Autoimmunity, Seizures and Epilepsy: a brief systematic review

Abstract

Introduction: Epilepsy is un chronic neurologic disorder marked by recurrent convulsive seizures. It is one of the most prevalent neurologic disorders around the world. One of the etiologies that has become more relevant in the last few years is autoimmunity, which has explained many cases of idiopathic epilepsy or refractory to conventional treatments. Methods: an advanced search associated to filters at the platform PubMed with the terms “epilepsy” and “autoimmunity” was made. 17 articles from a total of 98 published, from 2010 on were selected, those that provided more data from this physiopathology. Results: Based on literature, the main autoimmunity mechanisms causing epilepsy are described. Among them are generation of autoantibodies, deregulation of the cytokines profile and loss of control of T auto reactive lymphocytes. Such phenomenon causes neuroinflammation and is caused by infections, paraneoplastic syndromes, maternal autoimmunity transferred to the baby, autoimmune encephalitis, among others. Conclusions: During the last few years great progress has been made in understanding autoimmune epilepsy; however, there is still much to understand. Despite the promising discovery of antibodies, still there are many cases epilepsy with seronegativity, or cases with presence of antibodies, but not autoimmune epilepsy. It is important to highlight that some effective/specific diagnosis mechanisms must be determined in order to implement suitable and resolutive therapeutic protocols.

Key Words: Epilepsy, autoimmunity, antibodies.

INTRODUCTION

Epilepsy is one of the most common neurologic diseases around the world. It affects people of all ages, and it is the third most usual disease, after Parkinson and Alzheimer¹. Around 70 million people around the world are estimated to have this disease. It has an incidence of 67.8 cases every 100,000 inhabitants. Most of them are in more vulnerable countries, probably due to the higher risk caused by certain endemic conditions ^1,2.

This disease may have its origin both, in congenital and acquired factors. Among the latter are cortical damage caused by traumatism, cerebrovascular accidents, neoplasies, genetic mutations, autoimmune diseases, infections of the central nervous system, among others. However, a significant percentage of people affected by epilepsy have an unknown etiology ³.

In time, autoimmunity as an etiology of epilepsy has become stronger, particularly for idiopathic forms or those refractory to conventional antiepileptic treatments, as a correlation has been established between systemic autoimmune processes and development of convulsions. A series of neuronal serumal autoantibodies or in the cerebrospinal fluid ⁴ have been discovered which are associated to typical epileptic phenotype, both in clinical practice and in RMI ⁵ findings. That is why the International League Against Epilepsy (ILAE) has recognized autoimmune epilepsy as a separated clinical, regarding its classification ⁶.

In this article we propose an updated view of the existing evidence on autoimmune mechanisms and biochemical findings involved in various epileptic syndromes, in order to put into perspective, the importance of this approach regarding comprehension of various clinical pictures, and also its relevant diagnosis/therapeutical dimensions.

METHODS

An advanced search using the platform PubMed was made, using the terms “epilepsy” and “autoimmunity” in the title and in the abstract of the publication. Articles published during the last 10 years and performed in humans were included.

The initial search retrieved 98 articles. According to the analysis of the titles and summaries, 43 publications were preselected as they were part of the focus of this Article. After fully analyzing the texts, 17 articles were finally included as they were useful to describe the epidemiology and physiopathology of the autoimmune phenomenon involved in the evolution of this disease.

For making this text other 12 articles were quoted as conceptual support is required; 6 additional articles are quoted in the introduction in order to provide a wider vision about this topic.

RESULTS

General Mechanisms:

In the pathogenesis of various central nervous system disorders autoimmune mechanisms causing neuroinflammation are involved. This is the first step of various pathological and clinical ⁷ events. The action spectrum the immune system may have in the development of autoimmune epilepsy is wide. It may go from the production of cytokines and pro-inflammatory chemokines causing a phenomenon of hiperexcitability associated to convulsions ⁷, or development of anti NMDA antibodies, among others to be specified in this document, which modify basal excitability of the neurons. Contrariwise, it has been described that convulsive seizures, in turn, generate malfunction of the hematoencephalic barrier, thus allowing cells to pass, such as T auto reactive lymphocytes ⁸.

In literature various antibodies related with appearance of epilepsy have been described, whether it is isolated or in the context of other autoimmune disorders ⁹.

These antibodies are linked both to surface antigens of the cell membrane, as intra cellular antigens, affecting the dynamics of synaptic complexes when binding to components, such as ion channels or to synaptic receptors of neurotransmitters ¹⁰.

Table 1 depicts various action mechanisms that have been correlated with various autoantibodies involved in development of autoimmune epilepsy.

Autoimmunity Sources in Epilepsy

Paraneoplasies

Some of the foregoing antibodies are produced in the context of paraneoplastic ⁵ syndromes. This has been explained as the tumoral tissue has molecularly similar antigens to those present in the nervous system. In this way the antitumoral response of the immune system is responsible for antigens compromise inside the encephalon. On the other hand, activation of  T auto reactive lymphocytes by tumoral mediators would cause inflammatory and autoimmune phenomena as those previously described ¹¹.

This is how the neoplastic context may cause cross cutting autoimmunity reactions, where antibodies against antigens produced by the tumor recognize nuclear and cytoplasmic antigens of the central nervous system, thus generating antibodies as a response by the immune system, just as  described in Table 1, among them antibodies ANNA-1, anti CRMP-5, anti Ma2/Ta, anti amphiphysin are highlighted among others, which are mentioned in numerous studies describing its potential correlation with epilepsy¹².

In the central nervous system this molecular mimetism may cause various pathological expressions, such as limbic encephalitis and paraneoplastic encephalomyelitis (T auto reactive lymphocytes and onconeuronal antibodies), entities that may cause convulsions ¹¹.

Infection caused by Herpes Virus 

Infections caused by Herpesviridae, within the neurotropic pathogens, are a well-known cause of encephalitis as an epileptogenic factor. Apart from neuroinflammation, the capacity to induce autoimmunity against various components of the pre and post synaptic central nervous system due to crossed reactivity has been established, and by the formation of autoantibodies ¹³.

Particularly, antibodies against the receptor of N-Methyl-D-aspartate) at a serumal level and in the cerebrospinal fluid have been identified. However, cases of positive patients for infection of Herpes Virus simple 1 and 2 with seronegativity for autoantibodies against NMDAR in other type of viral infections have been reported ¹⁴.

Autoimmune systemic diseases

Although the first description of permanent/provisional compromise of the central nervous system were made in patients with Hashimoto’s thyroiditis, today there is evidence in various disease models, such as Diabetes Mellitus 1, Psoriasis, Rheumatoid arthritis, Graves Disease, among others ^4,15. Currently is estimated there is a risk 3.8 to 5.2 times higher to have epilepsy in the context of an autoimmune disease in adults and children, respectively ¹⁶. In case of epileptic patients with systemic lupus erythematosus, the high values of anticardiolipin antibodies are correlated with a higher risk of convulsions. More generally, it has been observed that peripheral production of pro-inflammatory cytokines is related with appearance of convulsive events (4.17).

Maternal autoimmunity and epilepsy in Childhood

The correlation between rheumatoid arthritis in fathers or mothers and the occurrence of early epilepsy has been verified in series with about two million patients ¹⁸. Additionally, it has been proposed that this early compromise could be caused by the transference of autoantibodies or active lymphocytes that, during the embryonic growth, would compromise structural integrity of the SNC ¹⁹.

Spread Acute Encephalomyelitis:

It is a immune mediated disease characterized by a progressive demyelination  and neurologic poli-focal symptoms, given mainly in children  between 5-8 years old and generally it starts after 2 to 4 weeks of having  a viral infection ²¹. Its clinical scenario is varied and includes fever, cephalea and focal neurologic symptoms, such as convulsions, paresis, visual disturbances, among others ²². There is a correlation between antibodies anti myelin oligodendrocyte glycoprotein (MOG) and spread acute encephalomyelitis ²³. Given this situation, the unleashed neuroinflammatory and demyelmating process may involve isolated convulsions ²⁴ or even as an initial manifestation, in absence of  full clinic and pathological episode ²⁵.

Autoimmune Encephalitis

 It is highly likely that with inflammatory compromise of the encephalon convulsions may appear. Next, various forms of encephalitis with autoimmune and/or inmunomediated etiologies are described:

• Encephalitis associated to antibodies anti NMDA: this is the most common encephalitis mediated by antibodies, which usually starts with an unspecified fever syndrome which changes within a couple of weeks into anxiety episode, hallucinations, loss of short-term memory and convulsions which are usually tonic clonic type. In time, this scenario turns into orofacial dyskinesia and affectation of the autonomous nervous system. The electroencephalogram shows generalized delta activity, while magnetic resonance evidence hyperintensities in neocortical areas, turning in time into generalized cerebral atrophy ¹⁵. Encephalitis that, to a lesser extent, are associated to antibodies against Receptors GABA_A²⁶, GABA_B²⁷, mGlu5, AMPA, TPO (Thyroid Peroxidase), TG (thyroglobulin), GAD65, VGKC, etc¹⁵ have been observed.
• Rasmussen's encephalitis: with chronic behavior chronic. It appears mostly in pediatric patients, affecting only one brain hemisphere. The inflammation usually causes refractory convulsions. Initially these are focal or unilateral, progressing till they become multifocal. These usually appear along with hemiparesis, aphasia, and cognitive deficit. At a molecular level, there are antibodies against the receptor of glutamate GluR3^4,28. At anatomopathological level, it has been proved the presence of limited population of T lymphocytes in the brain, apart from inflammatory changes as perineuronal lymphocytes and clusters of perivascular T lymphocytes, and neurophagia ²⁸.
• Epileptic syndrome related with fever infections (FIRES): Also known as New-Onset Refractory Status Epilepticus (NORSE) or Acute Encephalitis with repetitive partial seizures (AERRPS). It is featured due to fever episodes decreasing before a sudden start of convulsions. This podromal fever episode has been correlated with pneumonia and infections of the upper air way ²⁹. When analyzing the cerebrospinal fluid (LCE), pleocitosis, and high levels of proteins are usually found, but with no evidence of antibodies or positivity in fluids culture. However, high levels of cytokines, pro-inflammatory and proconvulsions chemokines have been described, such as IL-6, MIF (macrophage migration inhibitory factor), IL-8, CXCL10, among others ^15,30.

Limbic encephalitis: regional inflammation of the encephalon, due to paraneoplastic infectious causes. This mainly affects the lobe temporal, although it may affect other lobe. Its main symptomatology is behavior and cognition alterations. In case of paraneoplastic etiologies onconeuronal antibodies have been described, such as Hu ³¹, Ma/Ta, CRMP5, Amphiphysin, VGCC, LGI1, among others ³².  Antibodies anti NMDA, anti GAD65³³ and VGKC have also been described which provide an autoimmunity character to this disease and whose manifestation usually includes convulsive crisis ¹⁵.

Diagnostic/Therapeutic Considerations under Development:

Presence of autoantibodies is not conclusive in the diagnosis, as there are seronegative patients with symptomatology suggesting autoimmune epilepsy. Some of these cases may satisfactorily respond to immunosuppression ³⁴. In theory, detection of autoantibodies include detection of immunoglobulines against GAD65 (glutamic acid decarboxylase), and neuronal antigens, such as NMDAR and complexes of voltage activated potassium channels (VGKC), LGl complexes 1, and CASPR2 (contactin-associated proteinlike 2), among others, at serumal level and in LCR ⁴.

Imagery studies also provide information about encephalon inflammation. Magnetic resonance allows to identify inflammatory signs, such as edema, hypertension areas in T2 and FLAIR, catching of medium contrast, etc. Nuclear medicine techniques, additionally, (for instance PET with F18-flurodeoxyglucose (F-FDG-PET)), may identify areas of hypermetabolism when the cortex has an acute reactive state, or hypometabolism in atrophic areas. However, structural/functional results of magnetic resonance and F-FDG-PET may not be congruent ^9,35.

At a therapeutic level, plasmapheresis has proved to reduce convulsions frequency and improve neurological function, while treatment with corticosteroids, immunoglobulin, monoclonal antibodies, among others, have had incongruent results in Rasmussen´s Encephalitis (4.28). Success, whether partial or total, of these therapeutical strategies is a wide proof of the role of the immune system, both in generation and in maintaining convulsive seizures and epileptic syndromes.

CONCLUSIONS

Epilepsy as a specific disease, and also relevance of convulsive seizures as a main/accessory clinical manifestation of various symptomatologies have prevalence enough to justify the state-of-the-art review in this field. Additionally, the estimated frequency with which autoimmune mechanisms participate in the generation of these cases, remaining as idiopathical to date makes possible to consider mechanisms described in this article, at least globally. Notwithstanding the foregoing, it is important to recognize that availability of serological measurements or imagery, necessary for the study with this approach, to date is usually limited in various clinical contexts.

Significant advances in understanding autoimmune mechanisms of the disease have been observed during the last few years, implementing possible therapeutical options in fields that, during the last decades were considered out of the medical treatment spectrum, observing new opportunities to influence the disease evolution and quality of life of the people affected. The various types of convulsive seizures and epileptic syndromes described here have a wide variability, regarding results of the serological, clinical and imagery study. That is why, in various areas of those encompassed in this article, the conclusive evidence is scarce. An updated view of the state of the art will give the reader a perspective of the investigation opportunities in this field and the relative significance of considering inmunomediated mechanisms for understanding clinical and therapeutical definitions.

References

1. GBD 2015 Disease and Injury Incidence and Prevalence Collaborators (2016). Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study. Lancet 2015; 388: 1545–1602.
2. Fisher RS, Cross JH, French JA, Higurashi N, Hirsch E, Jansen FE, et al. Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017; 58: 522–530.
3. Devinsky O, Vezzani A, O’Brien TJ, Jette N, Scheffer IE, de Curtis M, et al. Epilepsy. Nat Rev Dis Primers 2018; 4: 18024.
4. Greco A, Rizzo MI, De Virgilio A, Conte M, Gallo A, Attanasio G, et al. Autoimmune epilepsy. Autoimmun Rev 2016;15: 221-5.
5. Quek AML, O'Toole O. Autoimmune Epilepsy: The Evolving Science of Neural Autoimmunity and Its Impact on Epilepsy Management. Semin Neurol 2018; 38: 290-302.
6. Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017; 58: 512–521.
7. Vezzani A, French J, Bartfai T, Baram TZ. The role of inflammation in epilepsy. Nat Rev Neurol 2011; 7: 31-40.
8. Librizzi L, Noè F, Vezzani A, de Curtis M, Ravizza T. Seizure-induced brain-borne inflammation sustains seizure recurrence and blood-brain barrier damage. Ann Neurol 2012; 72: 82-90.
9. Quek AM, Britton JW, McKeon A, So E, Lennon VA, Shin C, et al. Autoimmune epilepsy: clinical characteristics and response to immunotherapy. Arch Neurol 2012; 69: 582-93.
10. McKeon A, Pittock SJ. Paraneoplastic encephalomyelopathies: pathology and mechanisms. Acta Neuropathol 2011; 122: 381–400.
11. Lancaster E. Paraneoplastic Disorders. Continuum (Minneap Minn) 2017; 23: 1653-1679.
12. Dubey D, Singh J, Britton JW, Pittock SJ, Flanagan EP, Lennon VA, et al. Predictive models in the diagnosis and treatment of autoimmune epilepsy. Epilepsia 2017; 58: 1181–1189.
13. Lucchese G. Herpesviruses, autoimmunity and epilepsy: Peptide sharing and potential cross-reactivity with human synaptic proteins. Autoimmun Rev 2019; 18: 102367.
14. Poulheim F, Esposito L, Elger CE, Eis-Hübinger AM, Becker AJ, Niehusmann P. Large-scale analysis of herpesviridae in epilepsy-patients with signs of autoimmune encephalitis. Seizure 2017; 53: 100-102.
15. Gaspard N. Autoimmune Epilepsy. Continuum (Minneap Minn) 2016; 22: 227-45.
16. Ong MS, Kohane IS, Cai T, Gorman MP, Mandl KD. Population-level evidence for an autoimmune etiology of epilepsy. JAMA Neurol 2014; 71: 569-74.
17. Lin Z, Si Q, Xiaoyi Z. Association between epilepsy and systemic autoimmune diseases: A meta-analysis. Seizure 2016; 41: 160-6.
18. Rom AL, Wu CS, Olsen J, Jawaheer D2, Hetland ML2, Christensen J, et al. Parental rheumatoid arthritis and childhood epilepsy: a nationwide cohort study. Neurology 2016; 87: 2510–2516.
19. Dale RC, Brenton JN. Maternal autoimmunity is a risk factor for common neurologic diseases of childhood. Neurology 2016; 87: 2502-2503.
20. Brimberg L, Sadiq A, Gregersen PK, Diamond B. Brain-reactive IgG correlates with autoimmunity in mothers of a child with an autism spectrum disorder. Mol Psychiatry 2013; 18: 1171–1177.
21. Gray MP1, Gorelick MH. Acute Disseminated Encephalomyelitis. Pediatr Emerg Care 2016; 32: 395-400.
22. Leake JA, Albani S, Kao AS, Senac MO, Billman GF, Nespeca MP, et al. Acute disseminated encephalomyelitis in childhood: epidemiologic, clinical and laboratory features. Pediatr Infect Dis J 2004; 23: 756–764.
23. Ramanathan S, Mohammad S, Tantsis E, Nguyen TK, Merheb V, Fung VSC, et al. Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination. J Neurol Neurosurg Psychiatry 2018; 89: 127–37.
24. Hacohen Y, Wong YY, Lechner C, Jurynczyk M, Wright S, Konuskan B, et al. Disease course and treatment responses in children with relapsing myelin oligodendrocyte glycoprotein antibody associated disease. JAMA Neurol 2018; 75: 478–87.
25. Ramanathan S, O'grady GL, Malone S, Spooner CG, Brown DA, Gill D, Brilot F, Dale RC. Isolated seizures during the first episode of relapsing myelin oligodendrocyte glycoprotein antibody-associated demyelination in children. Dev Med Child Neurol 2019; 61: 610-614.
26. Petit-Pedrol M, Armangue T, Peng X, Bataller L, Cellucci T, Davis R, et al. Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies. Lancet Neurol 2014; 13: 276Y286.
27. Lancaster E, Lai M, Peng X, Hughes E, Constantinescu R, Raizer J, et al. Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol 2010; 9: 67Y76.
28. Yeshokumar AK, Pardo CA. Autoimmune Epilepsies. Semin Pediatr Neurol. 2017; 24: 161-167.
29. van Baalen A, Häusler M, Boor R, Rohr A, Sperner J, Kurlemann G, et al. Febrile infection-related epilepsy syndrome (FIRES): a nonencephalitic encephalopathy in childhood. Epilepsia 2010; 51: 1323–8.
30. Sakuma H, Tanuma N, Kuki I, Takahashi Y, Shiomi M, Hayashi M. Intrathecal overproduction of proinflammatory cytokines and chemokines in febrile infection-related refractory status epilepticus. J Neurol Neurosurg Psychiatry 2015; 86: 820Y822.
31. Honnorat J, Didelot A, Karantoni E, Ville D, Ducray F, Lambert L, et al. Autoimmune limbic encephalopathy and anti-Hu antibodies in children without cancer. Neurology 2013; 80: 2226Y2232.
32. Voltz R, Gultekin SH, Rosenfeld MR, Gerstner E, Eichen J, Posner JB, et al. A serologic marker of paraneoplastic limbic and brain-stem encephalitis in patients with testicular cancer. N Engl J Med 1999; 340: 1788Y1795.
33. Boronat A, Sabater L, Saiz A, Dalmau J, Graus F. GABA(B) receptor antibodies in limbic encephalitis and anti-GAD-associated neurologic disorders. Neurology 2011; 76: 795Y800.
34. Toledano M, Pittock SJ. Autoimmune Epilepsy. Semin Neurol 2015; 35: 245-58.
35. Guerin J, Watson RE, Carr CM, Liebo GB, Kotsenas AL. Autoimmune epilepsy: findings on MRI and FDG-PET. Br J Radiol. 2019; 92: 20170869.