WRAPPER study: Real-world effectiveness and tolerability of adjunctive perampanel for people with drug-resistant epilepsy in Hong Kong.

OBJECTIVE: The Prince of Wales Hospital (PWH) Real-world Analysis of People with Drug-Resistant Epilepsy (DRE) on PERampanel (WRAPPER) study assessed effectiveness and tolerability of adjunctive perampanel in people with DRE attending PWH. METHODS: This was a prospective single-center real-world observational study involving 70 people with DRE between July 2016 and June 2021. A post hoc analysis after the initial study period of 16 weeks assessed outcomes for an extended period up to 52 weeks. RESULTS: After 16 weeks, median dose of perampanel was 2 mg (IQR 24 mg). 50% responder rates were 40.0%, 41.5%, and 48.7% at 16, 26, and 52 weeks. Seizure freedom was 12.9%, 20.7%, and 25.6% at 16, 26, and 52 weeks. Monthly seizure frequency reduced from 3.0 (IQR 3.0-6.6) at baseline to 2.0 (IQR 2.0-6.0, p = 0.005) at 16 weeks; 2.0 (IQR 2.0-5.0, p = 0.01) at 26 weeks; and 2.0 (IQR 0.0-4.0, p = 0.018) at 52 weeks. Older age predicted 50% responders (OR 1.08, 95% CI 1.01-1.14, p = 0.048). At 16 weeks, 51.4% (36/70) had treatment-emergent adverse effects (TEAEs). Most common was seizure exacerbation at 35.7% (25/70) followed by fatigue at 15.7% (11/70). NPI-12 and ZBI scores indicated no increase in neuropsychiatric symptoms on perampanel. SIGNIFICANCE: Low-dose 2-4 mg adjunctive perampanel for people with DRE conferred appreciable improvements in seizure reduction without significant neuropsychiatric adverse effects in the real-world setting at a tertiary center in Hong Kong and had better antiseizure effect with advancing age. PLAIN LANGUAGE SUMMARY: This real-world study from Hong Kong found low-dose perampanel was effective and tolerable for people with drug-resistant epilepsy. Furthermore, perampanel was also potentially more effective with advancing age.

Limb girdle myasthenia with digenic RAPSN and a novel disease gene AK9 mutations.

Though dysfunction of neuromuscular junction (NMJ) is associated with congenital myasthenic syndrome (CMS), the proteins involved in neuromuscular transmission have not been completely identified. In this study, we aimed to identify a novel CMS gene in a consanguineous family with limb-girdle type CMS. Homozygosity mapping of the novel CMS gene was performed using high-density single-nucleotide polymorphism microarrays. The variants in CMS gene were identified by whole-exome sequencing (WES) and Sanger sequencing. A 20 MB-region of homozygosity (ROH) was mapped on chromosome 6q15-21. This was the only ROH that present in all clinically affected siblings and absent in all clinically unaffected siblings. WES showed a novel variant of AK9 gene located in this ROH. This variant was a start-gain mutation and introduced a cryptic 5'-UTR signal in intron 5 of the AK9 gene. The normal splicing signal would be interfered by the cryptic translation signal leading to defective splicing. Another 25 MB-ROH was found on chromosome 11p13-q12 in all siblings. WES showed a homozygous RAPSN pathogenic variant in this ROH. Since RAPSN-associated limb-girdle type CMS was only manifested in AK9 homozygous variant carriers, the disease phenotype was of digenic inheritance, and was determined by the novel disease modifier AK9 which provides NTPs for N-glycosylation. This is the first time that this specific genotype-phenotype correlation is reported. Importantly, the AK9-associated nucleotide deficiency may replete by dietary supplements. Since AK9 is a disease modifier, enhancing N-glycosylation by increasing dietary nucleotides may be a new therapeutic option for CMS patients.

Predictors of good functional outcome in counterpulsation-treated recent ischaemic stroke patients.

OBJECTIVES: External counterpulsation (ECP) is a non-invasive method being investigated for ischaemic stroke. We aimed to explore predictors of good functional outcome for ECP-treated ischaemic stroke patients who completed a minimum of 10 sessions. METHODS: We analysed our ECP registry of ischaemic stroke patients with cerebral large artery stenosis who underwent ECP therapy at the Prince of Wales Hospital from 2004 to 2010. We included 155 patients who completed at least 10 sessions of ECP and had 3-month follow-up data as well as 52 medical controls. Functional outcomes were dichotomised into good outcome (modified Rankin Scale (mRS) 0-2) and bad outcome (mRS 3-6). We compared the differences in two groups in terms of demographics, medical history and parameters of ECP treatment. RESULTS: At 3 months after stroke, 70.5% of patients who finished the whole course of ECP had a good outcome (only 46.5% in the unfinished group and 38.5% in the medical group). Among all 207 recruited cases, 119 (57.5%) patients had a good outcome at 3 months after stroke. Compared with the bad outcome group, patients in the good outcome group were younger and had a lower baseline National Institutes of Health Stroke Scale (NIHSS) and longer ECP therapy duration. Multivariate logistic regression showed that ECP duration (OR 1.032), baseline NIHSS (OR 0.734) and age (OR 0.961) were independent predictors for a favourable outcome. CONCLUSIONS: Duration of ECP therapy is first found to be an important predictor for good outcome of ECP-treated ischaemic stroke patients, in addition to the well-known prognostic factors such as age and NIHSS.

Familial aggregation of narcolepsy.

OBJECTIVES: To determine the familial aggregation of narcolepsy from perspectives of clinical symptomatology, polysomnographic data, and human leukocyte antigen (HLA) typing. METHODS: This was a Family study at the University-affiliated hospital. The participants were narcolepsy probands and their first degree relatives, and, also, age and sex matched unrelated healthy controls. Interventions were not applicable. MEASUREMENTS AND RESULTS: All study subjects underwent structured interviews, overnight polysomnography followed by a multiple sleep latency test (MSLT), and HLA typing. Altogether, 33 probands and 81 first degree relatives (response rate 65%) were recruited. Among the relatives, 12.3% were diagnosed with narcolepsy and 39.5% had narcolepsy spectrum as defined by unexplained abnormal MSLT (shortened MSL and SOREMP) results. The relative risk of narcolepsy in first degree relatives was 361.8. Familial aggregation of narcolepsy symptoms, excessive daytime sleepiness, HLA status, abnormal MSLT, and nocturnal polysomnographic findings were observed. CONCLUSIONS: The familial risk of narcolepsy among first degree relatives is much higher than previously reported. There exists a spectrum of narcolepsy features among relatives, ranging from full clinical tetrads to asymptomatic abnormal MSLT findings.