Gian Pal

Initial management of Parkinson’s disease

Parkinson’s disease is one of the most common neurodegenerative disorders seen in the United States and United Kingdom. The disease is characterised by two processes—cellular degeneration and the resulting biochemical deficiency of dopamine. Although these processes are inter-related, they are approached separately in the clinical setting. Currently, no proven neuroprotective or disease modifying treatment is available for Parkinson’s disease. Several agents can be used to treat the motor symptoms associated with dopamine deficiency, and it is important to choose wisely when starting treatment. Drugs can have mild, moderate, or high potency, and the patient’s goals, comorbidities, and the short and long term implications of choosing a specific agent should be taken into account when selecting the appropriate agent. Non-motor symptoms, such as depression, fatigue, and disorders of sleep and wakefulness, also need to be evaluated and treated. Research is under way to deliver dopaminergic therapy more effectively, but studies aimed at slowing or stopping disease progression have not shown promise.

Assessing Bradykinesia in Parkinsonian Disorders

Objective: Bradykinesia is one of the clinical hallmarks of Parkinson’s disease (PD) and atypical Parkinsonian syndromes. Clinical ratings scales and technology-based assessments have been developed to measure bradykinesia. We review the different tools that exist for measurement of bradykinesia and analyze their reliability and applicability to PD and atypical Parkinsonian syndromes. Methods: We summarize data on the factor structure of the two primary scales used to assess PD, the Unified Parkinson’s Disease Rating Scale (UPDRS) and Movement Disorder Society revision of the UPDRS, the MDS-UPDRS. We review how these scales have been used in atypical Parkinsonian syndromes, specifically Progressive Supranuclear Palsy (PSP). Finally, we report on the different technology-based tools being used to assess bradykinesia. Results: The UPDRS is a useful measure of PD function and disability with six clinically distinct factors, three of which pertain to bradykinesia. The MDS-UPDRS has shown high internal consistency and correlation with the original UPDRS. Factor analysis of the UPDRS in PSP reveals five clinically distinct factors, two of which are independent bradykinesia factors. Thus the UPDRS and MDS-UPDRS are reliable and applicable scales for PD and the UPDRS can be used to assess bradykinesia in PSP. Technology-based tools for measuring bradykinesia include gyrosensors, Coordination Ability Test System, Brain Test, quantitative digitography, Motus motion analysis system, precision real-time image-based motion analysis, and the At-Home Testing Device. These tools have been compared to the UPDRS motor subscale and are effective in assessing bradykinesia. Conclusion: The UPDRS and MDS-UPDRS are well-established measures of bradykinesia that are applicable and useful in PD. The UPDRS is also been shown to be applicable to PSP. Different technologies exist to measure bradykinesia, though further work is needed to validate these assessment tools and bring them to clinical practice.

Deep Brain Stimulation in Tourette's Syndrome.

Objective Tourette’s syndrome (TS) is defined by 1 year of persistent motor and vocal tics. Often, the tics are refractory to conventional pharmacologic and psychobehavioral interventions. In these patients, deep brain stimulation (DBS) may be an appropriate intervention. This paper reviews different DBS targets in TS, discusses existing evidence on the efficacy of DBS in TS, highlights adverse effects of the procedure, discusses indications and patient selection as well as future directions for DBS in TS. Methods A literature review searching PubMed database entries between 2000 and 2015. Search terms included “DBS in Tourette Syndrome”, “Deep brain stimulation in Tourette syndrome,” and “Surgical management of Tourette Syndrome.” Results Though there are no universally accepted guidelines defining ideal DBS candidates for TS, age, tic severity, and treatment refractoriness are important factors to consider in patient selection. A variety of targets exist for DBS in TS, but thalamic targets and GPi are the most widely studied. Psychiatric side effects that are target specific should be monitored closely and it is possible that these adverse effects may be resolved with programing. Small randomized controlled trials support the efficacy of DBS in TS. Conclusion DBS for TS is safe and feasible, but large multi-center clinical trials are needed to determine the ideal target and optimal location within a particular target.

Abnormal lipopolysaccharide binding protein as marker of gastrointestinal inflammation in Parkinson disease

Objective: An inflammation-driven model of PD has been proposed based on the endotoxin lipopolysaccaride (LPS), a potential source of inflammation in the gastrointestinal system linked to neurotoxicity. Systemic exposure to bacterial endotoxin (LPS) can be determined by measuring plasma LPS binding protein (LBP). We aimed to evaluate whether lipopolysaccharide binding protein (LBP) can be used to distinguish PD subjects from control subjects and to assess whether LBP levels correlate with PD disease severity. Methods: We measured plasma LBP (ng/ml) using an ELISA kit in 94 PD subjects of various stages and 97 control subjects. Disease severity was assessed using the UPDRS and Hoehn and Yahr staging. The LBP level between the PD and control groups was compared using analysis of covariance. Spearman correlation was used to explore the relationship between LBP level and disease severity. Results: The mean LBP level in PD subjects (n = 94) was significantly different from control subjects (n = 95, p = 0.018). In PD subjects, we did not find a correlation between mean LBP level and disease severity. Conclusions: Our data suggests that LBP is one GI biomarker related to LPS induced neurotoxicity. However, there was significant variability in LBP levels within the PD and control groups, limiting its utility as a stand-alone biomarker. This study supports the role of LPS induced neurotoxicity in PD and further exploration of this pathway may be useful in developing sensitive and specific biomarkers for PD.

Genetic and Clinical Predictors of Deep Brain Stimulation in Young-Onset Parkinson's Disease.

In a cohort of patients with young‐onset Parkinsons disease (PD), the authors assessed (1) the prevalence of genetic mutations in those who enrolled in deep brain stimulation (DBS) programs compared with those who did not enroll DBS programs and (2) specific genetic and clinical predictors of DBS enrollment.

Comparison of neuropathology in Parkinson's disease subjects with and without deep brain stimulation

Background: The aim of this postmortem study was to compare, in Parkinsons disease subjects with and without bilateral subthalamic nucleus deep brain stimulation (STN‐DBS), the loss of pigmented neurons within the substantia nigra and pathological alpha‐synuclein density within the SN and other brain regions.

Use of intraoperative CT to predict the accuracy of microelectrode recording during deep brain stimulation surgery. A proof of concept study.

OBJECTIVES Intraoperative computed tomography (iCT) is currently used to confirm the target location of the microelectrode (ME) during microelectrode recording (MER) and ultimate location of deep brain stimulation (DBS) leads at our institution. We evaluated whether iCT can be used to predict the trajectory and accuracy of the ME track. PATIENTS AND METHODS Intraoperative imaging profiles of ten consecutive patients who had undergone DBS surgery were retrospectively reviewed. We found that cranial iCT, in addition to visualizing the target, also visualizes the extra-cranial segment of the guide tube (ECGT) used to insert the ME. We propose a hypothetical technique that extrapolates the trajectory of only the ECGT down to target depth using planning software. In order to provide a proof of concept analysis of this hypothetical technique, we retrospectively assessed post MER placement iCT studies and used planning software to visualize only the ECGT. An extrapolated vector was drawn along the long axis of the ECGT down to the same depth (z) as the ME. The obtained x and y coordinates were subsequently recorded and compared to the x and y coordinates of the ME tip to validate this technique. RESULTS The average radial error between ECGT trajectory coordinates and final ME tip coordinates was 0.93±0.1mm (mean±SEM). CONCLUSION The use of iCT to predict accuracy of microelectrode location is feasible. In the future, performing iCT before guide tube penetration of dura can allow for trajectory prediction and if needed, correction of the ME, thereby potentially improving accuracy and reducing the number of MER tracks.

Improving the accuracy of microelectrode recording in deep brain stimulation surgery with intraoperative CT

Microelectrode recording (MER) is used to confirm electrophysiological signals within intended anatomic targets during deep brain stimulation (DBS) surgery. We describe a novel technique called intraoperative CT-guided extrapolation (iCTE) to predict the intended microelectrode trajectory and, if necessary, make corrections in real-time before dural opening. Prior to dural opening, a guide tube was inserted through the headstage and rested on dura. Intraoperative CT (iCT) was obtained, and a trajectory was extrapolated along the path of the guide tube to target depth using targeting software. The coordinates were recorded and compared to initial plan coordinates. If needed, adjustments were made using the headstage to correct for error. The guide tube was then inserted and MER ensued. At target, iCT was performed and microelectrode tip coordinates were compared with planned/adjusted track coordinates. Radial error between MER track and planned/adjusted track was calculated. For comparison, MER track error prior to the iCTE technique was assessed retrospectively in patients who underwent MER using iCT, whereby iCT was performed following completion of the first MER track. Forty-seven MER tracks were analyzed prior to iCTE (pre-iCTE), and 90 tracks were performed using the iCTE technique. There was no difference between radial error of pre-iCTE MER track and planned trajectory (2.1±0.12mm) compared to iCTE predicted trajectory and planned trajectory (1.76±0.13mm, p>0.05). iCTE was used to make trajectory adjustments which reduced radial error between the newly corrected and final microelectrode tip coordinates to 0.84±0.08mm (p<0.001). Inter-rater reliability was also tested using a second blinded measurement reviewer which showed no difference between predicted and planned MER track error (p=0.53). iCTE can predict and reduce trajectory error for microelectrode placement compared with the traditional use of iCT post MER.

The Neuropsychiatric and Motor Profile of GBA‐Associated Parkinson's Disease: A Review

Cognitive and motor decline, along with psychiatric symptoms, have a major impact on independence, nursing home admission, caregiver burden, and mortality in Parkinsons disease (PD). The single most common genetic risk factor for developing PD is a mutation in the glucocerebrosidase (GBA) gene.

The Core Assessment Program for Surgical Interventional Therapies in Parkinson's Disease (CAPSIT‐PD): Tolerability of Preoperative Neuropsychological Testing for Deep Brain Stimulation in Parkinson's Disease

We examined tolerability of preoperative neuropsychological testing (the Core Assessment Program for Surgical Interventional Therapies in Parkinsons Disease [CAPSIT‐PD] protocol) for DBS. We also examined factors that may influence tolerability, including fatigue, global cognitive function, depression, and patient‐based characteristics.