International Veterinary Epilepsy Task Force Consensus Proposal: Outcome of therapeutic interventions in canine and feline epilepsy

Common criteria for the diagnosis of drug resistance and the assessment of outcome are needed urgently as a prerequisite for standardized evaluation and reporting of individual therapeutic responses in canine epilepsy. Thus, we provide a proposal for the definition of drug resistance and partial therapeutic success in canine patients with epilepsy. This consensus statement also suggests a list of factors and aspects of outcome, which should be considered in addition to the impact on seizures. Moreover, these expert recommendations discuss criteria which determine the validity and informative value of a therapeutic trial in an individual patient and also suggest the application of individual outcome criteria. Agreement on common guidelines does not only render a basis for future optimization of individual patient management, but is also a presupposition for the design and implementation of clinical studies with highly standardized inclusion and exclusion criteria. Respective standardization will improve the comparability of findings from different studies and renders an improved basis for multicenter studies. Therefore, this proposal provides an in-depth discussion of the implications of outcome criteria for clinical studies. In particular ethical aspects and the different options for study design and application of individual patient-centered outcome criteria are considered

International Veterinary Epilepsy Task Force consensus proposal: Medical treatment of canine epilepsy in Europe

In Europe, the number of antiepileptic drugs (AEDs) licensed for dogs has grown considerably over the last years. Nevertheless, the same questions remain, which include, 1) when to start treatment, 2) which drug is best used initially, 3) which adjunctive AED can be advised if treatment with the initial drug is unsatisfactory, and 4) when treatment changes should be considered. In this consensus proposal, an overview is given on the aim of AED treatment, when to start long-term treatment in canine epilepsy and which veterinary AEDs are currently in use for dogs. The consensus proposal for drug treatment protocols, 1) is based on current published evidence-based literature, 2) considers the current legal framework of the cascade regulation for the prescription of veterinary drugs in Europe, and 3) reflects the authors’ experience. With this paper it is aimed to provide a consensus for the management of canine idiopathic epilepsy. Furthermore, for the management of structural epilepsy AEDs are inevitable in addition to treating the underlying cause, if possible

SNP array-based whole genome homozygosity mapping as the first step to a molecular diagnosis in patients with Charcot-Marie-Tooth disease

Considerable non-allelic heterogeneity for autosomal recessively inherited Charcot-Marie-Tooth (ARCMT) disease has challenged molecular testing and often requires a large amount of work in terms of DNA sequencing and data interpretation or remains unpractical. This study tested the value of SNP array-based whole-genome homozygosity mapping as a first step in the molecular genetic diagnosis of sporadic or ARCMT in patients from inbred families or outbred populations with the ancestors originating from the same geographic area. Using 10 K 2.0 and 250 K Nsp Affymetrix SNP arrays, 15 (63%) of 24 CMT patients received an accurate genetic diagnosis. We used our Java-based script eHoPASA CMT—easy Homozygosity Profiling of SNP arrays for CMT patients to display the location of homozygous regions and their extent of marker count and base-pairs throughout the whole genome. CMT4C was the most common genetic subtype with mutations detected in SH3TC2, one (p.E632Kfs13X) appearing to be a novel founder mutation. A sporadic patient with severe CMT was homozygous for the c.250G > C (p.G84R) HSPB1 mutation which has previously been reported to cause autosomal dominant dHMN. Two distantly related CMT1 patients with early disease onset were found to carry a novel homozygous mutation in MFN2 (p.N131S). We conclude that SNP array-based homozygosity mapping is a fast, powerful, and economic tool to guide molecular genetic testing in ARCMT and in selected sporadic CMT patients

Neuromuscular adaptations to muscle fatigue during submaximal isometric contractions in man

Neuromuscular Adaptations to Muscle Fatigue during Submaximal Isometric Contractions in Man Wolfgang N. Löscher Doctoral thesis from the Department of Neuroscience, Karolinska Institute,Stockholm,Sweden . During a sustained contraction, the force producing capacity of a muscle gradually decreases. Inorder to maintain a constant force output, the neuromuscular system has to adapt to the contractile fatigueprocess. The aim of the present work was to study these adaptations during short- and long-lastingcontractions by analysing voluntary and reflex myoelectric activities, muscle twitch responses and forcetremor. During brief isometric handgrips, a linear relationship between the amplitude of the surfaceelectromyogram (EMG) and the force output was found, while tremor increased initially and then decreasedat high contraction levels. Both EMG and tremor changes reflected effort related modulations of motor unitrecruitment and motor unit firing rates. The maximal voluntary and involuntary EMG amplitude was reduced at decreased gastrocnemiusmuscle lengths. This reduction originated from either an impairment of neuromuscular transmission orchanges in the geometry of muscle fibres, the latter resulting in a reduced number of fibres located withinthe pick-up volume of the recording electrode. During isometric contractions of the triceps surae, sustained at 30% of a maximum voluntarycontraction until endurance limit, the net excitatory drive to the a-motoneuron pool increased, as assessedby twitch occlusion and H-reflexes. In parallel, EMG and tremor amplitude increased, which appeared topredominantly result from recruitment of unfatigued motor units and bursting EMG activity. The increasedexcitatory drive was found to additionally modulate Renshaw interneurons, as recurrent inhibition of soleusa-motoneurons, evaluated by paired H-reflexes, was reduced after ten minutes of a fatiguing plantar flexion. Toward endurance limit of a long-lasting submaximal plantar flexion, tremor amplitude increased ina non-linear fashion. When la-afferent input to the a-motoneuron pool was reduced by either tendonvibration or an ischemic block, the tremor increase was significantly diminished. This demonstrates thesignificance of stretch reflex activity for the enhancement of tremor. It appears that la-afferent input triggersoscillations in the stretch reflex arc during a fatiguing contraction, which result in bursting EMG activityand augmented tremor. At endurance limit, EMG and twitch occlusion results indicated that central fatigue had occurred, ascomplete muscle activation was not achievable. However, after one minute of electrical stimulation to thesame torque level, subjects were able to voluntarily continue the contraction and finally achieve full muscleactivation. As the electrical stimulation allowed for muscle spindle, supraspinal and motoneuronal recovery,while metabolic stress and contractile fatigue continued, it appeared that central fatigue was not caused bymetabo-receptor or nociceptor mediated peripheral reflex inhibition of the a-motoneuron pool. In conclusion, during a long-lasting submaximal constant-force contraction of the triceps surae, theneuromuscular system adapts to contractile fatigue mainly by recruitment of new motor units, facilitated byan increased excitatory drive to the a-motoneuron pool and by a reduction of Renshaw inhibition. Theincrease in excitatory drive seems to additionally increase the probability of oscillations in the stretch reflexloop, resulting in enhancement of tremor during fatigue. Despite this increase, excitatory drive fails to reachits maximum at endurance limit. Thus, central fatigue occurs, which appears to be independent of peripheralreflex inhibition, but due to fatigue at the muscle spindle, the motoneuronal and/or the supraspinal level.Key words. isometric, electromyography, tremor, H-reflex, twitch, motoneuron, recruitment, la-afferents,recurrent inhibition, central fatigue, excitatory drive, gastrocnemius, soleus, triceps surae, tendon vibration,ischemia, Renshaw cellStockholm 1995 ISsN: 91-628-1757-

Early-onset Hirayama disease in a female

Objectives: Hirayama disease is a rare myelopathy, occurring predominantly in males with onset in the teens. Methods and results: Here, we report a young female patient who developed the first signs of Hirayama disease at 10.5 years of age. Prior to onset, she had experienced a growth spurt and grew about 8 cm. The disease progressed over 3 years and the typical clinical, electrophysiological, and neuroimaging signs of Hirayama disease were found. After this period and achievement of her final height, no further progression was noticed. Conclusions: This case highlights that pediatric neurologists should be aware of Hirayama disease, which can also occur in girls in early adolescence