Frédéric Dubas

Extracranial and intracranial vertebrobasilar dissections: diagnosis and prognosis

OBJECTIVES To compare the diagnosis and prognosis of extracranial versus intracranial vertebral artery dissections without intracerebral haemorrhage. METHODS Twenty two vertebral artery dissections were defined by intra-arterial angiography and classified in two groups: group 1, nine extracranial dissections (seven patients) and group 2, 13 intracranial dissections (nine patients), involving the basilar artery in five cases. Bilateral dissections were found in 38% of the population. Before angiography, all the patients had been investigated by continuous wave Doppler, colour coded Doppler, and transcranial Doppler. Mean follow up was 44 months. RESULTS The two most important symptoms of both dissections (81% of patients) were unbearable pain preceding stroke and progressive onset of stroke within a few hours. Severe ultrasonic abnormalities were present in 94% of the patients whereas specific ultrasonic signs (segmental dilation with eccentric channel) were rare (19%) in both groups. Major strokes and brainstem strokes represented respectively 67% and 78% in intracranial versus 43% and 29% in extracranial dissections. Severe sequelae (permanent disabling motor or cerebellar deficit) were more often associated with intracranial (44%) than with extracranial dissections (14%). No recurrence of dissection and no cerebral haemorrhage were found under heparin. Significant factors of poor outcome (P< 0.05) were the initial severity of the stroke and the bilateral location of dissections. CONCLUSION The combination of a pain and a progressive onset of the stroke, corroborated by ultrasonic findings, could have helped to recognise most of these types of dissections. Intracranial dissections have a poorer prognosis than extracranial dissections.

Fibromuscular Dysplasia May Herald Symptomatic Recurrence of Cervical Artery Dissection

Background: The prevalence of fibromuscular dysplasia (FMD) in patients with cervical artery dissection (CAD) is unknown. Our objectives were to assess the risk of CAD recurring as a stroke or a transient ischemic attack and the association of these events with FMD. Methods: We prospectively included and followed 103 consecutive patients who had been admitted for a CAD. The median follow-up was 4 years (range 4 months to 10 years). The main criteria for inclusion were a mural hematoma demonstrated by cervical magnetic resonance imaging and/or signs suggesting CAD on 2 other investigations. FMD was diagnosed on the so-called string of beads pattern by digital subtraction angiography. Results: Five patients had CAD recurrence (60% occurred late). Four of these 5 patients had FMD. In 4 patients, CAD recurrence involved another cervical artery. Conclusion: The rate of symptomatic CAD recurrence was 1% per year and was often related to FMD.

Mitochondrial complex I deficiency in GDAP1-related autosomal dominant Charcot-Marie-Tooth disease (CMT2K)

Mutations in GDAP1, an outer mitochondrial membrane protein responsible for recessive Charcot-Marie-Tooth disease (CMT4A), have also been associated with CMT2K, a dominant form of the disease. The three CMT2K patients we studied carried a novel dominant GDAP1 mutation, C240Y (c.719G > A). Mitochondrial respiratory chain complex I activity in fibroblasts from CMT2K patients was 40% lower than in controls, whereas the tubular mitochondria were 33% larger in diameter and the mitochondrial mass was 20% greater. Thus, besides the regulatory role GDAP1 plays in mitochondrial network dynamics, it may also be involved in energy production and in the control of mitochondrial volume.

Hereditary spastic paraplegia-like disorder due to a mitochondrial ATP6 gene point mutation.

Hereditary spastic paraplegia refers to a genetically heterogeneous syndrome. We identified five members of a family suffering from a late-onset spastic paraplegia-like disorder, carrying the homoplasmic m.9176 T>C mutation in the mitochondrial ATP6 gene. The clinical severity of the disease observed in the family was correlated with the biochemical and assembly defects of the ATP synthase. The m.9176 T>C mutation has been previously associated to Leigh syndrome or familial bilateral striatal necrosis. Other factors such as modifying genes may be involved in the phenotypic expression of the disease. The family belongs to the mitochondrial haplogroup J, previously shown to play a role in modulating the phenotype of mitochondrial diseases and be associated with longevity. Moreover other nuclear modifying genes or environmental factors may contribute to the disease phenotype. This finding extends the genetic heterogeneity of the hereditary spastic paraplegia together with the clinical spectrum of mutations of the ATP6 gene.

Mitochondrial dysfunction and pathophysiology of Charcot–Marie–Tooth disease involving GDAP1 mutations

Charcot-Marie-Tooth (CMT) disease represents a large group of clinically and genetically heterogeneous disorders leading to inherited peripheral neuropathies affecting motor and sensory neurons. Mutations in the ganglioside-induced differentiation-associated-protein 1 gene (GDAP1), which encodes a protein anchored to the mitochondrial outer membrane, are usually associated with the recessive forms of CMT disease and only rarely with the autosomal dominant forms. The function of GDAP1 is not fully understood but it plays a role in mitochondrial dynamics by promoting fission events. We present an overview of GDAP1 and the corresponding protein together with the complete spectrum of the 41 gene mutations described so far. We examine the relationship between the genotype and the phenotype in the various forms of CMT disease related to GDAP1 mutations, and discuss the pathophysiological hypotheses that link peripheral neuropathies to mitochondrial dysfunction and GDAP1 mutations. The meta-analysis of the literature reveals the great heterogeneity of phenotypic presentations and shows that the recessive forms of CMT disease, i.e. CMT4A and AR-CMT2, are far more severe than the dominant form, i.e. CMT2K. Among patients with recessive forms of the disease, those carrying truncating mutations are more seriously affected, often becoming wheelchair-bound before the end of the third decade. At the neuronal level, GDAP1 mutations may lead to perturbed axonal transport and impaired energy production as in other neurodegenerative diseases due to mutations in genes involved in mitochondrial dynamics.

mtDNA haplogroup J: a contributing factor of optic neuritis.

Optic neuritis frequently occurs in multiple sclerosis (MS), and shares several similarities with the optic neuritis of Lebers hereditary optic neuropathy (LHON), which is mainly due to maternally transmitted mitochondrial DNA (mtDNA) mutations. Our report shows for the first time that a mitochondrial DNA background could influence the clinical expression of MS. One European mtDNA haplogroup was found only in MS patients with optic neuritis but not in MS patients without visual symptoms. Therefore, we hypothesize that mtDNA haplogroup J might constitute a risk factor for optic neuritis occurrence when it is coincidentally associated with MS, but not be a risk factor for developing MS per se as suggested previously.

A second pedigree with autosomal dominant nemaline myopathy caused by TPM3 mutation: a clinical and pathological study.

The slow alpha-tropomyosin (TPM3) gene has to date been associated with few cases of both dominant and recessive nemaline myopathies. We report the identification of a p.Arg167His mutation in a four-generation family presenting with a mild classical form of the disease. Clinically, there was no correlation between the age at presentation and the severity of the disease. The dominant-negative p.Arg167His mutation is a recurrent mutation, previously reported in one sporadic case. Histological studies showed discrepancy between the two reports. While a type II fibre predominance was described in the sporadic case, we observed an almost complete type I fibre predominance. This study emphasizes the variability in histopathological phenotypes seen with TPM3 mutations.

Accuracy of Color-Doppler in the Quantification of Proximal Vertebral Artery Stenoses

Background: Vertebrobasilar (VB) strokes appear to have the same causes as carotid strokes. Obstructive lesions of proximal vertebral arteries probably occur in about 30% of stroke patients. Purpose: Our aim was to assess the validity of color Doppler sonography compared to selective intra-arterial angiography in the quantification of proximal vertebral artery stenoses. Materials and Methods: A prospective blind study of 316 vertebral arteries was undertaken between 1996 and 1998. One hundred and fifty-eight patients with cerebrovascular disorders without cerebral hemorrhage were studied consecutively by frequency or amplitude color Doppler flow imaging and intra-arterial angiography. The lesions were quantified by morphological and hemodynamic criteria and classified into 6 groups: 0% 207 arteries; 1–29% 32 arteries; 30–49% 29 arteries; 50–69% 13 arteries; 70–99% 23 arteries; 100% 12 arteries. Results: Ten of the 12 occlusions were identified, the 2 false-negatives were due to 2 revascularized vessels. Moderate stenoses (<50%) were differentiated from tight stenoses (>50%) using hemodynamic criteria. The majority of false-negative stenoses (38) in the different groups were related to intrathoracic or very deep origin of the artery, anechogenic stenosis or a tortuous vessel. Stenoses greater than 70% were diagnosed in 71% of cases with a specificity of 99%. The ĸ value was 0.80. Conclusion: Duplex sonography should be proposed first in VB attacks or stroke to detect and quantify vertebral artery stenoses for surgery and angioplasty.

Detection of vertebrobasilar intracranial stenoses : Transcranial Doppler sonography versus angiography

Vertebrobasilar intracranial stenoses seem to carry a higher risk of brain stem ischemia than proximal vertebral artery stenoses. Our aim was to assess the value of transcranial Doppler sonography versus angiography in detecting and quantifying these intracranial stenoses. All consecutive patients who underwent transcranial Doppler sonography prior to angiography from 1989 to 1994 and whose sonograms showed a stenosis of greater than 50% of one vertebral artery (21 cases) or of the basilar artery (eight cases) were included in the study. These patients were compared with 60 other consecutive stroke patients studied via transcranial Doppler sonography prior to normal vertebrobasilar angiography The transcranial Doppler sonographic criteria for stenosis were a peak systolic frequency shift greater than 2 KHz. A tight stenosis was identified by this pattern combined with direct and reverse low frequencies of high spectrum energy. The sensitivity of transcranial Doppler sonography using a peak systolic frequency shift in diagnosing stenoses reached 80% and its specificity was 97% if only atheromatous stenoses were considered. The main diagnostic failures concerned bilateral stenoses or contralateral occlusion, tandem lesions, and upper basilar artery stenosis. Transcranial Doppler sonography underestimated the degree of stenosis compared to angiography in 55% of the cases. We conclude that transcranial Doppler sonography is accurate in recognizing a stenosed vessel in the intracranial vertebrobasilar circulation, but if this finding will alter therapy, the examination must be complemented by magnetic resonance angiography.

Colour Doppler and duplex sonography and angiography of the carotid artery bifurcations

We undertook a prospective double-blind study of 128 carotid artery bifurcations using colour Doppler and duplex sonography and angiography. Sixty-four patients with cerebrovascular events were admitted for angiography. All underwent sonography within 24 h of angiography. Standard duplex sonography and colour Doppler imaging without spectral analysis were performed, on the same device, by two sonographers, using defined morphological and haemodynamic criteria. Digital radiological data on vessel diameter were interpreted independently by two radiologists.The two sonographic methods gave similar grading of stenosis, compared to angiography, with an accuracy ranging from 96% in severe to 83% in minor stenoses. Colour Doppler studies gave better area measurements than standard duplex sonography, except for major stenoses. Discrepancies between ultrasonography and angiography were due mainly, to minor stenoses and large plaques of calcification on the vessel walls, which masked very segmental 70% stenoses in 2 cases. Angiography is limited by its own resolution, does not show uncalcified vessel walls and does not give cross-sectional data. It would therefore be inappropriate for showing small plaques, the full extent of ectasia or for defining the carotid bulb accurately.The advantages of colour methods were in investigating sinuous or deep vessels and hypoechoic plaques. Analysis of the residual lumen of a stenosis and its extent could be determined more rapidly. Haemodynamic quantification of stenoses by standard duplex sonography may be difficult because of limited sample volume and error in estimation of angle, whereas colour Doppler allows semiquantitative estimation of haemodynamics. Standard duplex sonography permits good analysis of vessel wall over a limited distance and quantification of velocity; colour Doppler affords overall demonstration of turbulence, acceleration and backward flow.