Mustafa S. Siddiqui

AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial

BACKGROUND Gene transfer of glutamic acid decarboxylase (GAD) and other methods that modulate production of GABA in the subthalamic nucleus improve basal ganglia function in parkinsonism in animal models. We aimed to assess the effect of bilateral delivery of AAV2-GAD in the subthalamic nucleus compared with sham surgery in patients with advanced Parkinsons disease. METHODS Patients aged 30-75 years who had progressive levodopa-responsive Parkinsons disease and an overnight off-medication unified Parkinsons disease rating scale (UPDRS) motor score of 25 or more were enrolled into this double-blind, phase 2, randomised controlled trial, which took place at seven centres in the USA between Nov 17, 2008, and May 11, 2010. Infusion failure or catheter tip location beyond a predefined target zone led to exclusion of patients before unmasking for the efficacy analysis. The primary outcome measure was the 6-month change from baseline in double-blind assessment of off-medication UPDRS motor scores. This trial is registered with ClinicalTrials.gov, NCT00643890. FINDINGS Of 66 patients assessed for eligibility, 23 were randomly assigned to sham surgery and 22 to AAV2-GAD infusions; of those, 21 and 16, respectively, were analysed. At the 6-month endpoint, UPDRS score for the AAV2-GAD group decreased by 8·1 points (SD 1·7, 23·1%; p<0·0001) and by 4·7 points in the sham group (1·5, 12·7%; p=0·003). The AAV2-GAD group showed a significantly greater improvement from baseline in UPDRS scores compared with the sham group over the 6-month course of the study (RMANOVA, p=0·04). One serious adverse event occurred within 6 months of surgery; this case of bowel obstruction occurred in the AAV2-GAD group, was not attributed to treatment or the surgical procedure, and fully resolved. Other adverse events were mild or moderate, likely related to surgery and resolved; the most common were headache (seven patients in the AAV2-GAD group vs two in the sham group) and nausea (six vs two). INTERPRETATION The efficacy and safety of bilateral infusion of AAV2-GAD in the subthalamic nucleus supports its further development for Parkinsons disease and shows the promise for gene therapy for neurological disorders. FUNDING Neurologix.

Brain penetration effects of microelectrodes and DBS leads in STN or GPi

Objective: To determine how intraoperative microelectrode recordings (MER) and intraoperative lead placement acutely influence tremor, rigidity, and bradykinesia. Secondarily, to evaluate whether the longevity of the MER and lead placement effects were influenced by target location (subthalamic nucleus (STN) or globus pallidus interna (GPi)). Background: Currently most groups who perform deep brain stimulation (DBS) for Parkinson disease (PD) use MER, as well as macrostimulation (test stimulation), to refine DBS lead position. Following MER and/or test stimulation, however, there may be a resultant “collision/implantation” or “microlesion” effect, thought to result from disruption of cells and/or fibres within the penetrated region. These effects have not been carefully quantified. Methods: 47 consecutive patients with PD undergoing unilateral DBS for PD (STN or GPi DBS) were evaluated. Motor function was measured at six time points with a modified motor Unified Parkinson Disease Rating Scale (UPDRS): (1) preoperatively, (2) immediately after MER, (3) immediately after lead implantation/collision, (4) 4 months following surgery—off medications, on DBS (12 h medication washout), (5) 6 months postoperatively—off medication and off DBS (12 h washout) and (6) 6 months—on medication and off DBS (12 h washout). Results: Significant improvements in motor scores (p<0.05) (tremor, rigidity, bradykinesia) were observed as a result of MER and lead placement. The improvements were similar in magnitude to what was observed at 4 and 6 months post-DBS following programming and medication optimisation. When washed out (medications and DBS) for 12 h, UPDRS motor scores were still improved compared with preoperative testing. There was a larger improvement in STN compared with GPi following MER (p<0.05) and a trend for significance following lead placement (p<0.08) but long term outcome was similar. Conclusion: This study demonstrated significant acute intraoperative penetration effects resulting from MER and lead placement/collision in PD. Clinicians rating patients in the operating suite should be aware of these effects, and should consider pre- and post-lead placement rating scales prior to activating DBS. The collision/implantation effects were greater intraoperatively with STN compared with GPi, and with greater disease duration there was a larger effect.

Influence of type 2 diabetes on brain volumes and changes in brain volumes: Results from the Women's Health Initiative Magnetic Resonance Imaging Studies

OBJECTIVE To study how type 2 diabetes adversely affects brain volumes, changes in volume, and cognitive function. RESEARCH DESIGN AND METHODS Regional brain volumes and ischemic lesion volumes in 1,366 women, aged 72–89 years, were measured with structural brain magnetic resonance imaging (MRI). Repeat scans were collected an average of 4.7 years later in 698 women. Cross-sectional differences and changes with time between women with and without diabetes were compared. Relationships that cognitive function test scores had with these measures and diabetes were examined. RESULTS The 145 women with diabetes (10.6%) at the first MRI had smaller total brain volumes (0.6% less; P = 0.05) and smaller gray matter volumes (1.5% less; P = 0.01) but not white matter volumes, both overall and within major lobes. They also had larger ischemic lesion volumes (21.8% greater; P = 0.02), both overall and in gray matter (27.5% greater; P = 0.06), in white matter (18.8% greater; P = 0.02), and across major lobes. Overall, women with diabetes had slightly (nonsignificant) greater loss of total brain volumes (3.02 cc; P = 0.11) and significant increases in total ischemic lesion volumes (9.7% more; P = 0.05) with time relative to those without diabetes. Diabetes was associated with lower scores in global cognitive function and its subdomains. These relative deficits were only partially accounted for by brain volumes and risk factors for cognitive deficits. CONCLUSIONS Diabetes is associated with smaller brain volumes in gray but not white matter and increasing ischemic lesion volumes throughout the brain. These markers are associated with but do not fully account for diabetes-related deficits in cognitive function.

A Case of Mania following Deep Brain Stimulation for Obsessive Compulsive Disorder

Deep brain stimulation (DBS) of the basal ganglia is an effective treatment for select movement disorders, including Parkinson’s disease, essential tremor and dystonia. Based on these successes, DBS has been explored as an experimental treatment for medication-resistant neuropsychiatric disease. During a multiyear experience employing DBS to treat patients for obsessive compulsive disorder (OCD) we encountered several unanticipated stimulation-induced psychiatric side effects. We present a case of a young woman treated for OCD with DBS of the anterior limb of the internal capsule and nucleus accumbens region, who subsequently manifested a manic episode. We aim to discuss the case details, treatment and potential neuroanatomical underpinnings of this response.

Smile and Laughter Induction and Intraoperative Predictors of Response to Deep Brain Stimulation for Obsessive Compulsive Disorder

We recently treated six patients for OCD utilizing deep brain stimulation (DBS) of the anterior limb of the internal capsule and the nucleus accumbens region (ALIC-NA). We individually tested leads via a scripted intraoperative protocol designed to determine DBS-induced side effects and mood changes. We previously published qualitative data regarding our observations of induced emotional behaviors in our first five subjects. We have now studied these same behaviors in the full cohort of six patients over 2 years of follow-up and have examined the relationship of these behaviors to intraoperative mood changes and postoperative clinical outcomes. Five patients experienced at least one smile response during testing. At higher voltages of stimulation, some of these smiles progressed to natural laughter. Smiles and laughter were associated with mood elevation. At stimulation locations at which smiles were observed, voltage and mood were significantly correlated (p=0.0004 for right brain and p<0.0001 for left brain). In contrast, at contacts where smiles were not observed, mood was negatively correlated with voltage (p=0.0591 for right brain and p=0.0086 for left). Smile and laughter-inducing sites were located relatively medial, posterior, and deep in the ALIC-NA. The presence of stimulation induced laughter predicted improvement in OCD symptoms at 2 years. The higher the percentage of laugh conditions experienced in an individual patient, the greater the reduction in YBOCS (24 months, p=0.034). Other correlations between clinical outcomes and percent of smile/laugh conditions were not significant. These stimulation-induced behaviors were less frequently observed with 1 and 2-month postoperative test stimulation and were not observed at subsequent test stimulation sessions. Intraoperative stimulation-induced laughter may predict long-term OCD response to DBS. Identifying other potential response predictors for OCD will become increasingly important as more patients are implanted with DBS devices. A larger study is needed to better delineate the relationship between induced intraoperative and postoperative emotional behavior and clinical outcome in patients treated with DBS therapy.

Brain penetration effects of microelectrodes and deep brain stimulation leads in ventral intermediate nucleus stimulation for essential tremor

OBJECT Microelectrode recording (MER) and macrostimulation (test stimulation) are used to refine the optimal deep brain stimulation (DBS) lead placement within the operative setting. It is well known that there can be a microlesion effect with microelectrode trajectories and DBS insertion. The aim of this study was to determine the impact of intraoperative MER and lead placement on tremor severity in a cohort of patients with essential tremor. METHODS Consecutive patients with essential tremor undergoing unilateral DBS (ventral intermediate nucleus stimulation) for medication-refractory tremor were evaluated. Tremor severity was measured at 5 time points utilizing a modified Tremor Rating Scale: 1) immediately before MER; 2) immediately after MER; 3) immediately after lead implantation; 4) 6 months after DBS implantation in the off-DBS condition; and 5) 6 months after implantation in the on-DBS condition. To investigate the impact of the MER and DBS lead placement, Wilcoxon signed-rank tests were applied to test changes in tremor severity scores over the surgical course. In addition, a generalized linear mixed model including factors that potentially influenced the impact of the microlesion was also used for analysis. RESULTS Nineteen patients were evaluated. Improvement was noted in the total modified Tremor Rating Scale, postural, and action tremor scores (p < 0.05) as a result of MER and DBS lead placement. The improvements observed following lead placement were similar in magnitude to what was observed in the chronically programmed clinic setting parameters at 6 months after lead implantation. Improvement in tremor severity was maintained over time even in the off-DBS condition at 6 months, which was supportive of a prolonged microlesion effect. The number of macrostimulation passes, the number of MER passes, and disease duration were not related to the change in tremor severity score over time. CONCLUSIONS Immediate improvement in postural and intention tremors may result from MER and DBS lead placement in patients undergoing DBS for essential tremor. This improvement could be a predictor of successful DBS lead placement at 6 months. Clinicians rating patients in the operating room should be aware of these effects and should consider using rating scales before and after lead placement to take these effects into account when evaluating outcome in and out of the operating room.

Inappropriate crying and laughing in Parkinson disease and movement disorders

Objective. To examine in a pilot study inappropriate crying and laughing (also termed pseudobulbar affect (PBA)) and underlying mood disturbances in a large clinic based population of Parkinsons disease and movement disorder patients. Background. PBA is characterized by uncontrollable laughter without mirth, or alternatively crying without the feeling of sadness. It is a common condition affecting more than one million people with neurological diseases. While PBA has been studied in many neurological diseases, little is known about its prevalence in movement disorders, or its relationship to more chronic mood disturbances. We carried out this pilot study to examine this relationship. Methods. Seven hundred and nineteen out of 860 consecutive patients who visited our Movement Disorders Center met inclusion criteria (i.e. ≥18 years of age, formal diagnosis by a movement disorder specialist, completion of PBA questionnaire, and absence of brain surgery including deep brain stimulation). All subjects were interviewed for symptoms of PBA during their visit. In addition, 661 of these patients completed both the Visual Analog Mood Scale (VAMS) and Beck Depression Inventory I (BDI-I). Results. Thirty-seven of the 719 reported PBA symptoms; 75.7% (28/37) had pathological ‘crying’, 13.5% (5/37) had pathological ‘laughing’ and 10.8% (4/37) had both. The prevalence of PBA in individual diagnostic categories was: 4.7% (18/387) of idiopathic Parkinsons disease (PD), 2.7% (2/74) of primary dystonia, 3.1% (2/65) of essential tremor (ET), 7.8% (8/108) of patients with other forms of Parkinsonism, 21.7% (5/23) of psychogenic movement disorders, 0% (0/18) of patients with combined PD and ET, and 4.5% (2/44) of other movement disorders. Patients with PBA had a higher total BDI score (P =0.0278) and VAMS ‘tiredness’ score (P=0.0109). In patients on antidepressant therapy the prevalence of PBA was 7.1% compared to 2.7% in the group not on therapy (P=0.0094). Conclusion. PBA was present in most movement disorders, but especially prevalent in parkinsonism. PBA patients in this cohort had more chronic depressive symptoms and tiredness.

Association between subthalamic nucleus deep brain stimulation and weight gain: Results of a case–control study

OBJECTIVE To evaluate whether weight change in patients with Parkinsons disease (PD) is different in those undergoing deep brain stimulation (DBS) of the subthalamic nucleus (STN) compared to those not undergoing DBS. PATIENTS AND METHODS A retrospective case-control study was performed in PD patients who had undergone STN DBS (cases) compared to matched PD patients without DBS (controls). Demographic and clinical data including Unified Parkinsons Disease Rating Scale (UPDRS) motor scores were collected. Repeated measures mixed model regression was used to identify variables associated with weight gain. RESULTS Thirty-five cases and 34 controls were identified. Baseline age, gender, diagnosis and weight were similar. Duration of diagnosis was longer in cases (6.3 vs 4.9 years, p=0.0015). At 21.3 months, cases gained 2.9 kg (+4.65%) while controls lost 1.8 kg (-3.05%, p<0.02). Postoperative UPDRS motor scores improved by 49% indicating surgical efficacy. Only younger age (p=0.0002) and DBS (p=0.008) were significantly associated with weight gain. CONCLUSION In this case-control study, PD patients undergoing STN DBS experienced post-operative weight gain that was significantly different from the weight loss observed in non-DBS PD controls. Patients, especially overweight individuals, should be informed that STN DBS can result in weight gain.

Deep brain stimulation in movement disorders.

After more than 2 decades since it was introduced, deep brain stimulation (DBS) has gained widespread popularity as a surgical treatment for medically refractory symptoms of Parkinson disease, essential tremor, and dystonia. In this chapter, authors review the benefits, risks, indications, limitations, and targets for DBS in patients with Parkinson disease, essential tremor, and dystonia. A brief outline of the DBS procedure and programming is also given.

Long-term follow-up of a randomized AAV2-GAD gene therapy trial for Parkinson’s disease

BACKGROUND. We report the 12-month clinical and imaging data on the effects of bilateral delivery of the glutamic acid decarboxylase gene into the subthalamic nuclei (STN) of advanced Parkinsons disease (PD) patients. METHODS. 45 PD patients were enrolled in a 6-month double-blind randomized trial of bilateral AAV2-GAD delivery into the STN compared with sham surgery and were followed for 12 months in open-label fashion. Subjects were assessed with clinical outcome measures and 18F-fluorodeoxyglucose (FDG) PET imaging. RESULTS. Improvements under the blind in Unified Parkinsons Disease Rating Scale (UPDRS) motor scores in the AAV2-GAD group compared with the sham group continued at 12 months [time effect: F(4,138) = 11.55, P < 0.001; group effect: F(1,35) = 5.45, P < 0.03; repeated-measures ANOVA (RMANOVA)]. Daily duration of levodopa-induced dyskinesias significantly declined at 12 months in the AAV2-GAD group (P = 0.03; post-hoc Bonferroni test), while the sham group was unchanged. Analysis of all FDG PET images over 12 months revealed significant metabolic declines (P < 0.001; statistical parametric mapping RMANOVA) in the thalamus, striatum, and prefrontal, anterior cingulate, and orbitofrontal cortices in the AAV2-GAD group compared with the sham group. Across all time points, changes in regional metabolism differed for the two groups in all areas, with significant declines only in the AAV2-GAD group (P < 0.005; post-hoc Bonferroni tests). Furthermore, baseline metabolism in the prefrontal cortex (PFC) correlated with changes in motor UPDRS scores; the higher the baseline PFC metabolism, the better the clinical outcome. CONCLUSION. These findings show that clinical benefits after gene therapy with STN AAV2-GAD in PD patients persist at 12 months. TRIAL REGISTRATION. ClinicalTrials.gov NCT00643890. FUNDING. Neurologix Inc.