Explore the vast range of titles available.

Objective To determine the clinical usefulness of systemic genetic testing in neuropathies without definite etiology. Methods We systematically performed genetic testing in all patients with neuropathy who did not have a definite etiology, seen at our neuromuscular clinic between 2017 and 2020. The testing consisted of an inherited neuropathy panel (72–81 genes), which used next-generation sequencing technology. Results We screened 200 patients. Pathogenic mutations were found in 30 (15%). PMP22, TTR and GJB1, accounted for 83.3% of positive mutations. The management was altered in four patients (2%). Two patients were found to have hereditary transthyretin amyloidosis and were started on TTR gene silencers. Two patients were being treated for demyelinating autoimmune neuropathy and were diagnosed with CMT1A and CMTX. Conclusion Screening for genetic mutations in patients with neuropathy without a definite etiology is useful. While only a minority of patients with unsuspected inherited neuropathy tested positive, the findings altered management in some, improving morbidity and, perhaps, mortality.

Background To report our experience with a group of patients referred for refractory CIDP who fulfilled “definite” electrodiagnostic EFNS criteria for CIDP but were found to have an alternate diagnosis. Methods Patients who were seen between 2017 and 2019 for refractory CIDP that fulfilled “definite” electrodiagnostic ENFS criteria for CIDP, but had an alternate diagnosis, were included. Patients who correctly had CIDP, anti MAG neuropathy, or MMN with conduction block, were excluded from the study. Demographics, clinical and electrophysiological characteristics, pertinent workup, final alternate diagnoses, and outcomes were collected. Results Seven patients were included: POEMS ( n  = 5), CANOMAD ( n  = 1), and neurolymphomatosis (n = 1). Most patients reported neuropathic pain and leg swelling ( n  = 6) or significant weight loss ( n  = 4). All patients had a monoclonal protein, and most patients who were tested had an elevated VEGF and CSF cyto-albuminologic dissociation. Electrophysiology showed pronounced intermediate more than distal demyelination, and axonal loss in the lower extremities. Response to steroids or IVIG varied, but some patients did respond to these treatments, especially early in the disease. Conclusion Pain, systemic symptoms, suggestive electrophysiological findings, and/or a serum monoclonal protein should raise suspicion for CIDP mimics. Initial response to steroids or IVIG, over reliance on CSF, and electrophysiology findings can all be misleading.

Objective We report the 12‐month follow‐up outcomes from a Phase 2 clinical trial (NCT04146051) evaluating Descartes‐08, a BCMA‐directed RNA chimeric antigen receptor T‐cell (rCAR‐T) therapy for refractory generalized myasthenia gravis (MG). These findings provide insight into the potential applicability of BCMA‐targeted rCAR‐T therapy for antibody‐mediated autoimmune diseases. Methods In the Phase 2a part of the study, Descartes‐08 was administered at 52.5 × 106 CAR+ cells/kg per infusion with varying dosing frequencies as an outpatient treatment and without lymphodepletion chemotherapy. A subset of participants received Descartes‐08 as six weekly infusions and were followed long term with assessments conducted at 2, 3, 6, 9, and 12 months. Results All seven participants who received six weekly infusions of Descartes‐08 exhibited clinically meaningful improvement in common MG severity scales (MG Composite, MG Activities of Daily Living, Quantitative MG scores, and Quality of Life 15‐revised) at Month 3 without significant toxicity. At Month 9 follow‐up, all participants continued to experience marked clinically meaningful improvements. Five out of seven participants maintained the response at Month 12. A third participant experienced a relapse approximately 6 months after completing on‐study follow‐up. All three participants who experienced loss of clinical effects were retreated. Two had rapid improvement in clinical scores with minimal symptom expression at Week 8, which was maintained through 12 months of retreatment follow‐up. The third participant experienced similar improvement in MG severity scores to their initial treatment. Interpretation These data support continued development of Descartes‐08 in myasthenia gravis and other autoantibody‐associated autoimmune disorders.

Background Immune-mediated necrotizing myopathy (IMNM) and dermatomyositis (DM) are characterized by weakness, hyperCKemia, associated autoantibodies, and varying extramuscular manifestations. Muscle MRI, currently subordinate to histopathology and serology in idiopathic inflammatory myopathy (IIM) classification, has an evolving role. Our study aims to define thigh muscle MRI involvement in IMNM and DM by direct comparison. Methods This single-center, retrospective, cross-sectional study included 25 participants, who met IIM classification criteria (14 IMNM, 11 DM) and had available thigh MRI. Clinical and paraclinical data were available and reviewed. 11 muscles were graded for edema on MRI using a semi-quantitative scale (0: normal, 1: <30% of muscle involvement, 2: 31–75%, 3: > 75%). For 3 participants with no significant muscle edema, muscle fatty infiltration was scored according to the same scale. Using linear mixed-effects models, muscle scores were compared between the two groups and a secondary analysis was performed of only edema scores, excluding the 3 participants with fatty infiltration scores. Results The most affected muscles in IMNM were the semimembranosus (3.0 [2.7-3.0] {median [IQR]}), biceps femoris-long head (BF-LH) (2.7 [2.0–3.0]), and adductors (2.5 [2.0–3.0]). In DM, the most affected muscles were the vastus lateralis (2.7 [2.3-3.0]), vastus intermedius (2.9 [2.2-3.0]), vastus medialis (2.3 [1.7–2.7]), semitendinosus (2.2 [1.0-2.7]), rectus femoris (RF) (2.0 [1.0-2.8]), biceps femoris-short head (BF-SH) (1.9 [1.0-2.7]), gracilis, and sartorius. Intergroup statistical difference of scores was significant ( p  < 0.01) for 10/11 thigh muscles excluding the RF ( p  = 0.19), supporting an inverse relationship of muscle involvement for DM and IMNM. The secondary comparative analysis of only muscle edema scores was significant ( p  < 0.05) for the same 10/11 muscles with a consistent direction for all comparisons. Conclusion DM and IMNM affect disparate thigh muscles on MRI. DM preferentially affects the anterior thigh, semitendinosus and BF-SH in the posterior thigh, and gracilis in the medial thigh, whereas IMNM preferentially affects the posterior thigh (semimembranosus and BF-LH) and adductors in the medial thigh.

BackgroundLate-onset Pompe disease (LOPD) is an often misdiagnosed inherited myopathy for which treatment exists. We noticed a bright tongue sign on brain MRIs of two patients who were admitted to the ICU for respiratory failure of unclear origin, and who were eventually diagnosed with LOPD. This led us to systematically review brain MRIs of patients with LOPD and various other neuromuscular disorders (NMD).Materials and methodsChart and brain MRI review of patients with LOPD and other NMD.ResultsAbnormalities of the tongue were observed in 11/33 of the patients studied. In 10/11 patients, no comments were made with regard to the tongue abnormalities in the radiology report. Bright tongue sign was seen in 4/6 patients with LOPD and 4/28 patients with other NMD. Tongue atrophy was seen in 3/6 patients with LOPD and 6/28 patients with other NMD.ConclusionTongue abnormalities on brain MRI are common in LOPD compared to other NMD. These abnormalities are not usually reported by the radiologist. Particular attention to the tongue when reviewing brain MRIs may be an important clue for diagnosis of a patient’s muscle weakness. A larger study is suggested to evaluate the sensitivity and specificity of tongue abnormalities in patients with LOPD.

Chimeric antigen receptor (CAR) T cells are highly effective in treating haematological malignancies, but associated toxicities and the need for lymphodepletion limit their use in people with autoimmune disease. To explore the use of CAR T cells for the treatment of people with autoimmune disease, and to improve their safety, we engineered them with RNA (rCAR-T)—rather than the conventional DNA approach—to target B-cell maturation antigen (BCMA) expressed on plasma cells. To test the suitability of our approach, we used rCAR-T to treat individuals with myasthenia gravis, a prototypical autoantibody disease mediated partly by pathogenic plasma cells. MG-001 was a prospective, multicentre, open-label, phase 1b/2a study of Descartes-08, an autologous anti-BCMA rCAR-T therapy, in adults (ie, aged ≥18 years) with generalised myasthenia gravis and a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 6 or higher. The study was done at eight sites (ie, academic medical centres or community neurology clinics) in the USA. Lymphodepletion chemotherapy was not used. In part 1 (phase 1b), participants with Myasthenia Gravis Foundation of America (MGFA) disease class III–IV generalised myasthenia gravis received three ascending doses of Descartes-08 to determine a maximum tolerated dose. In part 2 (phase 2a), participants with generalised myasthenia gravis with MGFA disease class II–IV received six doses at the maximum tolerated dose in an outpatient setting. The primary objective was to establish safety and tolerability of Descartes-08; secondary objectives were to assess myasthenia gravis disease severity and biomarkers in participants who received Descartes-08. This trial is registered with clinicaltrials.gov, NCT04146051. We recruited 16 individuals for screening between Jan 7, 2020 and Aug 3, 2022. 14 participants were enrolled (n=3 in part 1, n=11 in part 2). Ten participants were women and four were men. Two individuals did not qualify due to low baseline MG-ADL score (n=1) or lack of generalised disease (n=1). Median follow-up in part 2 was 5 months (range 3–9 months). There was no dose-limiting toxicity, cytokine release syndrome, or neurotoxicity. Common adverse events were headache (six of 14 participants), nausea (five of 14), vomiting (three of 14), and fever (four of 14), which resolved within 24 h of infusion. Fevers were not associated with increased markers of cytokine release syndrome (IL-6, IL-2, and TNF). Mean improvements from baseline to week 12 were –6 (95% CI –9 to –3) for MG-ADL score, –7 (–11 to –3) for Quantitative Myasthenia Gravis score, –14 (–19 to –9) for Myasthenia Gravis Composite score, and –9 (–15 to –3) for Myasthenia Gravis Quality of Life 15-revised score. In this first study of an rCAR-T therapy in individuals with an autoimmune disease, Descartes-08 appeared to be safe and was well tolerated. Descartes-08 infusions were followed by clinically meaningful decreases on myasthenia gravis severity scales at up to 9 months of follow-up. rCAR-T therapy warrants further investigation as a potential new treatment approach for individuals with myasthenia gravis and other autoimmune diseases. Cartesian Therapeutics and National Institute of Neurological Disorders and Stroke of the National Institutes of Health.

In a large cohort of patients with sarcoidosis, only 5% had neurological involvement, and in approximately 50% of this minority was the presenting manifestation neurological.1 Moreover, CSF analysis may be normal or show non-specific findings—according to one study in which CSF results were available for 42 patients, elevated protein was present in 62% of cases, pleocytosis in 57% and hypoglycorrhachia only in 17%.2 3 Common manifestations of neurosarcoidosis include cranial neuropathies, hypothalamic dysfunction, brain and spinal cord lesions, peripheral neuropathy, and myopathy. Whole-body PET-CT should be considered in the evaluation of suspected neurosarcoidosis as it may detect other organ involvement and identify the optimal biopsy site.5 Learning points Neurosarcoidosis should be considered in cases of radiculopathy not explained by infection, malignancy, or a structural lesion such as spondylosis. Whole-body positron emission tomography-CT should be considered in the evaluation of suspected neurosarcoidosis, when other imaging modalities are unrevealing, as it may detect other organ involvement and identify the optimal biopsy site. YA–directly involved in patient care, drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data; AW–drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data; DG–directly involved in patient care, drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data; NC–directly involved in patient care, drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data.

•Low GAA enzyme activity can be seen in people carrying pseudodeficiency alleles.•GAA enzyme activity testing, if abnormal, should be followed by genetic testing.•LOPD diagnosis should be questioned in patient with normal exam, CK levels and EMG.