Cardiac Investigations in Sudden Unexpected Death in DEPDC5-Related Epilepsy.

OBJECTIVE: Germline loss-of-function mutations in DEPDC5, and in its binding partners (NPRL2/3) of the mammalian target of rapamycin (mTOR) repressor GATOR1 complex, cause focal epilepsies and increase the risk of sudden unexpected death in epilepsy (SUDEP). Here, we asked whether DEPDC5 haploinsufficiency predisposes to primary cardiac defects that could contribute to SUDEP and therefore impact the clinical management of patients at high risk of SUDEP. METHODS: Clinical cardiac investigations were performed in 16 patients with pathogenic variants in DEPDC5, NPRL2, or NPRL3. Two novel Depdc5 mouse strains, a human HA-tagged Depdc5 strain and a Depdc5 heterozygous knockout with a neuron-specific deletion of the second allele (Depdc5c/- ), were generated to investigate the role of Depdc5 in SUDEP and cardiac activity during seizures. RESULTS: Holter, echocardiographic, and electrocardiographic (ECG) examinations provided no evidence for altered clinical cardiac function in the patient cohort, of whom 3 DEPDC5 patients succumbed to SUDEP and 6 had a family history of SUDEP. There was no cardiac injury at autopsy in a postmortem DEPDC5 SUDEP case. The HA-tagged Depdc5 mouse revealed expression of Depdc5 in the brain, heart, and lungs. Simultaneous electroencephalographic-ECG records on Depdc5c/- mice showed that spontaneous epileptic seizures resulting in a SUDEP-like event are not preceded by cardiac arrhythmia. INTERPRETATION: Mouse and human data show neither structural nor functional cardiac damage that might underlie a primary contribution to SUDEP in the spectrum of DEPDC5-related epilepsies. ANN NEUROL 2022;91:101-116.

Intensification of Diurnal Abnormal Movements During Sleep in Huntington's Disease.

Huntington's disease (HD) is a rare neurodegenerative disorder with a distinct phenotype, including involuntary movements, cognitive decline, and behavioral disturbances. Sleep disorder include insomnia, increased sleep onset latency, decrease in total sleep time with frequent nocturnal awakenings and excessive daytime sleepiness. Increased sleep motor activities and abnormal nocturnal agitation have been increasingly recognized as an important component affecting negatively the sleep quality. Here, we report a case of an intensification of diurnal choreic movement during the night, notably during REM-sleep in a patient with manifest HD. This case highlights the diversity of nocturnal sleep motor disorders encountered in HD.

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.

Frequent SLC35A2 brain mosaicism in mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE).

Focal malformations of cortical development (MCD) are linked to somatic brain mutations occurring during neurodevelopment. Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is a newly recognized clinico-pathological entity associated with pediatric drug-resistant focal epilepsy, and amenable to neurosurgical treatment. MOGHE is histopathologically characterized by clusters of increased oligodendroglial cell densities, patchy zones of hypomyelination, and heterotopic neurons in the white matter. The molecular etiology of MOGHE remained unknown so far. We hypothesized a contribution of mosaic brain variants and performed deep targeted gene sequencing on 20 surgical MOGHE brain samples from a single-center cohort of pediatric patients. We identified somatic pathogenic SLC35A2 variants in 9/20 (45%) patients with mosaic rates ranging from 7 to 52%. SLC35A2 encodes a UDP-galactose transporter, previously implicated in other malformations of cortical development (MCD) and a rare type of congenital disorder of glycosylation. To further clarify the histological features of SLC35A2-brain tissues, we then collected 17 samples with pathogenic SLC35A2 variants from a multicenter cohort of MCD cases. Histopathological reassessment including anti-Olig2 staining confirmed a MOGHE diagnosis in all cases. Analysis by droplet digital PCR of pools of microdissected cells from one MOGHE tissue revealed a variant enrichment in clustered oligodendroglial cells and heterotopic neurons. Through an international consortium, we assembled an unprecedented series of 26 SLC35A2-MOGHE cases providing evidence that mosaic SLC35A2 variants, likely occurred in a neuroglial progenitor cell during brain development, are a genetic marker for MOGHE.

Papilledema and Peripheral Neuropathies.

INTRODUCTION: Papilledema is a common sign in ophthalmology and is typically associated with increased intracranial pressure (ICP) in neurological diseases. Since the beginning of the 20th century, some cases of papilledema have been reported in association with acute or chronic inflammatory neuropathies. CASE REPORT: We describe a 42-year-old man with acute-onset inflammatory polyradiculoneuropathy and bilateral papilledema. CONCLUSIONS: Based on a personal case report and from an extensive review of the medical literature, we identify 2 distinct patterns. First, radiculoneuropathy may be a consequence of intracranial pressure (peripheral nerve involvement corresponding to a "false localizing sign"). Second, papilledema may occur after the onset of inflammatory neuropathy. For such cases, the pathophysiological mechanism remains unknown (eg, reactional inflammatory processes or actions of unknown autoantibodies) and requires further elucidation.

Weston-Hurst syndrome with acute hemorrhagic cerebellitis.

Weston-Hurst syndrome is an exceptional variant of ADEM characterized by brain hemorrhages. Lesions are usually supratentorial and death is a usual outcome. We report a cerebellar Weston-Hurst syndrome early treated by craniectomy, steroids and plasma exchange. This is the first case of infratentorial Weston-Hurst syndrome associated with a favorable outcome.