Why Are Stroke Rehabilitation Trial Recruitment Rates in Single Digits?

Background: Recruitment of patients in early subacute rehabilitation trials (<30 days post-stroke) presents unique challenges compared to conventional stroke trials recruiting individuals >6 months post-stroke. Preclinical studies suggest treatments be initiated sooner after stroke, thus requiring stroke rehabilitation trials be conducted within days post-stroke. How do specific inclusion and exclusion criteria affect trial recruitment rates for early stroke rehabilitation trials? Objectives: Provide estimates of trial recruitment based on screening and enrollment data from a phase II early stroke rehabilitation trial. Methods: CPASS, a phase II intervention trial screened ischemic stroke patients in acute care (18-months, N = 395) and inpatient rehabilitation (22-months, N = 673). Patients were stratified by upper extremity (UE) impairment into mild (NIHSS motor arm = 0, 1); moderate (NIHSS = 2, 3); severe (NIHSS = 4) and numbers of patients disqualified due to CPASS exclusion criteria determined. We also examined if a motor-specific evaluation (Action Research Arm Test, ARAT) increases the pool of eligible patients disqualified by the NIHSS motor arm item. Results: CPASS recruitment in acute care (5.3%) and inpatient rehabilitation (5%) was comparable to prior trials. In acute care, a short stay (7-17-days), prior stroke (13.5% in moderately; 13.2% in severely impaired) disqualified the majority. In inpatient rehabilitation, the majority (40.8%) were excluded for "too mild" impairment. The next majority were disqualified for reaching inpatient rehabilitation "too late" to participate in an early stroke trial (15% in moderately; 24% in severely impaired). Mean ARAT in the "too mild" showed significant impairment and potential to benefit from participation in select UE rehabilitation trials. Conclusions: Screening of ischemic stroke patients while they are still in acute care is crucial to successful recruitment for early stroke rehabilitation trials. A significant proportion of eligible patients are lost to "short length of stay" in acute care, and arrive to inpatient rehabilitation "too late" for an early rehabilitation trial. Additional screening of mildly impaired patients using a motor function specific scale will benefit the trial recruitment and generalizability. Trial Registration Number: http://www.clinicaltrials.gov Identifier: NCT02235974.

Lack of association between the MTHFR C677T variant and migraine with aura in an older population: could selective survival play a role?

BACKGROUND: Several studies, but not all, of primarily middle-aged or younger adults have suggested that the common MTHFR C677T variant is a genetic risk factor for migraine with aura (MA). Here, we consider whether this variant is associated with MA risk in an older non-clinical population (AGES-Reykjavik cohort). METHODS: Participants are a sub-sample ( N = 1976) of subjects from the Reykjavik Study (RS; mean age 50) and its continuation, AGES-RS (mean age 76). We estimated the relative odds of MA in TT versus CC carriers using multinomial logistic regression. As both MA and the TT genotype may be linked with modestly reduced longevity, we performed a simple simulation to illustrate the effect that selective survival may have had on our observed gene-disease association. RESULTS: TT versus CC carriers were at marginally reduced odds of MA (ORTT 0.55 (0.3-1.0), P = 0.07), significantly for women (ORTT 0.45 (0.2-0.9), P = 0.03). Assuming the 'true' (e.g. mid-life) effect of the TT genotype is ORTT 1.26, from a recent meta-analysis, our simulation suggested that if 25-year mortality had been (hypothetically) 13% higher in MA subjects with the TT versus CC genotype, the measured effect of the TT genotype on MA would have been attenuated to non-significance (e.g. ORTT 1.00). Our observed protective effect was consistent with the most extreme selective mortality scenario, in which essentially all of the previously reported increased mortality in MA subjects was (hypothetically) found in CT or TT carriers. CONCLUSION: The MTHFR 677TT genotype was associated with marginally reduced risk of MA in our older population. Our simulation illustrated how even modest selective survival might obscure the apparent effect of a genetic or other risk factor in older populations. We speculate that some of the heterogeneity previously observed for this particular genetic variant may be due to age range differences in the studied populations.

MTHFR C677T genotype as a risk factor for epilepsy including post-traumatic epilepsy in a representative military cohort.

The well-studied C677T variant in the methylenetetrahydrofolate reductase (MTHFR) enzyme is a biologically plausible genetic risk factor for seizures or epilepsy. First, plasma/serum levels of homocysteine, a pro-convulsant, are moderately elevated in individuals with the homozygote TT genotype. Furthermore, the TT genotype has been previously linked with migraine with aura-a comorbid condition-and with alcohol withdrawal seizures. Finally, several small studies have suggested that the TT genotype may be overrepresented in epilepsy patients. In this study, we consider whether the MTHFR C677T or A1298C variants are associated with risk of epilepsy including post-traumatic epilepsy (PTE) in a representative military cohort. Study subjects were selected from the cohort of military personnel on active duty during the years 2003 through 2007 who had archived serum samples at the DoD Serum Repository, essentially all active duty personnel during this time frame. We randomly selected 800 epilepsy patients and 800 matched controls based on ICD-9-CM diagnostic codes. We were able to isolate sufficient genetic material from the archived sera to genotype approximately 85% of our study subjects. The odds of epilepsy were increased in subjects with the TT versus CC genotype (crude OR=1.52 [1.04-2.22], p=0.031; adjusted OR=1.57 [1.07-2.32], p=0.023). In our sensitivity analysis, risk was most evident for patients with repeated rather than single medical encounters for epilepsy (crude OR=1.85 [1.14-2.97], p=0.011, adjusted OR=1.95 [1.19-3.19], p=0.008), and particularly for PTE (crude OR=3.14 [1.41-6.99], p=0.005; adjusted OR=2.55 [1.12-5.80], p=0.026). Our early results suggest a role for the common MTHFR C677T variant as a predisposing factors for epilepsy including PTE. Further exploration of baseline homocysteine and folate levels as predictors of seizure risk following traumatic brain injury is warranted.