Recruiting pedigrees in an ongoing North American stroke genomics study.
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Biomedical subjects
Publications and source records attributed to J F Meschia.
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Selecting an appropriate anticonvulsant for treatment of recipients of orthostatic liver transplants who have new-onset epileptic seizures can be challenging because first-line agents may contribute to worsening encephalopathy, alter the plasma concentration of immunosuppressive agents, and result in hepatotoxicity. We describe the case of a 55-year-old man who underwent orthotopic liver transplantation because of end-stage liver disease due to alcoholic cirrhosis and hepatitis C. He required two repeat transplantation procedures. After the last procedure, epileptic seizures developed, which were initially managed with phenytoin. However, the patient remained stuporous and mental status fluctuated. Breakthrough seizures later developed in the setting of rejection. Levetiracetam (500 mg orally, twice a day) was chosen for its favorable pharmacokinetic properties as an alternative to phenytoin. By the third day of levetiracetam therapy, the patient became more responsive. At most recent follow-up, 3 months after the start of levetiracetam therapy, the patient was still treated with levetiracetam monotherapy, and seizure control was judged to be excellent.
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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.
The aim of this study was to determine the extent of change in platelet and coagulation markers in the acute phase of ischemic stroke and to assess the utility of marker measurement in stroke subtype classification. Urinary 11-dehydro-thromboxane B(2) (11-dTXB2), a marker of in vivo platelet activation, and markers of coagulation activation, including prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT), and fibrinogen, were measured in 25 patients with ischemic stroke within 24 h of onset of symptoms. Marker levels in patients with ischemic stroke were compared with those in 19 age-matched controls who had not taken aspirin for at least 2 weeks before sampling and 25 healthy controls. Median marker levels were significantly increased in stroke over those in age-matched controls for fibrinogen (344 vs. 289 mg/dl; P=0.030), F1+2 (1.40 vs. 0.80 nmol/l; P=0.003), and TAT (6.65 vs. 2.20 microg/l; P<0.0001). Median marker levels for seven patients with cardioembolic stroke and 18 with non-cardioembolic stroke were not significantly different for any marker test. Eight patients taking aspirin at the time of the stroke had significantly lower 11-dTXB2 values than patients not taking aspirin (964 vs. 4,314 pg/mg of creatinine; P=0.007). Stroke patients not taking aspirin had significantly higher 11-dTXB2 concentration than age-matched controls (4,314 vs. 1,788 pg/mg of creatinine; P=0.006). Coagulation and platelet activation markers are increased in the acute phase of stroke regardless of the clinical mechanism. This finding suggests that the markers may not be useful for predicting clinical subtype of ischemic stroke in the acute phase.
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In 1995, a two-part randomized trial showed the efficacy of intravenous tissue plasminogen activator (tPA) when given within 3 hours of onset of symptoms of acute ischemic stroke. Two subsequent trials were unable to extend the therapeutic window of intravenous tPA beyond 3 hours. A phase IV study performed by experienced stroke centers showed an acceptably low symptomatic intracerebral hemorrhage rate for intravenous tPA of only 3%, whereas a review of the Cleveland area experience showed a disturbingly high rate of symptomatic intracerebral hemorrhage of 15.7%. The Prolyse in Acute Cerebral Thromboembolism (PROACT) II study showed efficacy of intra-arterial pro-urokinase and intravenous heparin over intravenous heparin alone when given within 6 hours of onset of symptoms to patients with thrombotic occlusion of the proximal middle cerebral artery. Additional controlled investigations of intra-arterial thrombolytic therapy are needed. Neuroprotectants in combination with intravenous tPA have yet to show improved efficacy over the use of tPA alone.
OBJECTIVE: The clinical presentation of capsular genu infarct varies. Prominent faciolingual weakness and subcortical dementia are the rule, but symptoms depend on the precise location and extension of the lesion beyond the genu. The aim was to characterise the radiographic, electroencephalographic, and neuropsychometric abnormalities in a woman who had a history of recurrent transient memory loss. METHOD: Case report. RESULTS: Magnetic resonance imaging showed an infarct in the genu of the left internal capsule. Positron emission tomography scan demonstrated decreased metabolic activity in the ipsilateral temporal, occipitotemporal, and contralateral cerebellar hemispheres. Electroencephalography showed intermittent rhythmic delta activity in the left frontotemporal region, and findings on neuropsychometric evaluation were consistent with cognitive impairment. Follow up evaluation 7 months after the stroke showed improvement in some areas of the cognitive domain, but residual neuropsychometric and neurophysiological abnormalities persisted. CONCLUSION: This case illustrates that cerebral and cerebellar diaschisis may contribute to the symptomatic presentation and recovery from capsular genu infarct, although its precise role remains elusive.
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.
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.
Every patient with acute stroke who presents to a medical center that has appropriate resources should undergo evaluation for intravenous tPA therapy. Such therapy should not be given unless the patient meets strict eligibility criteria based on clinical, radiographic, and laboratory data. Intra-arterial thrombolysis may be a promising alternative to intravenous tPA therapy, but it should still be regarded as experimental. Daily aspirin therapy should be initiated immediately in most patients who do not receive intravenous tPA therapy and after 24 hours in most patients who receive this treatment. Measures should be taken to prevent medical complications, such as aspiration pneumonia, deep vein thrombosis, contractures, and pressure sores. Early initiation of rehabilitation can maximize stroke recovery. Whenever feasible, institutions should have stroke teams or units to streamline care and provide expertise for patients with acute stroke.
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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a familial vascular disorder associated with migraines, recurrent ischemic strokes, and early-onset multiinfarct dementia. The diagnosis of CADASIL is made ultrastructurally by finding characteristic granular, electron-dense, osmiophilic material attached to vascular smooth muscle cells. These changes have been found in brain, skeletal muscle, nerve, and skin. We describe a woman with CADASIL diagnosed on the basis of brain and skin electronmicroscopic findings. Dermatologists and dermatopathologists need to be aware of this disorder because characteristic electronmicroscopic changes on a skin biopsy specimen are diagnostic.
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BACKGROUND AND PURPOSE: Case-control, cohort, and twin studies support a genetic contribution to ischemic stroke risk. Sibling pair linkage methods require identification of concordant or discordant siblings or both. We designed and tested a structured telephone interview to verify the stroke-free phenotype. METHODS: A coordinator unaware of medical record data used an 8-item questionnaire to conduct a structured telephone interview of 70 outpatients aged >60 years. The questionnaire inquired about the sudden onset of deficits in strength, sensation, vision, and language. A subject was defined as stroke free by interview if responses to all items on the questionnaire were negative. Results of the telephone interview were compared with data obtained from a systematic medical record review (benchmark). RESULTS: Interview time was 5 minutes or less for all subjects. All subjects who began the interview completed it. Records were reviewed in all subjects. Medical record review detected ischemic stroke or transient ischemic attack (TIA), or both, in 5 patients (7%). There were no significant differences in sex distribution or risk factor rates in patients who were designated stroke free or not stroke free by interview. Having 1 or more positive items on the questionnaire was significantly associated with finding stroke (P<0.001), TIA (P<0.001), or either stroke or TIA (P<0.001), on medical record review. The telephone interview had a sensitivity of 1.0 (95% CI 0.48 to 1.0), specificity of 0.86 (95% CI 0.75 to 0.93), positive predictive value of 0.36 (95% CI 0.13 to 0.65), and negative predictive value of 1.0 (95% CI 0.94 to 1.0). CONCLUSIONS: Our instrument can identify the stroke-free individual with a high degree of confidence in a very efficient manner. It may be particularly suited for centralized verification of stroke discordancy in multicentered sib-pair genetic studies.
Catastrophic neurologic events occur rarely postoperatively and must be diagnosed quickly. A 63-year-old woman who had undergone uneventful total hip arthroplasty experienced obtundation after admission to the postanesthesia care unit. Cranial magnetic resonance imaging revealed multiple lesions consistent with ischemia or infarction, and fat cerebral embolism was diagnosed. We describe the numerous complications that may occur in patients in the postanesthesia care unit and review the differential diagnosis of altered mental status in such patients. Paradoxical cerebral fat embolization must be considered in the differential diagnosis of altered mental status after pelvic or long bone fracture or lower extremity major joint replacement, and this condition may occur despite normal pulmonary function and no patent foramen ovale or right-to-left intracardiac shunt. Magnetic resonance imaging with T2-weighted sequences is the cranial imaging study of choice for early evaluation of patients with sudden multifocal neurologic deficits and suspected fat embolism syndrome.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetically linked neurologic disease characterized by recurrent strokes and progressive or stepwise dementia, with or without migraine-like headaches, seizures, and pseudobulbar palsy. We describe a patient referred with a diagnosis of treatment-refractory primary angiitis of the central nervous system. Meningocortical and skin biopsies confirmed that the patient had CADASIL. Clinical and radiographic differences in these disorders may be subtle, but awareness of them is crucial if the patient is to avoid unnecessary exposure to potentially deleterious immunosuppressive therapy.