Rasmussen encephalitis and comorbid autoimmune diseases: A window into disease mechanism? Dina Amrom, Demet Kinay, Yvonne Hart, et al. Neurology 2014;83;1049-1055 Published Online before print August 20, 2014 DOI 10.1212/WNL.0000000000000791 This information is current as of August 20, 2014
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.neurology.org/content/83/12/1049.full.html
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Rasmussen encephalitis and comorbid autoimmune diseases A window into disease mechanism?
Dina Amrom, MD Demet Kinay, MD Yvonne Hart, MD Samuel F. Berkovic, MD, FRS Ken Laxer, MD Frederick Andermann, MD Eva Andermann, MD, PhD Amit Bar-Or, MD
Correspondence to Dr. Bar-Or: [email protected] or Dr. Amrom: [email protected]
Supplemental data at Neurology.org
ABSTRACT
Objective: To describe a potential association between comorbid autoimmune disease and Rasmussen encephalitis (RE) and discuss potential insights into underlying RE pathogenesis.
Methods: We report a case series of 4 patients with RE in whom a comorbid autoimmune disease was subsequently diagnosed and review the literature on possible common susceptibility factors.
Results: In 4 patients who presented with typical clinical features of RE, a comorbid autoimmune disease was subsequently diagnosed: Hashimoto thyroiditis, ulcerative colitis, Crohn disease, and systemic lupus erythematosus. We discuss the possible common predisposing factors.
Conclusions: The association of RE, a rare entity, with a comorbid autoimmune disease raises the possibility of shared mechanisms of susceptibility, including common immunogenetic and/or environmental risk factors. Neurology® 2014;83:1049–1055 GLOSSARY a7nAChR 5 a7 nicotinic acetylcholine receptors; AID 5 autoimmune disease; ANA 5 antinuclear antibodies; CD 5 Crohn disease; GWAS 5 genome-wide association studies; HT 5 Hashimoto thyroiditis; Ig 5 immunoglobulin; IVIg 5 IV immunoglobulin; RE 5 Rasmussen encephalitis; SLE 5 systemic lupus erythematosus; T1D 5 type 1 diabetes; UC 5 ulcerative colitis.
“Chronic encephalitis and epilepsy” was first reported by Theodore Rasmussen et al.1 in 1958. Classical histopathology of early Rasmussen encephalitis (RE) shows perivascular lymphocytic cuffing, microglial nodules, and thickened meninges with lymphocytic infiltration (predominantly T lymphocytes). A viral etiology was suggested given these observations, as well as reports of preceding infectious or inflammatory events in about 50% of patients2 and similarities with Russian tick-borne encephalitis.3 However, studies to detect viral particles in RE brain specimens have yielded inconsistent results.4–6 The disease progresses toward severe panlaminar or multifocal neuronal loss, astrogliosis, microglial activation, and finally cavitation; in advanced stages, lymphocytic infiltration and cell damage extend to subcortical white matter regions, including loss of myelin and axons.7,8 While antiepileptic and immune therapies may be helpful early on, the benefits are usually transitory, and functional hemispherectomy remains the treatment of choice in many cases, with remarkable results in terms of seizure outcome and quality of life.9 We previously reported the occurrence of RE and Behçet disease, a rare immune-mediated condition, in 2 first-degree relatives and suggested that RE might have shared genetic susceptibility to autoimmune conditions.10 Here we report 4 additional patients with RE identified at 4 tertiary-care referral hospitals (among approximately 29 patients with RE diagnosed in these institutions over a 20-year span) who were subsequently diagnosed with comorbid immunemediated conditions. Patient 1 had RE and Hashimoto thyroiditis (HT); patient 2 had RE (partially reported in reference 11) and 7 years later was diagnosed with ulcerative colitis (UC); patient 3 had RE and Crohn disease (CD); and patient 4 had RE and systemic lupus erythematosus (SLE). From the Neurogenetics Unit (D.A., E.A.), Epilepsy Clinic (F.A.), and Neuroimmunology Unit (A.B.-O.), Montreal Neurological Hospital and Institute, Quebec, Canada; Departments of Neurology & Neurosurgery (D.A., F.A., E.A., A.B.-O.), Pediatrics (F.A.), and Human Genetics (E.A.), McGill University, Montreal, Quebec, Canada; Okmeydani Education and Research Hospital (D.K.), Istanbul, Turkey; Royal Victoria Infirmary (Y.H.), Newcastle-upon-Tyne, UK; Epilepsy Research Center (S.F.B.), Department of Medicine (Neurology), University of Melbourne, Australia; and Department of Neurology (K.L.), University of California at San Francisco. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. © 2014 American Academy of Neurology
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CASE HISTORIES Patient 1. A 17-year-old boy was initially admitted to the hospital in Istanbul, Turkey when he presented at the age of 2 with an episode of right facial and arm twitching during a febrile illness (table 1 and table e-1 on the Neurology® Web site at Neurology.org). The parents are Turkish and nonconsanguineous. Eight months later he had several attacks over a 5-hour period, each commencing with right-sided clonic movements and right head turning and each becoming secondarily generalized. He was started on phenobarbital (table e-1) and remained seizure-free until age 8, when he developed 4 to 7 focal clonic seizures per day involving the right face, arm, and sometimes the leg, and secondarily generalized tonic-clonic seizures every 3 months. A CT scan performed at age 8 years 6 months showed mild left hemisphere atrophy. Carbamazepine was then added, with the further addition of valproate at age 14, though seizures remained refractory and he developed progressive right-sided spastic hemiparesis, dysphasia, and developmental delay. EEGs consistently showed slow-wave and multifocal epileptic activity over the left hemisphere, particularly over the posterior temporal and parietal regions. The first MRI, performed at age 11 years 9 months, showed diffuse atrophy of the left hemisphere, more prominent over the parieto-occipital region. A second MRI at age 13 years 2 months showed progressive atrophy of the affected hemisphere. CSF analysis revealed normal cell counts and normal chemical profile. Serum antiNMDA and anti-VGKC testing was negative. Antibodies to GluR3, AMPA3, AChRa7, and Munc18 were not tested. A diagnosis of RE was based on previously reported diagnostic criteria.3 His family did not give consent for hemispherectomy, and he continued to have episodes of partial and generalized status epilepticus lasting 2–3 days several times a year during his follow-up. IV immunoglobulin (IVIg; 0.4 g/kg/day for 3 days every month) was added for an 18-month period at age 15, though this did not appear to improve seizure frequency. At the age of 14 years 7 months (prior to IVIg treatment), he developed a mild goiter with hypothyroidism. Thyroid ultrasound showed diffuse hypoechogenicity and pseudonodules. Serum antibodies to thyroglobulin and thyroperoxidase were present, while the remainder of the rheumatologic screening, including antinuclear antibodies (ANA) and anti-neutrophil cytoplasmic antibody, was negative. His brother had type 1 diabetes (T1D) diagnosed at age 14, and also had serum antibodies to thyroglobulin and thyroperoxidase but normal thyroid function tests.
side that according to the parents had been occurring for 17 days, although school contacts mentioned the falls had begun about 9 months earlier. The parents are of Moroccan origin and nonconsanguineous. On admission, action myoclonic jerks of the right side, myoclonic-atonic seizures, simple partial seizures involving the right face and limbs, right hemiparesis, and dyskinesia were noted, as well as a variable walk over the day ranging from normal to increased basis, sudden myoclonus and fall, or asymmetric with right hemiparesis. She had herpes labialis. Brain CT scan without contrast revealed extensive left frontal cortical atrophy. Several antiepileptic drugs were given but with poor or no effect: a trial of diphenylhydantoin (table e-1) was discontinued after 1 week due to increase of seizures, and a trial of carbamazepine was stopped after 3 weeks and replaced by lamotrigine. A month later, lamotrigine was stopped and replaced by topiramate. Intractable partial epilepsy developed over the following weeks, often secondarily generalized, with progressive deterioration of memory and language. Brain MRI 1 month following presentation showed left frontotemporal atrophy and T2 hypersignal. Serum ANA were measured at 1:640 dilution, in the absence of drugs known to induce these. CSF cell count and chemistry were normal, although protein electrophoresis showed 2 pronounced and 2 weak immunoglobulin (Ig) G oligoclonal bands. AntiGluR3B antibodies were found to be elevated in both serum and CSF. Regular treatments with highdose pulse methylprednisolone and IVIg were initiated 1 month following her presentation. After a transitory improvement over several months, her clinical status progressively worsened and epilepsia partialis continua appeared. Motor and cognitive functions as well as speech deteriorated. A left functional hemispherectomy was performed after 22 months of disease evolution, resulting in cessation of seizures with no need for further antiepileptic therapy. Neuropathologic findings were consistent with RE. Rehabilitation was provided, her speech recovered, and she learned to write with her left hand. At the age of 10 years and 10 months, she was found to have anemia due to rectorrhagia. Gastrointestinal workup demonstrated aggressive ulcerative rectocolitis. Interventions included immune-targeted treatment with prednisolone and azathioprine and a low-sodium and low-fiber diet. Compliance with treatment and diet was difficult because of a low socioeconomic background, and she experienced recurrence of several episodes of hemorrhagic rectocolitis.
Patient 2. This right-handed girl initially presented in Brussels, Belgium at age 3 years 9 months because of recurrent falls accompanied by jerking of the right
Patient 3. This boy initially presented at age 3 with a single episode of loss of consciousness in association with chicken pox, originally thought to have been a
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Table 1
Summary of clinical findings
Sex
Patient 1
Patient 2
Patient 3
Patient 4
Male
Female
Male
Female
Handedness
Right
Right
Right
Right
Ethnicity
Turkish
Moroccan
Caucasian
Malaysian
Consanguinity
No
No
No
No
Previous neurologic development
Normal
Normal
Normal
Normal
Preexisting event
Febrile illness at 2 years, with first partial seizure
Herpes simplex labialis
Throat infection at 6 years, with partial complex seizures
Age at RE onset
8 years 6 months
3 years 9 months
8 years
Brain CT/MRI findings
CT at age 8 years 6 months: mild left hemisphere atrophy. First MRI at age 11 years 9 months: diffuse left hemisphere atrophy, predominating in the posterior temporal and parietal region. MRI at age 13 years 2 months: progressive atrophy of the left hemisphere
CT scan at age 3 years 9 months: extensive left frontal cortical atrophy. MRI at age 3 years 10 months: left frontotemporal atrophy and T2 hypersignal
CT scan at age 8 years 4 months: Left frontal left peripheral attenuation in the left hyperintensity changes frontotemporal cortex. MRI at age 9 years: area of abnormal signal in the left frontal lobe that involved both the gray matter and the underlying white matter, consistent with an area of focal encephalitis. MRI at age 14 years: left hemispheric atrophy
Immunotherapy
IVIg
Pulse corticosteroids, IVIg
High-dose corticosteroids, IVIg, plasma exchange, high-dose cyclophosphamide
High-dose corticosteroids, IVIg
Effectiveness
Temporary
Temporary
Temporary
Temporary effect of corticosteroids, favorable effect of IVIg
Pathologic confirmation
No
Yes, hemispherectomy
Yes, hemispherectomy
Yes, brain biopsy at 28 years
14 years
Comorbid AID
HT
UC
CD
SLE
Age at onset of comorbid AID
14 years 7 months
10 years 10 months
16 years
33 years
Family history of AID
Brother with T1D
No
No
No
Abbreviations: AID 5 autoimmune disease; CD 5 Crohn disease; HT 5 Hashimoto thyroiditis; IVIg 5 IV immunoglobulin; RE 5 Rasmussen encephalitis; SLE 5 systemic lupus erythematosus; T1D 5 type 1 diabetes; UC 5 ulcerative colitis.
febrile seizure but later queried as a syncopal event. At age 6 he presented in Oxford, England with a complex partial seizure characterized by lip smacking, jaw jerking, head turning to the right, and drooling. This occurred in association with a throat infection. The parents are Caucasian and nonconsanguineous. At age 7 he became lost in a supermarket, was found with a blank stare, appeared pale, was confused for 10 minutes, and then slept. He was started on controlled-release carbamazepine (table e-1) but had an increasing number of seizures. At age 8 he was admitted in partial status, with complex partial seizures characterized by lip smacking and a right facial droop, during which he was still able to cooperate with requests. Sodium valproate was added, and subsequently phenobarbital, lamotrigine, and topiramate were added. Thereafter he had ongoing twitching of the right hand and arm and deteriorating motor and cognitive functions. By age 8 years 4 months he was noted to have switched to become left-handed. CT scan showed peripheral attenuation in the left frontotemporal cortex. A brain MRI performed 1 year later showed an area
of abnormal signal in the left frontal lobe that involved both the gray matter and the underlying white matter, consistent with an area of focal encephalitis. CSF analysis revealed 2 white cells and 60 red cells with moderate total protein elevation and equivocal presence of oligoclonal bands. Serum anti-GluR3 antibody testing was negative; antibodies to AMPA3, AChRa7, Munc-18, NMDA, and VGKC were not tested. Immunotherapy initiated at that time for the clinical diagnosis of RE included high-dose steroids, which appeared to be associated with considerable improvement, although he continued to have seizures. He was subsequently treated at various times with IVIg, which initially appeared to have good results, plasma exchange, and a course of high-dose cyclophosphamide. By age 12, while being treated with a combination of carbamazepine, sodium valproate, and vigabatrin, his condition appeared to stabilize to a certain extent, but a year later he had a relapse of refractory partial status epilepticus. By age 14 he was treated with levetiracetam, oxcarbazepine, and tiagabine. MRI scan showed clear left hemispheric atrophy, Neurology 83
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and he underwent left modified anatomic hemispherectomy (Adams type) at age 15. Neuropathologic findings were consistent with RE. He became seizure-free. Six months later he developed swollen lips and palatal ulcers. Three months later he had chronic swollen lips as well as a history of intermittent loose bowel motions. Endoscopy revealed inflamed lower stomach and small intestine, and biopsies led to a diagnosis of oral CD. He was treated with mesalazine with good effect. Patient 4. This 35-year-old right-handed woman initially
presented in Melbourne, Australia at age 14 with intractable partial epilepsy. The parents are of Malaysian origin and nonconsanguineous. A diagnosis of RE was made at age 28 on the basis of the clinical presentation of intractable partial epilepsy from childhood (in spite of multiple antiepileptic agents including diphenylhydantoin [table e-1]), brain MRI changes consistent with the diagnosis, and a confirmatory pathologic examination on brain biopsy. CSF analysis was normal. No autoantibody studies were performed. Treatment with high-dose corticosteroids was initiated at age 28, although this did not appear to be effective and was complicated by psychosis and weight gain. IVIg was also initiated from 28 years of age and appeared to be helpful but was suspended at age 33 when profound leukopenia was observed. From the age of 31 she began experiencing recurrent pleural effusions, and at age 33 she developed subpleural pulmonary nodules. She also developed alopecia, premature ovarian failure, and renal disease consistent with lupus nephritis. Serum anti–double-stranded DNA titer was significantly elevated to 68 (negative: ,30.0 IU/mL), and increased ANA were measured at a 1:640 dilution, in the absence of drugs known to induce these. She also had perinuclear anti-neutrophil cytoplasmic antibodies of 31 without associated anti-myeloperoxidase or anti-proteinase-3 antibodies. Treatment of SLE with azathioprine and hydroxychloroquine was begun with good effect on all symptoms including seizures. DISCUSSION While several lines of evidence have implicated immune-mediated mechanisms in RE pathogenesis, an ongoing challenge has been to distinguish the extent to which abnormal immuneresponse profiles observed in patients with RE directly contribute to tissue injury or represent consequences of the tissue injury. Early studies considered an antibody-mediated process based on Ig deposits in cortical pathology of one patient12 and subsequent reports of increased serum titers of autoantibodies against the postsynaptic GluR3 protein.13 However, these antibodies have not been consistently demonstrated in all patients with RE,14 and their presence could also be demonstrated in other forms of severe epilepsy,15 suggesting that 1052
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they may reflect responses to injured CNS tissue. Subsequently, serum IgG autoantibodies against a7 nicotinic acetylcholine receptors (a7nAChR) were reported in a subset of patients with RE and described as specifically blocking the function of the neuronal a7nAChR,16 an inflammatory regulator thought to play a role in blood-brain barrier regulation, which is likely to be damaged in RE.17,18 In 2 independent studies, serum antibodies against the presynaptic SM (Sec1/Munc18-like) protein Munc-18 were found in a subset of patients with RE during early disease stages, with description of altered neurotransmitter release.19,20 In addition to the potential contribution of B cells/plasma cells and antibodies, involvement of effector T cells has been suggested based on immunohistochemical analysis of the RE inflammatory lesion, highlighting that most of the infiltrating lymphocytes were cytotoxic CD81 T cells containing granzyme B.6,21–23 These and subsequent findings have suggested that important pathogenic mechanisms may involve antigen-driven, major histocompatibility complex class I–restricted CD81 T cells and possibly interferon-g responses of both CD4 (Th1) and CD8 (Tc1) T cells, targeting (as yet unknown) antigen(s) on neurons and/or astrocytes in the CNS.24,25 Further support of an immune contribution to RE pathogenesis is based on largely empiric experience of years of immune intervention, including variable use of high-dose corticosteroids, IgG immunoadsorption, IVIg, plasma exchange, and tacrolimus.26 These interventions appeared to result in some clinical improvement and/or stabilization, at least in some patients, when administered during the acute phase of the disease. Rituximab, an anti-CD20 monoclonal antibody that efficiently depletes circulating B cells (and as a result can also affect both CD41 and CD81 T-cell responses)27 was reported to be effective in seizure control in one case report.28 Subsequently, a pilot clinical trial of rituximab in 10 patients with RE exhibited good tolerability, feasibility, and efficacy (Ken Laxer, MD, personal communication). Altogether, the apparent response of at least some patients with RE to immune-directed therapies supports a role of dysregulated immune responses in disease pathogenesis. We report 4 unrelated patients who developed chronic encephalitis and epilepsy fulfilling diagnostic criteria of RE.3,26 Three (patients 1–3) had childhood-onset, rapidly progressive RE, and one (patient 4) had late-onset, slowly progressive RE. Each patient subsequently developed a comorbid autoimmune disease (AID), including HT, UC, CD, and SLE. The duration between the RE diagnosis and the diagnosis of a comorbid AID in our patients ranged between 6 and 19 years (mean: 9 years, 3.5 months; median: 7 years), although symptoms that were
retrospectively attributed to the AID may have started earlier. These cases were identified among approximately 29 patients with RE seen over a 20-year period in 4 large tertiary-care referral centers (approximately 14%). This would appear to be higher than the expected prevalence in the background populations. In prior reports, sequential occurrence or cooccurrence of RE and uveitis, either ipsilateral or bilateral, has been noted.29–32 Although uveitis can be caused by various infections, up to approximately 40% of patients have uveitis associated with a systemic immune-mediated disease.33 The sequential development of RE and comorbid immune-mediated diseases in the same patients raises the question of whether this is a mere unfortunate coincidence or whether it reflects some common pathophysiologic susceptibility. An immunogenetic predisposition for the development of RE was already postulated 2 decades ago.34 We cannot entirely exclude an alternate possibility that the comorbid AID developed as a consequence of the RE treatment (with antiepileptics or immune therapy), though possibly arguing against this is the fact that patient 1 developed initial symptoms of HT before receiving immunotherapy and patient 2 developed initial symptoms of the UC 5 years after discontinuation of both antiepileptics and immunotherapy (table e-1). The etiology of most complex human AIDs is thought to involve both genetic and environmental factors, with the genetic predisposition conferred by multiple genes, each contributing a relatively small amount of risk. A number of the relatively common AIDs, such as T1D, inflammatory bowel disease, and multiple sclerosis, share some similarities with respect to implicated cellular responses and molecular immune pathways. Examples of more than a single immune-mediated disorder occurring in individual patients and within families initially suggested common hereditary factors.35–37 The more recent genome wide association studies (GWAS) in various AIDs not including RE have pointed to multiple shared risk alleles across these conditions, contributing to the shared-network view of AID susceptibility.35–39 The same susceptibility allele or different susceptibility alleles on the same gene may be associated with 2 or 3 AIDs; a few of them were even associated with 4 AIDs. In some patients, the same allele might confer increased risk for one AID and protection for another (http://www.grc.nia.nih.gov/branches/rrb/ dna/comparativegenomics.htm and table e-2).40,41 To our knowledge, no twin or familial aggregation of RE has been reported so far for this very rare disease. Since no GWAS or next-generation sequencing studies have been reported on RE, data on susceptibility loci are not available.
A key question raised by our small case series is what proportion of patients with RE would be expected to have a comorbid AID based on the background frequency of these conditions in the study population. While some estimate of the chance likelihood of such comorbidity could be calculated based on the prevalence of these different conditions, the relevant data are not readily available. The prevalence rates of HT, UC, CD, and SLE vary with ethnicity, diagnostic methodologies, access to medical services, and different geographic areas, while data on the true incidence or prevalence of RE are also lacking because no comprehensive epidemiologic studies have been done for this very rare disease. In the largest single cohort reported to date, 48 patients diagnosed with RE were investigated and operated on at the Montreal Neurological Hospital and Institute between 1958 and 1991. These included patients referred from many centers worldwide, such that commenting on regional prevalence was not possible.2 In a nationwide survey performed in Japan, 27 patients with RE were reported.32 Considering a population estimate in Japan of 127,614,000 individuals in 2009, this would mean a prevalence rate of 0.021 per 100,000 individuals. Certainly the cases identified here suggest that collecting such data is warranted. The co-occurrence of RE with AIDs for which multiple immune risk alleles have already been established provides new indirect evidence that RE onset may be conditioned by immunogenetic predisposition that could interact with as-yet-undefined environmental factors. In patients with RE, targeted analysis of the susceptibility genes found to be shared across several human AIDs (table e-2) would seem warranted. Data that may support consideration of RE as part of the AID spectrum could potentially increase general interest and funding for larger studies, which will be required to unravel the genetic background, initiating a cascade of pathophysiologic events in this uncommon and often devastating condition. Given its rarity, establishing national and international RE registries is paramount not only to better estimate the prevalence, geographical distribution, and risk factors for this condition but also to facilitate much-needed studies of pathogenesis and ultimately intervention. AUTHOR CONTRIBUTIONS Dina Amrom: patient recruitment, writing of the manuscript, revisions of the manuscript. Demet Kinay: patient recruitment, writing of the first draft. Yvonne Hart: patient recruitment. Samuel F. Berkovic: patient recruitment. Ken Laxer: revision of the manuscript. Frederick Andermann: revision of the manuscript. Eva Andermann: revision of the manuscript. Amit Bar-Or: Writing of the manuscript, revisions of the manuscript.
STUDY FUNDING No targeted funding reported. Neurology 83
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DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
16.
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Rasmussen encephalitis and comorbid autoimmune diseases: A window into disease mechanism? Dina Amrom, Demet Kinay, Yvonne Hart, et al. Neurology 2014;83;1049-1055 Published Online before print August 20, 2014 DOI 10.1212/WNL.0000000000000791 This information is current as of August 20, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/83/12/1049.full.html
Supplementary Material
Supplementary material can be found at: http://www.neurology.org/content/suppl/2014/08/20/WNL.00000 00000000791.DC1.html http://www.neurology.org/content/suppl/2014/10/24/WNL.00000 00000000791.DC2.html
References
This article cites 34 articles, 7 of which you can access for free at: http://www.neurology.org/content/83/12/1049.full.html##ref-list1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): All Clinical Neurology http://www.neurology.org//cgi/collection/all_clinical_neurology All Epilepsy/Seizures http://www.neurology.org//cgi/collection/all_epilepsy_seizures All Genetics http://www.neurology.org//cgi/collection/all_genetics Autoimmune diseases http://www.neurology.org//cgi/collection/autoimmune_diseases Encephalitis http://www.neurology.org//cgi/collection/encephalitis
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Rasmussen encephalitis and comorbid autoimmune diseases A window into disease mechanism?
Dina Amrom, MD Demet Kinay, MD Yvonne Hart, MD Samuel F. Berkovic, MD, FRS Ken Laxer, MD Frederick Andermann, MD Eva Andermann, MD, PhD Amit Bar-Or, MD
Correspondence to Dr. Bar-Or: [email protected] or Dr. Amrom: [email protected]
Supplemental data at Neurology.org
ABSTRACT
Objective: To describe a potential association between comorbid autoimmune disease and Rasmussen encephalitis (RE) and discuss potential insights into underlying RE pathogenesis.
Methods: We report a case series of 4 patients with RE in whom a comorbid autoimmune disease was subsequently diagnosed and review the literature on possible common susceptibility factors.
Results: In 4 patients who presented with typical clinical features of RE, a comorbid autoimmune disease was subsequently diagnosed: Hashimoto thyroiditis, ulcerative colitis, Crohn disease, and systemic lupus erythematosus. We discuss the possible common predisposing factors.
Conclusions: The association of RE, a rare entity, with a comorbid autoimmune disease raises the possibility of shared mechanisms of susceptibility, including common immunogenetic and/or environmental risk factors. Neurology® 2014;83:1049–1055 GLOSSARY a7nAChR 5 a7 nicotinic acetylcholine receptors; AID 5 autoimmune disease; ANA 5 antinuclear antibodies; CD 5 Crohn disease; GWAS 5 genome-wide association studies; HT 5 Hashimoto thyroiditis; Ig 5 immunoglobulin; IVIg 5 IV immunoglobulin; RE 5 Rasmussen encephalitis; SLE 5 systemic lupus erythematosus; T1D 5 type 1 diabetes; UC 5 ulcerative colitis.
“Chronic encephalitis and epilepsy” was first reported by Theodore Rasmussen et al.1 in 1958. Classical histopathology of early Rasmussen encephalitis (RE) shows perivascular lymphocytic cuffing, microglial nodules, and thickened meninges with lymphocytic infiltration (predominantly T lymphocytes). A viral etiology was suggested given these observations, as well as reports of preceding infectious or inflammatory events in about 50% of patients2 and similarities with Russian tick-borne encephalitis.3 However, studies to detect viral particles in RE brain specimens have yielded inconsistent results.4–6 The disease progresses toward severe panlaminar or multifocal neuronal loss, astrogliosis, microglial activation, and finally cavitation; in advanced stages, lymphocytic infiltration and cell damage extend to subcortical white matter regions, including loss of myelin and axons.7,8 While antiepileptic and immune therapies may be helpful early on, the benefits are usually transitory, and functional hemispherectomy remains the treatment of choice in many cases, with remarkable results in terms of seizure outcome and quality of life.9 We previously reported the occurrence of RE and Behçet disease, a rare immune-mediated condition, in 2 first-degree relatives and suggested that RE might have shared genetic susceptibility to autoimmune conditions.10 Here we report 4 additional patients with RE identified at 4 tertiary-care referral hospitals (among approximately 29 patients with RE diagnosed in these institutions over a 20-year span) who were subsequently diagnosed with comorbid immunemediated conditions. Patient 1 had RE and Hashimoto thyroiditis (HT); patient 2 had RE (partially reported in reference 11) and 7 years later was diagnosed with ulcerative colitis (UC); patient 3 had RE and Crohn disease (CD); and patient 4 had RE and systemic lupus erythematosus (SLE). From the Neurogenetics Unit (D.A., E.A.), Epilepsy Clinic (F.A.), and Neuroimmunology Unit (A.B.-O.), Montreal Neurological Hospital and Institute, Quebec, Canada; Departments of Neurology & Neurosurgery (D.A., F.A., E.A., A.B.-O.), Pediatrics (F.A.), and Human Genetics (E.A.), McGill University, Montreal, Quebec, Canada; Okmeydani Education and Research Hospital (D.K.), Istanbul, Turkey; Royal Victoria Infirmary (Y.H.), Newcastle-upon-Tyne, UK; Epilepsy Research Center (S.F.B.), Department of Medicine (Neurology), University of Melbourne, Australia; and Department of Neurology (K.L.), University of California at San Francisco. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. © 2014 American Academy of Neurology
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CASE HISTORIES Patient 1. A 17-year-old boy was initially admitted to the hospital in Istanbul, Turkey when he presented at the age of 2 with an episode of right facial and arm twitching during a febrile illness (table 1 and table e-1 on the Neurology® Web site at Neurology.org). The parents are Turkish and nonconsanguineous. Eight months later he had several attacks over a 5-hour period, each commencing with right-sided clonic movements and right head turning and each becoming secondarily generalized. He was started on phenobarbital (table e-1) and remained seizure-free until age 8, when he developed 4 to 7 focal clonic seizures per day involving the right face, arm, and sometimes the leg, and secondarily generalized tonic-clonic seizures every 3 months. A CT scan performed at age 8 years 6 months showed mild left hemisphere atrophy. Carbamazepine was then added, with the further addition of valproate at age 14, though seizures remained refractory and he developed progressive right-sided spastic hemiparesis, dysphasia, and developmental delay. EEGs consistently showed slow-wave and multifocal epileptic activity over the left hemisphere, particularly over the posterior temporal and parietal regions. The first MRI, performed at age 11 years 9 months, showed diffuse atrophy of the left hemisphere, more prominent over the parieto-occipital region. A second MRI at age 13 years 2 months showed progressive atrophy of the affected hemisphere. CSF analysis revealed normal cell counts and normal chemical profile. Serum antiNMDA and anti-VGKC testing was negative. Antibodies to GluR3, AMPA3, AChRa7, and Munc18 were not tested. A diagnosis of RE was based on previously reported diagnostic criteria.3 His family did not give consent for hemispherectomy, and he continued to have episodes of partial and generalized status epilepticus lasting 2–3 days several times a year during his follow-up. IV immunoglobulin (IVIg; 0.4 g/kg/day for 3 days every month) was added for an 18-month period at age 15, though this did not appear to improve seizure frequency. At the age of 14 years 7 months (prior to IVIg treatment), he developed a mild goiter with hypothyroidism. Thyroid ultrasound showed diffuse hypoechogenicity and pseudonodules. Serum antibodies to thyroglobulin and thyroperoxidase were present, while the remainder of the rheumatologic screening, including antinuclear antibodies (ANA) and anti-neutrophil cytoplasmic antibody, was negative. His brother had type 1 diabetes (T1D) diagnosed at age 14, and also had serum antibodies to thyroglobulin and thyroperoxidase but normal thyroid function tests.
side that according to the parents had been occurring for 17 days, although school contacts mentioned the falls had begun about 9 months earlier. The parents are of Moroccan origin and nonconsanguineous. On admission, action myoclonic jerks of the right side, myoclonic-atonic seizures, simple partial seizures involving the right face and limbs, right hemiparesis, and dyskinesia were noted, as well as a variable walk over the day ranging from normal to increased basis, sudden myoclonus and fall, or asymmetric with right hemiparesis. She had herpes labialis. Brain CT scan without contrast revealed extensive left frontal cortical atrophy. Several antiepileptic drugs were given but with poor or no effect: a trial of diphenylhydantoin (table e-1) was discontinued after 1 week due to increase of seizures, and a trial of carbamazepine was stopped after 3 weeks and replaced by lamotrigine. A month later, lamotrigine was stopped and replaced by topiramate. Intractable partial epilepsy developed over the following weeks, often secondarily generalized, with progressive deterioration of memory and language. Brain MRI 1 month following presentation showed left frontotemporal atrophy and T2 hypersignal. Serum ANA were measured at 1:640 dilution, in the absence of drugs known to induce these. CSF cell count and chemistry were normal, although protein electrophoresis showed 2 pronounced and 2 weak immunoglobulin (Ig) G oligoclonal bands. AntiGluR3B antibodies were found to be elevated in both serum and CSF. Regular treatments with highdose pulse methylprednisolone and IVIg were initiated 1 month following her presentation. After a transitory improvement over several months, her clinical status progressively worsened and epilepsia partialis continua appeared. Motor and cognitive functions as well as speech deteriorated. A left functional hemispherectomy was performed after 22 months of disease evolution, resulting in cessation of seizures with no need for further antiepileptic therapy. Neuropathologic findings were consistent with RE. Rehabilitation was provided, her speech recovered, and she learned to write with her left hand. At the age of 10 years and 10 months, she was found to have anemia due to rectorrhagia. Gastrointestinal workup demonstrated aggressive ulcerative rectocolitis. Interventions included immune-targeted treatment with prednisolone and azathioprine and a low-sodium and low-fiber diet. Compliance with treatment and diet was difficult because of a low socioeconomic background, and she experienced recurrence of several episodes of hemorrhagic rectocolitis.
Patient 2. This right-handed girl initially presented in Brussels, Belgium at age 3 years 9 months because of recurrent falls accompanied by jerking of the right
Patient 3. This boy initially presented at age 3 with a single episode of loss of consciousness in association with chicken pox, originally thought to have been a
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Table 1
Summary of clinical findings
Sex
Patient 1
Patient 2
Patient 3
Patient 4
Male
Female
Male
Female
Handedness
Right
Right
Right
Right
Ethnicity
Turkish
Moroccan
Caucasian
Malaysian
Consanguinity
No
No
No
No
Previous neurologic development
Normal
Normal
Normal
Normal
Preexisting event
Febrile illness at 2 years, with first partial seizure
Herpes simplex labialis
Throat infection at 6 years, with partial complex seizures
Age at RE onset
8 years 6 months
3 years 9 months
8 years
Brain CT/MRI findings
CT at age 8 years 6 months: mild left hemisphere atrophy. First MRI at age 11 years 9 months: diffuse left hemisphere atrophy, predominating in the posterior temporal and parietal region. MRI at age 13 years 2 months: progressive atrophy of the left hemisphere
CT scan at age 3 years 9 months: extensive left frontal cortical atrophy. MRI at age 3 years 10 months: left frontotemporal atrophy and T2 hypersignal
CT scan at age 8 years 4 months: Left frontal left peripheral attenuation in the left hyperintensity changes frontotemporal cortex. MRI at age 9 years: area of abnormal signal in the left frontal lobe that involved both the gray matter and the underlying white matter, consistent with an area of focal encephalitis. MRI at age 14 years: left hemispheric atrophy
Immunotherapy
IVIg
Pulse corticosteroids, IVIg
High-dose corticosteroids, IVIg, plasma exchange, high-dose cyclophosphamide
High-dose corticosteroids, IVIg
Effectiveness
Temporary
Temporary
Temporary
Temporary effect of corticosteroids, favorable effect of IVIg
Pathologic confirmation
No
Yes, hemispherectomy
Yes, hemispherectomy
Yes, brain biopsy at 28 years
14 years
Comorbid AID
HT
UC
CD
SLE
Age at onset of comorbid AID
14 years 7 months
10 years 10 months
16 years
33 years
Family history of AID
Brother with T1D
No
No
No
Abbreviations: AID 5 autoimmune disease; CD 5 Crohn disease; HT 5 Hashimoto thyroiditis; IVIg 5 IV immunoglobulin; RE 5 Rasmussen encephalitis; SLE 5 systemic lupus erythematosus; T1D 5 type 1 diabetes; UC 5 ulcerative colitis.
febrile seizure but later queried as a syncopal event. At age 6 he presented in Oxford, England with a complex partial seizure characterized by lip smacking, jaw jerking, head turning to the right, and drooling. This occurred in association with a throat infection. The parents are Caucasian and nonconsanguineous. At age 7 he became lost in a supermarket, was found with a blank stare, appeared pale, was confused for 10 minutes, and then slept. He was started on controlled-release carbamazepine (table e-1) but had an increasing number of seizures. At age 8 he was admitted in partial status, with complex partial seizures characterized by lip smacking and a right facial droop, during which he was still able to cooperate with requests. Sodium valproate was added, and subsequently phenobarbital, lamotrigine, and topiramate were added. Thereafter he had ongoing twitching of the right hand and arm and deteriorating motor and cognitive functions. By age 8 years 4 months he was noted to have switched to become left-handed. CT scan showed peripheral attenuation in the left frontotemporal cortex. A brain MRI performed 1 year later showed an area
of abnormal signal in the left frontal lobe that involved both the gray matter and the underlying white matter, consistent with an area of focal encephalitis. CSF analysis revealed 2 white cells and 60 red cells with moderate total protein elevation and equivocal presence of oligoclonal bands. Serum anti-GluR3 antibody testing was negative; antibodies to AMPA3, AChRa7, Munc-18, NMDA, and VGKC were not tested. Immunotherapy initiated at that time for the clinical diagnosis of RE included high-dose steroids, which appeared to be associated with considerable improvement, although he continued to have seizures. He was subsequently treated at various times with IVIg, which initially appeared to have good results, plasma exchange, and a course of high-dose cyclophosphamide. By age 12, while being treated with a combination of carbamazepine, sodium valproate, and vigabatrin, his condition appeared to stabilize to a certain extent, but a year later he had a relapse of refractory partial status epilepticus. By age 14 he was treated with levetiracetam, oxcarbazepine, and tiagabine. MRI scan showed clear left hemispheric atrophy, Neurology 83
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and he underwent left modified anatomic hemispherectomy (Adams type) at age 15. Neuropathologic findings were consistent with RE. He became seizure-free. Six months later he developed swollen lips and palatal ulcers. Three months later he had chronic swollen lips as well as a history of intermittent loose bowel motions. Endoscopy revealed inflamed lower stomach and small intestine, and biopsies led to a diagnosis of oral CD. He was treated with mesalazine with good effect. Patient 4. This 35-year-old right-handed woman initially
presented in Melbourne, Australia at age 14 with intractable partial epilepsy. The parents are of Malaysian origin and nonconsanguineous. A diagnosis of RE was made at age 28 on the basis of the clinical presentation of intractable partial epilepsy from childhood (in spite of multiple antiepileptic agents including diphenylhydantoin [table e-1]), brain MRI changes consistent with the diagnosis, and a confirmatory pathologic examination on brain biopsy. CSF analysis was normal. No autoantibody studies were performed. Treatment with high-dose corticosteroids was initiated at age 28, although this did not appear to be effective and was complicated by psychosis and weight gain. IVIg was also initiated from 28 years of age and appeared to be helpful but was suspended at age 33 when profound leukopenia was observed. From the age of 31 she began experiencing recurrent pleural effusions, and at age 33 she developed subpleural pulmonary nodules. She also developed alopecia, premature ovarian failure, and renal disease consistent with lupus nephritis. Serum anti–double-stranded DNA titer was significantly elevated to 68 (negative: ,30.0 IU/mL), and increased ANA were measured at a 1:640 dilution, in the absence of drugs known to induce these. She also had perinuclear anti-neutrophil cytoplasmic antibodies of 31 without associated anti-myeloperoxidase or anti-proteinase-3 antibodies. Treatment of SLE with azathioprine and hydroxychloroquine was begun with good effect on all symptoms including seizures. DISCUSSION While several lines of evidence have implicated immune-mediated mechanisms in RE pathogenesis, an ongoing challenge has been to distinguish the extent to which abnormal immuneresponse profiles observed in patients with RE directly contribute to tissue injury or represent consequences of the tissue injury. Early studies considered an antibody-mediated process based on Ig deposits in cortical pathology of one patient12 and subsequent reports of increased serum titers of autoantibodies against the postsynaptic GluR3 protein.13 However, these antibodies have not been consistently demonstrated in all patients with RE,14 and their presence could also be demonstrated in other forms of severe epilepsy,15 suggesting that 1052
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they may reflect responses to injured CNS tissue. Subsequently, serum IgG autoantibodies against a7 nicotinic acetylcholine receptors (a7nAChR) were reported in a subset of patients with RE and described as specifically blocking the function of the neuronal a7nAChR,16 an inflammatory regulator thought to play a role in blood-brain barrier regulation, which is likely to be damaged in RE.17,18 In 2 independent studies, serum antibodies against the presynaptic SM (Sec1/Munc18-like) protein Munc-18 were found in a subset of patients with RE during early disease stages, with description of altered neurotransmitter release.19,20 In addition to the potential contribution of B cells/plasma cells and antibodies, involvement of effector T cells has been suggested based on immunohistochemical analysis of the RE inflammatory lesion, highlighting that most of the infiltrating lymphocytes were cytotoxic CD81 T cells containing granzyme B.6,21–23 These and subsequent findings have suggested that important pathogenic mechanisms may involve antigen-driven, major histocompatibility complex class I–restricted CD81 T cells and possibly interferon-g responses of both CD4 (Th1) and CD8 (Tc1) T cells, targeting (as yet unknown) antigen(s) on neurons and/or astrocytes in the CNS.24,25 Further support of an immune contribution to RE pathogenesis is based on largely empiric experience of years of immune intervention, including variable use of high-dose corticosteroids, IgG immunoadsorption, IVIg, plasma exchange, and tacrolimus.26 These interventions appeared to result in some clinical improvement and/or stabilization, at least in some patients, when administered during the acute phase of the disease. Rituximab, an anti-CD20 monoclonal antibody that efficiently depletes circulating B cells (and as a result can also affect both CD41 and CD81 T-cell responses)27 was reported to be effective in seizure control in one case report.28 Subsequently, a pilot clinical trial of rituximab in 10 patients with RE exhibited good tolerability, feasibility, and efficacy (Ken Laxer, MD, personal communication). Altogether, the apparent response of at least some patients with RE to immune-directed therapies supports a role of dysregulated immune responses in disease pathogenesis. We report 4 unrelated patients who developed chronic encephalitis and epilepsy fulfilling diagnostic criteria of RE.3,26 Three (patients 1–3) had childhood-onset, rapidly progressive RE, and one (patient 4) had late-onset, slowly progressive RE. Each patient subsequently developed a comorbid autoimmune disease (AID), including HT, UC, CD, and SLE. The duration between the RE diagnosis and the diagnosis of a comorbid AID in our patients ranged between 6 and 19 years (mean: 9 years, 3.5 months; median: 7 years), although symptoms that were
retrospectively attributed to the AID may have started earlier. These cases were identified among approximately 29 patients with RE seen over a 20-year period in 4 large tertiary-care referral centers (approximately 14%). This would appear to be higher than the expected prevalence in the background populations. In prior reports, sequential occurrence or cooccurrence of RE and uveitis, either ipsilateral or bilateral, has been noted.29–32 Although uveitis can be caused by various infections, up to approximately 40% of patients have uveitis associated with a systemic immune-mediated disease.33 The sequential development of RE and comorbid immune-mediated diseases in the same patients raises the question of whether this is a mere unfortunate coincidence or whether it reflects some common pathophysiologic susceptibility. An immunogenetic predisposition for the development of RE was already postulated 2 decades ago.34 We cannot entirely exclude an alternate possibility that the comorbid AID developed as a consequence of the RE treatment (with antiepileptics or immune therapy), though possibly arguing against this is the fact that patient 1 developed initial symptoms of HT before receiving immunotherapy and patient 2 developed initial symptoms of the UC 5 years after discontinuation of both antiepileptics and immunotherapy (table e-1). The etiology of most complex human AIDs is thought to involve both genetic and environmental factors, with the genetic predisposition conferred by multiple genes, each contributing a relatively small amount of risk. A number of the relatively common AIDs, such as T1D, inflammatory bowel disease, and multiple sclerosis, share some similarities with respect to implicated cellular responses and molecular immune pathways. Examples of more than a single immune-mediated disorder occurring in individual patients and within families initially suggested common hereditary factors.35–37 The more recent genome wide association studies (GWAS) in various AIDs not including RE have pointed to multiple shared risk alleles across these conditions, contributing to the shared-network view of AID susceptibility.35–39 The same susceptibility allele or different susceptibility alleles on the same gene may be associated with 2 or 3 AIDs; a few of them were even associated with 4 AIDs. In some patients, the same allele might confer increased risk for one AID and protection for another (http://www.grc.nia.nih.gov/branches/rrb/ dna/comparativegenomics.htm and table e-2).40,41 To our knowledge, no twin or familial aggregation of RE has been reported so far for this very rare disease. Since no GWAS or next-generation sequencing studies have been reported on RE, data on susceptibility loci are not available.
A key question raised by our small case series is what proportion of patients with RE would be expected to have a comorbid AID based on the background frequency of these conditions in the study population. While some estimate of the chance likelihood of such comorbidity could be calculated based on the prevalence of these different conditions, the relevant data are not readily available. The prevalence rates of HT, UC, CD, and SLE vary with ethnicity, diagnostic methodologies, access to medical services, and different geographic areas, while data on the true incidence or prevalence of RE are also lacking because no comprehensive epidemiologic studies have been done for this very rare disease. In the largest single cohort reported to date, 48 patients diagnosed with RE were investigated and operated on at the Montreal Neurological Hospital and Institute between 1958 and 1991. These included patients referred from many centers worldwide, such that commenting on regional prevalence was not possible.2 In a nationwide survey performed in Japan, 27 patients with RE were reported.32 Considering a population estimate in Japan of 127,614,000 individuals in 2009, this would mean a prevalence rate of 0.021 per 100,000 individuals. Certainly the cases identified here suggest that collecting such data is warranted. The co-occurrence of RE with AIDs for which multiple immune risk alleles have already been established provides new indirect evidence that RE onset may be conditioned by immunogenetic predisposition that could interact with as-yet-undefined environmental factors. In patients with RE, targeted analysis of the susceptibility genes found to be shared across several human AIDs (table e-2) would seem warranted. Data that may support consideration of RE as part of the AID spectrum could potentially increase general interest and funding for larger studies, which will be required to unravel the genetic background, initiating a cascade of pathophysiologic events in this uncommon and often devastating condition. Given its rarity, establishing national and international RE registries is paramount not only to better estimate the prevalence, geographical distribution, and risk factors for this condition but also to facilitate much-needed studies of pathogenesis and ultimately intervention. AUTHOR CONTRIBUTIONS Dina Amrom: patient recruitment, writing of the manuscript, revisions of the manuscript. Demet Kinay: patient recruitment, writing of the first draft. Yvonne Hart: patient recruitment. Samuel F. Berkovic: patient recruitment. Ken Laxer: revision of the manuscript. Frederick Andermann: revision of the manuscript. Eva Andermann: revision of the manuscript. Amit Bar-Or: Writing of the manuscript, revisions of the manuscript.
STUDY FUNDING No targeted funding reported. Neurology 83
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DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
16.
Received July 2, 2013. Accepted in final form June 20, 2014. 17. REFERENCES 1. Rasmussen T, Olszewski J, Lloydsmith D. Focal seizures due to chronic localized encephalitis. Neurology 1958;8: 435–445. 2. Oguni H, Andermann F, Rasmussen TB. The natural history of the syndrome of chronic encephalitis and epilepsy: a study of the MNI series of forty-eight cases. In: Andermann F, editor. Chronic Encephalitis and Epilepsy: Rasmussen’s Syndrome. Boston, MA: Butterworth-Heinemann; 1991:7–35. 3. Hart Y, Andermann F. Rasmussen syndrome. In: Oxbury J, Polkey CE, Duchowny M, editors. Intractable Focal Epilepsy. London, New York: W.B. Saunders; 2000: 233–248. 4. Asher DM, Gajdusek DC. Virologic studies in chronic encephalitis. In: Andermann F, editor. Chronic Encephalitis and Epilepsy: Rasmussen’s Syndrome. Boston, MA: Butterworth-Heinemann; 1991:147–158. 5. Atkins MR, Terrell W, Hulette CM. Rasmussen’s syndrome: a study of potential viral etiology. Clin Neuropathol 1995;14:7–12. 6. Bien CG, Wiendl H, Elger CE. Advances in pathogenic concepts and therapeutic agents in Rasmussen’s encephalitis. Expert Opin Investig Drugs 2002;11:981–989. 7. Robitaille Y. Neuropathologic aspects of chronic encephalitis. In: Andermann F, editor. Chronic Encephalitis and Epilepsy: Rasmussen’s Syndrome. Boston, MA: Butterworth-Heinemann; 1991:79–110. 8. Farrell MA, Droogan O, Secor DL, Poukens V, Quinn B, Vinters HV. Chronic encephalitis associated with epilepsy: immunohistochemical and ultrastructural studies. Acta Neuropathol 1995;89:313–321. 9. Marras CE, Granata T, Franzini A, et al. Hemispherotomy and functional hemispherectomy: indications and outcome. Epilepsy Res 2010;89:104–112. 10. Kinay D, Bebek N, Vanli E, Gurses C, Gokyigit A, Andermann F. Rasmussen’s encephalitis and Behcet’s disease: autoimmune disorders in first degree relatives. Epileptic Disord 2008;10:319–324. 11. Ganor Y, Goldberg-Stern H, Amrom D, et al. Autoimmune epilepsy: some epilepsy patients harbor autoantibodies to glutamate receptors and dsDNA on both sides of the blood-brain barrier, which may kill neurons and decrease in brain fluids after hemispherotomy. Clin Dev Immunol 2004;11:241–252. 12. Andrews JM, Thompson JA, Pysher TJ, Walker ML, Hammond ME. Chronic encephalitis, epilepsy, and cerebrovascular immune complex deposits. Ann Neurol 1990; 28:88–90. 13. Rogers SW, Andrews PI, Gahring LC, et al. Autoantibodies to glutamate receptor GluR3 in Rasmussen’s encephalitis. Science 1994;265:648–651. 14. Watson R, Jiang Y, Bermudez I, et al. Absence of antibodies to glutamate receptor type 3 (GluR3) in Rasmussen encephalitis. Neurology 2004;63:43–50. 15. Mantegazza R, Bernasconi P, Baggi F, et al. Antibodies against GluR3 peptides are not specific for Rasmussen’s encephalitis but are also present in epilepsy patients with
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Neurology 83
September 16, 2014
1055
Rasmussen encephalitis and comorbid autoimmune diseases: A window into disease mechanism? Dina Amrom, Demet Kinay, Yvonne Hart, et al. Neurology 2014;83;1049-1055 Published Online before print August 20, 2014 DOI 10.1212/WNL.0000000000000791 This information is current as of August 20, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/83/12/1049.full.html
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Supplementary material can be found at: http://www.neurology.org/content/suppl/2014/08/20/WNL.00000 00000000791.DC1.html http://www.neurology.org/content/suppl/2014/10/24/WNL.00000 00000000791.DC2.html
References
This article cites 34 articles, 7 of which you can access for free at: http://www.neurology.org/content/83/12/1049.full.html##ref-list1
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