High prevalence of CACNA1A truncations and broader clinical spectrum in episodic ataxia type 2.

OBJECTIVE: To characterize the nature of CACNA1A mutations in episodic ataxia type 2 (EA2), to search for mutations in sporadic cases, and to delineate better the clinical spectrum. BACKGROUND: EA2 is an autosomal dominant disorder characterized by recurrent acetazolamide-responsive attacks of cerebellar ataxia. The mutated gene, CACNA1A, located on chromosome 19, encodes the alpha1A subunit of a voltage-dependent calcium channel. So far, only three CACNA1A mutations have been identified-in two EA2 families and in one sporadic case. These three mutations disrupted the reading frame and led to truncated proteins. Interestingly, distinct types of CACNA1A mutations have been identified in familial hemiplegic migraine (missense mutations) and spinocerebellar ataxia type 6 (SCA-6) progressive cerebellar ataxia (expanded CAG repeats). However, except for SCA-6, these genotype-phenotype correlations relied on the analysis of very few families. METHODS: To characterize CACNA1A mutations, eight familial and seven sporadic EA2 patients were selected. All 47 exons of CACNA1A were screened by a combination of single-strand conformer polymorphism and sequencing analysis. In addition, the length of the CAG repeat has been determined in all patients. RESULTS: Seven new mutations were detected in four multiple case families and three sporadic cases. Six of them lead most likely to truncated or aberrant proteins. CAG repeat sizes were in the normal range. CONCLUSION: These data clearly establish the specificity of EA2 mutations compared with SCA-6 and familial hemiplegic migraine. Detailed clinical analysis of the mutation carriers showed the highly variable penetrance and expression of this disorder: Several of the carriers did not show any clinical symptom; others displayed atypical or permanent neurologic symptoms (such as recurrent, transient diplopia or severe, permanent, and isolated cerebellar ataxia).

[Detection and peripheral or central localization of sensory pathway involvement of the lower limbs by somatosensory evoked potentials]. / Détection et localisation périphérique ou centrale des atteintes des voies sensitives par les potentiels évoqués somesthésiques des membres inférieurs.

In the presence of more or less atypical sensory or sensorimotor symptoms the questions that arise most frequently concern the authenticity of the disorders and the precise level of the lesion. In this study, somatosensory evoked potentials (SEPs) to stimulation of the tibial nerve at the ankle were recorded at different levels in 35 healthy subjects and 32 patients with sensory disorders. Recording electrodes were placed at the popliteal fossa (peripheral sensory nerve conduction velocity), at the T12-L1 level (medullary potential: N21) and at the vertex (P40 wave). The spine to cortex time interval was measured. A systematic study of evoked responses to median nerve stimulation was performed. The 32 patients were divided into 4 groups: Group I (3 cases) had slowed sensory conduction velocity (SCV), similar delay in N21 latency and normal N21-P40: peripheral neuropathy. Group II (4 cases) had normal SCV, delayed N21 latency and normal N21-P40: radicular or conus medullaris injury. Group III (19 cases) had normal SCV, normal N21 latency and lengthened N21-P40 interval. A study of responses to median nerve stimulation made it possible to discriminate between spinal and cortical or subcortical impairment. Group IV (6 cases) had abnormalities from any two of the three groups defined above. In 24 out of 32 patients (75 p. 100), further investigations (myelography, MRI, EMG) confirmed the localization determined by evoked responses. In the other 8 patients (25 p. 100) whose clinical picture suggested a medullary or radicular impairment, SEPs alone clearly revealed an injury. SEPs can distinctly show a spinal impairment and determine the choice of further investigations.

Combined low-dose acetylsalicylic acid and dihydroergotamine in migraine prophylaxis. A double-blind, placebo-controlled crossover study.

The efficacy of the combination of dihydroergotamine (10 mg) with acetylsalicylic acid (80 mg) (DHE + ASA) in the prophylaxis of migraine was studied in a double-blind, placebo-controlled crossover trial (8 weeks twice). Of 45 patients who entered the study, 38 completed it. The number of attacks was significantly (p = 0.003) reduced during active treatment (11.5 +/- 6.2) compared with placebo (16.6 +/- 9.9). The mean duration, the mean severity, and the mean score for symptomatic acute medication of attacks did not differ significantly. The overall assessment made by the patients themselves was in favor of DHE + ASA (p = 0.001). These results indicate a moderately beneficial effect of the dihydroergotamine/low-dose acetylsalicylic acid combination in migraine prophylaxis.

Urinary 5-HIAA in migraine: evidence of lowered excretion in young adult females.

Urinary 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were determined in 44 young adult migraine patients (35 women, 9 men) between attacks and in 33 healthy controls (23 women, 10 men). HVA excretion was equivalent in all groups. 5-HIAA was unaltered in men but was significantly decreased in female migraine patients when compared with their sex-matched controls (-31%, p less than 0.01). No relationship was found between 5-HIAA excretion and the various characteristics of migraine, such as the time that had elapsed since the last attack and the presence or absence of oral contraception. The relatively marked decrease in 5-HIAA excretion in female migraine patients can hardly be accounted for by a reduction in either neuronal or platelet serotonin metabolism alone. A reduction in the intestinal contribution to urinary 5-HIAA might be the crucial factor.

[A 15oxygen positron study of relative local perfusion and oxygen extraction of the brain in lacunar hemiparesis (author's transl)]. / Débit sanguin cérébral et extraction d'oxygène dans les hémiplégies lacunaires. Etude semi-quantitative par l'oxygène-15 et la tomographie d'émission.

The oxygen-15 non-invasive continuous inhalation technique coupled with positron emission tomography (PET) allows the local study of cerebral blood flow and oxygen metabolism. Recent PET studied have demonstrated the frequent occurrence of widespread metabolic depression remote from the site of middle cerebral artery territory infarct per se, especially over the cortical mantle and thalamus ipsilaterally, and over the cerebellar hemisphere contralaterally. These phenomena have been taken as indicative of a transneural depression (i.e. diaschisis). We thought interesting to study the possible occurrence of such abnormalities in patients with lacunar syndromes. We have applied the 15O technique to seven patients (2 with pure motor hemiplegia, 5 with ataxic hemiparesis) in whom no large causal ischemic lesion could be demonstrated on CT Scans; in only one patient was a lacunar lesion, presumably responsible for the clinical deficit, evidenced. Compared to a set of 19 patients without brain disease, the semi-quantitative results (analyzed in terms of asymmetry indices between homologous brain regions) in our patients did not disclose any pathophysiologically significant abnormality. More specifically, no evidence of physiological dysfunction similar to that reported in internal carotid artery territory infarcts, was detected over the cerebral or the cerebellar cortices. These original findings are commented upon in view of the presumably small size and the uncertain topography of the causal lesion.