Cerebral folate deficiency: a treatable cause of late deterioration in epilepsy with developmental delay.

A 25-year-old woman with childhood-onset refractory epilepsy and developmental delay experienced a gradually progressive marked deterioration in mobility and seizure control, with language regression. Investigation identified a homozygous deletion within the contactin-associated protein-like 2 gene (CNTNAP2), underlying her early presentation, but also cerebral folate deficiency that most likely contributed to her later deterioration. Following antiseizure medication adjustment and treatment with folinic acid, she stabilised with improved seizure control and limited improvement in language and motor function; she has remained neurologically stable for more than a decade. That the previously observed neurological decline was halted by folinic acid replacement supports this being due to cerebral folate deficiency. Metabolic conditions are less well recognised in adults and can be under-diagnosed. They are potentially treatable and should be considered even in the presence of another cause, particularly when the presentation is not fully compatible.

Therapeutic options for nocturnal problems in Parkinson's disease and atypical parkinsonian disorders.

Sleep disturbances in Parkinson's disease and parkinsonism (such as atypical parkinsonian disorders like multiple system atrophy, progressive supranuclear palsy, dementia with Lewy bodies and corticobasal degeneration) are multifactorial and as such treatment needs to be tailored to the specific patient case and sleep dysfunction. One also has to consider drug-related effects on sleep architecture. This article provides an overview of the therapeutic options for nocturnal problems in Parkinson`s disease and atypical parkinsonian disorders.

The complexities underlying epilepsy in people with glioblastoma.

Seizures are among the most common clinical signs in people with glioblastoma. Advances over the past 5 years, including new clinical trial data, have increased the understanding of why some individuals with glioblastoma are susceptible to seizures, how seizures manifest clinically, and what implications seizures have for patient management. The pathophysiology of epilepsy in people with glioblastoma relates to a combination of intrinsic epileptogenicity of tumour tissue, alterations in the tumour and peritumoural microenvironment, and the physical and functional disturbance of adjacent brain structures. Successful management of epilepsy in people with glioblastoma remains challenging; factors such as drug-drug interactions between cancer therapies and antiseizure medications, and medication side-effects, can affect seizure outcomes and quality of life. Advances in novel therapies provide some promise for people with glioblastoma; however, the effects of these therapies on seizures are yet to be fully determined. Looking forward, insights into electrical activity as a driver of tumour cell growth and the intrinsic hyperexcitability of tumour tissue might represent useful targets for treatment and disease modification. There is a pressing need for large randomised clinical trials in this field.

Prone position plexopathy: an avoidable complication of prone positioning for COVID-19 pneumonitis?

Prone positioning is a mainstay of management for those presenting to the intensive care unit with moderate-to-severe acute respiratory distress syndrome due to COVID-19. While this is a necessary and life-saving intervention in selected patients, careful positioning and meticulous care are required to prevent compression and traction of the brachial plexus, and resultant brachial plexopathy. We describe two patients who developed a brachial plexus injury while undergoing prone positioning for management of COVID-19 pneumonitis. Both patients were diabetic and underwent prolonged periods in the prone position during which the plexopathy affected arm was abducted for 19 and 55 hours, respectively. We discuss strategies to reduce the risk of this rare but potentially disabling complication of prone positioning.

Intracranial monitoring contributes to seizure freedom for temporal lobectomy patients with nonconcordant preoperative data.

OBJECTIVE: The question of whether a patient with presumed temporal lobe seizures should proceed directly to temporal lobectomy surgery versus undergo intracranial monitoring arises commonly. We evaluate the effect of intracranial monitoring on seizure outcome in a retrospective cohort of consecutive subjects who specifically underwent an anterior temporal lobectomy (ATL) for refractory temporal lobe epilepsy (TLE). METHODS: We performed a retrospective analysis of 85 patients with focal refractory TLE who underwent ATL following: (a) intracranial monitoring via craniotomy and subdural/depth electrodes (SDE/DE), (b) intracranial monitoring via stereotactic electroencephalography (sEEG), or (c) no intracranial monitoring (direct ATL-dATL). For each subject, the presurgical primary hypothesis for epileptogenic zone localization was characterized as unilateral TLE, unilateral TLE plus (TLE+), or TLE with bilateral/poor lateralization. RESULTS: At one-year and most recent follow-up, Engel Class I and combined I/II outcomes did not differ significantly between the groups. Outcomes were better in the dATL group compared to the intracranial monitoring groups for lesional cases but were similar in nonlesional cases. Those requiring intracranial monitoring for a hypothesis of TLE+had similar outcomes with either intracranial monitoring approach. sEEG was the only approach used in patients with bilateral or poorly lateralized TLE, resulting in 77.8% of patients seizure-free at last follow-up. Importantly, for 85% of patients undergoing SEEG, recommendation for ATL resulted from modifying the primary hypothesis based on iEEG data. SIGNIFICANCE: Our study highlights the value of intracranial monitoring in equalizing seizure outcomes in difficult-to-treat TLE patients undergoing ATL.

Non-convulsive status epilepticus: COVID-19 or clozapine induced?

We present a case of non-convulsive status epilepticus in a 57-year-old woman with a schizoaffective disorder, without an antecedent seizure history, with two possible aetiologies including SARS-CoV-2 infection and clozapine uptitration. We discuss the presentation, investigations, differential diagnosis and management. In particular, we focus on the electroencephalogram (EEG) findings seen in this case and the electroclinical response to antiepileptic medication. We review the literature and discuss the relevance of this case to the SARS-CoV-2 global pandemic. We emphasise the importance of considering possible neurological manifestations of SARS-CoV-2 infection and highlight seizure disorder as one of the possible presentations. In addition, we discuss the possible effects of clozapine on the electroclinical presentation by way of possible seizure induction as well as discuss the possible EEG changes and we highlight that this needs to be kept in mind especially during rapid titration.

Language dysfunction-associated EEG findings in patients with CAR-T related neurotoxicity.

Chimeric antigen receptor-modified T cells (CAR-T) have emerged as a promising immunotherapeutic approach in relapsed/refractory haematolgical malignancies. Broader application is limited by unique toxicities, notably, neurotoxicity (NTX). Language dysfunction is among the most frequent symptoms of NTX, the underlying mechanisms of which remain to be elucidated. Electroencephalogram (EEG) is an important tool to monitor for NTX and may provide insights into language dysfunction. AIM: We aimed to characterise language dysfunction and define electroencephalographic signatures after CAR-T cell therapy. METHODS: We reviewed the clinical presentation and EEG findings of 20 adult patients presenting with language dysfunction after CAR-T cell infusion. The cohort included a subset of patients treated with investigational CD19-directed CAR-T cells for non-Hodgkin's lymphoma (n=17), acute lymphoblastic leukaemia (n=1), follicular lymphoma (n=1) and chronic lymphocytic leukaemia (n=1). RESULTS: Language dysfunction presented within 14 days of CAR-T cell infusion in 16 (84%) patients. Ten (50%) patients had mild word-finding difficulties and 10 (50%) had marked dysphasia with profound word-finding difficulties; the latter were all associated with generalised rhythmic delta activity or generalised periodic discharges on EEG. CONCLUSIONS: Language dysfunction after CAR-T cell therapy is associated with generalised EEG abnormalities.

Comparison of rates of safety issues and reporting of trial outcomes for medical devices approved in the European Union and United States: cohort study.

OBJECTIVE:  To evaluate safety alerts and recalls, publication of key trial outcomes, and subsequent US approval of high profile medical devices introduced in the European Union. DESIGN:  Cohort study. SETTING:  Novel cardiovascular, orthopedic, and neurologic devices approved in the EU through Conformité Européenne marking between 2005 and 2010. DATA SOURCES:  Public and commercial databases searched up to January 2016 for press releases and announcements of approvals; public Food and Drug Administration and European regulatory authority databases for US approvals and safety alerts and recalls; and Medline, Embase, and Web of Science for peer reviewed publications. MAIN OUTCOME MEASURES:  We categorized the novelty of the devices in the study sample as a "major innovation" or an "other change," and extracted descriptive data about the devices and information on any safety alerts and withdrawals. Linear regression models examined factors associated with differential EU and US approvals. Cox proportional hazards regression models were used to evaluate factors associated with safety alerts and recalls and the publication of trial outcomes for devices categorized as major innovations. Models controlled for time, therapeutic category, regulatory pathway, size of sponsoring company, and indicator variables for devices approved first in the EU and devices approved only in the EU. RESULTS:  67% (206/309) of devices identified were approved in both the US and the EU, of which 63% (129/206) were approved first in the EU. The unadjusted rate of safety alerts and recalls for devices approved first in the EU was 27% (62/232) compared with 14% (11/77) for devices approved first in the US. The adjusted hazard ratio for safety alerts and recalls was 2.9 (95% confidence interval 1.4 to 6.2) for devices approved first in the EU. The results of pivotal trials were published for 49% (37/75) of devices categorized as major innovations, with an overall publication rate of 37% five years after approval. CONCLUSIONS:  Devices approved first in the EU are associated with an increased risk of post-marketing safety alerts and recalls. Poor trial publication rates mean that patients and clinicians need greater regulatory transparency to make informed decisions about treatment.

Untimed Design Fluency in Aging and Alzheimer's Disease: Psychometrics and Normative Data.

Design fluency tests, commonly used in both clinical and research contexts to evaluate nonverbal concept generation, have the potential to offer useful information in the differentiation of healthy versus pathological aging. Although normative data for older adults (OAs) are available for multiple timed versions of this test, similar data have been unavailable for a previously published untimed test, the Graphic Pattern Generation Test (GPG). Time constraints common to almost all of the available design fluency tests may cloud interpretation of higher-level executive abilities-for example, in individuals with slow processing speed. The current study examined the psychometric properties of the GPG and presents normative data in a sample of 167 healthy OAs and 110 individuals diagnosed with Alzheimer's disease (AD). Results suggest that a brief version of the GPG can be administered reliably and that this short form has high test-retest and interrater reliability. Number of perseverations was higher in individuals with AD as compared with OAs. A cutoff score of 4 or more perseverations showed a moderate degree of sensitivity (76%) and specificity (37%) in distinguishing individuals with AD and OAs. Finally, perseverations were associated with nonmemory indexes, thereby underscoring the nonverbal nature of this error in OAs and individuals with AD.

Plasma ß-amyloid and cognitive decline.

OBJECTIVES: To determine if plasma ß-amyloid (Aß) levels (1) can be linked to specific cognitive changes that constitute conversion to Alzheimer disease (AD) and (2) correspond to cognitive change independent of dementia. DESIGN: Longitudinal study including 3 visits during approximately 4¹/2 years (2000-2006). SETTING: Northern Manhattan community. PARTICIPANTS: Eight hundred eighty individuals from a population-based and ethnically diverse sample who had 2 plasma Aß measurements and were dementia free at the time of the first Aß sample; 481 remained cognitively healthy, 329 were cognitively or functionally impaired but not demented at any point, and 70 developed AD. MAIN OUTCOME MEASURES: General estimating equations tested the association between plasma Aß (baseline and change in values) and cognitive change (composite score and memory, language, and visuospatial indices). RESULTS: High baseline plasma Aß42 (P = .01) and Aß40 (P = .01) and decreasing/relatively stable Aß42 (P = .01) values were associated with faster decline in multiple cognitive domains. In those who remained cognitively healthy, high baseline plasma Aß42 (P = .01) and decreasing/relatively stable plasma Aß42 (P = .01) was associated with faster cognitive decline, primarily in memory. CONCLUSIONS: The association between plasma Aß and multiple aspects of cognition more clearly specifies the previously documented downward trajectory of plasma Aß with AD onset. The predominant association with memory seen only in healthy elderly individuals also suggests that plasma Aß is linked with even earlier neurologic changes that may or may not culminate in dementia.