NMDA receptor antibody encephalitis presenting as Transient Epileptic Amnesia.

Transient Epileptic Amnesia (TEA) is a subtype of temporal lobe epilepsy, typically presenting in a person's early 60s, and of unknown aetiology. Encephalitis caused by antibodies to NMDA receptors (NMDARE) has not previously been documented in TEA. We describe a 47-year-old male who satisfied criteria for TEA, but given his atypical symptoms, was also screened for autoimmune epilepsy. High levels of serum NMDAR antibodies were found, suggesting NMDARE. Immunosuppressive treatment gradually eliminated the NMDA receptor antibodies. Our case extends the clinical spectrum associated with neuronal cell-surface autoantibodies to include atypical cases of TEA.

Mesial temporal lobe epilepsy with hippocampal sclerosis is infrequently associated with neuronal autoantibodies.

Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is characterized by its well-defined clinical profile. Limbic encephalitis is increasingly recognized as a possible etiology of adult-onset MTLE-HS, and neuronal autoantibodies have been detected in patients even without previous signs of encephalitis. The aim of this study is to analyze the frequency of specific autoantibodies in patients with MTLE-HS. A case-control study was carried out with 100 patients with MTLE-HS and 50 healthy controls. Sera samples from subjects were tested by indirect immunofluorescence assay for detection of anti-N-methyl-d-aspartate receptor (NMDA-R), anti-contactin-associated protein-like 2 (CASPR2), anti-leucine-rich glioma inactivated 1 (LGI1), anti-gamma aminobutyric acid B receptor (GABA-B-R), anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid 1 and 2 receptors (AMPA-1-R and AMPA-2-R), and enzyme-linked immunosorbent assay for detection of anti-glutamic acid decarboxylase 65 (GAD65). Mean age of patients and controls was 41.2 vs 42 years, and 55% vs 56% were female. Mean duration of epilepsy was 27.2 years. No neuronal autoantibodies were found in either group, except for anti-GAD65 in 3 patients and 2 controls. This study adds to the mounting evidence that, in Brazilian patients, MTLE-HS without signs and symptoms of autoimmune encephalitis may be infrequently associated with these autoantibodies. Differences regarding accuracy of used methodologies for autoantibody detection and genetic and environmental characteristics are discussed. Further works with different methodologies tested simultaneously in different populations may help clarify the incongruent study results about autoantibodies in MTLE-HS.

Antiglutamic acid decarboxylase 65 (GAD65) antibody-associated epilepsy.

Glutamic acid decarboxylase (GAD) antibody-associated encephalitis causes both acute seizures and chronic epilepsy with predominantly temporal lobe onset. This condition is challenging in diagnosis and management, and the incidence of GAD antibody (Ab)-related epilepsy could be much higher than commonly believed. Imaging and CSF evidence of inflammation along with typical clinical presentations, such as adult onset temporal lobe epilepsy (TLE) with unexplained etiology, should prompt testing for the diagnostic antibodies. High serum GAD Ab titer (≥2000U/mL or ≥20nmol/L) and evidence of intrathecal anti-GAD Ab synthesis support the diagnosis. Unlike other immune-mediated epilepsies, antiglutamic acid decarboxylase 65 (GAD65) antibody-mediated epilepsy is often poorly responsive to antiepileptic drugs (AEDs) and only moderately responsive to immune therapy with steroids, intravenous immunoglobulin (IVIG), or plasma exchange (PLEX). Long-term treatment with more aggressive immunosuppressants such as rituximab (RTX) and/or cyclophosphamide is often necessary and may be more effective than current immunosuppressive approaches. The aim of this review is to review the physiology, pathology, clinical presentation, related ancillary tests, and management of GAD Ab-associated autoimmune epilepsy by searching the keywords and to promote the recognition and the initiation of proper therapy for this condition.

Status epilepticus does not induce acute brain inflammatory response in the Amazon rodent Proechimys, an animal model resistant to epileptogenesis.

Mesial temporal lobe epilepsy is a serious brain disorder in adults that is often preceded by an initial brain insult, such as status epilepticus (SE), that after a latent period leads to recurrent seizures. Post-SE models are widely used for studies on epileptogenic processes. Previous findings of our laboratory suggested that the Neotropical rodents Proechimys exhibit endogenous antiepileptogenic mechanisms in post-SE models. Strong body of research supports that SE triggers a rapid and dramatic upregulation of inflammatory mediators and vascular endothelial growth factor (VEGF). In this work we found that, in the epilepsy-resistant Proechimys, hippocampal and cortical levels of inflammatory cytokines (IL-1ß, IL-6, IL-10, TNF-α) and VEGF remained unchanged 24h after SE, strongly contrasting to the high levels of post-SE changes observed in Wistar rats. Furthermore, substantial differences in the brain baseline levels of these proteins were encountered between animal species studied. Since inflammatory cytokines and VEGF have been recognized as major orchestrators of the epileptogenic process, our results suggest their role in the antiepileptogenic mechanisms previously described in Proechimys.

Immunopathology in drug resistant mesial temporal lobe epilepsy with different types of hippocampal sclerosis.

PURPOSE: There is evidence that autoimmunity has a specific role in temporal lobe seizures of limbic encephalitis patients. Our aim in this study was to investigate any histopathological clues of autoimmune process in refractory temporal lobe epilepsy (TLE) patients with different pathologically proven hippocampal sclerosis (HS) types. METHODS: 22 patients who had undergone epilepsy surgery due to mesial TLE-HS were included. The sera of patients are tested for neuronal antibodies to N-methyl-D-aspartate receptors (NMDAR), leucine-rich, glioma inactivated 1 (LGI1), contactin-associated protein 2 (CASPR2), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), gamma-aminobutyric acid B receptor (GABABR) and glutamic acid decarboxylase (GAD). Pathological and immunohistochemical investigations including neuronal nuclei (NeuN), NMDAR, GAD, glial fibrillary acidic protein (GFAP), CD8+-CD3+ lymphocytes and immunoglobulin G (IgG) were done. Patients were grouped according to type of HS. Clinical features and immunohistochemical changes were defined in these groups. RESULTS: Available sera of 15 patients did not have any neuronal antibodies. Thirteen of 22 patients had HS type 1, three had HS type 2 and two had HS type 3. According to immunohistochemical investigations CD3+ and CD8+ T cell infiltration was more prominent in the hippocampus of patients with classical HS (International League Against Epilepsy (ILAE) Type 1 HS) and there was a significant negative correlation between epilepsy duration and numbers of CD3+-CD8+ lymphocytes in temporal lobe parenchyma. CONCLUSION: The role of T cell-mediated immunopathology and immunopathological difference in a variety of drug resistant TLE-H2S patients was suggested. These findings can be helpful in understanding the epileptogenicity of HS.

Epilepsy surgery in drug resistant temporal lobe epilepsy associated with neuronal antibodies.

We assessed the outcome of patients with drug resistant epilepsy and neuronal antibodies who underwent epilepsy surgery. Retrospective study, information collected with a questionnaire sent to epilepsy surgery centers. Thirteen patients identified, with antibodies to GAD (8), Ma2 (2), Hu (1), LGI1 (1) or CASPR2 (1). Mean age at seizure onset: 23 years. Five patients had an encephalitic phase. Three had testicular tumors and five had autoimmune diseases. All had drug resistant temporal lobe epilepsy (median: 20 seizures/month). MRI showed unilateral temporal lobe abnormalities (mainly hippocampal sclerosis) in 9 patients, bilateral abnormalities in 3, and was normal in 1. Surgical procedures included anteromesial temporal lobectomy (10 patients), selective amygdalohippocampectomy (1), temporal pole resection (1) and radiofrequency ablation of mesial structures (1). Perivascular lymphocytic infiltrates were seen in 7/12 patients. One year outcome available in all patients, at 3 years in 9. At last visit 5/13 patients (38.5%) (with Ma2, Hu, LGI1, and 2 GAD antibodies) were in Engel's classes I or II. Epilepsy surgery may be an option for patients with drug resistant seizures associated with neuronal antibodies. Outcome seems to be worse than that expected in other etiologies, even in the presence of unilateral HS. Intracranial EEG may be required in some patients.

Value of Functionalized Superparamagnetic Iron Oxide Nanoparticles in the Diagnosis and Treatment of Acute Temporal Lobe Epilepsy on MRI.

Purpose. Although active targeting of drugs using a magnetic-targeted drug delivery system (MTDS) with superparamagnetic iron oxide nanoparticles (SPIONs) is a very effective treatment approach for tumors and other illnesses, successful results of drug-resistant temporal lobe epilepsy (TLE) are unprecedented. A hallmark in the neuropathology of TLE is brain inflammation, in particular the activation of interleukin-1ß (IL-1ß) induced by activated glial cells, which has been considered a new mechanistic target for treatment. The purpose of this study was to determine the feasibility of the functionalized SPIONs with anti-IL-1ß monoclonal antibody (mAb) attached to render MRI diagnoses and simultaneously provide targeted therapy with the neutralization of IL-1ß overexpressed in epileptogenic zone of an acute rat model of TLE. Experimental Design. The anti-IL-1ß mAb-SPIONs were studied in vivo versus plain SPIONs and saline. Lithium-chloride pilocarpine-induced TLE models (n = 60) were followed by Western blot, Perl's iron staining, Nissl staining, and immunofluorescent double-label staining after MRI examination. Results. The magnetic anti-IL-1ß mAb-SPION administered intravenously, which crossed the BBB and was concentrated in the astrocytes and neurons in epileptogenic tissues, rendered these tissues visible on MRI and simultaneously delivered anti-IL-1ß mAb to the epileptogenic focus. Conclusions. Our study provides the first evidence that the novel approach enhanced accumulation and the therapeutic effect of anti-IL-1ß mAb by MTDS using SPIONs.

Circulating CD4 and CD8 T cells expressing pro-inflammatory cytokines in a cohort of mesial temporal lobe epilepsy patients with hippocampal sclerosis.

OBJECTIVE: To compare the proinflammatory and anti-inflammatory cytokine expression profile of CD4(+) and CD8(+) T lymphocytes between drug resistant mesial Temporal Lobe Epilepsy (mTLE) patients and healthy subjects. METHODS: mTLE patients were enrolled at the Neurology Center of Santa Casa de Misericórdia de Belo Horizonte (SCM-BH) and healthy volunteers were selected at Universidade Federal de Minas Gerais. Individuals from both groups accepted to participate in this study and signed an informed consent. Peripheral venous blood samples were collected using sodium heparin vacuum tubes on the day before the surgery and in the interictal period, isolated from whole blood using Ficoll/Hypaque followed by flow cytometry analysis. Data analysis was performed using FlowJo. RESULTS: Compared to healthy individuals, mTLE patients showed reduced frequency of CD8(+) T lymphocytes expressing IFN-γ, TNF-α, IL-17 and IL-4. Moreover, mTLE patients presented increased frequency of CD4(+) T lymphocytes expressing IL-6 when compared to healthy volunteers. DISCUSSION: Epilepsy is the third most common chronic brain disorder. Mesial temporal lobe epilepsy (mTLE) is a major and severe form of epilepsy and 30% of the mTLE patients do not respond to conventional medications. Our data suggest that mTLE patients have distinct immunological profiles that are related to disease pathophysiology.

Treatment of immune-mediated temporal lobe epilepsy with GAD antibodies.

PURPOSE: Temporal lobe epilepsy with antibodies (abs) against the glutamic acid decarboxylase 65 isoform (GAD-TLE) is known as an immune-mediated neurological syndrome. Here we evaluate the therapy response to various immunotherapies and epilepsy surgery in this syndrome. METHOD: All patients with GAD-TLE and follow-up data and stored serum and CSF samples, identified and treated at the Bonn centre from 2002 to 2010, were studied retrospectively. Seizure freedom for ≥1 year and reduction of ≥50%, i.e. therapy response, were assessed. GAD-ab titres and neuropsychological performances were documented prior and after individual interventions. RESULTS: Thirteen patients with GAD-TLE were identified with the following seizure responses: corticosteroids (5 responders out of 11 treated patients); i.v. immunoglobulins (1/5), apheresis therapy (1/8); and natalizumab (1/1), selective amygdala-hippocampectomy (2/3). None of the patients achieved sustained seizure freedom apart from one patient. This patient was on antiepileptic drug treatment after discontinuation of immunotherapy. CONCLUSION: The seizure response to immunotherapies in patients with GAD-TLE was poor. Corticosteroids were the most effective regarding seizure response. Especially the poor effects of apheresis therapies support the idea that GAD-abs are not directly pathogenic. None of three patients was seizure-free after temporal lobe surgery suggesting that GAD-TLE patients respond worse than others to this type of intervention. Our results reflect the chronic course of the disease with low likelihood for patients with GAD-TLE to attain long-term seizure freedom.

Quantitative FLAIR analysis indicates predominant affection of the amygdala in antibody-associated limbic encephalitis.

PURPOSE: Limbic encephalitis is an autoimmune-mediated disease leading to temporal lobe epilepsy, mnestic deficits, and affective disturbances. Magnetic resonance imaging (MRI) usually shows signal and volume changes of the temporomesial structures. However, these abnormalities may be subtle, thereby hampering the diagnosis by conventional visual assessment. In the present study we evaluated the diagnostic value of a fully automated MRI postprocessing technique in limbic encephalitis and hippocampal sclerosis. METHODS: The MRI postprocessing was based largely on a recently described method allowing for an observer-independent quantification of the fluid-attenuated inversion recovery (FLAIR) signal intensities of amygdala and hippocampus. A 95% confidence region was calculated from the FLAIR intensities of 100 healthy controls. We applied this analysis to the MRI data of 39 patients with antibody-associated limbic encephalitis and 63 patients with hippocampal sclerosis. Moreover, the results were compared to those of visual assessment by an experienced neuroradiologist. KEY FINDINGS: The method detected limbic encephalitis and hippocampal sclerosis with a high sensitivity of 85% and 95%, respectively. The detection rate of the automated approach in limbic encephalitis was significantly superior to visual analysis (85% vs. 51%; p = 0.001), whereas no statistically significant difference for the detection rate in hippocampal sclerosis was found. Patients with limbic encephalitis had significantly higher absolute intensity values of the amygdala and a significantly higher percentage fell outside of the amygdalar confidence region compared to those with hippocampal sclerosis (79% vs. 27%; p < 0.001), whereas we found opposite results in the hippocampal analysis (38% vs. 95%; p < 0.001). SIGNIFICANCE: The FLAIR analysis applied in this study is a powerful tool to quantify signal changes of the amygdala and hippocampus in limbic encephalitis and hippocampal sclerosis. It significantly increases the diagnostic sensitivity in limbic encephalitis in comparison to conventional visual analysis. Furthermore, the method provides an interesting insight into the distinct properties of these two disease entities on MRI, indicating a predominant affection of the amygdala in limbic encephalitis, whereas the affection of the hippocampus is far less pronounced when compared to hippocampal sclerosis.

An unusual presentation of anti-Hu-associated paraneoplastic limbic encephalitis.

Paraneoplastic limbic encephalitis is a rare disorder characterized by personality changes, seizures, memory loss, and psychiatric symptoms often associated with antineuronal antibodies. It is well described in the adult literature but is still underreported in the pediatric literature. Symptoms are usually multifocal and subacute in presentation, occurring over days to weeks; however, in rare cases, symptom onset can be more gradual. We report the case of a 9-year-old male with anti-Hu-associated paraneoplastic limbic encephalitis that presented as episodic ataxia and behavioral changes evolving to intractable epilepsy and worsening behavioral changes over the course of a year. This case highlights the importance of considering a paraneoplastic disorder in the differential diagnosis for unexplained multifocal neurological symptoms of subacute or chronic onset as earlier detection and treatment may result in an improved outcome.

Immunoproteasome expression is induced in mesial temporal lobe epilepsy.

Immunoproteasome has been associated to neurodegenerative and autoimmune diseases as a marker and regulator of inflammatory mechanisms. Its expression in the brain may occur upon neuroinflammation in different cell types and affect a variety of homeostatic and inflammatory pathways including the oxidized protein clearance and the self-antigen presentation. In the present study we investigated the immunoproteasome expression in hippocampi and cortex of patients affected by different histopathological forms of pharmaco-resistent mesial temporal lobe epilepsy. We identified a pathology-specific pattern of immunoproteasome expression, which could provide insight into the complex neuroinflammatory pathogenic components of this disease.

The influence of epileptic neuropathology and prior peripheral immunity on CNS transduction by rAAV2 and rAAV5.

Adeno-associated virus (AAV) provides a promising platform for clinical treatment of neurological disorders owing to its established efficacy and lack of apparent pathogenicity. To use viral vectors in treating neurological disease, however, transduction must occur under neuropathological conditions. Previous studies in rodents have shown that AAV5 more efficiently transduces cells in the hippocampus and piriform cortex than AAV2. Using the kainic acid (KA) model of temporal lobe epilepsy and AAV2 and 5 carrying a hybrid chicken ß-actin promoter driving green fluorescent protein (GFP), we found that limbic seizure activity caused substantial neuropathology and resulted in a significant reduction in subsequent AAV5 transduction. Nonetheless, this reduced transduction still was greater than AAV2 transduction in control rats. Although KA seizures compromise blood-brain barrier function, potentially increasing exposure of target tissue to circulating neutralizing antibodies, we observed no interaction between KA seizure-induced damage and immunization status on AAV transduction. Finally, while we confirmed the near total neuronal-specific transgene expression for both serotypes in control rats, AAV5-GFP expression was increasingly localized to astrocytes in seizure-damaged areas. Thus, the pathological milieu of the injured brain can reduce transduction efficacy and alter viral tropism- both relevant concerns when considering viral vector gene therapy for neurological disorders.

Doublecortin (DCX) immunoreactivity in hippocampus of chronic refractory temporal lobe epilepsy patients with hippocampal sclerosis.

INTRODUCTION: Status epilepticus increases the production of new neurons (hippocampal neurogenesis) and promotes aberrant migration. However chronic experimental models of epilepsy and studies performed in human epilepsy showed controversial results suggesting a reduction in hippocampal neurogenesis in late stages of the disease. Doublecortin (DCX) has been validated to determine alterations in the production of new neurons in the human hippocampus. OBJECTIVES: Determine DCX expression in human hippocampal sclerosis (HS) from patients who underwent epilepsy surgery for refractory temporal lobe epilepsy (TLE). METHODS: Hippocampal sections of 9 patients with HS and TLE who underwent surgery, were processed using immunoperoxidase for DCX. Archival material from 5 normal post-mortem hippocampus were simultaneously processed. RESULTS: Significantly lower staining intensity was observed in DCX-positive neurons localized in dentate gyrus (DG) and in CA1 of epileptic hippocampus; lower DCX reactive area was observed in pyramidal layers of CA1; and a reduced in the mean number of DCX-positive neurons were determined in DG compared to normal hippocampus (p<0.05). CONCLUSIONS: This study found a decrease in DCX expression in hippocampus of patients with HS and chronic and refractory TLE suggesting alterations in NG and hippocampal synaptogenesis with potential cognitive and emotional repercussion.

Innate but not adaptive immune responses contribute to behavioral seizures following viral infection.

PURPOSE: To examine the role of innate immunity in a novel viral infection-induced seizure model. METHODS: C57BL/6 mice, mouse strains deficient in interleukin (IL)-1RI, IL-6, tumor necrosis factor (TNF)-RI, or myeloid differentiation primary response gene 88 (MyD88), or transgenic mice (OT-I) were infected with Theiler's murine encephalomyelitis virus (TMEV) or were mock infected. Mice were followed for acute seizures. Tissues were examined for neuron loss, the presence of virus (viral RNA and antigen), perivascular cuffs, macrophages/microglia, and gliosis, and mRNA expression of IL-1, TNF-alpha, and IL-6. RESULTS: IL-1 does not play a major role in seizures, as IL-1RI- and MyD88-deficient mice displayed a comparable seizure frequency relative to controls. In contrast, TNF-alpha and IL-6 appear to be important in the development of seizures, as only 10% and 15% of TNF-RI- and IL-6-deficient mice, respectively, showed signs of seizure activity. TNF-alpha and IL-6 mRNA levels also increased in mice with seizures. Inflammation (perivascular cuffs, macrophages/microglia, and gliosis) was greater in mice with seizures. OT-I mice (virus persists) had a seizure rate that was comparable to controls (no viral persistence), thereby discounting a role for TMEV-specific T cells in seizures. DISCUSSION: We have implicated the innate immune response to viral infection, specifically TNF-alpha and IL-6, and concomitant inflammatory changes in the brain as contributing to the development of acute seizures. This model is a potential infection-driven model of mesial temporal lobe epilepsy with hippocampal sclerosis.

Adult-onset drug-refractory seizure disorder associated with anti-voltage-gated potassium-channel antibody.

Voltage-gated potassium channels are widely expressed throughout the entire nervous system. These channels play a critical role in establishing the resting membrane potential and generation of neuronal action potentials. There is mounting evidence that autoantibodies reactive to neuronal cell surface antigens, such as voltage-gated potassium channels, play a pathogenic role in a wide spectrum of central and peripheral nervous system disorders. We report a case of new-onset drug-refractory seizure disorder associated with the presence of high levels of serum anti-voltage-gated potassium channel antibodies that responded only to immunotherapy. As demonstrated by this case report, anti-voltage-gated potassium channel antibody associated drug-refractory seizure disorder, although rare, should be considered in patients with unexplained adult-onset seizure activity. Once the diagnosis has been established the initiation of immunotherapy should be undertaken without delay.

Interleukin-6 levels are increased in temporal lobe epilepsy but not in extra-temporal lobe epilepsy.

Previous studies have reported activation of inflammatory cytokines in seizures, but clinical characteristics of epilepsy associated with cytokine activation have not been well established. In this study, serum levels of interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1RA) were measured, and clinical characteristics of epilepsy were assessed in 86 well-evaluated patients with refractory focal epilepsy and in 5 patients with controlled focal epilepsy. Epilepsy was evaluated based on patient histories, electroclinical findings, and high-resolution brain MRI scans. Sixty-three healthy blood donors served as controls. IL-6 concentrations were chronically increased in epilepsy patients (11%) compared with healthy controls (0%) (P = 0.007). Increased levels of IL-6 were more prevalent in patients with temporal lobe epilepsy (TLE) compared to patients with extra-TLE (P = 0.028). Also the mean and the median serum levels of IL-6 were higher in patients with TLE than in patients with extra-TLE (P = 0.042). Concentrations of IL-1RA were not significantly different in patients compared with controls. Indicated by increased levels of IL-6 in TLE, epilepsy type is important in determining chronic overproduction of cytokines in refractory focal epilepsy. The results may reflect a chronic immunological process in the brain in patients with refractory epilepsy.

Non-paraneoplastic limbic encephalitis associated with antibodies to potassium channels leading to bilateral hippocampal sclerosis in a pre-pubertal girl.

Limbic encephalitis (LE) is increasingly recognized as a precipitating factor of adult onset temporal lobe epilepsy frequently associated with bilateral hippocampal damage. So far, clinical data in children are rare and only comprise paraneoplastic forms of LE. We describe a 13-year-old pre-pubertal girl in whom non-paraneoplastic LE was diagnosed according to diagnostic criteria proposed by Bien and Elger (2007). The girl presented with a subacute syndrome comprising memory impairment, affective disturbances, and refractory temporal lobe seizures. Serial MRI scans demonstrated an initial temporo-medial swelling with T2/FLAIR signal increase progressing to bilateral hippocampal atrophy within seven months. Two years after onset of symptoms, antibodies to potassium channels were found to be slightly elevated. Immunosuppressive therapy with steroid-pulses was followed by a transient reduction of seizure frequency, even though this was started more than two years after onset of first symptoms. However, extended immunotherapy was refused by the patient's parents, so no full assessment of the treatment response was possible. In conclusion, this case shows that non-paraneoplastic LE leading to mesial temporal lobe epilepsy is not restricted to adult patients. The proposed diagnostic criteria therefore should be adapted for paediatric patients. Patients may profit from immunosuppressive therapy even when it is started at a late stage with already overt hippocampal sclerosis.

Hippocampal sclerosis in refractory temporal lobe epilepsy is associated with gluten sensitivity.

BACKGROUND: Previous studies have associated coeliac disease (CD) and gluten sensitivity (defined as the presence of anti-gliadin antibodies and positive immunogenetics) with cerebellar degeneration and epilepsy with occipital calcifications. Hippocampal sclerosis (HS) in temporal lobe epilepsy (TLE) is a potentially progressive disorder with unknown aetiology; however, autoimmunity has been implicated as one of the possible mechanisms leading to HS. The purpose of this study is to analyze CD-associated antibodies and gluten sensitivity in a well-characterised group of patients with refractory focal epilepsy. METHODS: We measured anti-gliadin, anti-tissue-transglutaminase and anti-endomysium antibodies, and coeliac-type human leukocyte antigen (DQ2 and DQ8), in 48 consecutive patients with therapy-resistant, localisation-related epilepsy. The patients were categorised into the following three groups on the basis of ictal electro-clinical characteristics and the findings of high resolution MRI: TLE with HS (n = 16), TLE without HS (n = 16) and extratemporal epilepsy (n = 16). Patients with suspected CD or gluten sensitivity underwent duodenal biopsies. RESULTS: Seven patients in total were gluten sensitive; all of these patients fell in the TLE with HS group. On the other hand, none of the TLE without HS patients or those with extratemporal epilepsy were gluten sensitive (p<0.0002). The results of duodenal biopsies showed that three of the seven gluten-sensitive patients had histological evidence of CD and four had inflammatory changes consistent with early CD without villous atrophy. Four of the patients with gluten sensitivity had evidence of dual pathology (HS+another brain lesion), whereas none of the remaining patients did (p<0.0002). CONCLUSIONS: The present study demonstrates a previously unrecognised link between gluten sensitivity and TLE with HS. This association was very robust in this well-characterised group of patients; thus gluten sensitivity should be added to the list of potential mechanisms leading to intractable epilepsy and HS.

Hypothermia in VGKC antibody-associated limbic encephalitis.

Voltage-gated potassium channel antibody (VGKC-Ab)-associated limbic encephalitis (LE) is a recently described syndrome that broadens the spectrum of immunotherapy-responsive central nervous system disorders. Limbic encephalitis is typically characterised by a sub-acute onset of disorientation, amnesia and seizures, but the clinical spectrum is not yet fully defined and the syndrome could be under-diagnosed. We here describe the clinical profile of four patients with VGKC-Ab-associated LE who had intermittent, episodic hypothermia. One of the patients also described a prodrome of severe neuropathic pain preceding the development of limbic symptoms. Both of these novel symptoms responded well to immunosuppressive therapy, with concurrent amelioration of amnesia/seizures.