Design A 2-year open-label trial of patients with aggressive relapsing-remitting multiple sclerosis (RRMS) given an immunoablative regimen of HiCy (50 mg/kg/d for 4 consecutive days) with no subsequent immunomodulatory therapy unless disease activity reappeared that required rescue therapy.
Setting The Johns Hopkins University Multiple Sclerosis Center, Baltimore, Maryland.
Patients A total of 21 patients with RRMS were screened for eligibility and 9 patients were enrolled in the trial. Patients were required to have 2 or more gadolinium-enhancing lesions on each of 2 pretreatment magnetic resonance imaging scans, at least 1 clinical exacerbation in the 12 months prior to HiCy treatment, or a sustained increase of 1.0 point or higher on the Expanded Disability Status Scale (EDSS) in the preceding year.
Intervention Patients received 50 mg/kg/d of cyclophosphamide intravenously for 4 consecutive days, followed by 5 µg/kg/d of granulocyte colony–stimulating factor 6 days after completion of HiCy treatment, until the absolute neutrophil count exceeded 1.0 x 109 cells/L for 2 consecutive days.
Main Outcome Measures The primary outcome of the study was the safety and tolerability of HiCy in patients with RRMS. Secondary outcome measures included a change in gadolinium-enhancing lesions on magnetic resonance images and a change in disability measures (EDSS and Multiple Sclerosis Functional Composite).
Results Nine patients were treated and followed up for a mean period of 23 months. Eight patients had failed conventional therapy and 1 was treatment naive. The median age at time of entry was 29 years (range, 20-47 years). All patients developed transient total or near-total pancytopenia as expected, followed by hematopoietic recovery in 10 to 17 days, stimulated by granulocyte colony–stimulating factor. There were no deaths or unexpected serious adverse events. There was a statistically significant reduction in disability (EDSS) at follow-up (mean [SD] decrease, 2.11 [1.97]; 39.4%; P = .02). The mean (SD) number of gadolinium-enhancing lesions on the 2 pretreatment scans were 6.5 (2.1) and 1.2 (2.3) at follow-up (81.4% reduction; P = .01). Two patients required rescue treatment with other immunomodulatory therapies during the study owing to MS exacerbations.
Conclusion Treatment with HiCy was safe and well tolerated in our patients with MS. Patients experienced a pronounced reduction in disease activity and disability after HiCy treatment. This immunoablative regimen of cyclophosphamide for patients with aggressive MS is worthy of further study and may be an alternative to bone marrow transplantation.
Published online June 9, 2008 (doi:10.1001/archneurol.65.8.noc80042).
]]>Objective To evaluate the effects of naproxen sodium and celecoxib on cognitive function in older adults.
Design Randomized, double-masked chemoprevention trial.
Setting Six US memory clinics.
Participants Men and women aged 70 years and older with a family history of Alzheimer disease; 2117 of 2528 enrolled had follow-up cognitive assessment.
Interventions Celecoxib (200 mg twice daily), naproxen sodium (220 mg twice daily), or placebo, randomly allocated in a ratio of 1:1:1.5, respectively.
Main Outcome Measures Seven tests of cognitive function and a global summary score measured annually.
Results Longitudinal analyses showed lower global summary scores over time for naproxen compared with placebo (– 0.05 SDs; P = .02) and lower scores on the Modified Mini-Mental State Examination over time for both treatment groups compared with placebo (– 0.33 points for celecoxib [P = .04] and – 0.36 points for naproxen [P = .02]). Restriction of analyses to measures collected from persons without dementia attenuated the treatment group differences. Analyses limited to measures obtained while participants were being issued study drugs produced results similar to the intention-to-treat analyses.
Conclusions Use of naproxen or celecoxib did not improve cognitive function. There was weak evidence for a detrimental effect of naproxen.
Trial Registration clinicaltrials.gov identifier:
Published online May 12, 2008 (doi:10.1001/archneur.2008.65.7.nct70006).
]]>Design Prospective study.
Setting The Parkinson Research Examination of CEP-1347 Trial (PRECEPT) study, which investigated the effects of a potential neuroprotectant on rates of PD progression, was conducted between April 2002 and August 2005 (average follow-up time 21.4 months).
Participants Eight hundred four subjects with early PD enrolled in the PRECEPT study.
Main Outcome Measures The primary study end point was progression to clinical disability sufficient to warrant dopaminergic therapy. Cox proportional hazards models were used to estimate the hazard ratio (HR) of reaching end point according to quintiles of baseline serum urate concentration, adjusting for sex, age, and other potential covariates. Change in striatal uptake of iodine I 123–labeled 2-beta-carbomethoxy-3-beta-(4-iodophenyl)tropane ([123I]β-CIT), a marker for the presynaptic dopamine transporter, was assessed with linear regression for a subset of 399 subjects.
Results The adjusted HR of reaching end point declined with increasing baseline concentrations of urate; subjects in the top quintile reached the end point at only half the rate of subjects in the bottom quintile (HR, 0.51; 95% confidence interval [CI], 0.37-0.72; P for trend < .001). This association was markedly stronger in men (HR, 0.39; 95% CI, 0.26-0.60; P for trend < .001) than in women (HR, 0.77; 95% CI, 0.39-1.50; P for trend = .33). The percentage of loss in striatal [123I]β-CIT uptake also improved with increasing serum urate concentrations (overall P for trend = .002; men, P = .001; women, P = .43).
Conclusions These findings identify serum urate as the first molecular factor directly linked to the progression of typical PD and suggest that targeting urate or its determinants could be an effective disease-modifying therapy in PD.
Trial Registration clinicaltrials.gov Identifier:
Published online April 14, 2008 (10.1001/archneur.2008.65.6.nct70003).
]]>Design Subjects in the Optic Neuritis Treatment Trial, who were enrolled between July 1, 1988, and June 30, 1991, were followed up prospectively for 15 years, with the final examination in 2006.
Setting Neurologic and ophthalmologic examinations at 13 clinical sites.
Participants Three hundred eighty-nine subjects with acute optic neuritis.
Main Outcome Measures Development of MS and neurologic disability assessment.
Results The cumulative probability of developing MS by 15 years after onset of optic neuritis was 50% (95% confidence interval, 44%-56%) and strongly related to presence of lesions on a baseline non–contrast-enhanced magnetic resonance imaging (MRI) of the brain. Twenty-five percent of patients with no lesions on baseline brain MRI developed MS during follow-up compared with 72% of patients with 1 or more lesions. After 10 years, the risk of developing MS was very low for patients without baseline lesions but remained substantial for those with lesions. Among patients without lesions on MRI, baseline factors associated with a substantially lower risk for MS included male sex, optic disc swelling, and certain atypical features of optic neuritis.
Conclusions The presence of brain MRI abnormalities at the time of an optic neuritis attack is a strong predictor of the 15-year risk of MS. In the absence of MRI-detected lesions, male sex, optic disc swelling, and atypical clinical features of optic neuritis are associated with a low likelihood of developing MS. This natural history information is important when considering prophylactic treatment for MS at the time of a first acute onset of optic neuritis.
]]>Objectives To quantify the early risk of ischemic stroke in the territory of a stenotic intracranial artery after TIA and to identify clinical and imaging features associated with increased risk of stroke in the territory among patients with TIA.
Design Cohort study.
Setting Academic research.
Patients The Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) study enrolled patients having TIA or nondisabling stroke within the preceding 3 months and demonstrating corresponding 50% to 99% stenosis of a major intracranial artery on angiography.
Main Outcome Measures We calculated the cumulative risk of stroke in the territory of the symptomatic artery during the first 90 days after randomization among patients having TIA alone as a qualifying event compared with patients having stroke alone. We assessed selected factors for association with stroke among patients having TIA as the qualifying event.
Results The 90-day risk of ischemic stroke in the arterial territory was 6.9% (95% confidence interval, 4.2%-11.2%) after TIA compared with 4.7% (95% confidence interval, 2.7%-8.4%) after stroke (P =.32). Among patients having TIA alone as the qualifying event, 60.0% (15 of 25) of all strokes in the arterial territory occurred in the first 90 days compared with 34.4% (11 of 32) among patients having stroke alone as the qualifying event (P =.05). Among subjects with TIA, the presence of cerebral infarct on baseline neuroimaging was the only statistically significant predictor of higher risk of early stroke (hazard ratio, 4.7; 95% confidence interval, 1.4-15.5; P =.006).
Conclusions Among individuals having intracranial atherosclerotic disease with TIA, most subsequent strokes in the territory of a stenotic intracranial artery occur early (ie, ≤90 days). Prompt management of TIA in patients having intracranial stenosis, particularly those demonstrating cerebral infarction on brain imaging, is indicated.
]]>Objective To determine the effects of 1-Hz repetitive transcranial magnetic stimulation (rTMS) of the contralesional M1 on movement kinematics and neural activation within the motor system in the subacute phase after subcortical stroke.
Design Crossover investigation.
Setting A university hospital.
Methods Fifteen right-handed patients with impaired dexterity due to subcortical middle cerebral artery stroke received 1-Hz rTMS for 10 minutes applied to the vertex (control stimulation) and contralesional M1. For behavioral testing, patients performed finger and grasp movements with both hands at 2 baseline conditions, separated by 1 week, and following each rTMS application. For functional magnetic resonance imaging, patients performed hand grip movements with their affected or unaffected hand before and after each rTMS application.
Results Application of rTMS to the contralesional M1 improved the kinematics of finger and grasp movements in the affected hand. At the neural level, rTMS applied to the contralesional M1 reduced overactivity in the contralesional primary and nonprimary motor areas. There was no significant correlation between the rTMS-induced reduction in blood oxygen level–dependent responses within the contralesional M1 and the degree of behavioral improvement of the affected hand. Overactivity of the contralesional dorsal premotor cortex, contralesional parietal operculum, and ipsilesional mesial frontal cortex at baseline predicted improvement of movement kinematics with the affected hand after rTMS of the contralesional M1.
Conclusion The functional magnetic resonance imaging data suggest that rTMS of the contralesional M1 may normalize neural activation within the cortical motor network after subcortical stroke. Identifying patients suitable for rTMS intervention based on individual patterns of cortical activation may help to implement rTMS in motor rehabilitation after stroke.
]]>Design Mesenchymal stromal cells were obtained from the bone marrow of naïve C57BL and green fluorescent protein–transgenic mice and cultured with Eagle minimum essential medium/alpha medium after removal of adhering cells. Following 2 to 3 passages, MSCs were injected intraventricularly or intravenously into mice in which chronic EAE had been induced with myelin oligodendrocyte glycoprotein 35-55 peptide.
Results In 8 separate experiments, the intravenously and intraventricularly injected green fluorescent protein–positive MSCs were attracted to the areas of central nervous system inflammation and expressed galactocerebroside, O4, glial fibrillary acidic protein, and β-tubulin type III. The clinical course of chronic EAE was ameliorated in MSC-treated animals (0% mortality; mean [SE] maximal EAE score, 1.76 [1.01] and 1.8 [0.46] in the intraventricular and intravenous groups, respectively, vs 13% and 21% mortality and 2.80 [0.79] and 3.42 [0.54] mean maximal score in the controls). A strong reduction in central nervous system inflammation, accompanied by significant protection of the axons (86%-95% intact axons vs 45% in the controls) was observed in the animals injected with MSCs (especially following intraventricular administration). Mesenchymal stromal cells injected intravenously were detected in the lymph nodes and exhibited systemic immunomodulatory effects, downregulating proliferation of lymphocytes in response to myelin antigens and mitogens. Mesenchymal stromal cells cultured with fibroblast growth factor and brain-derived neurotrophic factor in vitro acquired neuronal-lineage cell morphology and expressed β-tubulin type III, nestin glial fibrillary acidic protein, and O4.
Conclusions Our results indicate that stem cells derived from bone marrow may provide a feasible and practical way for neuroprotection, immunomodulation, and possibly remyelination and neuroregeneration in diseases such as multiple sclerosis.
]]>Objective To examine the effect of simvastatin, a cholesterol-lowering drug, on prion disease progression and survival.
Design Controlled animal study.
Setting University medical center research laboratory.
Subjects Female mice from the FVB/N strain.
Interventions Peripheral and central nervous system inoculations with scrapie Rocky Mountain Laboratory inoculum.
Main Outcome Measures Clinical, immunological, pathological, and molecular assays were performed.
Results Simvastatin delayed disease progression, leading to increased survival in peripheral as well as central nervous system inoculations. Simvastatin's beneficial effect is mediated through the
Conclusions Simvastatin delays prion disease progression and increases survival in vivo, independently of the pathogenic conversion of PrPC to PrPSc. We show that simvastatin's effects on neuroprotection are correlated with downregulation of Cox2 levels and induction of microglial activation in prion-infected mouse brains.
]]>Design Longitudinal study across a mean (SD) of 4.2 (2.6) years with assessments at approximately 6- to 12-month intervals.
Setting Outpatient care.
Patients A cohort of 122 patients having a clinical diagnosis of probable Alzheimer disease, each with at least 2 assessments across time.
Main Outcome Measures Scores on the cognitive Information-Memory-Concentration subscale of the Blessed Dementia Scale and the functional Weintraub Activities of Daily Living Scale.
Results Low plasma levels of Aβ40, Aβ42, and high-sensitivity C-reactive protein were associated with a significantly more rapid cognitive decline, as indexed using the Blessed Dementia Scale, than were high levels. Low levels of Aβ42 and high-sensitivity C-reactive protein were significantly associated with more rapid functional decline on the Weintraub Activities of Daily Living Scale than were high levels. These plasma markers contributed about 5% to 12% of the variance accounted for on the Blessed Dementia Scale and the Activities of Daily Living Scale by fixed-effects predictors. Measures of folic acid metabolism were not associated with changes on either the Blessed Dementia Scale or the Activities of Daily Living Scale.
Conclusions Plasma markers of amyloid precursor protein metabolism and C-reactive protein may be associated with the rate of cognitive and functional decline in patients with Alzheimer disease.
]]>Objective To determine whether a lower dose of sucrose administered closer in time to exercise could have a similar beneficial effect on exercise capacity in patients with McArdle disease.
Design Placebo-controlled crossover.
Setting Neuromuscular Research Unit at the Department of Neurology, Rigshospitalet, Copenhagen, Denmark.
Patients Six patients with biochemically and genetically diagnosed McArdle disease.
Interventions On separate days, the patients were tested after ingestion of either 75 g of sucrose or a placebo 40 minutes before exercise, or 37 g of sucrose or a placebo 5 minutes before exercise. Patients were blinded to test substances.
Main Outcome Measures Treatment effectiveness was assessed by monitoring heart rate and perceived exertion during exercise.
Results Both sucrose treatments dramatically improved exercise tolerance, compared with the placebo. The low-dose, 5-minute sucrose trial had a more sustained effect on exercise capacity than the 40-minute trial. The more sustained effect was probably related to more continuous glucose uptake from the intestine and correspondingly higher circulating glucose levels later during exercise.
Conclusions This study shows that 37 g of sucrose ingested shortly before exercise has a marked and prolonged effect on exercise tolerance in patients with McArdle disease. This treatment is more convenient for the patients and saves more calories than the currently recommended sucrose treatment.
]]>Objectives To determine frequency and topography of microbleeds in Alzheimer disease (AD) and to assess their association with leukoaraiosis and cognition.
Design Case-control cross-sectional analysis. Microbleeds were counted using GRE imaging. Leukoaraiosis was rated on T2-weighted and proton density–weighted scans using the Age-Related White Matter Changes Rating Scale (ARWMC). Neuropsychological tests indexed cognition.
Setting The Cognitive Neurology Clinic, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
Patients Individuals with probable AD (n = 80) and healthy controls (n = 25) from a longitudinal cohort with GRE sequences as part of standard imaging protocol (2002-2006).
Results Microbleeds occurred in 29% of patients with AD and 12% of controls and were multiple (> 1) in 48% of patients with AD and 33% of controls. There was lobar (vs centrencephalic) predominance in 92% of AD patients, with occipital lobes accounting for 57% of these microbleeds. The ARWMC scores (P < .005) were significantly higher in AD patients with microbleeds than in those without, and microbleeds correlated with total (r = 0.39, P = .01) and parietooccipital (r = 0.28, P < .01) ARWMC scores. We were unable to demonstrate an association between microbleeds (or leukoaraiosis) and cognitive performance.
Conclusions Occipital predominance of microbleeds with corresponding parietooccipital leukoaraiosis has not been well described in prior imaging studies of AD. Microbleeds were frequent, often multiple, and predicted greater leukoaraiosis. These findings illustrate the complexity of AD vasculopathy and the need for additional studies in dementia and stroke populations.
]]>Objectives To measure selective structural changes in early CBDS using diffusion tensor imaging and voxel-based morphometry and to evaluate the structural correlates of limb apraxia.
Design Patient and control group comparison.
Setting Referral center for dementia and movement disorders.
Participants Twenty patients with CBDS and 21 matched control subjects.
Interventions Clinical and standardized neuropsychological evaluations, including assessment of limb apraxia.
Main Outcome Measures Gray and white matter changes in early CBDS.
Results Diffusion tensor imaging revealed decreases in fractional anisotropy in the long frontoparietal connecting tracts, the intraparietal associative fibers, and the corpus callosum. Fractional anisotropy was also reduced in the sensorimotor projections of the cortical hand areas. Voxel-based morphometry showed a prevalent gray matter reduction in the left hemisphere (in the inferior frontal and premotor cortices, parietal operculum, superotemporal gyrus, and hippocampus). The pulvinar, bilaterally, and the right cerebellar cortex also showed atrophy. Limb apraxia correlated with parietal atrophy and with fractional anisotropy reductions in the parietofrontal associative fibers (P < .01). The limb-kinetic component of apraxia correlated with reduction of hand sensorimotor connecting fibers.
Conclusions The present integrative approach to in vivo structural anatomy combines hodologic imaging, describing patterns of white matter connections between cortical areas, with neuropsychological data. This provides new evidence of gray matter and fiber tract abnormalities in early-phase disease and contributes to clarifying the neural basis of apraxia in CBDS.
]]>Design Retrospective clinical and genetic review.
Setting University hospital.
Patients We performed extensive mutation analyses of PINK1 in 414 PD patients negative for parkin mutations (mean [SD] age at onset, 42.8 [14.3] years), including 391 unrelated patients (190 patients with sporadic PD and 201 probands of patients with familial PD) from 13 countries.
Results We found 10 patients with PD from 9 families with PINK1 mutations and identified 7 novel mutations (2 homozygous mutations [p.D297MfsX22 and p.W437R] and 5 single heterozygous mutations [p.A78V, p.P196QfsX25, p.M342V, p.W437R, and p.N542S]). No compound heterozygous mutations were found. The frequency of homozygous mutations was 4.26% (2 of 47) in families with autosomal recessive PD and 0.53% (1 of 190) in patients with sporadic PD. The frequency of heterozygous mutations was 1.89% (2 of 106) in families with potential autosomal dominant PD and 1.05% (2 of 190) in patients with sporadic PD. The mean (SD) age at onset in patients with single heterozygous mutations (53.6 [11.1] years; range, 39-69 years) was higher than that in patients with homozygous mutations (34.0 [20.3] years; range, 10-55 years). Myocardial iodine-123 metaiodobenzylguanidine uptake was low in patients with heterozygous mutations but not in those with homozygous mutations.
Conclusions Our results suggest that homozygous PINK1 mutations tend to be diagnosed as the early-onset autosomal recessive form of PD. Single heterozygous mutations may contribute to the development of sporadic PD and also could be an additional genetic predisposition for developing familial PD. The reduced myocardial iodine-123 metaiodobenzylguanidine uptake observed in patients with single heterozygous PINK1 mutations is similar to that seen in patients with sporadic PD.
]]>Objective To investigate the association between VDDR I and MS.
Design Case studies.
Setting Haukeland University Hospital, Bergen, Norway.
Patients Three patients in 2 families with a co-occurrence of VDDR I and MS.
Results All 3 patients had VDDR I verified by genetic testing and fulfilled the Poser criteria for MS. Two of the patients have undergone magnetic resonance imaging, which confirmed the diagnosis of long-lasting MS.
Conclusions Vitamin D–dependent rickets type I is a very uncommon genetic subtype of rickets. We have identified 3 patients with this disease who later developed MS. We propose that VDDR I and possibly other hereditary rickets mutations that influence vitamin D metabolism could be risk factors for this disease.
]]>Objective To describe the perivenous association of MS lesions on high-resolution and high-contrast 7-T susceptibility-sensitive MRI.
Design Case study.
Setting University hospital.
Patients Two women with clinically definite relapsing-remitting MS.
Results We demonstrated markedly enhanced detection of unique microvascular involvement associated with most of the visualized MS lesions with abnormal signals on and around the venous wall on 7-T compared with 3-T MRI.
Conclusions These findings, which have never been shown on conventional fields of MRI, not only allow for direct evidence of vascular pathogenesis in MS in vivo but also have important implications for monitoring lesion activity and therapeutic response.
]]>Objective To describe a family with EA2 having a novel mutation deleting several exons of CACNA1A.
Design Clinical and molecular study of a family manifesting EA2 attacks.
Setting Academic research.
Patients DNA was extracted from blood samples of 3 family members.
Main Outcome Measures Microsatellite genotyping of CACNA1A, quantitative multiplex polymerase chain reaction of short fluorescent fragments (QMPSF), and sequencing were performed.
Results Genotyping of CACNA1A showed nonmendelian inheritance of a CAG repeat located at the 3' end of the gene in a mother and daughter, suggesting a deletion event, which was subsequently confirmed by QMPSF analysis and sequencing. This 39.5-kilobase deletion removes the last 16 coding exons of the gene.
Conclusion Deletion of several exons of CACNA1A may cause EA2 and should be assessed in patients having EA2 without a CACNA1A point mutation.
]]>Objective To describe the course of a patient with severe BBE and multiple medical complications.
Design Case report.
Setting Academic medical center.
Patient An 81-year-old woman with BBE who fully recovered. The patient had transient and very frequent episodes of brainstem dysfunction during the recovery phase.
Main Outcome Measures Clinical and biochemical evaluation with magnetic resonance imaging.
Conclusions Bickerstaff brainstem encephalitis is a potentially reversible syndrome that needs early diagnosis (facilitated by magnetic resonance imaging) and prompt aggressive and supportive treatment. Frequent episodes of transient brainstem dysfunction occurred in our patient during recovery, possibly due to ephaptic transmission.
]]>Objective To describe a patient with progressive supranuclear palsy (PSP) who presented with WEBINO syndrome.
Design Case report and review of literature.
Setting A university hospital.
Patient A 72-year-old man began to display akinesia, freezing of gait, postural instability, mild rigidity of the neck, and vertical supranuclear palsy, including downward gaze limitation, at 66 years of age. At 68 years, he started to develop diplopia. At 70 years, he had bilateral medial longitudinal fasciculus syndrome. Later, his eye positions gradually showed alternating exotropia.
Results A diagnosis of probable PSP was made based on the National Institute of Neurological Disorders and Stroke and the Society for Progressive Supranuclear Palsy criteria. He showed alternating exotropia in the forward gaze, and adduction paresis and monocular nystagmus of the abducted eye in the horizontal gaze, 2 clinical symptoms of WEBINO syndrome.
Conclusion This is the first reported case of a patient with PSP presenting with WEBINO syndrome. Because bilateral medial longitudinal fasciculus lesions are commonly observed in PSP as clinical and pathological findings, particular attention should be given to WEBINO syndrome in patients with PSP.
]]>Design A pilot phase 2, randomized, double-blind, placebo-controlled, parallel-group trial. The study occurred in hospital-based outpatient clinics and in clinical trial units. Patients with advanced PD and levodopa-related motor fluctuations were enrolled. Tesofensine (0.125, 0.25, 0.5, or 1 mg) or placebo tablets were administered once daily for 14 weeks.
Main Outcome Measures Coprimary end points were the changes from baseline in Unified Parkinson Disease Rating Scale (UPDRS) subscale II (activities of daily living) plus subscale III (motor function) total score and in percentage of waking hours spent in "off" time noted in self-scoring diaries. Secondary end points were safety, pharmacokinetics, responder analysis (≥20% reduction in UPDRS score and in off time), and changes in percentage of waking hours spent in "on" time with and without troublesome dyskinesia.
Results The adjusted mean differences (relative to placebo) were –4.7 points in UPDRS subscale II plus subscale III total score (P =.005) with tesofensine, 0.5 mg, and –7.1% in off time (–68 minutes, P =.02) with tesofensine, 0.25 mg. Other dosages did not induce statistically significant effects. The plasma concentration increased with the dosage, but no clear dose-response relationship was observed. Gastrointestinal tract and neuropsychiatric adverse events were more frequent with tesofensine than with placebo, especially at the higher dosages.
Conclusions Patients with PD in advanced stages showed modest improvements in UPDRS subscale II plus subscale III total score and in off time when treated with tesofensine, but a dose-response relationship could not be established for efficacy, while adverse drug reactions tended to be more frequent at higher dosages.
Trial Registration clinicaltrials.gov Identifier:
Objective To assess whether prior use of AP drugs is related to outcome following intravenous tissue plasminogen activator therapy in patients with ischemic stroke.
Design, Setting, and Patients A single-center prospective observational cohort study of the relation between prior AP therapy, occurrence of SICH, and functional outcome of consecutive patients with ischemic stroke undergoing intravenous thrombolysis with tissue plasminogen activator in a university hospital between April 1, 2002, and November 30, 2006.
Main Outcome Measures The occurrence of SICH and favorable outcome reflecting independence defined as a modified Rankin Scale score of 2 or lower at 3 months.
Results Of the 301 patients who received intravenous tissue plasminogen activator, 89 used AP drugs prior to thrombolysis. Symptomatic intracerebral hemorrhage occurred in 12 patients (13.5%; 95% confidence interval, 7.8%-22.3%) who had received AP drugs and in 6 patients (2.8%; 95% confidence interval, 1.2%-6.2%) without prior AP therapy (P = .001). Multivariate analysis revealed that prior AP therapy was an independent predictor of SICH (odds ratio, 6.0; 95% confidence interval, 2.0-17.1). Nonetheless, prior AP therapy was independently associated with a favorable outcome (odds ratio, 2.0; 95% confidence interval, 1.0-4.3).
Conclusion Despite a higher incidence of SICH, the net benefit of intravenous tissue plasminogen activator therapy for acute ischemic stroke was greater in patients using AP drugs.
Published online March 10, 2008 (doi:10.1001/archneur.65.5.noc70077).
]]>Objective To evaluate whether reimplantation of electrodes in the STN can produce improvement in patients with poor results from surgery and with suspected electrode misplacement based on imaging findings.
Design Prospective follow-up study.
Setting Academic research.
Patients A 1-year postoperative study was undertaken in 7 consecutive patients with Parkinson disease who, despite bilateral STN stimulation, experienced persistent motor disability and who were operated on for reimplantation a median of 16.9 months later.
Main Outcome Measures The primary outcome was measured as the change in the Unified Parkinson Disease Rating Scale (UPDRS) motor score 1 year after reimplantation. The secondary outcome was measured as the extent of pharmacologic and electrical treatments required and the threshold at which the first stimulation-induced adverse effect appeared. The distances between the electrode contacts used for chronic stimulation and the STN theoretical effective target, defined as the mean position of the clinically efficient contact from 193 previously implanted electrodes, were compared.
Results Except for a single patient, all patients displayed improvement following reimplantation. Under off-medication (ie, the patient is taking no medication) condition, STN stimulation improved the basal state UPDRS motor score by 26.7% before reimplantation and by 59.4% at 1 year after reimplantation. The median off-medication Schwab and England score improved from 51% to 76%. The median levodopa equivalent daily dose was reduced from 1202 mg to 534 mg. The stimulation varibles changed from a mean of 2.6 V/73.0 µs/163.0 Hz to 2.8 V/60. 0 µs/ 140.0 Hz. The mean threshold of the first stimulation-induced adverse effect increased from 2.6 to 4.4 V. The mean distance between the contacts used for chronic stimulation and the theoretical effective target decreased from 5.4 to 2.0 mm. This distance correlated inversely with the percentage improvement in theUPDRS motor score.
Conclusion Patients demonstrating poor response to STN stimulation as a result of electrode misplacement can benefit from reimplantation in the STN closer to the theoretical target.
]]>Objective