Migraine-Associated Common Genetic Variants Confer Greater Risk of Posterior vs. Anterior Circulation Ischemic Stroke☆.

OBJECTIVE: To examine potential genetic relationships between migraine and the two distinct phenotypes posterior circulation ischemic stroke (PCiS) and anterior circulation ischemic stroke (ACiS), we generated migraine polygenic risk scores (PRSs) and compared these between PCiS and ACiS, and separately vs. non-stroke control subjects. METHODS: Acute ischemic stroke cases were classified as PCiS or ACiS based on lesion location on diffusion-weighted MRI. Exclusion criteria were lesions in both vascular territories or uncertain territory; supratentorial PCiS with ipsilateral fetal posterior cerebral artery; and cases with atrial fibrillation. We generated migraine PRS for three migraine phenotypes (any migraine; migraine without aura; migraine with aura) using publicly available GWAS data and compared mean PRSs separately for PCiS and ACiS vs. non-stroke control subjects, and between each stroke phenotype. RESULTS: Our primary analyses included 464 PCiS and 1079 ACiS patients with genetic European ancestry. Compared to non-stroke control subjects (n=15396), PRSs of any migraine were associated with increased risk of PCiS (p=0.01-0.03) and decreased risk of ACiS (p=0.010-0.039). Migraine without aura PRSs were significantly associated with PCiS (p=0.008-0.028), but not with ACiS. When comparing PCiS vs. ACiS directly, migraine PRSs were higher in PCiS vs. ACiS for any migraine (p=0.001-0.010) and migraine without aura (p=0.032-0.048). Migraine with aura PRS did not show a differential association in our analyses. CONCLUSIONS: Our results suggest a stronger genetic overlap between unspecified migraine and migraine without aura with PCiS compared to ACiS. Possible shared mechanisms include dysregulation of cerebral vessel endothelial function.

Prevalence of Previously Undiagnosed Abdominal Aortic Aneurysms in Patients with Intracranial Aneurysms: From the Brain and Aortic Aneurysms Study (BAAS).

BACKGROUND: A relationship between intracranial and abdominal aortic aneurysms (AAA) has been appreciated through genome-wide association studies suggesting a shared pathophysiology. However, the actual prevalence of AAA in patients presenting with ruptured intracranial aneurysms is not known. Our aim was to estimate the prevalence of previously undiagnosed AAA in patients presenting with aneurysmal subarachnoid hemorrhage (aSAH) to see if it may be high enough to justify formally testing the utility of screening. METHODS: A prospective, observational inception cohort study of 81 consecutive patients presenting to Mayo Clinic Florida with aSAH was performed from August 14, 2011 to February 10, 2014. These individuals were then screened using an abdominal ultrasound technique for an AAA. Our primary end point was detection of AAA. Our secondary end points were 30-day good-to-fair functional status (modified Rankin scale < 4) and all-cause mortality. RESULTS: We detected an AAA in 10 patients (rate: 12%; 95% CI 6-22%) with aSAH. The mean diameter of these AAA was 3.4 ± 1.0 cm. Among these 10 patients, there was one death within the first month of aSAH hospitalization. There were no significant differences in demographic or clinical characteristics based on AAA detection status. Mean follow-up time was 4.7 years. The rate of good-to-fair functional status at 30-days was 79%. All-cause mortality during follow-up at 1-year was higher for patients with AAA (36%; 95% CI 0-61%) compared to patients without AAA (7%; 95% CI 1-14%) (log-rank p = 0.045). CONCLUSIONS: The co-prevalence of AAA in patients presenting with ruptured brain aneurysms may be sufficiently high such that screening for AAA among likely survivors of aSAH might be appropriate. Larger studies would be needed to establish a net clinical benefit from screening AAA and then treating newly identified large AAAs in this morbid population.

Stroke-related epilepsy.

Stroke is the cause of about 10% of all epilepsy and 55% of newly diagnosed seizures among the elderly. Although recent advances in acute stroke therapy have improved longevity, there has been a consequent rise in the prevalence of stroke-related epilepsy (STRE). Many clinical studies make a distinction between early (within 7 days of onset of stroke) and late (beyond 7 days of onset of stroke) seizures based on presumed pathophysiological differences. Although early seizures are thought to be the consequence of local metabolic disturbances without altered neuronal networks, late seizures are thought to occur when the brain has acquired a predisposition for seizures. Overall, STRE has a good prognosis, being well controlled by antiepileptic drugs. However, up to 25% of cases become drug resistant. STRE can also result in increased morbidity, longer hospitalization, greater disability at discharge and greater resource utilization. Additional controlled trials are needed to explore the primary and secondary prevention of STRE as well as to provide high-quality evidence on efficacy and tolerability of antiepileptic drugs to guide treatment of STRE. Robust pre-clinical and clinical prediction models of STRE are also needed to develop treatments to prevent the transformation of infarcted tissue into an epileptic focus.

Ischaemic stroke.

There are about 25.7 million stroke survivors worldwide. Ischaemic stroke remains the most common type of stroke. Numerous modifiable risk factors have been identified, including behaviors such as cigarette smoking and sedentary lifestyle and treatable medical comorbidities such as hypertension, hyperlipidemia and atrial fibrillation. Once considered irreversible, acute ischaemic stroke is now amenable to acute medical and endovascular therapies to reduce infarct volume. Many advances are expected in the years to come, particularly in the areas of prevention and recovery.

Partial loss of function of colony-stimulating factor 1 receptor in a patient with white matter abnormalities.

BACKGROUND AND PURPOSE: Mutations in colony-stimulating factor 1 receptor (CSF1R) cause adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). Patients with ALSP can be misdiagnosed as having acute ischemic stroke due to hyperintensity lesions on diffusion-weighted magnetic resonance imaging. Mutant CSF1R proteins identified in ALSP show a complete loss of autophosphorylation of CSF1R. METHODS: We conducted mutation screening of CSF1R in 123 patients with definite acute ischemic cerebrovascular syndrome and positive family history of stroke. The pathogenicity of identified variants was evaluated using functional analyses. The levels of autophosphorylation of CSF1R in response to treatment with ligands of CSF1R were examined in cells transfected with wild-type and mutant CSF1R. RESULTS: We identified eight CSF1R variants, six were known non-pathogenic polymorphisms, whereas the other two were missense variants inducing substitution of amino acid residues (p.Glu573Lys and p.Gly747Arg). Functional assay showed that the levels of autophosphorylation of p.Gly747Arg were similar to those of wild-type when treated with ligands. The autophosphorylation of p.Glu573Lys was detectable, but significantly decreased compared with those of wild-type CSF1R (P < 0.001, two-way anova with Bonferroni). The clinical presentation of the patient with p.Glu573Lys was consistent with cerebral embolism. The patient did not have typical clinical findings of ALSP. However, periventricular white matter abnormalities, unrelated to the recent infarct, were evident on brain magnetic resonance imaging. CONCLUSIONS: In contrast to ALSP-associated missense mutations, CSF1R p.Glu573Lys variant in a patient with acute ischemic cerebrovascular syndrome showed a partial loss of autophosphorylation of CSF1R; its clinical significance warrants further investigation.

Multi-Center Study of Diffusion-Weighted Imaging in Coma After Cardiac Arrest.

BACKGROUND: The ability to predict outcomes in acutely comatose cardiac arrest survivors is limited. Brain diffusion-weighted magnetic resonance imaging (DWI MRI) has been shown in initial studies to be a simple and effective prognostic tool. This study aimed to determine the predictive value of previously defined DWI MRI thresholds in a multi-center cohort. METHODS: DWI MRIs of comatose post-cardiac arrest patients were analyzed in this multi-center retrospective observational study. Poor outcome was defined as failure to regain consciousness within 14 days and/or death during the hospitalization. The apparent diffusion coefficient (ADC) value of each brain voxel was determined. ADC thresholds and brain volumes below each threshold were analyzed for their correlation with outcome. RESULTS: 125 patients were included in the analysis. 33 patients (26%) had a good outcome. An ADC value of less than 650 × 10(-6) mm(2)/s in ≥10% of brain volume was highly specific [91% (95% CI 75-98)] and had a good sensitivity [72% (95% CI 61-80)] for predicting poor outcome. This threshold remained an independent predictor of poor outcome in multivariable analysis (p = 0.002). An ADC value of less than 650 × 10(-6) mm(2)/s in >22% of brain volume was needed to achieve 100% specificity for poor outcome. CONCLUSIONS: In patients who remain comatose after cardiac arrest, quantitative DWI MRI findings correlate with early recovery of consciousness. A DWI MRI threshold of 650 × 10(-6) mm(2)/s in ≥10% of brain volume can differentiate patients with good versus poor outcome, though in this patient population the threshold was not 100% specific for poor outcome.

Low density lipoprotein receptor related protein 1 and 6 gene variants and ischaemic stroke risk.

BACKGROUND AND PURPOSE: Low density lipoprotein receptor related proteins (LRPs) 1 and 6 have been implicated in cerebral ischaemia. In addition, genetic variation in LRP1 and LRP6 has been linked with various factors that are related to risk of ischaemic stroke. The aim of this study was to examine the association of LRP1 and LRP6 gene variants with risk of ischaemic stroke as part of the Ischemic Stroke Genetics Study (ISGS). METHODS: A Caucasian series (434 stroke patients, 319 controls) and an African American series (161 stroke patients, 116 controls) were included. Fourteen LRP6 variants and three LRP1 variants were genotyped and assessed for association with ischaemic stroke. RESULTS: In the Caucasian series, significant associations with ischaemic stroke were observed for LRP6 rs2075241 [odds ratio (OR) 0.42, P = 0.023], rs2302685 (OR 0.44, P = 0.049), rs7975614 (OR 0.07, P = 0.017), rs10492120 (OR 0.62, P = 0.036) and rs10743980 (OR 0.66, P = 0.037). Risk of ischaemic stroke was significantly lower for carriers of any of these five protective LRP6 variants (24.0% of subjects) compared to non-carriers (OR 0.57, P = 0.003). The protective association for LRP6 rs2075241 was observed at a similar magnitude across ischaemic stroke subtypes, whilst the effects of rs23022685, rs10492120 and rs10743980 were most apparent for cardioembolic and large vessel stroke. In the African American series, LRP1 rs11172113 was associated with an increased risk of stroke (OR 1.89, P = 0.006). CONCLUSIONS: The results of our preliminary study provide evidence that LRP6 and LRP1 variants may be associated with risk of ischaemic stroke. Validation in larger studies is warranted.

Heritability of young- and old-onset ischaemic stroke.

BACKGROUND AND PURPOSE: Although the genetic contribution to stroke risk is well known, it remains unclear if young-onset stroke has a stronger genetic contribution than old-onset stroke. This study aims to compare the heritability of ischaemic stroke risk between young and old, using common genetic variants from whole-genome array data in population-based samples. METHODS: This analysis included 4050 ischaemic stroke cases and 5765 controls from six study populations of European ancestry; 47% of cases were young-onset stroke (age < 55 years). To quantify the heritability for stroke risk in these unrelated individuals, the pairwise genetic relatedness was estimated between individuals based on their whole-genome array data using a mixed linear model. Heritability was estimated separately for young-onset stroke and old-onset stroke (age ≥ 55 years). RESULTS: Heritabilities for young-onset stroke and old-onset stroke were estimated at 42% (±8%, P < 0.001) and 34% (±10%, P < 0.001), respectively. CONCLUSIONS: Our data suggest that the genetic contribution to the risk of stroke may be higher in young-onset ischaemic stroke, although the difference was not statistically significant.

Genetic variants associated with myocardial infarction in the PSMA6 gene and Chr9p21 are also associated with ischaemic stroke.

BACKGROUND: Ischaemic stroke shares common traditional risk factors with coronary artery disease (CAD) and myocardial infarction (MI). This study evaluated whether genetic risk factors for CAD and MI also affect susceptibility to ischaemic stroke in Caucasians and African Americans. METHODS: Included in the study were a Caucasian series (713 ischaemic stroke patients, 708 controls) and a small African American series (166 ischaemic stroke patients, 117 controls). Twenty single-nucleotide polymorphisms (SNPs) previously shown to be associated with CAD or MI were genotyped and assessed for association with ischaemic stroke and ischaemic stroke subtypes using odds ratios (ORs) from multivariable logistic regression models. RESULTS: In Caucasians, four SNPs on chromosome 9p21 were significantly associated with risk of cardioembolic stroke, the strongest of which was rs1333040 (OR 1.55, P = 0.0007); similar but weaker trends were observed for small vessel stroke, with no associations observed regarding large vessel stroke. Chromosome 9p21 SNPs were also associated with risk of ischaemic stroke in African Americans (rs1333040, OR 0.65, P = 0.023; rs1333042, OR 0.55, P = 0.070; rs2383207, OR 0.55, P = 0.070). The PSMA6 SNP rs1048990 on chromosome 14q13 was associated with overall ischaemic stroke in both Caucasians (OR 0.80, P = 0.036) and African Americans (OR 0.31, P = 0.020). CONCLUSIONS: Our results provide evidence that chromosome 9p21 variants are associated with cardioembolic ischaemic stroke in Caucasians and with overall ischaemic stroke in African Americans. The PSMA6 variant rs1048990 also appears to affect susceptibility to ischaemic stroke in both populations. These findings require validation, particularly the preliminary findings regarding African Americans given the small size of that series.

Detailed phenotyping of posterior vs. anterior circulation ischemic stroke: a multi-center MRI study.

OBJECTIVE: Posterior circulation ischemic stroke (PCiS) constitutes 20-30% of ischemic stroke cases. Detailed information about differences between PCiS and anterior circulation ischemic stroke (ACiS) remains scarce. Such information might guide clinical decision making and prevention strategies. We studied risk factors and ischemic stroke subtypes in PCiS vs. ACiS and lesion location on magnetic resonance imaging (MRI) in PCiS. METHODS: Out of 3,301 MRIs from 12 sites in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN), we included 2,381 cases with acute DWI lesions. The definition of ACiS or PCiS was based on lesion location. We compared the groups using Chi-squared and logistic regression. RESULTS: PCiS occurred in 718 (30%) patients and ACiS in 1663 (70%). Diabetes and male sex were more common in PCiS vs. ACiS (diabetes 27% vs. 23%, p < 0.05; male sex 68% vs. 58%, p < 0.001). Both were independently associated with PCiS (diabetes, OR = 1.29; 95% CI 1.04-1.61; male sex, OR = 1.46; 95% CI 1.21-1.78). ACiS more commonly had large artery atherosclerosis (25% vs. 20%, p < 0.01) and cardioembolic mechanisms (17% vs. 11%, p < 0.001) compared to PCiS. Small artery occlusion was more common in PCiS vs. ACiS (20% vs. 14%, p < 0.001). Small artery occlusion accounted for 47% of solitary brainstem infarctions. CONCLUSION: Ischemic stroke subtypes differ between the two phenotypes. Diabetes and male sex have a stronger association with PCiS than ACiS. Definitive MRI-based PCiS diagnosis aids etiological investigation and contributes additional insights into specific risk factors and mechanisms of injury in PCiS.

Prestroke physical activity and early functional status after stroke.

BACKGROUND: The importance of physical activity as a modifiable risk factor for stroke in particular and cardiovascular disease in general is well documented. The effect of exercise on stroke severity and stroke outcomes is less clear. This study aimed to assess that effect. METHODS: Data collected for patients enrolled in the Ischemic Stroke Genetics Study were reviewed for prestroke self-reported levels of activity and four measures of stroke outcome assessed at enrollment and approximately 3 months after enrollment. Logistic regression was used to assess the association between physical activity and stroke outcomes, unadjusted and adjusted for patient characteristics. RESULTS: A total of 673 patients were enrolled; 50.5% reported aerobic physical activity less than once a week, 28.5% reported aerobic physical activity one to three times weekly, and 21% reported aerobic physical activity four times a week or more. Patients with moderate and high levels of physical activity were more likely to have higher Barthel Index (BI) scores at enrollment. A similar association was detected for exercise and good outcomes for the Oxford Handicap Scale (OHS). After 3 months of follow-up, moderate activity was still associated with a high BI score. No significant association was detected for activity and the OHS or Glasgow Outcome Scale at follow-up after adjustment for patient characteristics. CONCLUSIONS: Higher levels of self-reported prestroke physical activity may be associated with functional advantages after stroke. Our findings should be seen as exploratory, requiring confirmation, ideally in a longitudinal study of exercise in an older population.

Primary central nervous system vasculitis: comparison of patients with and without cerebral amyloid angiopathy.

OBJECTIVES: To describe the clinical features and outcomes of patients with primary central nervous system vasculitis (PCNSV) and cerebral amyloid angiopathy (CAA) from a large cohort of consecutive patients with PCNSV treated at a single institution. METHODS: We identified 101 consecutive patients with PCNSV admitted between January 1983 and December 2003. PCNSV diagnoses were based on findings from a central nervous system (CNS) biopsy (n = 31) and conventional angiography (n = 70). CNS tissue specimens from 49 cases were examined histologically, and 49 were stained for amyloid deposits. Those with vascular amyloid deposits (CAA) were compared with those without histological evidence of amyloid deposition. RESULTS: Eight cases (26%) with CNS biopsy specimens positive for PCNSV also showed findings of CAA. Compared with patients with PCNSV only, these patients were older at diagnosis, predominantly male, had a more acute onset, a higher frequency of cognitive dysfunction and showed prominent gadolinium-enhanced leptomeningeal lesions with MRI. Histologically, all had a granulomatous vascular inflammatory pattern. Six patients responded promptly to therapy. Outcomes at last follow-up were similar in the two groups. CONCLUSIONS: PCNSV with CAA appears to form a clinical subset of PCNSV. The vasculitis influences the clinical findings to a greater degree than the presence of amyloid deposits in the vessels.

Undiagnosed Partial Ornithine Transcarbamylase Deficiency Presenting Postoperatively as Agitated Delirium.

Partial ornithine transcarbamylase deficiency (pOTCD), an enzymatic defect within the urea cycle, is an increasingly recognized etiology for hyperammonemia of unclear source following a stressor within female adults. Here we present a case of newly diagnosed pOTCD following a systemic stressor and prolonged hospitalization course. From a neurological perspective, prompt recognition provided the patient with a swift and near complete recovery. We briefly review the pertinent literature pertaining to this genetically based condition including historical context and current therapeutic approaches. Given the potential morbidity of prolonged hyperammonemia, neurohospitalists need to be aware of partial ornithine transcarbamylase as an entity.

Validating the Questionnaire for Verifying Stroke-Free Status (QVSFS) by neurological history and examination.

BACKGROUND AND PURPOSE: The Questionnaire for Verifying Stroke-Free Status (QVSFS) is an 8-item structured interview designed to identify stroke-free individuals. Previously, the QVSFS was validated with medical record review in a cohort with a low prevalence (7.1%) of stroke or transient ischemic attack (TIA). The objective of this study was to evaluate the validity of the QVSFS by comparing it with stroke status as determined by neurological history and examination in a population with a higher prevalence of stroke. METHODS: A research assistant administered the QVSFS to outpatients from Veterans Administration stroke and general medicine clinics. Subjects were defined as QVSFS negative if responses to all 8 questions were negative. Questions requiring rephrasing or clarification were noted. Neurologists, blinded to QVSFS scores, interviewed and examined all subjects to determine stroke-free status, defined as no history or examination findings of previous stroke and/or TIA. RESULTS: One hundred fifty-five subjects were examined; mean age was 70 years; 98.1% were male. Seventy-eight subjects were determined to be stroke free by the neurologist. The negative predictive value of the QVSFS was 0.96, with positive predictive value of 0.71. No question required rephrasing or clarification >5 times. Twenty-two subjects (14.2%) required rephrasing or clarification of at least 1 question. CONCLUSIONS: The QVSFS can effectively identify stroke-free individuals with a high degree of accuracy, even in a population with a large proportion of patients with prior stroke or TIA. Accuracy for identifying subjects with stroke and/or TIA is lower, but the QVSFS may still be useful as a screening tool in that regard.

Ethical and methodological issues in pedigree stroke research.

BACKGROUND: Stroke is a complex genetic disorder with a variable phenotype. Investigations of heritable factors in complex genetic disorders use pedigree and genetic techniques, which pose different ethical and methodological challenges than those routinely encountered in therapeutic research. Building consensus on acceptable research practices in this field is vital to the success of multicentered collaborations. SUMMARY OF REVIEW: We review important ethical and methodological concerns related to the collection, storage, and release of pedigree research information. The human studies aspects of pedigree research are complicated methodologically because individuals can be active or passive participants and pedigrees can be proband derived, partially validated, or fully validated. Current research ethics frameworks do not work well outside of a dyadic researcher-subject relationship. Privacy and confidentiality for family members must be considered in pedigree research. Investigators should anticipate potential conflicts of interest among family members when designing a pedigree research protocol. CONCLUSIONS: We propose a "proband-initiated contact" methodology in which the proband or the proband's designate allows identification of potential families without breaching the privacy of individuals in the family. In situations in which family history data are collected without direct contact between researchers and individuals in the proband's family, an Institutional Review Board may waive consent by family members after appropriate review of the protocol and application of rules for granting waivers of consent. Certificates of Confidentiality should be considered.

Feasibility of an affected sibling pair study in ischemic stroke: results of a 2-center family history registry.

BACKGROUND AND PURPOSE: We sought to determine pedigree availability for a concordant sibling pair study of genetic risk factors in ischemic stroke. METHODS: Probands with confirmed ischemic stroke were prospectively enrolled. Family histories were obtained by systematic interview. A study neurologist prospectively assigned stroke subtype. RESULTS: Of 310 probands (median age, 75 years; range, 26 to 97 years; 48% women), 75% had at least 1 living sibling; 10%, at least 1 concordant living sibling; 2%, at least 1 concordant sibling living in the same city; and 7%, at least 1 concordant living and 1 discordant living sibling. Likelihood of having a concordant sibling increased significantly with proband age, even after adjustment for sibship size (P=0.002). Positive family history of stroke was not related to either proband stroke subtype or risk factor profile. CONCLUSIONS: Approximately 10 probands were screened to find 1 potentially concordant living sibling. A concordant sibling pair study should be multicentered and enable enrollment of siblings from diverse geographic areas.

Reversible segmental cerebral arterial vasospasm and cerebral infarction: possible association with excessive use of sumatriptan and Midrin.

OBJECTIVE: To describe a patient who developed reversible segmental cerebral arterial vasospasm and cerebral infarction while taking excessive amounts of sumatriptan succinate and a combination drug (Midrin) consisting of isometheptene mucate, 65 mg, dichloralphenazone, 100 mg, and acetaminophen, 325 mg. DESIGN: Case report. SETTING: Tertiary care center. PATIENT: A 43-year-old man who developed a left occipital infarct after taking a total of 23 sumatriptan succinate tablets (25 mg per tablet) and 32 Midrin tablets during a 7-day period and who on digital subtraction angiography was shown to have segmental cerebral arterial narrowing in multiple vessels. An extensive evaluation for other possible risk factors for cerebral infarction was unrevealing. MAIN OUTCOME AND RESULTS: Discontinuation of sumatriptan and Midrin regimens and administration of nicardipine hydrochloride led to nearly total resolution of the angiographic findings, and the patient had no recurrent strokes. CONCLUSIONS: One should consider the diagnosis of drug-induced vasospasm in patients with cerebral infarction and a history of excessive use of sumatriptan and Midrin. The initial angiographic abnormalities may resemble those found in patients with primary angiitis of the central nervous system.

Is hormone replacement a risk factor for ischemic stroke in women with factor V Leiden mutation?

OBJECTIVE: To describe a patient with multifocal cerebral ischemia whose only identified potential risk factors were use of postmenopausal hormone replacement and heterozygosity to factor V Leiden mutation. DESIGN: A case report. SETTING: A tertiary care center. PATIENT: A 51-year-old woman taking hormone replacement (0.625 mg/d of estrogen alternating with 10 mg/d of medroxyprogesterone) presented with a generalized tonic-clonic seizure. She had persistent multifocal non-enhancing lesions on magnetic resonance imaging of the brain. A stereotactic biopsy of the brain performed to exclude gliomatosis cerebri was consistent with cerebral ischemia. An extensive evaluation to uncover the cause of stroke revealed only heterozygosity to factor V Leiden mutation. MAIN OUTCOME AND RESULTS: Hormonal replacement was discontinued and the patient had no recurrent ischemic strokes. CONCLUSIONS: Postmenopausal hormonal replacement may be a risk factor for ischemic stroke in women with the factor V Leiden mutation. Ongoing trials of hormonal replacement provide an opportunity to test this hypothesis.