inpatient reimbursement, health care resource utilization, and availability of biologics in different hospital systems prevented recommending the use of specific biologics during hospitalization. The one exception was in the case of a hospitalized patient who was already receiving infliximab for HS: there was consensus on ensuring the patient dosing was maximized, if appropriate, to 10 mg/kg.12 Ertapenem use also was controversial, with some participants using it as a bridge therapy to either outpatient biologic use or surgery, while others felt it was onerous and difficult to establish reliable access to secure intravenous administration and regular dosing once the patient left the inpatient setting.13 Others said they have experienced objections from infectious disease colleagues on the use of intravenous antibiotics, citing antibiotic stewardship concerns.
Patient Care in the Inpatient Setting—Prior literature suggests patients admitted as inpatients for HS tend to be of lower socioeconomic status and are admitted to larger urban teaching hospitals.14,15 Patients with lower socioeconomic status have increased difficulty accessing health care resources; therefore, inpatient admission serves as an opportunity to provide a holistic HS assessment and coordinate resources for chronic outpatient management.
Study Limitations—This Delphi consensus study has some limitations. The existing literature on inpatient management of HS is limited, challenging our ability to assess the extent to which these published recommendations are already being implemented. Additionally, the study included HS and inpatient dermatology experts from the United States, which means the recommendations may not be generalizable to other countries. Most participants practiced dermatology at large tertiary care academic medical centers, which may limit the ability to implement recommendations in all US inpatient care settings such as small community-based hospitals; however, many of the supportive care guidelines such as pain control, wound care, nutritional support, and social work should be achievable in most inpatient care settings.
Conclusion
Given the increase in inpatient and ED health care utilization for HS, there is an urgent need for expert consensus recommendations on inpatient management of this unique patient population, which requires complex multidisciplinary care. Our recommendations are a resource for providers to utilize and potentially improve the standard of care we provide these patients.
Acknowledgment—We thank the Wake Forest University Clinical and Translational Science Institute (Winston- Salem, North Carolina) for providing statistical help.
Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that affects approximately 0.1% of the US population.1,2 Severe disease or HS flares can lead patients to seek care through the emergency department (ED), with some requiring inpatient admission. 3 Inpatient hospitalization of patients with HS has increased over the last 2 decades, and patients with HS utilize emergency and inpatient care more frequently than those with other dermatologic conditions.4,5 Minority patients and those of lower socioeconomic status are more likely to present to the ED for HS management due to limited access to care and other existing comorbid conditions. 4 In a 2022 study of the Nationwide Readmissions Database, the authors looked at hospital readmission rates of patients with HS compared with those with heart failure—both patient populations with chronic debilitating conditions. Results indicated that the hospital readmission rates for patients with HS surpassed those of patients with heart failure for that year, highlighting the need for improved inpatient management of HS.6
Patients with HS present to the ED with severe pain, fever, wound care, or the need for surgical intervention. The ED and inpatient hospital setting are locations in which physicians may not be as familiar with the diagnosis or treatment of HS, specifically flares or severe disease. 7 The inpatient care setting provides access to certain resources that can be challenging to obtain in the outpatient clinical setting, such as social workers and pain specialists, but also can prove challenging in obtaining other resources for HS management, such as advanced medical therapies. Given the increase in hospital- based care for HS and lack of widespread inpatient access to dermatology and HS experts, consensus recommendations for management of HS in the acute hospital setting would be beneficial. In our study, we sought to generate a collection of expert consensus statements providers can refer to when managing patients with HS in the inpatient setting.
Methods
The study team at the Wake Forest University School of Medicine (Winston-Salem, North Carolina)(M.N., R.P., L.C.S.) developed an initial set of consensus statements based on current published HS treatment guidelines,8,9 publications on management of inpatient HS,3 published supportive care guidelines for Stevens-Johnson syndrome, 10 and personal clinical experience in managing inpatient HS, which resulted in 50 statements organized into the following categories: overall care, wound care, genital care, pain management, infection control, medical management, surgical management, nutrition, and transitional care guidelines. This study was approved by the Wake Forest University institutional review board (IRB00084257).
Participant Recruitment—Dermatologists were identified for participation in the study based on membership in the Society of Dermatology Hospitalists and the Hidradenitis Suppurativa Foundation or authorship of publications relevant to HS or inpatient dermatology. Dermatologists from larger academic institutions with HS specialty clinics and inpatient dermatology services also were identified. Participants were invited via email and could suggest other experts for inclusion. A total of 31 dermatologists were invited to participate in the study, with 26 agreeing to participate. All participating dermatologists were practicing in the United States.
Delphi Study—In the first round of the Delphi study, the participants were sent an online survey via REDCap in which they were asked to rank the appropriateness of each of the proposed 50 guideline statements on a scale of 1 (very inappropriate) to 9 (very appropriate). Participants also were able to provide commentary and feedback on each of the statements. Survey results were analyzed using the RAND/ UCLA Appropriateness Method.11 For each statement, the median rating for appropriateness, interpercentile range (IPR), IPR adjusted for symmetry, and disagreement index (DI) were calculated (DI=IPR/IPR adjusted for symmetry). The 30th and 70th percentiles were used in the DI calculation as the upper and lower limits, respectively. A median rating for appropriateness of 1.0 to 3.9 was considered “inappropriate,” 4.0 to 6.9 was considered “uncertain appropriateness,” and 7.0 to 9.0 was “appropriate.” A DI value greater than or equal to 1 indicated a lack of consensus regarding the appropriateness of the statement. Following each round, participants received a copy of their responses along with the group median rank of each statement. Statements that did not reach consensus in the first Delphi round were revised based on feedback received by the participants, and a second survey with 14 statements was sent via REDCap 2 weeks later. The RAND/UCLA Appropriateness Method also was applied to this second Delphi round. After the second survey, participants received a copy of anonymized comments regarding the consensus statements and were allowed to provide additional final commentary to be included in the discussion of these recommendations.
Results
Twenty-six dermatologists completed the first-round survey, and 24 participants completed the second-round survey. All participants self-identified as having expertise in either HS (n=22 [85%]) or inpatient dermatology (n=17 [65%]), and 13 (50%) participants self-identified as experts in both HS and inpatient dermatology. All participants, except 1, were affiliated with an academic health system with inpatient dermatology services. The average length of time in practice as a dermatologist was 10 years (median, 9 years [range, 3–27 years]).
Of the 50 initial proposed consensus statements, 26 (52%) achieved consensus after the first round; 21 statements revealed DI calculations that did not achieve consensus. Two statements achieved consensus but received median ratings for appropriateness, indicating uncertain appropriateness; because of this, 1 statement was removed and 1 was revised based on participant feedback, resulting in 13 revised statements (eTable 1). Controversial topics in the consensus process included obtaining wound cultures and meaningful culture data interpretation, use of specific biologic medications in the inpatient setting, and use of intravenous ertapenem. Participant responses to these topics are discussed in detail below. Of these secondround statements, all achieved consensus. The final set of consensus statements can be found in eTable 2.
Comment
Our Delphi consensus study combined the expertise of both dermatologists who care for patients with HS and those with inpatient dermatology experience to produce a set of recommendations for the management of HS in the hospital care setting. A strength of this study is inclusion of many national leaders in both HS and inpatient dermatology, with some participants having developed the previously published HS treatment guidelines and others having participated in inpatient dermatology Delphi studies.8-10 The expertise is further strengthened by the geographically diverse institutional representation within the United States.
The final consensus recommendations included 40 statements covering a range of patient care issues, including use of appropriate inpatient subspecialists (care team), supportive care measures (wound care, pain control, genital care), disease-oriented treatment (medical management, surgical management), inpatient complications (infection control, nutrition), and successful transition back to outpatient management (transitional care). These recommendations are meant to serve as a resource for providers to consider when taking care of inpatient HS flares, recognizing that the complexity and individual circumstances of each patient are unique.
Delphi Consensus Recommendations Compared to Prior Guidelines—Several recommendations in the current study align with the previously published North American clinical management guidelines for HS.8,9 Our recommendations agree with prior guidelines on the importance of disease staging and pain assessment using validated assessment tools as well as screening for HS comorbidities. There also is agreement in the potential benefit of involving pain specialists in the development of a comprehensive pain management plan. The inpatient care setting provides a unique opportunity to engage multiple specialists and collaborate on patient care in a timely manner. Our recommendations regarding surgical care also align with established guidelines in recommending incision and drainage as an acute bedside procedure best utilized for symptom relief in inflamed abscesses and relegating most other surgical management to the outpatient setting. Wound care recommendations also are similar, with our expert participants agreeing on individualizing dressing choices based on wound characteristics. A benefit of inpatient wound care is access to skilled nursing for dressing changes and potentially improved access to more sophisticated dressing materials. Our recommendations differ from the prior guidelines in our focus on severe HS, HS flares, and HS complications, which constitute the majority of inpatient disease management. We provide additional guidance on management of secondary infections, perianal fistulous disease, and importantly transitional care to optimize discharge planning.
Differing Opinions in Our Analysis—Despite the success of our Delphi consensus process, there were some differing opinions regarding certain aspects of inpatient HS management, which is to be expected given the lack of strong evidence-based research to support some of the recommended practices. There were differing opinions on the utility of wound culture data, with some participants feeling culture data could help with antibiotic susceptibility and resistance patterns, while others felt wound cultures represent bacterial colonization or biofilm formation.
Initial consensus statements in the first Delphi round were created for individual biologic medications but did not achieve consensus, and feedback on the use of biologics in the inpatient environment was mixed, largely due to logistic and insurance issues. Many participants felt biologic medication cost, difficulty obtaining inpatient reimbursement, health care resource utilization, and availability of biologics in different hospital systems prevented recommending the use of specific biologics during hospitalization. The one exception was in the case of a hospitalized patient who was already receiving infliximab for HS: there was consensus on ensuring the patient dosing was maximized, if appropriate, to 10 mg/kg.12 Ertapenem use also was controversial, with some participants using it as a bridge therapy to either outpatient biologic use or surgery, while others felt it was onerous and difficult to establish reliable access to secure intravenous administration and regular dosing once the patient left the inpatient setting.13 Others said they have experienced objections from infectious disease colleagues on the use of intravenous antibiotics, citing antibiotic stewardship concerns.
Patient Care in the Inpatient Setting—Prior literature suggests patients admitted as inpatients for HS tend to be of lower socioeconomic status and are admitted to larger urban teaching hospitals.14,15 Patients with lower socioeconomic status have increased difficulty accessing health care resources; therefore, inpatient admission serves as an opportunity to provide a holistic HS assessment and coordinate resources for chronic outpatient management.
Study Limitations—This Delphi consensus study has some limitations. The existing literature on inpatient management of HS is limited, challenging our ability to assess the extent to which these published recommendations are already being implemented. Additionally, the study included HS and inpatient dermatology experts from the United States, which means the recommendations may not be generalizable to other countries. Most participants practiced dermatology at large tertiary care academic medical centers, which may limit the ability to implement recommendations in all US inpatient care settings such as small community-based hospitals; however, many of the supportive care guidelines such as pain control, wound care, nutritional support, and social work should be achievable in most inpatient care settings.
Conclusion
Given the increase in inpatient and ED health care utilization for HS, there is an urgent need for expert consensus recommendations on inpatient management of this unique patient population, which requires complex multidisciplinary care. Our recommendations are a resource for providers to utilize and potentially improve the standard of care we provide these patients.
Acknowledgment—We thank the Wake Forest University Clinical and Translational Science Institute (Winston- Salem, North Carolina) for providing statistical help.
- Garg A, Kirby JS, Lavian J, et al. Sex- and age-adjusted population analysis of prevalence estimates for hidradenitis suppurativa in the United States. JAMA Dermatol. 2017;153:760-764.
- Ingram JR. The epidemiology of hidradenitis suppurativa. Br J Dermatol. 2020;183:990-998. doi:10.1111/bjd.19435
- Charrow A, Savage KT, Flood K, et al. Hidradenitis suppurativa for the dermatologic hospitalist. Cutis. 2019;104:276-280.
- Anzaldi L, Perkins JA, Byrd AS, et al. Characterizing inpatient hospitalizations for hidradenitis suppurativa in the United States. J Am Acad Dermatol. 2020;82:510-513. doi:10.1016/j.jaad.2019.09.019
- Khalsa A, Liu G, Kirby JS. Increased utilization of emergency department and inpatient care by patients with hidradenitis suppurativa. J Am Acad Dermatol. 2015;73:609-614. doi:10.1016/j.jaad.2015.06.053
- Edigin E, Kaul S, Eseaton PO, et al. At 180 days hidradenitis suppurativa readmission rate is comparable to heart failure: analysis of the nationwide readmissions database. J Am Acad Dermatol. 2022;87:188-192. doi:10.1016/j.jaad.2021.06.894
- Kirby JS, Miller JJ, Adams DR, et al. Health care utilization patterns and costs for patients with hidradenitis suppurativa. JAMA Dermatol. 2014;150:937-944. doi:10.1001/jamadermatol.2014.691
- Alikhan A, Sayed C, Alavi A, et al. North American clinical management guidelines for hidradenitis suppurativa: a publication from the United States and Canadian Hidradenitis Suppurativa Foundations: part I: diagnosis, evaluation, and the use of complementary and procedural management. J Am Acad Dermatol. 2019;81:76-90. doi:10.1016/j .jaad.2019.02.067
- Alikhan A, Sayed C, Alavi A, et al. North American clinical management guidelines for hidradenitis suppurativa: a publication from the United States and Canadian Hidradenitis Suppurativa Foundations: part II: topical, intralesional, and systemic medical management. J Am Acad Dermatol. 2019;81:91-101. doi:10.1016/j.jaad.2019.02.068
- Seminario-Vidal L, Kroshinsky D, Malachowski SJ, et al. Society of Dermatology Hospitalists supportive care guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults. J Am Acad Dermatol. 2020;82:1553-1567. doi:10.1016/j .jaad.2020.02.066
- Fitch K, Bernstein SJ, Burnand B, et al. The RAND/UCLA Appropriateness Method: User’s Manual. Rand; 2001.
- Oskardmay AN, Miles JA, Sayed CJ. Determining the optimal dose of infliximab for treatment of hidradenitis suppurativa. J Am Acad Dermatol. 2019;81:702-708. doi:10.1016/j.jaad.2019.05.022
- Join-Lambert O, Coignard-Biehler H, Jais JP, et al. Efficacy of ertapenem in severe hidradenitis suppurativa: a pilot study in a cohort of 30 consecutive patients. J Antimicrob Chemother. 2016;71:513-520. doi:10.1093/jac/dkv361
- Khanna R, Whang KA, Huang AH, et al. Inpatient burden of hidradenitis suppurativa in the United States: analysis of the 2016 National Inpatient Sample. J Dermatolog Treat. 2022;33:1150-1152. doi:10.1080/09 546634.2020.1773380
- Patel A, Patel A, Solanki D, et al. Hidradenitis suppurativa in the United States: insights from the national inpatient sample (2008-2017) on contemporary trends in demographics, hospitalization rates, chronic comorbid conditions, and mortality. Cureus. 2022;14:E24755. doi:10.7759/cureus.24755
- Garg A, Kirby JS, Lavian J, et al. Sex- and age-adjusted population analysis of prevalence estimates for hidradenitis suppurativa in the United States. JAMA Dermatol. 2017;153:760-764.
- Ingram JR. The epidemiology of hidradenitis suppurativa. Br J Dermatol. 2020;183:990-998. doi:10.1111/bjd.19435
- Charrow A, Savage KT, Flood K, et al. Hidradenitis suppurativa for the dermatologic hospitalist. Cutis. 2019;104:276-280.
- Anzaldi L, Perkins JA, Byrd AS, et al. Characterizing inpatient hospitalizations for hidradenitis suppurativa in the United States. J Am Acad Dermatol. 2020;82:510-513. doi:10.1016/j.jaad.2019.09.019
- Khalsa A, Liu G, Kirby JS. Increased utilization of emergency department and inpatient care by patients with hidradenitis suppurativa. J Am Acad Dermatol. 2015;73:609-614. doi:10.1016/j.jaad.2015.06.053
- Edigin E, Kaul S, Eseaton PO, et al. At 180 days hidradenitis suppurativa readmission rate is comparable to heart failure: analysis of the nationwide readmissions database. J Am Acad Dermatol. 2022;87:188-192. doi:10.1016/j.jaad.2021.06.894
- Kirby JS, Miller JJ, Adams DR, et al. Health care utilization patterns and costs for patients with hidradenitis suppurativa. JAMA Dermatol. 2014;150:937-944. doi:10.1001/jamadermatol.2014.691
- Alikhan A, Sayed C, Alavi A, et al. North American clinical management guidelines for hidradenitis suppurativa: a publication from the United States and Canadian Hidradenitis Suppurativa Foundations: part I: diagnosis, evaluation, and the use of complementary and procedural management. J Am Acad Dermatol. 2019;81:76-90. doi:10.1016/j .jaad.2019.02.067
- Alikhan A, Sayed C, Alavi A, et al. North American clinical management guidelines for hidradenitis suppurativa: a publication from the United States and Canadian Hidradenitis Suppurativa Foundations: part II: topical, intralesional, and systemic medical management. J Am Acad Dermatol. 2019;81:91-101. doi:10.1016/j.jaad.2019.02.068
- Seminario-Vidal L, Kroshinsky D, Malachowski SJ, et al. Society of Dermatology Hospitalists supportive care guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults. J Am Acad Dermatol. 2020;82:1553-1567. doi:10.1016/j .jaad.2020.02.066
- Fitch K, Bernstein SJ, Burnand B, et al. The RAND/UCLA Appropriateness Method: User’s Manual. Rand; 2001.
- Oskardmay AN, Miles JA, Sayed CJ. Determining the optimal dose of infliximab for treatment of hidradenitis suppurativa. J Am Acad Dermatol. 2019;81:702-708. doi:10.1016/j.jaad.2019.05.022
- Join-Lambert O, Coignard-Biehler H, Jais JP, et al. Efficacy of ertapenem in severe hidradenitis suppurativa: a pilot study in a cohort of 30 consecutive patients. J Antimicrob Chemother. 2016;71:513-520. doi:10.1093/jac/dkv361
- Khanna R, Whang KA, Huang AH, et al. Inpatient burden of hidradenitis suppurativa in the United States: analysis of the 2016 National Inpatient Sample. J Dermatolog Treat. 2022;33:1150-1152. doi:10.1080/09 546634.2020.1773380
- Patel A, Patel A, Solanki D, et al. Hidradenitis suppurativa in the United States: insights from the national inpatient sample (2008-2017) on contemporary trends in demographics, hospitalization rates, chronic comorbid conditions, and mortality. Cureus. 2022;14:E24755. doi:10.7759/cureus.24755
Practice Points
- Given the increase in hospital-based care for hidradenitis suppurativa (HS) and the lack of widespread inpatient access to dermatology and HS experts, consensus recommendations for management of HS in the acute hospital setting would be beneficial.
- Our Delphi study yielded 40 statements that reached consensus covering a range of patient care issues (eg, appropriate inpatient subspecialists [care team]), supportive care measures (wound care, pain control, genital care), disease-oriented treatment (medical management, surgical management), inpatient complications (infection control, nutrition), and successful transition to outpatient management (transitional care).
- These recommendations serve as an important resource for providers caring for inpatients with HS and represent a successful collaboration between inpatient dermatology and HS experts.
Targeting JAK Inhibitors in Severe Alopecia Areata
Alopecia areata (AA) is an autoimmune disease that affects 2% of the population. Janus kinase (JAK) signaling has been shown to improve outcomes for many patients with severe AA, as outlined by Dr Brittany Craiglow, associate professor adjunct, Yale School of Medicine, New Haven, Connecticut.
Dr Craiglow reports that in AA, hair loss can be caused by key cytokines, including interleukin 15 and interferon gamma. These cytokines use the JAK-STAT pathway to transmit their signal. JAK inhibitors, which interfere with that pathway, are showing to be an effective treatment that can lead to hair growth.
Two JAK inhibitors have received US Food and Drug Administration approval for treatment of severe AA. Oral JAK1/2 inhibitor baricitinib has been approved for patients aged 18 years or older. The oral JAK3 inhibitor ritlecitinib has been approved for patients aged 12 years or older.
Dr Craiglow looks at clinical trials involving these JAK inhibitors. The results show that patients are more likely to respond to treatment earlier in the disease process. The study also found that patients with less severe hair loss (50%-94%) respond better than did those with severe hair loss.
Finally, Dr Craiglow explores the topic of JAK inhibitor selection. She notes that different medications will hit different JAK proteins, the failure of one JAK inhibitor does not always predict failure of another. Dr Craiglow points to current efficacy of these targeted therapies and expresses optimism about the future of personalized medicine in treating patients with severe AA.
--
Brittany Craiglow, MD, Associate Professor Adjunct, Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut
Brittany Craiglow, MD, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for:
AbbVie; BiologicsMD; Dermavant; Incyte; Eli Lilly; Pfizer; Regeneron; Sanofi-Genzyme; Sun Pharmaceuticals
Serve(d) as a speaker or a member of a speaker’s bureau for: AbbVie; Incyte; Eli Lilly; Pfizer; Regeneron; Sanofi-Genzyme
Alopecia areata (AA) is an autoimmune disease that affects 2% of the population. Janus kinase (JAK) signaling has been shown to improve outcomes for many patients with severe AA, as outlined by Dr Brittany Craiglow, associate professor adjunct, Yale School of Medicine, New Haven, Connecticut.
Dr Craiglow reports that in AA, hair loss can be caused by key cytokines, including interleukin 15 and interferon gamma. These cytokines use the JAK-STAT pathway to transmit their signal. JAK inhibitors, which interfere with that pathway, are showing to be an effective treatment that can lead to hair growth.
Two JAK inhibitors have received US Food and Drug Administration approval for treatment of severe AA. Oral JAK1/2 inhibitor baricitinib has been approved for patients aged 18 years or older. The oral JAK3 inhibitor ritlecitinib has been approved for patients aged 12 years or older.
Dr Craiglow looks at clinical trials involving these JAK inhibitors. The results show that patients are more likely to respond to treatment earlier in the disease process. The study also found that patients with less severe hair loss (50%-94%) respond better than did those with severe hair loss.
Finally, Dr Craiglow explores the topic of JAK inhibitor selection. She notes that different medications will hit different JAK proteins, the failure of one JAK inhibitor does not always predict failure of another. Dr Craiglow points to current efficacy of these targeted therapies and expresses optimism about the future of personalized medicine in treating patients with severe AA.
--
Brittany Craiglow, MD, Associate Professor Adjunct, Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut
Brittany Craiglow, MD, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for:
AbbVie; BiologicsMD; Dermavant; Incyte; Eli Lilly; Pfizer; Regeneron; Sanofi-Genzyme; Sun Pharmaceuticals
Serve(d) as a speaker or a member of a speaker’s bureau for: AbbVie; Incyte; Eli Lilly; Pfizer; Regeneron; Sanofi-Genzyme
Alopecia areata (AA) is an autoimmune disease that affects 2% of the population. Janus kinase (JAK) signaling has been shown to improve outcomes for many patients with severe AA, as outlined by Dr Brittany Craiglow, associate professor adjunct, Yale School of Medicine, New Haven, Connecticut.
Dr Craiglow reports that in AA, hair loss can be caused by key cytokines, including interleukin 15 and interferon gamma. These cytokines use the JAK-STAT pathway to transmit their signal. JAK inhibitors, which interfere with that pathway, are showing to be an effective treatment that can lead to hair growth.
Two JAK inhibitors have received US Food and Drug Administration approval for treatment of severe AA. Oral JAK1/2 inhibitor baricitinib has been approved for patients aged 18 years or older. The oral JAK3 inhibitor ritlecitinib has been approved for patients aged 12 years or older.
Dr Craiglow looks at clinical trials involving these JAK inhibitors. The results show that patients are more likely to respond to treatment earlier in the disease process. The study also found that patients with less severe hair loss (50%-94%) respond better than did those with severe hair loss.
Finally, Dr Craiglow explores the topic of JAK inhibitor selection. She notes that different medications will hit different JAK proteins, the failure of one JAK inhibitor does not always predict failure of another. Dr Craiglow points to current efficacy of these targeted therapies and expresses optimism about the future of personalized medicine in treating patients with severe AA.
--
Brittany Craiglow, MD, Associate Professor Adjunct, Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut
Brittany Craiglow, MD, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for:
AbbVie; BiologicsMD; Dermavant; Incyte; Eli Lilly; Pfizer; Regeneron; Sanofi-Genzyme; Sun Pharmaceuticals
Serve(d) as a speaker or a member of a speaker’s bureau for: AbbVie; Incyte; Eli Lilly; Pfizer; Regeneron; Sanofi-Genzyme