Current clinical management of CIDP with immunoglobulins in France: An expert opinion.

Treatment strategies in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) must be adapted on a case-to-case basis. Validated and reproducible tools for monitoring treatment response are required at diagnosis, when initiating treatment and throughout follow-up. A task force of French neurologists, experts in neuromuscular disease reference centers, was assembled to provide expert advice on the management of typical CIDP with intravenous immunoglobulins (Ig), and to harmonize treatment practices in public and private hospitals. The task force also referred to the practical experience of treating CIDP with Ig at the diagnostic, induction and follow-up stages, including the assessment and management of Ig dependence, and following the recommendations of the French health agency.

Identification of novel pathogenic copy number variations in Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease (CMT) is a hereditary sensory-motor neuropathy characterized by a strong clinical and genetic heterogeneity. Over the past few years, with the occurrence of whole-exome sequencing (WES) or whole-genome sequencing (WGS), the molecular diagnosis rate has been improved by allowing the screening of more than 80 genes at one time. In CMT, except the recurrent PMP22 duplication accounting for about 60% of pathogenic variations, pathogenic copy number variations (CNVs) are rarely reported and only a few studies screening specifically CNVs have been performed. The aim of the present study was to screen for CNVs in the most prevalent genes associated with CMT in a cohort of 200 patients negative for the PMP22 duplication. CNVs were screened using the Exome Depth software on next generation sequencing (NGS) data obtained by targeted capture and sequencing of a panel of 81 CMT associated genes. Deleterious CNVs were identified in four patients (2%), in four genes: GDAP1, LRSAM1, GAN, and FGD4. All CNVs were confirmed by high-resolution oligonucleotide array Comparative Genomic Hybridization (aCGH) and/or quantitative PCR. By identifying four new CNVs in four different genes, we demonstrate that, although they are rare mutational events in CMT, CNVs might contribute significantly to mutational spectrum of Charcot-Marie-Tooth disease and should be searched in routine NGS diagnosis. This strategy increases the molecular diagnosis rate of patients with neuropathy.

Different HLA class II (DRB1 and DQB1) alleles determine either susceptibility or resistance to NMO and multiple sclerosis among the French Afro-Caribbean population.

BACKGROUND: Despite similarities, neuromyelitis optica (NMO) can be distinguished from multiple sclerosis (MS) by clinical, radiological and serological findings. OBJECTIVE: This case-control study aimed to determine whether patients with NMO or with MS in an Afro-Caribbean population originating from French West Indies shared the same or different HLA class I and II pattern distribution. METHODS: The association with HLA class II (DRB1 and DQB1) alleles was tested in 42 NMO patients, 163 MS patients and 150 healthy controls. HLA-DRB1 and DQB1 typing was undertaken on genomic DNA extracted from peripheral blood leucocytes. RESULTS: By comparison with healthy controls, significantly increased frequency of HLA-DRB1 03 (26.2% vs. 13%, odds ratio 2.4, 95% confidence interval 1.31-4.28, p after correction, cp 0.045) was observed in patients with NMO. By contrast, in MS patients, HLA-DRB1 15 (24.8% vs. 13%, odds ratio 2.21, 95% CI 1.45-3.36, cp < 0.0015), but not DRB1 03 allele, was positively associated with the disease. Moreover, a modest protective effect of HLA-DRB1 11 in the MS group, independently of DRB1 15 association, was found (13.7% vs. 7% in controls, odds ratio 0.48, p 0.006), but did not survive Bonferroni correction. CONCLUSION: In conclusion, comparison of the HLA-DRB1 and DQB1 distribution in NMO and MS in this Afro-Caribbean population shows important differences in the HLA associations among NMO and MS.

[Sensory ataxic neuromyelopathy in acquired copper deficiency]. / Ataxie proprioceptive et carence en cuivre masquée.

INTRODUCTION: Neurological involvement associated with copper deficiency has been reported recently in humans and may be under-recognized. CASE REPORT: A 65-year-old patient, with past history of gastrectomy 40 years earlier, developed a myelodysplastic syndrome and then subacute onset of progressive gait ataxia and paresthesias in the lower extremities. Serum vitamin B12 level was low but neurological deterioration persisted, despite vitamin replacement therapy and normal cobalamin level. Further diagnostic investigations revealed severe copper deficiency. Copper supplementation led to hematologic improvement and neurological stabilization. CONCLUSION: Copper and vitamin B12 deficiency, due to malabsorption as a cause of progressive neuromyelopathy and hematologic manifestations, may coexist.

MS and neuromyelitis optica in Martinique (French West Indies).

BACKGROUND AND OBJECTIVE: A population-based study is reported of MS in French Afro-Caribbeans (FAC) in Martinique. FAC are descendants of interracial mating that occurred between French Caucasians and black Africans in the 17th and the 18th centuries. METHODS: The authors surveyed the entire island of Martinique (area 1,128 km(2), population 357,000) between November 1997 and October 1999. RESULTS: Sixty-two patients (46 females, 16 males, ratio 2.9:1) were identified with definite or probable disease by the Poser criteria. Prevalence for all patients on December 31, 1998, was 17.4/10(5) (95% CI 13.1 to 21.7) and 14.3/10(5) (95% CI 10.4 to 18.2) for clinically definite cases (n = 51). Age range of patients on prevalence day was 17 to 73 years (mean +/- SD 39 +/- 11.3 years). Mean age at onset was 31.2 +/- 11 years. Overall, 9.7% had primary progressive disease and 19.4% had benign MS. A low proportion of definite and probable MS cases had oligoclonal bands in CSF (50.9%). Seventeen patients, 13 of whom were alive on prevalence day, had a relapsing form of neuromyelitis optica. CONCLUSION: The island of Martinique appears to have a low to medium prevalence of MS. MS was almost unknown in FAC in Martinique until the late 1970s. The apparent recent increase may be explained by improved recognition of patients, increased availability of MRI for diagnosis, increased disease awareness among physicians, increased survival of MS patients, or an actual increase in disease frequency.

Autosomal dominant cerebellar ataxia type I in Martinique (French West Indies): genetic analysis of three unrelated SCA2 families.

Autosomal dominant cerebellar ataxias (ADCAs) are a group of neurodegenerative disorders that are clinically and genetically heterogeneous. We report here a genetic linkage study, with five chromosome 12q markers, of three Martinican families with ADCA type 1, for which the spinocerebellar ataxia 1 (SCA1) locus was excluded. Linkage to the SCA2 locus was demonstrated with a maximal lead score of 6.64 at theta = 0.00 with marker D12S354. Recombinational events observed by haplotype reconstruction demonstrated that the SCA2 locus is located in an approximately 7-cM interval flanked by D12S105 and D12S79. Using the z(max)-1 method, multipoint analysis further reduced the candidate interval for SCA2 to a region of 5 cM. Two families shared a common haplotype at loci spanning 7 cM, which suggests a founder effect, whereas a different haplotype segregated with the disease in the third family. Finally, a mean anticipation of 12+/-14 years was found in parent-child couples, with no parental sex effect, suggesting that the disease might be caused by an expanded and unstable triplet repeat.

Autosomal dominant cerebellar ataxia type I in Martinique (French West Indies). Clinical and neuropathological analysis of 53 patients from three unrelated SCA2 families.

Autosomal dominant cerebellar ataxia type I was diagnosed in three unrelated families from Martinique (French West Indies), and linkage to the locus for spinocerebellar ataxia 2 (SCA2) was established. Neuropathological findings in two patients were those of olivopontocerebellar atrophy without oligodendroglial cytoplasmic inclusions. Cerebellar ataxia was associated with hyporeflexia in 68% of 31 examined patients, with slowed and/or limited eye movements in 65% and with dementia in 29%. No patients had optic atrophy, pigmentary retinal degeneration, spasticity or parkinsonism. Mean age at onset was 33 +/- 16 years, and onset before the age of 20 years was correlated with a more rapid and severe course of the disease. Movement disorders, oculomotor disturbances, sphincter disturbances and cognitive impairment were significantly more frequent in early than in late onset patients. This explains why the phenotype was strikingly different in one family, in which mean age at onset was much earlier. Comparison with previously described SCA2 families indicated similarities, such as reduced saccade velocity, supranuclear ophthalmoplegia and decreased reflexes, although phenotypic heterogeneity remains the outstanding feature of this disorder.

A search for human T-cell leukemia virus type I in the lesions of patients with tropical spastic paraparesis and polymyositis.

We searched for the presence of human T-cell leukemia virus type I (HTLV-I) sequences in central nervous system and muscle lesions of 3 patients with tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM) and 3 patients with HTLV-I-associated polymyositis. Proviral DNA coding for the Tax protein was found by polymerase chain reaction amplification in DNA extracted from lesions of every patient with TSP/HAM or HTLV-I-associated polymyositis. In contrast, viral RNA was found occasionally by in situ hybridization in muscle lesions of some patients with polymyositis, but was never found in central nervous system lesions of TSP/HAM patients.

Clinical characteristics of HTLV-1 associated dermato-polymyositis. Seven cases from Martinique.

Myositis linked to HTLV-1 is unfrequent. Over a period of 8 years, 14 patients with inflammatory myopathy were diagnosed in Martinique. Seven were seropositive for HTLV 1 antibody; the clinical and pathological data of whom are presented herein. Five patients presented with polymyositis, two with dermatomyositis. All seven patients had extra-muscular clinical features including neuropathy (4/7) and myelopathy (6/7), resulting in a quite peculiar clinical picture. Muscle biopsy showed a neurogenic process combined with myositic changes in 3/7 patients. Corticotherapy led to dramatic improvement in only one case, but with no sustained effect. HTLV 1 may be considered the etiological agent of this form of dermato-polymyositis, characterized by a clearly distinctive clinico-pathological picture, and a poor response to corticotherapy. As in the case of tropical spastic paraparesis/HTLV 1 associated myelopathy, careful assessment of non-steroidal therapy is now warranted.

[Involvements of the peripheral nervous system and skeletal muscles in HTLV1-related paraplegia. Study of 70 cases seen in Martinique]. / Atteintes du système nerveux périphérique et du muscle squelettique au cours des paraplégies associées au virus HTLV1. Etude de 70 cas observés en Martinique.

The main neurological manifestation due to Human T-Cell Lymphotropic Virus type (HTLV1) infection is a chronic spastic paraparesis called HTLV1-associated paraparesis (HAP). Since 1985, we observed in Martinique (French West Indies) 276 cases of HAP. Among them, 70 patients fulfilled clinical, electrophysiological or histological criteria of associated peripheral nervous system involvement (42/70), myositis (8/70), or both (20/70). Muscle biopsy revealed neurogenic atrophy of muscle fibers or myositic changes in 41/70. Neuromuscular involvement was only mild in 19/70. On the other hand, 25 patients presented with a syndrome mimicking amyotrophic lateral sclerosis, and 7 other patients with features of polymyositis. This study shows that neurological manifestations associated to HTLV1 infection may be more complex than the well-known chronic spastic paraparesis, since 25.4% of the HAP Martinican patients exhibit neuropathic or myositic features.

Uncompacted myelin lamellae in polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes syndrome. Ultrastructural study of peripheral nerve biopsy from 22 patients.

Mechanisms of peripheral neuropathies in polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) syndrome are poorly understood. A peripheral nerve biopsy was performed in 22 patients. Of these 9 had histological features of Castleman's disease on lymph node biopsies, and 19 had a monoclonal lambda light chain in their serum. Certain nerve fragments were paraffin embedded, others were frozen and studied by direct immunofluorescence, and others were fixed for ultrastructural examination. Paraffin-embedded fragments did not show any amyloid deposits, and at direct immunofluorescence there was no immunoglobulin fixation. At ultrastructural examination, features of uncompacted myelin lamellae (UML) were present in 19 patients, and their frequency varied from 1% to 16% of myelinated fibres. Up to now UML have been reported only in 7 patients with POEMS syndrome in the literature. UML have also been noticed in a few cases of inflammatory demyelinating polyradiculoneuritis and inherited tendency to pressure palsy.

Immunological findings in selected aspects of HTLV-1-associated neurological disease - abstract

The discovery in 1985 in Martinique of an association between human T lymphotrophic virus type (HTLV -1) and tropical spastic paraparesis (TSP) (Gessain et al, 1985) opened a new chapter in the search for viruses in chronic human neurological disease. A few HTLV-1 seropositive patients have been reported to present with a clinical picture of a slowly progressive disorder resembling amyotrophic lateral sclerosis (ALS), but with a slower evolution (Vernant et al, 1989). In addition, pathological findings in some TSP cases have included anterior horn neuron depletion (Robertson and Cruickshank, 1972; Arimura et al, 1989). We have monitored selected humoral immune factors as well as levels of inflammatory proteins in asymptomatics and normal controls, using a computer-aided electrophoresis technique. The results showed a significant presence of hypergamma-globulinaemia, predominantly IgC in TSP patients. Interestingly enough, as well, immune complexes, complement cascade activation in those HTLV-1 seropositive patients with anterior horn-like neurological disorders. These data are consistent with the hypothesis of the occurrence of an immune complex-mediated vasculitis phenomenon in the latter subjects. Monitoring of these biological factors may represent a useful tool in the diagnosis and understanding of the physiopathological mechanisms of these disorders (AU)

[Paraplegia associated with HTLV 1 in Martinique. Study of 271 cases including 70 with neuromuscular involvement]. / Paraplégie associée à l'HTLV1 en Martinique. Etude de 271 cas dont 70 avec atteinte neuromusculaire.

To date, 271 cases of HTLV1-associated paraplegia have been observed in Martinique (French West Indies). The clinical picture consisted mostly in a spastic paraparesis or paraplegia with sphincter disturbances (80%) and lower limbs pains (60%). The severity of the disease appeared variable: after a mean disease duration of 6.5 years, 40% of the patients could walk without help, 35% used a single crutch, and 25% used a couple of crutches or were confined to a wheelchair. A variable neuromuscular component was observed in 70 cases (25.4%). In 38 cases, the peripheral signs (SIGNS) or the myositis were only mild. In contrast, 25 patients presented with severe amyotrophy evoking amyotrophic lateral sclerosis, and 7 other had features of dermatopolymyositis. Lastly, an extra-neural spreading of the disease was extremely frequent, including lymphocytic alveolitis (76%), sicca syndrome (69%) and more rarely uveitis, arthritis or vasculitis.

[Neurologic manifestations related to HTLV-1 viruses]. / Manifestations neurologiques associées au virus HTLV-1.

The human T-cell leukaemia virus type 1 was the first human retrovirus to be isolated in 1980 by R. Gallo and coworkers. As its name indicates, this virus is responsible for adult T-cell leukaemia. In 1985, the neurological manifestations associated with this disease were isolated from the tropical spastic paraplegia group in Martinique. Since that time, such manifestations have been reported in non-tropical countries in other foci of viral endemia and sporadically outside these regions. These neurological manifestations are totally independent of the haematological manifestations with which they are virtually never associated. Frequent in areas of viral endemia, they may be encountered in other countries open to human migrations, where they are too often overlooked.

[Cerebrovascular complications of sickle-cell anemia]. / Complications cérébro-vasculaires de la drépanocytose.

Cerebrovascular disorders are frequent in sickle-cell anemia. They occur mainly in homozygous children. Traditionally, they were believed to result from an arteriolar sickle-cell thrombosis, the "sludge" phenomenon, which is generally responsible for sickle cell anemia disorders. It is now well known that several other kinds of cerebral damages are involved such as moya-moya syndrome, cerebral hemorrhage, subdural hematoma, extra-dural hematoma and cerebral thrombophlebitis. In this disease, the identification of these different processes cannot be always made by a simple clinical examination. However, specific therapies are sometimes necessary, such as neurosurgical intervention in the case of aneurysm or hematoma, and, according to some authors, the necessity of repeated appropriate transfusions, in the case of moya-moya. So it is imperative to carry out without delay a complete neuroradiological assessment of the lesions. At present, the most widely accepted theory to explain the arteriolar lesions, is that they result from a sickle-cell thrombosis of the vasa-vasorum, but, we think it is not the only valid hypothesis and we think that other phenomena may be involved with a genetic factor (patients with connective tissue disorders may have a particular genotype), and with infectious or autoimmune or coagulation disorders, the latter being frequently observed in this disease.

Ultrastructural study of peripheral nerve in arteritic diabetic patients.

The peripheral nerve was taken from 25 diabetic patients with arteritis just before or after amputation of a leg. The ultrastructural study of myelinated fibers showed several alterations. Loss of fibers varied greatly from case to case. This was accompanied in some cases by hypertrophy of the Schwann cells around demyelinated fibers as has been observed in some ordinary diabetic neuropathies. Unusual abnormalities consisted of particular axonal degeneration and evidence of aberrant remyelination. This axonal injury was peculiar because of the accumulation of organelles which tended to transform some of the fibers into enlarged axons. Such a lesion might correspond to a hypoxic axonopathy.