Natural History of Infratentorial Intracerebral Hemorrhages: Two Subgroups with Distinct Presentations and Outcomes.

BACKGROUND/OBJECTIVE: Infratentorial intracerebral hemorrhage (ICH) is associated with worse prognosis than supratentorial ICH; however, infratentorial ICH is often excluded or underrepresented in clinical trials of ICH. We sought to evaluate the natural history of infratentorial ICH stratified by brainstem or cerebellar location using a prospective observational study inclusive of all spontaneous ICH. METHODS: Using a prospective, single center cohort of patients with spontaneous ICH between 2008-2019, we conducted a descriptive analysis of baseline demographics, severity of injury scores, and long-term functional outcomes of infratentorial ICH stratified by cerebellar or brainstem location. RESULTS: Infratentorial ICH occurred in 82 (13%) of 632 patients in our ICH cohort. Among infratentorial ICH, cerebellar ICH occurred in 45 (55%) and brainstem ICH occurred in 37 (45%). Compared to cerebellar ICH, patients with brainstem ICH had significantly worse severity of injury scores, including lower admission Glasgow Coma Scale (median 14 [7.0 - 15.0] versus 4 [3.0 - 8.0], respectively; P < 0.001) and higher ICH Score (median 2 [1.0 - 3.0] versus 3 [2.75 - 4.0], respectively; P =  0.02). Patients with cerebellar ICH were more likely to be discharged home or to acute rehabilitation (OR 4.8, 95% CI 1.8 - 12.8) but there was no difference in in-hospital mortality (OR 0.4, 95% CI 0.1 - 1.1, P =  0.08) or cause of death (P =  0.5). Modified Rankin Scale scores at 3 months were significantly better in patients with cerebellar ICH compared to brainstem ICH (median 3.5 [1.8 - 6.0] versus median 6 [5.0 - 6.0], P =  0.03). CONCLUSIONS: Location of infratentorial ICH is an important determinant of admission severity and clinical outcome in unselected patients with ICH. Patients with cerebellar ICH have less severe symptoms at presentation and more favorable functional outcomes compared to patients with brainstem ICH.

Functional evidence implicating a novel TOR1A mutation in idiopathic, late-onset focal dystonia.

BACKGROUND: TOR1A encodes a chaperone-like AAA-ATPase whose Delta GAG (Delta E) mutation is responsible for an early onset, generalised dystonia syndrome. Because of the established role of the TOR1A gene in heritable generalised dystonia (DYT1), a potential genetic contribution of TOR1A to the more prevalent and diverse presentations of late onset, focal dystonia has been suggested. RESULTS: A novel TOR1A missense mutation (c.613T-->A, p.F205I) in a patient with late onset, focal dystonia is reported. The mutation occurs in a highly evolutionarily conserved region encoding the AAA-ATPase domain. Expression assays revealed that expression of F205I or Delta E, but not wildtype TOR1A, produced frequent intracellular inclusions. CONCLUSIONS: A novel, rare TOR1A variant has been identified in an individual with late onset, focal dystonia and evidence provided that the mutation impairs TOR1A function. Together these findings raise the possibility that this novel TOR1A variant may contribute to the expression of dystonia. In light of these findings, a more comprehensive genetic effort is warranted to identify the role of this and other rare TOR1A variants in the expression of late onset, focal dystonia.