Diagnosis and follow-up evaluation of central nervous system vasculitis: an evaluation of vessel-wall MRI findings.

OBJECTIVE: To approach the clinical value of MRI with vessel wall imaging (VWI) in patients with central nervous system vasculitis (CNSV), we analyzed patterns of VWI findings both at the time of initial presentation and during follow-up. METHODS: Stenoocclusive lesions, vessel-wall contrast enhancement (VW-CE) and diffusion-restricted lesions were analyzed in patients with a diagnosis of CNSV. On available VWI follow-up, progression, regression or stability of VW-CE were evaluated and correlated with the clinical status. RESULTS: Of the 45 patients included, 28 exhibited stenoses visible on MR angiography (MRA-positive) while 17 had no stenosis (MRA-negative). VW-CE was found in 2/17 MRA-negative and all MRA-positive patients (p < 0.05). 79.1% (53/67) of stenoses showed VW-CE. VW-CE was concentric in 88.3% and eccentric in 11.7% of cases. Diffusion-restricted lesions were found more frequently in relation to stenoses with VW-CE than without VW-CE (p < 0.05). 48 VW-CE lesions in 23 patients were followed over a median time of 239.5 days. 13 VW-CE lesions (27.1%) resolved completely, 14 (29.2%) showed partial regression, 17 (35.4%) remained stable and 4 (8.3%) progressed. 22/23 patients received immunosuppressive therapy for the duration of follow-up. Patients with stable or progressive VW-CE were more likely (p < 0.05) to have a relapse (14/30 cases) than patients with partial or complete regression of VW-CE (5/25 cases). CONCLUSION: Concentric VW-CE is a common finding in medium/large-sized vessel CNSV. VW-CE might represent active inflammation in certain situations. However, follow-up VWI findings proved ambiguous as persisting VW-CE despite immunosuppressive therapy and clinical remission was a frequent finding.

Extended stereotactic brain biopsy in suspected primary central nervous system angiitis: good diagnostic accuracy and high safety.

OBJECTIVE: To evaluate the diagnostic accuracy and safety of extended stereotactic brain biopsy (ESBB) in a single center cohort with suspected primary angiitis of the central nervous system (PACNS). METHODS: A standardized stereotactic biopsy targeting MRI-positive lesions and collecting samples from the meninges and the cortex as well as from the white matter was performed in 23 patients with clinically suspected PACNS between 2010 and 2017. The relationship between biopsy yield and clinical characteristics, cerebrospinal fluid parameters, MR-imaging, time point of biopsy and exact localization of biopsy as well as number of tissue samples were examined. RESULTS: PACNS was confirmed in 7 of 23 patients (30.4%). Alternative diagnoses were identified in 7 patients (30%). A shorter time period between the onset or worsening of symptoms (p = 0.018) and ESBB significantly increased the diagnostic yield. We observed only minor and transient postoperative complications in 3 patients (13.0%). ESBB led to a direct change of the therapeutic regime in 13 of 23 patients (56.5%). Careful neuropathological analysis furthermore revealed that cortical samples were crucial in obtaining a diagnosis. CONCLUSION: ESBB is a safe approach with good feasibility, even in critically ill patients, and high diagnostic accuracy in patients with suspected PACNS changing future therapies in 13 of 23 patients (56.5%). Early biopsy after symptom onset/worsening is crucial and (sub)acute MRI-lesions should be targeted with a particular need for biopsy samples from the cortical layer.

Idarucizumab administration in emergency situations: the Munich Registry of Reversal of Pradaxa® in clinical routine (MR REPAIR).

OBJECTIVES: To evaluate daily life management and functional outcome of Idarucizumab administration in case of emergency situations in patients with Dabigatran treatment. DESIGN: Multicenter observational registry study. SETTING: All hospitals with full neurological departments (n = 6) in Munich, Germany INCLUDED PATIENTS: All patients treated with Idarucizumab from 01/2016 to 03/2019. ANALYZED DATA: Indication and application of Idarucizumab, demographics and clinical parameters, and further interventions and treatments; clinical outcome was assessed with the modified Rankin scale (mRS) at 3 months after Idarucizumab administration RESULTS: Idarucizumab was administered to 32 patients for severe bleeding complications and ischemic strokes, more precisely for the following specific indications: intracranial bleeding (17 patients, 53%), ischemic stroke (8 patients, 25%), gastrointestinal bleeding (3 patients, 9%), femoral fracture, aortic dissection, and abdominal trauma and ileus (1 patient each, 3%). Additional coagulation management was performed in 7 patients (22%). Nine patients (28%) underwent emergency surgery. Seven patients (22%) received Idarucizumab before intravenous thrombolysis due to ischemic stroke and 4 of these 7 patients (13%) received mechanical thrombectomy in addition. Indication was mainly based on the history of Dabigatran intake and was irrespective of laboratory testing. At follow-up, 25% of the investigated patients had a mRS 0-2, while 25% had an unfavorable outcome (mRS 4-5). Mortality was 31%. CONCLUSION: In our study, we have shown that the administration of Idarucizumab is a rare intervention and restricted to patients with severe bleeding complications or ischemic stroke. The clinical outcome of patients who received Idarucizumab in emergency situations was poor.

Brain diffusion tensor imaging changes in cerebrotendinous xanthomatosis reversed with treatment.

Cerebrotendinous xanthomatosis (CTX, MIM 213700) is a rare autosomal recessive lipid storage disorder caused by CYP27A1 mutations. Treatment with chenodeoxycholic acid (CDCA) may slow the progression of the disease and reverse some symptoms in a proportion of patients. In a non-consanguineous Caucasian family, two siblings with CTX were evaluated before treatment and prospectively followed-up every 6 months after starting CDCA therapy, using systematic clinical examination, neuropsychological tests, laboratory tests, electroencephalography (EEG) and brain MRI, diffusion tensor imaging (DTI) and tractography. A 30-year-old patient and her 27-year-old brother were referred for progressive spastic paraparesis. Both had epilepsy, learning difficulties, chronic diarrhoea and juvenile-onset cataracts. CTX was diagnosed by increased cholestanol levels and compound heterozygosity for CYP27A1 mutations. Therapy with CDCA led to resolution of chronic diarrhoea, normalisation of serum cholestanol and EEG, and a progressive improvement in gait, cognition and seizure control. Before treatment, conventional brain MRI showed no CTX-related abnormalities for the proband and no cerebellar abnormalities for the brother, while DTI showed reduced fractional anisotropy (FA) and tract-density in the cerebellum and widespread cerebral reductions of FA in both patients, compared to a group of 35 healthy controls. Repeated DTI after starting therapy showed progressive increases of cerebellar tract density and of cerebral FA. In patients with CTX, therapy with CDCA may lead to significant clinical improvement, with normalisation of biochemical and electrophysiological biomarkers. DTI and tractography may detect changes when the conventional MRI is unremarkable and may provide potential neuroimaging biomarkers for monitoring treatment response in CTX, while the conventional MRI remains unchanged.

TDP-43 loss of function inhibits endosomal trafficking and alters trophic signaling in neurons.

Nuclear clearance of TDP-43 into cytoplasmic aggregates is a key driver of neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), but the mechanisms are unclear. Here, we show that TDP-43 knockdown specifically reduces the number and motility of RAB11-positive recycling endosomes in dendrites, while TDP-43 overexpression has the opposite effect. This is associated with delayed transferrin recycling in TDP-43-knockdown neurons and decreased ß2-transferrin levels in patient CSF Whole proteome quantification identified the upregulation of the ESCRT component VPS4B upon TDP-43 knockdown in neurons. Luciferase reporter assays and chromatin immunoprecipitation suggest that TDP-43 represses VPS4B transcription. Preventing VPS4B upregulation or expression of its functional antagonist ALIX restores trafficking of recycling endosomes. Proteomic analysis revealed the broad reduction in surface expression of key receptors upon TDP-43 knockdown, including ErbB4, the neuregulin 1 receptor. TDP-43 knockdown delays the surface delivery of ErbB4. ErbB4 overexpression, but not neuregulin 1 stimulation, prevents dendrite loss upon TDP-43 knockdown. Thus, impaired recycling of ErbB4 and other receptors to the cell surface may contribute to TDP-43-induced neurodegeneration by blocking trophic signaling.