Transthyretin amyloid polyneuropathy in France: A cross-sectional study with 413 patients and real-world tafamidis meglumine use (2009-2019).

OBJECTIVE: We aimed to describe characteristics of patients with ATTR variant polyneuropathy (ATTRv-PN) and ATTRv-mixed and assess the real-world use and safety profile of tafamidis meglumine 20mg. METHODS: Thirty-eight French hospitals were invited. Patient files were reviewed to identify clinical manifestations, diagnostic methods, and treatment compliance. RESULTS: Four hundred and thirteen patients (296 ATTRv-PN, 117 ATTRv-mixed) were analyzed. Patients were predominantly male (68.0%) with a mean age of 57.2±17.2 years. Interval between first symptom(s) and diagnosis was 3.4±4.3 years. First symptoms included sensory complaints (85.9%), dysautonomia (38.5%), motor deficits (26.4%), carpal tunnel syndrome (31.5%), shortness of breath (13.3%), and unexplained weight loss (16.0%). Mini-invasive accessory salivary gland or punch skin and nerve biopsies were most common, with a performance of 78.8-100%. TTR genetic sequencing, performed in all patients, revealed 31 TTR variants. Tafamidis meglumine was initiated in 156/214 (72.9%) ATTRv-PN patients at an early disease stage. Median treatment duration was 6.00 years in ATTRv-PN and 3.42 years in ATTRv-mixed patients. Tafamidis was well tolerated, with 20 adverse events likely related to study drug among the 336 patients. CONCLUSION: In France, ATTRv patients are usually identified early thanks to the national network and the help of diagnosis combining genetic testing and mini-invasive biopsies.

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.

French recommendations for the management of adult & pediatric chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare autoimmune disorder of the peripheral nervous system, primarily affecting the myelin sheath. The pathophysiology of CIDP is complex, involving both humoral and cellular immunity. The diagnosis of CIDP should be suspected in patients with symmetrical proximal and distal motor weakness and distal sensory symptoms of progressive onset, associated with decreased/abolished tendon reflexes. Treatments include intraveinous immunoglobulins, steroids and plasma exchange, with usually an induction phase followed by a maintenance therapy with progressive weaning. Treatment should be rapidly initiated to prevent axonal degeneration, which may compromise recovery. CIDP outcome is variable, ranging from mild distal paresthesiae to complete loss of ambulation. There have been several breakthroughs in the diagnosis and management of CIDP the past ten years, e.g. discovery of antibodies against the node of Ranvier, contribution of nerve ultrasound and magnetic resonance imaging to diagnosis, and demonstration of subcutaneous immunoglobulins efficiency. This led us to elaborate French recommendations for the management of adult & pediatric CIDP patients. These recommendations include diagnosis assessment, treatment, and follow-up.

IVIg increases interleukin-11 levels, which in turn contribute to increased platelets, VWF and FVIII in mice and humans.

The mechanisms of action of intravenous immunoglobulins (IVIg) in autoimmune diseases are not fully understood. The fixed duration of efficacy and noncumulative effects of IVIg in immune thrombocytopenia (ITP) and acquired von Willebrand disease (AVWD) suggest other mechanisms besides immunological ones. Additionally to the peripheral destruction of platelets in ITP, their medullary hypoproduction emerged as a new paradigm with rescue of thrombopoietin receptor agonists (TPO-RA). In an ITP mouse model, interleukin (IL)-11 blood levels increase following IVIg. IL-11 stimulates the production of platelets and other haemostasis factors; recombinant IL-11 (rIL-11) is thus used as a growth factor in post-chemotherapy thrombocytopenia. We therefore hypothesized that IVIg induces IL-11 over-production, which increases platelets, VWF and factor VIII (FVIII) levels in humans and mice. First, in an ITP mouse model, we show that IVIg or rIL-11 induces a rapid increase (72 h) in platelets, FVIII and VWF levels, whereas anti-IL-11 antibody greatly decreased this effect. Secondly, we quantify for the first time in patients with ITP, AVWD, inflammatory myopathies or Guillain-Barré syndrome the dramatic IL-11 increase following IVIg, regardless of the disease. As observed in mice, platelets, VWF and FVIII levels increased following IVIg. The late evolution (4 weeks) of post-IVIg IL-11 levels overlapped with those of VWF and platelets. These data may explain thrombotic events following IVIg and open perspectives to monitor post-IVIg IL-11/thrombopoietin ratios, and to assess rIL-11 use with or without TPO-RA as megakaryopoiesis co-stimulating factors to overcome the relative hypoproduction of platelets or VWF in corresponding autoimmune diseases, besides immunosuppressant.

Antibody- and macrophage-mediated segmental demyelination in chronic inflammatory demyelinating polyneuropathy: clinical, electrophysiological, immunological and pathological correlates.

BACKGROUND AND PURPOSE: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a heterogeneous autoimmune disorder critically lacking diagnostic biomarkers. Autoantibodies to nodal and paranodal components have recently been described in a small subset of patients. Here, the diagnostic value of immune reactivity toward the myelin compartment was investigated. METHODS: Ninety-four French CIDP patients were retrospectively studied. The reactivity toward the peripheral nerve was investigated. Sural nerve biopsies were examined by electron microscopy and immunofluorescence. RESULTS: Twenty-one patients (22%) and three patients (3%) presented with a strong immunoglobulin G or immunoglobulin M reactivity respectively against the myelin compartment. The clinical, electrophysiological and morphological features were examined in nine of these patients for whom sural nerve biopsies were available. Seven patients were electrodiagnosed with definite CIDP, one with possible CIDP and one was unclassifiable but sural nerve biopsy argued for CIDP diagnosis. Electron microscopy of sural nerve biopsies demonstrated the presence of macrophage-mediated demyelination restricted to the internode in all nine patients. Immunolabelling for voltage-gated sodium channels, myelin and axonal markers confirmed the presence of segmental demyelination and of remyelination. The nodal and paranodal regions, however, were unaffected in these patients. Nerve conduction studies corroborated the multifocal and segmental profile, and seven patients showed increased duration of proximal (1.5-5.1 times) and/or distal (1.2-3.4 times) compound muscle action potential in at least two nerves. CONCLUSION: Antibody- and macrophage-mediated demyelination appears responsible for conduction alterations in CIDP patients and nerve immunostaining assays may serve as a supportive diagnostic biomarker.

Phenotypic spectrum of Charcot-Marie-Tooth disease due to LITAF/SIMPLE mutations: a study of 18 patients.

BACKGROUND AND PURPOSE: Charcot-Marie-Tooth (CMT) 1C due to mutations in LITAF/SIMPLE is a rare subtype amongst the autosomal dominant demyelinating forms of CMT. Our objective was to report the clinical and electrophysiological characteristics of 18 CMT1C patients and compare them to 20 patients with PMP22 mutations: 10 CMT1A patients and 10 patients with hereditary neuropathy with liability to pressure palsies (HNPP). METHODS: Charcot-Marie-Tooth 1C patients were followed-up in referral centres for neuromuscular diseases or were identified by familial survey. All CMT1A and HNPP patients were recruited at the referral centre for neuromuscular diseases of Pitié-Salpêtrière Hospital. RESULTS: Two phenotypes were identified amongst 18 CMT1C patients: the classical CMT form ('CMT-like', 11 cases) and a predominantly sensory form ('sensory form', seven cases). The mean CMT neuropathy score was 4.45 in CMT1C patients. Motor nerve conduction velocities in the upper limbs were significantly more reduced in CMT1A than in CMT1C patients. On the other hand, the motor nerve conduction velocity of the median nerve was significantly lower in CMT1C compared to the HNPP group. Distal motor latency was significantly more prolonged in CMT1A patients compared to the CMT1C and HNPP groups, the latter two groups having similar distal motor latency values. Molecular analysis revealed five new LITAF/SIMPLE mutations (Ala111Thr, Gly112Ala, Trp116Arg, Pro135Leu, Arg160Cys). CONCLUSIONS: Our study delineates CMT1C as mostly a mild form of neuropathy, and gives clinical and electrophysiological clues differentiating CMT1C from CMT1A and HNPP. Delineating phenotypes in CMT subtypes is important to orient molecular diagnosis and to help to interpret complex molecular findings.

Classifications of neurogenetic diseases: An increasingly complex problem.

Neurodegenerative disorders represent a wide group of diseases affecting the central and/or peripheral nervous system. Many of these disorders were described in the 19th century, but our genetic knowledge of them is recent (over the past 25 years). However, the continual discovery of disease-causing gene mutations has led to difficulties in the classification of these diseases. For this reason, our present proposals for updating and simplifying the classification of some of these conditions (Charcot-Marie-Tooth diseases, distal hereditary motor neuropathies, hereditary sensory and autonomic neuropathies, hereditary spastic ataxias, hereditary spastic paraplegias and hereditary spastic ataxias) are expounded here.

Recommendations for useful serum testing with suspected multiple sclerosis.

Several practical questions useful for management of patients with multiple sclerosis remain unanswered in the current scientific literature. Decisions are often made individually, without the support of solid scientific evidence. In order to facilitate concurring practices, we present guidelines concerning useful serum exams for the diagnosis of multiple sclerosis. The methodology used was that of a formal expert consensus. A working group performed a systematic analysis of the literature, taking into account both previously existing recommendations and original articles, and then drafted guideline proposals. These proposals were subjected to the critical review of a rating group. Three written drafts, followed by rating of the guideline proposals culminated in a consensual document, which was submitted for review to a second independent reading group. The final resulting document provided the material for the present article, in which each recommendation is presented with its grade according to the level of proof or its degree of consensus in the absence of scientific proof.

Recommendations for the management of multiple sclerosis relapses.

The aim of the Multiple Sclerosis Think Tank (Groupe de Réflexion sur la Sclérose en Plaques [GRESEP]), composed of hospital neurologists involved in the management of patients with multiple sclerosis, is to provide recommendations in response to clinical questions that are raised when managing these patients. After work done on the themes of useful serum testing with suspected multiple sclerosis, detection and management of cognitive disorders early in the course of the disease, and definition and early management of the disease, GRESEP wanted to develop recommendations on the management of multiple sclerosis (MS) relapse. Following a systematic analysis of the literature, the procedure of formal expert consensus enabled consensual recommendations among a working group, a rating group and a reading group to be written. Each recommendation is presented with its grade or the degree of consensus that it was accorded.

Recommendations for a definition of multiple sclerosis in support of early treatment.

The aim of the Multiple Sclerosis Think Tank (Groupe de Réflexion sur la Sclérose en Plaques: GRESEP), composed of hospital neurologists involved in the management of patients with multiple sclerosis, is to provide recommendations in response to clinical questions that are raised when managing these patients. After work done on the themes on useful serum testing with suspected multiple sclerosis, as well as the detection and management of cognitive disorders early in the course of the disease, the subject of the present work is the early definition and early treatment of the disease. Following a systematic literature review, a RAND/UCLA appropriateness-derived method enabled consensual recommendations among a working group, a rating group and a reading group to be developed and formulated. Each recommendation is presented with the degree of consensus that it was accorded.

Recommendations for the detection and therapeutic management of cognitive impairment in multiple sclerosis.

The aim of the Multiple Sclerosis Think Tank (Groupe de réflexion sur la sclérose en plaques [GRESEP]) is to prescribe recommendations following a systematic literature search and using a Rand Corporation and California University (RAND/UCLA) appropriateness derived method, in response to practical questions that are raised in the management of patients with multiple sclerosis (MS). The topics of this working program were chosen because they were not addressed in the French recommendations and because of the few data in the literature that enabled practices to be based on validated data. Following the theme on useful serum testing with suspected multiple sclerosis, the subjects of the present work concern the detection and management of cognitive impairment in the beginning stages of the disease course. Two clinical questions were asked: which complementary exams (besides physical examination and neuropsychological tests) would help in the screening of cognitive impairment at the beginning of the disease? What care management should the person with MS and cognitive impairment be offered (treatments and neurocognitive rehabilitation)? The recommendations are the result of a consensus amongst a working group, a rating group and a reading group comprised of hospital neurologists involved in the management of patients with multiple sclerosis. Each recommendation is presented with the degree of consensus that it was accorded.

[What's new in immune-mediated neuropathies?]. / Actualités des neuropathies dysimmunitaires (hors traitement).

Many papers have been published in the field of immune-mediated neuropathies in 2010. Various topics have been covered: diagnostic criteria and clinical forms, pain and its risk factors, clinical evaluation and new immunological markers. Additionally, as nerve biopsy is still useful for evaluating patients with peripheral neuropathy, French and international guidelines have been published. This paper aims to summarize recent discoveries in the field of immune-mediated neuropathies.

[Management of stroke in sub-Saharan Africa: current issues]. / Prise en charge des accidents vasculaires cérébraux en Afrique subsaharienne.

In sub-Saharan Africa, stroke is likely to present an increasingly important public health problem with a larger relative share of overall morbidity and mortality. Overall, sub-Saharan Health Care is characterized by a lack of human resources, lack of facilities for special investigations, and especially an absence of specific programs addressing the prevention of cardiovascular conditions. Current data on the epidemiology of stroke in sub-Saharan Africa, although sparse and fragmentary, indicate a comparatively high incidence of cerebral hemorrhage associated with high blood pressure, while ischemic stroke in black Africans still appears to be related primarily to small artery disease, HIV infection, and sickle cell disease. With urbanization, the role of large-vessel atherosclerosis is increasing. It is thus essential to coordinate government funding, health care professionals and development agencies to address this rising health problem. Access to health care needs to be better structured, and screening programs should be developed in order to identify and treat vascular risk factors. Improved training of health care professionals is also required in the areas of prevention, diagnosis and management of stroke. Implementation of best-practice recommendations for the management of stroke adapted to the specificities and resources of African countries would help rationalize the scarce resources currently available.

Implication of the SH3TC2 gene in Charcot-Marie-Tooth disease associated with deafness and/or scoliosis: Illustration with four new pathogenic variants.

The autosomal recessive demyelinating form of Charcot-Marie-Tooth can be due to SH3TC2 gene pathogenic variants (CMT4C, AR-CMTde-SH3TC2). We report on a series of 13 patients with AR-CMTde-SH3TC2 among a French cohort of 350 patients suffering from all type of inheritance peripheral neuropathy. The SH3TC2 gene appeared to be the most frequently mutated gene for demyelinating neuropathy in this series by NGS. Four new pathogenic variants have been identified: two nonsense variants (p.(Tyr970*), p.(Trp1199*)) and two missense variants (p.(Leu1126Pro), p.(Ala1206Asp)). The recurrent variant p.Arg954* was present in 62%, and seems to be a founder mutation. The phenotype is fairly homogeneous, as all these patients, except the youngest ones, presented scoliosis and/or hearing loss.

Contribution of electron microscopy to the study of neuropathies associated with an IgG monoclonal paraproteinemia.

A typical monoclonal IgG dysglobulinemia whether benign (monoclonal gammopathy of undetermined significance, MGUS) or malignant can give rise to peripheral neuropathy by damaging nerves. At first, neurotoxicity of the chemotherapy if the patient is treated must be ruled out in such cases. Indeed, a variety of other mechanisms have been described: endoneurial deposits of immunoglobulin, infiltration of the immunoglobulin within myelin sheaths, POEMS syndrome, deposits of amyloid, chronic inflammatory demyelinating polyradiculoneuropathy and infiltration of malignant cells. Ultrastructural examination of a nerve biopsy can be decisive in combination with routine histological and immunopathological examinations. Characterization of the mechanism of the neuropathy in a dysglobulinemic context is important as it governs therapeutic options, which in certain cases are particularly beneficial.

[Diagnostic strategy for chronic inflammatory demyelinating polyradiculoneuropathy. Recommendations of the French working group]. / Démarche diagnostique des polyradiculonévrites inflammatoires démyélinisantes chroniques. Recommandations du groupe d'étude français.

The diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) requires a careful clinical and neurophysiological evaluation, often completed by CSF analysis. In numerous cases, this diagnosis is straightforward and leads to rapid initiation of an immunomodulatory treatment. However, some patients are not diagnosed because of atypical clinical and/or neurophysiological features, and do not benefit from a potentially effective treatment. In this context, a working group was composed with the task of establishing recommendations on diagnostic strategies for CIDP in the main clinical situations where this diagnosis may be suspected. We have summarized these recommendations and tried to present them in the form of a decision-making algorithm.

[Peripheral neuropathies: Diagnostic strategy]. / Neuropathies périphériques : démarche diagnostique.

Diagnosing a peripheral neuropathy is sometimes challenging, as the causes are diverse and the clinical pictures heterogeneous. Overall, diagnosing a patient with peripheral neuropathy will require some knowledge in almost every field of medicine. Therefore, it appears crucial to adopt a diagnostic strategy that is based on solid clinical and neurophysiological grounds. The present paper describes a three-step diagnostic strategy: (1) to delineate a clinico-pathologic entity from clinical and electrodiagnostic findings; (2) to propose a list of plausible causes based on step one, history and clinical context; (3) to use appropriate workup in order to determine the cause or mechanism of the neuropathy. The three steps of this diagnostic strategy necessitate a high level of expertise and interaction between physicians is highly desirable. Finally, an aggressive course and a severe impairment should lead to relentlessly look for a curable cause.

Pain as the presenting symptom of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).

Numerous clinical forms of CIDP have been described, but pain is generally considered a rare or secondary sign. We describe here the clinical, electrophysiological and neuropathological characteristics of five patients with CIDP and pain as the main presenting symptom, and their course with treatment. Between January 2003 and December 2004, we selected five patients with prominent or isolated pain among 27 patients diagnosed with CIDP. All patients were subjected to clinical and electrophysiological examinations, and had a complete laboratory work up to exclude other causes of neuropathy. In view of the atypical clinical presentation, all five patients underwent nerve biopsy. There were two men and three women. The mean age at onset of neuropathy was 70+/-7.39 years. All patients initially presented with pain in the lower limbs associated with modest motor impairment (1 case), distal paresthesia (4 cases), cramps (1 case) and fatigue (2 cases). CSF was normal in three cases. On electrophysiological examination, three patients had nerve conduction abnormalities with subtle or clear signs of demyelination: three (case 1, 2 and 4) fulfilled the criteria of Rotta et al. and two (case 2 and 4) the criteria of both Nicolas et al and the INCAT group. Patients were all given symptomatic treatment and four patients received an immunomodulatory treatment, which was constantly effective. Pain may be a major and disabling symptom in patients with CIDP, so this diagnosis has to be considered in patients referred for a painful polyneuropathy. Moreover, immunomodulatory treatment has to be considered in such patients as symptomatic therapy may be ineffective.