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Overview

Background

Churg-Strauss syndrome or disease (CSD), now known as eosinophilic granulomatosis with polyangiitis (EGPA), is a specific variant of the group of diseases characterized by necrotizing vasculitis of small- and medium-sized systemic blood vessels. This type of vasculitis includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and polyarteritis nodosa (PAN). The classic distinction of CSD/EGPA from the other diseases in the category is the coexistence of asthma, rhinosinusitis, and presence of peripheral eosinophilia.^[1] Although these conditions are not thought to be directly infectious, microbial superantigens may play a role in provoking the onset of the dysregulated immune response that gives rise to these conditions.^[2]

Sir William Osler possibly described the clinical aspects of CSD in 1900. However, it was not until 1951 that Jacob Churg and Lotte Strauss clearly identified it as a distinct entity, naming it allergic granulomatosis and angiitis. They reported 13 individuals with severe asthma who developed fever, eosinophilia, cardiac and renal failure, and peripheral neuropathy. Most also had pulmonary infiltrates, sinusitis, hypertension, abdominal pain, bloody diarrhea, and skin changes. Eleven of the 13 patients died, as corticosteroids were not yet widely available.^[1]

Churg and Strauss defined the disease with three parameters: eosinophilic infiltration, necrotizing vasculitis of small- and medium-sized vessels, and extravascular granuloma formation. However, patients rarely present with all three features, necessitating more clinically relevant criteria. In 1982, Lanham et al proposed a definition including bronchial asthma, blood eosinophilia over 1500/microliter, and vasculitis involving at least two extrapulmonary organs.^[3]This definition often delayed diagnosis.

Subsequent attempts to refine diagnostic criteria have incorporated more clinical features, reflecting the lack of a single pathognomonic feature or discrete biological marker for this condition.^{[4, 5, 6]}

The American College of Rheumatology proposed new classification criteria in 1990 where 4 out of 6 features needed to be identified:^[6]

Asthma
Migratory infiltrates in lung
Paranasal sinus abnormalities
Mono or polyneuropathy
Peripheral blood eosinophilia (greater than 10% total leucocyte count)
Eosinophilic tissue infiltrates in the biopsy

This classification system rendered a 99.7% specificity and 85% sensitivity for diagnosis.^[6]

In 2022, updated criteria were published jointly by the American College of Rheumatology and the European Alliance of Associations for Rheumatology (EULAR). These criteria assign positive points to criteria that support and negative points to criteria that refute the diagnosis.^[7]

Criteria that support a diagnosis:^[7]

Eosinophil count of ≥ 1 × 10^9/L = 5 points
Evidence of obstructive airway disease = 3 points
Evidence of nasal polyps = 3 points
Extravascular eosinophilic predominant inflammation = 2 points
Diagnosis of mononeuritis multiplex/motor neuropathy not due to radiculopathy = 1 point

Criteria that refutes diagnosis139:

Cytoplasmic antineutrophil cytoplasmic antibody (ANCA) or anti-proteinase 3 (anti-PR3) ANCA = -3 points
Presence of hematuria = -1 point

EGPA diagnosis requires a cumulative score of ≥ 6 points. These criteria have a reported specificity of 99% (95% CI: 98–100%) and sensitivity of 85% (95% CI: 77–91%).^[7]

Next: Pathophysiology

Pathophysiology

The pathophysiology of Churg-Strauss disease (CSD), now known as eosinophilic granulomatosis with polyangiitis (EGPA), particularly the triggering circumstances, is not well understood and still under investigation. In their original description of antineutrophil cytoplasmic antibodies (ANCAs), Daives et al^[2] suggested that arboviral infection-related superantigens might stimulate the production of ANCAs that attack host tissues because of molecular mimicry or some other abnormality of immune tolerance. Triggering of these vasculitides by infection has remained a pathophysiological consideration.^[8] ANCAs in part mediate vascular endothelial injury in CSD/EGPA, as they do in polyarteritis nodosa (PAN), microscopic polyangiitis (MPA), and Wegener's granulomatosis (WG). In these various conditions, ANCAs may promote polymorphonuclear (PMN) cell adherence to vascular endothelial cells, with ensuing lytic vascular endothelial injury. An independent or adjuvant role in this activation may be played by tumor necrosis factor (TNF).

The major change that occurred over the years is the understanding that not every patient with different types of EGPA has overt vasculitis. Hence, there have been efforts in recent years to sub-classify the clinical phenotypes based on the presence or absence of vasculitis, somewhat counterintuitive to the nomenclature itself.^[9]

The vasculitic phenotype is more common among patients with positive ANCA. ANCA is positive in close to 40% of patients suffering from EGPA. These patients more commonly have myalgia, migrating polyarthralgia, weight loss, mononeuritis multiplex, and renal involvement either as crescentic or necrotizing glomerulonephritis.140 For patients with negative ANCA, the dominant phenotype is not vasculitis but rather eosinophilia with much higher incidence of myocarditis.

The presence of ANCA was proven to suggest vasculitis but not necessarily for diagnosis. In 2017, Cottin et al found that almost half of patients with overt vasculitis (47%) had negative ANCA results. They also found that in almost 30% of cases, the seropositivity of ANCA did not correlate with vasculitis.^[10] Due to this, they suggested a new categorization of EGPA based on phenotypes at presentation.

Vasculitic phenotype

Definitive vasculitis features:

Biopsy-proven necrotizing vasculitis of any organ
Biopsy-proven necrotizing glomerulonephritis or crescentic glomerulonephritis
Palpable purpura
Alveolar hemorrhage
Coronary arteritis causing myocardial infarction

Surrogates of vasculitis:

Hematuria with red casts greater than 10%, dysmorphic RBC, and/or 2+ protein
Leucocytoclastic capillaritis
Mononeuritis
Presence of ANCA

Asthma phenotype

It is customary to define all cases that are not of the vasculitic phenotype as asthma-related. The motivation behind early diagnosis of this specific phenotype is treatment. Patients can benefit from early recognition and targeted treatment. Hence, cases that have myocarditis with no other evidence of vasculitis should receive the same attention as patients with the asthma phenotype.

The primary trigger in pathogenesis at the cellular level seems to be an aberrant T-helper cell pathway.^[11]

Role of the T-helper pathway in diagnosis and differentiation

The pathogenic role of T cells in EGPA was shown to have specific clonally expanded subpopulations of T cells as well as increased frequency of related HLA alleles.^{[12, 13]}In EGPA there is high serum level of IL-10, which leads to suppression of Th-1 cells, thus leading to relative elevation of serum Th-2. This is the main subgroup currently associated with the diagnosis of EGPA (Th-2 Cell subgroup). It was previously found that this subgroup has abnormal activity in EGPA and the hypothesis in regard to the pathophysiology included allergies, infections, and specific medications. Yet, none of these potential triggers were found to be significant enough in previous studies.^[11]Some previous publications found association between EGPA and airway colonization with Aspergillus or Actinomyces. Allergy was found to be a factor in only in 30% of cases of EGPA. Bibby et al reviewed the US FDA database from 1996 to 2003 to report 181 cases of EGPA in which a pharmacological trigger was suspected. They found high correlation to leukotriene receptor antagonists in 90% of the cases. However, others disagree with this finding.^[14]Onset of EGPA after the use of anti-leukotrienes for the treatment of asthma has suggested that these agents may provoke an idiosyncratic drug-induced form of EGPA. In particular, an association has been detected with the use of cysteinyl leukotriene receptor type-1 (CysLT1) antagonists (eg, zafirlukast, pranlukast, montelukast) and onset of EGPA as mentioned above.^[15] However, some authorities appear to regard this association as the result of the "unmasking" of preexisting EGPA, as the introduction of leukotriene inhibitors permits corticosteroid doses to be reduced.^{[16, 15, 17, 18, 19, 20]}

On the other hand, zafirlukast treatment has been associated with idiosyncratic development of drug-induced lupus; hence, a primary role for such agents in induction of EGPA must also be considered.^[21] Despite some continued degree of etiologic uncertainty, it can be said that it remains particularly important to consider unmasked EGPA as the underlying cause of EGPA-related deterioration in patients with severe asthma undergoing steroid dosage-reduction during a period of anti-leukotriene therapy–associated improvement in pulmonary disease.

Anti-asthmatic agents, such as beclomethasone, cromolyn sodium, or other drugs, may provoke pulmonary eosinophilia. However, it is important to carefully distinguish pulmonary eosinophilia from EGPA.Others suggested theories of activation of certain lines of T-cell subsets as possible immunology involvement in the development of EGPA.^[22]Studies of affected peripheral nerve tissues show that once the stage of epineural necrotic vasculitis has been achieved, activated cytotoxic T-lymphocyte clones (CD8⁺ suppressor and cytotoxic and CD4⁺ helper cells) begin to outnumber eosinophils and predominate in the inflammatory exudate. Occasionally, CD20⁺ B lymphocytes are found in the inflammatory exudate, and less prominent deposits of immunoglobulin (IgG), immunoglobulin E (IgE), and C3d antibodies may also be detected.

Eosinophils-mediated damage

Serum level of IL-5 highly correlates with disease progression and activity. IL-5 as well as IL-3 are produced by the Th-2 cells and are significant for the maturation of eosinophils. These two factors are also important in the survival of eosinophilic cells and hence their levels correlate well with the level of activity of the eosinophils.^{[23, 24, 25]}Histological findings in EGPA are characterized by eosinophilic infiltrates in walls of small- and medium-sized blood vessels as well as extravascular tissue spaces. Hence, when tissue diagnosis is obtained, either by bronchoalveolar lavage or intestinal biopsy, the sample is usually observed to have significant eosinophilic load.^[26]Different cytokines and chemokines are involved in the associated immune response in EGPA. For example, when epithelial and endothelial cells are activated by the Th-2 cytokines, they secrete a series of chemokines (eg, CCL26, CCL17, CCL22)^{[27, 28]}that act on CCR4 in order to facilitate more eosinophilic recruitment in the end organs and thus augment the immune cascade. As a result, like with IL-5, some of these chemokines can be used as disease activity markers.^[29]Eosinophils in turn secrete many cytokines that, like IL-5, augment in return the function of the eosinophils. IL-4 and IL-13 are two other potent cytokines of Th-2 profile immune response and may play an important role in tissue infiltration and degranulation of eosinophils.^[30]

Other cytokines participate in the autoimmune process that is seen in the development of EGPA. Patients with EGPA have markedly increased serum levels of interferon alpha and interleukin 2 (IL-2) and moderate increases of TNF-alpha and interleukin 1 beta (IL-1beta) similar to those observed in PAN. Elevations of serum interleukin 6 (IL-6) concentrations have been shown to precede the rise in serum rheumatoid factors that may accompany the onset of an exacerbation of the EGPA’s vasculitis phenotype. Thus, IL-6 may be an important triggering factor. The rheumatoid factors are chiefly of IgG and immunoglobulin M (IgM) classes, rather than immunoglobulin A (IgA) or IgE.^[31]

ANCA

Elevated perinuclear ANCA (p-ANCA) with myeloperoxidase (MPO)+ is the most common finding in terms of ANCA, yet less than 50% are positive. Rarely a cytoplasmic pattern with specificity for neutrophil proteinase 3 (c- ANCA) is seen.

Presence of ANCA correlates with an increased incidence of glomerulonephritis, alveolar hemorrhage, mononeuritis, and biopsy-proven vasculitis. Yet, the level of p-ANCA correlates poorly with the disease activity. Endothelial injury in ANCA-associated vasculitis is, however, neutrophil-mediated with the generation of reactive oxygen species and proteolytic enzymes from cytoplasmic granules.^{[32, 33, 34]}

The 2 subset hypothesis in clinical phenotyping of EGPA has been further substantiated by a recent demonstration of increased frequency of HLA- DRB4 in EGPA patients with ANCA positivity. There has been some evidence of the role of Th17 lymphocytes in the occurrence and maintenance of vasculitis response in the disease, particularly with regards to the balance between Th17 and Treg cells.^[35] Some reports have suggested that Th17 cells are associated with vasculitis, as occurs in giant cell arteritis,^[36] Henoch-Schönlein purpura,^[37] ANCA-associated vasculitis,^[35]granulomatosis polyangiitis or Wegener’s granulomatosis,^[38]and EGPA.^{[25, 39, 40]}

Pathology

Unlike most noninfectious vasculitides, EGPA is fairly distinctive in its pathology, owing to the abundance of eosinophils in the inflammatory perivenular exudate. However, EGPA is a condition with a wide variety of presentations and associated signs and symptoms and other entities may provoke eosinophilic vasculitis. Therefore, EGPA remains a clinicopathologic rather than a histopathologic entity.

Eosinophilic infiltration of the upper respiratory tracts and lungs is the most common finding in EGPA, while similar infiltrative pathology is also often found in the gastrointestinal tract. The infiltrative appearance may change into eosinophilic vasculitis with worsening disease. Such clinical manifestations as weight loss, fever, and myalgia are common diagnostic clues to the possibility that EGPA is in evolution. These manifestations are found in more than half of all individuals with EGPA. Sinusitis has similar prevalence. The characteristic vasculopathy of EGPA is predominantly an arteriopathy, tending to affect small- and medium-sized arteries much more than arterioles, veins, or capillaries. This predilection is also found in PAN and some other conditions. However, the predominance of eosinophils sets EGPA apart from these other conditions. Epithelioid and giant cells are also found in the inflammatory exudate of patients with EGPA.

The inflammatory arteriopathy evolves into granulomatous fibrinoid necrosis of the vascular media. The result of this process includes the development of collagenolytic or necrobiotic noninfectious granulomata. The granulomatous material surrounds altered vascular elastic fibers and collagen as well as acellular pigmented debris, which is helpful in pathologically distinguishing one form of granulomatous vasculitis from another. EGPA is associated with "red" collagenolytic granulomas.

The lungs are the chief organs involved in patients with EGPA vasculopathy, and they almost invariably develop regions of angiopathy as the disease progresses. In a series of 96 individuals with EGPA, asthma was the first evidence of EGPA in 92%; one third developed asthma severe enough to require oral corticosteroid administration.^[26] Typical manifestations include granuloma formation, which occurs within vascular walls and in adjacent pulmonary tissues. Similar angiopathic changes develop in the heart (approximately 85%), skin (70%), peripheral nervous system (66%), central nervous system (60%), kidneys (40%), gastrointestinal tract (40%), and musculoskeletal system (20%).

Vasculitic involvement of the heart was found in as many as 85% of cases described in early reports, typically manifesting as low-output congestive cardiac failure. However, myocardial involvement (which was associated with poor prognosis) was identified in only 14% of the large series of patients with EGPA reported by Guillevin et al.^[26] EGPA should be considered in adults with asthma and eosinophilia who develop chest pain, shortness of breath, and cardiogenic shock.^[41]

Cardiac evaluation may demonstrate eosinophilic pericarditis, cardiomegaly, restrictive cardiomyopathy/perimyocarditis, and diminished myocardial contractility due to myocardial or endocardial eosinophilic vasculitis or associated tissue infarction. These changes and pericardial effusion are important prognostic factors that obviously bear upon the degree and time course of EGPA-associated heart failure.^[42]

Both systolic and diastolic dysfunction may be discerned.
Steady decline in myocardial shortening fraction often follows.
Heart failure is an important cause of death in EGPA and is a major determinant of prognosis. In the series by Guillevin et al, 8% of patients with EGPA died from cardiac disease in the acute phase of the illness.^[26]

Skin and nervous tissues are the systems next most commonly involved in patients with EGPA.

The skin is involved in 65%–70% of cases that have progressed to the systemic vasculitic phase. The pathology most commonly encountered in skin biopsies is small-vessel leukocytoclastic vasculitis with ensuing blood vessel necrosis of either small or large vessels. The cutaneous vasculopathy may be associated with the development of purpura, nodules, or areas of infarction. Similar pathological changes account for mononeuropathy multiplex and myositis due to EGPA and are also found in kidneys if glomerulonephritis develops.
Eosinophilic granulomatous changes in the gallbladder wall may result in obstructive jaundice or pain and require cholecystectomy.^[43]
Approximately 64%–80% of patients in the systemic phase of EGPA develop peripheral neuropathy, usually in the pattern of mononeuritis multiplex.^[26] Mononeuritis multiplex is the second most common initial manifestation of systemic vasculitis in adults with EGPA.
Initial mononeuritic findings often progress to asymmetrical polyneuropathy, which is restricted to the limbs. As with PAN, both motor and sensory deficits are detectable, especially in the legs; thus, the sciatic nerves (including peroneal and tibial branches) are involved more frequently than radial, median, or cubital nerves.
Sensory disturbances may include hypoesthesia or hyperesthesia, allodynia, and pain.
Polyneuropathy may regress with treatment.
Vasculitis of muscle develops in slightly more than 20% of patients.

Approximately 60% of adults with EGPA develop CNS vasculitis. This is unlike PAN, in which CNS manifestations are rare. However, CNS vasculitis has not been reported in children with EGPA. It does occur in adolescents, albeit rarely.

Manifestations include intellectual and motor disturbances. These may be abrupt in onset, and seizures may occur.
Acute cerebral hemorrhage is among the important causes of sudden death in EGPA. In some but not all instances, hemorrhage occurs in individuals who have hypertension.

Gastrointestinal dysfunction develops in 30%–60% of individuals with EGPA (prevalence higher in earlier series than in more recent case series). Most commonly, this takes the form of mesenteric vasculitis, similar to that seen in PAN. The most common manifestations are bloody diarrhea and abdominal pain.

Arteritis of medium-sized blood vessels of the kidneys develops in 20%–50% of cases. However, hypertension is less common in EGPA than in PAN.

As in PAN, the predominant renal pathology is eosinophilic interstitial pauci-immune segmental glomerulonephritis.^[43]
Crescentic necrotic glomerulopathy may develop in some instances, as is also found in microscopic polyangiitis.
IgA glomerulonephropathy may develop, as also is the case in microscopic polyangiitis, but rarely. This is a pathological change that is more typical of Schönlein-Henoch purpura.
In early reports of EGPA, uremia was an occasional cause of death. Current management has considerably reduced the risk of uremia, and, in most cases of EGPA, renal involvement is mild. Even if the renal involvement is severe, renal disease usually responds well to corticosteroid treatment.

Testicular pain, with or without epididymitis, may occur in men with EGPA.

Next: Pathophysiology

Etiology

Genetic factors

Several lines of evidence suggest a genetic predisposition to Churg-Strauss disease (CSD), now known as eosinophilic granulomatosis with polyangiitis (EGPA), which may entail an inherited tendency to dysregulation of the cellular immune system. The features of this dysregulation are discussed in Pathophysiology.

The variation in age at onset of illness is not understood, but this variation suggests the possibility that secondary factors, such as environmental influences, may hasten the onset of disease for some individuals.

Environmental factors

Environmental factors may contribute to the development of EGPA. For example, the inhalation of fungal spores, such as those produced by actinomycetes and Aspergillus species, has been implicated in the pathogenesis of some cases.

Exposure to pigeons and the molds associated with their roosts may provoke the development of EGPA.

Smoking free-base cocaine was documented carefully as a circumstance preceding individual bouts of an illness similar to or identical to EGPA in one individual. The illness in that case was not sustained endogenously, recurring only with additional episodes of cocaine smoking.^[44]

In summary, some environmental factors appear to provoke transient effects that resemble EGPA, but do not represent a chronic and self-perpetuating disease.

Drugs

Carbamazepine, macrolide antibiotics, and cysteinyl leukotriene-receptor antagonists have been implicated as provocative causes of EGPA. Leukotriene-receptor antagonists may be especially important in terms of provoking chronic EGPA that does not resolve with discontinuation of the inciting drug.

Leukotriene-receptor antagonists are used in some patients who are undergoing withdrawal of steroid treatment for asthma. This has prompted some clinicians to ascribe the onset of EGPA to steroid withdrawal rather than to direct effects of the leukotriene-receptor antagonist. They propose that EGPA manifestations were masked or perhaps prevented by the higher steroid doses. However, several patients who were not in the midst of a steroid taper have developed EGPA after administration of leukotriene-receptor antagonists. Some authorities now recommend the use of inhaled steroids rather than leukotriene-receptor antagonists when attempting to taper systemically administered steroid treatment of asthma.

EGPA has developed in the wake of Basedow disease with autoimmune thyroiditis; whether this is a chance association is not known.

Next: Pathophysiology

Epidemiology

The estimated prevalence of Churg-Strauss disease (CSD), now known as eosinophilic granulomatosis with polyangiitis (EGPA), is 10.7 to 14 per million adults worldwide. There is no gender difference in the incidence of the disease. The age distribution is wide with reports of patients as young as 4 years and as old as 74 years; median age at presentation is 40 years old.^[45]

Next: Pathophysiology

Prognosis

Once an appropriate therapeutic intervention is undertaken, a good response usually is achieved within 4 weeks. Thereafter, Churg-Strauss disease (CSD), now known as eosinophilic granulomatosis with polyangiitis (EGPA), can usually be well controlled with low maintenance steroid doses. Most individuals who showed favorable response to corticosteroid treatment of EGPA associated neuropathy do not manifest disease relapse within the ensuing 8 months. Individuals with neuropathy associated with EGPA who show poor response to initial corticosteroid treatment may experience improvement once cyclophosphamide is administered.

With modern therapy, the outlook for EGPA appears to be much better than in early reports. More than 90% of patients achieve remission after initial steroid treatment. Whether the apparently improved outlook, as compared to earlier reports, represents a change in the average severity of disease, improved recognition and diagnosis of milder cases, or improvements in therapy is not well understood. Patients demonstrating a favorable response usually retain an independent existence on steroid maintenance therapy. The relapse rate is approximately 25%–30%.

Characteristically, patients with severe systemic vasculitis have a poor response to the initial phases of treatment. Both systolic and diastolic dysfunction associated with cardiomyopathy may improve with steroid therapy, although very low myocardial shortening fractions may not improve with this therapy. The outlook for patients with severe systemic vasculitis is guarded because they have a considerable risk for dependent existence and progressive decline or premature death. The overall mortality rate may be as high as 25% within 5 years of diagnosis, half of these patients dying directly from vasculitis and half from secondary complications of vasculitis. The patients at highest risk for death or severe morbidity are those with severe myocardial or gastrointestinal vasculitis.

The chief causes of mortality related to EGPA are severe asthma, cardiopulmonary failure, or gastrointestinal complications. In general, the long-term outcome of EGPA does not differ greatly from that of PAN. In addition to overall severity of EGPA, both myocardial disease and severe gastrointestinal disease were found by Guillevin et al to be independent predictors of poor prognosis.^[26]

Across the years there has been a constant decrease in the mortality rate of patients who suffered from EGPA. Most (85%) of the index cases reported by Churg and Strauss in 1951 had died from their illness. The development of effective strategies for treatment in ensuing decades (particularly oral corticosteroids) has improved survival considerably, though the disease remains a serious one. To some extent, improved survival may relate to recognition of milder cases.

The 5-year survival rate reported in the 30-patient series of EGPA that Chumbley et al reported in 1977 was 62%.^[46] In 1999, Guillevin et al reported a 72% 6-year survival rate in a series of 96 patients with EGPA.^[26] Elderly patients may have as much as 50% greater risk of death from their EGPA and compared to middle-aged or young individuals with this disease.^[47] Yet, the mortality among the young population does not differ much from the adult population because of relatively high prevalence of cardiac involvement.

In most cases of EGPA, morbidity is chiefly cardiopulmonary. Raynaud phenomenon, arthralgias, or joint effusions are occasional complications. Painful arthritis, arthralgia, neuritis, and myalgia are recurrent manifestations. Particularly characteristic complications of the second phase of EGPA, are chronic eosinophilic pneumonia and eosinophilic gastroenteritis. Abdominal pain, diarrhea, gastrointestinal bleeding, and bowel perforation are less common but important complications. Necrotizing glomerulonephritis occurs in fewer than half of patients. It tends to affect older patients, who as a group have particularly poor outcomes. Early diagnosis of this renal complication improves outcome.^[48] Leukopenia due to immunosuppressive therapy enhances risk for sepsis and death and therefore should be avoided.^[48] The chief neurologic morbidity is, as in PAN, peripheral neuropathy.

Treatment-related complications include those associated with immunosuppression (eg, risk for infection) and other effects of anti-inflammatory medications such as Cushing ulcer with or without gastrointestinal perforation.

Clinical Presentation

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Author

Nir Shimony, MD Assistant Professor of Neurological Surgery, Division of Pediatric Neurosurgery, Department of Surgery, St Jude Children’s Research Hospital, Le Bonheur Neuroscience Institute, Le Bonheur Children’s Hospital, Baptist Children’s Hospital, and Semmes Murphey Clinic, University of Tennessee Health Science Center College of Medicine; Adjunct Faculty, Department of Neurosurgery, Johns Hopkins University School of Medicine

Nir Shimony, MD is a member of the following medical societies: American Association of Neurological Surgeons, American Epilepsy Society, Congress of Neurological Surgeons, International Society of Pediatric Neurosurgery, Society for Neuro-Oncology

Disclosure: Nothing to disclose.

Coauthor(s)

George I Jallo, MD Professor of Neurosurgery, Pediatrics, and Oncology, Director, Clinical Pediatric Neurosurgery, Department of Neurosurgery, Johns Hopkins University School of Medicine

George I Jallo, MD is a member of the following medical societies: American Association of Neurological Surgeons, American Medical Association, American Society of Pediatric Neurosurgeons

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP, FANA Professor of Pediatrics, Neurology, Neurosurgery, and Psychiatry, Medical Director, Tulane Center for Autism and Related Disorders, Tulane University School of Medicine; Pediatric Neurologist and Epileptologist, Ochsner Hospital for Children; Professor of Neurology, Louisiana State University School of Medicine

Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP, FANA is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Neurology, American Academy of Pediatrics, American Epilepsy Society, American Medical Association, American Neurological Association, The Society of Federal Health Professionals (AMSUS), Child Neurology Society, Southern Pediatric Neurology Society

Disclosure: Nothing to disclose.

Additional Contributors

Robert J Baumann, MD Professor of Neurology and Pediatrics, Department of Neurology, University of Kentucky College of Medicine

Robert J Baumann, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, Child Neurology Society

Disclosure: Nothing to disclose.

Robert Stanley Rust, Jr, MD, MA Former Thomas E Worrell Jr Professor of Epileptology and Neurology, Co-Director of FE Dreifuss Child Neurology and Epilepsy Clinics, Director, Child Neurology, University of Virginia School of Medicine; Chair-Elect, Child Neurology Section, American Academy of Neurology

Robert Stanley Rust, Jr, MD, MA is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, American Headache Society, American Neurological Association, Child Neurology Society, International Child Neurology Association, Society for Pediatric Research

Disclosure: Nothing to disclose.

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