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.

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.

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.

The Causative Classification of Stroke system: an international reliability and optimization study.

BACKGROUND: Valid and reliable ischemic stroke subtype determination is crucial for well-powered multicenter studies. The Causative Classification of Stroke System (CCS, available at http://ccs.mgh.harvard.edu) is a computerized, evidence-based algorithm that provides both causative and phenotypic stroke subtypes in a rule-based manner. We determined whether CCS demonstrates high interrater reliability in order to be useful for international multicenter studies. METHODS: Twenty members of the International Stroke Genetics Consortium from 13 centers in 8 countries, who were not involved in the design and development of the CCS, independently assessed the same 50 consecutive patients with acute ischemic stroke through reviews of abstracted case summaries. Agreement among ratings was measured by kappa statistic. RESULTS: The κ value for causative classification was 0.80 (95% confidence interval [CI] 0.78-0.81) for the 5-subtype, 0.79 (95% CI 0.77-0.80) for the 8-subtype, and 0.70 (95% CI 0.69-0.71) for the 16-subtype CCS. Correction of a software-related factor that generated ambiguity improved agreement: κ = 0.81 (95% CI 0.79-0.82) for the 5-subtype, 0.79 (95% CI 0.77-0.80) for the 8-subtype, and 0.79 (95% CI 0.78-0.80) for the 16-subtype CCS. The κ value for phenotypic classification was 0.79 (95% CI 0.77-0.82) for supra-aortic large artery atherosclerosis, 0.95 (95% CI 0.93-0.98) for cardioembolism, 0.88 (95% CI 0.85-0.91) for small artery occlusion, and 0.79 (0.76-0.82) for other uncommon causes. CONCLUSIONS: CCS allows classification of stroke subtypes by multiple investigators with high reliability, supporting its potential for improving stroke classification in multicenter studies and ensuring accurate means of communication among different researchers, institutions, and eras.

Conservative management of extra-axial hematomas diagnosed by CT.

Our purpose was to assess the role of serial CT in recently traumatized patients with clinically stable extra-axial intracranial hematomas (EACH) and a midline shift of less than 0.5 cm. A retrospective review of 91 imaging studies in 41 patients (with 45 EACH) was done to assess the time between trauma and CT; the presence and type of skull fracture; the volume, type, and location of the EACH; the presence of associated edema and/or contusion. Over a 19-day follow-up, 11% of the dense EACH increased in volume and 27% decreased. An adjacent skull fracture was seen most frequently in patients with a decrease in EACH volume. Clinical data remain the key to determining the need for neurosurgical intervention in patients with EACH. Follow-up CT afforded no data which altered the medical management of these patients. However, it may be said to have alerted the clinician to an increase in the size of the EACH in 11% of cases, which could mandate close observation of this group.

Physician credentialing. A centralized verification system.

The current system for credentialing physicians in the U.S. is staggeringly redundant, prone to error, and expensive. The process for establishing a recent graduate's practice can involve an average of five applications to have privileges at several hospitals and HMOs. A centralized verification system needs to be developed to streamline this process. The amount of information that would have to be stored for all physicians in the country would be immense. However, the technology currently exists to store such information on a much grander scale. Credit unions, banks, and insurance companies utilize such computer systems effectively and with reasonable confidentiality.

CT-guided brachial plexus biopsy.

We describe a technique for conducting a CT-guided biopsy of the brachial plexus region, report two illustrative cases, discuss potential complications, and conclude that, in selected cases, biopsy of lesions in the region of the brachial plexus can be performed safely with CT guidance.

CT demonstration of periorbital graft-versus-host disease.

A 13-year-old boy who had undergone allogenic bone marrow transplantation for treatment of acute lymphocytic leukemia presented with bilateral periorbital rash and swelling. A CT scan showed bilateral symmetric periorbital swelling, subconjunctival fluid collections, and lacrimal gland enlargement. The patient was initially treated for presumed cellulitis. However, persistently negative regional cultures (eye, nasopharynx), a rapid response to immunosuppressive therapy after several days of nonresponse to intravenous antibiotic therapy, and ultimately, results of a skin biopsy confirmed the diagnosis of acute graft-versus-host disease.

A high speed optical multichannel analyzer.

An optical multichannel analyzer capable of recording spectra at sampling rates up to 100 kHz is described. The instrument, designed to gather data on the kinetic reaction mechanisms of biological preparations such as cytochrome oxidase and bacteriorhodopsin, features a massively parallel approach in which each photosensing element of the detector array has a dedicated amplifier, integrator, analog to digital converter, and sample buffer. The design has 92 such elements divided in two separate arrays, each of which sits at the focal plane of a 1/4 m Ebert spectrometer. The spectrometers may be tuned to cover independent, 130 nm wide, regions of the spectrum from 350 nm to 900 nm with a dispersion of 2.8 nm per element. Each detection channel has 12-bit resolution with an electronic dark count of 1 count and may be sampled 1024 times during a single experiment with dynamically variable sampling intervals from 10 microseconds to several seconds. Time averaging of up to thousands of consecutive laser-initiated kinetic cycles allows analyses of spectral changes < 0.001 optical density units. A personal computer with custom software provides a number of features: entry of experiment parameters; transfer of data from temporary buffers to permanent files; real time display; multiple spectrum averaging; and control and synchronization of associated system hardware. Optical fibers or lenses provide coupling from a parabolic reflector Xenon arc monitoring light source, through the sample chamber, to the entry slit of the monochromator. The instrument has been used for extensive studies on the rapid kinetics and definition of reaction sequences of the energy-transducing enzymes cytochrome oxidase and bacteriorhodopsin. Some results from these studies are discussed.

Intrapleural photodynamic therapy: results of a phase I trial.

BACKGROUND: The management of pleural neoplasms, specifically mesothelioma, remains difficult. We performed a phase I trial in 54 patients with isolated hemithorax pleural malignancy to determine (a) the feasibility of intraoperative, intrapleural photodynamic therapy after debulking surgery; (b) the influence of light dose/sensitizer interval on postoperative morbidity in order to define the photodynamic therapy (PDT) maximal tolerated dose (MTD); and (c) whether first order dosimetry could be applied to this complex geometry. METHODS: Cohorts of three patients were given escalating intraoperative light doses of 15-35 J/cm2 48 h after i.v. delivery of 2.0 mg/kg Photofrin II (Quadra Logic Technologies, Vancouver, British Columbia, Canada), and then escalating light doses of 30-32.5 J/cm2 after a 24-h sensitizer/operation interval. Twelve patients could not be debulked to the prerequisite 5 mm residual tumor thickness. The remaining 42 patients underwent 19 modified pleuropneumonectomies, five lobectomy-pleurectomies, and 18 pleurectomies. Intrapleural PDT was delivered using 630 nm light from two argon pump-dye lasers, and real-time and cumulative light doses were monitored using seven uniquely designed, computer-interfaced photodiodes. RESULTS: There was one 30-day mortality from intraoperative hemorrhage. In the 48-h sensitizer/operation group (n = 33), possible PDT-related complications included an empyema with late hemorrhage in one of three patients at 17.5 J/cm2 and a bronchopleural fistula at 35 J/cm2. At each of these light doses, three additional patients were treated without complication. Two patients subjected to 24-h sensitizer dosing and 32.5 J/cm2 developed esophageal perforations after pleuropneumonectomy at identical sites. The MTD was declared as 30 J/cm2 light with a 24-h dosing interval when none of the six patients (three original, three repeat) at that level developed toxicity. CONCLUSIONS: These data demonstrate that resection and intrapleural PDT can be performed safely with currently available sensitizers and lasers. Phase II and III trials are now warranted at this MTD in a homogeneous population of patients with pleural malignancies.

Phase I study of debulking surgery and photodynamic therapy for disseminated intraperitoneal tumors.

PURPOSE: Phase I study designed to determine the maximum tolerated dose of intraoperative photodynamic therapy (PDT) at laparotomy/debulking surgery in patients with refractory or recurrent, disseminated intraperitoneal tumors. METHODS AND MATERIALS: Patients received dihematoporphyrin ethers (DHE) 1.5-2.5 mg/kg by i.v. injection prior to surgery. Patients resected to < or = 5 mm of residual disease underwent laser light delivery to all peritoneal surfaces. RESULTS: Fifty-four patients entered the study. Thirty-nine underwent resection and light delivery/PDT. PDT dose was escalated by increasing DHE from 1.5 to 2.5 mg/kg, shortening the interval between DHE injection and surgery from 72 to 48 hr, and increasing the light dose. Initially, 630 nm red light alone was used. In this group, PDT of 2.8-3.0 J/cm2 induced small bowel edema and resulted in 3 small bowel perforations after bowel resection or enterotomy. Further light dose escalation, however, was achieved by switching to less penetrating 514 nm green light to the bowel/mesentery. In later patients, whole peritoneal PDT was supplemented with boost doses of 10-15 J/cm2 red light or 5-7.5 J/cm2 green light to high risk areas. Small bowel complications were not seen after switching to less penetrating green light. Dose limiting toxicities occurred in 2 of 3 patients at the highest light dose of 5.0 J/cm2 green light with boost. These patients had pleural effusions that required thoracentesis and postoperative respiratory support for 7-9 days, while one had a gastric perforation. At potential follow-up times of 3.8-43.1 months (median 22.1 months), 30/39 patients are alive and 9/39 are free of disease. CONCLUSION: The maximum tolerated dose of intraoperative PDT following debulking surgery performed 48 hr after intravenous administration 2.5 mg/kg DHE is 3.75 J/cm2 of 514 nm green light to the entire peritoneal surface with boosts to 5.0-7.5 J/cm2 of 514 nm green light or 10-15 J/cm2 of 630 nm red light to sites of gross disease encountered at surgery.

Transcutaneous determination of tissue dihematoporphyrin ether content. A device to optimize photodynamic therapy.

Photodynamic therapy involves the use of light of appropriate wavelength to excite a photosensitizer resulting in tissue destruction. The photosensitizer dihematoporphyrin ether is selectively retained in tumors allowing for tumor destruction while sparing normal structures. Accessibility of skin tumors makes them well suited for photodynamic therapy. Tissue and tumor dihematoporphyrin ether content is estimated based on the amount of dihematoporphyrin ether administered. In our study, skin dihematoporphyrin ether content was measured in guinea pigs transcutaneously by a hand-held fluorometer and compared with dihematoporphyrin ether determinations done on skin biopsy specimens. Fluorometry was performed on guinea pigs receiving 0, 2.5, 5, 10, and 25 mg/kg of dihematoporphyrin ether. Transcutaneous measurements of skin fluorescence increased with increasing dihematoporphyrin ether dose and correlated well with skin dihematoporphyrin ether content as determined by extracting dihematoporphyrin ether from skin samples. Transcutaneous fluorescent measurements of guinea pigs given 0 and 2.5, 2.5 and 5, 5 and 10, and 10 and 25 mg/kg of dihematoporphyrin ether differed in a statistically significant manner. Transcutaneous fluorometric determination of dihematoporphyrin ether content and extraction of dihematoporphyrin ether from skin samples were able to reflect differences in dihematoporphyrin ether dosing and presumably skin dihematoporphyrin ether content. However, transcutaneous fluorometry provides an instantaneous estimate of tissue dihematoporphyrin ether without the need for a tissue sample. This may provide a clinical tool to predict more accurately the optimal light dose necessary to maximize photodynamic therapy.

Technique of photodynamic therapy for disseminated intraperitoneal malignant neoplasms. Phase I study.

Patients with disseminated intraperitoneal malignant neoplasms were given intra-abdominal photodynamic therapy. Patients received dihematoporphyrin ethers intravenously 48 to 72 hours before laparotomy at doses of 1.5 to 3.0 mg/kg. At operation, as much tumor as possible was resected. Red light (630 nm) was delivered to all peritoneal surfaces from an argon-pumped dye laser at doses ranging from 0.2 to 3.0 J/cm2 in an escalating fashion. Viscera and peritoneal surfaces were anatomically isolated and exposed to light for intervals calculated to deliver the prescribed energy. Light was delivered to mesentery and bowel by a flat-cut optical fiber, while other areas, including diaphragm, viscera, omental bursa, gutters, and pelvis, were delivered light through a diffusing wand. Twenty-three patients (13 with ovarian cancer, eight with sarcoma, and two with pseudomyxoma peritoneii) underwent photodynamic therapy. Five of eight patients cleared positive peritoneal cytologies after treatment. Six patients remained clinically free of disease for up to 18 months, and five patients had treatment-related complications. Intraperitoneal phototherapy is technically feasible and deserving of clinical evaluation.

Urinary beta 2-microglobulin in full-term newborns: evidence for proximal tubular dysfunction in infants with meconium-stained amniotic fluid.

Urinary concentrations of beta 2-microglobulin (beta 2M) and creatinine were measured in normal term infants and in those born with meconium-stained amniotic fluid. None of the infants or their mothers had conditions known to modify beta 2M excretion. Measurements of beta 2M were made on urines collected by bagging; urines obtained from diapers were not satisfactory. Urinary beta 2M concentrations increased significantly (P less than .02) in the normal infants from the first day (0.36 +/- 0.29 mg/L: n = 29) to the third day (0.60 +/- 0.43 mg/L: n = 21) postpartum. Compared with the normal infants, values for the infants with meconium-stained amniotic fluid were increased significantly on days 1 (1.64 +/- 2.16 mg/L: n = 25: P less than .005) and 3 (2.12 +/- 2.04 mg/L: n = 23: P less than .005). Levels exceeded two standard deviations above the normal mean in 12 of the 26 infants with meconium-stained amniotic fluid on postpartum day 1, and 12 of the 23 infants with meconium-stained amniotic fluid on day 3. Urinary creatinine levels were similar in both the normal infants and those with meconium-stained amniotic fluid. All infants with meconium-stained amniotic fluid with a one-minute Apgar score of 6 or less had an elevated urinary beta 2M concentration. The elevated levels of urinary beta 2M in infants with meconium-stained amniotic fluid indicate the existence of tubular dysfunction, probably mild acute tubular necrosis secondary to hypoxia.

The use of meditation--relaxation techniques for the management of stress in a working population.

The efficacy of meditation-relaxation techniques has been widely researched in the laboratory, but their effectiveness for management of stress in organizational settings is still relatively unexplored. The present study compared relaxation and control conditions as part of a program of stress-reduction in industry. A total of 154 New York Telephone employees self-selected for stress learned one of three techniques--clinically standardized meditation (CSM), respiratory one method meditation (ROM) or progressive relaxation (PMR)--or served as waiting list controls. At 5.5 months, the treatment groups showed clinical improvement in self-reported symptoms of stress, but only the meditation groups (not the PMR group) showed significantly more symptom reduction than the controls. The meditation groups had a 78% compliance rate at 5.5 months with treatment effect seen whether subjects practiced their techniques frequently or occasionally. The safe and inexpensive semi-automated meditation training has considerable value for stress-management programs in organizational settings.