Pramipexole in patients with early Parkinson’s disease (PROUD): a randomised delayed-start trial.


In models of dopaminergic neuronal loss, the dopamine agonist pramipexole has exhibited neuroprotective properties. The Pramipexole On Underlying Disease (PROUD) study was designed to identify whether early versus delayed pramipexole initiation has clinical and neuroimaging benefits in patients with Parkinson’s disease (PD).


Between May 24, 2006, and April 22, 2009, at 98 centres, we recruited patients with PD diagnosed within 2 years and aged 30—79 years. We randomly assigned eligible patients (ratio 1:1), by a centralised, computerised randomisation schedule, to receive double-blind either placebo or pramipexole (1·5 mg a day) and followed them up for 15 months. At 9 months, or as early as 6 months if considered necessary, placebo recipients were assigned to pramipexole. In a neuroimaging substudy, striatal dopamine-transporter binding was assessed by SPECT. All patients, investigators, and independent raters were masked to study treatment. The primary endpoint was the 15-month change from baseline in total score on the unified Parkinson’s disease rating scale (UPDRS). This trial is registered with, number NCT00321854.


Of 535 patients, 261 were randomly assigned to receive pramipexole and 274 to receive placebo. At 15 months (n=411), adjusted mean change in UPDRS total score showed no significant difference between early and delayed pramipexole (−0·4 points, 95% CI −2·2 to 1·4, p=0·65). 62 patients in the early pramipexole group and 61 patients in the delayed pramipexole group were included in the neuroimaging substudy, for which the adjusted mean 15-month change in striatal 123I-FP-CIT binding was −15·1% (SE 2·1) for early and −14·6% (2·0) for delayed pramipexole (difference −0·5 percentage points, 95% CI −5·4 to 4·4, p=0·84). Overall, 180 (81%) of patients given early pramipexole and 179 (84%) patients given delayed pramipexole reported adverse events (most frequently nausea), and 22 (10%) patients in the early pramipexole group and 17 (8%) in the delayed pramipexole group had serious events, two of which (hallucinations and orthostatic hypotension) were deemed related to study drug.


By clinical and neuroimaging measures, pramipexole showed little evidence differentiating 15-month usage from usage delayed for 6—9 months. The results do not support the hypothesis that pramipexole has disease-modifying effects.

Source: Lancet


Restless legs syndrome: pathophysiology and modern management.

Restless legs syndrome (RLS) is a common sensory motor neurological disorder that is characterised by an irresistible urge to move the legs that significantly affects the quality of life of the patient. Prevalence in the general population is 5-25% and it is twice as prevalent in women as in men. RLS is the most common movement disorder in pregnancy with a fourfold increased risk of developing this disorder later in life. The pathophysiology of RLS is centred on dopaminergic dysfunction, reduced central nervous system iron, genetic linkages, or alteration in neurotransmitters such as hypocretins, endorphins levels and immune dysfunction and inflammatory mechanisms. With the emergence of new evidence, there are changes to the previous treatment recommendations for RLS. There is sufficient evidence to conclude that dopamine agonists such as rotigotine transdermal patch, pramipexole, ropinirole, gabapentin enacarbil, pregabalin and gabapentin are effective in the short-term treatment of RLS and rotigotine, followed by gabapentin enacarbil, ropinirole, pramipexole and gabapentin for long-term treatment. Based on expert consensus, the recommendation for daily RLS is dopamine agonists or gabapentin or low-potency opioids. Levodopa is less preferred for treating daily RLS due to its high risk of augmentation. For intermittent RLS, it is levodopa or dopamine agonists or low-potency opioids or benzodiazepines. For refractory RLS, the choice is to change to gabapentin or a different dopamine agonist, addition of a second agent like gabapentin or benzodiazepine to the existing drug or changing to a high-potency opioid or tramadol. Medications with safety record in pregnancy include opioids and antiepileptics such as carbamazepine and gabapentin. There are concerns that patients with RLS are at risk for metabolic deregulation, autonomic dysfunction and cardiovascular morbidity. However, a recent study concluded that RLS is not associated with increased risk of cardiovascular complications.

Source: Source: PMJ. BMJ


William P. Van Wagenen (1897–1961): pupil, mentor, and neurosurgical pioneer.


William Perrine (“Van”) Van Wagenen (1897–1961) was the first Chief of Neurosurgery at the University of Rochester Medical Center (URMC), serving from 1928 to 1954, and was a leading figure in 20th-century neurosurgery. He was a devoted pupil of Dr. Harvey Cushing and helped to found the Harvey Cushing Society (now the AANS) in honor of his mentor and was elected as its first President in 1932. He served as the 27th President of the Society of Neurological Surgeons in 1952. Upon his death in 1961 he bequeathed an endowment for the Van Wagenen Fellowship, which has advanced the education of many leaders in American neurosurgery. His legacy of operative skill, his commitment to resident education and research in neurological disease, his inspiration for the foundation of the Cushing Brain Tumor registry, and his contributions to organized neurosurgery form the foundation of the legacy of neurosurgery at URMC.

Source: JNS


Resting state magnetoencephalography functional connectivity in traumatic brain injury.



Traumatic brain injury (TBI) is one of the leading causes of morbidity worldwide. One mechanism by which blunt head trauma may disrupt normal cognition and behavior is through alteration of functional connectivity between brain regions. In this pilot study, the authors applied a rapid automated resting state magnetoencephalography (MEG) imaging technique suitable for routine clinical use to test the hypothesis that there is decreased functional connectivity in patients with TBI compared with matched controls, even in cases of mild TBI. Furthermore, they posit that these abnormal reductions in MEG functional connectivity can be detected even in TBI patients without specific evidence of traumatic lesions on 3-T MR images. Finally, they hypothesize that the reductions of functional connectivity can improve over time across serial MEG scans during recovery from TBI.


Magnetoencephalography maps of functional connectivity in the alpha (8- to 12-Hz) band from 21 patients who sustained a TBI were compared with those from 18 age- and sex-matched controls. Regions of altered functional connectivity in each patient were detected in automated fashion through atlas-based registration to the control database. The extent of reduced functional connectivity in the patient group was tested for correlations with clinical characteristics of the injury as well as with findings on 3-T MRI. Finally, the authors compared initial connectivity maps with 2-year follow-up functional connectivity in a subgroup of 5 patients with TBI.


Fourteen male and 7 female patients (17–53 years old, median 29 years) were enrolled. By Glasgow Coma Scale (GCS) criteria, 11 patients had mild, 1 had moderate, and 3 had severe TBI, and 6 had no GCS score recorded. On 3-T MRI, 16 patients had abnormal findings attributable to the trauma and 5 had findings in the normal range. As a group, the patients with TBI had significantly lower functional connectivity than controls (p < 0.01). Three of the 5 patients with normal findings on 3-T MRI showed regions of abnormally reduced MEG functional connectivity. No significant correlations were seen between extent of functional disconnection and injury severity or posttraumatic symptoms (p > 0.05). In the subgroup undergoing 2-year follow-up, the second MEG scan demonstrated a significantly lower percentage of voxels with decreased connectivity (p < 0.05) than the initial MEG scan.


A rapid automated resting-state MEG imaging technique demonstrates abnormally decreased functional connectivity that may persist for years after TBI, including cases classified as “mild” by GCS criteria. Disrupted MEG connectivity can be detected even in some patients with normal findings on 3-T MRI. Analysis of follow-up MEG scans in a subgroup of patients shows that, over time, the abnormally reduced connectivity can improve, suggesting neuroplasticity during the recovery from TBI. Resting state MEG deserves further investigation as a prognostic and predictive biomarker for TBI.

Source: JNS


However, the post-SRS median survival time difference, 0.9 months, between the two groups is not clinically meaningful. Furthermore, patients with 5 or more METs have noninferior results compared to patients with 1–4 tumors, in terms of neurological death, local recurrence, repeat SRS, maintenance of good neurological state, and SRS-related complications. A randomized controlled trial should be conducted to test this hypothesis.


Source: JNS


Predictive value of S-100β protein for prognosis in patients with moderate and severe traumatic brain injury: systematic review and meta-analysis.


Objectives To determine the ability and accuracy of the S-100β protein in predicting prognosis after a moderate or severe traumatic brain injury.

Design Systematic review and meta-analysis of randomised controlled trials and observational studies.

Data sources Medline, Embase, Cochrane Central Register of Controlled Trials, BIOSIS (from their inception to April 2012), conference abstracts, bibliographies of eligible articles, and relevant narrative reviews.

Study selection Two reviewers independently reviewed citations and selected eligible studies, defined as cohort studies or randomised control trials including patients with moderate or severe traumatic brain injury and evaluating the prognostic value of S-100β protein. Outcomes evaluated were mortality, score on the Glasgow outcome scale, or brain death.

Data extraction Two independent reviewers extracted data using a standardised form and evaluated the methodological quality of included studies. Pooled results were presented with geometric means ratios and analysed with random effect models. Prespecified sensitivity analyses were performed to explain heterogeneity.

Results The search strategy yielded 9228 citations. Two randomised controlled trials and 39 cohort studies were considered eligible (1862 patients). Most studies (n=23) considered Glasgow outcome score ≤3 as an unfavourable outcome. All studies reported at least one measurement of S-100β within 24 hours after traumatic brain injury. There was a significant positive association between S-100β protein concentrations and mortality (12 studies: geometric mean ratio 2.55, 95% confidence interval 2.02 to 3.21, I2=56%) and score ≤3 (18 studies: 2.62, 2.01 to 3.42, I2=79%). Sensitivity analysis based on sampling time, sampling type, blinding of outcome assessors, and timing of outcome assessment yielded similar results. Thresholds for serum S-100β protein values with 100% specificity ranged from 1.38 to 10.50 µg/L for mortality (six studies) and from 2.16 to 14.00 µg/L for unfavourable neurological prognosis as defined by the Glasgow outcome score.

Conclusions After moderate or severe traumatic brain injury, serum S-100β protein concentrations are significantly associated with unfavourable prognosis in the short, mid, or long term. Optimal thresholds for discrimination remain unclear. Measuring the S-100β protein could be useful in evaluating the severity of traumatic brain injury and in the determination of long term prognosis in patients with moderate and severe injury.


What is already known on this topic

  • Many indicators have been independently associated with prognosis after traumatic brain injury, but they are of limited clinical use when considered separately and current prognostic models do not have sufficient discriminative capacity to inform clinical decision making
  • S-100β protein concentrations have been shown to increase in blood and cerebrospinal fluid after a wide range of diseases or conditions leading to brain damage
  • S-100β protein serum concentrations correlate significantly with unfavourable prognosis in patients with moderate or severe traumatic brain injury, as defined by mortality, Glasgow outcome score ≤3, or brain stem death, with or without concomitant traumatic injuries
  • The association between serum concentrations of S-100β protein and prognosis was observed at discharge from intensive care and at one, three, and six months.
  • Serum threshold values ranging from 1.38 µg/L to 10.50 µg/L and from 2.16 µg/L to 14.00 µg/L were associated with 100% specificity for mortality and a Glasgow outcome score ≤3, respectively.

What this study adds


Cognitive function and other risk factors for mild traumatic brain injury in young men: nationwide cohort study.


Objective To investigate cognitive function and other risk factors for mild traumatic brain injury in young men.

Design Nationwide prospective cohort study.

Setting Sweden.

Participants 305 885 men conscripted for military service from 1989 to 1994.

Main outcome measure mild traumatic brain injuries in relation to cognitive function and other potential risk factors assessed at conscription and follow-up.


Results Men with one mild traumatic brain injury within two years before (n=1988) or after cognitive testing (n=2214) had about 5.5% lower overall cognitive function scores than did men with no mild traumatic brain injury during follow up (P<0.001 for both). Moreover, men with at least two mild traumatic brain injuries after cognitive testing (n=795) had 15% lower overall cognitive function scores compared with those with no such injury (P<0.001). Independent strong risk factors (P<1×10−10) for at least one mild traumatic brain injury after cognitive testing (n=12 494 events) included low overall cognitive function, a previous mild traumatic brain injury, hospital admission for intoxications, and low education and socioeconomic status. In a sub-cohort of twin pairs in which one twin had a mild traumatic brain injury before cognitive testing (n=63), both twins had lower logical performance and technical performance compared with men in the total cohort with no mild traumatic brain injury (P<0.05 for all).


Conclusion Low cognitive function, intoxications, and factors related to low socioeconomic status were strong independent risk factors for mild traumatic brain injuries in men. The low cognitive function in twin pairs discordant for mild traumatic brain injury suggests a genetic component to the low cognitive function associated with such injuries. The study included only men, so inferences to women should be made with caution.



Botulinum Toxin and Anticholinergic Therapy Yield Similar Outcomes in Urinary Incontinence.

Oral anticholinergic therapy and injectable onabotulinumtoxinA are similarly efficacious in treating urgency urinary incontinence, according to a New England Journal of Medicine study.

Some 250 women without neurological disease who had moderate-to-severe urgency incontinence were randomized either to a single injection of onabotulinumtoxinA into the detrusor muscle plus a daily oral placebo for 6 months, or to a single injection of saline plus dose-escalation with a daily oral anticholinergic for 6 months.

The primary outcome — the mean number of urgency incontinence episodes — was similarly reduced in the two groups (roughly 3 fewer episodes/day). OnabotulinumtoxinA recipients were twice as likely as anticholinergic recipients to report complete resolution of urgency incontinence (27% vs. 13%). Dry mouth was significantly more common with anticholinergic therapy, whereas urinary tract infections and incomplete bladder emptying requiring catheterization were significantly more common with onabotulinumtoxinA.

The researchers conclude that “the choice between these therapies should take into account the differing regimens and routes of administration and the side-effect profiles.”

Source: NEJM

Effect of slosh mitigation on histologic markers of traumatic brain injury.

Helmets successfully prevent most cranial fractures and skull traumas, but traumatic brain injury (TBI) and concussions continue to occur with frightening frequency despite the widespread use of helmets on the athletic field and battlefield. Protection against such injury is needed. The object of this study was to determine if slosh mitigation reduces neural degeneration, gliosis, and neuroinflammation.


Two groups of 10 adult male Sprague-Dawley rats were subjected to impact-acceleration TBI. One group of animals was fitted with a collar inducing internal jugular vein (IJV) compression prior to injury, whereas the second group received no such collar prior to injury. All rats were killed 7 days postinjury, and the brains were fixed and embedded in paraffin. Tissue sections were processed and stained for markers of neural degeneration (Fluoro-Jade B), gliosis (glial fibrillary acidic protein), and neuroinflammation (ionized calcium binding adapter molecule 1).


Compared with the controls, animals that had undergone IJV compression had a 48.7%–59.1% reduction in degenerative neurons, a 36.8%–45.7% decrease in reactive astrocytes, and a 44.1%–65.3% reduction in microglial activation.


The authors concluded that IJV compression, a form of slosh mitigation, markedly reduces markers of neurological injury in a common model of TBI. Based on findings in this and other studies, slosh mitigation may have potential for preventing TBI in the clinical population.

Source: Journal of neurosurgery.




Zonisamide: A Good Option for Newly Diagnosed Epilepsy?

A large practical monotherapy trial for the treatment of new-onset epilepsy in adults shows once-daily zonisamide to be generally as effective and safe as controlled-release, twice-daily carbamazepine.

Few new antiepileptic drugs (AEDs) are studied for efficacy as monotherapy, and most such studies involve medically intractable epilepsy. Therefore, despite numerous new-generation AEDs, little guidance is available for choice in newly diagnosed epilepsy patients. Now, researchers have designed a manufacturer-funded, randomized, double-blind, international trial to test the noninferiority of zonisamide (ZNS) to carbamazepine (CBZ) in adults with newly diagnosed epilepsy. The 583 patients enrolled had only generalized tonic–clonic seizures and no evidence of idiopathic generalized epilepsy, new-onset epilepsy (with at least two seizures in the previous year and at least one seizure in the preceding 3 months), and no prior treatment with an AED for >2 weeks. The study was powered such that it met strict noninferiority criteria. The primary endpoint was the proportion of patients achieving 6-month seizure freedom. Secondary endpoints were the proportion achieving 12-month seizure freedom and times to 6- and 12-month seizure freedom. Safety and tolerability were examined by measuring the incidence of treatment-related adverse events, withdrawal, and laboratory abnormalities.

Of the 456 patients who completed the protocol, 79% and 68% taking ZNS achieved 6-month and 12-month seizure freedom, compared with 84% and 75% taking CBZ — fulfilling the strict noninferiority criteria. Intention-to-treat results supported the results of the per-protocol analysis. The times to both 6- and 12-month endpoints were the same in both arms. Few patients in either group withdrew because of treatment-related adverse events — primarily rash, dizziness, fatigue, and memory impairment. Two cases of severe rash occurred in the CBZ arm. One case of mild purpura occurred in the ZNS arm. None of the other eight reported severe adverse events had a clear association with treatment. No clinically significant laboratory abnormalities occurred in either arm.

Comment: This remarkable clinical trial addresses an important clinical question: Whether a newer-generation AED may be used as first-line monotherapy in newly diagnosed epilepsy. Moreover, the trial was designed to reflect typical clinical practice, given the population involved and the use of flexible dosing regimens for a meaningful treatment duration. Both treatment arms were well balanced, including frequency of seizures pretreatment, a strong predictor of prognosis. Because ZNS has few drug interactions and is formulated for once-daily dosing, the finding that ZNS is generally as effective as CBZ may actually change clinical practice.

Source: Journal Watch Neurology