Is adjunctive Cannabidiol effective in controlling seizures for adult patients with Lennox-Gastaut Syndrome? - A single centre long term follow up study.

Epileptic encephalopathies are a disabling and life-limiting cause of childhood-onset epilepsy. Lennox Gastaut syndrome (LGS) is a characteristic example. In spite of the development of multiple medical and surgical therapies, many patients with these conditions remain treatment refractory Cannabidiol was licenced by The National Institute for Health and Care Excellence (NICE) in December 2019 for the adjunctive treatment of seizures associated with Lennox Gastaut syndrome [TA 615]. As the largest complex epilepsy centre in the Midlands, we describe our findings from a single centre retrospective study in 50 adults (aged 16 and over) with LGS- associated epilepsy. Our outcome measure was the efficacy of Cannabidiol on seizures of differing types over a 6-24-month period. Patients were treated with adjunctive Cannabidiol (with Clobazam, as per NICE recommendations). Each patient's usual anti-seizure medications (ASMs) were continued. Patients with a Vagal Nerve Stimulator (VNS) in situ remained on this treatment. Gradual titration of Cannabidiol from 1 mg/kg/day up to 10 mg/ kg/ day reduced the frequency of both focal and generalised seizures with ≥ 50 % seizure reduction in 76 % of the cohort. No patients became seizure free. Cannabidiol was well tolerated; 94 % of the cohort remained on the drug at last follow up.

Biallelic variants in ZNF142 lead to a syndromic neurodevelopmental disorder.

Biallelic variants of the gene encoding for the zinc-finger protein 142 (ZNF142) have recently been associated with intellectual disability (ID), speech impairment, seizures, and movement disorders in nine individuals from five families. In this study, we obtained phenotype and genotype information of 26 further individuals from 16 families. Among the 27 different ZNF142 variants identified in the total of 35 individuals only four were missense. Missense variants may give a milder phenotype by changing the local structure of ZF motifs as suggested by protein modeling; but this correlation should be validated in larger cohorts and pathogenicity of the missense variants should be investigated with functional studies. Clinical features of the 35 individuals suggest that biallelic ZNF142 variants lead to a syndromic neurodevelopmental disorder with mild to moderate ID, varying degrees of delay in language and gross motor development, early onset seizures, hypotonia, behavioral features, movement disorders, and facial dysmorphism. The differences in symptom frequencies observed in the unpublished individuals compared to those of published, and recognition of previously underemphasized facial features are likely to be due to the small sizes of the previous cohorts, which underlines the importance of larger cohorts for the phenotype descriptions of rare genetic disorders.

Nonepileptic attacks in patients with brain tumor-related epilepsy.

Epileptic seizures are well recognized as a presenting symptom in patients with brain tumors, however much less is known about coexisting nonepileptic attack disorder (NEAD) in this population. Establishing a diagnosis of NEAD can be challenging, especially in those with concomitant epilepsy. Nonepileptic attack disorder is associated with a high rate of morbidity, often due to coexisting psychological factors which may require the input of multiple services. In an era where early aggressive management of tumors is enabling patients to live longer, the associated psychological impact of adjusting to physical disease is increasingly apparent. In this case series, we present a narrative summary of 9 patients referred to neurology with brain tumor-related epilepsy (BTRE) over a five-year period (2015-2020) who also experienced NEAD. We describe their tumor characteristics, treatment course, and factors potentially contributing to their presentation. We conducted a case note review of patients presenting to the epilepsy service with BTRE, in whom NEAD was diagnosed based on clinical features and correlation with their EEG. Patients ranged in age from 26 to 63 years. Two patients were diagnosed with grade 1, three with grade 2 and four with grade 3 tumors. Tumors localized to frontal or temporal regions in seven cases. All patients presented initially with BTRE and developed nonepileptic seizures subsequently. Four patients developed NEAD within 1 month of their tumor diagnosis. One patient developed NEAD 79 months following diagnosis. The diagnosis of NEAD was established in 8 patients by direct visualization of attacks (two during concomitant EEG recording). In the remaining patient, diagnosis was based on history (patient and witness). Six patients were diagnosed with concomitant low mood and/ or anxiety and three were commenced on antidepressant medication. At the time of last review, the predominant attacks were nonepileptic in all but one patient.

A case series of lacosamide as adjunctive therapy in refractory sleep-related hypermotor epilepsy (previously nocturnal frontal lobe epilepsy).

The aim of this study was to evaluate the efficacy and tolerability of open-label lacosamide in patients with refractory sleep-related hypermotor epilepsy. The study was a case review of eight patients with refractory sleep-related hypermotor epilepsy treated with lacosamide. Seizure diaries compared the mean baseline seizure frequency with the most recent 3 months of follow-up. Five (62.5%) patients were responders, defined as ≥50% reduction in seizure frequency, over a mean duration of exposure of 21.5 months. The mean maintenance dose of lacosamide was 400 mg/day. No-one reported worsening of seizures. Lacosamide was well tolerated with initial fatigue being the main side-effect. Lacosamide is a potentially efficacious adjunctive therapy in patients with refractory sleep-related hypermotor epilepsy. A double-blind placebo-controlled study would determine its efficacy.

A practical guide to the use of anti-epileptic drugs by neurosurgeons.

Initiation of anti-epileptic drugs is increasingly relevant to daily neurosurgical practice. Intracranial pathologies ranging from brain tumours to subarachnoid haemorrhage and traumatic brain injury are commonly associated with the subsequent development of seizures. The scope and range of anti-epileptic drugs available has increased dramatically in recent years and understanding the evidence base behind this class of drugs in addition to their interaction/side effect profiles is essential. In this review we aim to generate a practical guide for neurosurgeons regarding the use of different anti-epileptic medications in common neurosurgical conditions, including considerations for their use in pregnancy.

Cognitive impairment in adults with epilepsy: The relationship between subjective and objective assessments of cognition.

AIM: This study aimed to assess the relationship between objective measures of cognition and subjective perception of cognitive functioning reported by patients with epilepsy and their caregivers. METHODS: One hundred patients with epilepsy attending hospital neurology outpatient clinics and their caregivers were enrolled in this study. The EpiTrack (version 1) brief cognitive screening tool was used to measure objective impairment, the ABNAS questionnaire (A-B Neuropsychological Assessment Schedule) to assess subjective cognitive performance, and a version of the ABNAS designed to be completed by caregivers (C-ABNAS) to document caregivers' views. Patient anxiety and depression were measured using the Hospital Anxiety and Depression Scale (HADS) and considered as covariates. Patients with an uncertain diagnosis of epilepsy or likely severe comorbid mood or anxiety disorders were excluded. RESULTS: Data from 82 patients were analyzed after exclusion of patients with uncertain diagnoses or likely severe comorbid mood or anxiety disorders. Fifty-nine (72%) had a degree of objective cognitive impairment. Fifty (84.7%) of these 59 patients had 'high' ABNAS scores concordant with the objective assessment, and 43 (72.9%) had high C-ABNAS scores matching the abnormalities detected by objective screening. Of the 23 (28%) patients without objective cognitive impairment, seven (30.4%) had concordantly low ABNAS scores, and 10 (43.4%) had concordantly low C-ABNAS scores. Patient memory impairment was more often reported by patients themselves than by caregivers (p=0.011). Carers were significantly more likely to rate patients as having impaired motor coordination than patients themselves. A small part of the variance of the EpiTrack score was predicted by the C-ABNAS. Objective cognitive performance did not predict ABNAS or C-ABNAS scores. CONCLUSIONS: Self-report or caregiver report questionnaires identify patients with epilepsy and objective cognitive impairment more accurately than patients with intact cognition. Those without objective evidence of cognitive impairment may, nevertheless, perceive themselves as having memory dysfunction; it is these patients, therefore, who most require both subjective and objective assessments of cognition, including carers' assessments, in order to establish the nature of their symptoms. None of these assessment measures can be used as a reliable proxy for another, each contributes individually to a comprehensive assessment of cognition, and all must be used in conjunction with measures of mood and anxiety.

Test-retest reliability of the "Home Town Walk" fMRI paradigm for memory activation and lateralization in the pre-surgical evaluation of patients with temporal lobe epilepsy.

Introduction: Functional magnetic resonance imaging (fMRI) can be used to assess language and memory function as part of pre-surgical decision making in refractory epilepsy. Although language paradigms are well established, memory paradigms are not widely used in clinical practice due to a lack of evidence for robust and reliable methods. Here, we aim to investigate the clinical utility of the Home Town Walk (HTW) paradigm for personalized treatment decisions in medial temporal lobe epilepsy. Methods: A cohort of 123 consecutive patients having HTW-fMRI as part of routine MRI scans over a 7.5 year period were included in this retrospective study. Of these, 111 patients underwent repeated HTW-fMRI in two scanning sessions one to three days apart. fMRI analysis was performed at the time of the scans using clinically approved software and retrospectively validated using FSL. We assessed the test-retest within subject reliability of activations within the posterior parahippocampal gyri (pPHG) at the individual subject level. Results and discussion: Activations within the pPHG region were observed for 101 patients (91%) in at least one of the fMRI sessions and for 88 patients (79%) in both fMRI sessions, with 82 patients showing overlapping unilateral or bilateral activations and 8 further patients showing overlapping activations in one of the hemispheres but not the other. Reproducibility was evaluated using metrics based on the concordance ratios for size (Rsize) and location (Roverlap) within the pPHG region, as well as the lateralization index (LI) metric to reflect the asymmetry of hemispheric activations, which is of crucial relevance to inform surgery. Test-retest reliability of visuospatial memory LIs, assessed by an intra-class correlation coefficient (ICC) yielded a value of 0.76, indicating excellent between session stability of memory lateralization. Conclusion: The HTW-fMRI paradigm shows reproducible activations in the medial temporal lobes of individual epilepsy patients sufficient to consistently lateralize visuospatial memory function, demonstrating the clinical utility of HTW memory fMRI and its potential for application in the pre-surgical assessment of people with temporal lobe epilepsy.

Demyelinating neuropathy with anti-CRMP5 antibodies predating diagnosis of breast carcinoma: favorable outcome after cancer therapy.

INTRODUCTION: Breast cancer is exceptionally associated with anti-collapsin response mediator protein 5 (anti-CRMP5) antibody or demyelinating neuropathy. This paraneoplastic antibody is itself not associated with demyelinating neuropathy. METHODS: Herein we describe a patient with a predominantly sensory ataxic demyelinating neuropathy associated with an IgG-kappa monoclonal gammopathy of uncertain significance (MGUS). Further investigations led to identification of anti-CRMP5 antibodies. An initial search for a malignancy proved negative. No immunomodulatory therapy was administered. RESULTS: The patient developed breast carcinoma 2 years after the initial neurological symptoms, which was effectively treated by surgery, chemotherapy, hormone therapy, and radiotherapy. At neurological follow-up, 16 months after cancer treatment, she remained in remission and had made substantial neurological recovery. Electrophysiology showed significant amelioration, and serum anti-CRMP5 antibodies were undetectable. MGUS paraprotein level was unchanged. CONCLUSION: This case widens the range of paraneoplastic manifestations of breast carcinoma to include anti-CRMP5 antibody-positive sensory ataxic demyelinating neuropathy, which, in this patient, improved after cancer treatment.

Predominantly nocturnal seizures post temporal lobectomy: Characteristics of an unusual outcome group.

PURPOSE: To describe the characteristics of a patient group who, after temporal lobectomy for predominantly diurnal seizures, experience a postoperative conversion from diurnal to predominantly nocturnal seizures, and compare this group to those who continue to have a diurnal seizure pattern postoperatively. METHODS: From a cohort of 470 surgical cases with long-term follow-up, we retrospectively identified 16 patients with a predominantly nocturnal seizure pattern, including five with nocturnal seizures only (median follow-up 21 years) and compared them with 20 predominantly diurnal seizure patients. RESULTS: Sustained postoperative improvement in seizure frequency was observed in 14/16 cases. Seizure recurrence after surgery occurred within the first postoperative year in 13/16 cases. In all but 3 cases the seizures were all predominantly nocturnal from the time of recurrence, whereas in 3 there was a period of diurnal seizures during the early postoperative years. One patient lapsed back to diurnal seizures after 16 years of predominantly nocturnal seizures. Compared to the predominantly diurnal group, these patients had a significantly later age at seizure onset and were older at the time of surgery. CONCLUSION: Patients with predominantly nocturnal seizures comprise a small but distinct post-operative outcome category. Although not formally assessed, this outcome appears associated with improved quality of life, such as with eligibility to drive, with 50% of the sample confirmed as driving. This finding may help with providing prognostic information and counseling to these patients when they are identified postoperatively.

Management and birth outcomes of pregnant women with Chiari malformations: A 14 years retrospective case series.

OBJECTIVE: The management of Chiari malformations in pregnancy is challenging due to the perceived risk of adverse maternal neurological outcomes and raising intracranial pressure during labour. Our aim was to evaluate the management and health outcomes of pregnant women cared for at a regional referral centre and highlight elements of best practice. STUDY DESIGN: A retrospective case series of all pregnant women diagnosed with Chiari malformation over fourteen years (January 2004-June 2018) at the Birmingham Women's Hospital - UK. RESULTS: Twenty-one women (23 pregnancies) with Chiari malformation were included, four had syringomyelia (4/21,19%) and six had previously undergone craniovertebral decompression (6/21, 29%). The median age was 34-years (range 20-41), the median gravidity was two (range 1-8), the median parity was one (range 0-6), and the median extent of tonsillar herniation was 11 mm (range 9-18). The majority of women received their preferred mode of delivery (15 normal vaginal deliveries (15/23, 65.2%) and 6 elective Caesarean sections (6/23, 26.1%)) with two pregnancies ending with an emergency caesarean section for obstetric complications (2/23, 8.7%). Five Caesarean section were performed under general anaesthetic, two under spinal (2/23, 8.7%) and one under epidural anaesthesia (1/23, 4.3%) with no neurological sequelae. There were no adverse neurological outcomes at discharge postnatally. CONCLUSIONS: Offering normal vaginal delivery with effective analgesia, for women with Chiari malformation, appears to be safe. Pregnancy care should be provided by a multi-disciplinary team with experience in managing Chiari malformation.

Clinical outcomes of VNS therapy with AspireSR® (including cardiac-based seizure detection) at a large complex epilepsy and surgery centre.

PURPOSE: To compare the efficacy of AspireSR® to preceding VNS battery models for battery replacements, and to determine the efficacy of the AspireSR® for new implants. METHODS: Data were collected retrospectively from patients with epilepsy who had VNS AspireSR® implanted over a three-year period between June 2014 and June 2017 by a single surgeon. Cases were divided into two cohorts, those in whom the VNS was a new insertion, and those in whom the VNS battery was changed from a previous model to AspireSR®. Within each group, the seizure burden was compared between the periods before and after insertion of AspireSR®. RESULTS: Fifty-one patients with a newly inserted AspireSR® VNS model had a significant reduction in seizure frequency (p < 0.001), with 59% (n = 30) reporting ≥50% reduction. Of the 62 patients who had an existing VNS, 53% (n = 33) reported ≥50% reduction in seizure burden when the original VNS was inserted. After the battery was changed to the AspireSR®, 71% (n = 44) reported a further reduction of ≥50% in their seizure burden. The size of this reduction was at least as large as that resulting from the insertion of their existing VNS in 98% (61/62) of patients. CONCLUSION: The results suggest that approximately 70% of patients with existing VNS insertions could have significant additional benefit from cardiac based seizure detection and closed loop stimulation from the AspireSR® device. For new insertions, the AspireSR® device has efficacy in 59% of patients. The 'rule of thirds' used in counseling patients may need to be modified accordingly.