Immunomodulatory Treatments in Epilepsy
Introduction
Epilepsy affects approximately 50 million people worldwide and is one of the most common disabling neurologic disorders. Pharmacotherapy continues to be the major approach to antiepileptic therapy. However, despite the introduction of a variety of new antiepileptic medications over the past decades, approximately 20%-30% of patients with epilepsy continue to have pharmacoresistant seizures.1, 2 Structural lesions and genetic disorders are often associated with refractory epilepsy. The pathogenic role of immunity and inflammation in epilepsy and particularly in refractory epilepsy has long been suspected, based on case observations regarding the effectiveness of immunomodulating therapies in the management of certain epilepsies. Subsequent findings of inflammatory markers, including autoantibodies in patients with a variety of epileptic disorders, have given further credence to the role of inflammation in epilepsy.3
Central nervous system (CNS) insults such as trauma, stroke, viral infection, febrile seizures, and status epilepticus (SE) are considered risk factors in the development of epilepsy. CNS inflammation develops immediately after these events, suggesting that a proinflammatory state in the brain might play a role in the development of epilepsy. Evidence for increased synthesis of inflammatory mediators in the brain during epileptogenesis has been corroborated by microarray analysis of transcripts of various classes of genes, showing prominently upregulated inflammatory genes.4 Pharmacologic studies in experimental models of acute or chronic seizures and assessment of seizure susceptibility in genetically modified mice demonstrated that proinflammatory mediators released from activated glia and neurons contribute to the mechanisms of ictogenesis.5
Experimental and clinical data suggest that both native and adaptive immunity may be involved in epilepsy. Native immunity results in an immediate, nonspecific response against pathogens via activation of immune cells and inflammatory mediators. This is thought to contribute to seizures and epileptogenesis. Adaptive immunity activates antigen-specific B and T lymphocytes or antibodies in the context of infections and autoimmune disorders. In the brain, native immunity cell types consisting of microglia, astrocytes, and neurons produce mediators of inflammation.
The full spectrum of inflammatory and autoantibody-associated epilepsies has not yet been determined. However, the association between autoantibodies and CNS disease is being increasingly recognized. Serum and cerebrospinal fluid (CSF) antibodies that bind to neuronal cell surface proteins including channels and receptors have the potential to be pathogenic and cause CNS disease. Recently, antibodies that bind extracellularly and are associated with CNS disorders have been called “neuronal surface antibodies” (NSAbs), and the disorders associated with these NSAbs are called “neuronal surface antibody syndromes”.6 The identification of specific and potentially pathogenic NSAbs is increasing, and the spectrum of the clinical syndromes associated with NSAbs is widening. There are well-defined CNS syndromes associated with NSAbs where seizures are an important feature. Examples include the epilepsies related with N-methyl-d-aspartate receptor (NMDAR), voltage gated potassium channel (VGKC) complex, and contactin-associated protein–like 2 antibodies.3 In addition, there are other epileptic conditions where an immune-mediated mechanism is suspected, such as febrile infection–related epilepsy syndrome in school-aged children.7
Evidence that the immune system and inflammation are involved in the pathophysiology of epilepsy has raised the prospect of new therapeutic approaches to treat epilepsy. The mounting evidence that inflammatory mediators contribute to the onset and recurrence of seizures in experimental seizure models, as well as the presence of inflammatory molecules in human epileptogenic tissue, gives rise to the possibility of targeting inflammation-related pathways with immunotherapies to control seizures that are resistant to available antiepileptic drugs (AEDs).8
Section snippets
Immunotherapies in Epilepsy
Immunotherapy options for treatment of epilepsy include medications such as corticosteroids, intravenous immunoglobulins (IVIg), plasmapheresis, and steroid-sparing drugs such as azathioprine. Recent options have included even more aggressive treatment with cyclophosphamide, the anti–pre-B-lymphocyte monoclonal antibody rituximab, or monoclonal antibodies such as efalizumab or natalizumab, which are presently employed for other inflammatory disorders.
Effects of AEDs on the Immune System
Although alterations of the immune system can cause epilepsy, the AEDs used to treat epilepsy can also cause changes in the immune system. AEDs can affect the immune system by altering either cellular or humoral responses. For example, vigabatrin can increase the percentage and absolute number of CD8 T-suppressor lymphocytes and increase the number and activity of natural killer cells.46 GABA A regulates inhibition of T-lymphocyte response and macrophage production of IL-6 and IL-12.
Yehuda et al
Conclusion
The early recognition of immune mechanisms in neurologic disorders is important as prompt treatment may lead to better outcomes especially in refractory epilepsy. Targeting inflammation and the immune system to treat or even prevent epilepsy and seizures can have multiple advantages compared with using antiepileptic medications. The side effects of AEDs can be avoided, and it may be possible to modify the actual course of the disease with immunotherapy. By addressing inflammation, we may be
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Repurposing multiple sclerosis drugs: a review of studies in neurological and psychiatric conditions
2019, Drug Discovery TodayCitation Excerpt :Natalizumab is also being investigated as adjunctive therapy in patients with drug-resistant focal epilepsy (NCT03283371). There is a rationale for using immunomodulatory treatments in epilepsy, because immunity and inflammation appear to be an integral part of the pathogenic processes associated with some seizures, particularly with refractory epilepsy [45]. Seizures can occur in MS patients, and the risk of epilepsy appears to be higher than in the general population.
Febrile infection-related epilepsy syndrome
2018, Acute Encephalopathy and Encephalitis in Infancy and Its Related DisordersChallenges in the treatment of convulsive status epilepticus
2017, SeizureCitation Excerpt :In these cases, even without finding positive antibodies, it might be appropriate to start immunosuppressive treatments (corticosteroids and IV immunoglobulins). However it should be also taken into account that these conditions may not be responsive to first-line drugs and that in some cases, also second-line immunosuppressive agents might be required such as cyclophosphamide, rituximab [92,93] or even cyclosporine A, tacrolimus and other immunosuppressants [94,95]. The authors received no funding for this study.
Autoimmune Epilepsies
2017, Seminars in Pediatric NeurologyCitation Excerpt :Marked neurological improvement as measured by modified Rankin scale score of 0-2, representing physical independence with or without residual symptoms, has been noted in approximately 80% of patients.17 Relapses occur in less than 25% of patients, typically less severe than the original presentation, and at least as equally responsive to immunotherapy.17,20 As most patients who experienced relapses received only first-line immunotherapy during the initial presentation, it is unclear if recurrence of symptoms represents a true relapse or incomplete treatment of the original clinical event.
Current and Emerging Therapies of Severe Epileptic Encephalopathies
2016, Seminars in Pediatric Neurology