The Queen's Medical Center, originally named and still commonly referred to as Queen's Hospital, is the largest private non-profit hospital in Honolulu, Hawaii. The institution was founded in 1859 by Queen Emma and King Kamehameha IV, and is located in Downtown Honolulu.
BACKGROUND:Recombinant factor VIIa has been shown to slow bleeding in patients with intracerebral haemorrhage (ICH), but no haemostatic agent has been shown to improve clinical outcomes. We aimed to evaluate the safety, clinical efficacy, and effect on growth of ICH and intraventricular haemorrhage (IVH) of recombinant factor VIIa in patients with acute spontaneous ICH who were most likely to benefit from treatment with this agent. METHODS:We conducted a multicentre, prospective, double-blind, randomised, placebo-controlled, adaptive, phase 3 trial (FASTEST) at 93 sites across the USA, Japan, Canada, Spain, Germany, and the UK. Adults aged 18-80 years with a spontaneous ICH of 2-60 mL, IVH in less than two-thirds of one lateral ventricle or in less than a third of both lateral ventricles, a Glasgow Coma Scale score of at least 8, no evidence of recent ischaemic stroke or myocardial infarction, no recent use of anticoagulation medication or other structural cause of ICH, and who had been treated with study medication within 2 h of stroke onset or last known well were eligible for inclusion. Patients were randomly assigned (1:1) by a simple randomisation scheme to either 80 μg/kg recombinant factor VIIa (intervention group) or an identical placebo (placebo group), administered intravenously over 2 min. All investigators and participants were masked to allocated group assignment. The primary outcome was functional outcome at 180 days, measured by modified Rankin Scale (mRS; score 0-2, 3, and 4-6) and analysed by intention to treat in all randomly assigned patients. The primary safety outcome was life-threatening thromboembolic events during the first 4 days, assessed in all randomly assigned participants. The secondary aim was change in ICH volume and ICH plus IVH volume between baseline and 24 h of treatment administration. We performed an ordinal logistic regression, adjusted for age, baseline ICH volume, baseline IVH volume, and pre-stroke mRS. Preplanned interim analyses, including adaptive sample size re-estimation and enrichment to a younger subgroup (aged ≤70 years), were also conducted. This trial is registered with ClinicalTrials.gov (NCT03496883) and is closed to new participants. FINDINGS:Between Dec 3, 2021, and Oct 1, 2025, we screened 3288 patients, of whom 626 participants were randomly assigned and included in the intention-to-treat analyses: 298 (48%) in the placebo group and 328 (52%) in the intervention group. 216 (35%) participants were female and 410 (65%) were male, with a mean age of 61 years (SD 12). Mean time from stroke onset to administration of study drug was 100 min (SD 22). The trial met the prespecified stopping criteria for futility at the second interim analysis. There was no differential effect in the primary clinical outcome measure of mRS at 180 days between the intervention group and placebo group (adjusted common odds ratio 1·09 [95% CI 0·79-1·51]; p=0·61). Life-threatening thromboembolic complications within 4 days occurred in 15 (<5%) participants in the intervention group and in four (1%) in the placebo group (relative risk 3·41 [95% CI 1·14-10·15]; p=0·020). Compared with placebo, recombinant factor VIIa was associated with decreased growth of ICH (-3·7 mL [95% CI -5·4 to -1·9]) and of ICH plus IVH growth (-5·2 mL [-7·6 to -2·8]) between baseline and CT scan at 24 h. INTERPRETATION:Recombinant factor VIIa administered within 2 h of ICH onset slowed haematoma growth, but did not improve functional outcomes and showed a small increased risk of life-threatening thromboembolic complications. Further testing of recombinant factor VIIa in patients with the greatest risk of continued bleeding is ongoing. FUNDING:National Institute of Neurological Diseases and Stroke, Japan Agency for Medical Research and Development, and Novo Nordisk.
Antibody‑mediated encephalitis due to leucine‑rich glioma‑inactivated 1 (LGI1) is a frequent cause of immune‑responsive paroxysmal motor phenomena in older adults. The disorder is commonly associated with brief, stereotyped involuntary movements traditionally labeled faciobrachial dystonic seizures (FBDS). However, the “faciobrachial” descriptor may underrepresent the true phenotypic spectrum. We report a case of LGI1‑associated autoimmune encephalitis presenting with leg‑predominant tonic-dystonic attacks, expanding the recognized clinical presentation and highlighting variability in semiology. A 62‑year‑old man presented following multiple falls caused by sudden, repetitive involuntary movements primarily affecting the left lower extremity. Episodes were short‑lived, painless, and occurred dozens of times daily, often provoked by initiation of voluntary movement and preceded by a brief sensory warning. Consciousness was consistently retained, although some attacks spread to involve the ipsilateral arm and face. Neurological examination, cognitive assessment, brain MRI, and EEG were unremarkable. Cerebrospinal fluid analysis demonstrated mildly elevated protein without pleocytosis. Antiseizure therapy provided no benefit. High‑dose intravenous corticosteroids resulted in minimal improvement, whereas plasma exchange led to complete symptom resolution. Serum autoimmune testing was positive for LGI1-IgG antibody and a low-titer P/Q-type calcium channel antibody, suggesting an autoimmune encephalitis— most likely LGI1 encephalitis. FDG-PET/CT showed no malignancies or hypermetabolic abnormalities. This case highlights that LGI1‑associated paroxysmal events may present as leg‑predominant tonic-dystonic attacks, rather than the more typical faciobrachial distribution. Clinicians should maintain a high index of suspicion for autoimmune causes in late‑onset paroxysmal movement disorders, as prompt immunotherapy can prevent falls, reduce morbidity, and significantly alter disease course. Recognition of serum‑positive, imaging‑negative LGI1 autoimmunity is particularly important, as such presentations may lack common cognitive or limbic features and risk diagnostic delay.
Hypothenar hammer syndrome (HHS) is a vascular injury from repetitive trauma to the hypothenar eminence, causing ulnar artery damage. Symptoms include digital pain and paresthesia and can progress to ulceration or necrosis. We report the case of a 54-year-old man with episodic pain and discoloration in the left middle, ring, and little digits not exacerbated by activity. His history included alcohol use disorder and frequent bicycle use. Imaging demonstrated reduced ulnar artery flow without aneurysm, and diagnostic angiography revealed mild tortuosity. Doppler examination revealed softer arterial signals at the ulnar-sided digits. Despite nondiagnostic imaging, his clinical picture supported a diagnosis of HHS. After conservative management failed, surgical exploration revealed a 1-cm ulnar artery aneurysmal dilation along a 2.2-mm nondiseased segment, requiring resection and repair with end-to-end anastomosis. This case underscores that HHS cannot be reliably excluded by imaging alone and highlights the importance of clinical judgment in diagnosis and management.
Disruption of intracellular ionic homeostasis is a convergent pathological feature across diverse neurological injuries and disorders, including ischaemic and haemorrhagic stroke, hypoxic–ischaemic brain injury, traumatic brain injury, epilepsy and brain tumour. Among stress‐activated ion channels implicated in these conditions, the transient receptor potential melastatin 7 (TRPM7) channel has emerged as a key mediator linking metabolic stress to sustained dysregulation of Ca 2+ , Mg 2+ and Zn 2+ signalling and downstream injury cascades. TRPM7 is a unique bifunctional protein composed of a divalent cation‐permeable ion channel fused with a C‐terminal α ‐kinase domain, enabling integration of ionic flux with intracellular signalling. Accumulating evidence from cellular, electrophysiological and in vivo studies demonstrates that TRPM7 contributes causally to neuronal injury, vascular dysfunction, network hyperexcitability and tumour cell malignancy across disease models. Natural products have historically played a central role in ion channel pharmacology, and growing evidence has identified structurally diverse natural product‐derived compounds as modulators of TRPM7 channel. In this review, we synthesize mechanistic and pharmacological evidence supporting TRPM7 as a tractable therapeutic target, with particular focus on representative natural product‐derived TRPM7 channel inhibitors including carvacrol, waixenicin A and xyloketal B, which span a spectrum of potency, selectivity and mechanistic complexity. We further discuss key translational challenges associated with targeting TRPM7 in neurological injury, including target selectivity, essential physiological roles, CNS exposure and context‐dependent disease effects. Collectively, available evidence positions TRPM7 as a pharmacologically actionable target and highlights the potential of natural product scaffolds to guide the development of next‐generation TRPM7‐directed therapies for neurological injury.
