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.

Clinical characteristics and outcomes of methamphetamine-associated intracerebral hemorrhage.

OBJECTIVE: To compare the clinical characteristics and outcomes of primary intracerebral hemorrhage (ICH) with and without methamphetamine exposure. METHODS: We performed a retrospective analysis of patients diagnosed with spontaneous, nontraumatic ICH over a 3-year period between January 2013 and December 2016. Demographics, clinical measures, and outcomes were compared between ICH patients with positive methamphetamine toxicology tests vs those with negative methamphetamine toxicology tests. RESULTS: Methamphetamine-positive ICH patients were younger than methamphetamine-negative ICH patients (52 vs 67 years, p < 0.001). Patients with methamphetamine-positive ICH had higher diastolic blood pressure (115 vs 101, p = 0.003), higher mean arterial pressure (144 vs 129, p = 0.01), longer lengths of hospital (18 vs 8 days, p < 0.001) and intensive care unit (ICU) stay (10 vs 5 days, p < 0.001), required more days of IV antihypertensive medications (5 vs 3 days, p = 0.02), and had more subcortical hemorrhages (63% vs 46%, p = 0.05). The methamphetamine-positive group had better premorbid modified Rankin Scale (mRS) scores (p < 0.001) and a greater change in functional ability as measured by mRS at the time of hospital discharge (p = 0.001). In multivariate analyses, methamphetamine use predicted both hospital length of stay (risk ratio [RR] 1.54, confidence interval [CI] 1.39-1.70, p < 0.001) and ICU length of stay (RR 1.36, CI 1.18-1.56, p < 0.001), but did not predict poor outcome (mRS 4-6). CONCLUSIONS: Methamphetamine use is associated with earlier age at onset of ICH, longer hospital stays, and greater change in functional ability, but did not predict outcome.

Admission Heart Rate Variability is Associated with Fever Development in Patients with Intracerebral Hemorrhage.

BACKGROUND: Fever is associated with worse outcome after intracerebral hemorrhage (ICH). Autonomic dysfunction, commonly seen after brain injury, results in reduced heart rate variability (HRV). We sought to investigate whether HRV was associated with the development of fever in patients with ICH. METHODS: We prospectively enrolled consecutive patients with spontaneous ICH in a single-center observational study. We included patients who presented directly to our emergency department after symptom onset, had a 10-second electrocardiogram (EKG) performed within 24 h of admission, and were in sinus rhythm. Patient temperature was recorded every 1-4 h. We defined being febrile as having a temperature of ≥ 38 °C within the first 14 days, and fever burden as the number of febrile days. HRV was defined by the standard deviation of the R-R interval (SDNN) measured on the admission EKG. Univariate associations were determined by Fisher's exact, Mann-Whitney U, or Spearman's rho correlation tests. Variables associated with fever at p ≤ 0.2 were entered in a logistic regression model of being febrile within 14 days. RESULTS: There were 248 patients (median age 63 [54-74] years, 125 [50.4%] female, median ICH Score 1 [0-2]) who met the inclusion criteria. Febrile patients had lower HRV (median SDNN: 1.72 [1.08-3.60] vs. 2.55 [1.58-5.72] msec, p = 0.001). Lower HRV was associated with more febrile days (R = - 0.22, p < 0.001). After adjustment, lower HRV was independently associated with greater odds of fever occurrence (OR 0.92 [95% CI 0.87-0.97] with each msec increase in SDNN, p = 0.002). CONCLUSIONS: HRV measured on 10-second EKGs is a potential early marker of parasympathetic nervous system dysfunction and is associated with subsequent fever occurrence after ICH. Detecting early parasympathetic dysfunction may afford opportunities to improve ICH outcome by targeting therapies at fever prevention.

Evidence that the gene encoding ZDHHC8 contributes to the risk of schizophrenia.

Using a relatively dense genetic map of 72 single-nucleotide polymorphisms (SNPs) distributed across the entire 1.5-Mb locus on chromosome 22q11 associated with susceptibilit to schizophrenia, we previously identified two subregions that were consistently associated with the disease. In the distal subregion, we detected an association signal with five neighboring SNPs distributed over a haplotypic block of 80 kb encompassing six known genes. One of these five SNPs, rs175174, had the strongest association of all 72 SNPs that we tested. Here we show that rs175174 regulates the level of the fully functional transcript by modulating the retention of intron 4 of the gene ZDHHC8, which encodes a putative transmembrane palmitoyltransferase. Zdhhc8-knockout mice had a sexually dimorphic deficit in prepulse inhibition, a gene dosage-dependent decrease in exploratory activity in a new environment and a decreased sensitivity to the locomotor stimulatory effects of the psychomimetic drug dizocilpine (MK801). SNP rs175174 shows differences in transmission distortion between sexes in individuals with schizophrenia. Our results indicate that there is an unexpected connection between impaired palmitate modification of neuronal proteins and the psychiatric phenotypes associated with microdeletions of chromosome 22q11.