Maureen Gartner

Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial.

IMPORTANCEnConvergent biological, epidemiological, and clinical data identified urate elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD).nnnOBJECTIVEnTo determine the safety, tolerability, and urate-elevating capability of the urate precursor inosine in early PD and to assess its suitability and potential design features for a disease-modification trial.nnnDESIGN, SETTING, AND PARTICIPANTSnThe Safety of Urate Elevation in PD (SURE-PD) study, a randomized, double-blind, placebo-controlled, dose-ranging trial of inosine, enrolled participants from 2009 to 2011 and followed them for up to 25 months at outpatient visits to 17 credentialed clinical study sites of the Parkinson Study Group across the United States. Seventy-five consenting adults (mean age, 62 years; 55% women) with early PD not yet requiring symptomatic treatment and a serum urate concentration less than 6 mg/dL (the approximate population median) were enrolled.nnnINTERVENTIONSnParticipants were randomized to 1 of 3 treatment arms: placebo or inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation using 500-mg capsules taken orally up to 2 capsules 3 times per day. They were followed for up to 24 months (median, 18 months) while receiving the study drug plus 1 washout month.nnnMAIN OUTCOMES AND MEASURESnThe prespecified primary outcomes were absence of unacceptable serious adverse events (safety), continued treatment without adverse event requiring dose reduction (tolerability), and elevation of urate assessed serially in serum and once (at 3 months) in cerebrospinal fluid. RESULTS Serious adverse events (17), including infrequent cardiovascular events, occurred at the same or lower rates in the inosine groups relative to placebo. No participant developed gout and 3 receiving inosine developed symptomatic urolithiasis. Treatment was tolerated by 95% of participants at 6 months, and no participant withdrew because of an adverse event. Serum urate rose by 2.3 and 3.0 mg/dL in the 2 inosine groups (P <u2009.001 for each) vs placebo, and cerebrospinal fluid urate level was greater in both inosine groups (P =u2009.006 and <.001, respectively). Secondary analyses demonstrated nonfutility of inosine treatment for slowing disability.nnnCONCLUSIONS AND RELEVANCEnInosine was generally safe, tolerable, and effective in raising serum and cerebrospinal fluid urate levels in early PD. The findings support advancing to more definitive development of inosine as a potential disease-modifying therapy for PD.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier: NCT00833690.

At-home training with closed-loop augmented-reality cueing device for improving gait in patients with Parkinson disease

Shuffling and freezing while walking can impair function in patients with Parkinson disease (PD). Open-loop devices that provide fixed-velocity visual or auditory cues can improve gait but may be unreliable or exacerbate freezing of gait in some patients. We examined the efficacy of a closed-loop, accelerometer-driven, wearable, visual-auditory cueing device in 13 patients with PD with off-state gait impairment at baseline and after 2 weeks of twice daily (30 minute duration) at-home use. We measured gait velocity, stride length, and cadence using a validated electronic gait-analysis system. Subjects underwent standard motor assessment and completed a self-administered Freezing of Gait Questionnaire (FOGQ) (range 0-24; lower is better). After training, device use enhanced walking velocity (61.6 ± 20.1 cm/s to 72.6 ± 26.5 cm/s, p = 0.006) and stride length (74.3 ± 16.4 cm to 84.0 ± 18.5 cm, p = 0.004). Upon device removal, walking velocity (64.5 ± 21.4 cm/s to 75.4 ± 21.5 cm/s, p < 0.001) and stride length (79.0 ± 20.3 cm to 88.8 ± 17.7 cm, p = 0.003) exhibited a greater magnitude of change, suggesting immediate residual benefits. Also upon device removal, nearly 70 percent of subjects improved by at least 20 percent in either walking velocity, stride length, or both. An overall improvement in gait was measured by the FOGQ (14.2 ±1.9 to 12.4 ± 2.5, p = 0.02). Although issues related to compliance and response variability render a definitive interpretation of study outcome difficult, devices using closed-loop sensory feedback appear to be effective and desirable nonpharmacologic interventions to improve walking in selected individuals with PD.

Methylphenidate for gait impairment in Parkinson disease: A randomized clinical trial

Background: There is a paucity of therapies for gait impairment in Parkinson disease (PD). Open-label studies have suggested improved gait after treatment with methylphenidate (MPD). Objective: To evaluate the efficacy of MPD for the treatment of gait impairment in PD. Methods: Twenty-seven subjects with PD and moderate gait impairment were screened for this 6-month placebo-controlled, double-blind study. Subjects were randomly assigned to MPD (maximum, up to 80 mg/day) or placebo for 12 weeks and crossed over after a 3-week washout. The primary outcome measure was change in a gait composite score (stride length + velocity) between groups at 4 and 12 weeks. Secondary outcome measures included changes in motor function, as measured by the Unified Parkinsons Disease Rating Scale (UPDRS), Freezing of Gait Questionnaire (FOGQ), number of gait-diary freezing episodes, and measures of depression, sleepiness, and quality of life. Three-factor repeated-measures analysis of variance was used to measure changes between groups. Results: Twenty-three eligible subjects with PD were randomized and 17 completed the trial. There was no change in the gait composite score or treatment or time effect for any of the variables. Treatment effect was not modified by state or study visit. Although there was a trend for reduced frequency of freezing and shuffling per diary, the FOGQ and UPDRS scores worsened in the MPD group compared to placebo. There was a marginal improvement in some measures of depression. Conclusions: MPD did not improve gait and tended to worsen measures of motor function, sleepiness, and quality of life. Classification of evidence: This study provides Class III evidence for the lack of benefit of MPD on PD-associated gait impairment. Clinical trial registration: NCT00526630.

Deep brain stimulation of the ventral intermediate nucleus of the thalamus in medically refractory orthostatic tremor: preliminary observations.

Orthostatic tremor (OT) is a disabling movement disorder associated with postural and gait impairment in the elderly. Medical therapy often yields insufficient benefit. We report the clinical and electrophysiological data on two patients with medication‐refractory OT treated with deep brain stimulation of the ventral intermediate thalamic nucleus (Vim DBS). Patient 1 underwent bilateral deep brain stimulation (DBS) and Patient 2 unilateral Vim DBS following 28 and 30 years of disease duration, respectively. Both patients showed increased latency to symptom onset after rising from a seated position, improved tolerance for prolonged standing, and slower crescendo of tremor severity when remaining upright. Postoperative evaluation demonstrated decreased amplitude of electromyographic activity with persistence of well‐defined oscillatory behavior showing strong coherence at 15 Hz between all muscles tested in the upper and lower limbs. Postural sway was unchanged. Clinical benefits have been sustained for over 18 months in Patient 1, and receded after 3 months in Patient 2. These findings support the consideration of bilateral Vim DBS implantation as a therapeutic option in patients with medically refractory OT. Further efficacy studies on chronic stimulation to disrupt the abnormal oscillatory activity in this disorder are warranted.

Genotype and smoking history affect risk of levodopa‐induced dyskinesias in Parkinson's disease

Parkinsons disease (PD) patients vary widely in their response to levodopa treatment, and this variation may be partially genetic in origin. We determined whether particular dopamine and opioid receptor polymorphisms were associated with risk of earlier onset of dyskinesia side effects during levodopa therapy. Smoking status was also examined. The 92 subjects were recruited from the movement disorders clinic of a neurology practice associated with a medical school. All were adult‐onset PD patients who had been taking levodopa at least 5 years and/or had developed levodopa‐induced dyskinesia. Carrying the G‐allele of the A118G single nucleotide coding region polymorphism of the mu opioid receptor, as well as a history of never smoking, were independently associated with increased risk of earlier onset of dyskinesia (P = 0.05 and 0.02, respectively). One genotype of the D2 dopamine receptor intronic dinucleotide repeat polymorphism (14 repeats/15 repeats, with frequency of 6%) was also associated with earlier dyskinesia (P = 0.003). History of smoking has previously been associated with reduced risk of developing PD. Our results suggest that smoking history may also influence the response to levodopa, with contribution comparable to those of individual genes including the mu opioid receptor and D2 dopamine receptor.

Seizure control and extent of mesial temporal resection

SummaryControversy exists about the extent of mesial temporal lobe resection that improves seizure control in patients with temporal lobe epilepsy.In this retrospective study, 70 patients with mesial temporal seizure activity (without evidence of tumor or vascular malformation) were surgically treated and followed for at least 2 years. The extent of mesial temporal resection was based on the findings of interictal and ictal discharges using depth electrodes, which were inserted preoperatively or intraoperatively by the orthogonal approach to the amygdaloid and hippocampal regions. Only the amygdala was resected along with the limited lateral neocortex if no epileptiform activity involved the hippocampus. The amount of hippocampal excision was determined by the extent of interictal seizure activity.The following groups became seizure free: all 8 patients with only amygdalar resection; 6 of 10 patients with amygdalar and ⩽ 1cm hippocampal resection; 23 of 38 with 1–2 cm hippocampal removal, and 11 of 14 with > 2cm hippocampal excision. In cases where there was no hippocampal resection, neuropsychological outcome compared favorably with controls.Our results suggest that although most patients with temporal lobe epilepsy require hippocampal resection of varying degrees, there is a subset in whom the amygdala may be the crucial element of a mesial temporal epileptogenic network. These patients can undergo a surgical resection sparing the hippocampus without compromising seizure outcome.

Effect of Dopaminergic Medication on Postural Sway in Advanced Parkinson’s Disease

Background: The effect of dopaminergic therapy on balance in Parkinson’s disease (PD) remains unclear, including previous studies that excluded the effect of dyskinesias or other involuntary movements on postural sway. Additionally, medication’s effects may differ between fallers and non-fallers. In this study, the authors quantify the effect of dopaminergic medication on postural balance (sway) in advanced PD, with and without dyskinesias, and consider the patient’s history of falls. Methods: In 24 patients with advanced idiopathic PD, postural balance was measured using a strain-gage force platform. Before and after taking dopaminergic medication, the patient’s postural sway was measured at 30-s intervals to determine sway length (SL) and sway area (SA). Data analysis included the presence of dyskinesias during “ON” medication condition and history of previous falls. Results: No significant changes occurred in SL or SA with dopaminergic treatment for fallers without dyskinesias or non-fallers with dyskinesias. However, after dopaminergic treatment, SL and SA were 37.8 and 45% lower, respectively, in non-fallers without dyskinesias (indicating better balance) and were 87.4 and 162.8% higher, respectively, in fallers with dyskinesias (indicating poorer balance). In the ON-medication condition, SL and SA were larger in patients with dyskinesias when compared with patients without dyskinesias; SL was larger in fallers than non-fallers in both groups with or without dyskinesias. Conclusion: Dopaminergic medication effects on postural sway could be a predictive factor for fall risk in PD patients with and without dyskinesias: specifically, decreased sway could indicate minimal fall risk whereas no change or increased postural sway could indicate a high risk.

Botulinum toxin type A for Levodopa‐induced cervical dyskinesias in Parkinson's disease: Unfavorable risk‐benefit ratio

Peak-dose levodopa (L-dopa)-induced dyskinesias (LIDs) are disabling side effects of long-term L-dopa therapy in Parkinson’s disease (PD), affecting 45–85% of patients within a few years of treatment initiation. LIDs are a therapeutic challenge for neurologists as limited treatment options exist. Functional chemodenervation with botulinum toxin type A (BTX-A, Botox, Allergan), first-line treatment for cervical dystonia, may be considered a treatment strategy against this motor complication when predominantly affecting the cervical region. Although the pathophysiology of LID is distinct from that of CD, abnormal muscle contractions of antagonistic sets of muscles suggest a phenomenological overlap. We sought to determine the extent to which cervical intramuscular BTX-A injections can reduce cervicalpredominant LID in PD. Twelve consecutive L-dopa-treated PD patients with frequent and bothersome cervical-predominant LID, regardless of previous or concurrent antidyskinetic treatment, were invited to participate in this six-month double-blind, crossover clinical trial. Patients were randomized to receive standardized EMG-guided injections of BTX-A or equal-volume normal saline (placebo) into the sternocleidomastoid (25 U bilaterally), splenius capitis (50 U bilaterally, divided), and trapezius (25 U bilaterally) muscles from a blinded injector. The total BTX-A dose of 200 U (10:1 dilution) was selected as the average optimal dose used in cervical dystonia. Subjects were assessed always in their best ‘‘on’’ state, when maximal benefits and peak-dose LID were expected to occur. The timing for the greatest severity of LID was chosen at enrollment with patient and caregiver input, and all studyrelated assessments were carried out at the same time. Assessments occurred at 0, 1, 3 (crossover visit), 4, and 6 months after enrollment, with blinded injections administered at the 0and 3-month visits. Primary outcome measure was change in the Goetz dyskinesia rating scale (GDRS, 0– 4, higher is worse), modified for the cervical region, 1 month after each injection (1and 4-month study visits). The GDRS was obtained off-line by three blinded raters from randomized videotape sequences. Secondary outcomes included changes in the patient-reported clinical global impression of change (CGIC) and in the duration, severity, and pain of LID using items 32–34 of the UPDRS-IV. Nonparametric analyses to compare BTX-A with baseline and placebo groups were carried out with the Friedman or Wilcoxon ranked test, as appropriate. A two-point difference in the CGIC was prespecified as clinically significant. Institutional Review Board-approved informed consent was administered to all participating subjects. The study was registered in ClinicalTrials.gov as NCT00477802. From 12 eligible PD patients, 8 patients (4 men; 70.3 6 5.6 years; disease duration, 11.1 6 2.7 years; ‘‘on’’ UPDRS-III, 20.2; L-dopa-equivalent dose, 1375 6 601 mg) were randomized. Only 4 patients completed the 6-month study before it was voluntarily stopped due to safety concerns, namely excessive neck weakness (Supporting Information Fig. 1, Consort flow diagram). BTX-A was associated with improved GDRS scores for the resting but not action-induced dyskinesias (1.8 6 0.7 vs. 2.1 6 0.8, P 1⁄4 0.018; Table 1). There was a trend for reduction in ‘‘on’’ time with LID in the BTX-A group compared with baseline (UPDRS-IV, item 32, 1.7 6 1.0 vs. 2.5 6 1.0, P 1⁄4 0.16). CGIC in the BTX-A group ranged from mild worsening to marked improvement. Dyskinesias self-rated as moderately and severely disabling (UPDRS-IV, item 33, n 1⁄4 4/6) became either mildly (n 1⁄4 3/4) or not disabling with BTX-A. This intervention also converted moderately and severely painful dyskinesias (UPDRS-IV, item 34, n 1⁄4 4/6) into mildly or not painful dyskinesias (n 1⁄4 3/4). On average, the BTX-A group showed a one-point difference above placebo in the CGIC (mild improvement vs. unchanged, respectively), falling below the prespecified cutoff for clinical significance. Transient neck weakness was the most frequently reported adverse reaction (2 patients experiencing head drop and moderate dysphagia for 2 weeks). Only 1 subject requested BTX-A injections for ongoing poststudy management of his LID, which, uniquely, were exclusively restricted to the cervical region. Although BTX-A reduced cervical dyskinesia severity and pain, these benefits were outweighed by (1) the development of excessive neck weakness, leading to a larger-than-anticipated dropout rate and forcing a premature termination of the trial; and (2) the lack of a favorable effect on the actioninduced component of LID, which may be the most disabling component. This dichotomy of improvement on resting but not action-induced dyskinesias is similar to the antidyskinetic response reported for clozapine. Overall, the adverse risk-benefit ratio uncovered by the study’s paradigm precludes recommending the use of BTX-A for treatment of cervical LID. We recognize that in considering any future role of BTXA for individual PD patients with focal LID, clinicians will have to balance the discouraging outcome of this truncated randomized clinical trial with the observation that a -----------------------------------------------------------Additional Supporting Information may be found in the online version of this article. Allergan, Inc. had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Computer‐Guided Deep Brain Stimulation Programming for Parkinson's Disease

Pilot study to evaluate computer‐guided deep brain stimulation (DBS) programming designed to optimize stimulation settings using objective motion sensor‐based motor assessments.

Surgical management of epilepsy associated with developmental anomalies of the brain

BACKGROUNDnDisorders as the central nervous system forms during the pre-, peri-, or postnatal periods may cause developmental anomalies of the brain. Such maldevelopment, ranging from slight to severe disturbances, appears to be the mechanism for causing childhood seizure disorders. However, the surgical treatment of these lesions responsible for intractable partial seizures remains undefined.nnnMETHODnTwenty-two patients (8 males, 14 females) with chronic seizure disorders associated with structural lesions of the brain related to developmental anomalies were surgically treated (1983 to 1990). Imaging studies, intraoperative findings, and histology showed 12 lesions in the temporal lobe, 1 in the frontal lobe, and 9 of multilobular involvement. All patients had preoperative prolonged electroencephalography with sphenoidal electrodes. Sixteen patients had intraoperative electrocorticography. All underwent craniotomy and total excision of the epileptogenic zone unless the speech or motor cortex was involved.nnnRESULTSnResults of postoperative seizure control during the follow-up period (mean 5.5 years) were excellent (seizure-free) in 12 patients (including four with complete and eight with incomplete excision of the structural lesion), good in seven, fair in two, and poor in one.nnnCONCLUSIONnSeizure control is possible for patients with total excision of the epileptogenic zone, even including those with incomplete excision of a structural lesion caused by developmental brain anomalies.