Antibody Prevalence in Epilepsy before Surgery (APES) in drug-resistant focal epilepsy.

OBJECTIVE: There is a growing recognition of immune-mediated causes in patients with focal drug-resistant epilepsy (DRE); however, they are not systematically assessed in the pre-surgical diagnostic workup. Early diagnosis and initiation of immunotherapy is associated with a favorable outcome in immune-mediated seizures. Patients with refractory focal epilepsy with neuronal antibodies (Abs) tend to have a worse surgical prognosis when compared to other etiologies. METHODS: We studied the prevalence of serum Abs in patients ≥18 years of age with DRE of unknown cause before surgery. We proposed and calculated a clinical APES (Antibody Prevalence in Epilepsy before Surgery) score for each subject, which was modified based on Dubey's previously published APE2 score. RESULTS`: A total of 335 patients were screened and 86 subjects were included in final analysis. The mean age at the time of recruitment was 44.84 ± 14.86 years, with age at seizure onset 30.89 ± 19.88 years. There were no significant differences among baseline clinical features between retrospective and prospective sub-cohorts. The prevalence of at least one positive Ab was 33.72%, and central nervous system (CNS)-specific Abs was 8.14%. APES score ≥4 showed slightly better overall prediction (area under the curve [AUC]: 0.84 vs 0.74) and higher sensitivity (100% vs 71.4%), with slightly lower but similar specificity (44.3% vs 49.4%), when compared to APE2 score ≥4. For subjects who had available positron emission tomography (PET) results and all components of APES score (n = 60), the sensitivity of APES score ≥4 yielded a similar prediction potential with an AUC of 0.80. SIGNIFICANCE: Our findings provide persuasive evidence that a subset of patients with focal DRE have potentially immune-mediated causes. We propose an APES score to help identify patients who may benefit from a workup for immune etiologies during the pre-surgical evaluation for focal refractory epilepsy with unknown cause.

Antibodies Contributing to Focal Epilepsy Signs and Symptoms Score.

OBJECTIVE: Diagnosing autoimmune encephalitis (AIE) is difficult in patients with less fulminant diseases such as epilepsy. However, recognition is important, as patients require immunotherapy. This study aims to identify antibodies in patients with focal epilepsy of unknown etiology, and to create a score to preselect patients requiring testing. METHODS: In this prospective, multicenter cohort study, adults with focal epilepsy of unknown etiology, without recognized AIE, were included, between December 2014 and December 2017, and followed for 1 year. Serum, and if available cerebrospinal fluid, were analyzed using different laboratory techniques. The ACES score was created using factors favoring an autoimmune etiology of seizures (AES), as determined by multivariate logistic regression. The model was externally validated and evaluated using the Concordance (C) statistic. RESULTS: We included 582 patients, with median epilepsy duration of 8 years (interquartile range = 2-18). Twenty patients (3.4%) had AES, of whom 3 had anti-leucine-rich glioma inactivated 1, 3 had anti-contactin-associated protein-like 2, 1 had anti-N-methyl-D-aspartate receptor, and 13 had anti-glutamic acid decarboxylase 65 (enzyme-linked immunosorbent assay concentrations >10,000IU/ml). Risk factors for AES were temporal magnetic resonance imaging hyperintensities (odds ratio [OR] = 255.3, 95% confidence interval [CI] = 19.6-3332.2, p < 0.0001), autoimmune diseases (OR = 13.31, 95% CI = 3.1-56.6, p = 0.0005), behavioral changes (OR 12.3, 95% CI = 3.2-49.9, p = 0.0003), autonomic symptoms (OR = 13.3, 95% CI = 3.1-56.6, p = 0.0005), cognitive symptoms (OR = 30.6, 95% CI = 2.4-382.7, p = 0.009), and speech problems (OR = 9.6, 95% CI = 2.0-46.7, p = 0.005). The internally validated C statistic was 0.95, and 0.92 in the validation cohort (n = 128). Assigning each factor 1 point, an antibodies contributing to focal epilepsy signs and symptoms (ACES) score ≥ 2 had a sensitivity of 100% to detect AES, and a specificity of 84.9%. INTERPRETATION: Specific signs point toward AES in focal epilepsy of unknown etiology. The ACES score (cutoff ≥ 2) is useful to select patients requiring antibody testing. ANN NEUROL 2021;89:698-710.

Clinical features which predict neuronal surface autoantibodies in new-onset focal epilepsy: implications for immunotherapies.

OBJECTIVE: To generate a score which clinically identifies surface-directed autoantibodies in adults with new-onset focal epilepsy, and evaluate the value of immunotherapy in this clinical setting. METHODS: Prospective clinical and autoantibody evaluations in a cohort of 219 consecutive patients with new-onset focal epilepsy. RESULTS: 10.5% (23/219) of people with new-onset focal epilepsy had detectable serum autoantibodies to known or novel cell surface antigenic targets. 9/23 with autoantibodies were diagnosed with encephalitis, by contrast to 0/196 without autoantibodies (p<0.0001). Multivariate analysis identified six features which predicted autoantibody positivity (area under the curve=0.83): age ≥54 years, ictal piloerection, lowered self-reported mood, reduced attention, MRI limbic system changes and the absence of conventional epilepsy risk factors. 11/14 (79%) patients with detectable autoantibodies, but without encephalitis, showed excellent long-term outcomes (modified Rankin Score=0) despite no immunotherapy. These outcomes were superior to those of immunotherapy-treated patients with confirmed autoantibody-mediated encephalitis (p<0.05). CONCLUSIONS: Seizure semiology, cognitive and mood phenotypes, alongside inflammatory investigation findings, aid the identification of surface autoantibodies among unselected people with new-onset focal epilepsy. The excellent immunotherapy-independent outcomes of autoantibody-positive patients without encephalitis suggests immunotherapy administration should be guided by clinical features of encephalitis, rather than autoantibody positivity. Our findings suggest that, in this cohort, immunotherapy-responsive seizure syndromes with autoantibodies largely fall under the umbrella of autoimmune encephalitis.

Seizures in autoimmune encephalitis: Findings from an EEG pooled analysis.

PURPOSE: Seizures are common in autoimmune encephalitis (AE), and an extensive work-up is required to exclude alternative etiologies. The aim of our study was to identify possible clinical/EEG peculiarities suggesting the immune-mediated origin of late-onset seizures. METHODS: Thirty patients diagnosed with AE (19 men, median age 68 years, 18 seronegative) were included. Overall 212 video-electroencephalographic (EEG) and 31 24-h ambulatory EEG (AEEG) recordings were retrospectively reviewed. Posterior dominant rhythm, interictal epileptiform discharges (IEDs), clinical (CSs) and subclinical seizures (SCSs) were analyzed. RESULTS: Six-hundred-nineteen ictal events were recorded in 19/30 subjects, mostly (568/619) during AE acute stage. Among ten patients with CSs other than faciobrachial dystonic seizures, 7 showed prominent autonomic and emotional manifestations. SCSs were detected in 11 subjects, mainly via AEEG (260/287 SCSs vs 150/332 CSs, p < 0.001). Eight patients presented seizures during hyperventilation. IEDs, documented in 21 cases, were bilateral in 14 and focal temporal in 13. Multiple ictal EEG patterns were detected in 9/19 patients, 6 of whom had both CSs and SCSs, bilateral asynchronous seizures and ictal activities arising from temporal and extra-temporal regions. No correlation was found between the lateralization of MRI alterations and that of EEG findings. CONCLUSION: Our study confirms that adult-onset, high frequency focal seizures with prominent autonomic and emotional manifestations should be investigated for AE. Multiple ictal EEG patterns could represent a 'red flag', reflecting a widespread neuronal excitability related to the underlying immune-mediated process. Finally, our work enhances the crucial role of long-lasting EEG monitoring in revealing subclinical and relapsing seizures.

Peripheral blood expression levels of inflammasome complex components in two different focal epilepsy syndromes.

BACKGROUND: Although the role of inflammation in epilepsy pathogenesis has been extensively investigated, the inflammasome complex, a key component of neuroinflammation, has been understudied in epilepsy patients. METHODS: To better understand the involvement of this system in epilepsy, levels of inflammasome complex components (NLRP1, NLRP3, CASP1, ASC), end-products of inflammasome complex activity [IL-1ß, IL-18, nitric oxide synthase (NOS) isoforms] and other inflammatory factors (NFκB, IL-6, TNF-α) were measured in peripheral blood of patients with focal epilepsy of unknown cause (FEoUC) (n = 47), mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) (n = 35) and healthy controls using real time qPCR and/or ELISA. RESULTS: Inflammasome complex associated factors were either downregulated or unchanged in epilepsy patients. Likewise, flow cytometry studies failed to show an increase in ratios of NLRP3-expressing CD3+ and CD14+ peripheral blood mononuclear cells (PBMC) in epileptic patients. Anti-neuronal antibody positive epilepsy patients showed increased NLRP1 and neuronal NOS mRNA expression levels, whereas patients under poly-therapy showed reduced serum inflammasome levels. FEoUC patients demonstrated increased PBMC NFκB mRNA expression levels and serum IL-1ß and IL-6 levels. Both MTLE-HS and FEoUC patients displayed higher ratios of NFκB-expressing CD14+ PBMC than healthy controls. CONCLUSIONS: Although previous clinical studies have implicated increased inflammasome complex expression levels in epilepsy, our results indicate suppressed inflammasome complex activity in the peripheral blood of focal epilepsy patients. Alternatively, the IL-6-NFκB signaling pathway, appears to be activated in focal epilepsy, suggesting that factors of this pathway might be targeted for future theranostic applications.

Anti-Neuronal Autoantibodies in Both Drug Responsive and Resistant Focal Seizures with Unknown Cause.

BACKGROUND: and Objective Autoimmunity is an emerging field of research in the etiology of different neurological disorders including epilepsy. We aimed to investigate the presence of neuronal autoantibodies in focal epilepsy with unknown cause and their clinical correlates in both drug-responsive and resistant patients. METHOD: Between 2009 and 2010 94 patients were prospectively enrolled, had their antibodies tested and clinically followed." An additional 50 age- and gender-matched controls were also tested for antibodies. Age at examination, gender, age at onset, seizure frequency, risk factors, seizure precipitants, and type of seizures were noted. Plasma obtained from patients was frozen at -80°C and analysed for autoantibodies against VGKC-complex, VGCC, GAD, LGI1, CASPR2, NMDA, AMPA and GABAB receptors with immunocytochemistry and radioimmunoassay as required. RESULTS: Thirteen (13.8%) patients, but none of the controls, had antibodies (p=0.003). Antibodies were directed against the uncharacterized components of VGKC-complex in 5 patients (5.3%), GAD in 4 patients (4.2%), NMDA-R in 1 patient (1%), AMPA-R in 1 patient (1%) and both GAD and VGKC-complex in 2 patients (2.1%). Prognosis of epilepsy, in subsequent follow-up, did not correlate to general presence of anti-neuronal antibodies with slightly more patients with antibodies epilepsy control than without (76.9% vs. 69.1%, not-statistically significant. Three patients with suspected active autoimmunity and epilepsy who were treated, showed a response to treatment with a reduction in the seizure frequency. Although most clinical features were identical between seropositive and seronegative patient groups, seropositive patients were more likely to have inflammatory/autoimmune disorders in their medical history. DISCUSSION: In keeping with previous studies, we have shown anti-neuronal antibodies in a proportion of focal epilepsy patients. Although autoimmunity might merely occur as a bystander effect in many chronic neurological disorders, association of anti-neuronal antibodies with good response to immunotherapy and coexisting autoimmune disorders suggests that anti-neuronal autoimmunity might participate in seizure formation at least in a subgroup of focal epilepsy patients. CONCLUSION: Immunity may play a role in some patients with unknown etiology regardless of prognosis and immunmodulatuar treatment may be helpful in seropositive group.

LGI1-antibody encephalitis is characterised by frequent, multifocal clinical and subclinical seizures.

PURPOSE: To describe clinical and electrographic characteristics of seizures LGI1-antibody encephalitis, and their correlations with two-year outcomes. METHODS: Video-electroencephalography recordings were performed on a cohort of 16 consecutive patients with LGI1-antibodies from two UK neuroscience-centers over five-years. RESULTS: From 14 of 16 patients (13 males; age-range 53-92years), 86 faciobrachial dystonic seizures were recorded at a median frequency of 0.4 per hour (range 0.1-9.8), and ictal EEG changes accompanied 5/86 events. In addition, 11/16 patients showed 53 other seizures - subclinical (n=18), motor (n=16), or sensory (n=19) - at a median of 0.1 per hour (range 0.1-2) associated with temporal and frontal discharges. The sensory events were most commonly thermal sensations or body-shuddering, and the motor events were frequently automatisms or vocalisations. Furthermore, multifocal interictal epileptiform discharges, from temporal, frontal and parietal regions, and interictal slow-wave activity were observed in 25% and 69% of patients, respectively. Higher observed seizure frequency correlated with poorer functional recovery at two-years (p=0.001). CONCLUSIONS: Multiple frequent seizure semiologies, in addition to numerous subclinical seizures and interictal epileptiform discharges, are hallmarks of LGI1-antibody encephalitis. High overall seizure frequency may predict more limited long-term recovery. These observations should encourage closer monitoring and proactive treatment of seizure activity in these patients.

Focal epilepsy as a long term sequela of Parvovirus B19 encephalitis.

Human Parvovirus B19 (PVB19), the etiological agent of the fifth disease, is associated with a large spectrum of pathologies, among which is encephalitis. Since it has been detected from the central nervous system in children or in immunocompromised patients, its causative role in serious neurological manifestations is still unclear. Here we report the case of an 18-year-old healthy boy who developed encephalitis complicated by prolonged status epilepticus. The detection of PVB19 DNA in his serum and, subsequently, in his cerebrospinal fluid supports the hypothesis that this virus could potentially play a role in the pathogenesis of neurological complications. In addition, the detection of viral DNA and the presence of specific IgM and IgG antibodies in serum, together with clinical findings such as skin rash, support the presence of a disseminated viral infection. In the presence of neurological disorders, especially when there are no specific signs, but seizures and rash are present, it is important to search for PVB19 both in immunocompromised and immunocompetent patients. Moreover, the introduction of the PVB19 DNA test into diagnostic protocols of neuropathies, especially those undiagnosed, could clarify the etiological agent that otherwise could remain unrecognized.

Autoantibodies to neuronal antigens in children with focal epilepsy and no prima facie signs of encephalitis.

OBJECTIVE: There is increasing awareness of neuronal autoantibodies and their impact on the pathogenesis of epilepsy. We investigated children with focal epilepsy in order to provide an estimate of autoantibody frequency within a pediatric population without prima facie evidence of encephalitis using a broad panel of autoantibodies. This was done to assess the specificity of antibodies and to see whether antibodies might be of modifying influence on the course of focal epilepsies. METHOD: We searched for autoantibodies in 124 patients with focal epilepsy (1-18 years; mean 10; 6 years). Sera were tested using a broad panel of surface and intracellular antigens. RESULTS: We found autoantibodies in 5/124 patients (4%): high-positive GAD65 antibodies (n = 1), low-positive GAD65 antibodies (N = 1), VGKC complex antibodies not reactive with LGI1 or CASPR2 (n = 3). We did not find any distinctive features distinguishing antibody positive patients from those without antibodies. CONCLUSIONS: The antibodies found in this cohort are probably neither disease-specific nor pathogenic. This has been suggested before for these antigenic targets. Moreover, they do not seem to modify disease severity in the antibody-positive epilepsy patients.

Special Issues in Epilepsy: The Elderly, the Immunocompromised, and Bone Health.

PURPOSE OF REVIEW: This article discusses targeted special issues in epilepsy, including epilepsy in the elderly and immuncompromised populations and bone health in epilepsy. Although this is a broad and diverse set of topics, common themes can be identified by focusing on elderly patients and patients who are immunocompromised that provide a valuable framework for other groups. RECENT FINDINGS: An increasing incidence of epilepsy has been reported in patients 65 years of age and older. As people age, physiologic changes can alter antiepileptic drug metabolism, which can significantly impact dosing requirements and tolerability. Side effects of antiepileptic drugs may pose a significant challenge given the relatively high frequency of comorbid illnesses. When evaluating and treating immunocompromised patients, a broad range of potential etiologies for new-onset or worsening seizures must be considered. When choosing an antiepileptic drug, drug-drug interactions, the potential for increased side effects, and the overall impact of treatments on the underlying illness must be considered. The most recent findings and recommendations pertaining to bone health assessment and maintenance in various populations with epilepsy are summarized. SUMMARY: Treating epilepsy and seizures in special populations requires taking a broad view of patients' overall health status, including potentially complex treatment regimens and a unique predisposition to adverse events.

Pharmacoresistent Partial Epilepsy Secondary to Progressive Inflammatory Poliodystrophy.

BACKGROUND: Epilepsy with progressive cortical volume loss is described secondary to energy failure such as mitochondrial disorders, infectious, or inflammatory etiologies and associated with temporal lobe epilepsy. Postmortem studies do not support that spontaneous seizures even if present for prolonged periods universally result in cortical volume loss. MAIN FINDINGS: We describe two children with extratemporal pharmacoresistent epilepsy, slowly progressive gray matter volume loss over several years, and evidence of central nervous system inflammation. Brain magnetic resonance imaging changes and antibody profiles were not typical of a well-defined, antibody-mediated central nervous system syndrome such as N-methyl-D-aspartate receptor encephalitis. CONCLUSIONS: These patients illustrate a novel presentation of a subacute inflammatory central nervous system process with epilepsy and progressive cortical volume loss, supporting the role of sequential brain imaging in children with epilepsy.

Good outcome in adult-onset Rasmussen's encephalitis syndrome: is recovery possible?

A healthy 29-year-old man suffered from adult-onset epilepsy, characterized by polymorphic progressive seizures resistant to AEDs, leading to unilateral cortical deficits and atrophy of the left hemisphere. The disorder satisfied the clinical, EEG, and imaging criteria for a diagnosis of Rasmussen's encephalitis. During the acute phase of the disease, intrathecal synthesis of specific anti-CMV IgG was identified. This case was characterized by a very mild course and remission of seizures following a treatment with high-dose intravenous polyvalent immunoglobulins containing a high anti-CMV titre. The patient remained symptomless for more than 15 years from clinical onset and more than eight years after the discontinuation of immunological therapy. In agreement with a recent report, this case confirms that adult-onset Rasmussen's encephalitis syndrome may occur with a very mild clinical picture and persistent remission. In this case, the specific index for intrathecal production of anti-CMV antibodies suggested possible CMV involvement, indicating specific immuno-therapy as a treatment choice.

Focal epilepsies: immunologic and inflammatory mechanisms.

There is increasing evidence documenting activation of inflammatory processes in focal epilepsies. This review article summarizes current data regarding immune mediated inflammatory processes in patients with symptomatic partial epilepsies such as mesial temporal sclerosis, focal cortical dysplasia, and Rasmussen's encephalitis. We have also reviewed several neuronal surface antibody-associated syndromes, which have been recently described with focal seizures as an important part of clinical presentation, such as antibody-associated limbic encephalitis and N-methyl-D-aspartic acid receptor antibody syndrome. An autoimmune mechanism may be one pathogenic factor in some symptomatic epilepsies acting as a triggering event in the process leading to the development of epilepsy.

Persistent frequent subclinical seizures and memory impairment after clinical remission in smoldering limbic encephalitis.

AIM: To delineate a possible correlation between clinical course and EEG abnormalities in non-infectious "smoldering" limbic encephalitis. METHODS: Long-term clinical data, including video-EEG monitoring records, were analysed in two patients. RESULTS: The two patients were positive for anti-voltage-gated potassium channel complex antibody and unspecified antineuronal antibody, respectively. The latter patient had small cell lung carcinoma. Both patients had memory impairment and clinical seizures. EEG showed frequent subclinical seizure patterns in the bilateral temporal regions. Subclinical seizure patterns and memory impairment persisted over one to two years after clinical seizure remission. Therapy (prednisolone and chemoradiation in the two patients, respectively) resulted in decreased occurrence of subclinical seizure patterns and memory improvement. CONCLUSIONS: EEG seizure patterns may persist years after clinical seizure remission in "smoldering" limbic encephalitis and lead to memory impairment.

Glycine receptor antibodies in a boy with focal epilepsy and episodic behavioral disorder.

A wide range of clinical presentations including neuromuscular disorders and autoimmune encephalopathies is being recognized to be associated with various autoantibodies. Glycine receptor (GlyR) antibodies have so far been found mainly in adult patients with phenotypes comprising progressive encephalomyelitis with rigidity and myoclonus or stiff-person syndrome. We report a four-year-old boy who presented with a two-year-history of drug-resistant focal epilepsy with unusual seizure semiology, temper tantrums, headache, clumsiness, and intermittently impaired speech. While MRI and CSF were normal, screening for autoimmune antibodies revealed GlyR antibodies in serum. Immunomodulatory treatment with steroids resulted in rapid and complete resolution of symptoms. Our observation widens the spectrum of clinical presentations associated with GlyR antibodies and emphasizes the potential relevance of neuronal autoantibodies in epilepsies of unknown cause in children as well as in adults.

Investigation of neuronal autoantibodies in two different focal epilepsy syndromes.

OBJECTIVE: Neuronal antibodies have been identified in patients with seizures as the main or sole symptom. Our aim was to investigate the prevalence of these autoantibodies in patients with focal epilepsy of unknown cause (FEoUC) and in the group having mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). METHODS: We studied anti-neuronal antibodies of consecutive adult patients diagnosed with FEoUC and MTLE-HS in our epilepsy center. The clinical and laboratory features of antibody-positive patients were compared with those of seronegative patients. The responses to therapy have also been investigated. RESULTS: Sera from 81 patients with epilepsy were tested. We found antibodies against glycine receptor (GLY-R) in 5 (6.2%), contactin-associated protein 2 (CASPR-2) in 4 (4.9%), N-methyl-d-aspartate receptor (NMDA-R) in 2 (2.5%), and voltage-gated potassium channel (VGKC)-complex in 2 (2.5%) of our patients with epilepsy. Psychotic attacks and nonspecific magnetic resonance imaging (MRI) white matter changes (WMCs) showed significant associations in seropositive patients (p = 0.003 and p = 0.03, respectively). Poor drug-response rates and total seizure counts were also higher in the seropositive patients but without reaching statistical significance. Three seropositive patients with previous epilepsy surgery showed typical histopathologic results for MTLE-HS, but not inflammatory changes. Moreover, some patients harboring these antibodies partly benefited from immunotherapy. SIGNIFICANCE: We detected neuronal antibodies in one sixth of patients with focal epilepsy, GLY-R antibodies being the leading one. Psychosis or nonspecific MRI WMCs were frequent in the seropositive group. Our results suggested that relevant antibodies should be screened for a treatment possibility in these groups.

Effects of antibodies to glutamate on focal penicillin-induced epileptic activity.

The effects of intranasal pretreatment with antibodies against glutamate on focal penicillin-induced epileptic activity were studied by recording electrocorticogram in non-anesthetized freely moving male Wistar rats. Anticonvulsant effects of intranasal administration of anti-glutamate antibodies (300 µg/kg) 1 h before application of penicillin (30,000 U/ml) on the sensorimotor cortex was demonstrated: the latency of ictal discharges increased and their frequency decreased.

Emerging drugs for focal epilepsy.

INTRODUCTION: Epilepsy is one of the most common serious neurological disorders in adults, affecting approximately 50 million people worldwide at a total annual cost, in Europe, of approximately 15.5 billion Euros. AREAS COVERED: The present paper reviews current compounds in preclinical and clinical development for the treatment of focal epilepsies, namely, ganaxolone, perampanel, BGG-492, NS-1209, belnacasan, YKP-3089, brivaracetam. New formulations in clinical development, such as intranasal midazolam, diazepam auto-injection, a new formulation of valproic acid using drug targeting technology and controlled release formulations for topiramate and pregabalin, are also discussed. EXPERT OPINION: During the last 30 years, antiepileptic drugs (AEDs) development have been based on specific assumptions regarding the neurobiology of epilepsy but all marketed drugs have not changed the proportion of drug refractory patients. AEDs in development with new mechanisms of actions, especially anti-inflammatory agents, are of interest. AMPA blockers, especially water-soluble ones, being suitable for parenteral formulation, can be of relevance in treating refractory status epilepticus, a major life-threatening complication. Finally, new formulations, especially those adopting drug targeting technologies are promising in order to maximize the efficacy with very limited adverse effects.

An immunologic case study of acute encephalitis with refractory, repetitive partial seizures.

Acute encephalitis with refractory, repetitive partial seizures (AERRPS) is a neurologic syndrome characterized by extraordinarily frequent and refractory partial seizures, which immediately evolve into refractory epilepsy. To elucidate the pathophysiology of AERRPS, we performed an immunologic study of an affected boy, revealing decreased natural killer (NK) cell activity in the peripheral blood mononuclear cells. IgG antibodies against the glutamate receptor (GluR)ε2, ζ1, and δ2 subunits were all positive in both the serum and cerebrospinal fluid (CSF). There were raised plasma concentrations of interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor-α, and interferon-γ as well as an extremely elevated CSF level of IL-6. These findings suggest that AERRPS is immune-mediated encephalitis, in which both autoimmunity and exaggerated cytokine production are involved. NK cell dysfunction may be the underlying abnormality in this AERRPS case, which might have contributed to the production of GluR autoantibodies.

[A case of occipital epilepsy with anti-GluRepsilon2 antibody in cerebrospinal fluid, presenting as repeated visual disturbance and headache].

A 78-year-old man was admitted to our hospital with repeated attacks of headache and visual hallucinations, which had begun 10 days before. He also displayed left hemispatial neglect and left homonymous hemianopsia during attacks. Brain magnetic resonance imaging (MRI) showed an abnormal high-intense area in the right occipital lobe on diffusion weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR) weighted imaging; this lesion was demonstrated as an area of hyperperfusion on ECD-single photon emission computed tomography (SPECT) and hypoperfusion on 123I-BZ-SPECT. Electroencephalography during an attack demonstrated epileptogenic discharges in the right occipital region. Acute urinary retention due to meningoencephalitis appeared 2 weeks after onset of the first attack. Autoantibodies against glutamate receptor epsilon2 were detected in cerebrospinal fluid. We diagnosed the patient with occipital epilepsy due to anti-NMDA receptor antibody encephalitis. Epileptic attacks diminished and MRI and SPECT findings improved following two administrations of intravenous bolus steroid therapy.