New ILAE versus previous clinical status epilepticus semiologic classification: Analysis of a hospital-based cohort

Objectives

In 2015, the International League Against Epilepsy (ILAE) issued a new status epilepticus (SE) classification, including a detailed semiologic axis. This study assesses frequencies of SE forms in a cohort of adult patients, and explores differences and practical implications as compared to a seizure-type–bound classification.

Methods

The prospective adult SE registry of the Lausanne University Hospital (CHUV) was considered over 5 years (2011–2015); each SE episode was retrospectively reclassified for its semiology according to the new ILAE scheme. Mortality rates were retrieved for each subgroup of SE.

Results

Among 488 SE episodes, according to the seizure-type–bound classification, 230 (47%) had a generalized convulsive, and 29 (6%) had a nonconvulsive SE in coma; both categories overlapped almost perfectly between the two classifications. However, the 84 episodes with focal SE without consciousness impairment and the 141 episodes with consciousness impairment were each translated into two major (and five sub-) categories of the new ILAE classification, having markedly different mortality rates. In addition, of 140 episodes labeled as focal motor SE according to the new classification, 54% had concomitant consciousness impairment, whereas 46% did not; again, mortality rates were heterogeneous.

Significance

Although generalized convulsive and nonconvulsive SE in coma show an almost perfect correspondence across SE semiologic classifications, focal SE is markedly heterogeneous and appears to be better reflected in the new classification, offering more clinically relevant subdivisions, also differing in mortality rates. This refined knowledge may allow the development of clinical prognostic scores that are more precise than existing tools, and should be taken into account for epidemiologic studies.

Epilepsia 2016

Predictors of long-term disability accrual in relapse-onset multiple sclerosis

Objective

To identify predictors of 10-year Expanded Disability Status Scale (EDSS) change after treatment initiation in patients with relapse-onset multiple sclerosis.

Methods

Using data obtained from MSBase, we defined baseline as the date of first injectable therapy initiation. Patients need only have remained on injectable therapy for 1 day and were monitored on any approved disease-modifying therapy, or no therapy thereafter. Median EDSS score changes over a 10-year period were determined. Predictors of EDSS change were then assessed using median quantile regression analysis. Sensitivity analyses were further performed.

Results

We identified 2,466 patients followed up for at least 10 years reporting post-baseline disability scores. Patients were treated an average 83% of their follow-up time. EDSS scores increased by a median 1 point (interquartile range = 0–2) at 10 years post-baseline. Annualized relapse rate was highly predictive of increases in median EDSS over 10 years (coeff = 1.14, p = 1.9 × 10⁻²²). On-therapy relapses carried greater burden than off-therapy relapses. Cumulative treatment exposure was independently associated with lower EDSS at 10 years (coeff = −0.86, p = 1.3 × 10⁻⁹). Furthermore, pregnancies were also independently associated with lower EDSS scores over the 10-year observation period (coeff = −0.36, p = 0.009).

Interpretation

We provide evidence of long-term treatment benefit in a large registry cohort, and provide evidence of long-term protective effects of pregnancy against disability accrual. We demonstrate that high annualized relapse rate, particularly on-treatment relapse, is an indicator of poor prognosis. 

Ann Neurol 2016

Association of a Locus in the CAMTA1 Gene With Survival in Patients With Sporadic Amyotrophic Lateral Sclerosis

Importance  Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disorder with a poor prognosis and a median survival of 3 years. However, a significant proportion of patients survive more than 10 years from symptom onset.

Objective  To identify gene variants influencing survival in ALS.

Design, Setting, and Participants  This genome-wide association study (GWAS) analyzed survival in data sets from several European countries and the United States that were collected by the Italian Consortium for the Genetics of ALS and the International Consortium on Amyotrophic Lateral Sclerosis Genetics. The study population included 4256 patients with ALS (3125 [73.4%] deceased) with genotype data extended to 7 174 392 variants by imputation analysis. Samples of DNA were collected from January 1, 1993, to December 31, 2009, and analyzed from March 1, 2014, to February 28, 2015.

Main Outcomes and Measures  Cox proportional hazards regression under an additive model with adjustment for age at onset, sex, and the first 4 principal components of ancestry, followed by meta-analysis, were used to analyze data. Survival distributions for the most associated genetic variants were assessed by Kaplan-Meier analysis.

Results  Among the 4256 patients included in the analysis (2589 male [60.8%] and 1667 female [39.2%]; mean [SD] age at onset, 59 [12] years), the following 2 novel loci were significantly associated with ALS survival: at 10q23 (rs139550538; P = 1.87 × 10−9) and in the CAMTA1 gene at 1p36 (rs2412208, P = 3.53 × 10−8). At locus 10q23, the adjusted hazard ratio for patients with the rs139550538 AA or AT genotype was 1.61 (95% CI, 1.38-1.89; P = 1.87 × 10−9), corresponding to an 8-month reduction in survival compared with TT carriers. For rs2412208CAMTA1, the adjusted hazard ratio for patients with the GG or GT genotype was 1.17 (95% CI, 1.11-1.24; P = 3.53 × 10−8), corresponding to a 4-month reduction in survival compared with TT carriers.

Conclusions and Relevance  This GWAS robustly identified 2 loci at genome-wide levels of significance that influence survival in patients with ALS. Because ALS is a rare disease and prevention is not feasible, treatment that modifies survival is the most realistic strategy. Therefore, identification of modifier genes that might influence ALS survival could improve the understanding of the biology of the disease and suggest biological targets for pharmaceutical intervention. In addition, genetic risk scores for survival could be used as an adjunct to clinical trials to account for the genetic contribution to survival.

JAMA Neurology 2016

Association of HLA Genetic Risk Burden With Disease Phenotypes in Multiple Sclerosis

Importance  Although multiple HLA alleles associated with multiple sclerosis (MS) risk have been identified, genotype-phenotype studies in the HLA region remain scarce and inconclusive.

Objectives  To investigate whether MS risk-associated HLA alleles also affect disease phenotypes.

Design, Setting, and Participants  A cross-sectional, case-control study comprising 652 patients with MS who had comprehensive phenotypic information and 455 individuals of European origin serving as controls was conducted at a single academic research site. Patients evaluated at the Multiple Sclerosis Center at University of California, San Francisco between July 2004 and September 2005 were invited to participate. Spinal cord imaging in the data set was acquired between July 2013 and March 2014; analysis was performed between December 2014 and December 2015.

Main Outcomes and Measures  Cumulative HLA genetic burden (HLAGB) calculated using the most updated MS-associated HLA alleles vs clinical and magnetic resonance imaging outcomes, including age at onset, disease severity, conversion time from clinically isolated syndrome to clinically definite MS, fractions of cortical and subcortical gray matter and cerebral white matter, brain lesion volume, spinal cord gray and white matter areas, upper cervical cord area, and the ratio of gray matter to the upper cervical cord area. Multivariate modeling was applied separately for each sex data set.

Results  Of the 652 patients with MS, 586 had no missing genetic data and were included in the HLAGB analysis. In these 586 patients (404 women [68.9%]; mean [SD] age at disease onset, 33.6 [9.4] years), HLAGB was higher than in controls (median [IQR], 0.7 [0-1.4] and 0 [−0.3 to 0.5], respectively; P = 1.8 × 10−27). A total of 619 (95.8%) had relapsing-onset MS and 27 (4.2%) had progressive-onset MS. No significant difference was observed between relapsing-onset MS and primary progressive MS. A higher HLAGB was associated with younger age at onset and the atrophy of subcortical gray matter fraction in women with relapsing-onset MS (standard β = −1.20 × 10−1; P = 1.7 × 10−2 and standard β = −1.67 × 10−1; P = 2.3 × 10−4, respectively), which were driven mainly by the HLA-DRB1*15:01 haplotype. In addition, we observed the distinct role of the HLA-A*24:02-B*07:02-DRB1*15:01 haplotype among the other commonDRB1*15:01 haplotypes and a nominally protective effect of HLA-B*44:02 to the subcortical gray atrophy (standard β = −1.28 × 10−1; P = 5.1 × 10−3 and standard β = 9.52 × 10−2; P = 3.6 × 10−2, respectively).

Conclusions and Relevance  We confirm and extend previous observations linking HLA MS susceptibility alleles with disease progression and specific clinical and magnetic resonance imaging phenotypic traits.

JAMA Neurology 2016

Identification of mutations in the MYO9A gene in patients with congenital myasthenic syndrome

Congenital myasthenic syndromes are a group of rare and genetically heterogenous disorders resulting from defects in the structure and function of the neuromuscular junction. Patients with congenital myasthenic syndrome exhibit fatigable muscle weakness with a variety of accompanying phenotypes depending on the protein affected. A cohort of patients with a clinical diagnosis of congenital myasthenic syndrome that lacked a genetic diagnosis underwent whole exome sequencing in order to identify genetic causation. Missense biallelic mutations in the MYO9A gene, encoding an unconventional myosin, were identified in two unrelated families. Depletion of MYO9A in NSC-34 cells revealed a direct effect of MYO9A on neuronal branching and axon guidance. Morpholino-mediated knockdown of the twoMYO9A orthologues in zebrafish, myo9aa/ab, demonstrated a requirement for MYO9A in the formation of the neuromuscular junction during development. The morphants displayed shortened and abnormally branched motor axons, lack of movement within the chorion and abnormal swimming in response to tactile stimulation. We therefore conclude that MYO9A deficiency may affect the presynaptic motor axon, manifesting in congenital myasthenic syndrome. These results highlight the involvement of unconventional myosins in motor axon functionality, as well as the need to look outside traditional neuromuscular junction-specific proteins for further congenital myasthenic syndrome candidate genes

Brain 2016

A heterozygous 21-bp deletion in CAPN3 causes dominantly inherited limb girdle muscular dystrophy

Limb girdle muscular dystrophy type 2A is the most common limb girdle muscular dystrophy form worldwide. Although strict recessive inheritance is assumed, patients carrying a single mutation in the calpain 3 gene (CAPN3) are reported. Such findings are commonly attributed to incomplete mutation screening. In this investigation, we report 37 individuals (age range: 21–85 years, 21 females and 16 males) from 10 families in whom only one mutation in CAPN3 could be identified; a 21-bp, in-frame deletion (c.643_663del21). This mutation co-segregated with evidence of muscle disease and autosomal dominant transmission in several generations. Evidence of muscle disease was indicated by muscle pain, muscle weakness and wasting, significant fat replacement of muscles on imaging, myopathic changes on muscle biopsy and loss of calpain 3 protein on western blotting. Thirty-one of 34 patients had elevated creatine kinase or myoglobin. Muscle weakness was generally milder than observed in limb girdle muscular dystrophy type 2A, but affected the same muscle groups (proximal leg, lumbar paraspinal and medial gastrocnemius muscles). In some cases, the weakness was severely disabling. The 21-bp deletion did not affect mRNA maturation. Calpain 3 expression in muscle, assessed by western blot, was below 15% of normal levels in the nine mutation carriers in whom this could be tested. Haplotype analysis in four families from three different countries suggests that the 21-bp deletion is a founder mutation. This study provides strong evidence that heterozygosity for the c.643_663del21 deletion in CAPN3 results in a dominantly inherited muscle disease. The normal expression of mutated mRNA and the severe loss of calpain 3 on western blotting, suggest a dominant negative effect with a loss-of-function mechanism affecting the calpain 3 homodimer. This renders patients deficient in calpain 3 as in limb girdle muscular dystrophy type 2A, albeit in a milder form in most cases. Based on findings in 10 families, our study indicates that a dominantly inherited pattern of calpainopathy exists, and should be considered in the diagnostic work-up and genetic counselling of patients with calpainopathy and single-allele aberrations in CAPN3.

Brain 2016

A new saccadic indicator of peripheral vestibular function based on the video head impulse test

Objective: While compensatory saccades indicate vestibular loss in the conventional head impulse test paradigm (HIMP), in which the participant fixates an earth-fixed target, we investigated a complementary suppression head impulse paradigm (SHIMP), in which the participant is fixating a head-fixed target to elicit anticompensatory saccades as a sign of vestibular function.

Methods: HIMP and SHIMP eye movement responses were measured with the horizontal video head impulse test in patients with unilateral vestibular loss, patients with bilateral vestibular loss, and in healthy controls.

Results: Vestibulo-ocular reflex gains showed close correlation (R² = 0.97) with slightly lower SHIMP than HIMP gains (mean gain difference 0.06 ± 0.05 SD, p < 0.001). However, the 2 paradigms produced complementary catch-up saccade patterns: HIMP elicited compensatory saccades in patients but rarely in controls, whereas SHIMP elicited large anticompensatory saccades in controls, but smaller or no saccades in bilateral vestibular loss. Unilateral vestibular loss produced covert saccades in HIMP, but later and smaller saccades in SHIMP toward the affected side. Cumulative HIMP and SHIMP saccade amplitude differentiated patients from controls with high sensitivity and specificity.

Conclusions: While compensatory saccades indicate vestibular loss in conventional HIMP, anticompensatory saccades in SHIMP using a head-fixed target indicate vestibular function. SHIMP saccades usually appear later than HIMP saccades, therefore being more salient to the naked eye and facilitating vestibulo-ocular reflex gain measurements. The new paradigm is intuitive and easy to explain to patients, and the SHIMP results complement those from the standard video head impulse test.

Classification of evidence: This case-control study provides Class III evidence that SHIMP accurately identifies patients with unilateral or bilateral vestibulopathies.

Neurology 2016