Comparative Study of Paraneoplastic and Nonparaneoplastic Autoimmune Encephalitis With GABABR Antibodies.

BACKGROUND AND OBJECTIVES: While patients with paraneoplastic autoimmune encephalitis (AE) with gamma-aminobutyric-acid B receptor antibodies (GABABR-AE) have poor functional outcomes and high mortality, the prognosis of nonparaneoplastic cases has not been well studied. METHODS: Patients with GABABR-AE from the French and the Dutch Paraneoplastic Neurologic Syndromes Reference Centers databases were retrospectively included and their data collected; the neurologic outcomes of paraneoplastic and nonparaneoplastic cases were compared. Immunoglobulin G (IgG) isotyping and human leukocyte antigen (HLA) genotyping were performed in patients with available samples. RESULTS: A total of 111 patients (44/111 [40%] women) were enrolled, including 84 of 111 (76%) paraneoplastic and 18 of 111 (16%) nonparaneoplastic cases (cancer status was undetermined for 9 patients). Patients presented with seizures (88/111 [79%]), cognitive impairment (54/111 [49%]), and/or behavioral disorders (34/111 [31%]), and 54 of 111 (50%) were admitted in intensive care unit (ICU). Nonparaneoplastic patients were significantly younger (median age 54 years [range 19-88] vs 67 years [range 50-85] for paraneoplastic cases, p < 0.001) and showed a different demographic distribution. Nonparaneoplastic patients more often had CSF pleocytosis (17/17 [100%] vs 58/78 [74%], p = 0.02), were almost never associated with KTCD16-abs (1/16 [6%] vs 61/70 [87%], p < 0.001), and were more frequently treated with second-line immunotherapy (11/18 [61%] vs 18/82 [22%], p = 0.003). However, no difference of IgG subclass or HLA association was observed, although sample size was small (10 and 26 patients, respectively). After treatment, neurologic outcome was favorable (mRS ≤2) for 13 of 16 (81%) nonparaneoplastic and 37 of 84 (48%) paraneoplastic cases (p = 0.03), while 3 of 18 (17%) and 42 of 83 (51%) patients had died at last follow-up (p = 0.008), respectively. Neurologic outcome no longer differed after adjustment for confounding factors but seemed to be negatively associated with increased age and ICU admission. A better survival was associated with nonparaneoplastic cases, a younger age, and the use of immunosuppressive drugs. DISCUSSION: Nonparaneoplastic GABABR-AE involved younger patients without associated KCTD16-abs and carried better neurologic and vital prognoses than paraneoplastic GABABR-AE, which might be due to a more intensive treatment strategy. A better understanding of immunologic mechanisms underlying both forms is needed.

Resective epilepsy surgery and its impact on depression in adults: a systematic review, meta-analysis, and implications for future research.

BACKGROUND: How epilepsy surgery influences the bidirectional relationship of epilepsy and depression remains poorly defined. METHOD: For a better understanding of this question, we conducted a systematic review and meta-analysis of risk ratio on depression prevalence before and after epilepsy surgery, using Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Three databases were comprehensively screened for all studies assessing depression before and after resective surgery in adult epileptic patients until 8 October 2022. Studies were included if depression was assessed before and after epilepsy surgery regardless of the time of follow-up. A total of 1917 studies were screened for eligibility and 91 full-texts up for inclusion; 35 studies were finally included, 25 studies and 2563 patients were included in main meta-analysis and 10 for exploratory analysis. Risk of bias was assessed using Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) from Cochrane. To derive the pooled depression rates before and after surgery, a meta-analysis with inversed-variance was performed using random-effects logistic models with Peto's correction and a 95% CI. Heterogeneity was assessed with Cochran's Q-test along with its derived measure of inconsistency I2. RESULTS: Overall, the depression rates before and after resective epilepsy surgery were 0.70 (0.53 to 0.91) 95% CI, suggesting that the rate of depression at last follow-up evaluation tends to decrease after Resective Epilepsy Surgery (RES). Subgroup analysis suggest a positive long-term effect appears with a significant lower rates of depression already 6 months (0.61 (0.38 to 0.98)), after surgery which is maintained over time after 1 year (0.53 (0.31 to 0.90)), and after 2 years (0.62 (0.42 to 0.92)). CONCLUSION: This important finding should be taken in consideration before resective surgery for drug-resistant epilepsies. However, prospective studies should be conducted to characterise which patient, at the individual level, might be at risk of de novo or worsening of depression. PROSPERO REGISTRATION NUMBER: CRD42022355386.

Selective striatal fast-spiking interneuron inhibition induces cortical seizure.

Whether striatal fast-spiking interneurons are involved in cortical synchronization remains elusive. We performed acute microinjections of a selective FSI-AMPA receptor antagonist into the sensorimotor striatum of non-human primates to verify whether selective FSI inhibition within the sensorimotor striatum could potentially modify cortical excitability, thereby triggering focal seizures. Experiments were performed on three fascicularis monkeys. During each experimental session, low volumes of IEM-1460 (4-8 µL) were injected slowly at 1 µL/min. Spontaneous behavioral changes were classified according to the Racine scale modified for primates. These induced motor behaviors were correlated with electroencephalographic (EEG and EMG) measures. Power spectrum and time-frequency analysis were performed and compared between each period of interest. Pharmacological selective inhibition of striatal fast-spiking INs induced focal motor seizures. Back averaging confirmed that myoclonic activity was closely linked to cortical spikes-and-waves epileptic activity, with a significant increase in cortical EEG power in all studied frequency bands (p < .0001). Thus, striatal FSIs likely play a role in controlling cortical excitability through the cortico-striato-thalamo-cortical pathway. They may contribute to the pathophysiology of focal motor epilepsies by modulating the threshold at which focal motor seizures are triggered.

Revisiting anti-Hu paraneoplastic autoimmunity: phenotypic characterization and cancer diagnosis.

Anti-Hu are the most frequent antibodies in paraneoplastic neurological syndromes, mainly associated with an often limited stage small cell lung cancer. The clinical presentation is pleomorphic, frequently multifocal. Although the predominant phenotypes are well characterized, how different neurological syndromes associate is unclear. Likewise, no specific study assessed the performance of new-generation CT and PET scanners for cancer screening in these patients. Herein, we aimed to describe the clinical pattern and cancer screening in a retrospective cohort of 466 patients with anti-Hu autoimmunity from the French Reference Centre on Paraneoplastic Neurological Syndromes registry. Clinical presentation, cancer screening and diagnosis were analysed. Among the 466 patients, 220 (54%) had multifocal neurological involvement. A hierarchical cluster analysis grouped the patients into (i) mainly limbic encephalitis, (ii) predominantly peripheral neuropathy and (iii) broad involvement of the nervous system (mixed group). Compared with limbic encephalitis and mixed groups, patients in the neuropathy group more frequently had a chronic onset of symptoms (29 versus 13 and 17%), elevated CSF proteins (83 versus 47 and 67%) and died from cancer progression (67 versus 15 and 28%; all P < 0.05). No significant difference in overall survival was observed between groups. Dysautonomia and brainstem signs were associated with a higher risk of death from the neurological cause; cancer diagnosis was the main predictor of all-cause death, especially when diagnosed within 2 years from clinical onset (all P < 0.05). Three hundred and forty-nine (75%) patients had cancer: in 295 (84%) neurological symptoms preceded tumour diagnosis, being lung cancer in 262 (89%), thereof small cell lung cancer in 227 (87%). First CT scan revealed lung cancer in 205/241 (85%), and PET scan shortened the interval to diagnosis when the initial CT scan was negative [7 months (1-66) in 27 patients versus 14 months (2-45) in 6; P < 0.001]. Although cancer diagnosis mostly occurred within 2 years from clinical onset, 13/295 (4%) patients exceeded that threshold. Conversely, 33 patients (7%) were 'cancer-free' after 2 years of follow-up. However, 13/33 (39%) had initial suspicious imaging findings that spontaneously regressed. In conclusion, although anti-Hu autoimmunity clinical presentation is mostly multifocal, we observed patients with a predominant limbic syndrome or isolated sensory neuropathy. Early implementation of PET scan shortens the interval to cancer diagnosis, which was the strongest predictor of death, especially if diagnosed ≤2 years from clinical onset. As cancer was diagnosed >2 years after clinical onset in few patients, screening should be extended up to 5 years. In addition, tumour regression was suspected in a substantial proportion of 'cancer-free' patients.

Association of Peri-ictal MRI Abnormalities With Mortality, Antiseizure Medication Refractoriness, and Morbidity in Status Epilepticus.

BACKGROUND AND OBJECTIVES: Status epilepticus (SE) is a life-threatening emergency requiring a prompt assessment of patient prognosis to guide management. MRI allows the identification of peri-ictal MRI abnormalities (PMAs) and provides insight into brain structural modifications induced by SE. However, little is known about the significance of PMA in SE prognosis. The aim of this study was to determine whether PMAs are associated with an increased mortality in SE and to establish the association between PMA and refractoriness to antiseizure medications, complications encountered, and induced morbidity. METHODS: We conducted a retrospective observational cohort study including all eligible consecutive patients over 15 years old and hospitalized with SE at Bordeaux University Hospital (France) between January 2015 and December 2019. The primary end point was in-hospital mortality. A dedicated neuroradiologic reassessment was performed, together with a comprehensive medical review assessing baseline characteristics, in-hospital death, SE characterization, drug refractoriness, and following outcome in survivors. RESULTS: Of 307 patients included, 79 (26%) showed PMA related to SE. Demographic, functional status at baseline and median delay between SE onset and MRI examination were similar in the PMA-positive and PMA-negative groups. In-hospital death occurred in 15% (45/307) patients and was significantly higher in the PMA-positive group (27%, 21/79 vs 11%, 24/228; p < 0.001). In multivariate analysis, the presence of PMA (odds ratio [OR] 2.86, 95% CI 1.02-8.18; p = 0.045), together with SE duration (OR 1.01, 95% CI 1.01-1.02; p = 0.007), older age at SE onset (OR 1.05, 95% CI 1.01-1.09; p = 0.013), preexisting ultimately fatal comorbidity (OR 4.01, 95% CI 1.56-10.6; p = 0.004), and acute lesional SE etiology (OR 3.74, 95% CI 1.45-10.2; p = 0.007) were independent predictors associated with in-hospital death. Patients with PMA had a higher risk of refractory SE (71 vs 33%, p < 0.001). Among survivors, delayed-onset epilepsy (40% vs 21%, p = 0.009) occurred more frequently in the PMA-positive group. DISCUSSION: PMA-positive cases had a higher mortality rate in the largest cohort so far to assess the prognosis value of PMA in SE. As a noninvasive and easily available tool, PMA represents a promising structural biomarker for developing a personalized approach to prognostication in patients with SE receiving MRI.

Description of a multidisciplinary model of care in a French cohort of adult patients with tuberous sclerosis complex.

BACKGROUND: Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder. Due to the various manifestations of TSC and their potential complications, a multidisciplinary care approach is recommended by consensus guidelines. OBJECTIVES: Our study aimed to give a complete description of our TSC adult cohort and to evaluate the multidisciplinary and interdisciplinary management model. METHODS: Data on each adult patient diagnosed with TSC, including disease manifestations, interventions and outcomes, were collected at baseline and updated annually. A multidisciplinary TSC approach with all the recommended explorations was carried out annually. RESULTS: 90 patients were enrolled in Centre Hospitalier Universitaire de Bordeaux, between January 2000 and September 2018. Median age of patients at inclusion was 37 years (range, 27-47) and 20 years old at diagnosis of TSC. Regarding the occurrence of TSC manifestations, 97% of the patients had cutaneous lesions, 89% had neurological manifestations, 83% had renal manifestations and 100% had dental lesions with pits. More than half the patients had sclerotic bone lesions (68%), TSC-associated neuropsychiatric disorders (64%) and lymphangioleiomyomatosis (59%). A TSC multidisciplinary approach was developed including a global follow-up and an evaluation of TSC targeting organs, according to the recommendations. A satisfaction survey revealed global and entire satisfaction of patients with TSC. CONCLUSION: We obtained an accurate description of a cohort of adult patients with TSC. Our multidisciplinary approach model allowed us to provide optimal management of patients with TSC with a high level of patient satisfaction.

Acute Striato-Cortical Synchronization Induces Focal Motor Seizures in Primates.

OBJECTIVE: Whether the basal ganglia are involved in the cortical synchronization during focal seizures is still an open question. In the present study, we proposed to synchronize cortico-striatal activities acutely inducing striatal disinhibition, performing GABA-antagonist injections within the putamen in primates. METHOD: Experiments were performed on three fascicularis monkeys. During each experimental session, low volumes of bicuculline (0.5-4 µL) were injected at a slow rate of 1 µL/min. Spontaneous behavioral changes were classified according to Racine's scale modified for primates. These induced motor behaviors were correlated with electromyographic, electroencephalographic, and putaminal and pallidal local field potentials changes in activity. RESULTS: acute striatal desinhibition induced focal motor seizures. Seizures were closely linked to cortical epileptic activity synchronized with a striatal paroxysmal activity. These changes in striatal activity preceded the cortical epileptic activity and the induced myoclonia, and both cortical and subcortical activities were coherently synchronized during generalized seizures. INTERPRETATION: Our results strongly suggest the role of the sensorimotor striatum in the regulation and synchronization of cortical excitability. These dramatic changes in the activity of this "gating" pathway might influence seizure susceptibility by modulating the threshold for the initiation of focal motor seizures.

Confirmation and Expansion of the Phenotype Associated with the Recurrent p.Val837Met Variant in TRPM3.

Dyment et al. (2019) recently reported eight novel patients with intellectual disability and epilepsy associated with heterozygous de novo missense variants in TRPM3. We report a novel patient with the same recurrent de novo missense of TRPM3 found in seven of these eight cases, p.(Val837Met), providing an emphasis towards ocular and joints defects along with a non-mandatory epilepsy.

Dystonia and dopamine: From phenomenology to pathophysiology.

A line of evidence suggests that the pathophysiology of dystonia involves the striatum, whose activity is modulated among other neurotransmitters, by the dopaminergic system. However, the link between dystonia and dopamine appears complex and remains unclear. Here, we propose a physiological approach to investigate the clinical and experimental data supporting a role of the dopaminergic system in the pathophysiology of dystonic syndromes. Because dystonia is a disorder of motor routines, we first focus on the role of dopamine and striatum in procedural learning. Second, we consider the phenomenology of dystonia from every angle in order to search for features giving food for thought regarding the pathophysiology of the disorder. Then, for each dystonic phenotype, we review, when available, the experimental and imaging data supporting a connection with the dopaminergic system. Finally, we propose a putative model in which the different phenotypes could be explained by changes in the balance between the direct and indirect striato-pallidal pathways, a process critically controlled by the level of dopamine within the striatum. Search strategy and selection criteria References for this article were identified through searches in PubMed with the search terms « dystonia ¼, « dopamine", « striatum ¼, « basal ganglia ¼, « imaging data ¼, « animal model ¼, « procedural learning ¼, « pathophysiology ¼, and « plasticity ¼ from 1998 until 2018. Articles were also identified through searches of the authors' own files. Only selected papers published in English were reviewed. The final reference list was generated on the basis of originality and relevance to the broad scope of this review.

Cortico-striatal synchronization in human focal seizures.

Although a number of experimental and clinical studies have pointed out participation or an even more prominent role of basal ganglia in focal seizures, the mode of interaction between cortical and striatal signals remains unclear. In the present study, we took stereoelectroencephalographic (SEEG) recordings in drug-resistant epilepsy patients, to qualitatively and quantitatively analyse the ictal striatum activity as well as its synchronization with cerebral cortex. Eleven patients who underwent SEEG evaluation were prospectively included if they fulfilled two inclusion criteria: (i) at least one orthogonal intracerebral electrode contact explored the basal ganglia, in either their putaminal or caudate part; and (ii) at least two SEEG seizures were recorded. Cortical and subcortical regions of interest were defined and different periods of interest were analysed. SEEG was visually inspected and h2 non-linear correlation analysis performed to study functional connectivity between cortical region of interest and striatum. Six correlation indices were calculated. Two main patterns of striatal activation were recorded: the most frequent was characterized by an early alpha/beta activity that started within the first 5 s after seizure onset, sometimes concomitant with it. The second one was characterized by late, slower, theta/delta activity. A significant difference in h2 correlation indices was observed during the preictal and seizure onset period compared to background for global striatal index, mesio-temporal/striatal index, latero-temporal/striatal index, insular/striatal index, prefrontal/striatal index. In addition, a significant difference in h2 correlation indices was observed during the seizure termination period compared to all the other periods of interest for the six indices calculated. These results indicate that cortico-striatal synchronization can arise from the start of focal seizures. Depending on the ictal frequency pattern, desynchronization can occur later, but a late and terminal hypersynchronization progressively takes over. These changes in synchronization level between cortical and striatal activity might be part of an endogenous mechanism controlling the duration of abnormal oscillations within the striato-thalamo-cortical loop and thereby their termination. Pathophysiology of basal ganglia in focal seizures appears to be much more interlinked with the cortex than expected. Beyond the stereotypical features they could imprint to seizure semiology, their role in strengthening mechanisms underlying cessation of ictal propagation should inspire new rationales for deep brain stimulation in patients with intractable focal epilepsies.

[Non-epileptic psychogenic seizures: a renewal approach of conversion disorders]. / Crise non épileptique psychogène : le renouveau de l'abord des troubles de conversion.

Non-epileptic psychogenic seizures: a renewal approach of conversion disorders. Psychogenic non-epileptic seizures (PNES) are characterized by a paroxystic modification of behaviour or consciousness that resemble to an epileptic seizure. They are classified as dissociative or somatoform disorders. Their diagnostic remains difficult and the recording of a typical event through video-EEG is the gold standard. PNES are a symptom of the underlying disease related to disturbances in the management and regulation of emotions. Thus, the predisposing, the precipitating and the perpetuating factors must be evaluated carefully. A multidisciplinary diagnosis announcement is an essential and effective therapeutic step and treatment has to be adapted case by case.

Crise non épileptique psychogène : le renouveau de l'abord des troubles de conversion. Les crises non épileptiques psychogènes sont caractérisées par des changements brutaux de comportement ou de conscience ressemblant à des crises d'épilepsie. Elles sont classées parmi les troubles dissociatifs ou somatoformes. Leur diagnostic est difficile et passe par l'enregistrement vidéo-électroencéphalogramme d'un événement typique. Ces crises sont le symptôme d'une maladie sous-jacente liée à des perturbations de la gestion et la régulation des émotions. Ainsi, les facteurs prédisposants, précipitants et perpétuants des crises doivent être soigneusement évalués. L'annonce multidisciplinaire du diagnostic est une étape thérapeutique indispensable et efficace, et la prise en charge thérapeutique est adaptée au cas par cas.

Transcranial direct current stimulation in post-stroke aphasia rehabilitation: A systematic review.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-invasive tool that induces neuromodulation in the brain. Several studies have shown the effectiveness of tDCS in improving language recovery in post-stroke aphasia. However, this innovative technique is not currently used in routine speech and language therapy (SLT) practice. OBJECTIVE: This systematic review aimed to summarise the role of tDCS in aphasia rehabilitation. METHODS: We searched MEDLINE via PubMed and Scopus on October 5, 2018 for English articles published from 1996 to 2018. Eligible studies involved post-stroke aphasia rehabilitation with tDCS combined or not with SLT. RESULTS: We retained 5 meta-analyses and 48 studies. Among the 48 studies, 39 were randomised controlled trials (558 patients), 2 prospective studies (56 patients), and 5 case studies (5 patients). Two articles were sub-analyses of a randomised clinical trial. Methods used in these studies were heterogeneous. Only 6 studies did not find a significant effect of tDCS on language performance. As compared with earlier meta-analyses, the 2 latest found significant effects. CONCLUSION: Evidence from published peer reviewed literature is effective for post-stroke aphasia rehabilitation at the chronic stages. tDCS devices are easy to use, safe and inexpensive. They can be used in routine clinical practice by speech therapists for aphasia rehabilitation. However, further studies should investigate the effectiveness in the subacute post-stroke phase and determine the effect of the lesion for precisely identifying the targeted brain areas. We discuss crucial challenges for future studies.

Subcortical SISCOM hyperperfusion: Should we pay more attention to it?

PURPOSE: Demonstrating cerebral blood flow changes during seizures, ictal-interictal single photon emission computed tomography (SPECT) with co-registration to MRI (SISCOM) reflects brain activation and its pathways of spread. To investigate subcortical ictal hyperperfusion patterns during focal seizures, we retrospectively reviewed SISCOM analysis of patients who became seizure-free after cortical resection. Our aim was to evaluate the relationship between epileptogenic zones and subcortical hyperperfusion. METHOD: 67 patients were identified as having SISCOM evaluation and having remained seizure-free for at least one year after surgical resection. SISCOM analysis was blindly reviewed for localization of basal ganglia (BG), thalamic (TN) and cerebellar (CH) hyperperfusion based on three different thresholds. Subcortical activation and epilepsy characteristics were then compared between patients. For a given region of interest and threshold, the sensitivity, specificity and positive and negative predictive value for correct lateralization of the epilepsy side was calculated. RESULTS: Depending on the threshold used, BG hyperperfusion was found in 37.3-73.9% of patients, TN hyperperfusion in 31.3-68.1% and CH hyperperfusion in 13.5-29%. For a threshold of 1.5, the best predictive positive value for correct lateralization of the epilepsy side was obtained with BG/CH coactivation (89%). For a threshold of 2.0 and 2.5, it was obtained with BG/TN coactivation (88%) and BG activation (82%), respectively. CONCLUSION: Subcortical SISCOM hyperperfusion could offer additional clues in terms of lateralization.

Insulo-opercular cortex generates oroalimentary automatisms in temporal seizures.

OBJECTIVE: Oroalimentary automatisms (OAAs) resembling normal alimentary behavior are stereotyped complex movements that may occur during epileptic seizures. They are considered common clinical signs in temporal lobe seizures, but their anatomofunctional mechanisms are not established. We took the opportunity of presurgical intracerebral recordings to study the relations between the occurrence of OAAs and temporal/spatial features of ictal activities. METHODS: We retrospectively reviewed patients with medically intractable medial temporal lobe epilepsy who underwent stereoelectroencephalography (SEEG) at Cleveland Clinic between 2009 and 2016. Patients presenting oroalimentary automatisms during seizures, with intracerebral electrodes spanning temporal and extratemporal areas, were selected. SEEG-clinical correlations with latency measurements were done. Coherence analyses were performed on regions of interest as defined by the areas involved at the onset of oroalimentary automatisms. RESULTS: Fifteen patients (115 seizures) were analyzed. Sixty-nine seizures exhibited overt oroalimentary automatisms. Only insulo-opercular cortex ictal involvement was consistently related to the occurrence of OAAs, with a linear correlation between OAA onset and ictal oscillatory activity onset in the insulo-opercular cortex. SEEG signal processing showed an increase in theta coherence preceding oroalimentary automatism onset between mediobasal-temporal structures and insulo-opercular cortex, as well as between the 2 insulo-opercular regions. SIGNIFICANCE: The underlying mechanism for the production of oroalimentary automatisms in medial temporal seizures is based on temporal-insulo-opercular theta coherence leading to a synchronous state generating rhythmic patterned outputs from the cortical masticatory area.