Classic ketogenic diet versus further antiseizure medicine in infants with drug-resistant epilepsy (KIWE): a UK, multicentre, open-label, randomised clinical trial.

BACKGROUND: Many infancy-onset epilepsies have poor prognosis for seizure control and neurodevelopmental outcome. Ketogenic diets can improve seizures in children older than 2 years and adults who are unresponsive to antiseizure medicines. We aimed to establish the efficacy of a classic ketogenic diet at reducing seizure frequency compared with further antiseizure medicine in infants with drug-resistant epilepsy. METHODS: In this phase 4, open-label, multicentre, randomised clinical trial, infants aged 1-24 months with drug-resistant epilepsy (defined as four or more seizures per week and two or more previous antiseizure medications) were recruited from 19 hospitals in the UK. Following a 1-week or 2-week observation period, participants were randomly assigned using a computer-generated schedule, without stratification, to either a classic ketogenic diet or a further antiseizure medication for 8 weeks. Treatment allocation was masked from research nurses involved in patient care, but not from participants. The primary outcome was the median number of seizures per day, recorded during weeks 6-8. All analyses were by modified intention to treat, which included all participants with available data. Participants were followed for up to 12 months. All serious adverse events were recorded. The trial is registered with the European Union Drug Regulating Authorities Clinical Trials Database (2013-002195-40). The trial was terminated early before all participants had reached 12 months of follow-up because of slow recruitment and end of funding. FINDINGS: Between Jan 1, 2015, and Sept 30, 2021, 155 infants were assessed for eligibility, of whom 136 met inclusion criteria and were randomly assigned; 75 (55%) were male and 61 (45%) were female. 78 infants were assigned to a ketogenic diet and 58 to antiseizure medication, of whom 61 and 47, respectively, had available data and were included in the modifified intention-to-treat analysis at week 8. The median number of seizures per day during weeks 6-8, accounting for baseline rate and randomised group, was similar between the ketogenic diet group (5 [IQR 1-16]) and antiseizure medication group (3 [IQR 2-11]; IRR 1·33, 95% CI 0·84-2·11). A similar number of infants with at least one serious adverse event was reported in both groups (40 [51%] of 78 participants in the ketogenic diet group and 26 [45%] of 58 participants in the antiseizure medication group). The most common serious adverse events were seizures in both groups. Three infants died during the trial, all of whom were randomly assigned a ketogenic diet: one child (who also had dystonic cerebral palsy) was found not breathing at home; one child died suddenly and unexpectedly at home; and one child went into cardiac arrest during routine surgery under anaesthetic. The deaths were judged unrelated to treatment by local principal investigators and confirmed by the data safety monitoring committee. INTERPRETATION: In this phase 4 trial, a ketogenic diet did not differ in efficacy and tolerability to a further antiseizure medication, and it appears to be safe to use in infants with drug-resistant epilepsy. A ketogenic diet could be a treatment option in infants whose seizures continue despite previously trying two antiseizure medications. FUNDING: National Institute for Health and Care Research.

A survey of the European Reference Network EpiCARE on clinical practice for selected rare epilepsies.

Objective: Clinical care of rare and complex epilepsies is challenging, because evidence-based treatment guidelines are scarce, the experience of many physicians is limited, and interdisciplinary treatment of comorbidities is required. The pathomechanisms of rare epilepsies are, however, increasingly understood, which potentially fosters novel targeted therapies. The objectives of our survey were to obtain an overview of the clinical practice in European tertiary epilepsy centers treating patients with 5 arbitrarily selected rare epilepsies and to get an estimate of potentially available patients for future studies. Methods: Members of the European Reference Network for rare and complex epilepsies (EpiCARE) were invited to participate in a web-based survey on clinical practice of patients with Dravet syndrome, tuberous sclerosis complex (TSC), autoimmune encephalitis, and progressive myoclonic epilepsies including Unverricht Lundborg and Unverricht-like diseases. A consensus-based questionnaire was generated for each disease. Results: Twenty-six of 30 invited epilepsy centers participated. Cohorts were present in most responding centers for TSC (87%), Dravet syndrome (85%), and autoimmune encephalitis (71%). Patients with TSC and Dravet syndrome represented the largest cohorts in these centers. The antiseizure drug treatments were rather consistent across the centers especially with regard to Dravet syndrome, infantile spasms in TSC, and Unverricht Lundborg / Unverricht-like disease. Available, widely used targeted therapies included everolimus in TSC and immunosuppressive therapies in autoimmune encephalitis. Screening for comorbidities was routinely done, but specific treatment protocols were lacking in most centers. Significance: The survey summarizes the current clinical practice for selected rare epilepsies in tertiary European epilepsy centers and demonstrates consistency as well as heterogeneity in the treatment, underscoring the need for controlled trials and recommendations. The survey also provides estimates for potential participants of clinical trials recruited via EpiCARE, emphasizing the great potential of Reference Networks for future studies to evaluate new targeted therapies and to identify novel biomarkers.

Clinical and Genetic Features in a Series of Eight Unrelated Patients with Neuropathy Due to Glycyl-tRNA Synthetase (GARS) Variants.

Pathogenic variants in the Glycyl-tRNA synthetase gene cause the allelic disorders Charcot-Marie-Tooth disease type 2D and distal hereditary motor neuropathy type V. We describe clinical features in 8 unrelated patients found to have Glycyl-tRNA synthetase variants by Next Generation Sequencing. In addition to upper limb predominant symptoms, other presentations included failure to thrive, feeding difficulties and lower limb dominant symptoms. Variability in the age at testing ranged from 14 months to 59 years. The youngest being symptomatic from 3 months and ventilator-dependent. Sequence variants were reported as pathogenic, p.(Glu125Lys), p.(His472Arg); likely pathogenic, p.(His216Arg), p.(Gly327Arg), p.(Lys510Gln), p.(Met555Val); and of uncertain significance, p.(Arg27Pro). Our case series describes novel Glycyl-tRNA synthetase variants and demonstrates the clinical utility of Next Generation Sequencing testing for patients with hereditary neuropathy. Identification of novel variants by Next Generation Sequencing illustrates that there exists a wide spectrum of clinical features and supports the newer simplified classification of neuropathies.

Bilateral thoracic outlet syndrome: An uncommon presentation of a rare condition in children.

We report an adolescent girl who had left-sided neurogenic thoracic outlet syndrome (TOS) due to impingement of the scalenus anterior muscle with bilateral changes on nerve conduction studies and responded well to surgical decompression. A 13-year-old Caucasian girl presented with intermittent pain, swelling, erythema, tingling and numbness of the palmar aspect of her left hand. Nerve conduction studies revealed bilateral ulnar sensory and motor conduction abnormalities, suggesting early compressive neuropathy in the asymptomatic arm as well. She underwent surgical exploration when it was noted that the scalenus anterior itself was impinging on the brachial plexus. She had a good clinical response to scalenectomy. The diagnosis of neurogenic TOS remains difficult as no single test has been accepted as a gold standard. But, once diagnosed using clinical symptoms, nerve conduction studies, electromyography and radiological investigations, it is a treatable condition with good prognosis.

Direct costs of managing Parkinson's disease in India: concerns in a developing country.

Medicines and surgical interventions improve the quality of life of Parkinson's disease (PD) patients. These are still expensive options and are unaffordable to those living in developing countries. Managing PD in Indians who have a low annual gross national income (GNI; 450-540 US dollars) and for whom only a few (3%) have health insurance is a challenge. We interviewed 175 consecutive PD patients regarding health insurance and money spent for treatment. The annual income of nearly half the patients was less than rupees 50,000 (1,148.63 US dollars). Patients in this study spend nearly 16% to 41.7% of the average Indian GNI to buy medicines. Costs of treating PD in India are lower than those in developed nations but are still out of reach for most Indian patients.

Validity of a modified Parkinson's disease screening questionnaire in India: effects of literacy of participants and medical training of screeners and implications for screening efforts in developing countries.

The prevalence of Parkinson's disease (PD) is low among Indians, except in the Parsis. Data for Indians come from studies using different screening tools and criteria to detect PD. An epidemiological study in India, which has nearly a billion people, more than 18 spoken languages, and varying levels of literacy, requires development and validation of a screening tool for PD. The objectives of this study are to (1) validate a modified version of a widely used screening questionnaire for PD to suit the needs of the Indian population; (2) compare the use of a nonmedical assistant (NMA) with the use of a medical person during screening; and (3) compare the effect of literacy of participants on the validity of the screening tool. The validity of the questionnaire was tested on 125 participants from a home for the elderly. NMAs of similar background and medical personnel administered the modified screening questionnaire. A movement disorder neurologist blind to the responses on the questionnaire, examined participants independently and diagnosed if participants had PD. The questionnaire was validated in the movement disorders clinic, on known PD patients and their family members without PD. In the movement disorders clinic, sensitivity and specificity of the questionnaire were 100% and 89%, respectively. Fifty-seven participants were included for analysis. The questionnaire had a higher sensitivity when NMAs (75%) rather than the medical personnel (61%) administered it, and its specificity was higher with the medical personnel (61%) than with NMAs (55% and 25%). The questionnaire had a higher specificity in literates than illiterates, whereas sensitivity varied considerably. The modified questionnaire translated in a local Indian language had reasonable sensitivity and can be used to screen individuals for PD in epidemiological studies in India. This questionnaire can be administered by NMAs to screen PD and this strategy would reduce manpower costs. Literacy may influence epidemiological estimates when screening PD.