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Papers by Glenn Graham

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Cambridge University Press eBooks, Jun 18, 2018

Stroke, Dec 1, 1993

Background and Purpose: Proton magnetic resonance spectroscopy has documented declines in normal ... more Background and Purpose: Proton magnetic resonance spectroscopy has documented declines in normal metabolites and long-term elevation of lactate signal after stroke in humans. Within days of stroke, leukocytes infiltrating the infarct zone may produce much of the lactate seen in the subacute and chronic periods. Methods: We examined 10 patients by localized proton magnetic resonance spectroscopy with onedimensional spectroscopic imaging within the first 60 hours after acute nonhemorrhagic cerebral infarction, a period before abundant leukocyte infiltration. Follow-up studies on day 8 to 17 after stroke were performed on 7 of these patients. Results: Initially, the lactate magnetic resonance signal was elevated in all patients. The N-acetylaspartate peak within the lesion was reduced below contralateral normal brain in all but two. At subsequent examination, significant declines had occurred in lesion maximum lactate and N-acetylaspartate signals, with average changes of-36±11% per week and-29±9%O per week, respectively. Declines in lesion creatine/phosphocreatine and in choline-containing compound peaks occurred in some patients but did not attain statistical significance for the group as a whole. Estimated lesion volume correlated positively with both total (r=.75, P=.012) and lesion maximum (r=.74, P=.015) lactate signal. Conclusions: Elevated lactate signal is reliably detectable by magnetic resonance spectroscopy after acute cerebral infarction in humans. Clearance of lactate occurs despite the potential contribution of lactate-producing leukocytes in the subacute stage. Delayed loss of N-acetyl-aspartate signal in second examinations suggests that late death of viable cells may occur within the first 2 weeks after cerebral infarction. (Stroke. 1993;24:1891-1896.) KEY WoRDs * cerebral infarction * lactates * nuclear magnetic resonance

Chemischer Informationsdienst, Oct 7, 1980

Current Treatment Options in Neurology, Nov 1, 2002

Arteriovenous malformations (AVM) are a leading cause of intracerebral hemorrhage, especially amo... more Arteriovenous malformations (AVM) are a leading cause of intracerebral hemorrhage, especially among the young. Because they pose a lifelong risk of serious bleeding, definitive treatment to obliterate the AVM should be pursued in the majority of patients. Microsurgical resection of a small AVM located in the superficial or non- eloquent brain achieves high cure rates with low morbidity, and is the recommended choice for such lesions. Radiosurgery with gamma knife, linear accelerator, or heavy ion beam irradiation is an alternative therapy for AVM treatments less than 3 centimeters in diameter located in brain regions where surgery is likely to produce major neurologic deficits, or for patients unable or unwilling to undergo craniotomy and resection. Cure rates are lower than with microsurgery, and obliteration of the lesion may take 2 to 3 years, during which time the patient remains at risk for hemorrhage. Because rates of recurrent hemorrhage are higher than rates of initial bleeding, radiosurgery may be a good option for patients who have not yet had an intracranial hemorrhage. Endovascular embolization as sole therapy is curative only in a small percentage of cases, but is recommended as part of a multimodal approach to reduce the size of a large AVM, and decrease bleeding risk of lesions with multiple or inaccessible feeding vessels or associated aneurysms prior to surgery or radiotherapy. Currently, treatment decisions must rely solely on Class III evidence from case series and expert opinion. Randomized clinical trials are needed to provide objective guidelines for the future management of patients with an AVM.

Multiple Sclerosis Journal, Feb 2, 2017

This review systematically identifies and summarizes empirical evidence of modifiable risk factor... more This review systematically identifies and summarizes empirical evidence of modifiable risk factors that are related to MS progression. A companion paper summarizes the state of the evidence for interventions targeting these risk factors.

Neurology, Nov 14, 2000

Brief Communications MR spectroscopy study of dichloroacetate treatment after ischemic stroke Art... more Brief Communications MR spectroscopy study of dichloroacetate treatment after ischemic stroke Article abstract-In a double-blind, placebo-controlled study, we used 1 H MR spectroscopy to assess the effect of a single infusion of sodium dichloroacetate on lesion lactate 1 to 5 days after ischemic stroke. Apparent trends toward a reduction in lactate/N-acetyl compound ratios were seen at the higher drug doses employed, and in patients treated in the first 2 days following infarction. Use of spectroscopic measures as endpoints is feasible in acute stroke clinical trials.

Magnetic Resonance Imaging, 1994

Proton T2 relaxation times were measured in 13 stroke patients and 13 aged-matched normal subject... more Proton T2 relaxation times were measured in 13 stroke patients and 13 aged-matched normal subjects at 2.1 T. Spectra were acquired from an ~-CC volume using the STEAM sequence with echo times (TE) of 30.4 ms and 270.0 ms and repetition time of 2.8 s. Transverse relaxation times were estimated using two-point calculations. Percentage volume of infarct in the STEAM voxel was measured on spin-echo MRI encompassing the infarct and correlated with the peak amplitude of N-acetylated compounds (NA). T2 values of NA, creatine, and choline resonances showed no significant difference between patients and controls. T2 for lactate in patients was 780 f 257 ms, respectively (mean f SE, n = 7). In stroke patients, high inverse correlation was found between the absolute NA signal and partial volume of normal brain contributing to each spectrum (p < .OOl, r = 0.97). Together with unchanged T2, this suggests that NAA largely disappears from infarcted tissue within 24 hr postinfarct.

Clinical Interventions in Aging, Nov 1, 2015

Objective: Many stroke survivors experience poststroke spasticity and the related inability to pe... more Objective: Many stroke survivors experience poststroke spasticity and the related inability to perform basic activities, which necessitates patient management and treatment, and exerts a considerable burden on the informal caregiver. The current study aims to estimate burden, productivity loss, and indirect costs for caregivers of stroke survivors with spasticity. Methods: Internet survey data were collected from 153 caregivers of stroke survivors with spasticity including caregiving time and difficulty (Oberst Caregiver Burden Scale), Work Productivity and Activity Impairment measures, and caregiver and patient characteristics. Fractional logit models examined predictors of work-related restriction, and work losses were monetized (2012 median US wages). Results: Mean Oberst Caregiver Burden Scale time and difficulty scores were 46.1 and 32.4, respectively. Employed caregivers (n=71) had overall work restriction (32%), absenteeism (9%), and presenteeism (27%). Caregiver characteristics, lack of nursing home coverage, and stroke survivors' disability predicted all work restriction outcomes. The mean total lost-productivity cost per employed caregiver was US$835 per month ($10,000 per year; 72% attributable to presenteeism). Conclusion: These findings demonstrate the substantial burden of caring for stroke survivors with spasticity illustrating the societal and economic impact of stroke that extends beyond the stroke survivor.

Neurology, Oct 1, 1993

We studied two patients with Creutzfeldt-Jakob disease by in vivo proton magnetic resonance spect... more We studied two patients with Creutzfeldt-Jakob disease by in vivo proton magnetic resonance spectroscopy and obtained spectra from an extract of biopsy tissue from a third patient. In vivo spectra from the two patients, 3 months and less than 1 month after symptom onset, revealed only minor changes. A second study of one of the patients 10 months after symptom onset found a decrease in N-acetylaspartate and other metabolites. Spectroscopy of the biopsy extract obtained 4 months after onset of symptoms showed no reduction in metabolites measured by in vivo spectroscopy, in accord with quantitative pathology showing no overall neuronal loss. Changes in metabolites detectable by proton magnetic resonance spectroscopy are not an early feature of this disease.

Magnetic Resonance in Medicine, May 1, 1996

ABSTRACT A novel approach is presented for imaging macromolecule and metabolite signals in brain ... more ABSTRACT A novel approach is presented for imaging macromolecule and metabolite signals in brain by proton magnetic resonance spectroscopic imaging. The method differentiates between metabolites and macromolecules by T1 weighting using an inversion pulse followed by a variable inversion recovery time before localization and spectroscopic imaging. In healthy subjects, the major macromolecule resonances at 2.05 and 0.9 ppm were mapped at a nominal spatial resolution of 1 x 1 x 1.5 cm3 and were demonstrated to be highly reproducible between subjects. In subacute stroke patients, a highly elevated macromolecule resonance at 1.3 ppm was mapped to infarcted brain regions, suggesting potential applications for studying pathological conditions.

Stroke, Sep 1, 2005

Background-A panel of experts developed stroke rehabilitation guidelines for the Veterans Health ... more Background-A panel of experts developed stroke rehabilitation guidelines for the Veterans Health Administration and Department of Defense Medical Systems. Methods-Starting from previously established guidelines, the panel evaluated published literature through 2002, using criteria developed by the US Preventive Services Task Force. Recommendations were based on evidence from randomized clinical trials, uncontrolled studies, or consensus expert opinion if definitive data were lacking. Results-Recommendations with Level I evidence include the delivery of poststroke care in a multidisciplinary rehabilitation setting or stroke unit, early patient assessment via the NIH Stroke Scale, early initiation of rehabilitation therapies, swallow screening testing for dysphagia, an active secondary stroke prevention program, and proactive prevention of venous thrombi. Standardized assessment tools should be used to develop a comprehensive treatment plan appropriate to each patient's deficits and needs. Medical therapy for depression or emotional lability is strongly recommended. A speech and language pathologist should evaluate communication and related cognitive disorders and provide treatment when indicated. The patient, caregiver, and family are essential members of the rehabilitation team and should be involved in all phases of the rehabilitation process. These recommendations are available in their entirety at http://stroke.ahajournals.org/cgi/content/full/36/9/e100. Evidence tables for each of the recommendations are also in the full document. Conclusions-These recommendations should be equally applicable to stroke patients receiving rehabilitation in all medical system settings and are not based on clinical problems or resources unique to the Federal Medical System.

Archives of Physical Medicine and Rehabilitation, Sep 1, 2013

To investigate the relationship between anxiety/depression and caregiver burden in informal careg... more To investigate the relationship between anxiety/depression and caregiver burden in informal caregivers of stroke survivors with spasticity. Data were collected via online surveys from informal caregivers 18 years or older who cared for stroke survivors. Internet-based survey. 2007 through 2009 U.S. National Health and Wellness Survey database or Lightspeed Research general panel respondents (N=153). Not applicable. Anxiety and depression were self-reported by the caregiver as a physician diagnosis. Depression severity was measured by the Patient Health Questionnaire-9 (PHQ-9). Caregiver burden was measured by the Oberst Caregiving Burden Scale (OCBS) and the Bakas Caregiving Outcomes Scale (BCOS). Logistic regression analyses were conducted with anxiety, depression, and the PHQ-9 depression severity categories as a result of each caregiver burden scale. Data were analyzed for 153 informal caregivers; they were mostly women (70.6%) and white (78.4%), with a mean age of 51.6 years. For every 1-point increase in the OCBS Difficulty Scale, the odds of anxiety or depression were 2.57 times as great (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;.001) and 1.88 times as great (P=.007), respectively. The odds of PHQ-9 severe depression versus all other categories combined were 2.48 times as great (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;.001). For every 1-point decrease in the BCOS, the odds of anxiety or depression were 2.43 times as great (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;.001) and 2.27 times as great (P=.002), respectively. The odds of PHQ-9 severe depression versus all other categories combined were 4.55 times as great (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;.001). As caregiver burden increases, caregivers are more likely to have anxiety and depression. Depression severity also increases. Providing treatment to stroke survivors with spasticity that lessens the time and more importantly, the difficulty of caregiving may lead to a reduction in caregiver anxiety and depression.

Stroke, Feb 1, 2014

Aims: In 2011, the VA released the Acute Ischemic Stroke (AIS) Directive which mandated reorganiz... more Aims: In 2011, the VA released the Acute Ischemic Stroke (AIS) Directive which mandated reorganization of acute stroke care, including self-designation as Primary (P), Limited Hours (LH), or Supporting (S) stroke center. We conducted interviews across stroke centers to understand barriers and facilitators faced in response. Methods: The final sample included 38 (84% invited) facilities: 9 P, 24 LH, and 5 S facilities. In total, 107 persons were interviewed including ED Chiefs, Chiefs of Neurology, ED Nurse Managers/Nurses and other staff. Semi-structured interviews were based on the AIS Directive. Completed interviews were transcribed and analyzed using Nvivo 10. Results: Barriers reported were a lack of personnel assigned to coordinate the facility response to the directive. Data collection and lack of staff were likewise commonly reported as barriers. For thrombolysis measures, the low number of eligible Veterans was another major barrier. LH and S facilities reported some unique barriers: access to radiology and neurology services; EMS diverting stroke patients to nearby stroke centers, maintaining staff competency, and a lack of stroke clinical champions. Some solutions applied included cross training X-ray technicians to provide head CT coverage, developing stroke order sets and templates, and staff training. Larger facilities added a stroke code pager system and improved upon its use, and established ED nurses to become first alerts for an acute stroke patient. LH and S facilities also responded by attempting to secure additional services and by establishing formal transfer agreements to improve Veteran tPA access. Conclusions: The AIS Directive brought focused attention to reorganizing and improving stroke care across a range of facility types. Larger VA facilities tended to follow established practices for organizing stroke care, but the unique LH designation presented challenges to consistently organize systems. Since Veterans have financial interest in presenting to a VA facility, ongoing work to organize VA care and to improve access to thrombolysis at smaller VA facilities is needed. This protocol was supported by Genentech Inc. Protocol ML 28238, VA HSRD QUERI Rapid Response Project 11-374, and the VA Stroke QUERI Center.

Journal of the American Chemical Society, May 1, 1981

The method of the partial retention of diatomic differential overlap (PRDDO), coupled with the ap... more The method of the partial retention of diatomic differential overlap (PRDDO), coupled with the application of linear synchronous transits (LSTs) and orthogonal optimizations, is employed to construct reaction pathways for both the Markownikoff and anti-Markownikoff addition of borone to propylene and to cyanoethylene. Calculations at the 4-3 1G level including Mlaller-Plesset correlation corrections to third order on structures which had been optimized by using PRDDO reveal that the anti-Markownikoff addition to propylene and the Markownikoff addition to cyanoethylene are preferred by 1.1 and 1.6 kcal/mol, respectively. The regioselectivity of the hydroboration reaction is shown to arise from electronic effects induced by electron-donating or electron-withdrawing substituents in these situations, where steric effects are negligible. A description of the reaction in terms of the localized molecular orbitals is also presented.

Journal of the American Chemical Society, Aug 1, 1980

Paramagnetic lanthanide-induced shifts in the carboxyl resonance of EDTA as a function of tempera... more Paramagnetic lanthanide-induced shifts in the carboxyl resonance of EDTA as a function of temperature (Table IV) (1 page). Ordering information is given on any current masterhead page.

Stroke, Feb 1, 1995

Background and Purpose We sought to determine whether lactate and N -acetyl signals measured by p... more Background and Purpose We sought to determine whether lactate and N -acetyl signals measured by proton magnetic resonance spectroscopy (MRS) in the first days after stroke correlate with clinical measures of disability and functional outcome. Methods One-dimensional spectroscopic imaging was performed after stroke on 32 patients using a 2.1-T magnet. The Toronto Stroke Scale score at the time of the MRS study and the Barthel Index score at hospital discharge were determined from patient records. Lesion volume was estimated by a tracing algorithm from the scout magnetic resonance image obtained as part of the MRS study. The scaled lactate and N -acetyl signals from the voxel having the highest measured lactate were used to predict the clinical variables and lesion volume, as well as relative perfusion within the lesion, in those patients who underwent single-photon emission computed tomography (SPECT) blood flow imaging, using a multiple regression analysis. The correlation of lesion volume with the clinical variables was also evaluated. Results Lesion lactate signal was correlated with the Toronto Stroke Scale score, Barthel Index score, lesion volume, and SPECT score, all at P <.01. The N -acetyl level correlated with the Barthel Index score and lesion volume at P <.05. Lesion volume was also strongly correlated with the clinical variables ( P <.0001). Conclusions This is the first study to document the clinical predictive value of proton MRS measurements in patients after stroke. The association with functional outcome is stronger for lactate than for N -acetyl. Spectroscopic assessment of the metabolic status of cerebral tissues shortly after infarction may have significant clinical utility.

Stroke, Dec 1, 2003

Background and Purpose-Concerns persist regarding the safety of tissue plasminogen activator (tPA... more Background and Purpose-Concerns persist regarding the safety of tissue plasminogen activator (tPA) therapy for acute ischemic stroke. Numerous case series of clinical experience with tPA have been published that provide additional data on the safety of thrombolytic therapy. Methods-This is a meta-analysis of 15 published, open-label studies that broadly followed approved indications and guidelines for tPA use in nonselective patient populations. Results-In 2639 treated patients, the symptomatic intracerebral hemorrhage rate was 5.2% (95% confidence interval, 4.3 to 6.0), slightly lower than the 6.4% rate in the treated group of the randomized, placebo-controlled National Institute of Neurological Disorders and Stroke (NINDS) trial. The mean total death rate (13.4%) and proportion of subjects achieving a very favorable outcome (37.1%) were comparable to the NINDS trial results. Protocol deviations were reported in 19.8%. Comparing across studies showed that the mortality rate was correlated with the percentage of protocol violations (rϭ0.67, Pϭ0.018). Conclusions-Postapproval data support the safety of intravenous thrombolytic therapy with tPA for acute ischemic stroke, especially when established treatment guidelines are followed.