Tenecteplase for Stroke at 4.5 to 24 Hours with Perfusion-Imaging Selection.

BACKGROUND: Thrombolytic agents, including tenecteplase, are generally used within 4.5 hours after the onset of stroke symptoms. Information on whether tenecteplase confers benefit beyond 4.5 hours is limited. METHODS: We conducted a multicenter, double-blind, randomized, placebo-controlled trial involving patients with ischemic stroke to compare tenecteplase (0.25 mg per kilogram of body weight, up to 25 mg) with placebo administered 4.5 to 24 hours after the time that the patient was last known to be well. Patients had to have evidence of occlusion of the middle cerebral artery or internal carotid artery and salvageable tissue as determined on perfusion imaging. The primary outcome was the ordinal score on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability and a score of 6 indicating death) at day 90. Safety outcomes included death and symptomatic intracranial hemorrhage. RESULTS: The trial enrolled 458 patients, 77.3% of whom subsequently underwent thrombectomy; 228 patients were assigned to receive tenecteplase, and 230 to receive placebo. The median time between the time the patient was last known to be well and randomization was approximately 12 hours in the tenecteplase group and approximately 13 hours in the placebo group. The median score on the modified Rankin scale at 90 days was 3 in each group. The adjusted common odds ratio for the distribution of scores on the modified Rankin scale at 90 days for tenecteplase as compared with placebo was 1.13 (95% confidence interval, 0.82 to 1.57; P = 0.45). In the safety population, mortality at 90 days was 19.7% in the tenecteplase group and 18.2% in the placebo group, and the incidence of symptomatic intracranial hemorrhage was 3.2% and 2.3%, respectively. CONCLUSIONS: Tenecteplase therapy that was initiated 4.5 to 24 hours after stroke onset in patients with occlusions of the middle cerebral artery or internal carotid artery, most of whom had undergone endovascular thrombectomy, did not result in better clinical outcomes than those with placebo. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups. (Funded by Genentech; TIMELESS ClinicalTrials.gov number, NCT03785678.).

Reversion from chronic migraine to episodic migraine following treatment with erenumab: Results of a post-hoc analysis of a randomized, 12-week, double-blind study and a 52-week, open-label extension.

OBJECTIVE: To determine reversion rates from chronic migraine to episodic migraine during long-term erenumab treatment. METHODS: A daily headache diary was completed during the 12-week, double-blind treatment phase of a placebo-controlled trial comparing erenumab 70 mg, 140 mg, and placebo, and weeks 1-12, 21-24, 37-40, and 49-52 of the open-label treatment phase. Chronic migraine to episodic migraine reversion rates were assessed over the double-blind treatment phase; persistent reversion to episodic migraine over 24 weeks (double-blind treatment phase through the first 12 weeks in the open-label treatment phase), long-term persistent reversion to episodic migraine over 64 weeks (double-blind treatment phase plus open-label treatment phase); delayed reversion to episodic migraine through the first 12 weeks of the open-label treatment phase among patients remaining in chronic migraine during the double-blind treatment phase. RESULTS: In the double-blind treatment phase, 53.1% (95% confidence interval: 47.8-58.3) of 358 erenumab-treated completers had reversion to episodic migraine; monthly reversion rates to episodic migraine were typically higher among patients receiving 140 mg versus 70 mg. Among 181 completers (receiving erenumab for 64 weeks), 98 (54.1% [95% confidence interval: 46.6-61.6]) had reversion to episodic migraine during the double-blind treatment phase; of those, 96.9% (95% confidence interval: 91.3-99.4) had persistent reversion to episodic migraine, 96.8% (95% confidence interval: 91.1-99.3) of whom had long-term persistent reversion to episodic migraine. Delayed reversion to episodic migraine occurred in 36/83 (43.4% [95% confidence interval: 32.5-54.7]) patients; of these, 77.8% (95% confidence interval: 60.9-89.9) persisted in reversion through week 64. CONCLUSIONS: Patients with reversion to episodic migraine at week 12 will likely persist as episodic migraine with longer-term erenumab; others may achieve delayed reversion to episodic migraine.Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02066415.

Long-term safety and tolerability of erenumab: Three-plus year results from a five-year open-label extension study in episodic migraine.

BACKGROUND: Previously published three-month placebo-controlled and one-year open-label clinical trial data have provided information on the efficacy and safety of erenumab. METHODS: Interim analysis was undertaken from an ongoing five-year open-label treatment phase after all patients completed three years in the open-label treatment phase or discontinued the study. Adult patients with episodic migraine enrolled in the open-label treatment phase initially received 70 mg erenumab monthly. A protocol amendment increased the dosage to 140 mg monthly to assess long-term safety of the higher dose. Safety and tolerability were assessed by monitoring adverse events, electrocardiograms, laboratory assessments, and vital signs. RESULTS: Of 383 patients enrolled in the open-label treatment phase, at data cutoff 235 (61.3%) remained in the study, all received 140 mg for ≥1 year. Median (Q1, Q3) exposure (70 or 140 mg) for all patients enrolled was 3.2 (1.3, 3.4) years. The most frequent adverse events (≥4.0/100 patient-years) were reported as viral upper respiratory tract infection, sinusitis, influenza, and back pain. Exposure-adjusted serious adverse event rates were 4.2/100 patient-years. There was no increase in cardiovascular events over time. CONCLUSIONS: In this long-term study of a CGRP-receptor antibody, erenumab was found to be safe and well-tolerated with a spectrum and rate of adverse events consistent with shorter-term placebo-controlled studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT01952574.

Efficacy and Safety of Sildenafil in Men With Sexual Dysfunction and Spinal Cord Injury.

INTRODUCTION: Spinal cord injury (SCI) is estimated to affect approximately 276,000 individuals in the United States. Since 2010, the mean age of individuals at the time of the SCI has been 42 years, with nearly 80% of cases involving men. This means that individuals with SCI generally are young men who typically place a great deal of importance on normal sexual and reproductive function. AIM: To assess the effect of sildenafil treatment on erectile function and the frequency of ejaculation in men with SCI. METHODS: This study was a post hoc analysis of pooled data from two randomized, double-blinded, placebo-controlled, flexible-dose, crossover sildenafil trials conducted in Europe, Australia, and Turkey. Two hundred forty-eight men at least 18 years old with traumatic SCI of at least 6 months' duration, with erectile dysfunction solely attributed to SCI, and in a stable heterosexual relationship were treated sequentially with sildenafil and placebo. Exclusion criteria included taking nitrate therapy, severe cardiac failure, and recent stroke or myocardial infarction. The starting sildenafil dose was 50 mg, taken approximately 1 hour before sexual activity, with subsequent dose adjustment to 100 or 25 mg based on efficacy and safety during treatment. There was a 2-week washout between 6-week treatments. MAIN OUTCOME MEASURES: Change from baseline in International Index of Erectile Function question 3 (frequency of penetration), question 4 (maintaining erection after penetration), question 9 (frequency of ejaculation), and erectile function domain scores; intercourse success; and treatment preference. RESULTS: All International Index of Erectile Function outcomes, including achieving and maintaining erections and ejaculation frequency, were statistically significantly greater with sildenafil vs placebo, including the subgroup with complete SCI (P < .01 for all comparisons). The percentage of successful intercourse attempts with sildenafil (53% vs 12%) and preference for sildenafil (96% vs 4%) vs placebo were significant (P < .001), including the subgroup with complete SCI. The most common all-cause adverse events with sildenafil were headache (16.1%) and urinary tract infection (11.6%). CONCLUSION: Sildenafil significantly improves erections, intercourse success, and ejaculation frequency vs placebo, including in men with complete SCI. Sildenafil is an effective and well-tolerated treatment for sexual dysfunction in men with SCI. The increase in frequency of ejaculation could allow the possibility of having children without medical intervention in this patient population. Ohl DA, Carlsson M, Stecher VJ, Rippon GA. Efficacy and Safety of Sildenafil in Men With Sexual Dysfunction and Spinal Cord Injury. Sex Med Rev 2017;5:521-528.

Impaired health status, daily functioning, and work productivity in adults with excessive sleepiness.

OBJECTIVE: This study evaluated the effects of excessive sleepiness (ES) on health status, daily functioning, and work productivity. METHODS: From a survey performed in June to July 2006, people with or without ES in two groups (1758 with obstructive sleep apnea, depression, narcolepsy, multiple sclerosis, or shift work; 1977 without these conditions) were assessed on the Work Productivity and the Activity Impairment Scale, Short Form-12, Medical Outcomes study 6-item Cognitive Function Scale, and the Toronto Hospital Alertness Test. RESULTS: ES in both groups was associated with highly significant impairments in health status, daily activities, and work productivity for all measures (P < 0.0001), except for absenteeism (P = 0.0400 for group A, P = 0.8360 for group B). CONCLUSIONS: ES may have an incremental negative impact measurable above that of obstructive sleep apnea, multiple sclerosis, narcolepsy, depression, or shift work.

A double-blind, placebo-controlled study of armodafinil for excessive sleepiness in patients with treated obstructive sleep apnea and comorbid depression.

OBJECTIVE: Treatment of excessive sleepiness in the context of obstructive sleep apnea (OSA) may be particularly difficult in those with depression because depression and/or antidepressant medications may cause sleepiness and fatigue in addition to that due to the OSA. This study evaluating armodafinil, a nonamphetamine wakefulness-promoting medication, is the first trial for treatment of excessive sleepiness in patients with treated OSA and comorbid depression. METHOD: Men and women with OSA diagnosed using International Classification of Sleep Disorders criteria being treated with continuous positive airway pressure and comorbid major depressive disorder or dysthymic disorder according to DSM-IV-TR criteria were enrolled into a 12-week, randomized, double-blind, parallel-group study between September 2007 and March 2009 at 60 outpatient sites. Patients maintained on stable monotherapy with a serotonergic antidepressant and with a 17-item Hamilton Depression Rating Scale score < 17 received placebo or armodafinil (target dose: 200 mg once daily). Coprimary outcomes were the proportion of patients with at least minimal improvement on the Clinical Global Impression of Change (CGI-C) as related to excessive sleepiness and mean change from baseline in Maintenance of Wakefulness Test mean sleep latency at final visit; the key secondary outcome was mean change in the Epworth Sleepiness Scale score. RESULTS: 249 patients were enrolled: 125 in the armodafinil group and 124 in the placebo group. The proportion of patients with at least minimal improvement on the CGI-C was statistically significantly greater in the armodafinil group (69%) compared with the placebo group (53%, P = .012). Mean (SD) increase in Maintenance of Wakefulness Test sleep latency was numerically but not significantly greater following armodafinil (2.6 [7.1] min) versus placebo (1.1 [7.6] min, P = .30) treatment. Mean decrease in Epworth Sleepiness Scale score was greater in the armodafinil group (-6.3 [4.8]) than in the placebo group (-4.8 [4.9], nominal P = .003). Headache, dry mouth, and insomnia were the most common adverse events occurring with armodafinil treatment. There was no clinically significant effect on depression in either group as measured by the Quick Inventory of Depressive Symptomatology-Self-Report 16. CONCLUSIONS: Armodafinil significantly improved overall clinical condition related to excessive sleepiness as rated by the CGI-C and was well tolerated in patients with treated OSA and comorbid depression. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00518986.

Armodafinil improves wakefulness and long-term episodic memory in nCPAP-adherent patients with excessive sleepiness associated with obstructive sleep apnea.

Residual excessive sleepiness (ES) and impaired cognition can occur despite effective and regular nasal continuous positive airway pressure (nCPAP) therapy in some patients with obstructive sleep apnea (OSA). A pooled analysis of two 12-week, randomized, double-blind studies in nCPAP-adherent patients with ES associated with OSA evaluated the effect of armodafinil on wakefulness and cognition. Three hundred and ninety-one patients received armodafinil (150 or 250 mg) and 260 patients received placebo once daily for 12 weeks. Efficacy assessments included the Maintenance of Wakefulness Test (MWT), Cognitive Drug Research cognitive performance battery, Epworth Sleepiness Scale, and Brief Fatigue Inventory. Adverse events were monitored. Armodafinil increased mean MWT sleep latency from baseline to final visit by 2.0 min vs a decrease of 1.5 min with placebo (P < 0.0001). Compared with placebo, armodafinil significantly improved quality of episodic secondary memory (P < 0.05) and patients' ability to engage in activities of daily living (P < 0.0001) and reduced fatigue (P < 0.01). The most common adverse events were headache, nausea, and insomnia. Armodafinil did not adversely affect desired nighttime sleep, and nCPAP use remained high (approximately 7 h/night). Adjunct treatment with armodafinil significantly improved wakefulness, long-term memory, and patients' ability to engage in activities of daily living in nCPAP-adherent individuals with ES associated with OSA. Armodafinil also reduced patient-reported fatigue and was well tolerated.

An observational study of cognitive impairment in amyotrophic lateral sclerosis.

BACKGROUND: Cognitive impairment is increasingly recognized in patients with amyotrophic lateral sclerosis (ALS). Clinical and pathologic features overlap in frontotemporal lobar dementia and ALS. Demographics, respiratory status, bulbar site of onset, and disease severity are potential risk factors for cognitive impairment in ALS. OBJECTIVES: To further delineate the frequency, nature, and implications of cognitive impairment in ALS and to assess previously identified risk factors. DESIGN: Case-control and retrospective cohort study. SETTING: Academic referral center. PARTICIPANTS: Forty consecutive patients with ALS underwent baseline neurologic and neuropsychologic examinations. Cognitive test performance was compared in patients with ALS and matched controls. An exploratory analysis of the relationship between cognitive performance and ALS survival was performed. MAIN OUTCOME MEASURES: Neuropsychologic test performance, ALS severity, and survival. RESULTS: Twelve patients (30%) showed evidence of cognitive impairment, including 9 (23%) who met the neuropsychologic criteria for dementia. No statistically significant differences were found between demented and nondemented ALS groups regarding demographics, family history, site of onset, bulbar dysfunction, or ALS severity. Only 1 patient with dementia had bulbar-onset disease. An association was observed between increasing ALS severity and declining verbal fluency performance. Demented patients with ALS showed predominant impairment in free recall, executive function, and naming, with relative preservation of attention, psychomotor speed, and visuospatial function. No association was observed between cognition and survival, controlling for ALS severity. CONCLUSIONS: Nearly a third of the patients with ALS showed evidence of cognitive impairment in a pattern consistent with frontotemporal lobar dementia. Cognitive performance was not related to site of onset or survival.

Dementia in Parkinson's disease.

Dementia as a manifestation of idiopathic PD is an important feature of the disease in terms of QOL, prognosis, and clinical management. The pathophysiology of the disorder is likely a multifactorial process that encompasses derangement of multiple neuronal populations of both subcortical and cortical origin. This process results in a cognitive profile that largely reflects a dysexecutive syndrome. Currently, treatment of PDD is symptomatic. Further research is needed to elucidate the relationship of PDD to DLB and AD in hopes of developing and using appropriate therapeutic measures designed to address the underlying disease process.

Corticobasal syndrome with novel argyrophilic glial inclusions.

A 42-year-old, left-handed woman first noted impaired dexterity of the dominant hand, soon followed by dysarthria and cognitive decline. Over a 4-year period, she developed severe left-sided apraxia with eventual neglect of the left arm and progressive extrapyramidal signs. Cognitive testing showed progressive executive, visuospatial, fluency, and naming impairment with relative preservation of memory. Single-photon emission computed tomography demonstrated asymmetric right posterior frontal and superior parietal hypoperfusion. The clinical impression was corticobasal degeneration. At autopsy, severe atrophy was seen in the perirolandic and frontal regions. There was marked neuronal loss and gliosis in the posterior frontal and precentral regions and less severe pathology in prefrontal, temporal, and parietal areas. Mild to moderate gliosis and neuronal loss were also seen in the putamen, globus pallidus, subthalamic, and dentate nuclei. Gallyas silver stain revealed numerous inclusions adjacent to oligodendrocyte nuclei in white and gray matter of affected cortical and subcortical regions. The gracile inclusions were wavy, slender, and stained positively with antibodies to ubiquitin and alphaB-crystallin but not to microtubule-associated proteins (tau, MAP1B, MAP2), tubulin, neurofilaments, glial fibrillary acidic protein, or alpha-synuclein. The argyrophilic inclusions identified in this case are distinct from those previously described in neurodegenerative diseases.

Presenilin 1 mutation in an african american family presenting with atypical Alzheimer dementia.

BACKGROUND: Alzheimer disease (AD) is characterized by memory and visuospatial deficits with relative sparing of personality. Mutations in 3 genes (presenilin 1 and 2 and amyloid precursor protein) are associated with presenile AD. Presenilin 1 gene mutations have not been described in African Americans. METHODS: We studied an African American family with autosomal dominant rapidly progressive dementia and psychosis occurring early in the fifth decade of life. We performed neurologic evaluations, psychometrics, and neuroimaging. We sequenced the amyloid precursor protein gene, presenilin 1 and 2, and tau in affected and unaffected family members. One patient underwent a brain biopsy and subsequent autopsy. RESULTS: Personality change, auditory and visual hallucinations, delusions, memory impairment, word-finding difficulties, and subsequent rigidity, dystonia, myoclonus, and mutism developed in 2 brothers. Neuropsychometric testing in one was consistent with frontotemporal dementia or atypical AD. Neuroimaging studies showed diffuse cortical involvement. A clinical diagnosis of familial non-Alzheimer dementia was made. However, results of temporal lobe biopsy in one revealed amyloid neuritic plaques, and autopsy results confirmed the diagnosis of AD. Gene sequencing revealed a presenilin 1 point mutation (M139V) cosegregating with the disease. A tau polymorphism in exon 7 (A178T) was found in an affected brother and unaffected relatives. CONCLUSIONS: We report the first documented presenilin mutation in African American patients presenting with early personality change, psychosis, and memory loss with preserved praxis. The M139V mutation can present differently between kindreds, with some features suggestive of a frontal lobe syndrome. The M139V mutation can lead to atypical AD, and genetic background may have a role in determining the phenotype of genetically defined AD.