To report the clinical, biological, and imaging features and clinical course of a French cohort of patients with glial fibrillary acidic protein (GFAP) autoantibodies.
We retrospectively included all ...patients who tested positive for GFAP antibodies in the CSF by immunohistochemistry and confirmed by cell-based assay using cells expressing human GFAPα since 2017 from 2 French referral centers.
We identified 46 patients with GFAP antibodies. Median age at onset was 43 years, and 65% were men. Infectious prodromal symptoms were found in 82%. Other autoimmune diseases were found in 22% of patients, and coexisting neural autoantibodies in 11%. Tumors were present in 24%, and T-cell dysfunction in 23%. The most frequent presentation was subacute meningoencephalitis (85%), with cerebellar dysfunction in 57% of cases. Other clinical presentations included myelitis (30%) and visual (35%) and peripheral nervous system involvement (24%). MRI showed perivascular radial enhancement in 32%, periventricular T2 hyperintensity in 41%, brainstem involvement in 31%, leptomeningeal enhancement in 26%, and reversible splenial lesions in 4 cases. A total of 33 of 40 patients had a monophasic course, associated with a good outcome at last follow-up (Rankin Score ≤2: 89%), despite a severe clinical presentation. Adult and pediatric features are similar. Thirty-two patients were treated with immunotherapy. A total of 11/22 patients showed negative conversion of GFAP antibodies.
GFAP autoimmunity is mainly associated with acute/subacute meningoencephalomyelitis with prodromal symptoms, for which tumors and T-cell dysfunction are frequent triggers. The majority of patients followed a monophasic course with a good outcome.
Background
Treatments may become redundant in older patients with multiple sclerosis (MS). Our aim was to explore whether stopping treatments might be possible in patients aged over 50 with disease ...inactivity.
Methods
Patients over 50 were included from the population-based MS Lorraine registry if they had a relapsing–remitting course at onset and had experienced no relapse for ≥ 3 years. Patients who stopped treatments were defined as “stoppers”, and the others as “stayers”. The outcomes were the time to first relapse, to first disability progression, and to the occurrence of EDSS score of 6, assessed by multivariate analysis using a propensity score.
Results
132 stoppers and 366 stayers had a median follow-up of 7 years. There was no difference in Log-rank tests for the times to first relapse (
p
= 0.61) and to first disability progression (
p
= 0.22). In Cox models, stopping treatments was not associated with an increased risk of relapse (adjusted Hazard ratio (aHR) = 0.92 0.72–1.16;
p
= 0.47) or of an increase in EDSS score (aHR = 0.89 0.71–1.13;
p
= 0.34). However, stopping was associated with a higher risk of occurrence of EDSS score of 6 (aHR = 3.29 2.22–4.86;
p
< 0.0001), with a significant difference for the time to occurrence of EDSS score of 6 (
p
= 0.003).
Conclusion
Our study suggests that stopping injectable disease-modifying treatments, in patients over 50 with disease inactivity, is not associated with an increased risk of relapse or EDSS progression, but there might be a higher risk of reaching EDSS 6. These results have to be confirmed by interventional studies.
The manifestations of borreliosis in the peripheral nervous system (PNS) remain poorly described. As the symptoms of neuroborreliosis can be reversed with timely introduction of antibiotics, early ...identification could avoid unnecessary axonal loss. Our aim was to describe the characteristics of confirmed neuroborreliosis cases involving the PNS diagnosed between 2007 and 2017 in our neuromuscular disease center in a nonendemic area (La Pitié-Salpêtrière Hospital, Paris, France).Neuroborreliosis was defined as follows: compatible neurological symptoms without other cause of neuropathy; cerebrospinal fluid and serum analysis (positive serological tests with ELISA, confirmed by Western Blot); and improvement of symptoms with adapted antibiotherapy. All the patients consulting in our center between 2007 and 2017 underwent electrophysiological study.Sixteen confirmed cases of neuroborreliosis involving the PNS were included: 10 cases of meningoradiculoneuritis, 4 of axonal neuropathy, and 2 of demyelinating neuropathy (one acute and one chronic). Only 4 (25%) patients reported tick bites. Meningoradiculoneuritis was characterized by lymphocytic meningitis, intense pain, cranial nerve palsy, and contrast enhancement of nerve roots on imagery. The patients with axonal neuropathy presented sensory symptoms with intense pain but no motor deficit and meningitis was rare. Nerve biopsy of 1 patient revealed lymphocytic vasculitis. Electrophysiological testing showed sensory or sensorimotor axonal neuropathy (3 subacute and 1 chronic) of the lower limbs, with asymmetrical neuropathy in 1 patients, symmetrical neuropathy in one and monomelic sensory mononeuritis multiplex in another. We also found 1 case of acute demyelinating neuropathy, treated with antibiotherapy and immunoglobulins, and 1 chronic demyelinating neuropathy. Overall, diaphragmatic paralysis was frequent (18.6%). Antibiotherapy (mostly ceftriaxone 3-4 weeks) resulted in symptom resolution.This series gives an updated overview of the peripheral complications of neuroborreliosis to help identify this disease so that timely treatment could avoid axonal loss.
Proximal spinal muscular atrophy (SMA) is defined by a degeneration of the anterior horn cells resulting in muscle weakness predominantly in the proximal lower limbs. While most patients carry a ...biallelic deletion in the SMN1 gene (localized in chromosome 5q), little is known regarding patients without SMN1-mutation, and a genetic diagnosis is not always possible. Here, we report a cohort of 24 French patients with non-5q proximal SMA from five neuromuscular centers who all, except two, had next-generation sequencing (NGS) gene panel, followed by whole exome sequencing (WES) if gene panel showed a negative result. The two remaining patients benefited directly from WES or whole genome sequencing (WGS). A total of ten patients with causative variants were identified, nine of whom were index cases (9/23 families = 39%). Eight variants were identified by gene panel: five variants in DYNC1H1, and three in BICD2. Compound heterozygous causative variants in ASAH1 were identified directly by WES, and one variant in DYNC1H1 was identified directly by WGS. No causative variant was found using WES in patients with a previous panel with negative results (14 cases). We thus recommend using primarily NGS panels in patients with non-5q-SMA and using WES, especially when several members of the same family are affected and/or when trio analyses are possible, or WGS as second-line testing if available.
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.
ATL1
-related spastic paraplegia SPG3A is a pure form of hereditary spastic paraplegia. Rare complex phenotypes have been described, but few data concerning cognitive evaluation or molecular imaging ...of these patients are available. We relate a retrospective collection of patients with SPG3A from the Neurology Department of Nancy University Hospital, France. For each patient were carried out a
18
F-FDG PET (positron emission tomography), a electromyography (EMG), a sudoscan®, a cerebral and spinal cord MRI (magnetic resonance imaging) with measurement of cervical and thoracic surfaces, a neuropsychological assessment. The present report outlines standardised clinical and paraclinical data of five patients from two east-France families carrying the same missense pathogenic variation, NM_015915.4(ATL1): c.1483C > T p.(Arg495Trp) in
ATL1
. Mean age at onset was 14 ± 15.01 years. Semi-quantitatively and in comparison to healthy age-matched subjects, PET scans showed a significant cerebellar and upper or mild temporal hypometabolism in all four adult patients and hypometabolism of the prefrontal cortex or precuneus in three of them. Sudoscan® showed signs of small fibre neuropathy in three patients. Cervical and thoracic patients’ spinal cords were significantly thinner than matched-control, respectively 71 ± 6.59mm
2
(
p
= 0.01) and 35.64 ± 4.35mm
2
(
p
= 0.015). Two patients presented with a dysexecutive syndrome. While adding new clinical and paraclinical signs associated with
ATL1
pathogenic variations, we insist here on the variable penetrance and expressivity. We report small fibre neuropathy, cerebellar hypometabolism and dysexecutive syndromes associated with SPG3A. These cognitive impairments and PET findings may be related to a cortico-cerebellar bundle axonopathy described in the cerebellar cognitive affective syndrome (CCAS).
The efficacy of enzyme replacement therapy (ERT) in patients at an advanced stage of Pompe disease has only been addressed in a few studies. Our objective was to assess the long term effects of ERT ...in a cohort of patients with severe Pompe disease.
We identified patients from the French Pompe Registry with severe respiratory failure and permanent wheelchair use (assisted walk for a few meters was allowed) when starting ERT. Patients' medical records were collected and reviewed and respiratory and motor functions, before ERT initiation and upon last evaluation were compared.
Twelve patients (7 males) were identified. Median age at symptom onset was 24years IQR=15.5; 36.0. At baseline ventilation was invasive in 11 patients and noninvasive in one, with a median ventilation time of 24h IQR=21.88; 24.00 (min 20; max 24). ERT was initiated at a median age of 52.5years IQR=35.75; 66.50. Median treatment duration was 55months IQR=39.5; 81.0. During observational period no adverse reaction to ERT was recorded, five patients (41.67%) died, three decreased their ventilation time by 30, 60 and 90min and two increased their assisted walking distance, by 80 and 20m.
Some patients at a very advanced stage of Pompe disease may show a mild benefit from ERT, in terms of increased time of autonomous ventilation and of enlarged distance in assisted walk. ERT can be initiated in these patients in order to retain their current level of independence and ability to perform daily life activities.
•The efficacy of ERT in patients at an advanced stage of Pompe disease, confined in a wheelchair and ventilator dependent, has not been proven in a randomized trial.•We identified patients from the French Pompe Registry with severe respiratory failure and permanent wheelchair use (assisted walk for a few meters was allowed) when starting ERT.•During observational period no adverse reaction to ERT was recorded, five patients (41.67%) died, three decreased their ventilation time by 30, 60 and 90minutes and two increased their assisted walking distance, by 80 and 20meters.•Some patients at a very advanced stage of Pompe disease may show a mild benefit from ERT, in terms of increased time of autonomous ventilation and of enlarged distance in assisted walk.
The oral anti-angiogenic therapy nintedanib prolongs progression-free survival (PFS) when combined with chemotherapy after primary surgery for advanced epithelial ovarian cancer. The randomized phase ...II CHIVA trial evaluated the impact of combining nintedanib with neoadjuvant chemotherapy (NACT) for epithelial ovarian cancer.
Patients with newly diagnosed unresectable FIGO stage IIIC–IV epithelial ovarian cancer received 3–4 cycles of carboplatin plus paclitaxel every 3 weeks as NACT before interval debulking surgery (IDS), followed by 2–3 post-operative cycles. Patients were randomized 2:1 to receive either nintedanib 200 mg twice daily or placebo on days 2–21 every 3 weeks during NACT (omitting peri-operative cycles), and then as maintenance therapy for up to 2 years. The primary endpoint was PFS.
Between January 2013 and May 2015, 188 patients were randomized (124 to nintedanib, 64 to placebo). PFS was significantly inferior with nintedanib (median 14.4 versus 16.8 months with placebo; hazard ratio 1.50, p = 0.02). Overall survival (OS) was also inferior (median 37.7 versus 44.1 months, respectively; hazard ratio 1.54, p = 0.054). Nintedanib was associated with increased toxicity (grade 3/4 adverse events: 92% versus 69%, predominantly hematologic and gastrointestinal), lower response rate by RECIST (35% versus 56% before IDS), and lower IDS feasibility (58% versus 77%) versus placebo.
Adding nintedanib to chemotherapy and in maintenance as part of NACT for advanced epithelial ovarian cancer cannot be recommended as it increases toxicity and compromises chemotherapy efficacy (IDS, PFS, OS).
ClinicalTrials.govregistration: NCT01583322.
•CHIVA assessed nintedanib integrated into a neoadjuvant strategy for ovarian cancer.•Nintedanib was associated with worse progression-free survival (primary endpoint).•Nintedanib was associated with an increase in typical chemotherapy adverse effects but not surgical complications.•Nintedanib is not recommended as part of neoadjuvant therapy for ovarian cancer.
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