Cécile Cauquil

Regional difference and similarity of familial amyloidosis with polyneuropathy in France.

Familial amyloidosis with polyneuropathy (FAP) in France have a large genetic heterogeneity with 29 transthyretin (TTR) gene mutations; Met30-TTR is the most frequent one (62%); followed by Tyr77-TTR (11.8%) and Phe77-TTR (6.2%). Analysis of 60 FAP patients diagnosed during the period 2008–2010 showed amyloid polyneuropathy was initially suspected in only 38% patients. TTR Met30 of Portuguese ancestry is different from TTR Met30 of non Portuguese ancestry and other non Met30 variants in geographical distribution and clinical presentation. There are three additional phenotypes of the neuropathy including multifocal upper limbs neuropathy, ataxic polyneuropathy and motor neuropathy. Patients with Tyr77-TTR are characterized by a late onset (>50 years), frequent ataxic phenotype; they are localized mainly in north of France. The more frequent use of the TTR genetic tests and the French network for FAP will help in the future to improve diagnosis and care.

FAP neuropathy and emerging treatments.

Transthyretin familial amyloid polyneuropathy (TTR-FAP) classically presents as a length dependent small fiber polyneuropathy in endemic countries like Portugal. In nonendemic countries, it may mimic a variety of chronic polyneuropathies, with several phenotypes: ataxic, upper limb onset neuropathy, or motor. In these cases, there is usually a late onset and no positive family history. TTR gene sequencing appears the most pertinent first-line test for diagnosis. Cardiac involvement of various severities is common in FAP. Liver transplantation remains the standard antiamyloid therapy with better results in Val30Met TTR-FAP of early onset. Antiamyloid medication has been developed. (1) TTR stabilizers: Tafamidis was the first drug approved in Europe in stage 1 (walking unaided) TTR-FAP to slow progression of the disease; diflunisal has been assessed in a phase 3 clinical trial; (2) TTR gene silencing is a new strategy to inhibit production of both mutant and nonmutant TTR with antisense oligonucleotides or SiRNA (2 ongoing phase 3 clinical trials).

TTR kinetic stabilizers and TTR gene silencing: a new era in therapy for familial amyloidotic polyneuropathies

ABSTRACT Introduction: Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP) is a rare disease with autosomal dominant transmission due to a point mutation of the TTR gene. By removing the main source of systemic mutant TTR, liver transplantation (LT) has become the reference therapy of this severe and fatal polyneuropathy of adult-onset, stopping disease progression in subgroup of patients. Recently, new therapeutic strategies have emerged, which intend to stabilize TTR or to silence the TTR gene. Amongst them, the TTR kinetic stabilizer tafamidis is the first drug approved in the EU. Areas covered: We shall review the natural history of TTR-FAP and the best indications for LT. Data on the efficacy, safety and tolerability of the TTR kinetic stabilizers, tafamidis and diflunisal, have been reviewed, from the pivotal Phase III clinical trials published in PubMed medical journals or presented at international meetings. We will review the ongoing phase III clinical trials of TTR gene silencing with RNAi therapeutics and ASO published in clinicaltrialgov. Expert opinion: Due to the data on efficacy, tolerability, safety, tafamidis and diflunisal became the first line anti-amyloid treatment in stage 1 TTR-FAP. Both drugs slow progression of the disease. Only tafamidis got marketing authorization. We are waiting for results of the 2 phase III clinical trials of TTR gene silencing in varied stages of the disease.

Varicella-zoster virus acute myelitis in a patient with MS treated with natalizumab

We report a case of varicella-zoster virus (VZV) myelitis in a woman with relapsing-remitting multiple sclerosis (RRMS) receiving natalizumab, a humanized monoclonal antibody that induces an immunosuppression localized to the CNS.

Current and future treatment of amyloid neuropathies

Amyloid neuropathies of acquired or genetic origin are disabling and life-threatening, until recently there were few treatment options available. Poor prognosis is related to progressive neuropathy and associated, although often underdiagnosed, cardiac involvement in specific transthyretin (TTR) gene mutations. Recent progress has modified prognosis and management of amyloid neuropathies. In TTR-familial amyloidosis with polyneuropathy, major changes have occurred over the last 30 years: better knowledge concerning genetics, phenotypes and epidemiology, and the advent of possible treatments. Liver transplantation, first performed in 1990, stopped disease progression, thus doubling survival in early onset V30M patients. More recently tetramer stabilizers (Tafamidis and Diflunisal) showed a significant reduction of progression of neuropathic scores; Tafamidis is now recommended in Stage I patients. Two multicentric clinical trials are now ongoing to evaluate TTR gene silencing by antisense Oligonucleotides (ASO) or siRNA. In the near future we should have new therapeutical options for patients with amyloid neuropathy.

Contribution of plexus MRI in the diagnosis of atypical chronic inflammatory demyelinating polyneuropathies

Nerve enlargement has early been recognized in CIDP and plexus MRI hypertrophy has been reported in typical CIDP cases. Our aim is to determine plexus MRI value in the diagnosis of CIDP with an initial atypical presentation, which, up to now, has not been demonstrated. Retrospective study of 33 consecutive patients suspected of CIDP. Plexus MRI was performed on the most affected territory (brachial or lumbar). Were assessed: plexus trophicity, T2-STIR signal intensity and gadolinium enhancement. Final CIDP diagnosis was made after comprehensive workup. A histo-radiological correlation was performed. Final CIDP diagnosis was made in 25 (76%) including 21 with initial atypical clinical presentation. Eleven CIDP patients (52%) with initial atypical clinical presentation had abnormal plexus MRI including 9 suggestive of CIDP (43%) and none of the patients with an alternative diagnosis. Hypertrophy of the proximal plexus and/or extraforaminal roots was found in 8 cases and Gadolinium enhancement in 2 cases. Abnormalities were more frequent on brachial (86%) than lumbosacral MRIs (29%) and asymmetrical (72%) and most often associated with histological signs of demyelination. The nerve biopsy was suggestive of CIDP in 9/13 patients with normal MRI. Plexus MRI seems useful in the diagnostic strategy of patients with suspicion of CIDP with atypical presentation. Nerve biopsy remains important when other investigations are inconclusive.

Prediction of Long-Term Survival After Liver Transplantation for Familial Transthyretin Amyloidosis

Familial transthyretin amyloidosis (ATTR) is a rare, life-threatening, autosomal dominant disease involving mainly the heart and the peripheral nervous system due to a point mutation of the transthyretin ( TTR ) gene. By removing the main source of the mutated TTR , liver transplantation (LT) has

Significance of acute multiple infarcts in multiple cerebral circulations on initial diffusion weighted imaging in stroke patients

OBJECTIVES We attempted to assess the frequency, clinical and neuroradiological features of concomitant Acute Multiple Infarcts in Multiple Cerebral Circulations (AMIMCC) and to classify their causes. SUBJECTS AND METHODS Consecutive patients treated for MR DWI-confirmed infarcts were included in this cohort. We retrospectively analyzed all patients with AMIMCC of our prospective database, studying clinical and radiological features. Causes of stroke were classified using TOAST and ASCO system (atherosclerosis, small vessel disease, cardiac source, other causes). RESULTS Eighty AMIMCC were identified out of 824 consecutive patients with MR DWI-confirmed infarcts (9.7%). Compared with single infarct patients, AMIMCC patients presented similar age and risk factors. Only 24 AMIMCC patients (30%) presented symptoms suggesting multiple lesions before MRI. Cardiac origin existed in 39 of 80 patients (49%) including atrial fibrillation in 25 patients. Other sources of AMIMCC were hematologic diseases or coagulopathies such as intravascular coagulation in relation with cancer (n = 6; 7,5%) and vasculitis or systemic disorders (n = 5;6,5%). AMIMCC also appeared to originate from unilateral carotid diseases or intracranial stenosis, mostly atheromatous, in association with anatomic variations(n = 9;11%). In 21 patients, no cause was identified despite extensive investigations (26%). According to TOAST classification, 62% had a definite source for infarcts, 67% according to ASCO grade 1 classification. MRI data did not permit to orientate etiological explorations according to DWI appearance, associated leucoaraiosis or previous infarcts on FLAIR or microbleeding on gradient-echo sequences. CONCLUSIONS AMIMCC are not rare and mostly need MRI to be detected. Multiple and various etiologies are implicated, including cardioembolic diseases in half of them, but also hematologic disorders and angeitis.

Diffusion MRI and tensor tractography in ischemic optic neuropathy

Ischemic optic neuropathies (IONs) are among the most prevalent diseases causing visual impairment in middle-aged and elderly people. While arteritic ION is an ocular emergency and requires early diagnosis and immediate treatment with systemic high-dose corticosteroids to prevent further visual loss, treatment options for non-arteritic ION remain limited. We describe the case of a woman with unilateral right-sided non-arteritic posterior ischemic optic neuropathy. The diagnosis was made on clinical and radiographic grounds. Diffusion-weighted sequences and apparent diffusion coefficient maps revealed markedly restricted diffusion in the right optic nerve. It was very helpful to precise the posterior topography of the optic nerve lesion. Furthermore, we reported the diffusion tensor tractography study which appears to be an objective tool to assess the incomplete visual recovery. These MRI techniques including tensor tractography remain to be evaluated in large cohort of ION patients’ particularly in future therapeutic trials.

Anti-MAG antibodies in 202 patients: clinicopathological and therapeutic features

Objective To assess the clinicopathological and therapeutic features of patients with low (≥1000 to <10 000 Bühlmann Titre Units) (BTU), medium (10 000–70 000) or high (≥70 000) anti-myelin-associated glycoprotein (anti-MAG) antibody titres. Methods We retrospectively and prospectively analysed standardised report forms and medical records of 202 patients from 14 neuromuscular centres. Results Mean age at onset and mean time between symptom onset to last follow-up were respectively 62.6 years (25–91.4) and 8.4 years (0.3–33.3). Anti-MAG antibody titres at diagnosis were low, medium or high in 11%, 51% and 38% of patients. Patients presented with monoclonal gammopathy of undetermined significance in 68% of cases. About 17% of patients presented with ‘atypical’ clinical phenotype independently of anti-MAG titres, including acute or chronic sensorimotor polyradiculoneuropathies (12.4%), and asymmetric or multifocal neuropathy (3%). At the most severe disease stage, 22.4% of patients were significantly disabled. Seventy-eight per cent of patients received immunotherapies. Transient clinical worsening was observed in 12% of patients treated with rituximab (11/92). Stabilisation after rituximab treatment during the 7–12-month follow-up period was observed in 29% of patients. Clinical response to rituximab during the 6-month and/or 7–12-month follow-up period was observed in 31.5% of patients and correlated with anti-MAG titre ≥10 000 BTU. Conclusion Our study highlights the extended clinical spectrum of patients with anti-MAG neuropathy, which appears unrelated to antibody titre. Besides, it may also suggest beneficial use of rituximab in the early phase of anti-MAG neuropathy.