Resting tremor is considered to be a phenotype of Parkinson's disease. Isolated resting tremor of the lower limbs however is uncommon in Parkinson's disease. In this case series we report on three patients with isolated resting tremor of the lower limbs. One patient was diagnosed with Parkinson's disease, one with drug induced parkinsonism and in one a descriptive diagnosis of "benign tremulous parkinsonism" with a "Scan Without Evidence of Dopaminergic Deficit" was made. Deep brain stimulation of the ventral intermediate nucleus of the thalamus led to almost complete suppression of tremor in the Parkinson's disease patient. Our case series emphasizes the need to rethink the diagnosis of Parkinson's disease in patients with isolated resting tremor of the lower limbs and provides evidence for the ventral intermediate nucleus of the thalamus to be an effective target for Deep brain stimulation electrode placement in Parkinson's disease patients with isolated lower limb tremor.
A pathological communication between the basal ganglia (BG) and the cerebellum (Cb) at the level of the thalamus has been proposed to be causative for the generation of parkinsonian tremor. Recent studies, however, indicated, that altered Cb-thalamic circuitry is not only underlying the genesis of tremor, but is involved in the generation of other parkinsonian symptoms like bradykinesia and rigor. Hence, we studied the glucose metabolism of akinetic-rigid parkinsonian patients in (i) anatomical (anterior, medial, lateral, posterior) and (ii) projection territory-based (Cb- and BG-thalamic) subdivision of the human thalamus and compared them with healthy controls in order to predict disease progression irrespective of the symptom tremor. The dentate nucleus was representatively chosen as output station for Cb regions, BG regions comprised the pallidum. Regarding (i) the anatomical subdivision we found no significant difference between patients and controls in the glucose metabolism for the anterior and medial group (p > 0.05), but an increase of glucose metabolism for the lateral and posterior group (p < 0.05). The glucose metabolism under (ii) the tractography-based subdivision revealed significant differences between patients and controls in the left (p < 0.05) and right (p < 0.01) Cb-thalamic, but not the BG-thalamic projection territory (p > 0.05). In order to WA for disease specific alterations, we correlated bihemispherically averaged thalamic glucose metabolism for the anterior, medial, lateral and posterior thalamic group with disease progress (reflected by the Hoehn & Yahr score) and found a significant prediction of the glucose metabolism of the lateral thalamic group and the disease progression (p < 0.05; r = 0.4). A further subdivision into patients with right and left symptom onset evoked a group of 14 right- and 13 left affected patients. Again, we correlated clinical parameters of disease progression with the results of glucose metabolism and found a significant correlation of the right affected patients (p < 0.05) with the right Cb-thalamic region reflected by an up-regulation of glucose metabolism; right affected patients frequently show slower disease progression than left affected patients. Hence our results support a critical (maybe compensatory) role of the Cb-thalamic projections and forces a more straightforward thinking away from a pure "symptom-oriented" to a "dynamic-circuitry" approach due to functional changes in glucose metabolism with Cb and BG as one of the circuitry key elements defining the clinical parkinsonian phenotype.
Introduction: Aassessing movement disorders in daily life can provide information that might not be available during a short clinical visit. This review provides an overview of the currently available ambulatory registration methods to assess motor symptoms. Methods: A systematic review was performed of ambulatory registration methods, registering motor symptoms for at least 24 h. The following characteristics were studied: study goal, study population, data acquisition, outcome measures, and data interpretation. Results: For the classical subjective approach, a patient-kept diary, two types are widely applied: the ON/OFF diary to assess the medication response status in patients with Parkinson's Disease (PD), and the fall diary to assess fall frequency. Both diaries are established methods for clinical decision-making. However, both diaries have disadvantages, especially since self-report might not always agree with clinicians' ratings. An often-used alternative objective approach that employs accelerometry can assess activity levels and gait, monitor disease progression and distinguish between healthy controls and patients. However, accelerometry cannot reliably assess medication status in PD nor distinguish between different diseases. Also due to the heterogeneity in body locations for the accelerometer and outcome measures, there are no gold standards to rely on. Accelerometry to assess tremor can be used to obtain clinically valid measures. The combination of objective and subjective measurements is, at this point, mainly useful for scientific research. Conclusion: Subjective measurements of ON/OFF status and fall frequency remain the most widely adopted long-term registration methods. Most other methods first need more validation in a clinical setting before they can be applied in patient care.
Introduction The aim was to compare evoked potentials (EP) from the P300 paradigm against mismatch negativity (MMN) paradigm, both recorded in the subthalamic nucleus (STN), internal globus pallidus (GPi) and thalamus (Th) and thus electrophysiologically isolate conscious cognition component in these structures. Methods We included 8 patients in Deep brain stimulation program and recorded EP (patients with Parkinson's disease, Generalized dystonia, Essential tremor, Epilepsy). The two four-contacts intracerebral electrodes were implanted into the left and right STN, GPi or Th bilaterally. We computed local potentials on the left and right electrode and we studied the latency of cognitive response (from 200 to 400 ms). Results In the comparison of infrequent stimuli related P300 and MMN a significant difference was found in 14 from 16 electrodes. Comparing frequent answers we found significant difference in 13 from 16 electrodes. Conclusion The difference between evoked potentials of MMN and P300 protocols in 200–400 ms latency suggests that STN, GPi and Th are involved in conscious cognitive processes at the time of stimuli application.
•The levodopa/carbidopa intestinal gel is a device assisted therapy of particular value in patients with levodopa responsive advanced Parkinson disease.•Costs and procedural issues influence patient initiation and retention on treatment.•Optimising approaches in the pre-treatment and maintenance phases of therapy to address individual needs can maximise benefits of this form of therapy.
•First report of ataxic phenotype of SCA3 with parkinsonism responding to levodopa.•Modest CAG repeat expansion, which had been previously associated with parkinsonian phenotype.•Unusually, high dose levodopa caused motor fluctuations and peak-dose dyskinesias.•Therapeutic effect of levodopa and dyskinesias both likely due to presynaptic dopaminergic deficit.•This mimics idiopathic PD, therefore genetic testing may be considered for patients with otherwise typical parkinsonism.
Background: Familial Parkinson's Disease (familial PD) and Early-Onset Parkinson's Disease (EOPD) are both uncommon disorders. Genetic analyses of familial EOPD have been limited due to its rarity. Here, we report four members of a family with familial EOPD carrying a novel mtDNA variation. Case report: Four members of a family presenting with bradykinesia, muscular rigidity and resting tremor were diagnosed as having familial EOPD. The patients' peripheral blood was analyzed for the presence of three previously known mtDNA variations in PD, viz m.4216T > C, m.4917A > G, and m.15928G > A using PCR-RFLP; none of these variants were identified in the four patients. However, we found a novel mtDNA m.4079A > G variation in ND1 (NADH dehydrogenase 1) gene in all the tested four family members. Discussion: The m.4079A > G is a missense variation giving rise to a Tyr-Cys aminoacid substitution in ND1 protein (ND1:p.Tyr258Cys). This may lead to a defective protein influencing oxidative phosphorylation. Therefore, wider analyses of mRNA expression, protein transcription, and functional neuroimaging of brain energy metabolism are required in EOPD patients.
Cognitive impairments in Parkinson's disease have been studied with great interest, and decision-making abilities in particular have received attention over the past decade. The degree of decision-making impairments in Parkinson's disease has been debated in relation to different types of decision-making tasks and the possible effect of dopaminergic medication, among others. The present review presents a systematic overview of literature investigating decision-making in patients with Parkinson's Disease treated with dopaminergic medication. The aim of the review is to discuss decision-making impairments displayed by patients considering effects of dopaminergic medication. Patients with Parkinson's Disease on dopaminergic medication were found to be impaired in decision making tasks. Dopaminergic medication has a complex, but often significant, relationship with decision making impairments. Finally, the influence of methodological differences in the assessment of decision-making will be considered offering important implications for future research.
L-dopa is still the cornerstone symptomatic medication for Parkinson disease (PD), although it cannot stop the neurodegenerative process progression or even aggravate it. Filgrastim (G-CSF) is a hematopoietic growth factor, exhibited neurotrophic, antioxidant, anti-apoptotic, immunomodulating and neuroprotective potentialities. The present study assessed the possible modulating potentialities of filgrastim on L-dopa treatment's drawbacks in a mouse model of PD. Male BALB/c mice received 30 mg/kg/day rotenone suspended in 0.25 ml 0.5% CMC in PBS for 28 days orally from day 1st until the day 28th of the experiment for induction of PD. Since day 29th fill day 43rd, mice treated with either 10 mg/kg/day L-dopa and 2.5 mg/kg/day carbidopa suspended in 0.25 ml 0.5% CMC in PBS orally, 50 mu g/kg/day filgrastim in 0.1 ml 5% dextrose SC or a combination of both. Filgrastim, in the present study, able to alleviate the L-dopa therapy's drawbacks in PD that revealed by the restoration of the exhausted nigrostriatal GSH level, and the reduction of the elevated nigrostriatal MDA, NO and TNF-alpha levels that deteriorated by L-dopa therapy. Moreover, the co-therapy of filgrastim with L-dopa, considerably potentiated the deteriorated mice's working memory, and abrogated the nigrostriatal histopathological changes and caspase-3 immunohistochemical expression, failed to improve by L-dopa therapy. Furthermore, the filgrastim co-therapy with L-dopa demonstrated a remarkable improvement in the nigrostriatal dopamine level, and repression of rotenone-induced descent latency prolongation, as well as, stride length reduction than each alone. Therefore, filgrastim is promising, as a disease-modifying therapy, in amelioration of L-dopa therapy's drawbacks in PD.
Oromandibular dystonia (OMD) is a severely disabling disorder with limited available therapies. Current oral medications for OMD are ineffective and may pose further risks of aspiration particularly in combination states of jaw and tongue dystonia. We advocate the use of Botulinum neurotoxin (BoNT) injection with proper muscle site selection and dosing as the most effective treatment in OMD clinically. Targeting muscle for injection should involve not only an astute clinical examination and understanding the patient's history, but perhaps also guided by instrumentation. Based on our previous and present case series, we present specific localization techniques for BoNT in OMD patients subsequent to methodical patient selection, proper BoNT reconstitution and conversion. We believe adequate knowledge and appropriate technique will give our patients greatest benefit and will minimize risk of adverse events following treatment.
The patient was a 64-year-old man who presented with gait disturbance at the age of 58. He was later diagnosed with Parkinson's disease. At the age of 64, he felt severe right abdominal pain because his right abdomen was compressed by his abnormal posture. Neurological examinations showed axial flexion to the anterior and right sides, i.e. a combination of camptocormia and Pisa syndrome, and hypertrophy of the right lumbar paraspinal muscles in addition to parkinsonism. Surface electromyography and body computed tomography suggested axial dystonia, i.e. right dominant hyperactivity and hypertrophy of the lumbar paraspinal muscles. Botulinum toxin was injected into the right lumbar paraspinal muscles. One month later, his abnormal posture improved and his right abdominal pain was also relieved. In general, botulinum toxin treatment of the paraspinal muscles has the potential to improve Pisa syndrome but carries the risk of worsening camptocormia. However, in our case, not only Pisa syndrome but also camptocormia improved. Therefore, we should note that botulinum toxin treatment of paraspinal muscles is able to improve not only Pisa syndrome but also camptocormia. As a plausible explanation, botulinum toxin treatment could control the hyperactivity of the bilateral paraspinal muscles symmetrically, which might improve camptocormia in addition to Pisa syndrome.
Background: Freezing of gait (FoG) is one of the most incapacitating symptoms of Parkinson's disease (PD) and has been linked to imbalances in the dopaminergic and noradrenergic neurotransmitter systems. Methylphenidate blocks the reuptake of these neurotransmitters, increasing their extracellular concentrations in the striatum and prefrontal cortex. This quantitative pooled analysis was aimed at determining the efficacy and safety of high dose methylphenidate in the treatment of FoG, motor and non-motor symptoms in advanced PD. Methods: Electronic databases were searched for randomized, double-blind, placebo-controlled trials examining the efficacy and safety of methylphenidate (0.8-1.0 mg/kg/day) in FoG. Fixed effects analysis with mean difference of number of freezing episodes was used as primary outcome. Secondary outcomes included Unified Parkinson Disease Rating Scale (UPDRS) Part III score, Montgomery-Asberg Depression Rating Scale (MADRS) score, Epworth Sleepiness Scale (ESS) score and incidence of adverse events. Results: Two studies were included with a total of 92 patients. High dose methylphenidate was able to reduce the number of freezing episodes with a MD - 1.52 (95% CI - 2.91, -0.11, p = .03). However, the drug was not able to offer significant improvement in terms of UPDRS Part III score in the "off" (MD - 1.87; 95% CI -6.42, 2.69, p = .40) and the "on" state (MD 1.38; 95% CI -2.91, -0.11, p = 0.54), MADRS Score (MD -0.38, 95% CI -2.37, 1.60, p = .35) and ESS Score (MD -1.09, 95% CI -3.44, 1.26, p = .68). A small but statistically significant proportion of patients given high dose methylphenidate reported nausea, vomiting, and gastritis (MD 4.86, 95% CI 1.15, 20.56, p = .03) Conclusion: High dose methylphenidate can only marginally, however significantly reduce the number of freezing episodes in patients with advanced PD with a MD -1.52 (95% CI -2.91, -0.11, p = .03).
•Patients with autism have deficits in response inhibition, interference control.•Patients with autism are impaired in motor timing.•Some inhibitory tasks are not able to detect inhibitory deficits in autism.•Patients with autism show atypical brain activity of fronto-parietal network.•Future research should focus on inhibitory process in social-relevant context.
Introduction: Individuals with cervical dystonia (CD) often report difficulty with balance and an altered perception of vertical. Previous studies have suggested a decreased proprioceptive response to stretch of neck muscle spindles in these patients, and impaired dynamic balance changes in individuals with tremor. Methods: Participants with CD were divided into three groups based on severity of tremor and dystonic position on the Toronto Western Spasmodic Torticollis Rating Scale 2 (TWSTRS2). Unaffected controls completed assessments including Fukuda, modified Romberg, and subjective visual vertical tests. Participants with CD completed the same assessments at baseline and 4 to 6 weeks following botulinum toxin treatment. Results: CD participants with marked tremor and deviation had more difficulty perceiving what was vertical as demonstrated by a greater degree off midline on the subjective visual vertical test, compared to individuals with marked tremor with minimal deviation and controls, though this was not significant after adjustment for multiple comparisons. Individuals with CD also had more difficulty maintaining balance on a compliant surface with eyes closed compared to controls on the modified Romberg test. TWSTRS2 motor severity score was significantly associated with degrees off midline on the subjective visual vertical test at baseline for CD participants, but not after botulinum toxin treatment. Conclusions: Individuals with more severe tremor and dystonic posture appear to have an altered perception of vertical associated with CD severity and that may improve following botulinum toxin treatment. Modified Romberg testing suggests that visual cues may also be important to compensate for tremor and dystonic positions found in CD.
Background: Multiple system atrophy (MSA) is a sporadic, adult-onset and rapidly progressive neurodegenerative disorder. MSA clinically is characterized by prominent autonomic dysfunction with combinations of parkinsonism (MSA-P), cerebellar ataxia (MSA-C) and possible corticospinal signs. To date no disease-modifying treatment is available. Motor symptoms of certain patients with MSA-P, however, are somewhat responsive to dopaminergic medication. Objective: To present the analysis of symptomatic treatment options on 97 patients suffering from probable MSA-P. Methods: A retrospective survey was conducted on 97 patients from a specialized neurological acute care hospital, all meeting appropriate published criteria of probable MSA-P. We undertook a thorough analysis on patients' records regarding the dopaminergic drugs and amantadine. Results: Ten patients from our study cohort received no L-dopa, in the remaining 87 patients (89.69%) the mean L-dopa daily dose was 650.93 +/- 289.21 mg. Fifteen study patients received >= 1000 mg of L-dopa per day. For 31 MSA-P patients (31.96%) dopamine agonists were added as a second treatment option with pramipexole and ropinirole being the most frequently used. Further, two study patients received amantadine as an alternative medication. Conclusions: In the study the considerable proportion of MSA-P patients received high levels of dopaminergic medication chronically. Its efficacy on MSA is still uncertain and further studies with standardised clinical efficacy monitoring are highly welcome.
Objective: Several previous linkage and association studies and an expression analysis have suggested the gamma-aminobutyric acid type A receptor beta3 subunit (GABRB3) gene as an important candidate gene for autism. In addition, polymorphisms in the promoter region of GABRB3 might modulate the expression of this gene. In order to investigate the underlying mechanism of the role of GABRB3 in autism susceptibility, we designed a case-control study to analyze the association of the rs4906902 single nucleotide polymorphism (SNP) in the promoter region of the GABRB3 gene with autism spectrum disorder (ASD) in Iranian patients. Materials & methods: The rs4906902 polymorphism was genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The frequency of the risk allele and its association with disease was examined in 518 patients and 472 control individuals. Result: The results demonstrated that the genotype frequencies were in Hardy-Weinberg equilibrium in both the case and the control groups. The results shown that neither allelic frequencies nor genotypic distribution of the rs4906902 was significantly different between autism patients and healthy controls. In conclusion: It seems that the GABRB3 gene may influence the Autism susceptibility via a different SNPs in this gene. Also, another independent mechanisms like epigenetic effects should not be ignored when we want to explore the link between GABRB3 and ASD.
Thalamic stroke can be the cause of acute or delayed onset of movement disorders but it may also constitute their treatment. We report the case of an 89-year-old man with essential tremor in whom a right thalamic stroke caused long-term remission of severe contralateral tremor.
Few studies have assessed the treatment interval during repeated injections of botulinum toxin. In a double-blind (DB), single-treatment study followed by a long-term open-label (OL) extension study, abobotulinumtoxinA (aboBoNT-A, Dysport®) was efficacious and did not generate unexpected safety findings (Esquenazi et al. Am Acad Phys Med Rehabil 2016). This additional analysis reports the retreatment intervals for the lower limb in hemiparetic adults after repeated injections of aboBoNT-A. Phase III, international, multicentre, double-blind (DB), single-treatment study of aboBoNT-A in the hemiparetic lower limb, followed by a long-term open-label (OL) extension study with a maximum of 4 additional treatment cycles over a maximum of 18 months. Retreatment was per investigator's clinical judgement and possible at weeks 12, 16, 20, and 24. Among the subjects who received aboBoNT-A in the DB study and were treated in cycle 1 of the OL extension, 20% were re-injected at week 16 or later (10% at week 16, 5% at week 20, 5% at week 24 or later). For those who received a second cycle of treatment in the OL phase, 32% of subjects were re-injected at week 16 or later (17% at week 16, 9% at week 20, 7% at week 24). For those who received a third cycle of treatment in the OL phase, 15% of subjects were re-injected at week 16 or later. These data demonstrate the long duration of effect of aboBoNT-A in the spastic lower limb with 15–32% of subjects re-injected at week 16 or later across repeated cycles. A long duration of effect leading to a longer interval between injections may reduce the burden associated with frequency of injections for patients and their caregiver/families. This also highlights the need for a tailored approach in the treatment of the lower limb in hemiparesis.
