Congenital Myasthenic Syndromes in Belgium: Genetic and Clinical Characterization of Pediatric and Adult Patients.

BACKGROUND: Congenital myasthenic syndromes (CMS) are a group of genetic disorders characterized by impaired neuromuscular transmission. CMS typically present at a young age with fatigable muscle weakness, often with an abnormal response after repetitive nerve stimulation (RNS). Pharmacologic treatment can improve symptoms, depending on the underlying defect. Prevalence is likely underestimated. This study reports on patients with CMS followed in Belgium in 2022. METHODS: Data were gathered retrospectively from the medical charts. Only likely pathogenic and pathogenic variants were included in the analysis. RESULTS: We identified 37 patients, resulting in an estimated prevalence of 3.19 per 1,000,000. The patients harbored pathogenic variants in CHRNE, RAPSN, DOK7, PREPL, CHRNB1, CHRNG, COLQ, MUSK, CHRND, GFPT1, and GMPPB. CHRNE was the most commonly affected gene. Most patients showed disease onset at birth, during infancy, or during childhood. Symptom onset was at adult age in seven patients, caused by variants in CHRNE, DOK7, MUSK, CHRND, and GMPPB. Severity and distribution of weakness varied, as did the presence of respiratory involvement, feeding problems, and extraneuromuscular manifestations. RNS was performed in 23 patients of whom 18 demonstrated a pathologic decrement. Most treatment responses were predictable based on the genotype. CONCLUSIONS: This is the first pooled characterization of patients with CMS in Belgium. We broaden the phenotypical spectrum of pathogenic variants in CHRNE with adult-onset CMS. Systematically documenting larger cohorts of patients with CMS can aid in better clinical characterization and earlier recognition of this rare disease. We emphasize the importance of establishing a molecular genetic diagnosis to tailor treatment choices.

Quiz case: a clinical reasoning challenge in the emergency stroke setting.

A right-handed woman in her 80s was admitted to the emergency department 1 h after sudden-onset global aphasia and right-sided hemiparesis. Medical history included arterial hypertension, dyslipidemia, hyperuricemia, aortic stenosis, osteoporosis, and recent pulmonary embolism. Medication consisted of apixaban, bisoprolol, hydrochlorothiazide, allopurinol, fenofibrate, and vitamin D. Vital parameters (blood pressure, heart rate, body temperature, oxygen saturation) and glycemia were all within normal range. Electrocardiogram showed a first-degree atrioventricular block. The patient was promptly transported to the emergency computed tomography (CT) scanner. Non-contrast brain CT revealed a unilateral hyperdensity in the left caudate and lentiform nuclei. No other intracranial lesion was visualized. Laboratory studies were not yet available at the time of imaging. What is your diagnosis?

SARS-CoV-2-associated Guillain-Barré syndrome in four patients: what do we know about pathophysiology?

BACKGROUND: A growing number of Guillain-Barré syndrome (GBS) and Miller Fisher Syndrome (MFS) cases following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are reported. Nevertheless, this association is still debated, and pathophysiology remains unclear. METHODS: Between April and December 2020, in three hospitals located in Brussels, Belgium, we examined four patients with GBS following SARS-CoV-2 infection. RESULTS:  Neurological onset occurred 3 weeks after SARS-CoV-2 symptoms in all patients. Three patients presented with acute inflammatory demyelinating polyneuropathy (AIDP) and had negative anti-ganglioside testing: two suffered from a severe SARS-CoV-2 infection and had good clinical outcome after intravenous immunoglobulin (IVIG) treatment; one with mild SARS-CoV-2 infection had spontaneously favorable evolution without treatment. The fourth patient had critical SARS-CoV-2 infection and presented acute motor and sensory axonal neuropathy (AMSAN) with clinical features highly suggestive of brainstem involvement, as well as positive anti-ganglioside antibodies (anti-GD1b IgG) and had partial improvement after IVIG. CONCLUSIONS: We report four cases of SARS-CoV-2-associated GBS. The interval of 3 weeks between SARS-CoV-2 symptoms and neurological onset, the clinical improvement after IVIG administration, and the presence of positive anti-ganglioside antibodies in one patient further support the hypothesis of an immune-mediated post-infectious process. Systematic extensive antibody testing might help for a better understanding of physiopathology.

Immune-mediated neurological syndromes in SARS-CoV-2-infected patients.

BACKGROUND: Evidence of immune-mediated neurological syndromes associated with the severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection is limited. We therefore investigated clinical, serological and CSF features of coronavirus disease 2019 (COVID-19) patients with neurological manifestations. METHODS: Consecutive COVID-19 patients with neurological manifestations other than isolated anosmia and/or non-severe headache, and with no previous neurological or psychiatric disorders were prospectively included. Neurological examination was performed in all patients and lumbar puncture with CSF examination was performed when not contraindicated. Serum anti-gangliosides antibodies were tested when clinically indicated. RESULTS: Of the 349 COVID-19 admitted to our center between March 23rd and April 24th 2020, 15 patients (4.3%) had neurological manifestations and fulfilled the study inclusion/exclusion criteria. CSF examination was available in 13 patients and showed lymphocytic pleocytosis in 2 patients: 1 with anti-contactin-associated protein 2 (anti-Caspr2) antibody encephalitis and 1 with meningo-polyradiculitis. Increased serum titer of anti-GD1b antibodies was found in three patients and was associated with variable clinical presentations, including cranial neuropathy with meningo-polyradiculitis, brainstem encephalitis and delirium. CSF PCR for SARS-CoV-2 was negative in all patients. CONCLUSIONS: In SARS-Cov-2 infected patients with neurological manifestations, CSF pleocytosis is associated with para- or post-infectious encephalitis and polyradiculitis. Anti-GD1b and anti-Caspr2 autoantibodies can be identified in certain cases, raising the question of SARS-CoV-2-induced secondary autoimmunity.

Assessing thermal sensitivity using transient heat and cold stimuli combined with a Bayesian adaptive method in a clinical setting: A proof of concept study.

BACKGROUND: Quantitative sensory testing of thermal detection abilities is used as a clinical tool to assess the function of pain pathways. The most common procedure to assess thermal sensitivity, the 'method of limits', provides a quick but rough estimate of detection thresholds. Here, we investigate the potential of evaluating not only the threshold but also the slope of the psychometric functions for cold and warm detection. METHOD: A convenience sample of 15 patients with diabetes mellitus (DM) and 15 age-matched healthy controls (HC) was tested. Thirty brief (100 ms) stimuli of each modality were applied to the volar wrist and foot dorsum. Cold and warm stimuli were delivered with a Peltier thermode and a temperature-controlled CO2 laser, respectively. Stimulus intensities were dynamically selected using an adaptive Bayesian algorithm (psi method) maximizing information gain for threshold and slope estimation. ROC analyses were used to assess the ability of slopes, thresholds and the combination of both to discriminate between groups. RESULTS: Assessment of the slope and threshold of the psychometric function for thermal detection took about 10 min. The ability to detect warmth was not reduced in DM patients as compared to HC. Cold detection performance assessed using slope or threshold parameters separated DM from HC with good discriminative power. Discrimination was further increased when both parameters were used together (93% sensitivity and 87% specificity), indicating that they provide complementary information on patient status. CONCLUSION: The psi method may be an interesting alternative to the classical method of limits for thermal QST. SIGNIFICANCE: Current QST protocols provide an incomplete and potentially biased estimate of sensory detection performance. We propose a method that estimates the slope and the threshold of the psychometric function, defining heat and cold sensory detection performance, in only a few minutes. Furthermore, we provide preliminary evidence that combining slope and threshold parameters of cold detection performance leads to a better discriminative ability than relying solely on the threshold.