The relationship between the dopaminergic system and depressive symptoms in cervical dystonia.

PURPOSE: Cervical dystonia (CD) is associated with tremor/jerks (50%) and psychiatric complaints (17-70%). The dopaminergic system has been implicated in the pathophysiology of CD in animal and imaging studies. Dopamine may be related to the motor as well as non-motor symptoms of CD. CD is associated with reduced striatal dopamine D2/3 (D2/3) receptor and increased dopamine transporter (DAT) binding. There are differences in the dopamine system between CD patients with and without jerks/tremor and psychiatric symptoms. METHODS: Patients with CD and healthy controls underwent neurological and psychiatric examinations. Striatal DAT and D2/3 receptor binding were assessed using [123I]FP-CIT and [123I]IBZM SPECT, respectively. The ratio of specific striatal to non-specific binding (binding potential; BPND) was the outcome measure. RESULTS: Twenty-seven patients with CD and 15 matched controls were included. Nineteen percent of patients fulfilled the criteria for a depression. Striatal DAT BPND was significantly lower in depressed versus non-depressed CD patients. Higher DAT BPND correlated significantly with higher scores on the Unified Myoclonus Rating Scale (UMRS). The striatal D2/3 receptor BPND in CD patients showed a trend towards lower binding compared to controls. The D2/3 BPND was significantly lower in depressed versus non-depressed CD patients. A significant correlation between DAT and D2/3R BPND was found in both in patients and controls. CONCLUSIONS: Alterations of striatal DAT and D2/3 receptor binding in CD patients are related mainly to depression. DAT BPND correlates significantly with scores on the UMRS, suggesting a role for dopamine in the pathophysiology of tremor/jerks in CD.

Cerebellar Atrophy in Cortical Myoclonic Tremor and Not in Hereditary Essential Tremor-a Voxel-Based Morphometry Study.

Essential tremor (ET) presumably has a cerebellar origin. Imaging studies showed various cerebellar and also cortical structural changes. A number of pathology studies indicated cerebellar Purkinje cell pathology. ET is a heterogeneous disorder, possibly indicating different underlying disease mechanisms. Familial cortical myoclonic tremor with epilepsy (FCMTE), with evident Purkinje cell degeneration, can be an ET mimic. Here, we investigate whole brain and, more specifically, cerebellar morphological changes in hereditary ET, FCMTE, and healthy controls. Anatomical magnetic resonance images were preprocessed using voxel-based morphometry. Study 1 included voxel-wise comparisons of 36 familial, propranolol-sensitive ET patients, with subgroup analysis on age at onset and head tremor, and 30 healthy controls. Study 2 included voxel-wise comparisons in another nine ET patients, eight FCMTE patients, and nine healthy controls. Study 3 compared total cerebellar volume between 45 ET patients, 8 FCTME patients, and 39 controls. In our large sample of selected hereditary ET patients and ET subgroups, no local atrophy was observed compared to healthy controls or FCMTE. In ET patients with head tremor, a volume increase in cortical motor regions was observed. In FCMTE, a decrease in total cerebellar volume and in local cerebellar gray matter was observed compared to healthy controls and ET patients. The current study did not find local atrophy, specifically not in the cerebellum in hereditary ET, contrary to FCMTE. Volume increase of cortical motor areas in ET patients with head tremor might suggest cortical plasticity changes due to continuous involuntary head movements.

Phenotypes and genetic architecture of focal primary torsion dystonia.

BACKGROUND: The focal primary torsion dystonias (FPTDs) form a group of clinical heterogeneous syndromes and can be considered a genetic complex disease; it is thought to be primed by genetic variants with variable impact and triggered by non-genetic factors. Thorough clinical description of FPTDs cohorts is sparse but essential for further progress in genetic research. OBJECTIVE: To establish suggested relations between age at onset (AaO), site and family history in a large focal dystonias cohort and gain more insight into familial clustering for genetic research. PATIENTS AND METHODS: A prospective cohort study between March 2008 and March 2011, including 676 FPTD patients attending the botulinum toxin outpatient clinics of six Dutch movement disorder centres. RESULTS AND CONCLUSIONS: Of all of the FPTD patients, 25% had a familial predisposition; in 2.4% a Mendelian inheritance pattern was noted. With a stronger family history, a significantly lower AaO was seen in all focal dystonias. In both the sporadic and familial focal dystonia groups, AaO had an effect on the distribution of dystonia, with a caudal to cranial tendency. In all focal dystonia forms, women were more frequently affected, except for writer's cramp. Careful clinical characterisation will allow the formation of phenotype subgroups. We suggest that genetic research into FPTDs will benefit from this approach and discuss genetic research strategies to decipher the complex background of focal dystonias.

Deep brain stimulation for dystonia: patient selection and outcomes.

In a literature survey, 341 patients with primary and 109 with secondary dystonias treated with deep brain stimulation (DBS) of the internal segment of the globus pallidus (GPi) were identified. In general, the outcomes for primary dystonias were more favourable compared to the secondary forms. For some secondary dystonias--like tardive dystonia, myoclonus-dystonia (M-D), NBIA (PANK2), the outcome was very good. Only for the primary generalized dystonias, the efficacy of GPi-DBS has been confirmed in randomised controlled trials. Predictors of outcome are the experience and dedication of the stereotactic team, the selection of patients--the diagnosis and pre-operative screening--and the quality of the post-operative care. Predictors of negative outcome are long duration of the disease--with contractures or scoliosis--and concomitant symptoms like spasticity and cerebellar dysfunction. More studies are required to establish the role of GPi-DBS in the treatment of secondary dystonias.

Myoclonus-dystonia: clinical and genetic evaluation of a large cohort.

BACKGROUND: Myoclonus-dystonia (M-D) is an autosomal dominant inherited movement disorder. Various mutations within the epsilon-sarcoglycan (SGCE) gene have been associated with M-D, but mutations are detected in only about 30% of patients. The lack of stringent clinical inclusion criteria and limitations of mutation screens by direct sequencing might explain this observation. METHODS: Eighty-six M-D index patients from the Dutch national referral centre for M-D underwent neurological examination and were classified according to previously published criteria into definite, probable and possible M-D. Sequence analysis of the SGCE gene and screening for copy number variations were performed. In addition, screening was carried out for the 3 bp deletion in exon 5 of the DYT1 gene. RESULTS: Based on clinical examination, 24 definite, 23 probable and 39 possible M-D patients were detected. Thirteen of the 86 M-D index patients carried a SGCE mutation: seven nonsense mutations, two splice site mutations, three missense mutations (two within one patient) and one multiexonic deletion. In the definite M-D group, 50% carried an SGCE mutation and one single patient in the probable group (4%). One possible M-D patient showed a 4 bp deletion in the DYT1 gene (c.934_937delAGAG). CONCLUSIONS: Mutation carriers were mainly identified in the definite M-D group. However, in half of definite M-D cases, no mutation could be identified. Copy-number variations did not play a major role in the large cohort.

Multicentre European study of thalamic stimulation for parkinsonian tremor: a 6 year follow-up.

AIM: To evaluate the results of ventral intermediate (Vim) thalamic deep brain stimulation (DBS) in patients with tremor predominant Parkinson's disease (PD) at 6 years post surgery. METHODS: This was a prolonged follow-up study of 38 patients from eight centres who participated in a multicentre study, the 1 year results of which have been published previously. Total scores as well as scores for individual items of the motor part and the disability part of the Unified Parkinson's Disease Rating Scale were used for evaluation. RESULTS: Tremor was still effectively controlled by DBS and appendicular rigidity and akinesia remained stable compared with baseline. Axial scores (speech, gait and postural instability), however, worsened, and in parallel the initial improvement in activities of daily living scores at the 1 year follow-up had disappeared at 6 years, despite sustained improvement of tremor. Remarkably, neither daily doses of dopaminergic medication nor fluctuations and dyskinesias had changed at 6 years compared with baseline in this particular patient group. CONCLUSION: This study confirms that patients with tremor dominant PD who do not present with fluctuations and dyskinesias may have a relatively benign progression of the disease. Vim DBS, although having no effect on akinesia and rigidity, is a relatively lenient surgical procedure and may still have a place for long term symptomatic control of PD tremor in selected patients.

Motor procedural learning in Parkinson's disease.

Functional neuroimaging research has repeatedly implicated the striatum in motor procedural learning, but attempts to explore this relation in patients with Parkinson's disease (PD) have yielded inconsistent results. Furthermore, the functional impact of procedural learning impairment is unknown. The present study sought to examine the effects of PD on procedural learning and to determine whether impaired procedural learning affects functional status. The performance of 95 non-demented PD patients on the serial reaction time task (SRTT) was compared with that of 44 demographically matched control subjects. The SRTT is a four-choice reaction time task in which visual stimuli are presented in six blocks of 100 trials either in a repeating sequence of 10 stimuli or randomly. Learning was inferred from the reduction of response times over five successive blocks of repeating sequence trials and from the increase in response times in the sixth random block. In addition, neuropsychological tests of declarative memory, executive and visuospatial functions were administered to all participants. Patients also received quantitative ratings of functional outcome. The two groups did not differ in the learning rate across blocks of repeating sequence trials. However, PD patients were significantly less efficient than controls in acquiring sequence-specific knowledge, although this impairment was relatively small (d = 0.38). Patients with more advanced clinical symptoms tended to show worse performance. Separate analyses of a subgroup of 24 non-medicated patients in the early stages of PD revealed no differences in SRTT performance relative to controls. Neuropsychological testing showed impairments in attention and executive functions, immediate and delayed explicit memory and visuospatial skills in the PD group, but none of the cognitive measures were related to procedural learning. Reduced motor sequence learning in PD patients did not influence their functional status. These findings indicate that procedural learning impairment is not an early feature of PD, but is likely to emerge with progression of the disease, independently of cognitive dysfunction or dopaminergic medication.

Pathological gambling after bilateral subthalamic nucleus stimulation in Parkinson disease.

We describe a patient with advanced Parkinson's disease who developed pathological gambling within a month after successful bilateral subthalamic nucleus (STN) stimulation. There was no history of gambling. On neuropsychological testing, slight cognitive decline was evident 1 year after surgery. Stimulation of the most dorsal contact with and without medication induced worse performances on decision making tests compared with the more ventral contact. Pathological gambling disappeared after discontinuation of pergolide and changing the stimulation parameters. Pathological gambling does not seem to be associated with decision making but appears to be related to a combination of bilateral STN stimulation and treatment with dopamine agonists.

Botulinum toxin for writer's cramp: a randomised, placebo-controlled trial and 1-year follow-up.

BACKGROUND: Botulinum toxin type A (BoNT-A) has become the treatment of choice for most types of focal dystonia. OBJECTIVE: To investigate the efficacy of BoNT-A injections in patients with writer's cramp in a double-blind, randomised, placebo-controlled trial and to evaluate the follow-up results. METHODS: Forty participants were randomised to treatment with either BoNT-A or placebo injections in two sessions. Trial duration was 12 weeks. The primary outcome measure was the patients' choice to continue with the treatment, despite its possible disadvantages. Secondary outcome measures included several clinical rating scales on the levels of impairment and disability. Assessments were made at baseline and 2 months (secondary outcomes) and 3 months (primary outcome). Duration of follow-up was 1 year. RESULTS: 39 patients completed the trial. Fourteen of 20 patients (70%) receiving BoNT-A reported a beneficial effect and chose to continue treatment, versus 6 of 19 patients (31.6%) in the placebo group (p = 0.03). The changes on most of the clinical rating scales were significantly in favour of BoNT-A. Side effects reported were hand weakness, which was mostly mild and always transient, and pain at the injection site. After 1 year, 20 of 39 patients were still under treatment with a positive effect. CONCLUSION: Treatment with BoNT-A injections led to a significantly greater improvement compared with placebo, according to patients' opinion and clinical assessment scales. Weakness in the hand is an important side effect of BoNT-A injections, but despite this disadvantage, most patients preferred to continue treatment. About 50% of our patients were still under treatment after 1 year.

Sensory integration in writer's cramp: comparison with controls and evaluation of botulinum toxin effect.

OBJECTIVE: Abnormal temporal and spatial sensory integration have been described in mixed groups of dystonic patients. We tested somatosensory integration and the effect of botulinum toxin (BoNT) in patients with writer's cramp (WC). METHODS: Median and ulnar SEPs were recorded in 29 WC patients and in 10 controls. We performed: individual and simultaneous stimulation of median and ulnar nerves (MU) and paired stimulation of median nerve at interstimulus-interval (ISI) of 40 and 100 ms. All the trials were repeated after blinded randomized treatment with placebo or BoNT-A. RESULTS: We found no differences between patients and controls in standard SEPs. Spatial (except for N9) and temporal suppression after ISI 40 were present in both groups for all the waves; after ISI 100, suppression was present only for N70. There were no differences between patients and controls. After BoNT-A treatment, no changes were observed. CONCLUSIONS: In contrast with previous findings in heterogeneous dystonic groups, and although some studies suggest impairment of spatial and temporal sensory discrimination in patients with focal dystonia, in our large cohort of patients with WC we found no evidence of abnormal somatosensory integration investigated by means of SEPs and no changes in somatosensory variables after BoNT-A treatment. SIGNIFICANCE: Our findings may suggest pathophysiological differences between focal and generalized dystonia, and may also point to an inferior sensitivity of SEPs in detecting abnormalities in sensory discrimination as compared to methods based on subjective discrimination.

Lower serotonin transporter binding in patients with cervical dystonia is associated with psychiatric symptoms.

BACKGROUND: Cervical dystonia (CD) is often accompanied by depressive symptoms, anxiety, and jerks/tremor. The dopamine transporter (DAT) binding is related with both depressive symptoms and jerks/tremor in CD. Serotonergic and dopaminergic systems are closely related. As serotonin is involved in the pathophysiology of psychiatric symptoms and jerks, we expected an altered serotoninergic system in CD. We hypothesized that CD is associated with reduced serotonin transporter (SERT) binding, more specific that SERT binding is lower in CD patients with psychiatric symptoms and/or jerks/tremor compared to those without, and to controls. The balance between SERT and DAT binding can be altered in different CD phenotypes. RESULTS: In 23 CD patients and 14 healthy controls, SERT binding in the diencephalon/midbrain was assessed using [123I]FP-CIT SPECT, with a brain-dedicated system. The specific to non-specific binding ratio (binding potential; BPND) to SERT was the main outcome measure. There was a clear trend towards reduced SERT BPND in CD patients with psychiatric symptoms compared to those without (p = 0.05). There was no correlation between SERT binding and dystonia, jerks, or anxiety. There was a significant positive correlation between extrastriatal SERT and striatal DAT BPND in CD patients with jerks, but not in patients without jerks. CONCLUSION: CD patients with psychiatric symptoms have lower SERT binding in the midbrain/diencephalon, while dystonia and jerks appear unrelated to SERT binding. The balance between extrastriatal SERT and striatal DAT binding is different in CD with and without jerks.

Bilateral deep brain stimulation in Parkinson's disease: a multicentre study with 4 years follow-up.

Deep brain stimulation (DBS) is associated with significant improvement of motor complications in patients with severe Parkinson's disease after some 6-12 months of treatment. Long-term results in a large number of patients have been reported only from a single study centre. We report 69 Parkinson's disease patients treated with bilateral DBS of the subthalamic nucleus (STN, n = 49) or globus pallidus internus (GPi, n = 20) included in a multicentre study. Patients were assessed preoperatively and at 1 year and 3-4 years after surgery. The primary outcome measure was the change in the 'off' medication score of the Unified Parkinson's Disease Rating Scale motor part (UPDRS-III) at 3-4 years. Stimulation of the STN or GPi induced a significant improvement (50 and 39%; P < 0.0001) of the 'off' medication UPDRS-III score at 3-4 years with respect to baseline. Stimulation improved cardinal features and activities of daily living (ADL) (P < 0.0001 and P < 0.02 for STN and GPi, respectively) and prolonged the 'on' time spent with good mobility without dyskinesias (P < 0.00001). Daily dosage of levodopa was significantly reduced (35%) in the STN-treated group only (P < 0.001). Comparison of the improvement induced by stimulation at 1 year with 3-4 years showed a significant worsening in the 'on' medication motor states of the UPDRS-III, ADL and gait in both STN and GPi groups, and speech and postural stability in the STN-treated group. Adverse events (AEs) included cognitive decline, speech difficulty, instability, gait disorders and depression. These were more common in patients treated with DBS of the STN. No patient abandoned treatment as a result of these side effects. This experience, which represents the first multicentre study assessing the long-term efficacy of either STN or GPi stimulation, shows a significant and substantial clinically important therapeutic benefit for at least 3-4 years in a large cohort of patients with severe Parkinson's disease.

Effect of bilateral subthalamic nucleus stimulation on balance and finger control in Parkinson's disease.

We aimed to quantify the effects of bilateral subthalamic nucleus (STN) stimulation in Parkinson's disease (PD) on stance and gait ("axial"motor control), and related this to effects on finger movements ("appendicular" motor control). Fourteen PD patients and 20 matched controls participated. Subjects completed several balance and gait tasks (standing with eyes open or closed, on a normal or foam surface; retropulsion test; walking with eyes closed; walking up and down stairs; Get Up and Go test). Postural control was quantified using trunk sway measurements (angle and angular velocity) in the roll and pitch directions. Subjects further performed a pinch grip reaction time task, where we measured isometric grip forces, as well as movement and reaction times. Patients were examined with STN stimulators switched on or off (order randomised across patients), always after a supramaximal levodopa dosage. STN stimulation improved postural control, as reflected by a reduced trunk sway tremor during stance, a reduced duration for all gait tasks, an increased trunk pitch velocity while rising from a chair, and improved roll stability. STN stimulation also improved finger control, as reflected by a reduced time to reach maximum grip force, without altering reaction times and maximum force levels. Improvements in finger control timing did not correlate with reduced task durations during gait. We conclude that STN stimulation affords improvement of postural control in PD, over and above optimal drug treatment. STN stimulation also provides a simultaneous effect on distal and axial motor control. Because improvements in distal and axial motor control were not correlated, we assume that these effects are mediated by stimulation of different structures within the STN.

[Primary generalized dystonia and deep brain stimulation: a randomized, placebo-controlled, double-blind, multicentre study]. / Primaire gegeneraliseerde dystonie en diepe hersenstimulatie: een gerandomiseerd, placebogecontroleerd, dubbelblind, multicentrisch onderzoek.

Dystonia describes a group of movement disorders characterized by involuntary muscle contractions which cause twisting involuntary movements and/or abnormal postures. Primary generalized dystonia often begins in childhood and over a number of years leads to a serious and debilitating illness. The effects of medication and physiotherapy are often disappointing. In the Netherlands a randomized, placebo-controlled and double-blind study has been started to examine the effects and risks of long-term deep brain stimulation in patients with primary generalized dystonia.

Rhythmic finger tapping reveals cerebellar dysfunction in essential tremor.

INTRODUCTION: Cerebellar circuits are hypothesized to play a central role in the pathogenesis of essential tremor. Rhythmic finger tapping is known to strongly engage the cerebellar motor circuitry. We characterize cerebellar and, more specifically, dentate nucleus function, and neural correlates of cerebellar output in essential tremor during rhythmic finger tapping employing functional MRI. METHODS: Thirty-one propranolol-sensitive essential tremor patients with upper limb tremor and 29 healthy controls were measured. T2*-weighted EPI sequences were acquired. The task consisted of alternating rest and finger tapping blocks. A whole-brain and region-of-interest analysis was performed, the latter focusing on the cerebellar cortex, dentate nucleus and inferior olive nucleus. Activations were also related to tremor severity. RESULTS: In patients, dentate activation correlated positively with tremor severity as measured by the tremor rating scale part A. Patients had reduced activation in widespread cerebellar cortical regions, and additionally in the inferior olive nucleus, and parietal and frontal cortex, compared to controls. CONCLUSION: The increase in dentate activation with tremor severity supports involvement of the dentate nucleus in essential tremor. Cortical and cerebellar changes during a motor timing task in essential tremor might point to widespread changes in cerebellar output in essential tremor.

Multiple system atrophy and progressive supranuclear palsy. Diminished striatal D2 dopamine receptor activity demonstrated by 123I-IBZM single photon emission computed tomography.

OBJECTIVE: To measure D2 dopamine receptors in the striatum in patients with multiple system atrophy and progressive supranuclear palsy by I 3-iodo-6-methoxybenzamide labeled with iodine I 123 (123I-IBZM) single photon emission computed tomography and differentiate them from control subjects. DESIGN: Survey with the following as retrospective criterion standards: (1) parkinsonism, (2) negative apomorphine test, and (3) no or only slight reaction to dopaminergic medication. SETTING: Ambulatory or hospitalized care in an academic referral center. PATIENTS AND CONTROL SUBJECTS: Twenty-one patients with parkinsonism not responding to dopaminergic medication (17 with multiple system atrophy and four with progressive supranuclear palsy) and 21 control subjects without parkinsonism. INTERVENTION: In vivo imaging by single photon emission computed tomography using the D2 dopamine receptor specific radioligand 123I-IBZM. MAIN OUTCOME MEASURE: Striatum/occipital cortex ratio of count rate density as semiquantitative measurement for striatal D2 dopamine receptor density. RESULTS: A highly significant loss of striatal uptake of 123I-IBZM was observed in the patients in comparison to the control subjects with little or no overlap between values. CONCLUSIONS: The hypothesized loss of D2 receptors in multiple system atrophy has been confirmed. Use of 123I-IBZM single photon emission computed tomography may be a cost-effective alternative to positron emission tomography in the differential diagnosis of parkinsonism and in the selection of patients for dopaminergic therapy.

Long-term effect of botulinum toxin on impairment and functional health in cervical dystonia.

We investigated the long-term effect of botulinum toxin type A (BTA) on impairment as well as functional health in terms of disability, handicap, and quality of life in 64 patients with cervical dystonia. These patients, who first participated in a double-blind trial, were followed for another 12 months. Fifty-four patients continued treatment after 12 months of follow-up and showed improvement on all scales. Furthermore, this effectiveness appeared to increase during follow-up, which suggests a cumulative clinical effect of BTA.

Motor persistence of orbicularis oculi muscle in eyelid-opening disorders.

We describe clinical and EMG findings in three patients with an inability to reopen the eyes after voluntary closure of the eyelids. Synchronous EMG recording from the levator palpebrae (LP) and orbicularis oculi (OrbOc) muscles revealed that after voluntary closure of the eyelids and upon the command to open the eyes, all three patients were unable to inhibit the "voluntary" contraction of the OrbOc muscles, while on clinical examination there was no evidence of ongoing OrbOc muscle contraction. This "motor persistence" was restricted predominantly to the pretarsal portion of the OrbOc. In one patient, it occurred as an isolated abnormality of the eyelid movement and was recorded as an additional EMG abnormality in two patients with blepharospasm and involuntary LP inhibition. Clinical examination alone cannot differentiate this type of disorder of supranuclear control of eyelid movement from involuntary LP inhibition; simultaneous EMG recording from the LP and OrbOc muscles is required. Injection of botulinum toxin into the pretarsal portion of OrbOc muscles is helpful.

Blepharospasm in association with a lower pontine lesion.

A patient with neurofibromatosis type I and breast carcinoma developed a bilateral but asymmetric blepharospasm and paresis of the left abducens muscle over a 2-week course. MRI disclosed a small lesion in the left dorsomedial lower pontine region. Electrodiagnostic investigations revealed bilateral R1 responses after stimulation of the left supraorbital nerve and enhancement of R1 and R2 recovery curves. We concluded that lesions in the lower pontine tegmentum may cause blepharospasm.

A comparison of neuropsychological effects of thalamotomy and thalamic stimulation.

OBJECTIVE: The neuropsychological effects of thalamotomy and thalamic stimulation in patients with severe drug-resistant tremor due to PD, essential tremor (ET), or MS were compared in a randomized trial. METHODS: Complete neuropsychological evaluations at baseline and 6 months after surgery were obtained in 62 patients who underwent thalamotomy (n = 32: 21 PD, 6 ET, 5 MS) or thalamic stimulation (n = 30: 19 PD, 7 ET, 4 MS). RESULTS: Six months after thalamotomy, a decline was seen in the scores of the Stroop Color-Word Test, with the exception of the interference score. In the thalamic stimulation group, no significant changes were found on any of the cognitive tests. Age, diagnosis, disease severity, and baseline cognitive status were not correlated to cognitive changes. A difference in score changes between right- and left-sided surgery was found in verbal fluency and Stroop Test scores after both thalamotomy and thalamic stimulation. CONCLUSIONS: Both thalamotomy and thalamic stimulation are associated with a minimal overall risk of cognitive deterioration. Verbal fluency decreased after both left-sided thalamotomy and thalamic stimulation.