Julian P. Rodrigues

Dopamine dysregulation syndrome, impulse control disorders and punding after deep brain stimulation surgery for Parkinson's disease

Data regarding the effect of deep brain stimulation (DBS) surgery on the dopamine dysregulation syndrome (DDS), impulse control disorders (ICDs) and punding in Parkinsons disease (PD) are limited. We present a case series of 21 operated PD patients who had exhibited DDS, ICDs or punding at some stage during the disease. DDS remained unimproved or worsened post-operatively in 12/17 patients with pre-operative DDS (71%) (nine bilateral subthalamic nucleus [STN], one right-sided STN, two bilateral globus pallidus internus [GPi] DBS). DDS improved or resolved after bilateral STN DBS in 5/17 patients with pre-operative DDS. DDS apparently developed for the first time after bilateral STN DBS in two patients, although only after a latency of eight years in one case. One patient without reported pre-operative DDS or ICDs developed pathological gambling post-STN DBS. One patient had pathological gambling which resolved pre-operatively, and did not recur post-DBS. Thus, DDS, ICDs and punding may persist, worsen or develop for the first time after DBS surgery, although a minority of patients improved dramatically. Predictive factors may include physician vigilance, motor outcome and patient compliance.

Globus pallidus stimulation improves both motor and nonmotor aspects of quality of life in advanced Parkinson's disease

Our purpose was to measure the change in quality of life (QoL) following deep brain stimulation of the globus pallidus interna (GPi‐DBS) in advanced Parkinson s disease (PD), and identifies any associations with changes in motor features of the disease. Eleven patients (age range 54–69 years, 2 women) underwent GPi‐DBS (4 unilateral, 7 bilateral). Outcome measures included assessment of PD‐specific QoL (mean 8 months postsurgery) using the PDQ‐39 questionnaire, and standard motor assessments. Off‐period UPDRS III motor scores fell by (43 ± 8)% (mean ± SEM). Dyskinesia severity was reduced on the abnormal involuntary movement scale by (80 ± 3)% and UPDRS IVa by (58 ± 8)%. QoL as assessed by the PDQ39SI improved by (30 ± 5)%, with significant improvements in mobility, activities of daily living, bodily discomfort, emotional wellbeing, communication, and cognitions subscales. Bilateral and unilateral groups demonstrated equivalent PDQ39SI improvement. QoL improvement was highly correlated with dyskinesia reduction but not reduction in UPDRS score or age at surgery. GPi‐DBS markedly improves QoL in advanced PD. The impacts are broad and improve QoL domains not directly affected by the motor symptoms of the disease. Reduced dyskinesia plays a major role in the improvement of QoL in GPi‐DBS treated patients.

Clinical and Posturographic Correlates of Falling in Parkinson's Disease

Various clinical tests and balance scales have been used to assess postural stability and the risk of falling in patients with idiopathic Parkinsons disease (IPD). Quantitative posturography allows a more objective assessment but the findings in previous studies have been inconsistent and few studies have investigated which posturographic measures correlate best with a history of falling. The purpose of this study was to determine the efficacy of clinical tests, balance scales, and stable‐platform posturography in detecting postural instability and discriminating between fallers and non‐fallers in a home‐dwelling PD cohort. Forty‐eight PD subjects (Hoehn & Yahr stage 1–3) and 17 age‐matched controls had the following assessments: Activities‐specific Balance Confidence scale, Berg Balance Scale, Unified Parkinsons Disease Rating Scale (UPDRS) (motor), pull‐test, timed up‐and‐go, static posturography, and dynamic posturography to assess multidirectional leaning balance. Of the clinical assessments, all but the pull‐test were closely correlated with a history of falling. Static posturography discriminated between PD fallers and controls but not between PD fallers and non‐fallers, whereas dynamic posturography (reaction time, velocity, and target hit‐time) also discriminated between fallers and non‐fallers. Our findings suggest that this combination of clinical and posturographic measures would be useful in the prospective assessment of falls risk in PD patients. A further prospective study is now required to assess their predictive value.

Gabapentin can improve postural stability and quality of life in primary orthostatic tremor.

Primary orthostatic tremor (OT) is characterized by leg tremor and instability on standing. High frequency (13–18 Hz) tremor bursting is present in leg muscles during stance, and posturography has shown greater than normal sway. We report on an open‐label add‐on study of gabapentin in 6 patients with OT. Six patients were studied with surface electromyography, force platform posturography, and a modified Parkinsons disease questionnaire (PDQ‐39) quality of life (QOL) scale before and during treatment with gabapentin 300 mg t.d.s. If on other medications for OT, these were continued unchanged. Of the 6 patients, 4 reported a subjective benefit of 50 to 75% with gabapentin, 3 of whom showed reduced tremor amplitude and postural sway of up to 70%. Dynamic balance improved in all 3 patients who completed the protocol. QOL data from 5 patients showed improvement in all cases. No adverse effects were noted. Gabapentin may improve tremor, stability, and QOL in patients with OT, and symptomatic response correlated with a reduction in tremor amplitude and postural sway. The findings confirm previous reports of symptomatic benefit with gabapentin and provide justification for larger controlled clinical trials. Further work is required to establish the optimal dosage and to validate the methods used to quantify the response to treatment.

Blinded placebo crossover study of gabapentin in primary orthostatic tremor

Primary orthostatic tremor (OT) is a rare but disabling condition characterized by leg tremor and feelings of instability during stance. Previous studies have reported a reduction in OT symptoms with gabapentin treatment. In this study, we report on the benefits of gabapentin treatment in a double‐blind placebo‐controlled crossover study of 6 OT patients. First, the maximally effective gabapentin dosage (600–2,700 mg/day) for each patient was determined during an initial dose‐titration phase. Patients were then studied 7 days after drug withdrawal and again after two 2‐week periods of treatment with either gabapentin or placebo, using force platform posturography to quantify postural sway and tremor. Other medications for OT were continued unchanged. Symptomatic response was assessed by a patient‐rated severity scale and quality of life (QOL) questionnaire. All patients reported an increase in symptoms during the washout phase and symptom reduction (50%–75%) during gabapentin treatment. Tremor amplitude was reduced to 79% ± 11% and sway area to 71% ± 11% of the placebo state. QOL improved in all patients, no adverse drug effects were noted, and symptomatic benefit was maintained at follow‐up (mean = 19 months). The findings confirm that gabapentin is an effective treatment for OT, reducing both tremor and postural instability and improving quality of life, and support its use as add‐on or first‐line therapy for OT.

Deep brain stimulation for Parkinson’s disease: Australian referral guidelines ☆

The advent of deep brain stimulation (DBS) has been an important advance in the treatment of Parkinsons disease (PD). DBS may be employed in the management of medication-refractory tremor or treatment-related motor complications, and may benefit between 4.5% and 20% of patients at some stage of their disease course. In Australia, patients with PD are reviewed by specialised DBS teams who assess the likely benefits and risks associated with DBS for each individual. The aim of these guidelines is to assist neurologists and general physicians identify patients who may benefit from referral to a DBS team. Common indications for referral are motor fluctuations and/or dyskinesias that are not adequately controlled with optimised medical therapy, medication-refractory tremor, and intolerance to medical therapy. Early referral for consideration of DBS is recommended as soon as optimised medical therapy fails to offer satisfactory motor control.

Globus pallidus stimulation in advanced Parkinson’s disease

Deep brain stimulation (DBS) of the globus pallidus internus (GPi) has become an accepted therapeutic modality in selected Parkinsons disease (PD) patients with severe levodopa-induced dyskinesias (LID) and on-off motor fluctuations. In comparison to subthalamic nucleus DBS there is a paucity of data on GPi DBS outcomes. We present our experience with a group of 20 PD patients (9 unilateral, 11 bilateral) who underwent GPi stimulation. PD motor symptoms were assessed using the Unified Parkinsons Disease Rating Scale (UPDRS) part III scores and subscores, and dyskinesia using the Abnormal Involuntary Movement Scale (AIMS), UPDRS part IVa, and clinical global impression (CGI). At mean follow-up time of 7 months, bilateral stimulation reduced off-period motor scores by a mean of 46% and on-period motor scores by 18%. Unilateral stimulation reduced off-period motor scores by 18%. Dyskinesia severity was reduced by 76%, which was maintained after a mean follow-up time of 35 months. Antiparkinsonian medication dosage was unchanged. No major adverse effects were seen. Unilateral and bilateral GPi DBS provides lasting benefit in PD patients with severe LID. Beneficial effects on off-period motor symptoms are greater with bilateral stimulation; however, with maintenance of dopaminergic medication, unilateral procedures can also provide important and sustained benefits.

Changes in corticomotor excitability and inhibition after exercise are influenced by hand dominance and motor demand.

Previous studies on handedness have often reported functional asymmetries in corticomotor excitability (CME) associated with voluntary movement. Recently, we have shown that the degree of post-exercise corticomotor depression (PED) and increase in short-interval cortical inhibition (SICI) after a repetitive finger movement task was less when the task was performed at a maximal voluntary rate (MVR) than when it was performed at a submaximal sustainable rate (SR). In the current study, we have compared the time course of PED and SICI in the dominant (DOM) and nondominant (NDOM) hands after an MVR and SR finger movement task to determine the influence of hand dominance and task demand. We tracked motor-evoked potential (MEP) amplitude from the first dorsal interosseous muscle of the DOM and NDOM hand for 20 min after a 10-s index finger flexion-extension task at MVR and SR. For all hand-task combinations, we report a period of PED and increased SICI lasting for up to 8 min. We find that the least demanding task, one that involved index finger movement of the DOM hand at SR, was associated with the greatest change in PED and SICI from baseline (63.6±5.7% and 79±2%, P<0.001, PED and SICI, respectively), whereas the most demanding task (MVR of the NDOM hand) was associated with the least change from baseline (PED: 88.1±3.6%, SICI: 103±2%; P<0.001). Our findings indicate that the changes in CME and inhibition associated with repetitive finger movement are influenced both by handedness and the degree of demand of the motor task and are inversely related to task demand, being smallest for an MVR task of the NDOM hand and greatest for an SR task of the DOM hand. The findings provide additional evidence for differences in neuronal processing between the dominant and nondominant hemispheres in motor control.

Modulation of corticomotor excitability after maximal or sustainable-rate repetitive finger movement is impaired in parkinson's disease and is reversed by levodopa

OBJECTIVES In healthy subjects, fatiguing exercises induce a period of post-exercise corticomotor depression (PECD) that is absent in Parkinsons disease (PD). Our objective is to determine the time-course of corticomotor excitability changes following a 10-s repetitive index finger flexion-extension task performed at maximal voluntary rate (MVR) and a slower sustainable rate (MSR) in PD patients OFF and ON levodopa. METHODS In 11 PD patients and 10 healthy age-matched controls, motor evoked potentials (MEPs) were recorded from the extensor indicis proprius (EIP) and first dorsal interosseous (FDI) muscles of the dominant arm immediately after the two tasks and at 2-min intervals for 10 min. RESULTS In the OFF condition the PECD was absent in the two test muscles after both the MVR and MSR tasks. In the ON condition finger movement kinematics improved and a period of PECD comparable to that in controls was present after both tasks. CONCLUSION The absence of PECD in PD subjects off medication indicates a persisting increase in corticomotor excitability after non-fatiguing repetitive finger movement that is reversed by levodopa. SIGNIFICANCE Dopamine depletion is associated with impaired modulation of corticomotor excitability after non-fatiguing repetitive finger movement.

Spike-timing-related plasticity is preserved in Parkinson's disease and is enhanced by dopamine : evidence from transcranial magnetic stimulation

We sought to investigate the effects of dopamine on motor cortical plasticity in Parkinsons disease (PD) using a novel interventional transcranial magnetic stimulation protocol that targets spike-timing-dependent plasticity (iTMS). Six patients (3F, mean age 62 years) with mild-moderate PD (mean disease duration 6 years, UPDRS-off 13, UPDRS-on 3, H&Y stage 2, daily levodopa dosage 450 mg) were studied off and on levodopa on separate days. Paired TMS pulses at resting motor threshold with an inter-stimulus interval of 1.5 ms were given over the hand area of the motor cortex for 20 min at 0.2 Hz. Single-pulse motor evoked potential (MEP) amplitude and visually cued simple reaction time (SRT) were measured before and after iTMS. When on levodopa, MEP amplitude increased to 278+/-36% of baseline (p<0.01), and when off levodopa to 157+/-13% of baseline (p=0.02). All patients showed a significantly greater increase in MEP amplitude when on levodopa than off levodopa (p=0.01). SRT was reduced to 95% baseline after iTMS off levodopa (p=0.02), but did not change on levodopa. These findings indicate that motor cortex plasticity to iTMS is preserved in mild-moderate PD. The effects of this spike-timing-related TMS protocol on cortical excitability were consistent and were enhanced by levodopa. The results support the important role of dopamine in regulating synaptic plasticity and justify a larger crossover study to assess the therapeutic effects of iTMS in PD.