Rick Stell

Reversible reorganisation of the motor cortical representation of the hand in cervical dystonia

Previous work has suggested that there may be a widespread disturbance of motor control mechanisms in patients with cervical dystonia. In the present study, we used transcranial magnetic stimulation to investigate the topography of the corticomotor projection to the abductor pollicis brevis (APB) muscle in 10 subjects with idiopathic torticollis. Threshold‐adjusted stimuli were delivered at multiple scalp sites during a low‐level voluntary contraction of the APB, and maps were generated of motor evoked potential amplitude versus scalp site. The cortical maps for the APB on the side opposite to the direction of head rotation were displaced laterally or posteriorly in all subjects and reverted to a more normal position after botulinum toxin injection of the cervical muscles in 5 subjects. The findings point to a reversible reorganisation of the corticomotor representation of the hand on the same side as the sternocleidomastoid (SCM) muscle that is involved in producing the dystonia. These results provide further evidence for the involvement of cortical centres and for a more widespread abnormality of motor control mechanisms in focal dystonia. The findings also support the notion that head turning is chiefly mediated by the hemisphere ipsilateral to the direction of the head rotation by means of a corticomotor projection to the contralateral SCM.

Transcranial magnetic stimulation of the human frontal eye field

The region of cortex over which transcranial magnetic stimulation (TMS) can delay saccadic eye movement was investigated. With TMS delivered in the reaction time foreperiod of auditory-triggered saccades, saccade onset could be delayed by up to 60 ms. The area of cortex over which TMS could delay saccade onset was located near the inter-aural line, approximately 6 cm lateral to the vertex, and was situated between areas over which TMS could generate motor evoked potentials in muscles of the hand and face. It is concluded that this area corresponds to the human frontal eye field and is closely associated with the motor strip, at a level between the representations of the hand and the face, and that stimulation of this region can interfere with the programming and execution of externally triggered saccades.

Novel mutation in the myelin protein zero gene in a family with intermediate hereditary motor and sensory neuropathy

OBJECTIVES To determine the molecular basis for autosomal dominant intermediate hereditary motor and sensory neuropathy (HMSN) in a four generation family. The gene defects in families with intermediate HMSN are not known, but it has been suggested that most have X linked HMSN. METHODS All participating family members were examined clinically. Genomic DNA was obtained from 10 affected and seven unaffected members. Linkage analysis for the known HMSN loci was first performed. Mutations in the peripheral myelin protein zero gene (PMP0) were sought in two affected members, using one unaffected member for comparison, by amplification of the six exons of the gene followed by single strand conformation polymorphism (SSCP) analysis, dideoxy fingerprinting (ddF), and sequencing. Subsequently, the mutation was screened for in all affected and unaffected members in the family using Alu I digestion and in 100 unrelated control subjects using “snap back” SSCP analysis. Sequencing of cDNA from a sural nerve biopsy from an affected member was also performed. RESULTS The clinical phenotype was of variable severity, with motor nerve conduction velocities in the intermediate range. Linkage to PMP0 was demonstrated. Analysis of genomic DNA and cDNA for PMP0 identified a novel codon 35 GAC to TAC mutation. The mutation produces an inferred amino acid change of aspartate to tyrosine at codon six of the processed protein (Asp6Tyr) in the extracellular domain and was present in all affected family members but not in 100 unrelated controls. CONCLUSIONS The present findings further extend the range of phenotypes associated with PMP0 mutations and indicate that families with “intermediate” HMSN need not necessarily be X-linked as previously suggested.

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.

Modulation of primary orthostatic tremor by magnetic stimulation over the motor cortex

OBJECTIVES To study the role of corticomotor neuronal pathways in primary orthostatic tremor. METHODS Transcranial magnetic stimuli at an intensity 10% above the resting motor threshold were delivered over the leg motor cortex in two patients with primary orthostatic tremor while standing still. Electromyographic responses in both tibialis anterior muscles were recorded after 20 stimuli given randomly at intervals of 120 to 180 seconds. Differences between predicted and actual times of occurrence of tremor bursts after the stimuli were used to calculate a resetting index, with a value of 0 representing no resetting and a value of 1 representing complete resetting. RESULTS Transcranial magnetic stimulation evoked EMG responses in both tibialis anterior muscles, followed by transient suppression of tremor before reappearance of rhythmic EMG activity. Analysis of the timing of tremor bursts from EMG recordings before and after the magnetic stimuli disclosed that the phase of orthostatic tremor could be reset by brain stimulation (mean resetting indices 0.93 and 0.82). CONCLUSION The results suggest that a central oscillator, involving the motor cortex, has a crucial role in either the generation or modulation of orthostatic tremor.

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.