Peter J. Kelly

Variants conferring risk of atrial fibrillation on chromosome 4q25.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans and is characterized by chaotic electrical activity of the atria. It affects one in ten individuals over the age of 80 years, causes significant morbidity and is an independent predictor of mortality. Recent studies have provided evidence of a genetic contribution to AF. Mutations in potassium-channel genes have been associated with familial AF but account for only a small fraction of all cases of AF. We have performed a genome-wide association scan, followed by replication studies in three populations of European descent and a Chinese population from Hong Kong and find a strong association between two sequence variants on chromosome 4q25 and AF. Here we show that about 35% of individuals of European descent have at least one of the variants and that the risk of AF increases by 1.72 and 1.39 per copy. The association with the stronger variant is replicated in the Chinese population, where it is carried by 75% of individuals and the risk of AF is increased by 1.42 per copy. A stronger association was observed in individuals with typical atrial flutter. Both variants are adjacent to PITX2, which is known to have a critical function in left–right asymmetry of the heart.

Functional recovery following rehabilitation after hemorrhagic and ischemic stroke

OBJECTIVES To quantify recovery after rehabilitation therapy and to identify factors that predicted functional outcome in survivors of intracerebral hemorrhage (ICH) compared with cerebral infarction. DESIGN Retrospective study of consecutive ICH and cerebral infarction admissions to a rehabilitation hospital over a 4-year period. SETTING Free-standing urban rehabilitation hospital. PARTICIPANTS A total of 1064 cases met the inclusion criteria (545 women, 519 men; 871 with cerebral infarction, 193 with ICH). INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Functional status was measured using the FIM trade mark instrument, recorded at admission and discharge. Recovery was quantified by the change in FIM total score (DeltaFIM total score). Outcome measures were total discharge FIM score and DeltaFIM total score. Univariate and multivariate analyses were performed. RESULTS Total admission FIM score was higher in patients with cerebral infarction than in patients with ICH (59 vs 51, P=.0001). No difference in total discharge FIM score was present. Patients with ICH made a significantly greater recovery than those with cerebral infarction (DeltaFIM total score, 28 vs 23.3; P=.002). On multivariate analysis, younger age, longer length of stay, and admission FIM cognitive subscore independently predicted total discharge FIM and DeltaFIM total score. The severity of disability at admission, indicated by total admission FIM score, independently predicted total discharge FIM score, but not DeltaFIM total score. The ICH patients with the most severely disabling strokes had significantly greater recovery than cerebral infarction patients with stroke of similar severity. CONCLUSIONS The patients with ICH had greater functional impairment than the cerebral infarction patients at admission, but made greater gains. Patients with the most severely disabling ICH improved more than those with cerebral infarction of comparable severity. Initial severity of disability, age, and duration of therapy best predicted functional outcome after rehabilitation.

Functional Recovery After Rehabilitation for Cerebellar Stroke

Background and Purpose — Relatively few data exist concerning functional recovery after ischemic and hemorrhagic cerebellar stroke. We studied patients admitted to a rehabilitation hospital after cerebellar stroke to quantify recovery after rehabilitation therapy and to identify variables that predicted functional outcome. Methods — This study was a retrospective review of consecutive cases admitted in a 4-year period with new cerebellar infarct or hemorrhage. Clinical features of stroke were recorded and comorbidities scored with the Charlson Index. Follow-up information was obtained by telephone interview. The Functional Independence Measure (FIM) was scored at admission (AFIM), discharge (DFIM), and follow-up (FFIM). Outcome measures were DFIM and FFIM. Univariate and multivariate analyses were performed. Results — Fifty-eight cases were identified (mean age 69.2 years; 49 infarcts, 9 hemorrhages). Mean AFIM was 65.5, and mean DFIM was 89.8. Mean AFIM was significantly higher in the infarct than in the hemorrhage subgroup (70 versus 43, P =0.006). Mean DFIM was also higher in the infarct subgroup but did not reach statistical significance (93 versus 74, P =0.1). Follow-up information was obtained for 45 cases (78%) (mean interval 19.5 months). Median FFIM was 123.5. Outcome was significantly positively correlated with AFIM and initial presenting syndrome of vertigo/vomiting/ataxia/headache. Outcome correlated negatively with preexisting comorbidity score, altered level of consciousness at initial presentation, and superior cerebellar artery infarction. On multivariate analysis, AFIM and comorbidity score were independent predictors of outcome. Conclusions — Substantial improvement of mean FIM score frequently occurs after rehabilitation after cerebellar infarction. Functional outcome is best predicted by preexisting comorbidities and functional status at the time of discharge from acute hospitalization.

Low Vitamin B6 but Not Homocyst(e)ine Is Associated With Increased Risk of Stroke and Transient Ischemic Attack in the Era of Folic Acid Grain Fortification

Background and Purpose— The introduction of cereal grain folic acid fortification in 1998 has reduced homocyst(e)ine (tHcy) concentrations in the US population. We performed a case-control study to determine the risk of stroke and transient ischemic attack (TIA) associated with tHcy and low vitamin status in a postfortification US sample. Methods— Consecutive cases with new ischemic stroke/TIA were compared with matched controls. Fasting tHcy, folate, pyridoxal 5′-phosphate (PLP), B12, and MTHFR 677C→T genotype were measured. Results— Mean PLP was significantly lower in cases than controls (39.97 versus 84.1 nmol/L, P <0.0001). After stroke risk factors were controlled for, a strong independent association was present between stroke/TIA and low PLP (adjusted odds ratio [OR], 4.6; 95% CI, 1.4 to 15.1;P <0.001) but not elevated tHcy (OR, 0.92; 95% CI, 0.4 to 2.1). Conclusions— Low B6 but not tHcy was strongly associated with cerebrovascular disease in this postfortification, folate-replete sample.

Inflammation, Homocysteine, and Vitamin B6 Status After Ischemic Stroke

Background and Purpose— Epidemiological studies have described an association between low vitamin B6 (measured as pyridoxal 5′-phosphate [PLP]) and ischemic stroke, independent of homocysteine (tHcy). We investigated B6 status, tHcy, and inflammation (measured by C-reactive protein [CRP]) in patients with stroke and controls. Methods— Consecutive cases with new ischemic stroke were compared with matched controls. Fasting tHcy, PLP, and CRP were measured. Results— The adjusted odds ratio of low PLP in the highest compared with the lowest CRP quartile was 16.6 (2, 139.9, P =0.01). Age, CRP, supplemental vitamin use, and albumin were independent predictors of PLP (P <0.05 for all). No relationship was observed between CRP and tHcy. Conclusion— The relationship between inflammation and low B6 status may partially explain the findings of previous epidemiological studies.

Holter monitoring in the diagnosis of stroke mechanism

Abstract

Stroke in young patients with hyperhomocysteinemia due to cystathionine beta-synthase deficiency

Background: Although hyperhomocyst(e)inemia (Hyper-Hcy) may predispose to atherosclerosis and venous thrombosis, the mechanisms of stroke associated with Hyper-Hcy are not defined. Methods: Clinical and biochemical phenotypes and genetic features of three unrelated patients with premature stroke and severe Hyper-Hcy due to cystathionine beta-synthase (CBS) deficiency are described. Plasma Hcy and amino acids were measured by fluorescence polarization immune assay and ion exchange chromatography. Analysis of the CBS and methylenetetrahydrofolate reductase genes was performed by restriction enzyme digestion and sequence analysis. Results: Two of the three index cases had no known diagnosis of homocystinuria and initially presented with embolic cerebral and retinal infarction in mid-adulthood. Mechanisms of cerebrovascular disease were carotid intraluminal thrombosis, arterial dissection, and possible cardiac embolism. Family screening revealed additional members with clinically silent homocystinuria and severe Hyper-Hcy. Excluding tall stature in two individuals, all had mild phenotypes, without classic findings of CBS deficiency. Plasma total and free Hcy, methionine, and urine Hcy were elevated. Genotyping revealed heterozygous CBS mutations (I278T, D444N, G307S) in affected individuals. Conclusion: Artery-to-artery embolism and dissection may cause stroke in young adults with homocystinuria. The results also support a rationale for screening for Hyper-Hcy in young adults with stroke without a phenotype suggestive of classic homocystinuria.

Predictors of Feeding Gastrostomy Tube Removal in Stroke Patients With Dysphagia

Dysphagia is a common consequence of stroke, estimated to be present in 25% to 50% of the stroke rehabilitation population. Relatively few data exist concerning outcome following insertion of feeding gastrostomy/jejunostomy tubes (FGT) in stroke patients with dysphagia. Our aim was to identify variables predictive of FGT removal. We studied stroke patients admitted to a single rehabilitation hospital and identified consecutive stroke patients with FGT placement. Each patients medical records were reviewed, and demographic, clinical, and neuroimaging information were abstracted. Follow-up status was obtained by telephone interviews and review of state death certificates. Univariate and multivariate analyses were performed. Seventy-seven of the 664 (11.1%) stroke patients admitted in the 42-month study period had FGT insertion for dysphagia. Multivariate regression analysis revealed that bilateral stroke (bilateral vs unilateral; P < .022), aspiration during videofluoroscopic swallowing study (VSS; P < .012), and age greater than 52 years (P < .001) were negative predictors of FGT removal prior to discharge from the rehabilitation hospital. We identified three independent variables (bilateral stroke, aspiration during VSS, and age > 52) in stroke patients with severe dysphagia requiring FGT placement that are negative predictors of FGT removal prior to discharge from rehabilitation. These findings may help physicians and speech language pathologists predict who is likely to have a FGT removed before rehabilitation hospital discharge.

Focal Status Epilepticus as Atypical Presentation of Pyridoxine-Dependent Epilepsy

Pyridoxine-dependent epilepsy usually presents in the neonatal period or even in utero, is refractory to antiepileptic medications, and is treatable with lifelong administration of pyridoxine. The seizures are typically generalized tonic-clonic, although myoclonic seizures or infantile spasms have been described. We report an infant who presented at 5 months of age with a right-sided clonic seizure with fever. Subsequently, she had recurrent right focal or generalized seizures despite sequential treatment with various antiepileptic medications. At 7 months, she was hospitalized with status epilepticus, which was finally controlled with pyridoxine. After she became seizure free, she continued to have a strong left arm preference with mild weakness of the right arm and delayed language skill. Eventually, she outgrew these symptoms. This case illustrates that pyridoxine-dependent epilepsy, although rare, must be included in the differential diagnosis of focal seizures, especially when the seizures are refractory to traditional antiepileptic drugs. (J Child Neurol 2005;20:696—698).

Hyperhomocysteinemia, MTHFR 677C→T Polymorphism, and Stroke

To the Editor: We welcome the report from Madonna and co-workers examining the role of prothrombotic and homocysteine (Hcy) pathway polymorphisms in risk of ischemic stroke in young adults.1 We wish to comment on several issues raised by their article relating to the design of studies of genetic risk factors for complex phenotypes such as ischemic stroke, which we believe to be important when interpreting their findings. As the report points out, genetic predisposition to a complex human phenotype such as stroke is unlikely to be mediated by a large influence of 1 or 2 genes. Many observers agree that it is likely to result from a combination of relatively small individual effects of several genes, each predisposing to stroke via their influence on intermediate phenotypic traits, such as hypertension or hyperlipidemia.2–4⇓⇓ This assumption has several implications for the design of epidemiological studies examining candidate genetic risk factors for stroke. First, given the small anticipated effect size associated with any single candidate polymorphism, the group sample sizes required to robustly demonstrate an association will be very large. This is important to avoid a potentially erroneous conclusion that no association exists (type 2 error). This point is particularly relevant in the case of the MTHFR 677C→T polymorphism. Most prospective and retrospective studies to date have indicated that mildly elevated …