Peripheral nerve involvement in Fabry's disease: Which investigations? A case series and review of the literature.

BACKGROUND: Peripheral nerve system (PNS) involvement is common in Fabry's disease (FD), predominantly affecting the small nerve fibers that are difficult to investigate with conventional electrophysiological methods. PATIENTS AND METHODS: Eighteen patients followed for Fabry's disease underwent a prospective series of electroneurophysiological explorations, including a study of the cardiac parasympathetic autonomic nervous system (ANS) and electrochemical skin conductance (ESC) tests. Data were compared with those obtained in 18 matched healthy controls. RESULTS: All patients had at least one clinical sign suggestive of neuropathy: 16 reported an acrosyndrome and 12 had dyshidrosis. Cold hypoesthesia was found in 15 patients and heat hypoesthesia in 13. Electroneurophysiological investigations and study of the cardiac parasympathetic ANS were normal in all patients. The ESC was significantly lower in FD patients compared with controls. CONCLUSION: PNS involvement is common in FD and should be suspected in patients exhibiting an acrosyndrome, dyshidrosis and/or cold hypoesthesia. Conventional electrophysiological investigations are normal. New techniques, such as ESC, provide early diagnosis of small fiber involvement that currently requires more sophisticated tests difficult to apply in routine practice.

Search for ReCQL4 mutations in 39 patients genotyped for suspected Rothmund-Thomson/Baller-Gerold syndromes.

Three overlapping conditions, namely Rothmund-Thomson (RTS), Baller-Gerold (BGS) and RAPADILINO syndromes, have been attributed to RECQL4 mutations. Differential diagnoses depend on the clinical presentation, but the numbers of known genes remain low, leading to the widespread prescription of RECQL4 sequencing. The aim of our study was therefore to determine the best clinical indicators for the presence of RECQL4 mutations in a series of 39 patients referred for RECQL4 molecular analysis and belonging to the RTS (27 cases) and BGS (12 cases) spectrum. One or two deleterious RECQL4 mutations were found in 10/27 patients referred for RTS diagnosis. Clinical and molecular reevaluation led to a different diagnosis in 7/17 negative cases, including Clericuzio-type poikiloderma with neutropenia, hereditary sclerosing poikiloderma, and craniosynostosis/anal anomalies/porokeratosis. No RECQL4 mutations were found in the BGS group without poikiloderma, confirming that RECQL4 sequencing was not indicated in this phenotype. One chromosomal abnormality and one TWIST mutation was found in this cohort. This study highlights the search for differential diagnoses before the prescription of RECQL4 sequencing in this clinically heterogeneous group. The combination of clinically defined subgroups and next-generation sequencing will hopefully bring to light new molecular bases of syndromes with poikiloderma, as well as BGS without poikiloderma.

Myofibrillar myopathies: State of the art, present and future challenges.

Myofibrillar myopathies (MFM) have been described in the mid-1990s as a group of diseases sharing common histological features, including an abnormal accumulation of intrasarcoplasmic proteins, the presence of vacuoles and a disorganization of the intermyofibrillar network beginning at the Z-disk. The boundaries of this concept are still uncertain, and whereas six genes (DES, CRYAB, LDB3/ZASP, MYOT, FLNC and BAG3) are now classically considered as responsible for MFM, other entities such as FHL1 myopathy or Hereditary Myopathy with Early Respiratory Failure linked to mutations of titin can now as well be included in this group. The diagnosis of MFM is not always easy; as histological lesions can be focal, and muscle biopsy may be disappointing; this has led to a growing importance of muscle imaging, and the selectivity of muscle involvement has now been described in several disorders. Due to the rarity of these myopathies, if some clinical patterns (such as distal myopathy associated with cardiomyopathy due to desmin mutations) are now well known, surprises remain possible and should lead to systematic testing of the known genes in case of a typical histological presentation. In this paper, we aim at reviewing the data acquired on the six main genes listed above as well as presenting the experience from two French reference centres, Paris and Marseilles.

Revisiting the spectrum of lower motor neuron diseases with snake eyes appearance on magnetic resonance imaging.

BACKGROUND AND PURPOSE: The 'snake eyes' sign refers to bilateral hyperintensities of the anterior horns on axial spinal cord imaging. Based on sporadic reports, it has been associated with a range of lower motor neuron (LMN) syndromes, such as spondylotic amyotrophy and Hirayama disease, as well as spinal cord infarction. The objective of our study was to comprehensively characterize the full diagnostic spectrum of LMN syndromes with this radiological clue and discuss potential aetiological factors. METHODS: A large patient cohort with snake eyes sign and upper limb LMN degeneration was recruited from three French neuromuscular units. Patients underwent detailed electrophysiological, radiological, clinical and anamnestic profiling. RESULTS: Twenty-nine patients were ascertained and followed up for 9.5 ± 8.6 years. The majority of the patients were male (86.2%) with a mean age of 37.3 ± 14.4 years. Symptoms were bilateral in most cases (86.2%). Patients with predominantly proximal and distal deficits were equally represented (44.8% and 55.2%, respectively). A history of preceding trauma or intense physical activity was confirmed in 58.6% of the cases; 27.6% of the patients were given an initial clinical diagnosis of amyotrophic lateral sclerosis (ALS), and 51.7% were originally suspected to have multifocal motor neuropathy. None of the patients developed ALS on longitudinal follow-up. CONCLUSION: The snake eyes sign on magnetic resonance imaging is associated with a wide spectrum of neurological conditions and is more common in young men with a history of strenuous activity or antecedent trauma. The recognition of this syndrome is crucial as many of these patients are initially misdiagnosed with ALS.

Antibodies to clustered acetylcholine receptor: expanding the phenotype.

BACKGROUND AND PURPOSE: To provide a detailed phenotypical description of seronegative patients with generalized myasthenia gravis and antibodies to clustered acetylcholine receptors (AChRs) and to assess their frequency amongst a French seronegative generalized myasthenia gravis (SNMG) population. METHODS: A French SNMG database was created and the sera from the 37 patients included in it were analysed by immunofluorescence of cell-based assays using cotransfection of AChR subunit genes together with rapsyn to densely cluster the AChRs. RESULTS: Sixteen per cent (n = 6) of the SNMG patients were found to have antibodies to clustered AChR. They presented either with early onset MG and thymic hyperplasia, late onset MG and thymic involution, or thymoma associated MG. They responded well to cholinesterase inhibitors and immunosuppressants. CONCLUSIONS: Patients with antibodies to clustered AChR account for a significant proportion of SNMG patients and resemble patients with AChR antibodies detected by standard radio-immunoprecipitation.

[Metabolic and nutritional neuropathies: update in diabetes, vitamin B12 and copper deficiency]. / Neuropathies métaboliques et carentielles: mise au point sur le diabète, les carences en vitamine B12 et les carences en cuivre.

Metabolic and deficiency neuropathies retain a growing interest because of their important prevalence. The dismemberment of diabetic neuropathies is proceeded, letting distinct pathophysiological mechanisms appear. So, even if glycaemic control remains determining for preventing the neuropathy associated with type 1 diabetes, it seems to have a restricted role with type 2 diabetes in which other metabolic factors are involved. The diagnosis of neuropathy due to B12 vitamin deficiency remains a real challenge for the clinician. Indeed, positive and negative predictive values of serum B12 and metabolites assay are weak, only a good therapeutic response allows a reliable diagnostic. It is so recommended to know the clinical and contextual particularities of this etiology in order to not delay the vitamin substitution, determining for the functional outcome. Finally, copper deficiency remains an unknown cause of neuropathy which is suitable to raise in case of malabsorption but also and especially in case of abuse of dental adhesive rich in zinc.

[Metabolic neuropathies: overview in 2011]. / Neuropathies métaboliques : actualités 2011.

Metabolic diseases constitute a frequent etiologic group of axonal and small-fiber neuropathies. Recent works in this field are dominated by diabetic neuropathy (clinical presentation, prognostic factors) because of its prevalence. Vitamin B12 deficiency aroused several studies in 2011. This renewed interest for this well known entity ensues from the lack of sensibility of its biological markers underestimating its prevalence, its clinical spectrum and therefore, access to its therapy. Finally, 2011 highlighted the growing interest of the measure of the intra-epidermic nerve fibers density by skin biopsy for some metabolic disorders such as infra-clinical hypothyroïdism, chronic renal failure or Fabry disease.

[Successful treatment with rituximab in a refractory Stiff-person syndrome]. / Efficacité du rituximab dans le traitement d'un Syndrome de Stiff person réfractaire.

Stiff person syndrome is a rare autoimmune disorder characterized by axial and limb progressive stiffness with surimposed spasms and production of autoantibodies to glutamic acid decarboxylase (GAD). We report a case of a 50-year-old woman who developed a stiff person syndrome resistant to conventional immunosuppressive treatments. Eight months after treatment, indexes of stiffness and spasm frequency improved, while however, the blood and CSF rates of anti-GAD increased. This observation illustrates the complexity of stiff person syndrome immunopathogenesis as well as the relevance of rituximab in this indication.

[Clinical presentation suggesting Bickerstaff encephalitis and intracranial hypertension]. / Tableau d'encéphalite de Bickerstaff et hypertension intracrânienne.

A 20-year-old man had progressive headache, neck pain and visual loss after upper airway infection. After 3 weeks, he developed ophtalmoplegia, ataxia, areflexia, autonomic failure, four limbs paresis with impaired consciousness. Brain and cervical MRI were normal. Ophthalmological examination confirmed bilateral papilledema. Cerebro-spinal fluid pressure was high, cell count was normal and proteins were mildly elevated. Electromyography showed presence of both proximal and distal demyelination. Electroencephalogram was slowed, with diffuse delta and theta waves. Anti-GM1 and GQ1b antibodies were negative. The patient was treated with intravenous immunoglobulins (0.4 g/kg/day) for 5 days, associated with high doses of acetazolamide and corticosteroids for papilledema. His neurological condition improved for gait, strength, pain, ophtalmoplegia and ataxia. He kept severe visual loss with optic atrophy. Diagnosis is discussed: Bickerstaff encephalitis with intracranial hypertension or malignant pseudotumor cerebri?

Chronic ataxic neuropathies associated with anti-GD1b IgM antibodies: response to IVIg therapy.

OBJECTIVE: To determine the responses to treatment of patients with chronic sensory ataxic neuropathy associated with anti-GD1b IgM antibodies. METHODS: Patients with chronic sensory ataxic neuropathy associated with anti-GD1b IgM antibodies followed in our department for at least 12 months between 2001 and 2008 were identified and studied retrospectively. Patients were tested at regular intervals using the INCAT disability score. Patients whose disability scores improved by at least one point were taken to have responded to the treatment. Intravenous immunoglobulin (IVIg; 2 g/kg) was administered for 3 to 5 days once every 6 weeks or corticosteroids at an initial daily dose of 1 mg/kg. RESULTS: 13 patients treated during the 8-year period of interest were included in this study. Seven of 13 patients displayed IgM anti-GQ1b, GT1b and GD3 antibodies suggesting reactivity against disialosyl epitope. IgM gammopathy was detected in four of six of serum with anti-disialosyl antibodies and two of the seven other sera. Nine of the 13 patients improved in response to IVIg. Oral corticosteroid treatment was attempted on four patients prior to IVIg treatment, and partial recovery occurred in one, who became steroid-dependent and showed little benefit in the long term. CONCLUSIONS: Screening for anti-GD1b IgM antibodies should be carried out on all patients with chronic ataxic sensory neuropathies. In 69% of the cases studied, the patients' condition improved in response to IVIg. This study shows the short-term efficiency of this treatment. Sustained responses were obtained in the long term by continuing the infusions.

[Diagnosis of vitamin B12 deficiency: a case illustrating diagnostic pitfalls]. / Diagnostic d'une carence en vitamine B12 ou le signe de l'ordonnance.

INTRODUCTION: Vitamin B12 deficiency is a longstanding public health problem which affects more than 20% of the elderly population. Among multiple causes of vitamin B12 deficiency, Biermer's disease is currently mentioned in about 25% of the cases. OBSERVATION: We report the case of a 71-year-old woman, taking folate substitution therapy who, over 2 years, progressively developed spinal combined sclerosis, subacute dementia and severe neuropathy leading to a bedridden state. The initial assessment revealed normocytic anemia, without vitamin B12 deficiency and without increased plasma level of biological markers. The plasma folate level was high. Vitamin B12 assay was repeated leading to the diagnosis of deficiency associated with the presence of intrinsic factor antibodies. DISCUSSION: This observation illustrates the broad spectrum of clinical presentations of vitamin B12 deficiency. In the present case, the lack of sensitivity of biological markers delayed diagnosis and had a dramatic impact on outcome. This case highlights the importance of promoting factors such as isolated folate substitution in B12 deficient patients.

[Seronegative myasthenia and myasthenia gravis with anti-MuSK antibody: a retrospective study of 20 cases]. / Myasthénie séronégative et myasthénie avec anticorps anti-MuSK : une série rétrospective de 20 cas.

INTRODUCTION: Despite the fact that anti-muscle specific tyrosine kinase (MuSK) antibodies have been discovered for seven years, only a few studies have, until now, focused on myasthenia without acetylcholine-receptors antibodies (ab) (formerly known as "seronegative myasthenia"), and among them, anti-MuSK-antibody-positive and -negative patients. METHOD: We retrospectively studied 20 patients with "seronegative" myasthenia gravis, eight of them being anti-MuSK-ab positive, the remaining twelve being negative. We searched for clinical, neurophysiological, and therapeutic differences between the two groups (anti-MuSK-ab positive: anti-MuSK+ versus anti-MuSK-ab negative: anti-MuSK-). RESULTS: Anti-MuSK+ patients had more predominantly bulbar involvement and had more severe disease (these patients required referral to intensive care more frequently). There was no difference between the two groups concerning treatment efficiency and tolerance. Most of our patients were treated with acetylcholinesterase-inhibitors, and immunomodulatory or immunosuppressive drugs that could indirectly reflect greater severity. However, there was no difference in treatments for anti-MuSK+ versus anti-MuSK- patients. CONCLUSION: These results both confirm and complete the preexisting data on RACh-negative myasthenia, and especially on myasthenia associated with MuSK antibodies.

[Chronic inflammatory demyelinating polyneuropathy: Diagnosis and therapeutic update]. / Polyradiculoneuropathies inflammatoires démyélinisantes chroniques : mise au point diagnostique et thérapeutique.

Chronic inflammatory demyelinating polyradiculoneuropathies are acquired demyelinating neuropathies belonging to the group of autoimmune neuropathies. Since specific biological markers are present in less than 10% of cases, the diagnosis is based on the clinical and electrophysiological analysis of each patient. Furthermore, a decision-making algorithm ranking all other available paraclinical tools will guide the physician to the diagnosis of atypical forms. In nearly 80% of cases, these dysimmune neuropathies are responsive to first-line treatments, namely intravenous immunoglobulins, corticosteroids and plasma exchanges. A second line treatment may be proposed in case of no response, intolerance or inaccessibility to the three reference treatments. While some immunosuppressants or monoclonal antibodies can sometimes be very effective, there is currently no predictive marker or recommendation available to determine which treatment will be most appropriate for which patient.

Somatosensory evoked potentials in the assessment of peripheral neuropathies: Commented results of a survey among French-speaking practitioners and recommendations for practice.

BACKGROUND: Somatosensory evoked potentials (SSEPs) are increasingly performed for the assessment of peripheral neuropathies, but no practical guidelines have yet been established in this specific application. STUDY AIM: To determine the relevant indication criteria and optimal technical parameters for SSEP recording in peripheral neuropathy investigation. METHODS: A survey was conducted among the French-speaking practitioners with experience of SSEP recording in the context of peripheral neuropathies. The results of the survey were analyzed and discussed to provide recommendations for practice. RESULTS: SSEPs appear to be a second-line test when electroneuromyographic investigation is not sufficiently conclusive, providing complementary and valuable information on central and proximal peripheral conduction in the somatosensory pathways. CONCLUSIONS: Guidelines for a standardized recording protocol, including the various parameters to be measured, are proposed. CLINICAL RELEVANCE: We hope that these proposals will help to recognize the value of this technique in peripheral neuropathy assessment in clinical practice.

[Isolated right heart failure in acute lymphocytic myocarditis]. / Décompensation cardiaque droite isolée lors d'une myocardite aiguë lymphocytaire.

The authors report a case of acute myocarditis, presenting with signs of isolated right heart failure which was progressive and fatal. This is a very rare observation which poses diagnostic problems. A review of the literature showed only 4 previous reports, all diagnosed at autopsy, in which the diagnosis was not suspected in vivo. In our case, echocardiography raised the possibility of myocarditis at an early stage, although the initial clinical signs were atypical and did not indicate right ventricular disease. It is particularly important to detect right ventricular involvement, especially when associated with left ventricular disease, as the prognosis is very poor. This case report illustrates the difficulty of the differential diagnosis and shows the diagnostic and prognostic value of echocardiography when interpreted in the clinical and electrocardiographic context.

Primary neurolymphomatosis diagnosis and treatment: a retrospective study.

BACKGROUND: To discuss the therapeutic approach for primary neurolymphomatosis. METHODS: We report all primary neurolymphomatosis cases referred to our institution, with descriptions of clinical, radiological, electrophysiological, histological features and long-term follow-up. We treated all patients with a combination of high-dose methotrexate and alkylating agents. RESULTS: Five patients were diagnosed with histologically confirmed primary neurolymphomatosis. The majority of them presented with painful asymmetric sensory-motor neuropathy. Magnetic resonance imaging was abnormal in 4 of 5 patients, as shown with gadolinium enhancements. Electroneuromyography revealed denervation in all 4 cases with contributive examinations. All our patients received a chemotherapy combination of high-dose methotrexate and alkylating agent. Median progression-free survival was 8 months (2 complete responses and 2 partial responses), and overall survival was 24 months. CONCLUSIONS: Primary neurolymphomatosis is rare and polymorphic; it represents a difficult diagnosis of neuropathy. In our cohort, treatment with a chemotherapy combination with high-dose methotrexate showed encouraging results.

[Favourable outcome after treatment with rituximab in a case of seronegative non-paraneoplastic Lambert-Eaton myasthenic syndrome]. / Efficacité du rituximab dans un cas de syndrome de Lambert-Eaton non paranéoplasique séronégatif.

INTRODUCTION: Lambert-Eaton myasthenic syndrome is a rare and autoimmune presynaptic disorder of the neuromuscular junction, due in 85% of cases to autoantibodies directed against voltage-gated calcium channels. It is a paraneoplastic disorder in 50 to 60% of cases. Diagnosis involves a proximal muscle weakness and areflexia, associated with a significant increment after post-exercise stimulation in electrophysiological study. Symptomatic treatment is based on 3,4-diaminopyridine. No etiological treatment has proven its efficacy in both paraneoplastic and non-paraneoplastic Lambert-Eaton myasthenic syndrome. CASE REPORT: We report a 41-year-old man who presented with a seronegative non-paraneoplastic Lambert-Eaton myasthenic syndrome in whom conventional immunosuppressive treatments (corticosteroids, azathioprine) failed, and who eventually improved after treatment with rituximab. CONCLUSION: Rituximab was an effective and well-tolerated treatment in this case of seronegative non-paraneoplastic Lambert-Eaton myasthenic syndrome. Its indication should be discussed when conventional immunosuppressive therapy fails in both seropositive and seronegative patients.

[Subarachnoid hemorrhages form ruptured aneurysms as the presenting feature of lupus cerebral vasculitis]. / Hémorragies cérébro-méningées sur ruptures d'anévrismes inaugurales d'une vascularite cérébrale lupique.

Cerebral aneurysms secondary to cerebral vasculitis related to systemic lupus erythematosus are rare. We report a 31-year-old woman who presented with a lupus flare associated with inaugural generalized seizures. Computed tomography angiography showed subarachnoid hemorrhage by rupture of a cerebellar artery fusiform aneurysm. Later, despite the initiation of corticosteroids and cyclophosphamide, she presented a second cerebral hemorrhage due to the rupture of a new aneurysm in lenticulostriates arteries. The outcome was fatal. We discuss the frequency and management of this severe complication of systemic lupus erythematosus.

[Chronic inflammatory demyelinating polyradiculoneuropathy]. / Les polyradiculonévrites inflammatoires démyélinisantes chroniques.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a demyelinating chronic neuropathy of immune origin whose diagnosis is based upon clinical, biological and electrophysiological data; previously critical to the diagnosis the nerve biopsy is now restricted to the rare situations where accurate diagnosis cannot be reached using these data alone. CIDP are mainly idiopathic, but a few associated diseases must be sought for as they require specific attention. Such associated diseases must particularly be discussed when the manifestations are severe or resistant to immunomodulating or immunosuppressive agents. Indeed, idiopathic CIDP are usually responsive to these treatments. The effectiveness of these treatments is limited by the importance of the secondary axonal loss. The dependence or the resistance may sometimes justify the association of several immunomodulating treatments. A single randomized controlled trial support the use of cytotoxic drugs and none with rituximab.