Progressive myoclonus epilepsies due to SEMA6B mutations. New variants and appraisal of published phenotypes

Variants of SEMA6B have been identified in an increasing number of patients, often presenting with progressive myoclonus epilepsy (PME), and to lesser extent developmental encephalopathy, with or without epilepsy. The exon 17 is mainly involved, with truncating mutations causing the production of aberrant proteins with toxic gain of function. Herein, we describe three adjunctive patients carrying de novo truncating SEMA6B variants in this exon (c.1976delC and c.2086C > T novel; c.1978delC previously reported). These subjects presented with PME preceded by developmental delay, motor and cognitive impairment, worsening myoclonus, and epilepsy with polymorphic features, including focal to bilateral seizures in two, and non-convulsive status epilepticus in one. The evidence of developmental delay in these cases suggests their inclusion in the “PME plus developmental delay” nosological group. This work further expands our knowledge of SEMA6B variants causing PMEs. However, the data to date available confirms that phenotypic features do not correlate with the type or location of variants, aspects that need to be further clarified by future studie

factors underlying the development of chronic temporal lobe epilepsy in autoimmune encephalitis

Abstract Purpose Limbic encephalitis (LE) is an autoimmune condition characterized by amnestic syndrome, psychiatric features and seizures. Early diagnosis and prompt treatment are crucial to avoid long-term sequelae, including psycho-cognitive deficits and persisting seizures. The aim of our study was to analyze the characteristics of 33 LE patients in order to identify possible prognostic factors associated with the development of chronic epilepsy. Methods This is a retrospective cohort study including adult patients diagnosed with LE in the period 2010–2017 and followed up for ≥12 months. Demographics, seizure semiology, EEG pattern, MRI features, CSF/serum findings were reviewed. Results All 33 LE patients (19 M/14F, mean age 61.2 years) presented seizures. Thirty subjects had memory deficits; 22 presented behavioural/mood disorders. Serum and/or CSF auto-antibodies were detected in 12 patients. In 31 subjects brain MRI at onset showed typical alterations involving temporal lobes. All patients received immunotherapy. At follow-up, 13/33 had developed chronic epilepsy; predisposing factors included delay in diagnosis (p = .009), low seizure frequency at onset (p = .02), absence of amnestic syndrome (p = .02) and absence/rarity of inter-ictal epileptic discharges on EEG (p = .06). Conclusions LE with paucisymptomatic electro-clinical presentation seemed to be associated to chronic epilepsy more than LE presenting with definite and severe "limbic syndrome"

Brivaracetam as Early Add-On Treatment in Patients with Focal Seizures: A Retrospective, Multicenter, Real-World Study

Introduction In randomized controlled trials, add-on brivaracetam (BRV) reduced seizure frequency in patients with drug-resistant focal epilepsy. Most real-world research on BRV has focused on refractory epilepsy. The aim of this analysis was to assess the 12-month effectiveness and tolerability of adjunctive BRV when used as early or late adjunctive treatment in patients included in the BRIVAracetam add-on First Italian netwoRk Study (BRIVAFIRST). Methods BRIVAFIRST was a 12-month retrospective, multicenter study including adult patients prescribed adjunctive BRV. Effectiveness outcomes included the rates of sustained seizure response, sustained seizure freedom, and treatment discontinuation. Safety and tolerability outcomes included the rate of treatment discontinuation due to adverse events (AEs) and the incidence of AEs. Data were compared for patients treated with add-on BRV after 1-2 (early add-on) and >= 3 (late add-on) prior antiseizure medications. Results A total of 1029 patients with focal epilepsy were included in the study, of whom 176 (17.1%) received BRV as early add-on treatment. The median daily dose of BRV at 12 months was 125 (100-200) mg in the early add-on group and 200 (100-200) in the late add-on group (p < 0.001). Sustained seizure response was reached by 97/161 (60.3%) of patients in the early add-on group and 286/833 (34.3%) of patients in the late add-on group (p < 0.001). Sustained seizure freedom was achieved by 51/161 (31.7%) of patients in the early add-on group and 91/833 (10.9%) of patients in the late add-on group (p < 0.001). During the 1-year study period, 29 (16.5%) patients in the early add-on group and 241 (28.3%) in the late add-on group discontinued BRV (p = 0.001). Adverse events were reported by 38.7% and 28.5% (p = 0.017) of patients who received BRV as early and late add-on treatment, respectively. Conclusion Brivaracetam was effective and well tolerated both as first add-on and late adjunctive treatment in patients with focal epilepsy

Neuropsychiatric features and genetic aspects in 22q11.2 deletion syndrome

Introduction. 22q11.2 Deletion Syndrome (22q11.2DS; MIM #192430, MIM #188400) is the most common recurrent microdeletion in humans. The phenotypic spectrum of this syndrome encompasses a heterogeneous range of manifestations. The psychiatric and neurocognitive features have received an increasing attention over the last years and 22q11.2DS is considered as the genetic model of schizophrenia. However, the neurological manifestations are far from being fully clarified. Based on these considerations, in our study we selected an adult population of patients with an established molecular diagnosis of 22q11.2DS and we described the neuropsychiatric features focusing on the neurological manifestations and investigating their possible correlation with general clinical features and genomic size deletion. Methods. All subjects were evaluated by a multidisciplinary team. The neuropsychiatric features were investigated by means of clinical, neurophysiological evaluation (video-EEG) and neuroimaging (Brain MRI). All clinical data regarding patient's neuropsychiatric history and general medical comorbidities were collected and integrated with instrumental data. As regards the genomics, for each patient with an a-CGH test, we evaluated the deletion length and gene content. For selected cases also CNVs outside the 22q deleted region were considered Results. We enrolled 85 adult patients with a confirmed genetic diagnosis of 22q11.2DS. The molecular diagnosis was made by using FISH approach in 46 cases and a-CGH in 39 patients. Twenty-seven patients had a LCR22 A-D deletion. Further potential pathogenic CNVs were analyzed in 26/39 patients and only in six cases additional CNVs were detected. About 88% of patients has a de novo deletion. The 22q11.2 deletion results from variable-sized deleted regions, ranging from small deletions to a typically deleted region of ~3 Mb. Twenty-four patients were left-handed. Twenty-eight subjects had a low IQ, and 30 of 85 subjects had psychotic disorders. Twenty-two patients reported at least one seizure in their lifetime, and twelve were diagnosed with epilepsy. Video-EEG recordings revealed generalized epileptiform abnormalities in 34 of 85 cases. Besides, only one patient with epilepsy had a cardiac malformation. Lastly, 34 subjects presented with parkinsonism 19 of whom were taking neuroleptics. None of the 15 patients with parkinsonism, not related to neuroleptic therapy, was diagnosed with epilepsy. 52 patients performed a brain MRI that disclosed, in most of cases, a white matter gliosis not associated with specific pathologic entity. Conclusions. 22q11.2DS is characterized by left-handedness and neuropsychiatric features such as cognitive impairment, schizophrenia, epilepsy and parkinsonism. Generalized genetic epilepsy, mostly the juvenile myoclonic epilepsy phenotype, is the predominant epilepsy type. The significant association between 22q11.2DS and parkinsonian features confirms patients’ genetic susceptibility to parkinsonism. Despite the lack of conclusive evidence, our study suggests a possible relationship between the analyzed clinical variables: (1) an inverse correlation between low IQ/psychosis/epilepsy and major cardiac diseases; (2) a direct association between psychosis and both mental delay and epilepsy; and (3) an inverse correlation between parkinsonism and epilepsy. Referring the correlation to cytogenetic analysis, neuropsychiatric aspects appear to be part of the phenotype associated with the “typical” (LCR22-A to LCR22-D) deletion or “minimal critical” (LCR22-A to LCR22-B) deletion. This suggests that the relevant genes for neuropsychiatric manifestations could be located within the “minimal critical” region. Among the patients that performed a-CGH, six had a rare CNVs outside 22q11.2 deletion region. In all cases, patients carried the “typical” 22q11.2 deletion

Faciobrachial dystonic seizures: the borderland between epilepsy and movement disorders

Not available (for this type of publication

Ictal pain in focal non-convulsive status epilepticus

We report an adult with acute unilateral pain as isolated manifestation of acute symptomatic focal non-convulsive status epilepticus. Pain is rarely a manifestation of epileptic seizures. Traditionally, painful seizures have been thought to originate in either the parietal or temporal lobes, but their localising value is debatable. Recent functional neuroimaging studies and electrophysiological findings obtained by using intracerebral recordings have shown the involvement of the insular cortex along with several other brain structures in the processing of painful inputs, comprising a more widespread anatomo-functional network. Despite their rarity as a distinct clinical entity, especially in adults, painful somatosensory seizures can be disabling and misdiagnosis or delayed diagnosis is common; it is therefore essential to consider epilepsy as a possible cause of paroxysmal pain to ensure proper assessment and appropriate treatment

Ambroxol-Induced Focal Epileptic Seizure

It is well known that in epileptic patients some compounds and different drugs used for the treatment of comorbidities can facilitate or provoke seizures, this evidence regarding a wide spectrum of pharmacological categories. The potential facilitating factors usually include direct toxic effects or pharmacological interactions of either active ingredients or excipients. We report the case of a patient with drug-resistant epilepsy who experienced focal epileptic seizures, easily and constantly reproducible, after each administration of a cough syrup. This is, to our knowledge, the first electroencephalogram-documented case of focal epileptic seizures induced by cough syrup containing ambroxol as active ingredient

Ictal epileptic headache revealing non convulsive status epilepticus in a case of eyelid myoclonia with absences

Epileptic seizures and headache attacks are two common neurologic phenomena characterized by paroxysmal alteration of brain functions followed by complete restauration of the baseline condition. Headache and epilepsy are related in numerous ways, and they often co-occur. Although the link between these two diseases is not completely clear, several clinical, physiopathological and therapeutic features overlap. Headache is reported in association with epileptic seizures as a pre-ictal, ictal or post-ictal phenomenon. We present the case of a 40 year-old woman affected by eyelid myoclonia with absences (EMA) with a history of prolonged headache attacks. A video-EEG recording performed during one of these episodes showed subcontinuous epileptic activity consisting of generalized spike-and-wave discharges (GSWDs), clinically associated with tensive headache. Our work represents one of the few well EEG-documented cases of ictal epileptic headache in idiopathic generalized epilepsy (IGE)

Epilepsy, unawareness of seizures and driving license: The potential role of 24-hour ambulatory EEG in defining seizure freedom

Introduction: Seizures represent a potential source of accidents/death. Permission to drive may, therefore, be granted in a seizure-free period. Laws and regulations regarding this issue vary widely, and the onus of reporting seizures ultimately rests on the individual. Unfortunately, as some patients are unaware of their seizures, their reports may be unreliable. Methods: In this retrospective study, we selected, from a group of 1100 consecutive patients, 57 cases (26 males/31 females; mean age: 42.5. years) in whom the AEEG documented ictal events (UIEs) not reported in a self-kept diary. By means of a simple questionnaire, we interviewed all these patients to collect information on driving licenses. We, thus, assessed how many of these patients (both drug resistant and seizure free) drove regularly. Results: Our study shows a relatively large number of patients with epilepsy and UIEs. Fifteen patients suffered from idiopathic generalized epilepsy (IGE) while 42 had partial epilepsy (PE). The patients were seizure free in 21 cases and 36 had drug-resistant seizures. Many patients in both these subgroups had a driving license and drove normally (active driving in 12/36 drug-resistant patients and in 18/21 seizure-free patients). Worthy of note is the finding that an "apparently" seizure-free group of patients drove regularly. Conclusions: This study revealed a large number of patients (both drug resistant and seizure free) with AEEG-documented UIEs. This finding highlights the usefulness of AEEG in clinical practice as a means of more accurately ascertaining seizure freedom and supporting decisions involving the renewal or granting of a driving license. © 2012 Elsevier Inc