A single centre prospective study of three device-assisted therapies for Parkinson's disease.

Comparative studies assessing outcomes with the three device-assisted therapies could help to individualise treatment for patients living with Parkinson's disease. We designed a single-centre non-randomised prospective observational study assessing the quality of life (QoL), motor and non-motor outcomes at 6 and 12-months in patients treated with subcutaneous apomorphine continuous 16-hours infusion (APO), levodopa-carbidopa intestinal gel (LCIG) or subthalamic nucleus deep brain stimulation (STN-DBS). In this study, 66 patients were included (13 APO; 19 LCIG; 34 STN-DBS). At baseline, cognitive, non-motor and motor scores were significantly less severe in the STN-DBS group, whereas the LCIG group had a longer disease duration and higher non-motor scores. In the APO group, there were no statistically significant changes in non-motor, motor and QoL scales. The LCIG group had significant changes in QoL and motor scales that were significant after multiple comparison analysis at 6 and 12-months. The STN-DBS group showed improvement in QoL scores and non-motor and motor scores at 6 and 12-months after multiple comparison analysis. In this real-life prospective study, device-assisted therapies showed differences in their effects on QoL and motor and non-motor function at 12-months. However, there were also differences in baseline characteristics of the patient groups that were not based on pre-determined selection criteria. Differences in characteristics of patients offered and/or treatment with different device-assisted therapies may reflect within-centre biases that may, in turn, influence perceptions of treatment efficacy or outcomes. Treatment centres should be aware of this potential confounder when assessing and offering device-assisted treatment options to their patients and potential baseline differences need to be taken into consideration when comparing the results of non-randomised studies.

Neuroimaging Pearls from the MDS Congress Video Challenge. Part 2: Acquired Disorders.

The MDS Video Challenge continues to be the one of most widely attended sessions at the International Congress. Although the primary focus of this event is the presentation of complex and challenging cases through videos, a number of cases over the years have also presented an unusual or important neuroimaging finding related to the case. We reviewed the previous Video Challenge cases and present here a selection of those cases which incorporated such imaging findings. We have compiled these "imaging pearls" into two anthologies. The first focuses on pearls where the underlying diagnosis was a genetic condition. This second anthology focuses on imaging pearls in cases where the underlying condition was acquired. For each case we present brief clinical details along with neuroimaging findings, the characteristic imaging findings of that disorder and, finally, the differential diagnosis for the imaging findings seen.

Parkinsonism in PGK1 deficiency implicates the glycolytic pathway in nigrostriatal dysfunction.

BACKGROUND: Phosphoglycerate kinase-1 deficiency is caused by X-linked recessive mutations in PGK-1 and associated with haemolytic anaemia, rhabdomyolysis, myopathy and nervous system involvement. Some cases have been rarely associated with juvenile Parkinsonism however the causal relationship between PGK1 deficiency and nigrostriatal dysfunction causing Parkinsonism has not been determined. OBJECTIVE AND METHODS: To investigate the nigrostriatal system using 99mTc-TRODAT-1 SPECT binding and report the phenotype of three affected males with early onset levodopa responsive Parkinsonism harbouring the c.491 A > T/p.D164V pathogenic variant. RESULTS: All patients initially presented with infantile-onset encephalopathic and stroke-like episodes, haemolytic anaemia and epilepsy. Two patients had an early-onset and one juvenile-onset levodopa responsive Parkinsonism with motor fluctuations. 99mTc-TRODAT-1 SPECT showed severe bilateral reduced putaminal uptake in the three patients. None of the patients had structural lesions that could explain either pre- or postsynaptic dopaminergic dysfunction. CONCLUSION: These cases provide strong evidence of a causal relationship between PGK1 deficiency and nigrostriatal pathology causing Parkinsonism. These findings have potential implications for our understanding of the pathophysiology of nigrostriatal degeneration in sporadic PD.

24-hour levodopa-carbidopa intestinal gel may reduce troublesome dyskinesia in advanced Parkinson's disease.

Levodopa-carbidopa intestinal gel (LCIG) is effective for the control of motor fluctuations in Parkinson's disease (PD). The objective of this study is to report the reduction of dyskinesias after transitioning from 16 to 24-h/day LCIG infusion. From a cohort of 74 PD patients treated with LCIG for motor fluctuations, we identified 12 patients that were treated with 24-h per day infusion with the aim to control troublesome daytime dyskinesia. Clinical, demographic, dyskinesia rating scales were evaluated. Daytime dyskinesia was reduced in 75% (9/12) patients following treatment with 24-h therapy, including 7 who were compared with 16-h therapy and 2 that were transitioned from oral dopaminergic therapy to 24-h LCIG. Combining the data from all 12 subjects, troublesome dyskinesias were reduced during 24-h LCIG; UPDRS 4.1 (time spent with dyskinesias) mean change was -1.5 ± 0.75, p = 0.010 (Wilcoxon signed-rank test) and UPDRS 4.2 (functional impact of dyskinesias) mean change was -1.7 ± 0.90, p = 0.016, without changing their UPDRS part 3 "ON" scores (p = 0.138) or H&Y (p = 0.157). In 5 patients, improvement in dyskinesia occurred despite an overall increase in the total daily levodopa dose. None of the patients had worsening of dyskinesia after a median follow-up of 28 months. 24-h per day infusion of LCIG may be a useful strategy in the management of troublesome dyskinesias in PD patients with disabling dyskinesias resistant to attempts to optimise 16-hours per day therapy. We postulate that this may be due to a pharmacodynamic as opposed to pharmacokinetic mechanism.

Neurophysiological Features Of Hemiballism.

Hemiballism is a rare hyperkinetic movement disorder. The pathophysiology of hemiballism is poorly understood, and there have been few reports of neurophysiological recordings. The authors report three cases of hemiballism with associated radiological and neurophysiological findings. In patients 1 and 2, who were studied in the acute phase 4 and 14 days after presentation, irregularly timed and predominantly long-duration electromyographic (EMG) bursts were observed typically ranging from 200 to 1500 milliseconds in duration and occurring asynchronously or alternating in antagonist muscles. In patient 3, who was studied 6 weeks after presentation when the involuntary movements had become choreiform, the EMG bursts were still from 200 to 1000 milliseconds in duration but were more synchronous or co-contracting. The flailing movements of hemiballism appear to occur as a result of prolonged bursts of EMG activity generated in individual muscles unopposed by EMG bursting in the antagonist. During the subacute phase when the movements become more choreiform, the results indicate that EMG activity becomes more synchronous or co-contracting.

Intraduodenal levodopa-carbidopa intestinal gel infusion improves both motor performance and quality of life in advanced Parkinson's disease.

We report the efficacy and adverse effect profile of intraduodenal levodopa-carbidopa intestinal gel (LCIG) infusion from patients treated in a single Australian movement disorder centre. We conducted an open-label, 12 month prospective study of treatment with LCIG in patients with advanced Parkinson's disease in a single tertiary referral hospital unit specialising in movement disorders. Patients with levodopa-responsive, advanced Parkinson's disease with motor fluctuations despite optimal pharmacological treatment were enrolled and underwent a 16 hour daily infusion of LCIG for 12 months. Fifteen participants completed the trial. The mean (± standard deviation) improvement in Unified Parkinson's Disease Rating Scale part III was 37 ± 11%, mean daily "off" period reduced from 6.3 ± 2 to 1.9 ± 2 hours, total daily "on" time increased from 10.2 ± 3 to 13.7 ± 2 hours, "on" period without dyskinesia increased from 4.5 ± 3 to 7.5 ± 5 hours, and 39-item Parkinson's Disease Questionnaire Summary Index score improved by 32.5 ± 35%. The most common adverse event was reversible peripheral neuropathy secondary to vitamin B12 ± B6 deficiency (40%), local tube problems (40%), and impulse control disorder (ICD) (27%). No patient had stoma bleeding or peritonitis. All patients with ICD had a past psychiatric diagnosis of depression with or without anxiety and a higher daily levodopa intake at 6 and 12 months of LCIG infusion. Intraduodenal LCIG improves motor performance, quality of life and daily "on" period. Prior to and during duodenal LCIG infusion, clinicians should monitor for peripheral neuropathy and vitamin B12 and B6 deficiency, as supplementation can reverse peripheral neuropathy. This trial is registered at Clinicaltrials.gov as CT00335153.

24 h Levodopa-carbidopa intestinal gel may reduce falls and "unresponsive" freezing of gait in Parkinson's disease.

OBJECTIVE: We report a prospective, open label study of 24 h levodopa-carbidopa intestinal gel (LCIG) as treatment for levodopa "unresponsive" freezing of gait (FOG) associated with Parkinson's disease. METHOD: 5 patients with disabling FOG, documented as being levodopa "unresponsive", were commenced on continuous 24 h infusion LCIG therapy with the night-time rate at 50-80% of the daytime infusion rate. Patients underwent baseline, 3 and 6 month gait assessments, documentation of their falls frequency and completed FOG questionnaires. RESULT: Median 360° turn time improved by 54%, fall frequency score reduced from 3 to 0 at 6 months, FOG questionnaire score improved by 14% and Timed Up- and -Go 8 m walk was unchanged. CONCLUSION: 24 h LCIG therapy may reduce levodopa "unresponsive" FOG and associated falls. A larger prospective study is needed for confirmation.

Dramatic improvement of truncal tardive dystonia following globus pallidus pars interna deep brain stimulation.

Truncal predominant tardive dystonia is an uncommon presentation of dystonia, and may be associated with significant disability. We report a patient with near-complete resolution of severe, disabling truncal tardive dystonia following globus pallidus pars interna deep brain stimulation. Her unusual clinical presentation highlights the difficulties in diagnosing unusual forms of dystonia, and the therapeutic gains that can be achieved once the diagnosis is recognised.

Resolution of Othello Syndrome After Subthalamic Nucleus Deep Brain Stimulation in 3 Patients with Parkinson's Disease.

Psychiatric symptoms are historically thought a relative contraindication to DBS for advanced Parkinson's disease (PD). However, in the case of drug-induced mental illness, DBS may provide an acceptable alternative for the treatment of motor symptoms. This allows reduction of pharmacological dopaminergic therapy that might otherwise cause negative psychiatric consequences. For example, DBS is increasingly used to ameliorate specific complications of PD treatment, such as impulse control disorders. We present a series of 3 cases of young male patients who developed Othello syndrome (OS) during treatment with dopamine agonists. In each case, the OS resolved with withdrawal of the offending drug. Subsequent treatment with bilateral STN DBS improved motor symptoms and allowed reduction in their dopaminergic drug regimen. We therefore propose that drug-induced psychopathology may be an indication (rather than a contraindication) for DBS in selected cases.

Huntington's disease.

PURPOSE OF REVIEW: This review highlights the recent advances in Huntington's disease, with particular focus on clinical characterization of prodromal Huntington's disease, as well as the growing literature regarding pathophysiological mechanisms and their relevance to potential therapeutic targets. RECENT FINDINGS: Clinical and neuroradiological abnormalities can be demonstrated in gene-positive individuals prior to the onset of manifest Huntington's disease, even as far as 15 years before the disease onset. Although some measures show promise as potential markers of disease progression, further longitudinal studies are required. Several molecular pathways have been implicated in the process of neurodegeneration involved in Huntington's disease and provide potential therapeutic targets. SUMMARY: With predictive testing allowing the identification of gene-positive individuals prior to disease onset, the prodromal stage of Huntington's disease provides an ideal period for the use of disease-modifying therapy. A quantifiable and reliable biomarker for monitoring disease progression is crucial for clinical studies of neuroprotection, and this remains an area of active research. Understanding of the underlying pathophysiological mechanisms continues to grow, based mainly on cellular and animal models of Huntington's disease.

The phenotypic spectrum of dystonia in Mohr-Tranebjaerg syndrome.

Mohr-Tranebjaerg syndrome (MTS) is an X-linked recessive disorder characterized by deafness and dystonia. However the phenotypic expression of dystonia has not been systematically defined. We report clinical, neurophysiological, and ophthalmological data on 6 subjects from 3 Australian kindreds, including 2 with novel mutations, together with a systematic review of the literature, in order to define the phenotypic expression of dystonia. Profound hearing impairment in affected males develops by infancy and precedes the development of dystonia, which varies in time of onset from the first to the sixth decades, with a peak in the second and third decades. Dystonia in MTS tends to be focal, segmental, or multifocal in distribution at onset, with a predilection for the upper body, variably involving the head, neck, and upper limbs. The majority of patients have progression or generalization of their dystonia regardless of age of onset. Within our 3 kindreds, we observed relative intrafamilial homogeneity but interfamilial variation. The median time to the development of moderate-severely disabling dystonia in these subjects was 11 years. Associated features included progressive cognitive decline, pyramidal signs, and in 1 patient, gait freezing and postural instability. Optic atrophy and cortical visual impairment were both observed. We report for the first time a female patient who developed multiple disabling neurological complications of MTS. Our findings more clearly define and expand the phenotype of both the dystonia and other neurological features of MTS and have implications for the diagnosis and management of this condition.

Pain in Parkinson's disease.

Pain and other nonmotor symptoms in PD are increasingly recognized as a major cause of reduced health-related quality of life. Pain in PD may be categorized into a number of different subtypes, including musculoskeletal, dystonic, radicular neuropathic, and central pain. The onset of pain can vary in relation to motor symptoms, and may precede the appearance of motor symptoms by several years, or occur after the diagnosis of PD has been made. Pain in PD is frequently under-recognized and is often inadequately treated. Levodopa-related dystonia may respond to manipulation of dopaminergic medication. Dopaminergic therapy may also improve musculoskeletal pain related to rigidity and akinesia, as well as akathisia in PD. Botulinum toxin injections can be effective for treatment of painful focal dystonia. Pain and dysesthesia have been reported to improve with DBS, in some cases. Increased understanding of basal ganglia pathways has provided further insights into the pathogenesis of pain in PD, but the exact mechanism of pain processing and modulation remains unclear.

Convergence spasm in conversion disorders: prevalence in psychogenic and other movement disorders compared with controls.

BACKGROUND: Convergence spasm refers to transient ocular convergence, miosis and accommodation associated with disconjugate gaze mimicking abducens palsy. While it may be a manifestation of brainstem pathology, this sign is often associated with conversion (somatisation) disorders and, if unrecognised as a sign of a psychogenic disorder, it may lead to unnecessary and occasionally invasive evaluation. METHODS: To better characterise this neuro-ophthalmologic sign, 36 subjects were studied, 13 with psychogenic movement disorders, 11 with organic movement disorders and 12 normal controls. Patients were recorded during a manoeuvre to elicit convergence spasm and the videotapes were rated by two blinded raters on a scale of 0=normal, 1=mild convergence spasm and 2=marked convergence spasm. RESULTS: Convergence spasm was present in 9/13 (69%) psychogenic movement disorders cases, 4/11 (36%) non-psychogenic movement disorders cases and 4/12 (33%) controls (p=0.049 when psychogenic vs non-psychogenic disorders or controls were compared). Inter-rater reliability analysis of the presence (rating 1 or 2) versus absence (rating 0) showed good agreement (27/36 or 75%; kappa 0.491, SE 0.141, p=0.002). Analysis for the presence of marked convergence spasm (rating 2) yielded agreement in 32/36 (88.9%) examinations (kappa 0.652, SE 0.154, p<0.001) with a specificity of 87% (sensitivity 15%). CONCLUSION: Convergence spasm may provide benefit in the clinical examination of psychogenic movement disorders patients.

Intermediate CAG Repeats in Huntington's Disease: Analysis of COHORT.

BACKGROUND: There is emerging evidence that clinical and neuro-pathological manifestations of Huntington's disease (HD) may occur in individuals with intermediate length cytosine-adenine-guanine (CAG) repeats (27-35 CAG repeats) in the Huntingtin (HTT) gene. We aim to further define the clinical characteristics of individuals who possess CAG repeat lengths in this range. METHODS: Data from the Cooperative Huntington's Observational Research Trial (COHORT) were analyzed. Participants were categorized according to the number of CAG repeats into normal (≤26), intermediate (27-35) and HD (≥36) groups. The motor, cognitive and behavioral scores on the Unified Huntington's Disease Rating Scale (UHDRS) were compared between the intermediate and normal groups. RESULTS: Of 1985 individuals affected by HD or with a family history of HD who were genotyped, 50 (2.5%) had their larger CAG repeat in the intermediate range. There were statistically significant differences in scores of some motor, cognitive, and behavioral domains of UHDRS at baseline between normal and intermediate length CAG repeats. Furthermore, a significantly greater number of subjects with CAG repeats in the intermediate range reported at least one suicide attempt compared to the normal group. DISCUSSION: Our findings of motor, cognitive and behavioral abnormalities in individuals with intermediate CAG repeats suggest the presence of subtle, but relevant, disease manifestations in patients with intermediate CAG repeats. These results have important implications for the pathogenesis of the disease and genetic counseling.

An introduction to dyskinesia--the clinical spectrum.

The term movement disorder is used to describe a variety of abnormal movements, and may involve an excess or paucity of movement. Careful characterization of phenomenology is an essential component of diagnosis. Factors such as speed, amplitude, duration, distribution, rhythmicity, suppressibility and pattern of movement provide valuable information to guide the clinician in their assessment of the movement disorder. In this chapter, the clinical spectrum and phenomenology of dyskinesias will be reviewed.

Exploring the correlates of intermediate CAG repeats in Huntington disease.

OBJECTIVE: To explore the clinical phenotype in individuals with huntingtin gene CAG repeat lengths between 27 and 35, a range that is termed "intermediate" and below one traditionally considered diagnostic of Huntington disease (HD). BACKGROUND: The Prospective Huntington Disease At-Risk Observational Study (PHAROS) found that patients with intermediate CAG lengths overlapped with those diagnosed as HD (≥ 37 CAG repeats) on the Unified Huntington's Disease Rating Scale (UHDRS) behavioral measures. Furthermore, several patients with intermediate CAG repeats demonstrating clinical (and pathological) evidence of HD have been reported. METHODS: We reviewed all cases with intermediate CAG repeats who have presented to our clinic, as well as those reported in the literature. RESULTS: We describe 4 patients with intermediate repeats evaluated at our center whose clinical features were highly suggestive of HD. Investigations for HD phenocopies were negative. Anticipation was demonstrated in 1 case with supportive neuropathological evidence of HD. Additionally, we describe the clinical features of 5 other patients reported in the literature. CONCLUSION: Individuals with huntingtin gene CAG repeats in the intermediate (27-35) range should be considered at risk for the development of HD, particularly if they have a family history of HD, whether they exhibit clinical features of the disease.

The prevalence of symptomatic orthostatic hypotension in patients with Parkinson's disease and atypical parkinsonism.

Non-motor symptoms in Parkinson disease (PD) have been increasingly recognized as a major cause of declining health-related quality of life. We aimed to determine the prevalence of symptomatic orthostatic hypotension (OH) in patients with PD and atypical parkinsonism, and to evaluate the risk factors for OH in this population. We reviewed the records of 1318 patients diagnosed with PD or atypical parkinsonism at the Parkinson's Disease Center and Movement Disorders Clinic, Baylor College of Medicine. The frequency of symptomatic OH was 81% (21/26) in patients with multiple system atrophy (MSA), 18% (198/1125) of PD patients, and 19% (31/167) of patients with non-MSA atypical parkinsonism. Among PD patients, those with symptoms of OH were significantly older (p = 0.001), had more advanced Hoehn & Yahr stage (p = 0.007), a longer duration of PD symptoms (p = 0.031), and a greater range between their highest and lowest sitting systolic and diastolic BPs (p = 0.0001) over time. In the atypical parkinsonism group, excluding MSA, patients with symptoms of OH were taking more anti-hypertensive medications than those without symptoms of OH (p = 0.043). On the other hand, MSA patients with symptoms of OH were less likely to be taking anti-hypertensive medications than those without symptoms (p = 0.035). In conclusion, symptomatic OH is a common cause of disability in patients with PD, atypical parkinsonian disorders, and especially in patients with MSA.