REM and NREM Sleep Parasomnia in Anti-NMDA Receptor Encephalitis.

OBJECTIVES: Encephalitis with anti-N-methyl-d-aspartate receptor antibodies (anti-NMDARe) is a rare disorder characterized by cognitive impairment, psychosis, seizures, and abnormal movements. Abnormal behaviors during REM sleep have not been described in anti-NMDARe. METHODS: Patients were monitored by video-polysomnography on a first night followed by multiple sleep latency tests and 18 hours of bed rest. RESULTS: Two patients with anti-NMDARe developed during the acute and postacute phase parasomnias including REM sleep behavior disorder and continuous finalistic quiet gesturing during a mixed N2/R sleep. The parasomnia disorder was improved by gabapentin and clonazepam. DISCUSSION: Video-polysomnography avoids misdiagnosing these parasomnia behaviors for seizure or movement disorders and allows adequate treatment.

Long-term evolution and prognostic factors of epilepsy in limbic encephalitis with LGI1 antibodies.

OBJECTIVE: To characterize the evolution of epilepsy in patients with leucine-rich glioma inactivated 1 antibody-associated (LGI1ab) limbic encephalitis, including factors associated with drug-resistant epilepsy (DRE). METHODS: Retrospective analysis of patients with LGI1 encephalitis managed at two tertiary epilepsy centers between 2005 and 2019 and whose samples were confirmed by the French Reference Center of Paraneoplastic Neurological Syndromes. Raw clinical, biological, EEG, and MRI data were reviewed. Two endpoints were defined: (i) Epilepsy remission: patients seizure free and in whom anti-seizure medications (ASM) have been stopped for at least 1 year at the last follow-up visit (ii) DRE: patients with persistent seizures at the last follow-up despite at least two ASM used at efficacious daily dose. RESULTS: 39 patients with LGI1 encephalitis were included with a median follow-up duration of 42 months (range 13-169). All of them reported seizures at the acute phase, with faciobrachial dystonic seizures (FBDS) in 23 (59%) and other focal seizures in 38 (97%), including 4 patients (10%) with de novo status epilepticus. At the last follow-up visit, 11 patients (28%) achieved epilepsy remission. Among the 28 patients with persistent epilepsy, eight (29%) fulfilled criteria of DRE. The only factor significantly associated with epilepsy remission was the time from clinical onset of the encephalitis to initiation of the first immunomodulatory treatment, with longer delay in patients with persistent epilepsy (7.5 ± 8.9 vs 2.4 ± 1.7 months, p = 0.006). Evolution to DRE was only driven by MRI evolution. Eight of the 15 patients (53%) who developed hippocampal atrophy (p = 0.007) also suffered from drug-resistant seizures at the last follow-up. SIGNIFICANCE: In patients with LGI1 encephalitis, rapid initiation of immunomodulatory treatment favors long-term epilepsy remission. Evolution to DRE might primarily reflect the anatomical lesion of limbic structures. Determining what modalities of immune treatment may alter these outcomes requires prospective studies with long-term follow-up.

Epilepsy related to focal neuronal lipofuscinosis: extra-frontal localization, EEG signatures and GABA involvement.

Focal neuronal lipofuscinosis (FNL) is an uncommon epileptic disorder related to an excess of lipofuscin accumulation within dysmorphic-appearing neurons (DANs), whose epileptogenic mechanisms are still poorly understood. It shares some clinical and neuroimaging similarities with focal cortical dysplasia of type IIb (FCDIIb), but it represents a different pathological entity. Here, we identified two patients with FNL among a 10-year cohort of 323 patients who underwent neurosurgery for a focal pharmacoresistant epilepsy. We describe the electroclinical, metabolic and neuropathological features of both patients with FNL who benefited from a comprehensive presurgical investigation. While the previous reports showed frontal lobe localization of the lesion, FNL was identified in the temporal lobe, in one of our patients. EEG investigations in both patients showed striking focal and rich interictal activity resembling that described in FCDIIb. Besides focal intraneuronal lipofuscin accumulation, the neuropathological analysis demonstrated that somata of DANs were surrounded by a large amount of GABAergic presynaptic buttons, suggesting the involvement of interneurons in the epileptogenicity of FNL. To further explore the role of GABAergic transmission in the generation of epileptiform activity in FNL, we performed in vitro multi-electrode array recordings on the post-surgery tissue from one patient. Spontaneous interictal-like discharges (IILDs) were identified only in the restricted area displaying the highest density of lipofuscin-containing DANs, suggesting a close correlation between the density of lipofuscin-containing neurons and epileptogenicity. Moreover, IILDs were blocked by the GABAA receptor antagonist gabazine. All together, these findings showed how GABA signaling may contribute to the generation of interictal-like activity in FNL tissue.

Kv1.1 channels inhibition in the rat motor cortex recapitulates seizures associated with anti-LGI1 encephalitis.

Autoimmune encephalitis associated with antibodies directed against the leucine-rich glioma inactivated 1 (LGI1) protein is responsible for specific tonic-dystonic motor seizures. Although dysfunctions in neuronal excitability have been associated with anti-LGI1 autoantibodies, their relation to seizures remain inconclusive. We developed a new in vivo experimental rat model to determine whether inhibition of Kv1.1 channels by dentrotoxin-K (DTX) in the primary motor cortex (M1) could recapitulate the human seizures and to elucidate their subtending cortical mechanisms. Comparing electro-clinical features of DTX-induced seizures in rats with those recorded from a cohort of anti-LGI1 encephalitis patients revealed striking similarities in their electroencephalographic (EEG) signature, frequency of recurrence and semiology. By combining multi-site extracellular and intracellular recordings of M1 pyramidal neurons in DTX rats, we demonstrated that the blockade of Kv1.1 channels induced a sequence of changes in neuronal excitability and synaptic activity, leading to massive suprathreshold membrane depolarizations underlying the paroxysmal EEG activity. Our results suggest the central role of Kv1.1 channels disruption in the emergence of anti-LGI1-associated seizures and suggest that this new rodent model could serve future investigations on ictogenesis in autoimmune encephalitis.

When should we test patients with epilepsy for autoimmune antibodies? Results from a French retrospective single center study.

BACKGROUND AND PURPOSE: Seizures represent a core symptom of autoimmune encephalitides with specific therapeutic issues. To date, patients with new-onset seizures or established epilepsy are not systematically tested for autoimmune antibodies. We aimed to identify clinical and paraclinical criterion that could help to select patients requiring additional autoimmune antibodies serum and cerebrospinal fluid (CSF) detection. METHODS: In this retrospective single center study from the French Salpêtrière Hospital, data from 286 adult patients with epilepsy who received an autoantibody assay for the first time were analyzed. All patients were evaluated at our institution between January 2007 and December 2018 for assessment of new-onset epilepsy (n = 90) or established epilepsy (n = 196). We only analyzed patients that were screened for autoimmune antibodies. Demographic, clinical and neuroimaging measures were compared between patients with and without autoimmune encephalitis using Fisher's exact test for categorical variables and Welch's t test for continuous variables. Our primary goal was to identify significant factors that differentiated patients with and without autoimmune encephalitis. RESULTS: We identified 27 patients with autoimmune epilepsy (9.4% of the patients who had been tested for autoantibodies). The significant factors differentiating patients with and without autoimmune encephalitis were: (i) the existence of a new-onset focal epilepsy + (e.g., newly diagnosed epilepsy < 6 months associated with additional symptoms, mainly cognitive or psychiatric symptoms), (ii) the presence of faciobrachial dystonic seizures very suggestive of anti- Leucine-rich glioma inactivated 1 (LGI1) encephalitis, and (iii) the presence of magnetic resonance imaging (MRI) abnormalities suggestive of encephalitis. CONCLUSION: New-onset focal seizures combined with cognitive or psychiatric symptoms support the test for autoimmune antibodies. Further clinical already known red flags for an autoimmune origin are the presence of faciobrachial dystonic seizures and MRI signal changes consistent with encephalitis. On the other hand, isolated new-onset seizures and chronic epilepsy, even with associated symptoms, seem rarely linked to autoimmune encephalitis and should not lead to systematic testing.

The LGI1 protein: molecular structure, physiological functions and disruption-related seizures.

Leucine-rich, glioma inactivated 1 (LGI1) is a secreted glycoprotein, mainly expressed in the brain, and involved in central nervous system development and physiology. Mutations of LGI1 have been linked to autosomal dominant lateral temporal lobe epilepsy (ADLTE). Recently auto-antibodies against LGI1 have been described as the basis for an autoimmune encephalitis, associated with specific motor and limbic epileptic seizures. It is the second most common cause of autoimmune encephalitis. This review presents details on the molecular structure, expression and physiological functions of LGI1, and examines how their disruption underlies human pathologies. Knock-down of LGI1 in rodents reveals that this protein is necessary for normal brain development. In mature brains, LGI1 is associated with Kv1 channels and AMPA receptors, via domain-specific interaction with membrane anchoring proteins and contributes to regulation of the expression and function of these channels. Loss of function, due to mutations or autoantibodies, of this key protein in the control of neuronal activity is a common feature in the genesis of epileptic seizures in ADLTE and anti-LGI1 autoimmune encephalitis.