Is conventional brain MRI useful for the diagnosis of cluster headache in patients who meet ICHD-3 criteria? Experience in three hospitals in Spain.

OBJECTIVE: To assess the frequency of symptomatic structural lesions and the diagnostic yield of conventional brain MRI in cluster headache (CH). BACKGROUND: In contrast to migraine, brain MRI is recommended in patients with CH to exclude potential mimics. The prevalence of symptomatic CH is not known. METHODS: We retrospectively analysed in detail the brain MRIs of patients diagnosed as CH in 3 Neurology Services in Spain and reviewed their clinical history. Clinical diagnoses were reassessed based on the ICHD-3 criteria. RESULTS: We included 130 patients: 113 (86.9%) were male; mean age at diagnosis being 41.4 years (range 7-82). Forty-nine (37.7%) showed some abnormal MRI finding. Only in two cases potential symptomatic lesions were found: one trigeminal schwannoma and one craneopharyngioma, but both presented atypical features (facial hypoesthesia on examination and episodes of prolonged duration that had progressed to continuous refractory pain without specific pattern, respectively) and therefore did not fulfil the ICHD-3 CH criteria. The remaining abnormal MRI findings were: white matter lesions (24 patients; 18.4%), sinus inflammatory changes (13; 10.0%), small arachnoid cysts (5; 3.8%), empty sella turca (3; 2.3%), and other unspecific findings (8; 6.2%). All of them were not symptomatic based on neuroimaging characteristics, clinical course and response to treatment. CONCLUSIONS: Brain MRI in patients who meet ICHD-3 CH criteria, with no atypical clinical features, does not show any clinically-relevant findings, suggesting that these criteria are highly predictive of its primary origin and that systematic MRI is not useful for the diagnosis of typical CH.

Clinical, genetic and neuropathological characterization of spinocerebellar ataxia type 37.

The autosomal dominant spinocerebellar ataxias (SCAs) consist of a highly heterogeneous group of rare movement disorders characterized by progressive cerebellar ataxia variably associated with ophthalmoplegia, pyramidal and extrapyramidal signs, dementia, pigmentary retinopathy, seizures, lower motor neuron signs, or peripheral neuropathy. Over 41 different SCA subtypes have been described evidencing the high clinical and genetic heterogeneity. We previously reported a novel spinocerebellar ataxia type subtype, SCA37, linked to an 11-Mb genomic region on 1p32, in a large Spanish ataxia pedigree characterized by ataxia and a pure cerebellar syndrome distinctively presenting with early-altered vertical eye movements. Here we demonstrate the segregation of an unstable intronic ATTTC pentanucleotide repeat mutation within the 1p32 5' non-coding regulatory region of the gene encoding the reelin adaptor protein DAB1, implicated in neuronal migration, as the causative genetic defect of the disease in four Spanish SCA37 families. We describe the clinical-genetic correlation and the first SCA37 neuropathological findings caused by dysregulation of cerebellar DAB1 expression. Post-mortem neuropathology of two patients with SCA37 revealed severe loss of Purkinje cells with abundant astrogliosis, empty baskets, occasional axonal spheroids, and hypertrophic fibres by phosphorylated neurofilament immunostaining in the cerebellar cortex. The remaining cerebellar Purkinje neurons showed loss of calbindin immunoreactivity, aberrant dendrite arborization, nuclear pathology including lobulation, irregularity, and hyperchromatism, and multiple ubiquitinated perisomatic granules immunostained for DAB1. A subpopulation of Purkinje cells was found ectopically mispositioned within the cerebellar cortex. No significant neuropathological alterations were identified in other brain regions in agreement with a pure cerebellar syndrome. Importantly, we found that the ATTTC repeat mutation dysregulated DAB1 expression and induced an RNA switch resulting in the upregulation of reelin-DAB1 and PI3K/AKT signalling in the SCA37 cerebellum. This study reveals the unstable ATTTC repeat mutation within the DAB1 gene as the underlying genetic cause and provides evidence of reelin-DAB1 signalling dysregulation in the spinocerebellar ataxia type 37.

Rare Neurodegenerative Diseases: Clinical and Genetic Update.

More than 600 human disorders afflict the nervous system. Of these, neurodegenerative diseases are usually characterised by onset in late adulthood, progressive clinical course, and neuronal loss with regional specificity in the central nervous system. They include Alzheimer's disease and other less frequent dementias, brain cancer, degenerative nerve diseases, encephalitis, epilepsy, genetic brain disorders, head and brain malformations, hydrocephalus, stroke, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS or Lou Gehrig's Disease), Huntington's disease, and Prion diseases, among others. Neurodegeneration usually affects, but is not limited to, the cerebral cortex, intracranial white matter, basal ganglia, thalamus, hypothalamus, brain stem, and cerebellum. Although the majority of neurodegenerative diseases are sporadic, Mendelian inheritance is well documented. Intriguingly, the clinical presentations and neuropathological findings in inherited neurodegenerative forms are often indistinguishable from those of sporadic cases, suggesting that converging genomic signatures and pathophysiologic mechanisms underlie both hereditary and sporadic neurodegenerative diseases. Unfortunately, effective therapies for these diseases are scarce to non-existent. In this chapter, we highlight the clinical and genetic features associated with the rare inherited forms of neurodegenerative diseases, including ataxias, multiple system atrophy, spastic paraplegias, Parkinson's disease, dementias, motor neuron diseases, and rare metabolic disorders.

New subtype of spinocerebellar ataxia with altered vertical eye movements mapping to chromosome 1p32.

IMPORTANCE: To provide clinical and genetic diagnoses for patients' conditions, it is important to identify and characterize the different subtypes of spinocerebellar ataxia (SCA). OBJECTIVE: To clinically and genetically characterize a Spanish kindred with pure SCA presenting with altered vertical eye movements. DESIGN Family study of ambulatory patients. Electro-oculographic and genetics studies were performed in 2 referral university centers. SETTING: Primary care institutional center in Spain. PARTICIPANTS: Thirty-six participants from a large Spanish kindred were clinically examined, and 33 family members were genetically examined. Detailed clinical data were obtained from 9 affected relatives. Two ataxic siblings and 2 asymptomatic family members were examined using an enhanced clinical protocol for a follow-up period of 7 years. MAIN OUTCOMES AND MEASURES: High-density genome-wide single-nucleotide polymorphism arrays, along with microsatellite analysis, and genetic linkage studies were performed. Whole-exome sequencing was used for 2 affected relatives. For most patients, the initial symptoms included falls, dysarthria, or clumsiness followed by a complete cerebellar syndrome. For all 9 affected relatives, we observed altered vertical eye movements, as initial ocular signs for 3 of them and for the 2 asymptomatic family members, all having inherited the risk haplotype. Neuroimaging showed isolated cerebellar atrophy. RESULTS: Initial genome-wide linkage analysis revealed suggestive linkage to chromosome 1p32. Multipoint analysis and haplotype reconstruction further traced this SCA locus to a 0.66-cM interval flanked by D1S200 and D1S2742 (z(max) = 6.539; P < .0001). The causative mutation was unidentified by exome sequencing. CONCLUSIONS AND RELEVANCE: We report a new subtype of SCA presenting in patients as slow progressing ataxia with altered vertical eye movements linked to a 11-megabase interval on 1p32. The Human Genome Nomenclature Committee has assigned this subtype of ataxia the designation SCA37.

Ataxia rating scales--psychometric profiles, natural history and their application in clinical trials.

We aimed to perform a comprehensive systematic review of the existing ataxia scales. We described the disorders for which the instruments have been validated and used, the time spent in its application, its validated psychometric properties, and their use in studies of natural history and clinical trials. A search from 1997 onwards was performed in the MEDLINE, LILACS, and Cochrane databases. The web sites ClinicalTrials.gov and Orpha.net were also used to identify the endpoints used in ongoing randomized clinical trials. We identified and described the semiquantitative ataxia scales (ICARS, SARA, MICARS, BARS); semiquantitative ataxia and non-ataxia scales (UMSARS, FARS, NESSCA); a semiquantitative non-ataxia scale (INAS); quantitative ataxia scales (CATSYS 2000, AFCS, CCFS and CCFSw, and SCAFI); and the self-performed ataxia scale (FAIS). SARA and ICARS were the best studied and validated so far, and their reliability sustain their use. Ataxia and non-ataxia scores will probably provide a better view of the overall disability in long-term trials and studies of natural history. Up to now, no clear advantage has been disclosed for any of them; however, we recommend the use of specific measurements of gait since gait ataxia is the first significant manifestation in the majority of ataxia disorders and comment on the best scales to be used in specific ataxia forms. Quantitative ataxia scales will be needed to speed up evidence from phase II clinical trials, from trials focused on the early phase of diseases, and for secondary endpoints in phase III trials. Finally, it is worth remembering that estimation of the actual minimal clinically relevant difference is still lacking; this, together with changes in quality of life, will probably be the main endpoints to measure in future therapeutic studies.

Gentamicin-induced readthrough of stop codons in Duchenne muscular dystrophy.

OBJECTIVE: The objective of this study was to establish the feasibility of long-term gentamicin dosing to achieve stop codon readthrough and produce full-length dystrophin. Mutation suppression of stop codons, successfully achieved in the mdx mouse using gentamicin, represents an important evolving treatment strategy in Duchenne muscular dystrophy (DMD). METHODS: Two DMD cohorts received 14-day gentamicin (7.5mg/kg/day): Cohort 1 (n = 10) stop codon patients and Cohort 2 (n = 8) frameshift controls. Two additional stop codon DMD cohorts were gentamicin treated (7.5mg/kg) for 6 months: Cohort 3 (n = 12) dosed weekly and Cohort 4 (n = 4) dosed twice weekly. Pre- and post-treatment biopsies were assessed for dystrophin levels, as were clinical outcomes. RESULTS: In the 14-day study, serum creatine kinase (CK) dropped by 50%, which was not seen in frameshift DMD controls. After 6 months of gentamicin, dystrophin levels significantly increased (p = 0.027); the highest levels reached 13 to 15% of normal (1 in Cohort 3, and 2 in Cohort 4), accompanied by reduced serum CK favoring drug-induced readthrough of stop codons. This was supported by stabilization of strength and a slight increase in forced vital capacity. Pretreatment stable transcripts predicted an increase of dystrophin after gentamicin. Readthrough efficiency was not affected by the stop codon or its surrounding fourth nucleotide. In 1 subject, antigen-specific interferon-gamma enzyme-linked immunospot assay detected an immunogenic dystrophin epitope. INTERPRETATION: The results support efforts to achieve drug-induced mutation suppression of stop codons. The immunogenic epitope resulting from readthrough emphasizes the importance of monitoring T-cell immunity during clinical studies that suppress stop codons. Similar principles apply to other molecular strategies, including exon skipping and gene therapy.

Migraine with aura related to the percutaneous closure of an atrial septal defect.

We report a case of a 31-year-old woman who presented migraine attacks with aura within the 48 hr after transcatheter closure of an atrial septal defect with the Amplatzer septal occluder device. The migraine attacks persisted for 3 months, and all examinations performed to rule out a thromboembolic origin of migraine were negative.

Neuromuscular dysfunction in adult growth hormone deficiency.

BACKGROUND: Adult growth hormone deficiency (AGHD) is associated with fatigue, tiredness and myalgias, which improve after initiating recombinant human GH (rhGH) therapy. AIM: To conduct an extensive neuromuscular investigation of patients with AGHD in an attempt to explain their neuromuscular symptoms. PATIENTS AND METHODS: Twenty adult patients (11 males) with untreated GHD of whom 10 were childhood-onset (CO) underwent a prospective neurological protocol, including physical examination and a neurophysiological study that comprised sensory and motor neurography, repetitive stimulation, electromyogram (EMG) and interference pattern analysis (IPA). In the first seven patients (four CO), a biceps muscle biopsy was also performed for histochemical analysis and Western blot, and investigation of signal transducers and activators of transcription (STATs)-1 and -3 and the two isoforms STAT-5a and -5b. RESULTS: Neuromuscular examination, sensory and motor neurography and repetitive stimulation were normal in 20/20 patients. Fourteen [seven CO and seven adult-onset (AO)] of the 20 patients had abnormal EMG and/or IPA suggestive of a neurogenic involvement. In those seven patients with initially abnormal results, who also remained on regular rhGH for at least 1 year, repeated IPA was normal in six and improved in the remaining patient (P=0.004). The biceps muscle biopsy disclosed abnormal groupings in the seven cases tested, indicative of a neurogenic pattern. No changes in skeletal muscle STAT-1 and -3 were seen compared to controls, but a marked increase in both STAT-5 isoforms was observed in all seven patients. CONCLUSION: Skeletal muscle of patients with both adult-onset and childhood-onset adult GH deficiency shows a neuromuscular dysfunction, indicated by the muscle biopsy and the neurophysiological study, which in the subgroup of treated patients responds positively to rhGH therapy. The results obtained suggest that the STAT-5 signal transduction pathway in muscle is abnormal in adult GH deficiency.

Evidence for impaired axonal regeneration in PMP22 duplication: studies in nerve xenografts.

Whether axonal regeneration in Charcot-Marie-Tooth (CMT) neuropathies is impaired has not been addressed in detail. Our studies in nude mice harboring xenografts from patients with different primary Schwann cell (SC) genetic defects suggested an intimate association between the onset of myelination and impairment in the growth capacity of nude mice axons engulfed by the mutant SCs. To assess the effects of peripheral myelin protein 22 (PMP22) gene duplication on the regeneration process, we conducted morphometric studies to generate temporal growth profiles of myelinated axons within the xenografts obtained from CMT1A patients and from healthy controls. Axon size distribution histograms in controls at different time intervals revealed that size differentiation of myelinated fibers within the grafts is established as early as 2 weeks, and that the temporal pattern of myelination of different sized axons has striking similarities to myelination during development. In PMP22 duplication grafts, the onset of myelination is delayed and the regeneration capacity of all fiber sizes is impaired. This defect, however, is most pronounced for the large diameter axons. In addition, significant large fiber loss occurred after 12 weeks with a concomitant new cycle of regeneration of small size axons. These studies show that the PMP22 duplication in SCs have profound effects on the regeneration process, which might be a contributing factor to preferential distal axonal loss.