Emergence of the natural history of Myhre syndrome: 47 patients evaluated in the Massachusetts General Hospital Myhre Syndrome Clinic (2016-2023).

Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016-2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence-based guidelines in anticipation of disease-specific therapies.

Brain volume is a better biomarker of outcomes in ischemic stroke compared to brain atrophy.

Brain parenchymal fraction (BPF) has been used as a surrogate measure of global brain atrophy, and as a biomarker of brain reserve in studies evaluating clinical outcomes after brain injury. Total brain volume at the time of injury has recently been shown to influence functional outcomes, where larger brain volumes are associated with better outcomes. Here, we assess if brain volume at the time of ischemic stroke injury is a better biomarker of functional outcome than BPF. Acute ischemic stroke cases at a single center between 2003 and 2011, with MR neuroimaging obtained within 48 hours from presentation were eligible. Functional outcomes represented by the modified Rankin Score (mRS) at 90 days post admission (mRS<3 deemed a favorable outcome) were obtained via patient interview or per chart review. Deep learning enabled automated segmentation pipelines were used to calculate brain volume, intracranial volume (ICV), and BPF on the acute neuroimaging data. Patient outcomes were modeled through logistic regressions, and model comparison was conducted using the Bayes Information Criterion (BIC). 467 patients with arterial ischemic stroke were included in the analysis. Median age was 65.8 years, and 65.3% were male. In both models, age and a larger stroke lesion volume were associated with worse functional outcomes. Higher BPF and a larger brain volume were both associated with favorable functional outcomes, however, comparison of both models suggested that the brain volume model (BIC=501) explains the data better compared to the BPF model (BIC=511). The extent of global brain atrophy has been regarded as an important biomarker of post-stroke functional outcomes and resilience to acute injury. Here, we demonstrate that a higher global brain volume at the time of injury better explains favorable functional outcomes, which can be directly clinically assessed.

Intravenous Thrombolytics in the Treatment of Acute Ischemic Stroke.

Purpose of Review: To review the current evidence and ongoing clinical trials evaluating the efficacy and safety of tenecteplase (TNK), an alternative tissue plasminogen activator (tPA), in the acute management of arterial ischemic stroke (AIS). To date, alteplase is the only tPA approved by the United States FDA for use in AIS. Recent Findings: There have been multiple phase two and three trials investigating the safety and efficacy of TNK in AIS. In patients with AIS due to large vessel occlusion, one randomized controlled trial demonstrated superiority of TNK for vessel recanalization rates and long-term functional outcomes when compared to alteplase. A meta-analysis of all phase two and three trials evaluating TNK in AIS concluded that TNK has a comparable safety and efficacy profile to alteplase. The results of these trials prompted new recommendations in the Acute Stroke Guideline published by the AHA suggesting it may be reasonable to use as an alternative to alteplase. Furthermore, recent real-world data has also reported decreased door-to-needle time with TNK utilization. Summary: In patients with AIS, use of a thrombolytic agent is standard of care and has been shown to reduce neurological disability and improve functional outcome. Randomized controlled trials have demonstrated that TNK is non-inferior to alteplase from a clinical outcome and safety standpoint. The existing data evaluating the efficacy of TNK compared to alteplase in acute AIS within 4.5 h from symptom onset showed no significant difference between these two agents with regard to functional outcome at 90 days but improved median time to treatment and large vessel recanalization in TNK-treated patients. The results from ongoing TNK trials in larger patient cohorts and in wake-up stroke populations will be instrumental to the wide-scale utilization of TNK in acute AIS management.

Neuroimaging markers of patient-reported outcome measures in acute ischemic stroke.

Objectives: To determine the relationship between patient-reported outcome measures (PROMs) and volumetric imaging markers in acute ischemic stroke (AIS). Patients and Methods: Patients presenting at Massachusetts General Hospital between February 14, 2017 and February 5, 2020 with a confirmed AIS by MRI were eligible and underwent a telephone interview including PROM-10 questionnaires 3-15 months after stroke. White matter hyperintensity (VWMH) and brain volumes (VBrain) were automatically determined using admission clinical MRI. Stroke lesions were manually segmented and volumes calculated (VLesion). Multivariable and ordinal regression analyses were performed to identify associations between global and PROM-10 subscores with brain volumetrics and clinical variables. Results: Utilizing data from 167 patients (mean age: 64.7; 41.9% female), higher VWMH was associated with worse global physical (ß=-0.6), global mental (ß=-0.65), physical health (OR=0.68), social satisfaction (OR=0.66), fatigue (OR=0.69) and social activities (OR=0.59) scores. Higher VLesion was associated with poorer global mental (ß=-0.79), mental health (OR=0.68), physical (OR=0.66) and social activities (OR=0.55), and emotional distress (OR=0.68) scores. Higher VBrain was linked to better global mental (ß=0.93), global physical (ß=0.79), mental health (OR=1.54) and physical activities (OR=1.72) scores. Conclusions: Neuroimaging biomarkers were significantly associated with PROMs, where higher VWMH and VLesion led to worse outcome, while higher VBrain was protective. The inclusion of neuroimaging analyses and PROMs in routine assessment provides enhanced understanding of post-stroke outcomes.

A prospective open-label trial of a CBD/THC cannabis oil in dravet syndrome.

INTRODUCTION: Both Δ9 Tetrahydrocannabidiol (THC) and cannabidiol (CBD) components of cannabis, have been shown to have anticonvulsant effects. Cannabis oils are used to treat seizures in drug-resistant epilepsy (DRE). Recent trials provide data on dosing, side effects, and efficacy of CBD, yet there is a paucity of information on THC in epilepsy. Primary objective was to establish dosing and tolerability of TIL-TC150 - a cannabis plant extract produced by Tilray®, containing 100 mg/mL CBD and 2 mg/mL THC- in children with Dravet syndrome. Secondary objectives were to assess impact of therapy on seizures, electroencephalogram (EEG) and quality of life. METHODS: Twenty children received add-on therapy with TIL-TC150. The dose ranged from 2 to 16 mg/kg/day of CBD and 0.04 to 0.32 mg/kg/day of THC. Patients were monitored for tolerability and adverse events, and secondary objectives. RESULTS: Nineteen participants completed the 20-week intervention. Mean dose achieved was 13.3 mg/kg/day of CBD (range 7-16 mg/kg/day) and 0.27 mg/kg/day of THC (range 0.14-0.32 mg/kg/day). Adverse events, common during titration included somnolence, anorexia, and diarrhea. Abnormalities of liver transaminases and platelets were observed with concomitant valproic acid therapy. There was a statistically significant improvement in quality of life, reduction in EEG spike activity, and median motor seizure reduction of 70.6%, with 50% responder rate of 63%. CONCLUSIONS: TIL-TC150 was safe and well tolerated in our subjects. TIL-TC150 treatment resulted in a reduction in seizure counts, spike index on EEG, and improved quality of life measures. This study provides safety and dosing information for THC-containing cannabinoid preparations.

Sudden unexpected death in epilepsy following resective epilepsy surgery in two patients withdrawn from anticonvulsants.

We report sudden unexpected death in epilepsy (SUDEP) following resective epilepsy surgery in two patients who had been documented as seizure free. One patient had been weaned off of anticonvulsants and was leading a normal life. The other patient had discontinued only one anticonvulsant but had recently started working night shifts. Following resective epilepsy surgery, one of the major objectives among patients, caregivers, and the healthcare team is to safely wean patients off anticonvulsant medications. The main concern regarding anticonvulsant withdrawal is seizure recurrence. While SUDEP following surgical resection has been reported, to our knowledge, there have been no confirmed cases in patients who have been seizure free. Considering the patients reported here, and given that there are no concrete guidelines for the safe withdrawal of anticonvulsants following epilepsy surgery, the discontinuation of anticonvulsants should be considered carefully and must be accompanied by close monitoring and counseling of patients regarding activities that lower seizure threshold, even after successful epilepsy surgery.

Giant aneurysm of the ascending aorta.

An ascending aortic aneurysm is a rare entity. The authors encountered an 85-year-old female patient with an uncomplicated ascending aortic aneurysm measuring 9 cm in diameter. She underwent an urgent operation involving replacement of the ascending aorta. Postoperatively, she developed mild renal failure and atrial flutter requiring direct current cardioversion. However, further recovery was good. The authors present this case including the operative management and a brief overview of this rare condition to reiterate that with an ageing population, this procedure can be done with an acceptable morbidity.