Excellent response to anti-CD38 therapy with daratumumab in a patient with severe refractory CANOMAD.

BACKGROUND: Intravenous immunoglobulin (IVIG) and rituximab are considered the first-line and second-line treatments for Chronic Ataxic Neuropathy and Ophthalmoplegia with IgM-paraprotein, cold Agglutinins, and anti-Disialosyl antibodies (CANOMAD), with an overall clinical response around 50%. New anti-CD38 daratumumab, targeting long-lived plasma cells, has been reported as a promising therapy for treatment-refractory antibody-mediated disorders. We report the first case of a severe refractory CANOMAD, successfully treated with daratumumab. METHODS: A patient in their 70s with severe relapsing CANOMAD, refractory to IVIG, steroids, rituximab and ibrutinib developed severe tetraparesis and respiratory failure. Plasma exchange (PE) improved motor and ventilatory function; however, after 6 weeks, patient remained PE dependent. Intravenous daratumumab was initiated at 16 mg/kg weekly for 3 weeks, every 2 weeks for the second and third month, and monthly afterwards. RESULTS: After 3 weeks of starting daratumumab, PE was discontinued and, since then, the patient evolved to complete recovery. Antidisialosyl antibody titres decreased after PE and remained stable during daratumumab. Serum neurofilament light-chain levels were elevated in the exacerbation phase and normalised after daratumumab. The patient remains in clinical remission under monthly daratumumab, 12 months after initiation. CONCLUSIONS: The first patient with aggressive treatment-refractory CANOMAD treated with daratumumab provides proof-of-principle evidence that daratumumab may be an effective treatment in IgM-related neuropathies.

Clinical characteristics and outcome of amaurosis fugax due to transient retinal ischemia: Results from a contemporary cohort.

BACKGROUND: Whether presenting an episode of amaurosis fugax (AFx) increases the risk of ischemic stroke is controversial and there is a lack of consensus in the following management. We aimed to describe the clinical characteristics and prognosis of patients with AFx due to suspected transient retinal ischemia. METHODS: Observational, retrospective study of patients admitted in a Comprehensive Stroke Center with diagnosis of AFx due to suspected transient retinal ischemia between 2015 and 2020. Clinical characteristics and diagnostic-therapeutic data were collected, as well as recurrences (new episodes of amaurosis and/or ischemic strokes). Multivariable Cox regression analyses were performed to study factors associated with the risk of recurrence. RESULTS: We included 91 patients with a mean age of 67.9±14.8 years, 43(47.3%) were women. After the diagnostic workup 14(15.4%) AFx were attributed to an atherothrombotic etiology, 4(4.4%) cardioembolic source, 10(11%) other determined cause (TOAST-OC) and 63(69,2%) indeterminate etiology. 71(78%) patients started antiplatelet therapy and 2(2.2%) anticoagulant therapy. After a median follow-up of 3.5 years (IQR 1.8-5.2), at least one recurrence was recorded in eight (8.8%) patients (four new AFx and four cerebral infarctions). TOAST-OC (HR=9.66, 95% CI 2.41-38.70; p=0.001) and prior history of ischemic stroke (HR=4.21. 95% CI 1.01-17.66; p=0.049) were both independently associated with the risk of recurrence. CONCLUSIONS: In two out of three patients, AFx due to transient retinal ischemia was of undetermined cause. The risk of stroke recurrence after a first episode of AFx in our cohort was 8.8%. Patients with TOAST-OC etiology identified were at highest risk of recurrence.

Cerebellar Syndrome Induced by Hypomagnesemia: A Treatable Cause of Ataxia Not to be Missed. Report of Three Cases and a Review of the Literature.

Background: Magnesium is an important intracellular cation involved in essential enzymatic reactions. It is necessary for neuronal function and its depletion can produce neurological symptoms such as cramps or seizures. Clinical consequences of its deficit in the cerebellum are less known and the diagnosis can be delayed because of the lack of awareness on this condition. Cases: We present three cases of cerebellar syndrome (CS) due to hypomagnesemia: A midline CS with myoclonus and ocular flutter and two cases of hemispheric CS, one of them entailed a Schmahmann's syndrome and the other suffered a seizure. MRI findings revealed cerebellar vasogenic edema and the symptoms improved after magnesium replacement in all cases. Literature Review: We reviewed 22 cases of CS due to hypomagnesemia, all with subacute onset (days to weeks). Encephalopathy and/or epileptic seizures were common. MRI findings were vasogenic edema involving the cerebellar hemispheres, the vermis, or the nodule. Up to 50% of patients presented hypocalcemia and/or hypokalemia. All the patients showed symptomatic improvement after magnesium replacement, but 50% showed significant sequelae, and 46% relapsed. Conclusions: Hypomagnesaemia should always be considered in the differential diagnosis of CS as it has a potential treatment, and its early recognition can avoid recurrences and permanent cerebellar impairment.

Antibodies against the flotillin-1/2 complex in patients with multiple sclerosis.

Multiple sclerosis is a tissue-specific autoimmune disease of the central nervous system in which the antigen(s) remains elusive. Antibodies targeting the flotillin-1/2 complex have been described in 1-2% of the patients in a recent study. Other candidate antigens as anoctamin-2 or neurofascin-155 have been previously described in multiple sclerosis patients, although their clinical relevance remains uncertain. Our study aims to analyse the frequency and clinical relevance of antibodies against neurofascin-155, anoctamin-2 and flotillin-1/2 complex in multiple sclerosis. Serum (n = 252) and CSF (n = 50) samples from 282 multiple sclerosis patients were included in the study. The control group was composed of 260 serum samples (71 healthy donors and 189 with other neuroinflammatory disorders). Anti-flotillin-1/2, anti-anoctamin-2 and anti-neurofascin-155 antibodies were tested by cell-based assays using transfected cells. We identified six multiple sclerosis patients with antibodies against the flotillin-1/2 complex (2.1%) and one multiple sclerosis patient with antibodies against anoctamin-2 (0.35%). All multiple sclerosis patients were negative for anti-neurofascin-155 antibodies. Three of the anti-flotillin-1/2 positive patients showed anti-flotillin-1/2 positivity in other serum samples extracted at different moments of their disease. Immunoglobulin G subclasses of anti-flotillin-1/2 antibodies were predominantly one and three. We confirm that antibodies targeting the flotillin-1/2 complex are present in a subgroup of patients with multiple sclerosis. Further studies are needed to understand the clinical and pathological relevance of anti-flotillin-1/2 autoantibodies in multiple sclerosis.

Impact of Cerebral Microbleeds in Stroke Patients with Atrial Fibrillation.

OBJECTIVES: Cerebral microbleeds are associated with the risks of ischemic stroke and intracranial hemorrhage, causing clinical dilemmas for antithrombotic treatment decisions. We aimed to evaluate the risks of intracranial hemorrhage and ischemic stroke associated with microbleeds in patients with atrial fibrillation treated with vitamin K antagonists, direct oral anticoagulants, antiplatelets, and combination therapy (i.e. concurrent oral anticoagulant and antiplatelet). METHODS: We included patients with documented atrial fibrillation from the pooled individual patient data analysis by the Microbleeds International Collaborative Network. Risks of subsequent intracranial hemorrhage and ischemic stroke were compared between patients with and without microbleeds, stratified by antithrombotic use. RESULTS: A total of 7,839 patients were included. The presence of microbleeds was associated with an increased relative risk of intracranial hemorrhage (adjusted hazard ratio [aHR] = 2.74, 95% confidence interval = 1.76-4.26) and ischemic stroke (aHR = 1.29, 95% confidence interval = 1.04-1.59). For the entire cohort, the absolute incidence of ischemic stroke was higher than intracranial hemorrhage regardless of microbleed burden. However, for the subgroup of patients taking combination of anticoagulant and antiplatelet therapy, the absolute risk of intracranial hemorrhage exceeded that of ischemic stroke in those with 2 to 4 microbleeds (25 vs 12 per 1,000 patient-years) and ≥ 11 microbleeds (94 vs 48 per 1,000 patient-years). INTERPRETATION: Patients with atrial fibrillation and high burden of microbleeds receiving combination therapy have a tendency of higher rate of intracranial hemorrhage than ischemic stroke, with potential for net harm. Further studies are needed to help optimize stroke preventive strategies in this high-risk group. ANN NEUROL 2023;94:61-74.

A new homozygous missense variant in LMOD3 gene causing mild nemaline myopathy with prominent facial weakness.

Nemaline myopathy (NEM) type 10, caused by biallelic mutations in LMOD3, is a severe congenital myopathy clinically characterized by generalized hypotonia and muscle weakness, respiratory insufficiency, joint contractures, and bulbar weakness. Here, we describe a family with two adult patients presenting mild nemaline myopathy due to a novel homozygous missense variant in LMOD3. Both patients presented mild delayed motor milestones, frequent falls during infancy, prominent facial weakness and mild muscle weakness in the four limbs. Muscle biopsy showed mild myopathic changes and small nemaline bodies in a few fibers. A neuromuscular gene panel revealed a homozygous missense variant in LMOD3 that co-segregated with the disease in the family (NM_198271.4: c.1030C>T; p.Arg344Trp). The patients described here provide evidence of the phenotype-genotype correlation, suggesting that non-truncating variants in LMOD3 lead to milder phenotypes of NEM type 10.

Frequency, Predictors, Etiology, and Outcomes for Deep Intracerebral Hemorrhage without Hypertension.

OBJECTIVES: Some patients with deep intracerebral hemorrhage (ICH) have a transient hypertensive response and they may be erroneously classified as secondary to hypertension. We investigated frequency, risk factors, and outcomes for patients with deep ICH without hypertension. MATERIALS AND METHODS: We consecutively recruited patients with spontaneous ICH attending two Spanish stroke centers (January 2015-June 2019). Excluded were patients with lobar/infratentorial ICH and patients who died during hospitalization. We defined deep ICH without hypertension when the bleeding was in a deep structure, no requirement for antihypertensive agents during follow-up and no evident chronic hypertension markers evaluated by transthoracic echocardiography, 24 h ambulatory blood pressure monitoring and/or electrocardiography. We compared clinical, radiological, and 3-month functional outcome data for deep-ICH patients with hypertension versus those without hypertension. RESULTS: Of 759 patients with ICH, 219 (mean age 69.6 ± 15.4 years, 54.8% men) met the inclusion criteria and 36 (16.4%) did not have hypertension. Of these 36 patients, 19 (52.7%) had a transient hypertensive response. Independent predictors of deep ICH without hypertension were age (adjusted OR:0.94;95%CI:0.91-0.96) and dyslipidemia (adjusted OR:0.27;95% CI:0.08-0.85). One third of deep ICH without hypertension were secondary to vascular malformations. Favorable outcomes (modified Rankin Scale 0-2) were more frequent in patients with deep ICH without hypertension compared to those with hypertension (70.9% vs 33.8%; p < 0.001). CONCLUSION: Of patients with deep ICH, 16.4% were unrelated with hypertension, around half showed hypertensive response, and around a third had vascular malformations. We suggest studying hypertension markers and performing a follow-up brain MRI in those patients with deep ICH without prior hypertension.