Hereditary transthyretin amyloidosis in middle-aged and elderly patients with idiopathic polyneuropathy: a nationwide prospective study.

BACKGROUND: Hereditary transthyretin amyloidosis (ATTRv) is an adult-onset autosomal dominant disease resulting from TTR gene pathogenic variants. ATTRv often presents as a progressive polyneuropathy, and effective ATTRv treatments are available. METHODS: In this 5 year-long (2017-2021) nationwide prospective study, we systematically analysed the TTR gene in French patients with age >50 years with a progressive idiopathic polyneuropathy. RESULTS: 553 patients (70% males) with a mean age of 70 years were included. A TTR gene pathogenic variant was found in 15 patients (2.7%), including the Val30Met TTR variation in 10 cases. In comparison with patients with no TTR gene pathogenic variants (n = 538), patients with TTR pathogenic variants more often presented with orthostatic hypotension (53 vs. 21%, p = .007), significant weight loss (33 vs 11%, p = .024) and rapidly deteriorating nerve conduction studies (26 vs. 8%, p = .03). ATTRv diagnosis led to amyloid cardiomyopathy diagnosis in 11 cases, ATTRv specific treatment in all cases and identification of 15 additional ATTRv cases among relatives. CONCLUSION: In this nationwide prospective study, we found ATTRv in 2.7% of patients with age >50 years with a progressive polyneuropathy. These results are highly important for the early identification of patients in need of disease-modifying treatments.

Anti-disialosyl-immunoglobulin M chronic autoimmune neuropathies: a nationwide multicenter retrospective study.

BACKGROUND AND PURPOSE: In this retrospective study involving 14 university hospitals from France and Switzerland, the aim was to define the clinicopathological features of chronic neuropathies with anti-disialosyl ganglioside immunoglobulin M (IgM) antibodies (CNDA). RESULTS: Fifty-five patients with a polyneuropathy evolving for more than 2 months and with at least one anti-disialosyl ganglioside IgM antibody, that is, anti-GD1b, -GT1b, -GQ1b, -GT1a, -GD2 and -GD3, were identified. Seventy-eight percent of patients were male, mean age at disease onset was 55 years (30-76) and disease onset was progressive (82%) or acute (18%). Patients presented with limb sensory symptoms (94% of cases), sensory ataxia (85%), oculomotor weakness (36%), limb motor symptoms (31%) and bulbar muscle weakness (18%). Sixty-five percent of patients had a demyelinating polyradiculoneuropathy electrodiagnostic profile and 24% a sensory neuronopathy profile. Anti-GD1b antibodies were found in 78% of cases, whilst other anti-disialosyl antibodies were each observed in less than 51% of patients. Other features included nerve biopsy demyelination (100% of cases), increased cerebrospinal fluid protein content (75%), IgM paraprotein (50%) and malignant hemopathy (8%). Eighty-six percent of CNDA patients were intravenous immunoglobulins-responsive, and rituximab was successfully used as second-line treatment in 50% of cases. Fifteen percent of patients had mild symptoms and were not treated. CNDA course was progressive (55%) or relapsing (45%), and 93% of patients still walked after a mean disease duration of 11 years. CONCLUSION: Chronic neuropathies with anti-disialosyl ganglioside IgM antibodies have a recognizable phenotype, are mostly intravenous immunoglobulins-responsive and present with a good outcome in a majority of cases.

Sensory neuronopathies: new genes, new antibodies and new concepts.

Degeneration of dorsal root ganglia (DRG) and its central and peripheral projections provokes sensory neuronopathy (SN), a rare disorder with multiple genetic and acquired causes. Clinically, patients with SN usually present with proprioceptive ataxia, patchy and asymmetric sensory abnormalities, widespread areflexia and no weakness. Classic causes of SN include cancer, Sjögren's syndrome, vitamin deficiency, chemotherapy, mitochondrial disorders and Friedreich ataxia. More recently, new genetic and dysimmune disorders associated with SN have been described, including RFC1 gene-linked cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) and anti-FGFR3 antibodies. In this review, we detail the pathophysiology of DRG degeneration, and the genetic and acquired causes of SN, with a special focus on the recently described CANVAS and anti-FGFR3 antibodies. We also propose a user-friendly and easily implemented SN diagnostic strategy.

Central nervous system Aquaporin4 autoimmunity revealed by a single pseudotumoral encephalic lesion.

The radiological spectrum of neuromyelitis optica has become broader since the detection of aquaporin4 antibodies. We report a case of neuromyelitis optica patient with pseudotumoral encephalic lesion. A 66 year-old woman presented with sudden left lateral homonymous hemianopsia. A brain MRI showed an isolated and extensive right temporo-parieto-occipital lesion, involving periventricular white matter and the corpus callosum, with strong enhancement on post-gadolinium T1 weighted images, highly suggestive of lymphoma. Spinal cord MRI and body CT scan were unremarkable. Lumbar puncture showed pleocytosis, raised total protein level without abnormal cells or oligoclonal bands. A brain biopsy demonstrated non-specific demyelination. Serum aquaporin4 antibodies were positive, which was consistent with the diagnosis of neuromyelitis optica. Cases of central nervous system aquaporin4 autoimmunity presenting with an isolated brain lesion without optic neuritis or myelitis are extremely rare: this is the second case so far and the first one with advanced magnetic resonance characterization. Pseudotumoral encephalic lesions should include a large differential diagnosis, and testing aquaporin4 antibodies must be considered in order to avoid brain biopsy.

Association between Ischemic Stroke and Erdheim-Chester Disease: A Case Report and Review of Literature.

Erdheim-Chester disease (ECD) is a rare form of non-Langerhans cell histiocytosis characterized by a xanthogranulomatous infiltration of tissues by spumous histiocytes. Neurological involvement is frequent, but ischemic strokes have been exceptionally described. We report the case of a 68-year-old woman who presented with an acute ischemic stroke associated with a multisystemic disorder including insipidus diabetes, infiltration of the aorta and the carotid arteries, perirenal infiltration, aortitis, and lytic bone lesions. The surgical biopsy of a lumbar vertebra revealed an infiltration of spumous macrophages consistent with ECD. Many ischemic symptoms can occur in ECD. Ischemic strokes, infrequently reported, might be caused by perivascular infiltration and adventitial fibrosis of the supra-aortic trunks or intracranial arteries.