Immuno-epileptology

KEYWORDS:

• Immunology
• epilepsy
• immuno-epileptology

1. Epilepsies live in shadow

Epilepsies are heterogeneous disorders that can be very debilitating for everyone and decrease life expectancy, especially if they start early in childhood. The median annual incidence has been estimated approximately 82 per 100,000 people in low-income countries which is nearly double the median annual incidence in high-income ones [1]. Epilepsies are collectively the most commonly seen neurological conditions to which a lot of stigma is attached. They are complex conditions which appear to be associated with rare genetic variants (including copy number variants, single-nucleotide polymorphisms, de novo mutations, and genomic hotspots) rather than common genetic loci [2–4]. Shared genetic loci between epilepsy and neurodevelopmental disorders explain the increased occurrence of epilepsies in patients with neurodevelopmental disorders, especially autism [5] and fragile X syndrome [6], and that it is in support of the viewpoint that epilepsy is a chronic neurodevelopmental disorder [7]. In addition to the genetic background effects, acquired factors, for example, head injury, brain lesions, congenital brain malformations, and infections, might contribute somewhat to febrile and epileptic seizures [7–9]. Recent research suggests that specific epigenetic mechanisms are also involved in neuronal death, abnormal neurogenesis, and related cognitive sequels following neuronal hyperexcitability and epileptic activity [10,11]. Despite much effort and investment, the exact etiology of epilepsy has remained elusive. This may be at least in part due to the fact that epilepsy has not a single entity, but it has discrete entities, of which many live in shadow.

2. Immuno-epileptology

Immune response represents both individual and familial variability, and its modulation is recognized as a core to the etiology of seizures. Here, we glance briefly at different aspects of the immunology of epilepsy, the so-called immuno-epileptology.

3. Immune-related genes and epilepsy

Increased susceptibility to epileptic seizures in patients who experience febrile seizures depends upon factors mainly including patient (previous history of neurologic disease) and first febrile seizure characteristics (atypical or prolonged seizures) [12,13]. There may be shared genetic contribution between febrile and epileptic seizures as described in detail elsewhere [9,14]. Genes that have been shown to be associated with both febrile and epileptic seizures include SCN1A, IL-1β, CHRNA4, and GABRG2. Therefore, individual’s genetic background may also interfere in the matter of increased susceptibility to epilepsy following febrile seizures, and immune-related genes, e.g. IL-1β, are implicated in this genetic background [9]. Mutations in the IL-1β gene associated with febrile seizures and epilepsy boost body’s production of IL-1β, an inflammatory cytokine that plays an important role in many human health/disease scenarios, favorably neurodegeneration [15]. Interestingly, IL-1B−511 homozygosity (TT) has been shown to be associated with temporal lobe epilepsy with hippocampal sclerosis, a serious condition that is characterized by neurodegeneration and gliosis [16].

4. Autoimmune epilepsy

Autoimmunity is an immune factor which helps enormously in paving the way for epilepsy. Studies use different sets of criteria for diagnosis of autoimmune epilepsy [17–19]. However, most studies seem to agree that people are diagnosed with autoimmune epilepsy if they meet at least one of the following criteria: (1) N-methyl-D-aspartate receptor (NMDAR) encephalitis or limbic encephalitis, (2) central nervous system (CNS) inflammation (indicated in cerebrospinal fluid or magnetic resonance imaging), (3) positive antibody test or history (personal or family) of autoimmune diseases, and (4) responsiveness to immunotherapy [18]. A large sample study showed that patients with autoimmune diseases are in general at almost fourfold increased risk of epilepsy, and the risk is increased to more than fivefold for children [20]. Studies have shown that as much as 90% of patients with clinically probable autoimmune epilepsy have a positive antibody test [21]. However, this percentage would fall to almost 50% in studies of patients with different types of epilepsy [22]. In particular, antibodies identified in these cases have been reported, mostly from antibodies against cell-surface membrane proteins (voltage-gated potassium channel complex and NMDAR) and to a lesser extent from antibodies against intracellular antigens (glutamic acid decarboxylase and collapsing response-mediator protein) [21,23]. Other antibodies present in patients with epilepsy were generated against ganglionic acetylcholine receptor, glutamate receptor 3, and also double-stranded DNA [22]. Importantly, most patients with autoimmune epilepsy do not respond to conventional treatment of epilepsy with antiepileptic drugs (AEDs) [21]; instead, they should be considered for immunotherapy [18].

5. Epilepsy as an inflammatory brain disease

Epilepsy is seen as an inflammatory brain disease [24,25]. The theory suggests that nonneuronal cells (i.e. glial cells) induce inflammation of the brain, and this makes neuronal cells to be synchronized more. Interestingly, epilepsy per se exacerbates inflammation. Simply stated, the story of epilepsy is stepping out of the shadow of inflammation and then moving into it. Therefore, epilepsy treatment is supposed to contain immunosuppressant as well. However, current AEDs are only able to prevent hypersynchronization but not neuroinflammation. In fact, AEDs must be considered as symptomatic treatment.

6. Epilepsy and infections

Fever has proven to be an effective mechanism for seizure development. It can be considered as a probable mechanism by which infections of the CNS (such as meningitis and encephalitis) increase risk of seizures, especially febrile seizures [26]. In this regard, viruses (including influenza viruses, human immunodeficiency virus, and human herpesvirus-6) show the most seizurogenic effect [27–29]. On the other hand, an impaired immune system that is especially seen in immunocompromised patients and infants may lead to seizures through reactivation of latent viral reservoir [30].

7. Immunotherapy for epilepsy

Immunotherapy can be considered for patients suspected to have immune-mediated epilepsy, e.g. autoimmune epilepsy and infection-triggered seizure. Epilepsy immunotherapy is performed using corticosteroids (methylprednisolone) in combination with intravenous immune globulin [21,31]. If initial therapy is ineffective, patients are changed to chemotherapeutic agents (cyclophosphamide) or to therapy with monoclonal antibodies (rituximab) [32]. Along with these, some studies have used plasmapheresis [21,31]. Following initial therapy, maintenance therapy with oral immunosuppressant drugs is advocated. In comparison with patients with antibodies against intracellular antigens, patients with autoimmune epilepsy who have antibodies to cell-surface membrane proteins are more likely to benefit from immunotherapy [33]. This indicates that antineural antibodies not only can help us establishing a diagnosis of autoimmune epilepsy but may allow us to predict treatment response as well.

8. Immuno-epileptology into perspective: nutrition, epigenetics, and immuno-epileptology

Aberrant status of micronutrients precludes epigenetic mechanisms potentially affecting immune system programming [34]. Therefore, early life nutrition must be considered of critical importance in early programming of the immune system [35] and thereby in prevention of diseases in later life [36]. Essential nutrients have been shown to be altered in patients with febrile seizures and epilepsy [37]. Whether these alterations are a cause or consequence of epileptic activity is ambiguous. More important, however, is the effects that antiepileptic medications can have on micronutrient status. In particular, accumulation of trace metals has been associated with seizure development and related neurodegeneration, in which both immune and epigenetic mechanisms are involved. On the contrary, deficiency of these elements (for example, zinc) which can be caused by some AEDs [37] leads to inflammation via affecting epigenetic mechanisms [38].

This summary provided answers to how immune response is remarkably impressed by epilepsy-associated factors (gene–environment interactions) and to how immunology might help to improve our understanding of epilepsy. An effective vision of the future should link epigenetic mechanisms to immuno-epileptology.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This article was not funded.