Usefulness of combined nerve and muscle biopsy in the diagnosis of amyloid neuropathy--a study of 6 new cases.

OBJECTIVE: Most cases of familial amyloid polyneuropathy are identified by molecular genetic analysis of the transthyretin (TTR) gene. However, it is not uncommon to find unexpected amyloid deposits marked by the anti-TTR serum in the endoneurium of aged patients. Light chain amyloid deposits may also be found in the endoneurium. During these past 5 years, we studied the muscle and nerve biopsies from 6 patients which revealed amyloid deposits. There were 2 patients with an idiopathic polyneuropathy and 4 with monoclonal gammopathy (MG). METHODS: In each case, specimens from the superficial peroneal nerve and peroneus brevis muscle were taken by the same cutaneous incision. RESULTS: Amyloid deposits were visible in the endoneurium of 2 cases and only on muscle specimens in 3 other cases, 1 with a MG and 2 with an idiopathic polyneuropathy. Amyloid deposits were strongly stained with the anti-TTR serum in the muscle specimens of the 2 idiopathic cases, mainly located in vessel walls. In one patient with polyneuropathy and MG, a small endoneurial amyloid deposit surprisingly revealed to be immunostained by the anti-TTR serum. In another case, a small amyloid deposit in close relationship with a macrophage was only visible in the endoneurium by electron microscopy. COMMENTS: Amyloid deposits were only visible on muscle fragments in 3 cases and were strongly marked by the anti-TTR serum in 2 of them, indicating their familial origin. Combining muscle and nerve biopsy raises the number of cases with visible amyloid deposits.

Sarcoid neuropathy: clinico-pathological study of 4 new cases and review of the literature.

There are several reviews devoted to neurosarcoidosis and a few reports restricted to sarcoid neuropathy. Since 1989, we have investigated 4 new cases of sarcoid neuropathy, 1 with chronic sensory motor neuropathy (CSMN), another with painful neuropathy and 2 with atypical chronic inflammatory demyelinating polyneuropathy (CIDP). In each case, biopsy specimens from the superficial peroneal nerve and peroneus brevis muscle were taken by the same cutaneous incision and studied on paraffin sections, semi-thin sections and under electron microscope. We compared neuropathological findings from our 4 cases with those from 34 well-studied nerve biopsies previously reported in the literature, and which concerned 16 cases of CSMN, 13 cases ofmononeuropathy multiplex, 2 cases of painful neuropathy and three cases of CIDP. In all of these 38 cases of sarcoid neuropathy, the characteristic noncaseiting granulomas (NCG) were observed on the nerve in 11 cases, on the muscle alone in 5, on both muscle and nerve in 10, and in the nerve and another parenchyma in 4. In the 8 remaining cases, NCG were observed in another parenchyma, mainly lung or lymph nodes. Moreover, necrotizing vasculitis was present in nerve biopsies from 8 cases and microvasculitis without obvious necrosis in 2 others. Nerve fiber lesions, which are mainly axonal, are probably related to mechanical compression by NCG and/or to an ischemic process due to vasculitis. Cytokines and immune factors may also play a role, especially in certain cases with a clinical presentation of CIDP.

[Lambert-Eaton Myasthenic Syndrome associated with vocal cord carcinoma]. / Syndrome myasthénique de Lambert-Eaton associé à un carcinome épidermoïde de la corde vocale.

INTRODUCTION: Lambert-Eaton Myasthenic Syndrome (LEMS) is an autoimmune channelopathy in which patients produce autoantibodies directed against voltage-gated calcium channels. LEMS is paraneoplastic in 50% of patients, most frequently associated with small cell lung carcinoma. We describe a case of paraneoplastic LEMS associated with a vocal cord carcinoma. OBSERVATION: A 64-year-old man developed in five months muscle weakness affecting gait. Clinical examination showed proximal muscular deficiency, areflexia and dysphonia. Electrophysiologic study showed potentiation greater than 500% after post exercise facilitation and 76 percent increment response at high-rate repetitive nerve stimulation (20Hz). Diagnosis of LEMS was confirmed by electrophysiologic study and anti-voltage gated calcium channel antibodies (90pM, positive value greater or equal to 70pM). Left vocal cord lesion histology showed epidermoid carcinoma. A combination of vocal cord tumor removal by endoscopy and treatment by pyridostigmine, 3-4 diaminopyridine and intravenous human immunoglobulin improved neurological symptoms. CONCLUSION: Paraneoplastic syndromes in association with cancers of the larynx and hypopharynx are unusual. Only two cases are reported with LEMS associated with larynx carcinoma. We describe an unusual case of LEMS associated with a left vocal cord carcinoma.

Epsilon sarcoglycan mutations and phenotype in French patients with myoclonic syndromes.

BACKGROUND: Myoclonus dystonia syndrome (MDS) is an autosomal dominant movement disorder caused by mutations in the epsilon-sarcoglycan gene (SGCE) on chromosome 7q21. METHODS: We have screened for SGCE mutations in index cases from 76 French patients with myoclonic syndromes, including myoclonus dystonia (M-D), essential myoclonus (E-M), primary myoclonic dystonia, generalised dystonia, dystonia with tremor, and benign hereditary chorea. All coding exons of the SGCE gene were analysed. The DYT1 mutation was also tested. RESULTS: Sixteen index cases had SGCE mutations while one case with primary myoclonic dystonia carried the DYT1 mutation. Thirteen different mutations were found: three nonsense mutations, three missense mutations, three splice site mutations, three deletions, and one insertion. Eleven of the SGCE index cases had M-D and five E-M. No SGCE mutations were detected in patients with other phenotypes. The total number of mutation carriers in the families was 38, six of whom were asymptomatic. Penetrance was complete in paternal transmissions and null in maternal transmissions. MDS patients with SGCE mutation had a significantly earlier onset than the non-carriers. None of the patients had severe psychiatric disorders. CONCLUSION: This large cohort of index patients shows that SGCE mutations are primarily found in patients with M-D and to a lesser extent E-M, but are present in only 30% of these patients combined (M-D and E-M).

[Chronic inflammatory demyelinating polyradiculoneuropathy: diagnostic strategy. Guidelines of the French CIDP study group]. / Polyradiculonévrites inflammatoires démyélinisantes chroniques: stratégie diagnostique. Recommandations du groupe d'Etude français des PIDC.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) comprises a group of dysimmune neuropathies easily diagnosed in more than half of the patients. Diagnosis is based on clinical, electrophysiological and biological clues. In some patients, diagnosis is unclear because of the debated value of the available clues. In such circumstances, dysimmune neuropathies may not be diagnosed, leading to insufficient treatment. This is an important category of patients because immunomodulatory drugs have proven efficacy. The CIDP spectrum includes a relatively wide range of diseases. Besides the easily recognized classic forms, there are many clinical variants, sometimes with a paucisymptomatic presentation leading to uncertain diagnosis. The French CIDP study group has established guidelines for diagnostic strategy in CIDP patients. The first part of this paper is devoted to the clinical aspects of the disease, classical forms and variants. In the second part, the results of electrophysiological studies are reported. In a third chapter, complementary examinations useful for diagnosis are discussed. The fourth chapter deals with the diagnostic strategy, discussed in relation to the different situations which may be encountered in clinical practice. details the technical modalities of appropriate electrophysiological studies and presents normal results together with those indicating demyelinating neuropathy. Nerve biopsy technique and results are given in appendix II.

[Cramp-fasciculation syndrome]. / Le syndrome crampes-fasciculations.

The cramp-fasciculation syndrome is a rare clinical entity in comparison with the frequency of cramps and isolated fasciculations in the general population. It is recognized as a benign syndrome without weakness and atrophy, however a few reports suggest that it may precede the occurrence of a motor neuron disease. Most often, the cramp-fasciculation syndrome is idiopathic and may be a component of a hyperexcitable peripheral nerve syndrome including other activities such as myokymia and neuromyotonia where antibodies to voltage-gated potassium channels (VGKCs) appear to be one of the effector mechanisms. The most complete form of this hyperexcitable peripheral nerve syndrome is Isaacs' syndrome. The central nervous system is also concerned with anti-VGKC antibodies found in Morvan's disease and limbic encephalitis which is often a paraneoplastic condition. These findings extend the spectrum of the anti-VGKC syndrome that may be associated with other auto-immune diseases, chiefly myasthenia gravis with thymoma. Carbamazepine and phenytoin cause reduction of the clinical and electrophysiological signs of the nerve hyperexcitability, and plasmapheresis and (or) immunosuppressors are useful when an auto-immune origin is considered.

Neuropathy resembling CIDP in patients receiving tumor necrosis factor-alpha blockers.

Tumor necrosis factor-alpha (TauNuFalpha) blockers are effective in the treatment of inflammatory arthritis but can induce autoimmune disorders including multiple sclerosis. Described are two patients who developed chronic inflammatory demyelinating polyneuropathy after initiation of anti-TNFalpha treatment.

[Single-fibre electromyography]. / L'electromyographie de fibre unique.

Single-fibre electromyography (SF-EMG) is the most sensitive electrophysiological test for myasthenia gravis and other neuromuscular junction pathology. It is also useful in the assessment of motor unit morphology in some neuromuscular diseases. A special needle with a 25 microm recording surface is used to record the time-locked potentials of 2 muscle fibers belonging to the same motor unit. Jitter is the variability in the arrival time of action potentials to the recording surface between consecutive discharges. The junctional part of the jitter depends on the amount of Ach released and on the sensitivity of the postsynaptic membrane and is related to the safety margin of neuromuscular transmission. Thus, SF-EMG can detect subclinical impairment of neuromuscular transmission, which cause an increased jitter. However, an increased jitter is not specific of neuromuscular transmission disorders, because it may be due to unstable conduction in motor nerves and muscle fibers. It is the extrajunctional part of the jitter. SFEMG is performed either during slight voluntary contraction (volitional SFEMG) or by axonal stimulation (stimulated SFEMG). Jitter is expressed as the mean of the absolute consecutive differences (MCD) of the latency between the time-locked potentials (volitional SFEMG) or from the stimulus to the negative peak of the potential (stimulated SFEMG). Recording is judged abnormal when more than 10% of the collected pairs are abnormal. On the other hand, single use coaxial needle electrodes which are cheaper could be an alternative for neuromuscular transmission analysis, because the jitter analysed with this type of needle was found highly comparable to that analysed with SF electrode. Moreover, jitter measurements coupled with fiber density estimates provide valuable information on the pathophysiology of the motor units in various neuromuscular disorders.

[POEMS syndrome (or Crow-Fukase syndrome)]. / Le syndrome POEMS (ou syndrome de Crow-Fukase).

POEMS is an acronym for polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes. POEMS syndrome is also called Crow-Fukase syndrome, chiefly in Japan. The 5 above mentioned features are not always present at the first examination. The minimal criteria to establish the diagnosis are the presence of a demyelinating and axonal polyneuropathy associated with an IgA or IgG monoclonal gammopathy, the light chain being almost always lambda, and at least 2 of the 8 other features: sclerosing plasmocytoma, endocrinopathy, skin changes, organomegaly, Castleman's disease, anasarca, papillary edema or thrombocytosis. Among these features, only cutaneous glomeruloid angioma are specific. Ultrastructural identification of uncompacted myelin lamellae on the peripheral nerve biopsy is also a strong argument in favor of the diagnosis. An associated "osteosclerotic" bone lesion must be carefully searched, because its treatment may improve the other features of the syndrome, especially the neuropathy. Cytokines and the vascular growth endothelial factor might play a role in the pathogenesis of this rare multisystemic disorder.

Serum IgG antibodies to P0 dimer and 35 kDa P0 related protein in neuropathy associated with monoclonal gammopathy.

BACKGROUND: Peripheral neuropathies (PN) associated with monoclonal gammopathy (MG) are widely considered as autoimmune disorders, but the putative role of incriminated antigens is still not understood. OBJECTIVE: Fifty five patients with PN associated with MG were studied to investigate whether new antigens could be found, and to evaluate their relation to clinical manifestations. METHODS: An immunological study was conducted on patient sera to identify autoreactivities against nerve proteins by western blotting. Antigen proteins were purified and analysed by proteomic tools. Correlation with ultrastrucural and clinical features was then studied. RESULTS: Of the 55 patients suffering from PN associated with MG, 17 exhibited IgG autoantibodies directed against peripheral nerve proteins of 35, 58, and 60 kDa. N-terminal microsequencing and mass spectrometry analyses of the 35 kDa protein revealed perfect peptidic matching with 47% of the amino acid sequence of P0, whereas the 58 and 60 kDa proteins were identified as the reduced and non-reduced forms of a P0 dimer. Deglycosylation did not affect IgG binding to the 35 kDa P0 related protein, suggesting a peptidic epitope. In contrast, deglycosylation abolished IgG recognition of the P0 dimer protein, so that a carbohydrate moiety may be implicated in the epitope formation. This confirmed the existence of two different types of IgG, one recognising the 58 and 60 kDa proteins and one directed against the 35 kDa protein. CONCLUSIONS: This is the first report of antibody activity directed against the dimeric association of P0. Although P0 oligomerisation and adhesion properties play a crucial part in the myelin sheath compaction, the pathogenic significance of these autoantibodies needs further investigations to be elucidated.

Improvement of norfloxacin oral bioavailability by EDTA and sodium caprate.

The EDTA and sodium caprate (Na caprate) effects on the oral bioavailability of norfloxacin were tested. It was found that absorption kinetic of norfloxacin was markedly accelerated when mixed with EDTA or Na caprate in a ratio of 1:1. When mixed with the absorption enhancers in a ratio of 1:5, only Na caprate improved norfloxacin bioavailability significantly. In vitro dissolution tests demonstrated that EDTA and Na caprate increased norfloxacin dissolution kinetic. However, the correlation between bioavailability and in vitro dissolution improvement was not clearly established. So, we can conclude that the solubilizing property of EDTA and Na caprate did not take a prominent part in norfloxacin absorption.

[Progressive supranuclear palsy: a clinical, natural history and disability study]. / Paralysie supranucléaire progressive: étude clinique, histoire naturelle et progression du handicap.

We studied the clinical features, the natural history and disability in 47 progressive supranuclear palsy patients and brain imaging aspects by routinely performed MRI in a subgroup of 25. Unexplained falls together with atypical parkinsonism (symmetric, levodopa unresponsive without resting tremor) are good clinical pointers of the early diagnosis, since they occurred within the first year. Cognitive slowness and unspecific visual complains are also early symptoms, while usual cardinal signs such as supranuclear palsy are more delayed. Blepharospasm and eyelid opening apraxia as well as deep sighs are also quite characteristic clinical features (1/3 of cases). Cardinal signs (falls, pseudobulbar signs, supranuclear gaze palsy) worsened rapidly (20 to 30 months) towards a major disability. In the 20 patients deceased during follow-up, the mean survival time was about 5 years. The MRI study showed typical cortical fronto-temporo-parietal atrophy, mesencephalic and quadrigeminal plate atrophy with third ventricle dilatation. In conclusion, unexplained falls associated with atypical parkinsonism are contributive for the early clinical diagnosis. Non specific visual complains could be useful pointers in the absence of supranuclear ophthalmoplegia. MRI contributes to the clinical diagnosis even in the first 3 years of the disease course.

Peripheral neuropathy associated with mitochondrial disorders: 8 cases and review of the literature.

Forty-three cases of peripheral neuropathy (PN) have been reported in the literature with a proven mitochondria (mt) DNA mutation, and 21 had a peripheral nerve biopsy (PNB). We studied 8 patients, 1 of whom had severe sensory PN, 3 mild PN, and 4 subclinical PN. Nerve biopsy was performed in every case; all patients showed axonal degeneration and 4 showed features of primary myelin damage. In addition, there were 2 crystalline-like inclusions in the Schwann cell cytoplasm of a patient with MERRF, and 1 in a patient with multiple deletions on the mtDNA. There are 11 cases of PNB in the literature with axonal lesions, 5 with demyelination, and 4 with mixed lesions. One PNB was not modified. A few crystalline-like inclusions were seen in 1 case of MERRF. Such inclusions were first reported in the Schwann cell cytoplasm of unmyelinated fibers in a patient with Refsum disease and were considered to be modified mitochondria. However, their mitochondrial origin remains debatable.

Minimal tissue damage after stimulation of the motor thalamus in a case of chorea-acanthocytosis.

Autopsy findings are reported from a patient with chorea-acanthocytosis treated for 2 years by deep brain stimulation (DBS) of the motor thalamus. Postoperative testing showed a progressive improvement in axial truncal spasms. Although relatively high currents were used for 2 years in this patient, postmortem analysis showed minimal tissue damage in the vicinity of the electrode tip. It is concluded that DBS has little impact on the surrounding tissues.

[Botulinum toxin in the management of spastic hip adductors in non-ambulatory cerebral palsy children]. / Toxine botulinique dans la spasticité des adducteurs de hanche chez les enfants IMC et IMOC non marchants.

PURPOSE OF THE STUDY: Spasticity of the hip adductors is a challenging problem for children with severe motor impairment due to cerebral palsy. It inhibits motor development and is also a risk factor for hip dislocation. Botulinum toxin has been found to be an effective means of treating spastic pes equinus in walking cerebral palsy patients and could have other indications. We conducted a prospective study to determine the functional and orthopedic contribution of botulinum toxin in the treatment of spastic hip adductors in non-ambulatory cerebral palsy children. MATERIAL AND METHODS: The study included 11 quadriplegic children with cerebral palsy (mean age 5 years 9 months). Seven of the children had unilateral migration of the hip at study onset (> 40% radiographically). The children were given a single injection of botulinum toxin (Dysport: 20 units/kg/hip) in the adductor muscles (21 treated hips). The children were seen again at months 1, 3, 6 and 12 after treatment (with the exception of one patient not seen after the 6(th) month at the request of the parents). Spasticity was measured with the modified Ashworth scale. The motor level was determined with 8 position and motor items and with the GMFCS classification. Hip x-rays were obtained at study onset and once or twice during the follow-up. RESULTS: There were no adverse effects of the treatment. Spasticity decreased by one point or more on the Ashworth scale in 20 hips at month 1 and remained low at month 3 in 14, and at month 6 in 12 of the 21 hips treated. The effect of the anti-spasticity treatment faded out from the 6(th) to the 12(th) month. Three children who experienced pain in the lower limbs were definitively relieved after treatment. Nine children achieved functional improvement (progress in at least one of the motor items). Three children were able to walk with a walker and two of them improved from level IV to level III on the GMFCS. The best functional responses appeared to occur in the younger children and in those who had good results at months 3 and 6. Among the 7 children whose hip was displaced by more than 40%, 5 had an unfavorable radiological progression and underwent surgery. DISCUSSION: This study demonstrates that the botulinum toxin can be effective against spasticity of the hip adductors and that its effect is still significant 6 months after the injection in more than half the hips treated. It has an analgesic effect. This treatment has a functional impact even in children with severe motor impairment. The benefit has been modest but three children were able to progress to walking with a walker. The best functional results were observed in the younger children and in those whose spasticity had declined at month 3 and 6. It could thus be favored either by innate potential for motor development or by the treatment itself. The botulinum toxin did not improve the orthopedic prognosis of the children: 5 of the 7 with a risk of luxation worsened. Nevertheless, our study suggests that the botulinum toxin is a well-tolerated anti-spasticity treatment that is effective for the hip adductors providing an important contribution to the management of non-ambulatory cerebral palsy children.

Progressive bulbospinal amyotrophy in triple A syndrome with AAAS gene mutation.

Triple A (3A) syndrome, a rare autosomal recessive disorder, is characterized by adrenocorticotropic hormone-resistant adrenal insufficiency, achalasia of the cardia, alacrima, and variable autonomic and neurologic dysfunction. The gene responsible, AAAS, recently has been identified. We describe the neurologic phenotype of the first adult case of 3A syndrome presenting bulbospinal amyotrophy as the prominent sign in association with a homozygous nonsense mutation identified in the AAAS gene.