Seizures and risk of epilepsy in autoimmune and other inflammatory encephalitis

Abstract

Purpose of review

To assess the seizure manifestations and risk of epilepsy in encephalitis associated to antibodies against neuronal cell-surface (AE) or myelin-associated antigens, and to review several chronic epileptic disorders including, Rasmussen’s encephalitis (RE), fever-induced refractory epileptic syndromes (FIRES), and new-onset refractory status epilepticus (NORSE).

Recent findings

Seizures are a frequent manifestation of AE. Some AE may associate with characteristic features: faciobrachial dystonic seizures (anti-LGI1 encephalitis), EEG extreme delta brush (anti-NMDAR), or multifocal FLAIR-MRI abnormalities (anti-GABA_AR). In anti-LGI1 encephalitis, cortical, limbic, and basal ganglia dysfunction results in different types of seizures. AE or myelin-antibody associated syndromes are often immunotherapy-responsive and appear to have a low risk for chronic epilepsy. In contrast patients with seizures related to GAD65-antibodies (an intracellular antigen) frequently develop epilepsy and have suboptimal response to treatment (including surgery). RE or FIRES may occur with autoantibodies of unclear significance and rarely respond to immunotherapy. A study of patients with NORSE showed that 30% developed chronic epilepsy.

Summary

Although seizures are frequent in all types of AE, the risk for chronic epilepsy is dependent on the antigen: lower if located on the cell-surface, and higher if intracellular. For other disorders (RE, FIRES, NORSE) the prognosis remains poor.

INTRODUCTION

Epilepsy is a chronic neurological disease defined by the occurrence of at least one unprovoked seizure and the enduring predisposition to seizure recurrence.[1] The hypothesis that inflammation plays a role in epileptogenesis has long been suggested.[2*] This hypothesis has been reinforced by the identification of several autoimmune encephalitis (AE) that associate with seizures and occur with antibodies against neuronal cell-surface or myelin-related proteins. The study of these disorders has provided new insights into the relationship between neuroinflammation, autoimmunity, and seizure generation, giving rise to the concept of “autoimmune epilepsy”. In the context of AE, the development of seizures and status epilepticus usually represents an acute, symptomatic, manifestation of the brain inflammatory process, but little is known about the risk of developing chronic epilepsy. Chronic epilepsy might potentially result from an ongoing inflammatory process that persists after the acute phase of encephalitis, or from irreversible changes that alter neuronal networks and persist after the inflammatory process resolves. Therefore, although neuroinflammation may trigger symptomatic seizures, this does not necessarily imply that the subsequent development of chronic seizures is inflammation-dependent. Likewise, herpes simplex encephalitis may cause acute seizures, but the subsequent development of chronic epilepsy is not defined as “infectious epilepsy”.

In this review we first discuss recent developments on the role of neuroinflammation in epileptogenesis. Then, we focus on seizure manifestations and risk of epilepsy in AE and acute demyelinating syndromes, and discuss several chronic epileptic disorders for which there is evidence that autoimmunity plays a pathogenic role such as Rasmussen’s encephalitis (RE), fever-induced refractory epileptic syndromes (FIRES), and new-onset refractory status epilepticus (NORSE).

Inflammation, autoimmunity, and epileptogenesis

A number of clinical observations have suggested that inflammatory pathways are involved in epileptogenesis[3,4] including, 1) the anticonvulsant effect of steroids in some pediatric forms of epilepsy, [5] 2) the role of fever in triggering febrile-related epilepsies, [6,7] 3) the higher frequency of epilepsy in systemic autoimmune diseases (e.g., systemic lupus erythematosus and others), [8–19] 4) the increased prevalence of serum autoantibodies in chronic epilepsy (e.g., antinuclear and antiphospholipid antibodies), [20,21] and 5) the involvement of immune-related genes in some types of epilepsy and febrile-seizure susceptibility.[22]

On the other hand, seizures and status epilepticus can cause neuroinflammation through several mechanisms including among others, 1) activation of the interleukin (IL)-1β system by microglia, resulting in a cascade of inflammatory processes involving neurons, endothelial cells, and astrocytes, and likely responsible for blood-brain barrier breakdown and neuronal dysfunction, with alteration of the balance between excitatory and inhibitory neurotransmission, [23,24*] and 2) the involvement of the high-mobility-group box 1 (HMGB1), a danger signal that results in activation of downstream inflammatory pathways through interaction with its receptor (Toll-like receptor 4).[2*]

The immune system, and in particular its adaptive arm, may contribute to epileptogenesis[2*] as suggested by experimental studies with antibodies from patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis.[25*] Autoantibodies targeting this and other neuronal antigens have been infrequently identified in adults or children with chronic epilepsy (0–9%) or status epilepticus (< 3%), [26–31,32*,33] and were found at higher frequency (15–37%) when the seizures were refractory to antiepileptic treatment.[34,35] However, with the exception of glutamic acid decarboxylase 65(GAD65) antibodies, the significance of antibodies in chronic epilepsy is unclear because they are usually identified only in serum and may disappear over time despite seizure recurrence.[31] Careful consideration should be given to the interpretation of antibodies against proteins interacting with voltage-gated potassium channels (VGKC complex). These antibodies are in fact directed against two neuronal cell-surface proteins, leucine-rich glioma inactivated-1 (LGI1) and contactin-associated protein-2 receptor (CASPR2), [36,37] and several unknown (probably intracellular) proteins. Whereas LGI1 or CASPR2 antibodies associate with several syndromes that often occur with seizures (e.g., limbic encephalitis, Morvan syndrome), [38**,39*,40**,41*] the detection of VGKC-complex antibodies negative for LGI1 and CASPR2 has unclear clinical utility.[42,43**]

Autoimmune encephalitis with neuronal cell-surface antibodies

Seizures are a frequent manifestation of AE. The risk of developing chronic epilepsy as sequelae of AE is largely unknown because studies rarely provide this information and the patients follow-up is often short considering that some AE recover very slowly.[38**,44] The AE that most frequently manifest with seizures and status epilepticus are those mediated by antibodies against the γ-aminobutyric acid receptor A (GABA_AR), GABA_BR and LGI1.[37,45–47, 48**,49,50*,51,52*] However, seizures can occur with any form of AE including those with antibodies against NMDAR, [44,53–55] α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid receptor (AMPAR), [56,57*] CASPR2, [39*,40**] dipeptidyl-peptidase-like protein-6 (DPPX), [58–60] metabotropic glutamate receptor 5 (mGluR5), [61–63] glycine receptor (GlyR)[64,65] and neurexin3α.[66*] Although seizures are not always the presenting symptom, they occur in the majority of patients during the acute or early stages of the disease (Table 1).[38**,44,53] In most AE, seizures occur in association with other symptoms including among other cognitive dysfunction, altered behavior, decreased level of consciousness, movement and sleep disorders, or dysautonomia.

Table 1.

Clinical features and seizure type in autoimmune encephalitis associated with antibodies to neuronal cell-surface antigens.

	LGI1 [38**,41*,48 **,49,50*]	GABAAR [47,52*,51]	GABABR [45,46]	NMDAR [44,53–55]	AMPAR [56,57*]	mGluR5 [61–63],§	DPPX [59,60]	GlyR [64,65]	CASPR2 [39*,40**]	Neurexin3α [66*]
Median age (y), Occurs in children, Gender	61 No M≫F	40 Yes F=M	62 No M>F	22 Yes F≫M	61 No F>M	29 Yes F=M	58 Rare M≫F	50 Yes F=M	61 No M≫F	43 No M<F
Seizure frequencyand type (% of all cases)	Any type 90%;FBDS 47%, focal 66%, generalized 63%	Any type 88%; focal 81%, generalized 69%	Any type 90–100%; focal 40%, generalized 93%	Any type 76%; focal 17%, generalized 53%	Any type 36–40%; focal 10%, generalized 30%	Any type 60%;§ focal 10%, generalized 55%	Any type 22%	In patients with encephalitis ~13%	Any type 53%; in patients with LE 90%	Any type 80%
Status epilepticus	Yes	Yes (42%)	Yes (20%)	Yes	Yes	Yes (20%§)	No data	Anecdotal case reports	No data	No data
Other clinical manifestations	LE	Alteration of memory, behavior; dyskinesias	LE	Anti-NMDAR encephalitis	LE	Confusion, memory deficit, altered behavior	Confusion, psychosis, hyperekplexia, tremor, myoclonus, ataxia; GI, weight loss	Progressive encephalomyelitis with rigidity and myoclonus, Stiff-person syndrome,	LE, Morvan syndrome, neuromyotonia	Confusion, decreased level of consciousness, dyskinesias, hypoventilation
Tumor	7–11 %	38%; mostly thymoma	50–58%, mostly SCLC	20–42%, mostly ovarian teratoma	64–70%, thymoma, SCLC, breast	60%§, mostly Hodgkin’s lymphoma	10%, B-cell tumors	9%, mostly thymoma	16–19%, mostly thymoma	No
Response to immunotherapy	80%	86%	60%	75–81%	70–90%	90%§	60–78%	77%	73–93%	75%
Risk of epilepsy	15%	15%	29%	Low§§	Low§§	Low§§	No data	No data	No data	No data
Relapse	27–35%	No	No	12%	16–50%	10%§	23%	11–14%	25–37%	No data

F=female; GI= prodromal gastrointestinal symptoms (diarrhea, constipation); LE= limbic encephalitis; M=males; SCLC= small-cell lung cancer.

^§Spatola and Dalmau, personal communication;

^§§Low = Probably <5%.

In anti-NMDAR encephalitis, seizures are more often the first clinical manifestation in men than in women, and in children younger than 12 years.[67,68] Age-related clinical differences have also been reported in anti-GABA_AR encephalitis in which children are more likely to develop generalized seizures compared to adults who predominantly develop focal seizures.[47,52*] Although there is substantial clinical overlap among different AE, some symptoms, EEG or MRI findings may suggest the autoantigen. For instance, the EEG pattern named extreme delta brush has been found in children and adults with anti-NMDAR encephalitis and is highly characteristic of this disorder although it is only detectable in a subgroup of patients.[54,69] Extensive multifocal cortical-subcortical T2/FLAIR MRI abnormalities occur in approximately 80% of patients with anti-GABA_AR encephalitis, but rarely occur in other AE.[47,52*]

Facio-brachial dystonic seizures (FBDS) typically precede the development of anti-LGI1 encephalitis, which often occurs in association with other seizures. FBDS are brief (typically 1–2 sec) uni- or bilateral motor seizures, affecting the limbs and face, with a frequency that can be over 100 times per day (median 40/day).[38**] Studies suggest that the type of seizures may change during the course of anti-LGI1 encephalitis with an initial predominance of FBDS and focal seizures (25–30% of the patients) and at later stages a predominance of focal or generalized seizures and impairment of consciousness (60–80% of the patients).[38**,41*,70**,71] Prompt recognition and treatment of FBDS may prevent the development of a full-blown limbic encephalitis.[71,72] A study using EEG, MRI, and FDG-PET suggested that FBDS originate in the motor cortex, while other seizure types and cognitive impairment result from involvement of mesio-temporal regions.[70**] Another study demonstrated that 42% of patients with FBDS have MRI FLAIR and T1 changes in the basal ganglia suggesting that dysfunction at this level might contribute to these seizures.[48**]

In patients with AE generalized seizures and status epilepticus substantially contribute to morbidity and mortality.[38**,44–46,53,52*] Overall, 70–80% of patients with AE respond to immunotherapy.[38**,44,46,47,57*,52*] Residual deficits may include cognitive dysfunction and persistent seizures. Among patients with anti-LGI1 encephalitis, 70–80% have residual cognitive deficits, and 30% of them are left with moderate to severe disability.[38**,41*,49] In most patients the seizures improved or resolved prior to improvement of cognitive functions; indeed, after a follow-up of 2 years, 85% of patients were seizure-free (71% without treatment, and 14% with antiepileptics) while 15% continued to have seizures despite antiepileptics.[38**,49] Similar findings have been reported in patients with anti-GABA_AR encephalitis.[52*]

In more than 70% of patients with AE the associated seizures are successfully treated with immunotherapy and antiepileptics, and most do not require chronic antiepileptic medication.[29,49,73,74] A study on AE associated with antibodies against neuronal cell-surface or intracellular antigens reported good seizure response to rituximab in cases refractory to corticosteroids, intravenous immunoglobulins and plasma exchange.[74] Overall, the risk of developing chronic epilepsy after AE appears low (10–15%) and varies according to the target autoantigen.[38**,49,52*] For example, in two cohorts of patients with anti-AMPAR and anti-GABA_BR encephalitis none of the survivors had persistent seizures.[45,56] Patients with anti-NMDAR encephalitis may have residual cognitive and behavioral deficits but rarely develop chronic seizures.[53]

In patients with anti-LGI1 encephalitis, a high seizure frequency associates with the development of mesial temporal lobe sclerosis (MTS).[75] In these patients the degree of hippocampal atrophy correlates with memory deficits and delay in implementing immunotherapy.[49,50*] In contrast, patients with anti-NMDAR encephalitis may develop hippocampal atrophy, which correlates with disease severity and long-term cognitive deficits, but rarely develop MTS.[76**]

Patients who have AE triggered by herpes simplex encephalitis frequently harbor NMDAR antibodies along with other antibodies against neuronal cell-surface antigens (GABA_AR, dopamine 2 receptor), and their outcome is worse (more frequent residual deficits and seizures) than that of patients with anti-NMDAR encephalitis unrelated to herpes simplex encephalitis.[52*,77,78*]

In patients with AE and seizures who do not respond to immunotherapy, epilepsy surgery has been suggested as an alternative treatment, however, this appears to be less effective than in patients with epilepsy unrelated to AE.[79–81]

Autoimmune demyelinating syndromes and MOG antibodies

Seizures occur in 11–43% of patients with acute disseminated encephalomyelitis (ADEM), including generalized (40%) and focal (< 20%) seizures, and in 0–14% of patients with clinically-isolated syndromes (CIS, mostly generalized seizures).[82–89,90*,91] There is limited information about the risk of chronic epilepsy in these patients. In a recent study, 3 of 8 children with ADEM had seizures at disease onset, and one developed epilepsy; however, the interval between ADEM and onset of epilepsy was 15 years, making it unclear if there was a link between the diseases.[88]

Antibodies against myelin oligodendrocyte glycoprotein (MOG) have been identified in about 40% of patients with ADEM and 0–38% of CIS, as well as in a variety of other demyelinating disorders that do not manifest with seizures.[82–89,90*] In patients with ADEM, the presence of MOG antibodies seems to predict a monophasic course and associates with younger age, larger bilateral brain MRI abnormalities, and better outcome.[84] Future studies should assess the long-term risk of epilepsy in ADEM and CIS, and investigate whether MOG antibodies segregate with a higher or lower risk of epilepsy.

Epilepsy associated with GAD65 antibodies

High titers of GAD65 antibodies may be found in patients with seizures in the context of limbic encephalitis, [92,93] and in patients with chronic epileptic syndromes without clinical or MRI evidence of active CNS inflammation.[92–95] In particular, GAD65 antibodies have been reported in 2–3% of adults and 6–7% of children with chronic epilepsy.[94,96] An important consideration in assessing the relationship of GAD65 antibodies with epilepsy and other neurological syndromes is that these antibodies also occur in 1% of healthy people and 80% of patients with type 1 diabetes mellitus.[97,98] Compared with healthy people or patients with diabetes, patients with neurological symptoms have substantially higher titers of serum antibodies (~100–1000 times higher), and the antibodies are detectable in CSF.[92,93,99]

Since GAD65 is an intracellular antigen and is not accessible to circulating antibodies, the pathogenic role of GAD65 antibodies is controversial. It is thought that other mechanisms, such as T-cell mediated processes or additional antibodies to yet unknown antigens might be involved.[100*] Patients with epilepsy and GAD65 antibodies show poor response to immunotherapy. In a retrospective study of 13 patients, only one patient remained seizure-free after discontinuation of immunotherapy, and similar results were obtained in another study.[101,102]

Epilepsy in Rasmussen’s encephalitis (RE)

RE is a rare chronic epileptic syndrome that predominantly affects previously healthy children but in rare instances may also occur in adults.[103–106] Patients develop frequent, unilateral motor seizures that evolve to intractable epilepsia partialis continua, hemiplegia, and cognitive decline, accompanied by progressive unilateral hemispheric atrophy.[107–109] Younger patients are more likely to develop more severe disease and a higher degree of hemispheric atrophy.[107] The cause of this disorder is unclear but cytotoxic T-cell mechanisms are thought to be involved.[110–113] Although a number of autoantibodies have been reported in patients with RE, [114–117] their pathogenic significance and clinical utility are uncertain. For example, antibodies against the GluA3 (or GluR3) subunit of AMPAR have been reported in 4–25% of patients with RE but also in 40–60% of patients with focal or generalized epilepsy unrelated to RE.[114–117] Antibodies against the GluN2 subunit of the NMDAR, as well as other neuronal proteins, have been inconsistently identified in some patients with RE.[115,118–121] Importantly, the AMPAR and NMDAR antibodies identified in RE are different from those associated with anti-AMPAR or NMDAR encephalitis: the target subunits are different (GluA1/GluA2 in anti-AMPAR encephalitis and GluN1 in anti-NMDAR encephalitis), the epitopes in RE are linear instead of conformational and are located in the intracellular and not extracellular domain of the receptors.[53,120,122,123] Moreover, the appearance of these antibodies in patients with RE is often delayed from the time of seizure onset, [124] and the findings are not reproducible across different laboratories.

Seizure control in RE is challenging: antiepileptics are inefficient and the response to immunotherapies is often poor or transient.[125–127] Natalizumab or rituximab have shown some efficacy, but these treatments have not been tested in controlled trials.[128–130] Functional hemispherectomy is the only therapeutic option to achieve long-term seizure control; it is efficacious in 70–80% of the patients but at the expense of irreversible loss of neurological functions.[131]

Fever-induced refractory epileptic syndrome (FIRES) and new onset refractory status epilepticus (NORSE)

FIRES is a devastating epileptic syndrome occurring in previously healthy children around the age of 5–12 years.[132] It is characterized by frequent seizures developing in the context of a nonspecific febrile episode that rapidly evolve to status epilepticus and chronic pharmacoresistant epilepsy associated with severe neurodevelopmental delay.[132–134] The brain MRI is initially normal but as the disease progresses, mesio-temporal T2/FLAIR hyperintensities become apparent and almost all patients eventually develop cerebral atrophy and MTS.[135] Due to the refractoriness of status epilepticus, patients frequently need pharmacologically-induced coma. Anesthetics are often inefficient and their prolonged use seems to negatively influence cognitive outcome.[136]

The etiology of FIRES is unclear.[133,134,137,138] Although inflammation is thought to play a pathogenic role, the evidence is inconclusive. CSF oligoclonal bands and testing for neuronal autoantibodies are usually negative.[133,134,139] A few patients have been reported with antibodies against VGKC complex (unknown antigen), GAD65, or GluA3, but these findings were not confirmed in other studies.[133,139] Immunotherapy is usually ineffective.[133,134,136]

NORSE is a descriptive term used to indicate the onset of refractory status epilepticus in adults or children without a previous history of epilepsy.[140] A multicenter study on patients with NORSE for whom the underlying etiology could not be determined during the first 48 hours of presentation, found that in 40% the cause was autoimmune and in the other 60% the cause remained unknown.[34] In recent reports, the use of immunotherapy improved the outcome of 42–75% of patients with NORSE but approximately 30% developed chronic epilepsy.[141,142]

CONCLUSIONS

In patients with AE and seizures associated to antibodies against neuronal cell-surface proteins, the response to immunotherapy is substantially better than in those with CNS disorders that appear to be related to T-cell mediated mechanisms, such as RE or GAD65 antibody-associated epilepsy. The long-term risk to develop epilepsy is low in neuronal cell-surface antibody-associated AE (<15%) and moderate in NORSE (30%). Future studies should assess whether early recognition of these disorders and prompt immunotherapy decrease the risk of chronic epilepsy, and whether T-cell targeted immunotherapies may have a role in some disorders. A better understanding of the inflammatory processes underlying chronic epileptogenesis is critical for developing novel treatments.

KEY POINTS.

• Most patients with AE associated to antibodies against neuronal cell-surface antigens develop seizures. However, after the encephalitis is successfully treated, the risk of developing chronic epilepsy is low (< 15%).

• The subtypes of AE that more frequently associate with seizures are those related to antibodies against GABA_AR, GABA_BR, LGI1, CASPR2, AMPAR, and NMDAR. Patients with ADEM or CIS may also develop seizures, and rarely develop epilepsy. Some of these patients have MOG antibodies.

• In AE, the assessment of symptoms, EEG, and MRI may suggest the underlying immune response. For example, FBDS characteristically occur in patients with LGI1 antibodies and often precede the development of a full-blown encephalopathy. The EEG pattern « extreme delta brush» associates with anti-NMDAR encephalitis. The occurrence of multiple cortical-subcortical FLAIR MRI abnormalities suggests anti-GABA_AR encephalitis.

• Patients with seizure disorders associated to antibodies against neuronal cell-surface proteins or receptors, or patients with ADEM, usually respond to immunotherapy. In contrast, patients with seizure disorders without these antibodies (RE, FIRES) or with antibodies against intracellular proteins (GAD65) are much less responsive to immunotherapy.