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Autoimmune epilepsy
AUTREV-01785; No of Pages 5 Autoimmunity Reviews xxx (2015) xxx–xxx
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Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev
Review
Autoimmune epilepsy Antonio Greco a, Maria Ida Rizzo a,b, Armando De Virgilio a,b,⁎, Michela Conte a, Andrea Gallo c, Giuseppe Attanasio a, Giovanni Ruoppolo a, Marco de Vincentiis a a b c
Department Organs of Sense, ENT Section, University of Rome “La Sapienza”, Viale del Policlinico 155, 00100 Roma, Italy Department of Surgical Science, University of Rome “La Sapienza”, Viale del Policlinico 155, 00100 Roma, Italy Department of Medico-Surgical Sciences and Biotechnologies, Otorhinolaryngology Section, University of Rome "La Sapienza", Corso della Repubblica, 79, 04100 Latina, LT, Italy
a r t i c l e
i n f o
a b s t r a c t
Article history: Received 4 November 2015 Accepted 18 November 2015 Available online xxxx
Despite the fact that epilepsy is the third most common chronic brain disorder, relatively little is known about the processes leading to the generation of seizures. Accumulating data support an autoimmune basis in patients with antiepileptic drug-resistant seizures. Besides, recent studies show that epilepsy and autoimmune disease frequently co-occur. Autoimmune epilepsy is increasingly recognized in the spectrum of neurological disorders characterized by detection of neural autoantibodies in serum or spinal fluid and responsiveness to immunotherapy. An autoimmune cause is suspected based on frequent or medically intractable seizures and the presence of at least one neural antibody, inflammatory changes indicated in serum or spinal fluid or on MRI, or a personal or family history of autoimmunity. It is essential that an autoimmune etiology be considered in the initial differential diagnosis of new onset epilepsy, because early immunotherapy assures an optimal outcome for the patient. © 2015 Elsevier B.V. All rights reserved.
Keywords: Epilepsy Autoimmune epilepsy Autoimmune disease Refractory epilepsy Autoimmune seizures
Contents 1. Introduction . . . . . . 2. Epidemiology . . . . . 3. Etiopathogenesis . . . . 4. Symptoms and diagnosis 5. Differential diagnosis . . 6. Prognosis . . . . . . . 7. Treatments. . . . . . . 8. Conclusions . . . . . . 9. Search strategy . . . . . Take-home messages . . . . References . . . . . . . . .
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1. Introduction Epilepsy is a debilitating neurological disorder, characterized by seizures (sporadic electrical storms) and cognitive impairment due to electrical disturbances in the brain, often with neither a known etiology nor an effective treatment.
⁎ Corresponding author at: Department Organs of Sense, ENT Section, University of Rome “La Sapienza”, Viale del Policlinico 155, 00100 Roma, Italy. Tel.: + 39 380 3408909; fax: +39 06 49976803. E-mail address: [email protected] (A. De Virgilio).
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Accumulating data support an autoimmune basis in patients with antiepileptic drug-resistant seizures. Identification of an immune basis is important because adjunctive immunotherapy may slow, halt, or even reverse the epileptogenic process in these patients [1–5]. Clinicians caring for patients with either autoimmune disorder or epilepsy should be aware of the strong association between them. A recent population-level study, investigating the relationship between epilepsy and several common autoimmune diseases, examined a total of 2,518,034 individuals (Table 1). It shows that nearly 1 in 5 patients with epilepsy has a coexisting autoimmune disorder [6]. Elevated epilepsy prevalence has been previously reported in autoimmune disorders. Rates of epilepsy in systemic lupus erythematosus vary
http://dx.doi.org/10.1016/j.autrev.2015.11.007 1568-9972/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: Greco A, et al, Autoimmune epilepsy, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.11.007
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A. Greco et al. / Autoimmunity Reviews xxx (2015) xxx–xxx
colitis, systemic lupus erythematosus, antiphospholipid syndrome, Sjögren syndrome, myasthenia gravis, and celiac disease [6].
Table 1 Demographic characteristics. From: Jama Neurol. 2014;71:569–574. Patients, n Gender, n (%) Female Male Age, n (%) Children (b18 years old) Adults (≤65 years old) Length of follow-up (days) (mean ± SD) Epilepsy prevalence, n (%) All ages Children (b18 years old) Adults (≤65 years old) Autoimmune disease prevalence, n (%) Type 1 diabetes Psoriasis Rheumatoid arthritis Ulcerative colitis Hashimoto's thyroiditis Grave's disease Systemic lupus erythematosus Crohn's disease Antiphospholipid syndrome Sjögren's Syndrome Celiac disorder Myasthenia gravis Any of the above AD Medicationsa Aminosalicylates Disease-modifying antirheumatic drugs Systemic glucocorticoids Anti-TNF agents Other biologics Non-steroidal anti-inflammatory agents
2,518,034
3. Etiopathogenesis
1,302,709 (51.7) 1,215,325 (48.3)
While brain tumors, trauma or infection can cause epilepsy, the condition can be inherited genetically within families. A growing body of literature demonstrates an autoimmune basis in the etiology of some forms of epilepsy. The link between autoimmune diseases and epilepsy without a recognized neurological cause has been documented for well over a decade [19]. For a long time, such theory lacked an experimental basis. The results of the last years, especially in patients with Rasmussen encephalitis (RE), have given new information about the possible relation between epileptic disorders and the immune system. RE is an autoimmune disorder of the central nervous system, where the serum of the patients contains antibodies to the glutamate receptor GluR3. Immunization of animals with GluR3 induces a disorder resembling the human disease [20–23]. Additional evidence that autoimmune mechanisms operate in RE is in Li's studies, which demonstrated restricted T-lymphocyte populations in the brains of patients with RE. Removal of antibodies by plasma exchange transiently reduces the seizure frequency and improves the neurologic function as the serum concentrations of GluR3 antibodies decrease. As antibodies to GluR3 are found in serum samples from immunized animals without apparent disease, a focal or a general disruption of the blood–brain barrier is essential for serum antibodies to reach the brain [24]. Findings that a substantial number of Rasmussen syndrome patients have increased IgG, CD4+ T cells, TNFα, and Granzyme B in cerebrospinal fluid, suggest that complex pathophysiologic mechanisms involving CD4 + T cells and CD8 + T cells change evolutionally during the progression of Rasmussen syndrome. A crucial cytotoxic process occurs in the early stage, and declines in the progressed stage [25]. The evidence for immunological mechanisms in epilepsy can be examined also in other immunologically mediated diseases. Epilepsy is more common in patients with systemic lupus erythematosus (SLE) who have antiphospholipid antibodies, and it is possible that these antibodies can lead to immune-mediated cortical damage. Between 10% and 20% of patients with SLE develop epileptic seizures at some stage of their disease. This is nearly 8 times the prevalence of epilepsy in the general population. This may mean that long-term treatment with antiepileptic drugs may precipitate SLE, or that epilepsy and SLE occur together as manifestations of a genetically determined predisposition [7–9,16,17]. The recent identification of mutations involving K + channels in benign familial neonatal epilepsy, neuronal nicotinic acetylcholine receptor in autosomal dominant nocturnal frontal lobe epilepsy, and Na+ channels in generalized epilepsy with febrile convulsions suggests that autoimmune attack of ion channels could similarly underlie some epileptic disorders. The effects of anticonvulsant drugs, which act on ion channels either to reduce excitatory neurotransmitter release or enhance inhibitory activity, support a role for ion channels in producing epilepsy. In addition, some ion channel drugs (for example 4aminopyridine, which inhibits K+ channels responsible for terminating the nerve action potential and thus prolongs the activation state) may precipitate seizures. Thus, for many reasons ion channels represent good candidate antigens for autoimmune epilepsy and a more widespread and systematic search for anti-ion channel antibodies is indicated [26]. Raised concentrations of serum antibodies, which recognize brain antigens, have been detected in groups of patients with isolated epilepsy [27,28]. A dramatic response to IVIg has been reported in a group of children with refractory seizures [40]. In addition more specific antibodies have been detected in such patients with epilepsy alone [29]. High titers of serum and CSF GABAA receptor antibodies are associated with a severe form of encephalitis with seizures, refractory status epilepticus, or both. The antibodies cause a selective reduction
476,805 (18.9) 2,041,229 (81.1) 2571 ± 490 10,041 (0.4) 1796 (0.4) 8245 (0.4) 43,704 (1.7) 23,542 (0.9) 22,890 (0.9) 10,690 (0.4) 9830 (0.4) 9758 (0.4) 9696 (0.4) 8774 (0.3) 5423 (0.2) 3614 (0.1) 1885 (0.1) 1070 (0.04) 137,398 (5.5) 24,303 (1.0) 33,557 (1.3) 790,045 (31.4) 7114 (0.3) 2915 (0.1) 945,892 (37.6)
Abbreviations: DMARDs, disease-modifying antirheumatic drugs; NSAIDs: nonsteroidal anti-inflammatory drugs; TNF, tumor necrosis factor. a Excluding medications taken after the first epileptic seizure.
between 4% and 51% and in antiphospholipid syndrome from 3% to 8% [7–11]. A high incidence of seizures also in Hashimoto thyroiditis is reported [12,13]. Autoantibodies have had a recognized role for many years in the genesis of paraneoplastic limbic encephalitis, which frequently has seizures as a prominent feature. Other studies have suggested a role for autoantibodies in epilepsy outside of the bounds of paraneoplastic limbic encephalitis [14]. Indeed, in a cohort study, autoimmune antibodies were detected in 14% of patients with epilepsy [15]. Especially, the role of neural autoantibodies is under investigation in the chronic refractory epilepsy. Besides that, to what extent the damage is caused by the antibodies itself or by the inflammatory reaction in the brain is also debatable. 2. Epidemiology Epilepsy is a debilitating condition affecting 0.5% to 1.0% of the world's population [6]. It is believed that as many as 10% may be categorized as autoimmune epilepsy, but the real prevalence of autoimmune epilepsy isn't known. The recent findings indicate that the risk of epilepsy is almost four times higher for patients with an autoimmune disease, with 17.5% of epilepsy patients also having an autoimmune disease [1,6]. Seizures tend to occur within the first 1 to 2 years after the autoimmune disorder diagnosis. The risk of epilepsy is consistently higher in children with autoimmune disorder compared with adults with the same autoimmune disorder. Data showed that female sex is associated with a higher risk of epilepsy [7,16–18]. A strong association between incidence of epilepsy and autoimmune diseases is in type 1 diabetes mellitus, psoriasis, rheumatoid arthritis, Graves' disease, Hashimoto's thyroiditis, Crohn's disease, ulcerative
Please cite this article as: Greco A, et al, Autoimmune epilepsy, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.11.007
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of synaptic GABAA receptors. The disorder often occurs with GABAergic and other coexisting autoimmune disorders and is potentially treatable [30]. Clinically, autoantibodies against GABA receptors play a pathogenic role in several neurological conditions, including some forms of encephalitis and autoimmune epilepsy. GABAergic drugs are widely used in medicine, and include benzodiazepines. GABAergic immunobiology is a recent area of research, which shows potential for the development of new therapies for autoimmune diseases [31]. A considerable portion of chronic refractory epilepsies is of unknown causes. The role of neural autoantibodies in these cases is under investigation. Besides that, to what extent the damage is caused by the antibodies itself or by the inflammatory reaction in the brain is also debatable. The finding of an immunological background for intractable epilepsy offers new modalities for treatment [32]. 4. Symptoms and diagnosis The predominant presenting symptom is recurrent, uncontrolled seizures. In addition to the presence of neural antibodies, clinical features suggestive of autoimmune epilepsy include: Acute to subacute onset, with seizures occurring every three months or less; multiple types of seizures or faciobrachial dystonic seizures; resistance to anti-seizure medication; personal or family history of autoimmunity; history of recent or past neoplasia; viral prodrome; and evidence of CNS inflammation. To identify autoimmune epilepsy, patients are also screened for a broad range of neural autoantibodies while MRI (Fig. 1), serum, and cerebrospinal fluid testing may help identify inflammatory changes. The Autoimmune Epilepsy Evaluation tests for autoantibodies directed against glutamic acid decarboxylase (GAD65) and neuronal cell surface antigens 1–5, such as N-methyl-D-aspartate receptor (NMDAR) and voltage gated potassium channel (VGKC)-complexes (leucine-rich glioma-inactivated protein 1 [LGI1] and contactin-associated proteinlike 2 [CASPR2]). These autoantibodies have been linked to epilepsy with acute or subacute onset (b12 weeks), either with or without encephalitis, and are included in proposed recommendations for identification of autoimmune epilepsy in children [1,15,33–38]. Detection of one or more neural autoantibodies in serum or spinal fluid is consistent with a diagnosis of autoimmune epilepsy. Figs. 2 and 3 show the evaluation algorithms proposed by Mayo Clinic. 5. Differential diagnosis Accurate diagnosis of the patient's specific form of epileptic disorder is critical. Some forms of epilepsy may be treated with antiepileptic pharmacotherapy or surgical procedures, but the type and efficacy of treatment depend on the specific epileptic disorder, among other factors. In the differential diagnosis, the following may be clues leading to an autoimmune cause and use of the autoantibody profiles: subacute
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onset of cognitive or other neuropsychiatric symptoms and treatmentresistant localization-related epilepsy of unknown cause. Thus evaluating with profiles of autoantibodies is appropriate. 6. Prognosis Therapies address manifestations rather than the underlying etiology, which remains unknown in most patients, one-third of whom have a condition that is refractory to antiepileptic therapy [39,40]. Surgical interventions in epilepsy are often ineffective, with seizures recurring in 50% of patients within 5 years of surgery [41], and the number of patients who remain seizure free decreases further over the years to 38% [42]. A deeper understanding of the underlying etiologies is necessary to develop new therapeutic approaches, and to improve the prognosis. Because of the potential benefit of early-initiated immunotherapy, it is essential that an autoimmune etiology be considered in the initial differential diagnosis of new onset epilepsy. Early treatment, and maintenance immunotherapy where appropriate, assures an optimal outcome for the patient. Misdiagnosis of a potentially reversible condition as a progressive neurodegenerative disorder may delay diagnosis beyond the window of reversibility (6–12 months) with devastating consequences for the patient and family. 7. Treatments When autoimmune epilepsy is suspected, clinical and serological clues suggest an autoimmune basis, first-line immune therapy with corticosteroids in addition to intravenous immunoglobulin or plasma exchange should be considered. Second-line therapy with rituximab or cyclophosphamide can be considered if the syndrome is severe. A response to immune therapy supports the diagnosis of autoimmune epilepsy [43]. Also when epilepsy is medically intractable, early-initiated immunotherapy may improve seizure outcome. Several author's clinical experience suggests that immunotherapy should not be used alone to control seizures but should be used in combination with antiepileptic drugs to optimize seizure control [1]. Reversibility is maintained with oral immunosuppressants such as prednisone, azathioprine, mycophenolate, methotrexate or rituximab, at the minimum effective dosage, to minimize side effects. 8. Conclusions Despite the fact that epilepsy is the third most common chronic brain disorder, relatively little is known about the processes leading to the generation of seizures [46].
Fig. 1. Representative neuroimaging abnormalities and evolution. Patient with a 10-month history of daily episodes of complex partial seizures. Despite normal MRI at presentation (A), subsequent preimmunotherapy MRI performed 9 months after seizure onset revealed left amygdala swelling (B) and bilateral hippocampal hyperintensity and atrophy (C). Radiolabeled fluorodeoxyglucose positron emission tomography brain scan showed hypermetabolism within the left amygdala (D) (arrow). From: Arch Neurol. 2012;69:582–593.
Please cite this article as: Greco A, et al, Autoimmune epilepsy, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.11.007
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Fig. 2. Serum algorithms for autoimmune epilepsy. From: http://www.mayomedicallaboratories.com/itmmfiles/Epilepsy_Autoimmune_Evaluation_Algorithm__Serum.pdf.
Recent studies show that epilepsy and autoimmune disease frequently co-occur. Therefore, patients with either condition should undergo surveillance for the other [6]. Patients with an autoimmune form of epilepsy often exhibit resistance to antiepileptic drugs. However, patients with neurological syndromes associated with antibodies toward neuronal cell surface
antigens have been shown to respond well to immunotherapy. Therefore, the identification of an autoimmune etiology in patients with antiepileptic drug-resistant seizures, including those lacking typical limbic encephalitis phenotypes, could permit the early initiation of immunotherapy. Treating these individuals may lead to improved outcomes [5,15,34–36].
Fig. 3. Cerebrospinal fluid algorithms for autoimmune epilepsy. From: http://www.mayomedicallaboratories.com/it-mmfiles/Epilepsy_Autoimmune_Evaluation_Algorithm__Spinal_Fluid.pdf.
Please cite this article as: Greco A, et al, Autoimmune epilepsy, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.11.007
A. Greco et al. / Autoimmunity Reviews xxx (2015) xxx–xxx
An autoimmune cause is suspected based on frequent or medically intractable seizures and the presence of at least one neural antibody, inflammatory changes indicated in spinal fluid or on MRI, or a personal or family history of autoimmunity. The time from onset of seizures to the start of immunotherapy is significantly shorter in patients who responded to treatment, indicating that early therapy favors a beneficial response [1,44,45]. 9. Search strategy PubMed, Google Scholar, and Scopus were databases. Key words were “Autoimmune epilepsy”; “Epilepsy AND autoimmune disease”; “Refractory epilepsy”; “Autoimmune seizures”; “Immunotherapy and epilepsy”; and “Autoantibody AND epilepsy”. Inclusion criteria were: original articles, case report, and review, with particular focus on the last years. Take-home messages • Epilepsy is a debilitating neurological disorder often with neither a known etiology nor an effective treatment. • Autoimmune epilepsy is not rare, is potentially treatable, is caused by antibodies or cytotoxic T cells attacking cerebral cortical autoantigens and is potentially amenable to arrest by early-initiated immunotherapy. • Diagnosis is aided by testing autoantibody profiles in serum and spinal fluid, and by a favorable response to an immunotherapy. • An autoimmune cause is suspected based on frequent or medically intractable seizures and the presence of at least one neural antibody, inflammatory changes indicated in spinal fluid or on MRI, or a personal or family history of autoimmunity. • It is essential that an autoimmune etiology be considered in the initial differential diagnosis of new onset epilepsy, because early immunotherapy assures an optimal outcome for the patient.
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Please cite this article as: Greco A, et al, Autoimmune epilepsy, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.11.007
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Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev
Review
Autoimmune epilepsy Antonio Greco a, Maria Ida Rizzo a,b, Armando De Virgilio a,b,⁎, Michela Conte a, Andrea Gallo c, Giuseppe Attanasio a, Giovanni Ruoppolo a, Marco de Vincentiis a a b c
Department Organs of Sense, ENT Section, University of Rome “La Sapienza”, Viale del Policlinico 155, 00100 Roma, Italy Department of Surgical Science, University of Rome “La Sapienza”, Viale del Policlinico 155, 00100 Roma, Italy Department of Medico-Surgical Sciences and Biotechnologies, Otorhinolaryngology Section, University of Rome "La Sapienza", Corso della Repubblica, 79, 04100 Latina, LT, Italy
a r t i c l e
i n f o
a b s t r a c t
Article history: Received 4 November 2015 Accepted 18 November 2015 Available online xxxx
Despite the fact that epilepsy is the third most common chronic brain disorder, relatively little is known about the processes leading to the generation of seizures. Accumulating data support an autoimmune basis in patients with antiepileptic drug-resistant seizures. Besides, recent studies show that epilepsy and autoimmune disease frequently co-occur. Autoimmune epilepsy is increasingly recognized in the spectrum of neurological disorders characterized by detection of neural autoantibodies in serum or spinal fluid and responsiveness to immunotherapy. An autoimmune cause is suspected based on frequent or medically intractable seizures and the presence of at least one neural antibody, inflammatory changes indicated in serum or spinal fluid or on MRI, or a personal or family history of autoimmunity. It is essential that an autoimmune etiology be considered in the initial differential diagnosis of new onset epilepsy, because early immunotherapy assures an optimal outcome for the patient. © 2015 Elsevier B.V. All rights reserved.
Keywords: Epilepsy Autoimmune epilepsy Autoimmune disease Refractory epilepsy Autoimmune seizures
Contents 1. Introduction . . . . . . 2. Epidemiology . . . . . 3. Etiopathogenesis . . . . 4. Symptoms and diagnosis 5. Differential diagnosis . . 6. Prognosis . . . . . . . 7. Treatments. . . . . . . 8. Conclusions . . . . . . 9. Search strategy . . . . . Take-home messages . . . . References . . . . . . . . .
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1. Introduction Epilepsy is a debilitating neurological disorder, characterized by seizures (sporadic electrical storms) and cognitive impairment due to electrical disturbances in the brain, often with neither a known etiology nor an effective treatment.
⁎ Corresponding author at: Department Organs of Sense, ENT Section, University of Rome “La Sapienza”, Viale del Policlinico 155, 00100 Roma, Italy. Tel.: + 39 380 3408909; fax: +39 06 49976803. E-mail address: [email protected] (A. De Virgilio).
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Accumulating data support an autoimmune basis in patients with antiepileptic drug-resistant seizures. Identification of an immune basis is important because adjunctive immunotherapy may slow, halt, or even reverse the epileptogenic process in these patients [1–5]. Clinicians caring for patients with either autoimmune disorder or epilepsy should be aware of the strong association between them. A recent population-level study, investigating the relationship between epilepsy and several common autoimmune diseases, examined a total of 2,518,034 individuals (Table 1). It shows that nearly 1 in 5 patients with epilepsy has a coexisting autoimmune disorder [6]. Elevated epilepsy prevalence has been previously reported in autoimmune disorders. Rates of epilepsy in systemic lupus erythematosus vary
http://dx.doi.org/10.1016/j.autrev.2015.11.007 1568-9972/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: Greco A, et al, Autoimmune epilepsy, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.11.007
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colitis, systemic lupus erythematosus, antiphospholipid syndrome, Sjögren syndrome, myasthenia gravis, and celiac disease [6].
Table 1 Demographic characteristics. From: Jama Neurol. 2014;71:569–574. Patients, n Gender, n (%) Female Male Age, n (%) Children (b18 years old) Adults (≤65 years old) Length of follow-up (days) (mean ± SD) Epilepsy prevalence, n (%) All ages Children (b18 years old) Adults (≤65 years old) Autoimmune disease prevalence, n (%) Type 1 diabetes Psoriasis Rheumatoid arthritis Ulcerative colitis Hashimoto's thyroiditis Grave's disease Systemic lupus erythematosus Crohn's disease Antiphospholipid syndrome Sjögren's Syndrome Celiac disorder Myasthenia gravis Any of the above AD Medicationsa Aminosalicylates Disease-modifying antirheumatic drugs Systemic glucocorticoids Anti-TNF agents Other biologics Non-steroidal anti-inflammatory agents
2,518,034
3. Etiopathogenesis
1,302,709 (51.7) 1,215,325 (48.3)
While brain tumors, trauma or infection can cause epilepsy, the condition can be inherited genetically within families. A growing body of literature demonstrates an autoimmune basis in the etiology of some forms of epilepsy. The link between autoimmune diseases and epilepsy without a recognized neurological cause has been documented for well over a decade [19]. For a long time, such theory lacked an experimental basis. The results of the last years, especially in patients with Rasmussen encephalitis (RE), have given new information about the possible relation between epileptic disorders and the immune system. RE is an autoimmune disorder of the central nervous system, where the serum of the patients contains antibodies to the glutamate receptor GluR3. Immunization of animals with GluR3 induces a disorder resembling the human disease [20–23]. Additional evidence that autoimmune mechanisms operate in RE is in Li's studies, which demonstrated restricted T-lymphocyte populations in the brains of patients with RE. Removal of antibodies by plasma exchange transiently reduces the seizure frequency and improves the neurologic function as the serum concentrations of GluR3 antibodies decrease. As antibodies to GluR3 are found in serum samples from immunized animals without apparent disease, a focal or a general disruption of the blood–brain barrier is essential for serum antibodies to reach the brain [24]. Findings that a substantial number of Rasmussen syndrome patients have increased IgG, CD4+ T cells, TNFα, and Granzyme B in cerebrospinal fluid, suggest that complex pathophysiologic mechanisms involving CD4 + T cells and CD8 + T cells change evolutionally during the progression of Rasmussen syndrome. A crucial cytotoxic process occurs in the early stage, and declines in the progressed stage [25]. The evidence for immunological mechanisms in epilepsy can be examined also in other immunologically mediated diseases. Epilepsy is more common in patients with systemic lupus erythematosus (SLE) who have antiphospholipid antibodies, and it is possible that these antibodies can lead to immune-mediated cortical damage. Between 10% and 20% of patients with SLE develop epileptic seizures at some stage of their disease. This is nearly 8 times the prevalence of epilepsy in the general population. This may mean that long-term treatment with antiepileptic drugs may precipitate SLE, or that epilepsy and SLE occur together as manifestations of a genetically determined predisposition [7–9,16,17]. The recent identification of mutations involving K + channels in benign familial neonatal epilepsy, neuronal nicotinic acetylcholine receptor in autosomal dominant nocturnal frontal lobe epilepsy, and Na+ channels in generalized epilepsy with febrile convulsions suggests that autoimmune attack of ion channels could similarly underlie some epileptic disorders. The effects of anticonvulsant drugs, which act on ion channels either to reduce excitatory neurotransmitter release or enhance inhibitory activity, support a role for ion channels in producing epilepsy. In addition, some ion channel drugs (for example 4aminopyridine, which inhibits K+ channels responsible for terminating the nerve action potential and thus prolongs the activation state) may precipitate seizures. Thus, for many reasons ion channels represent good candidate antigens for autoimmune epilepsy and a more widespread and systematic search for anti-ion channel antibodies is indicated [26]. Raised concentrations of serum antibodies, which recognize brain antigens, have been detected in groups of patients with isolated epilepsy [27,28]. A dramatic response to IVIg has been reported in a group of children with refractory seizures [40]. In addition more specific antibodies have been detected in such patients with epilepsy alone [29]. High titers of serum and CSF GABAA receptor antibodies are associated with a severe form of encephalitis with seizures, refractory status epilepticus, or both. The antibodies cause a selective reduction
476,805 (18.9) 2,041,229 (81.1) 2571 ± 490 10,041 (0.4) 1796 (0.4) 8245 (0.4) 43,704 (1.7) 23,542 (0.9) 22,890 (0.9) 10,690 (0.4) 9830 (0.4) 9758 (0.4) 9696 (0.4) 8774 (0.3) 5423 (0.2) 3614 (0.1) 1885 (0.1) 1070 (0.04) 137,398 (5.5) 24,303 (1.0) 33,557 (1.3) 790,045 (31.4) 7114 (0.3) 2915 (0.1) 945,892 (37.6)
Abbreviations: DMARDs, disease-modifying antirheumatic drugs; NSAIDs: nonsteroidal anti-inflammatory drugs; TNF, tumor necrosis factor. a Excluding medications taken after the first epileptic seizure.
between 4% and 51% and in antiphospholipid syndrome from 3% to 8% [7–11]. A high incidence of seizures also in Hashimoto thyroiditis is reported [12,13]. Autoantibodies have had a recognized role for many years in the genesis of paraneoplastic limbic encephalitis, which frequently has seizures as a prominent feature. Other studies have suggested a role for autoantibodies in epilepsy outside of the bounds of paraneoplastic limbic encephalitis [14]. Indeed, in a cohort study, autoimmune antibodies were detected in 14% of patients with epilepsy [15]. Especially, the role of neural autoantibodies is under investigation in the chronic refractory epilepsy. Besides that, to what extent the damage is caused by the antibodies itself or by the inflammatory reaction in the brain is also debatable. 2. Epidemiology Epilepsy is a debilitating condition affecting 0.5% to 1.0% of the world's population [6]. It is believed that as many as 10% may be categorized as autoimmune epilepsy, but the real prevalence of autoimmune epilepsy isn't known. The recent findings indicate that the risk of epilepsy is almost four times higher for patients with an autoimmune disease, with 17.5% of epilepsy patients also having an autoimmune disease [1,6]. Seizures tend to occur within the first 1 to 2 years after the autoimmune disorder diagnosis. The risk of epilepsy is consistently higher in children with autoimmune disorder compared with adults with the same autoimmune disorder. Data showed that female sex is associated with a higher risk of epilepsy [7,16–18]. A strong association between incidence of epilepsy and autoimmune diseases is in type 1 diabetes mellitus, psoriasis, rheumatoid arthritis, Graves' disease, Hashimoto's thyroiditis, Crohn's disease, ulcerative
Please cite this article as: Greco A, et al, Autoimmune epilepsy, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.11.007
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of synaptic GABAA receptors. The disorder often occurs with GABAergic and other coexisting autoimmune disorders and is potentially treatable [30]. Clinically, autoantibodies against GABA receptors play a pathogenic role in several neurological conditions, including some forms of encephalitis and autoimmune epilepsy. GABAergic drugs are widely used in medicine, and include benzodiazepines. GABAergic immunobiology is a recent area of research, which shows potential for the development of new therapies for autoimmune diseases [31]. A considerable portion of chronic refractory epilepsies is of unknown causes. The role of neural autoantibodies in these cases is under investigation. Besides that, to what extent the damage is caused by the antibodies itself or by the inflammatory reaction in the brain is also debatable. The finding of an immunological background for intractable epilepsy offers new modalities for treatment [32]. 4. Symptoms and diagnosis The predominant presenting symptom is recurrent, uncontrolled seizures. In addition to the presence of neural antibodies, clinical features suggestive of autoimmune epilepsy include: Acute to subacute onset, with seizures occurring every three months or less; multiple types of seizures or faciobrachial dystonic seizures; resistance to anti-seizure medication; personal or family history of autoimmunity; history of recent or past neoplasia; viral prodrome; and evidence of CNS inflammation. To identify autoimmune epilepsy, patients are also screened for a broad range of neural autoantibodies while MRI (Fig. 1), serum, and cerebrospinal fluid testing may help identify inflammatory changes. The Autoimmune Epilepsy Evaluation tests for autoantibodies directed against glutamic acid decarboxylase (GAD65) and neuronal cell surface antigens 1–5, such as N-methyl-D-aspartate receptor (NMDAR) and voltage gated potassium channel (VGKC)-complexes (leucine-rich glioma-inactivated protein 1 [LGI1] and contactin-associated proteinlike 2 [CASPR2]). These autoantibodies have been linked to epilepsy with acute or subacute onset (b12 weeks), either with or without encephalitis, and are included in proposed recommendations for identification of autoimmune epilepsy in children [1,15,33–38]. Detection of one or more neural autoantibodies in serum or spinal fluid is consistent with a diagnosis of autoimmune epilepsy. Figs. 2 and 3 show the evaluation algorithms proposed by Mayo Clinic. 5. Differential diagnosis Accurate diagnosis of the patient's specific form of epileptic disorder is critical. Some forms of epilepsy may be treated with antiepileptic pharmacotherapy or surgical procedures, but the type and efficacy of treatment depend on the specific epileptic disorder, among other factors. In the differential diagnosis, the following may be clues leading to an autoimmune cause and use of the autoantibody profiles: subacute
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onset of cognitive or other neuropsychiatric symptoms and treatmentresistant localization-related epilepsy of unknown cause. Thus evaluating with profiles of autoantibodies is appropriate. 6. Prognosis Therapies address manifestations rather than the underlying etiology, which remains unknown in most patients, one-third of whom have a condition that is refractory to antiepileptic therapy [39,40]. Surgical interventions in epilepsy are often ineffective, with seizures recurring in 50% of patients within 5 years of surgery [41], and the number of patients who remain seizure free decreases further over the years to 38% [42]. A deeper understanding of the underlying etiologies is necessary to develop new therapeutic approaches, and to improve the prognosis. Because of the potential benefit of early-initiated immunotherapy, it is essential that an autoimmune etiology be considered in the initial differential diagnosis of new onset epilepsy. Early treatment, and maintenance immunotherapy where appropriate, assures an optimal outcome for the patient. Misdiagnosis of a potentially reversible condition as a progressive neurodegenerative disorder may delay diagnosis beyond the window of reversibility (6–12 months) with devastating consequences for the patient and family. 7. Treatments When autoimmune epilepsy is suspected, clinical and serological clues suggest an autoimmune basis, first-line immune therapy with corticosteroids in addition to intravenous immunoglobulin or plasma exchange should be considered. Second-line therapy with rituximab or cyclophosphamide can be considered if the syndrome is severe. A response to immune therapy supports the diagnosis of autoimmune epilepsy [43]. Also when epilepsy is medically intractable, early-initiated immunotherapy may improve seizure outcome. Several author's clinical experience suggests that immunotherapy should not be used alone to control seizures but should be used in combination with antiepileptic drugs to optimize seizure control [1]. Reversibility is maintained with oral immunosuppressants such as prednisone, azathioprine, mycophenolate, methotrexate or rituximab, at the minimum effective dosage, to minimize side effects. 8. Conclusions Despite the fact that epilepsy is the third most common chronic brain disorder, relatively little is known about the processes leading to the generation of seizures [46].
Fig. 1. Representative neuroimaging abnormalities and evolution. Patient with a 10-month history of daily episodes of complex partial seizures. Despite normal MRI at presentation (A), subsequent preimmunotherapy MRI performed 9 months after seizure onset revealed left amygdala swelling (B) and bilateral hippocampal hyperintensity and atrophy (C). Radiolabeled fluorodeoxyglucose positron emission tomography brain scan showed hypermetabolism within the left amygdala (D) (arrow). From: Arch Neurol. 2012;69:582–593.
Please cite this article as: Greco A, et al, Autoimmune epilepsy, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.11.007
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Fig. 2. Serum algorithms for autoimmune epilepsy. From: http://www.mayomedicallaboratories.com/itmmfiles/Epilepsy_Autoimmune_Evaluation_Algorithm__Serum.pdf.
Recent studies show that epilepsy and autoimmune disease frequently co-occur. Therefore, patients with either condition should undergo surveillance for the other [6]. Patients with an autoimmune form of epilepsy often exhibit resistance to antiepileptic drugs. However, patients with neurological syndromes associated with antibodies toward neuronal cell surface
antigens have been shown to respond well to immunotherapy. Therefore, the identification of an autoimmune etiology in patients with antiepileptic drug-resistant seizures, including those lacking typical limbic encephalitis phenotypes, could permit the early initiation of immunotherapy. Treating these individuals may lead to improved outcomes [5,15,34–36].
Fig. 3. Cerebrospinal fluid algorithms for autoimmune epilepsy. From: http://www.mayomedicallaboratories.com/it-mmfiles/Epilepsy_Autoimmune_Evaluation_Algorithm__Spinal_Fluid.pdf.
Please cite this article as: Greco A, et al, Autoimmune epilepsy, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.11.007
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An autoimmune cause is suspected based on frequent or medically intractable seizures and the presence of at least one neural antibody, inflammatory changes indicated in spinal fluid or on MRI, or a personal or family history of autoimmunity. The time from onset of seizures to the start of immunotherapy is significantly shorter in patients who responded to treatment, indicating that early therapy favors a beneficial response [1,44,45]. 9. Search strategy PubMed, Google Scholar, and Scopus were databases. Key words were “Autoimmune epilepsy”; “Epilepsy AND autoimmune disease”; “Refractory epilepsy”; “Autoimmune seizures”; “Immunotherapy and epilepsy”; and “Autoantibody AND epilepsy”. Inclusion criteria were: original articles, case report, and review, with particular focus on the last years. Take-home messages • Epilepsy is a debilitating neurological disorder often with neither a known etiology nor an effective treatment. • Autoimmune epilepsy is not rare, is potentially treatable, is caused by antibodies or cytotoxic T cells attacking cerebral cortical autoantigens and is potentially amenable to arrest by early-initiated immunotherapy. • Diagnosis is aided by testing autoantibody profiles in serum and spinal fluid, and by a favorable response to an immunotherapy. • An autoimmune cause is suspected based on frequent or medically intractable seizures and the presence of at least one neural antibody, inflammatory changes indicated in spinal fluid or on MRI, or a personal or family history of autoimmunity. • It is essential that an autoimmune etiology be considered in the initial differential diagnosis of new onset epilepsy, because early immunotherapy assures an optimal outcome for the patient.
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Please cite this article as: Greco A, et al, Autoimmune epilepsy, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.11.007