Large hemispheric infarction (LHI), which usually caused by occlusion of the internal carotid artery or proximal middle cerebral artery (MCA), constitutes up to 10% of supratentorial ischemic strokes1. It is a widely accepted devastating condition with a high mortality rate of approximately 80% in two intensive care-based series2,3. Up to now, no pharmacological strategies have been proven effective by clinical trials4. Decompressive hemicraniectomy (DHC) conducted within 48 hours after symptom onset has been proven effective for LHI patients with malignant course5. However, only 0.3% of highly selected ischemic stroke patients would be eligible for DHC based on the strict eligibility criteria in the DHC trials6. Although lack of evidence, many neuropharmacological therapies are still used off-label due to the lack of effective treatment in conservatively treated LHI patients.
Amantadine was first synthesized more than 50 years ago and initially developed as an antiviral agent7. Further work has demonstrated the effectiveness of amantadine as an anti-parkinsonism agent8,9, as well as a treatment option for neuroleptic-induced extrapyramidal symptoms10,11 and neuroleptic malignant syndrome12. Amantadine hydrochloride is one of the most frequently prescribed drugs for patients with prolonged impaired consciousness after traumatic brain injury (TBI)13. The mechanism of action of amantadine is still not fully understood,but it is thought to act as an N-methyl-D-aspartate (NMDA) receptor antagonist increasing dopamine synthesis and release in the striatum14. Sufficient synaptic dopamine levels are necessary for many physiological functions including motivation, motor control, emotion, and cognitive processing15. The result of a small sample randomized trial in patients with TBI-associated diffuse axonal injury suggested that amantadine was effective in improving neuro-recovery and it was well tolerated at a dosage of 200 mg/day with no serious adverse side effects16. In a multicenter trial, amantadine at doses of 200-400 mg/day has successfully been demonstrated effective and safe in accelerating the pace of functional recovery in patients with severe TBI17. A clinical-experimental study conducted in Russian reported that amantadine exhibited significant restoration of consciousness and better regress of neurological deficit in the first day of ischemic stroke18.
So far, there is a lack of studies investigating amantadine for the treatment of patients with non-traumatic brain injuries such as severe stroke. The present study aimed to explore whether amantadine treatment is associated with better clinical outcomes in conservatively treated LHI patients.
Methods
Study design and subjects
From February 2012 to January 2015, we retrospectively and consecutively enrolled acute ischemic stroke patients admitted to the Department of Neurology, People’s Hospital of Deyang City. LHI was defined as an infarction involving more than 50% of the territory of the MCA in computed tomography (CT) and/or magnetic resonance imaging (MRI), no matter the involvement of the adjacent territories19. All patients completed brain CT before initial treatment. A second CT or MRI was performed within the first 7 days of hospitalization. Other CT scans were performed if patients suffered neurological deterioration, to identify brain edema or hemorrhagic transformation. Patients who met the following inclusion criteria were eligible for the present study: (1) age≥18 years, (2) LHI patients admitted to hospital within 24 hours of symptom onset. Patients were excluded if they met one of the following exclusion criteria: (1) received DHC during hospitalization; (2) prior treatment with amantadine; (3) history of severe renal disease; (4) history of epilepsy with more than one seizure in the previous month; (5) pregnancy; (6) incomplete hospital records or missing imaging that would prevent complete data collection; (7) any disability related to the central nervous system that predated the stroke; and (8) with a premorbid modified Rankin Scale (mRS, a scale of 0 to 6, with 0 indicating no symptoms and 6 indicating death) score of more than 2 and lived dependently20.
All LHI patients were treated with standard therapy (ST), including mechanical ventilation in maintaining a patent airway, head position, glucose, blood pressure and temperature management, parenteral and enteral feeding, osmotic therapy for brain edema, antibiotics, and other symptomatic treatment measures for stroke-related complications21. A persistent impaired consciousness was the main reason for amantadine hydrochloride treatment22. Early amantadine treatment in LHI patients was defined as amantadine hydrochloride initiated within 24 hours after stroke onset and continuing for at least three days. Amantadine hydrochloride was added at an oral dose of 100 mg twice daily. According to whether they did receive amantadine or not, the patients were divided into two groups: the amantadine group (amantadine combined with ST) and the ST group.
The study protocol was approved by the Ethics Committee of the people's hospital of Deyang city (approval No. 2011-04-134). We obtained informed consent from all patients or their legal representative if the patient lost the capacity to give informed consent before they were enrolled, for using the patient's data for research.
Data collection
A standardized structured form was used to collect the following data: patient demographics, prehospital delay, baseline blood pressure and serum glucose, baseline National Institutes of Health Stroke Scale (NIHSS) score and Glasgow coma scale (GCS) score, vascular risk factors, diagnostic tests, neurological imaging, in-hospital treatment, and stroke-related complications during hospitalization. Detailed methods for data collection have been described in our previous study23. The potential stroke etiology of LHI was categorized as large-artery atherosclerosis, cardio-embolism, stroke of other determined etiology and stroke of undetermined etiology based on the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria24. In-hospital treatments analyzed in our study included thrombolysis, mechanical ventilation, osmotic agents (such as mannitol). Stroke-related complications, including both neurological and medical complications during hospitalization25, were reviewed from hospital records when the patient was discharged by data collectors who were not aware of the study, which has been elaborated upon in our previous study26.
Outcome measurement
Patients were followed up at 3-month after stroke onset via telephone interview or letter inquiries using questionnaires. The primary outcomes were in-hospital death, 3-month mortality and 3-month unfavorable outcome (defined as an mRS score of 4 to 6)20. The secondary outcomes were stroke-related complications and adverse side effects recorded due to exposure to amantadine, including hypotension, livedo reticularis, seizure, hallucinations, etc.
Statistical analyses
All statistical analysis was performed using SPSS v22.0 (SPSS, Chicago, IL). Continuous variables are presented as means with standard deviations or median with range. Categorical variables are presented as frequencies with percentages. Intergroup differences in categorical variables were assessed for significance using the c2 tests or Fisher’s exact tests, while differences in continuous variables were assessed using Student's t-tests or the Mann-Whitney U test.
We performed a propensity score matching (PSM) algorithm including baseline characteristics that is assumed to be related to amantadine treatment via using multivariable logistic regression model, to calculate the propensity score (PS) for each patient. Then the LHI patients in the amantadine group were matched with the ST group by using the nearest neighbor approach (caliper 0.2, ratio 1:2) to minimize potential imbalances in the distribution of potential confounders between amantadine users and nonusers as previously described in detail27.
Univariate analysis was performed to test variables that may affect the outcomes. Multivariate logistic regression analyses were further performed to explore the association between amantadine treatment with in-hospital death, 3-month mortality and unfavorable outcomes, by using the forced entry method adjusting for variables with p﹤0.1 in univariate analyses. All analyses were repeated following PSM. 3-month survival was estimated by the Kaplan-Meier method and a log-rank test was used for survival comparisons in the final matched dataset. The 95% confidence intervals (CI) were calculated to describe the precision of the estimates. Two-sided P<0.05 was considered to be statistically significant.
Data availability
The data that support the findings of this study are available from the corresponding author on reasonable request.