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.

Myasthenia gravis treatment in the elderly presents with a significant iatrogenic risk: a multicentric retrospective study.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease treated with acetylcholinesterase inhibitors and immunosuppressant/immunomodulatory drugs. MG is frequently diagnosed in elderly patients, a fragile population in which treatment adverse effects (TAE) have not been evaluated until now. METHODS: We retrospectively analysed the files of all MG patients with disease onset after age 70 years in four French University Hospitals, including clinical, electrophysiological, biological, and treatment data, with an emphasis on TAE. MG outcomes were assessed using the Myasthenia Gravis Foundation of America (MGFA) status scale. RESULTS: We included 138 patients (59% of men) with a mean follow-up of 4.5 years (range 1-19). Mean age at diagnosis was 78 years (70-93). Anti-acetylcholine receptor antibodies were found in 87% of cases, electrophysiological abnormalities in 82%, and thymoma in 10%. MG outcome was good in a majority of cases, with 76% of treated patients presenting with alleviated symptoms at follow-up. TAE were observed in 41% of patients, including severe TAE in 14% of cases. Seven patients (5.1%) died, including four (2.9%) from MG-related respiratory failure, and three (2.2%) from MG treatment-related complications, i.e., sepsis in 2 cases and brain toxoplasmosis in 1 case. TAE were observed in 53% of patients treated with azathioprine, 23% of patients treated with corticosteroids, and 15% of patients treated with mycophenolate mofetil. CONCLUSIONS: This retrospective study demonstrates MG in the elderly presents with a significant iatrogenic risk, including fatal immunosuppressant-related infections.

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.

Impact of Coronavirus Disease 2019 in a French Cohort of Myasthenia Gravis.

OBJECTIVE: To describe the clinical characteristics and outcomes of coronavirus disease 2019 (COVID-19) among patients with myasthenia gravis (MG) and identify factors associated with COVID-19 severity in patients with MG. METHODS: The CO-MY-COVID registry was a multicenter, retrospective, observational cohort study conducted in neuromuscular referral centers and general hospitals of the FILNEMUS (Filière Neuromusculaire) network (between March 1, 2020, and June 8, 2020), including patients with MG with a confirmed or highly suspected diagnosis of COVID-19. COVID-19 was diagnosed based on a PCR test from a nasopharyngeal swab or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serology, thoracic CT scan, or typical symptoms. The main outcome was COVID-19 severity based on location of treatment/management (home, hospitalized in a medical unit, or in an intensive care unit). We collected information on demographic variables, general history, and risk factors for severe COVID-19. Multivariate ordinal regression models were used to identify factors associated with severe COVID-19 outcomes. RESULTS: Among 3,558 patients with MG registered in the French database for rare disorders, 34 (0.96%) had COVID-19. The mean age at COVID-19 onset was 55.0 ± 19.9 years (mean MG duration: 8.5 ± 8.5 years). By the end of the study period, 28 patients recovered from COVID-19, 1 remained affected, and 5 died. Only high Myasthenia Gravis Foundation of America (MGFA) class (≥IV) before COVID-19 was associated with severe COVID-19 (p = 0.004); factors that were not associated included sex, MG duration, and medium MGFA classes (≤IIIb). The type of MG treatment had no independent effect on COVID-19 severity. CONCLUSIONS: This registry-based cohort study shows that COVID-19 had a limited effect on most patients, and immunosuppressive medications and corticosteroids used for MG management are not risk factors for poorer outcomes. However, the risk of severe COVID-19 is elevated in patients with high MGFA classes (odds ratio, 102.6 [4.4-2,371.9]). These results are important for establishing evidence-based guidelines for the management of patients with MG during the COVID-19 pandemic.

Primary carnitine deficiency in a 57-year-old patient with recurrent exertional rhabdomyolysis.

Rhabdomyolysis is an emergency requiring rapid diagnosis and suitable aetiological treatment. We describe the case of a 57-year-old man with recurrent exertional rhabdomyolysis who was diagnosed with systemic primary carnitine deficiency (SPCD). Clinical examination was normal, creatine kinase levels were elevated, plasma free carnitine concentration was mildly decreased, muscle biopsy demonstrated lipid accumulation, carnitine uptake in cultured fibroblasts was decreased and genetic analysis identified a homozygous pathologic c.1181_1183del in the SLC22A5 gene. Rhabdomyolysis did not recur after treatment with oral L-carnitine was introduced. SPCD is a rare autosomal recessive disorder of carnitine transportation usually manifesting as an infantile (hepatic) or a childhood myopathic (cardiac) condition and rarely affecting adults. Our case indicates that SPCD should be considered in the aetiological evaluation of adult patients with recurrent exertional rhabdomyolysis, even in the absence of myopathy and cardiomyopathy.

Regressive pyridoxine-induced sensory neuronopathy in a patient with homocystinuria.

Pyridoxine (vitamin B6) is an essential vitamin playing a crucial role in amino acid metabolism. Pyridoxine is used for isoniazid side-effects prevention, pyridoxine-dependent epilepsy treatment and cystathionine beta-synthase deficiency (homocystinuria) treatment. However, vitamin B6 hypervitaminosis is neurotoxic and may provoke a progressive sensory neuronopathy (sensory ganglionopathy), usually when daily uptake is above 50 mg. We describe the case of a 30-year-old patient with homocystinuria who was treated with pyridoxine 1250-1750 mg/day for 20 years and developed progressive sensory neuropathy with ataxia and impaired sensation in the extremities. Electrodiagnostic testing demonstrated non-length-dependent abnormalities of sensory nerve potentials, and sensory ganglionopathy was diagnosed. Pyridoxine dosage was reduced to 500 mg/day, resulting in the disappearance of sensory symptoms and ataxia, and the normalisation of sensory nerve potentials. Our case indicates that pyridoxine-induced sensory ganglionopathy may be reversible, even after prolonged ingestion of high doses of vitamin B6 for more than 20 years.

Benign acute myositis in an adult patient.

The benign acute childhood myositis presents as a marked and painful oedema of leg muscles in the days following a viral illness. This disease is often considered as occurring only in children. We report the case of a 32-year-old patient who presented with severe pain and oedema of both legs associated with motor deficit of lower extremities. He suffered from a grippal syndrome for 4 days. Creatine kinase blood level rose up to 39 394 IU/L (n<200) and a muscle biopsy of left tibialis anterior found necrosisand regeneration of myocytes without inflammatory infiltrates. All clinical and paraclinical abnormalities spontaneously disappeared in a few days. This case illustrates that a disorder similar to benign acute childhood myositis may occur in adult patients. Muscle biopsy might be avoided in typical cases because of the favourable evolution.

Quantitative and qualitative normative dataset for intraepidermal nerve fibers using skin biopsy.

BACKGROUND: Skin biopsy is the most relevant tool to diagnose small-fiber neuropathy. A well-documented normal dataset for intraepidermal nerve fiber in the distal leg is required to improve its diagnostic value. METHODS: Three hundred healthy subjects were enrolled in the study, after clinical and biological screening to exclude neurological and systemic pathologies. A distal leg biopsy was taken and intraepidermal nerve fiber density after protein gene product-9.5 immunocytochemistry with brightfield microscopy was determined. Morphological variations of intraepidermal nerve fibers, previously described in small-fiber neuropathies, were analyzed. One hundred biopsies were also analyzed at the ultrastructural level. FINDINGS: The median number of fibers was lower in men compared to women and decreased with age. Using statistical modeling taking into account age and gender, we calculated the 5th percentile of intraepidermal nerve fiber density as follows: 7.6156-0.0769 x age (years) + 1.5506 x gender (woman = 1; man = 0). We observed a low frequency of large swellings or horizontal branchings but an increasing frequency of small swellings of intraepidermal nerve fibers and irregular distribution along the dermal-epidermal junction with age. Axonal diameter of unmyelinated fibers of the papillary dermis did not vary with age or gender. Ultrastructural analysis also showed that fiber endings in close apposition to Merkel cells should not be mistaken for small-fiber swellings. CONCLUSIONS: Our dataset allows accurate calculation of the normal density of intraepidermal nerve fibers for each year of age and provides original morphological observations that improve the diagnostic value of skin biopsy in the distal leg for small-fiber neuropathy.

Electromyography and muscle biopsy in chronic isolated Myalgia: A prospective study.

INTRODUCTION: Chronic muscle pain affects approximately 10% of the general population. It is unknown whether electromyographic (EMG) examination or muscle biopsy is most useful in this situation. METHODS: In a 7-year, single-center prospective study we investigated the EMG and muscle pathology characteristics of patients with: (1) diffuse muscle pain lasting >1 year; (2) normal clinical examination; (3) normal extensive blood tests; and (4) no evidence of a coexisting disorder. RESULTS: One hundred eighty consecutive patients were enrolled. In 178 patients (99%), EMG studies and muscle biopsies were normal. In 2 patients (1%), EMG studies demonstrated myotonia, and muscle biopsy showed mild myopathic features; 1 patient had myotonic dystrophy type 2, and the other had SCN4A-related muscle channelopathy. CONCLUSIONS: In this prospective study, EMG was an excellent screening test for diagnosing muscle disease in clinically normal patients with chronic diffuse muscle pain, and muscle biopsy was not useful. Muscle Nerve 54: 321-324, 2016.

Evaluation of clinical interest of anti-aquaporin-4 autoantibody followup in neuromyelitis optica.

Neuromyelitis optica (NMO) is an autoimmune disease in which a specific biomarker named NMO-IgG and directed against aquaporin-4 (AQP4) has been found. A correlation between disease activity and anti-AQP4 antibody (Ab) serum concentration or complement-mediated cytotoxicity has been reported, but the usefulness of longitudinal evaluation of these parameters remains to be evaluated in actual clinical practice. Thirty serum samples from 10 NMO patients positive for NMO-IgG were collected from 2006 to 2011. Anti-AQP4 Ab serum concentration and complement-mediated cytotoxicity were measured by flow cytometry using two quantitative cell-based assays (CBA) and compared with clinical parameters. We found a strong correlation between serum anti-AQP4 Ab concentration and complement-mediated cytotoxicity (P < 0.0001). Nevertheless, neither relapse nor worsening of impairment level was closely associated with a significant increase in serum Ab concentration or cytotoxicity. These results suggest that complement-mediated serum cytotoxicity assessment does not provide extra insight compared to anti-AQP4 Ab serum concentration. Furthermore, none of these parameters appears closely related to disease activity and/or severity. Therefore, in clinical practice, serum anti-AQP4 reactivity seems not helpful as a predictive biomarker in the followup of NMO patients as a means of predicting the onset of a relapse and adapting the treatment accordingly.

Chronic inflammatory demyelinating polyradiculoneuropathy in solid organ transplant recipients: a prospective study.

BACKGROUND: The prevalence and outcome of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in patients with solid organ transplantation is unknown, and there are no guidelines for the evaluation and treatment of such patients. METHODS: An 8 year long monocentric prospective study was conducted in which, in a population of 1557 solid organ transplant recipients, the characteristics of 10 consecutive patients (0.6%) who developed a syndrome that fulfilled the clinical, biological and electrophysiological criteria for definite CIDP were investigated. RESULTS: Five patients had liver transplantation, three had kidney transplantation, one had heart transplantation and one had lung transplantation. The mean interval between transplantation and CIDP was 10 months. Six patients developed CIDP after immunosuppressive therapy dosage was decreased and were treated with intravenous immunoglobulin (IVIG) and increased dosage of immunosuppressive therapy. Four patients were treated with IVIG only. Neuropathy improved in all cases, and CIDP had a monophasic course in all patients, with no relapse observed over a mean follow-up of 5 years. CONCLUSION: CIDP in solid organ transplant recipients is rare, appears in the first year after transplantation, has a monophasic course and is responsive to IVIG treatment. CIDP being treatable, it should be systematically considered in solid organ transplant recipients who develop a rapidly disabling sensorimotor polyneuropathy.

PET follow-up in a case of anti-NMDAR encephalitis: arguments for cingulate limbic encephalitis.

BACKGROUND: The lack of specific MRI abnormalities in anti-NMDA receptor encephalitis makes the identification of the most affected areas difficult. Functional neuroimaging could be useful to identify brain dysfunction associated with psychiatric symptoms, but few precise data are available up to now. CASE STUDY: A 27-year-old woman was referred for recent behavioural changes and jerks of the right foot. Serial left fronto-temporal seizures were recorded. Identification of anti-NMDA receptor antibodies in CSF indicated a diagnosis of anti-NMDA receptor encephalitis. Two foci of hypermetabolism, in the left prefrontal cortex and the anterior cingulate cortex, were identified using 18-fluorodeoxyglucose PET and both disappeared after treatment. Brain MRI was normal, except for a mild left prefrontal hypersignal. CONCLUSIONS: The increase in marker uptake in motor and premotor regions in our case probably corresponds to epileptic activity. Our data suggest that the anterior cingulate cortex could play an important role in psychiatric symptoms. Other studies are needed to better understand the pathophysiology of anti-NMDA receptor encephalitis.