Huntington’s disease (HD) is an autosomal dominant trinucleotide repeat disorder characterized by choreiform movements, dystonia and striatal neuronal loss. Amongst multiple cellular processes, abnormal neurotransmitter signalling and decreased trophic support from glutamatergic cortical afferents are major mechanisms underlying striatal degeneration. Recent work suggests that the thalamostriatal (TS) system, another major source of glutamatergic input, is abnormal in HD although its phenotypical significance is unknown. We hypothesized that TS dysfunction plays an important role in generating motor symptoms and contributes to degeneration of striatal neuronal subtypes. Our results using the R6/2 mouse model of HD indicate that neurons of the parafascicular nucleus (PF), the main source of TS afferents, degenerate at an early stage. PF lesions performed prior to motor dysfunction or striatal degeneration result in an accelerated dystonic phenotype and are associated with premature loss of cholinergic interneurons. The progressive loss of striatal medium spiny neurons and parvalbumin-positive interneurons observed in R6/2 mice is unaltered by PF lesions. Early striatal cholinergic ablation using a mitochondrial immunotoxin provides evidence for increased cholinergic vulnerability to cellular energy failure in R6/2 mice, and worsens the dystonic phenotype. The TS system therefore contributes to trophic support of striatal interneuron subtypes in the presence of neurodegenerative stress, and TS deafferentation may be a novel cell non-autonomous mechanism contributing to the pathogenesis of HD. Furthermore, behavioural experiments demonstrate that the TS system and striatal cholinergic interneurons are key motor-network structures involved in the pathogenesis of dystonia. This work suggests that treatments aimed at rescuing the TS system may preserve important elements of striatal structure and function and provide symptomatic relief in HD.
Neurogenic stunned myocardium (NSM) is a potentially fatal cause of sudden cardiogenic dysfunction due to an acute neurological event, most commonly aneurysmal subarachnoid hemorrhage in adults. Only two pediatric cases of hydrocephalus-induced NSM have been reported. Here the authors report a third case in a 14-year-old boy who presented with severe headache, decreased level of consciousness, and shock in the context of acute hydrocephalus secondary to fourth ventricular outlet obstruction 3 years after standard-risk medulloblastoma treatment. He was initially stabilized with the insertion of an external ventricular drain and vasopressor treatment. He had a profoundly reduced cardiac contractility and became asystolic for 1 minute, requiring cardiopulmonary resuscitation when vasopressors were inadvertently discontinued. Over 1 week, his ventricles decreased in size and his cardiac function returned to normal. All other causes of heart failure were ruled out, and his impressive response to CSF diversion clarified the diagnosis of NSM secondary to hydrocephalus. He was unable to be weaned from his drain during his time in the hospital, so he underwent an endoscopic third ventriculostomy and has remained well with normal cardiac function at more than 6 months’ follow-up. This case highlights the importance of prompt CSF diversion and cardiac support for acute hydrocephalus presenting with heart failure in the pediatric population.
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