Othello's syndrome (OS) is a delusion of infidelity. We describe seven cases of OS in Parkinson's disease (iPD) patients using dopamine agonists.
We searched the Mayo Clinic Medical Records System to identify all patients with OS. Clinical data abstracted include sex, age of onset of iPD, age of onset of OS, medications, effect of discontinuing the dopamine agonist, neuroimaging, and comorbidities.
Seven non-demented iPD patients with dopamine agonist implementation time locked to the development and resolution of OS are reported. The average age of iPD onset was 46.6 years (Standard deviation: 5.0 years), and OS onset was 53.7 years (7.1 years). All seven patients had significant marital conflict as a result of the delusions.
OS can be associated with dopamine agonist use and can lead to serious consequences. Dopamine agonist cessation eliminates the delusion of infidelity and should be the first treatment option.
Dopamine; Othello's syndrome; Parkinson's disease; Delusion
To determine the demographic distribution of Young Onset Parkinson’s Disease (YOPD) in the United States and to quantify the burden of neuropsychiatric disease manifestations.
Cross sectional study of 3,459,986 disabled Americans, aged 30 to 54, who were receiving Medicare benefits in the year 2005. We calculated race and sex distributions of YOPD and used logistic regression to compare the likelihood of common and uncommon psychiatric disorders between beneficiaries with YOPD and the general disability beneficiary population, adjusting for race, age, and sex.
We identified 14,354 Medicare beneficiaries with YOPD (prevalence = 414.9 per 100,000 disabled Americans). White men comprised the majority of cases (48.9%), followed by White women (34.7%), Black men (6.8%), Black women (5.0%), Hispanic men (2.4%), and Hispanic women (1.2%). Asian men (0.6%) and Asian women (0.4%) were the least common race sex pairs with a YOPD diagnosis in this population (chi square, p<0.001). Compared to the general population of medically disabled Americans, those with YOPD were more likely to receive medical care for depression (OR: 1.89, 1.83-1.95), dementia (OR: 7.73, 7.38-8.09), substance abuse/dependence (OR: 3.00, 2.99-3.01), and were more likely to be hospitalized for psychosis (OR: 3.36, 3.19-3.53), personality/impulse control disorders (OR: 4.56, 3.28-6.34), and psychosocial dysfunction (OR: 3.85, 2.89-5.14).
Young Onset Parkinson’s Disease is most common among white males in our study population. Psychiatric illness, addiction, and cognitive impairment are more common in YOPD than in the general population of disabled Medicare beneficiaries. These may be key disabling factors in YOPD.
Young Onset Parkinson’s Disease; Psychiatry; Addiction; Dementia; Medicare
Heterozygous glucocerebrosidase (GBA) mutations are the leading genetic risk factor for Parkinson disease, yet imaging correlates, particularly transcranial sonography, have not been extensively described.
To determine whether GBA mutation heterozygotes with Parkinson disease demonstrate hyperechogenicity of the substantia nigra, transcranial sonography was performed in Ashkenazi Jewish Parkinson disease subjects, tested for the eight most common Gaucher disease mutations and the LRRK2 G2019S mutation, and in controls. [18F]-fluorodeoxyglucose or [18F]-fluorodopa positron emission tomography is also reported from a subset of Parkinson disease subjects with heterozygous GBA mutations.
Parkinson disease subjects with heterozygous GBA mutations (n=23) had a greater median maximal area of substantia nigral echogenicity compared to controls (n=34, aSNmax=0.30 vs. 0.18, p=0.007). There was no difference in median maximal area of nigral echogenicity between Parkinson disease groups defined by GBA and LRRK2 genotype: GBA heterozygotes; GBA homozygotes/compound heterozygotes (n=4, aSNmax=0.27); subjects without LRRK2 or GBA mutations (n=32, aSNmax=0.27); LRRK2 heterozygotes/homozyogotes without GBA mutations (n=27, aSNmax=0.28); and GBA heterozygotes/LRRK2 heterozygotes (n=4, aSNmax=0.32, overall p=0.63). In secondary analyses among Parkinson disease subjects with GBA mutations, maximal area of nigral echogenicity did not differ based on GBA mutation severity or mutation number. [18F]-fluorodeoxyglucose (n=3) and [18F]-fluorodopa (n=2) positron emission tomography in Parkinson disease subjects with heterozygous GBA mutations was consistent with findings in idiopathic Parkinson disease.
Both transcranial sonography and positron emission tomography are abnormal in GBA mutation associated Parkinson disease, similar to other Parkinson disease subjects.
Parkinson disease; parkinsonism; diffuse Lewy body disease; Transcranial sonography; PET; Glucocerebrosidase; GBA; Gaucher disease; LRRK2
The hexanucleotide expanded repeat (GGGGCC) in intron 1 of the C9orf72 gene is recognized as the most common genetic form of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, as part of the clinical phenotype, some patients present with parkinsonism. The present study investigated the potential expansion or association of the C9orf72 repeat length with susceptibility to Parkinson’s disease and related disorders, essential tremor and restless legs syndrome. One restless legs syndrome patient was shown to harbor a repeat expansion, however on clinical follow-up this patient was observed to have developed frontotemporal dementia. There was no evidence of association of repeat length on disease risk or age-at-onset for any of the three disorders. Therefore the C9orf72 hexanucleotide repeat expansion appears to be specific to TDP-43 driven amyotrophic lateral sclerosis and dementia.
C9orf72; expanded repeat; PD; ET; RLS; genetic association
To determine whether the temporal onset of visual phenomena distinguishes Lewy body disease (LBD) from Alzheimer’s disease (AD), and to characterize the extent Lewy bodies and neurofibrillary tangles are associated with these clinical features.
Consecutive cases of autopsy-confirmed LBD (n=41), AD (n=70), and AD with amygdala-predominant Lewy bodies (AD-ALB) (n=14) with a documented clinical history of dementia were included. We mailed questionnaires to next-of-kin asking about symptoms during life. Lewy pathology and neurofibrillary tangle pathology were assessed.
The occurrence of visual hallucinations, misperceptions and family misidentification did not distinguish LBD from AD or AD-ALB, but the onset was earlier in LBD compared to AD and AD-ALB. When visual hallucinations developed within the first 5 years of dementia, the odds were 4 to 5 times greater for autopsy-confirmed LBD (or intermediate/high likelihood DLB) and not AD or AD-ALB. In LBD, limbic but not cortical Lewy body pathology was related to an earlier onset of visual hallucinations, while limbic and cortical Lewy body pathology were associated with visual misperceptions and misidentification. Cortical neurofibrillary tangle burden was associated with an earlier onset of misidentification and misperceptions in LBD and AD, but only with earlier visual hallucinations in AD/AD-ALB.
When visual hallucinations occur within the first 5 years of the dementia, a diagnosis of DLB was more likely than AD. Visual hallucinations in LBD were associated with limbic Lewy body pathology. Visual misperceptions and misidentification delusions were related to cortical Lewy body and neurofibrillary tangle burden in LBD and AD/AD-ALB.
Dementia with Lewy bodies; Lewy body disease; Alzheimer’s disease
By permitting remote assessments of patients and research participants, telemedicine has the potential to reshape clinical care and clinical trials for Parkinson disease. While the majority of the motor Unified Parkinson’s Disease Rating Scale (UPDRS) items can be conducted visually, rigidity and retropulsion pull testing require hands-on assessment by the rater and are less feasible to perform remotely in patients' homes.
In a secondary data analysis of the Comparison of the Agonist pramipexole vs. Levodopa on Motor complications in Parkinson’s Disease (CALM-PD) study, a randomized clinical trial, we assessed the cross-sectional (baseline and 2 years) and longitudinal (change from baseline to 2 years) reliability of a modified motor UPDRS (removing rigidity and retropulsion items) compared to the standard motor UPDRS (all items) using intraclass correlation coefficients (ICC), stratified by treatment group. Internal consistency of the modified UPDRS (mUPDRS) was measured using Cronbach’s alpha, and concurrent validity was assessed using Pearson’s correlation coefficient (r) between the standard motor UPDRS and mUPDRS.
The mUPDRS versus standard motor UPDRS is cross-sectionally (ICC ≥ 0.92) and longitudinally (ICC ≥ 0.92) reliable for both treatment groups. High internal consistencies were also observed (α ≥ 0.96). The mUPDRS had high concurrent validity with the standard UPDRS at both time points and longitudinally (r ≥ 0.93, p < 0.0001).
A modified version of the motor UPDRS without rigidity and retropulsion pull testing is reliable and valid and may lay the foundation for its use in remote assessments of patients and research participants.
Parkinson’s disease; UPDRS; telemedicine; motor; reliability; validity; CALM-PD
To assess for the presence of gastric dysmotility in familial and sporadic Parkinson disease (PD).
10 subjects with familial Parkinson disease (fPD), 35 subjects with sporadic Parkinson disease (sPD), and 15 controls, all from academic tertiary care movement disorders centers, were studied. fPD was defined as the presence of at least 2 affected individuals within 2–3 consecutive generations in a family. Molecular genetic analysis has not revealed, thus far, any known genomic abnormality in these families. Gastric emptying was assessed by dynamic abdominal scintigraphy over 92 min following ingestion of a solid meal containing 99mTc-labeled colloid of 40 MBq activity. The main outcome measures were gastric emptying half-time and radiotracer activity over the gastric area at 46 and at 92 min.
Gastric emptying time was delayed in 60% of subjects with PD. In comparison to mean t1/2 of 38 ± 7 min in controls, mean t1/2 was 58 ± 25 min in fPD (p = 0.02) and 46 ± 25 min in sPD (p = 0.10). Both fPD and sPD groups included subjects with delayed gastric emptying at an early stage of disease.
Patients with fPD showed significantly delayed gastric emptying in comparison to normal age-matched individuals. Further studies of gastrointestinal dysfunction in PD, particularly fPD, are warranted.
Gastric emptying; Familial; Parkinson disease; Radionuclide imaging
To explore current practices and opinions regarding hospital management of Parkinson disease (PD) patients in specialized PD Centers.
Fifty-one out of 54 National Parkinson Foundation (NPF) Centers worldwide completed an online survey regarding hospitalization of PD patients.
Many Centers were concerned about the quality of PD-specific care provided to their patients when hospitalized. Primary concerns were adherence to the outpatient medication schedule and poor understanding by hospital staff of medications that worsen PD. Few Centers had a policy with their primary hospital that notified them when their patients were admitted. Rather, notification of hospitalization came often from the patient or a family member. Several Centers (29%) reported not finding out about a hospitalization until a routine clinic visit after discharge. Quick access to outpatient PD care following discharge was a problem in many Centers. Elective surgery, fall/fracture, infection, and mental status changes, were identified as common reasons for hospitalization.
There is a perceived need for PD specialists to be involved during hospitalization of their patients. Improvement in communication between hospitals and PD Centers is necessary so that hospital clinicians can take advantage of PD specialists’ expertise. Education of hospital staff and clinicians regarding management of PD, complications of PD, and medications to avoid in PD is critical. Most importantly, outpatient access to PD specialists needs to be improved, which may prevent unnecessary hospitalizations in these patients.
Parkinson’s disease; Hospitalization; Complications; Deep brain stimulation; International care
Dopaminergic medications and subthalamic nucleus deep brain stimulation (STN-DBS) alleviate motor symptoms in Parkinson disease, but balance and gait are more variably affected. Balance reports are particularly inconsistent. Further, despite their prevalence in daily life, complex gait situations including backward and dual task gait are rarely studied. We aimed to assess how medications, STN-DBS, and both therapies combined affect balance and complex gait.
Twelve people with Parkinson disease were evaluated OFF medication with STN-DBS OFF and ON as well as ON medication with STN-DBS OFF and ON. Motor impairment was measured with the Movement Disorder Society Unified Parkinson Disease Rating Scale motor section (MDS-UPDRS-III). The Mini-Balance Evaluations Systems Test, timed-up-and-go, and dual task timed-up-and-go measured balance and mobility. Preferred-pace forward, fast as possible, backward, dual task forward, and dual task backward gait were also analyzed.
Medication improved MDS-UPDRS-III scores, dual task timed-up-and-go, and stride length across all gait tasks. STN-DBS improved MDS-UPDRS-III scores, balance scores, dual task timed-up-and-go, and stride length and velocity across all gait tasks. Medication and STN-DBS combined did not provide additional benefits over either therapy alone.
Overall, dopaminergic medications and STN-DBS provided similar improvements in balance and gait tasks, although the effects of STN-DBS were stronger, potentially due to reductions in medication doses after surgery. Lack of synergistic effect of treatments may suggest both therapies improve balance and gait by influencing similar neural pathways.
Parkinson Disease; Medication; Deep Brain Stimulation; Gait; Balance
Previous studies have demonstrated both clinical and neurochemical similarities between Parkinson’s disease (PD) and narcolepsy. The intrusion of REM sleep into the daytime remains a cardinal feature of narcolepsy, but the importance of these intrusions in PD remains unclear. In this study we examined REM sleep during daytime Maintenance of Wakefulness Testing (MWT) in PD patients.
Patients spent 2 consecutive nights and days in the sleep laboratory. During the daytime, we employed a modified MWT procedure in which each daytime nap opportunity (4 per day) was extended to 40 minutes, regardless of whether the patient was able to sleep or how much the patient slept. We examined each nap opportunity for the presence of REM sleep and time to fall asleep.
Eleven of 63 PD patients studied showed 2 or more REM episodes and 10 showed 1 REM episode on their daytime MWTs. Nocturnal sleep characteristics and sleep disorders were unrelated to the presence of daytime REM sleep, however, patients with daytime REM were significantly sleepier during the daytime than those patients without REM. Demographic and clinical variables, including Unified Parkinson’s Disease Rating Scale motor scores and levodopa dose equivalents, were unrelated to the presence of REM sleep.
A sizeable proportion of PD patients demonstrated REM sleep and daytime sleep tendency during daytime nap testing. These data confirm similarities in REM intrusions between narcolepsy and PD, perhaps suggesting parallel neurodegenerative conditions of hypocretin deficiency.
Parkinson’s Disease; Narcolepsy; REM Sleep
Recently, we evaluated two patients with corticobasal syndrome (CBS) who reported symptom onset after limb immobilization. Our objective was to investigate the association between trauma, immobilization and CBS.
The charts of forty-four consecutive CBS patients seen in the Mayo Clinic Alzheimer Disease Research Center were reviewed with attention to trauma and limb immobilization.
10 CBS patients (23%) had immobilization or trauma on the most affected limb preceding the onset or acceleration of symptoms. The median age at onset was 61. Six patients manifested their first symptoms after immobilization from surgery or fracture with one after leg trauma. Four patients had pre-existing symptoms of limb dysfunction but significantly worsened after immobilization or surgery.
23 percent of patients had immobilization or trauma of the affected limb. This might have implications for management of CBS, for avoiding injury, limiting immobilization and increasing movement in the affected limb.
Corticobasal syndrome; plasticity; immobilization
In Parkinson's disease the degree of motor impairment can be classified with respect to tremor dominant and akinetic rigid features. While tremor dominance and akinetic rigidity might represent two ends of a continuum rather than discrete entities, it would be important to have non-invasive markers of any biological differences between them in vivo, to assess disease trajectories and response to treatment, as well as providing insights into the underlying mechanisms contributing to heterogeneity within the Parkinson's disease population.
Here, we used magnetic resonance imaging to examine whether Parkinson's disease patients exhibit structural changes within the basal ganglia that might relate to motor phenotype. Specifically, we examined volumes of basal ganglia regions, as well as transverse relaxation rate (a putative marker of iron load) and magnetization transfer saturation (considered to index structural integrity) within these regions in 40 individuals.
We found decreased volume and reduced magnetization transfer within the substantia nigra in Parkinson's disease patients compared to healthy controls. Importantly, there was a positive correlation between tremulous motor phenotype and transverse relaxation rate (reflecting iron load) within the putamen, caudate and thalamus.
Our findings suggest that akinetic rigid and tremor dominant symptoms of Parkinson's disease might be differentiated on the basis of the transverse relaxation rate within specific basal ganglia structures. Moreover, they suggest that iron load within the basal ganglia makes an important contribution to motor phenotype, a key prognostic indicator of disease progression in Parkinson's disease.
Parkinson's disease; Motor subtypes; Basal ganglia; Iron; Magnetic resonance imaging
Neuropsychiatric findings described in essential tremor (ET) include depression and anxiety. There may be personality features as well; in 2004, we demonstrated higher harm avoidance (HA) scores in ET patients than controls. We now (1) determined whether this finding could be replicated in a new sample of cases and controls, and (2) analyzed HA sub-scores (HA1–HA4) to further understand case-control differences.
60 ET cases and 35 controls were evaluated using the Tridimensional Personality Questionnaire (TPQ), which assesses three domains of personality: HA, novelty seeking (NS), and reward dependence (RD).
Total HA and total NS scores were marginally higher in cases than controls (14.8 ± 7.6 vs. 12.4 ± 5.3, p = 0.09) and (13.8 ± 5.4 vs. 11.8 ± 4.9, p = 0.09), respectively. When adjusted for age and gender, cases and controls differed with respect to total HA score (p = 0.03) but not total NS score (p = 0.10). Further analysis of HA subscores demonstrated that HA1 (anticipatory worry and pessimism) and HA4 (fatigability and asthenia) were most robustly elevated in cases vs. controls (p = 0.04 and p = 0.01, respectively).
This study suggests that ET cases have a personality profile characterized by a greater HA, with certain domains of HA most affected. It is unclear whether this personality profile is pre-morbid or is a co-morbid feature of the illness, nor it is known whether the greater tendency towards HA in ET lessens receptivity to deep brain stimulation surgery and other therapies.
essential tremor; movement disorders; non-motor; personality; neuropsychiatric
Freezing of gait is a debilitating and common gait disturbance observed in individuals with Parkinson’s disease (PD). Although the underlying mechanisms of freezing remain unclear, bilateral coordination of steps, measured as a phase coordination index, has been suggested to be related to freezing. Phase coordination index has not, however, been measured during tasks associated with freezing such as turning and backward walking. Understanding how bilateral coordination changes during tasks associated with freezing may improve our understanding of the causes of freezing.
Twelve individuals with PD who freeze (freezers), 19 individuals with PD who do not freeze (non-freezers), and 10 healthy, age-matched older adults participated. General motor disease severity and freezing severity were assessed. Phase coordination index was calculated for all subjects during forward walking, backward walking, continuous turning in small radius circles, and turning in large radius circles.
Freezers and non-freezers had similar disease duration and general motor severity. Stepping coordination (measured as phase coordination index) was significantly worse in freezers compared to non-freezers and controls. Turning and backward walking, tasks related to freezing, resulted in worse coordination with respect to forward walking. Coordination was associated with severity of freezing scores such that worse coordination was correlated with more severe freezing.
These results provide evidence that stepping coordination is related to freezing in people with PD. Identifying variables associated with freezing may provide insights into factors underlying this symptom, and may inform rehabilitative interventions to reduce its occurrence in PD.
Parkinson Disease; coordination; freezing; gait; turning
Researchers have consistently observed in right-handed individuals across normal and disease states that the ‘dominant’ left hemisphere has greater ipsilateral control of the left side than the right hemisphere has over the right. We sought to determine whether this ipsilateral influence of the dominant hemisphere reported in Parkinson’s disease extends to treatments such as deep brain stimulation (DBS) and whether it affects outcome. We hypothesised that among Parkinson right-handers, unilateral left DBS would provide greater ipsilateral motor improvement compared with the ipsilateral motor improvement experienced on the right side.
A total of 73 Parkinson patients who underwent unilateral DBS of the subthalamic nucleus (STN) or globus palidus internus (GPi) participated. Left and right ‘composite scores’, were computed by separately adding all items on the left and right side from the motor section of the Unified Parkinson Disease Rating Scale. The change in the pre- and 4-month post-implantation score was the primary outcome measure. The mean motor scores improved by 4.96 ± 11.79 points (p < 0.001) post-surgery on the ipsilateral side of the DBS implantation. Regression analyses revealed that the side (left vs. right) and target (STN vs. GPi) did not significantly contribute in the effect of ipsilateral motor improvement (p = 0.3557).
While DBS on the ‘dominant’ left side failed to exert a greater ipsilateral influence compared with DBS on the non-dominant right side, significant ipsilateral motor improvements were observed after unilateral stimulation regardless of site of implantation and laterality.
Unilateral DBS; STN; GPi; Parkinson’s disease; UPDRS
The purpose of this review is to assess the current state of the literature on the topic of deep brain stimulation (DBS) and its effects on swallowing function in Parkinson’s disease (PD). Pubmed, Cochrane review, and web of science searches were completed on all articles addressing DBS that contained a swallowing outcome measure. Outcome measures included the penetration/aspiration scale, pharyngeal transit time, oropharyngeal residue, drooling, aspiration pneumonia, death, hyolaryngeal excursion, epiglottic inversion, UPDRS scores, and presence of coughing/throat clearing during meals. The search identified 13 studies specifically addressing the effects of DBS on swallowing. Critical assessment of the 13 identified peer-reviewed publications revealed nine studies employing an experimental design, (e.g. “on” vs. “off”, pre- vs. post-DBS) and four case reports. None of the nine experimental studies were found to identify clinically significant improvement or decline in swallowing function with DBS. Despite these findings, several common threads were identified across experimental studies and will be examined in this review. Additionally, available data demonstrate that, although subthalamic nucleus (STN) stimulation has been considered to cause more impairment to swallowing function than globus pallidus internus (GPi) stimulation, there are no experimental studies directly comparing swallowing function in STN vs. GPi. Moreover, there has been no comparison of unilateral vs. bilateral DBS surgery and the coincident effects on swallowing function. This review includes a critical analysis of all experimental studies and discusses methodological issues that should be addressed in future studies.
DBS; Dysphagia; Swallow; Aspiration pneumonia; Parkinson’s disease; Review
Complementary and Alternative Medicine (CAM) use is on the rise in both the US and Europe, despite questions about its safety, effectiveness and lack of national standards. We aimed to determine the prevalence and predictors of CAM and integrative medicine use (CAM-I) and perceived effectiveness compared to the standard treatment of botulinum toxin injections in patients with adult-onset primary dystonia.
This was a retrospective questionnaire study of 389 dystonia patients examining the effects age, gender, education level and number of anatomical regions affected on botulinum toxin and CAM-I use and their perceived effectiveness.
53% (208) of patients reported CAM-I use, while 90% (349) used the standard treatment (botulinum toxin), and 48% used both. Education was the only significant predictor of CAM-I use – individuals with bachelor’ s degrees were more likely to try CAM-I whereas those with high school diplomas were less likely. The mean effectiveness rate for botulinum toxin injections (59%) significantly exceeded that for and CAM-I (28%, p<0.0001).
Our work highlights the need for scientifically sound studies to determine the safety, effectiveness and expense of CAM-I treatments for dystonia and other neurological disorders given that CAM-I use is steadily increasing, there is great variability in what is classified as CAM-I, and the effectiveness of some modalities may be significantly less than conventional medical treatments.
Dystonia; Complementary and Alternative Medicine (CAM); Botulinum toxin; Integrative medicine; Spasmodic dysphonia
A woman from Italy presented with dystonic leg symptoms at the age of 59. Rapid-onset dystonia-parkinsonism (RDP) was not suspected until 3 affected children (2 male, 1 female) with presentations consistent with the disorder were recognized.
The mother and four of her children (3 with and 1 without dystonia) were evaluated with an extensive battery including standardized history questionnaire and rating scales. In addition, all four children had cognitive testing and three of the four children had psychiatric interviews.
In this family, a T613M mutation in the ATP1A3 gene was confirmed, the most common mutation present in patients with RDP. The proband's limb dystonia was atypical of RDP, symptoms of the others affected included dysarthria, asymmetric limb dystonia, and dysphagia more consistent with RDP. The two sons developed dystonia-parkinsonism in adolescence after consuming large amounts of alcohol. All 3 of those with psychiatric interviews reached diagnosable thresholds for mood disorder (bipolar or dysthymia) and some form of anxiety disorder.
The phenotype and age of onset is broader than previously reported in RDP, suggesting that it could be under-reported. Prior to this study, neuropsychologic symptoms associated with RDP were under-appreciated. Those patients who are at risk or suspected of having RDP should be cautioned to avoid excessive alcohol intake. Further study is needed to assess if the cognitive and psychiatric features are part of a broader RDP phenotype and this may have implications for future research into genetic susceptibility for psychiatric disease.
Dystonia; RDP; DYT-12; Rapid-onset dystonia-parkinsonism
Impairment in computerized dynamic posturography scores has been documented in Huntington disease patients. Tetrabenazine is approved to treat chorea in Huntington disease, but its effect on posturography scores, and balance in general, is unknown.
Materials and Methods
We designed a study to test computerized dynamic posturography performance while taking tetrabenazine and after stopping tetrabenazine for at least three days.
10 Huntington disease patients were studied both ON and OFF tetrabenazine. The composite score was statistically different between ON and OFF conditions and both conditions were significantly worse than reference scores. There was no significant difference between ON and OFF trials in the number of falls. A significant improvement on Sensory Orientation Test conditions 3 (sway-referenced vision) and 5 (sway-referenced motion of the support surface and eyes closed) was seen while ON tetrabenazine. Strategy scores 1–3 were also significantly different while ON tetrabenazine.
These findings suggest that tetrabenazine aided patients in gating out of abnormal visual cues when other sensory modalities were available, as well as in gating out abnormal kinesthetic cues when visual cues were not available. It could not help with gating out of simultaneous abnormal visual and somatosensory cues. Thus, tetrabenazine can improve postural stability when one sensory modality is irrelevant, but this effect is not sustained when multiple abnormal sensory modalities are present. This is the first study supporting the use of any medicine to treat balance problems in Huntington disease.
Huntington disease; posturography; tetrabenazine; postural stability
We sought to define the frequency of falls in early PD and assess potential risk factors for falls in this population.
We analyzed the data from two randomized, placebo controlled trials (NET-PD FS1 and FS-TOO) of 413 individuals with early PD over 18 months of follow-up in FS1 and 12 months in FS-TOO. Falls were defined as any report of falls on the UPDRS or the adverse event log. We assessed the frequency of falls overall and by age. The relationship between prespecified fall risk markers and the probability of falling was assessed using logistic and multiple logistic regression. A hurdle Poisson model was used to jointly model the probability of remaining fall-free and the number of falls.
During the follow-up period, 23% of participants fell, and 11% were habitual fallers. In a multiple logistic regression model, age, baseline UPDRS Falling score, and baseline PDQ-39 scores were associated with subsequent fall risk (P <0.001). Similarly, in a hurdle Poisson regression model, age, baseline UPDRS falling item, and baseline PDQ-39 were all significantly related to the probability of falling, but only UPDRS falling >0 was associated with the number of falls.
Falls are frequent and are associated with impaired quality of life, even in early PD. Current standard rating scales do not sufficiently explain future fall risk in the absence of a prior fall history. New assessment methods for falls and postural instability are required to better evaluate this important problem in clinical trials and clinical practice.
Falls; Parkinson’s disease
Few studies have assessed parkinsonian motor features features across variants of primary progressive aphasia (PPA). Our objective was to compare degree of parkinsonian motor features features between two PPA variants.
Parkinsonian motor features were assessed with the Unified Parkinson’s Disease Rating scale in prospectively recruited PPA subjects, classified based on recently published criteria. Comparisons across groups were performed with Fisher’s exact test for binary data and Mann-Whitney U test for continuous data.
Twenty-three PPA subjects were diagnosed with logopenic (n=11) or nonfluent/agrammatic (n=12) aphasia. There were no significant differences in illness duration (agrammatic=3.4 years; logopenic=3.3 years) or age at onset (nonfluent/agrammatic =67.3; logopenic=62.0), but those with logopenic aphasia were more impaired on Mini-Mental State Examination (21.7/30 points vs. 26.1/30; p=0.04). In contrast, those with logopenic aphasia had fewer parkinsonian motor features than those with agrammatic aphasia (5.7/132 vs. 16.8/132; p=0.003) which was driven by bradykinesia (p=0.02) and speech facial/expression (p=0.04); less so rigidity (p=0.06). Dysarthria was more frequent in the nonfluent/agrammatic subgroup.
Nonfluent/agrammatic subjects have more parkinsonian motor features than logopenic subjects, likely reflecting underlying tau pathology in the agrammatic variant.
Parkinsonism; primary progressive aphasia; logopenic aphasia; agrammatic aphasia; extrapyramidal
Little is known regarding genetic factors associated with motor or cognitive outcomes in Parkinson’s disease (PD).
To identify common genetic variants associated with motor and cognitive outcomes in PD.
The sample consisted of 443 PD cases included in the first genome-wide association study (GWAS) of PD. Methods included telephone interview assessments of motor and cognitive outcomes, a median 9 years following the initial clinical assessments. Analyses included Cox proportional hazard models to study the association of 198,345 single nucleotide polymorphisms (SNPs) with survival free of Hoehn-Yahr Stage ≥4 (motor outcome), and either TICS-M ≤27 or AD-8 ≥2 (cognitive outcomes).
The SNP rs10958605 in the C8orf4 gene had the smallest p-value in analyses of the motor outcome (HR = 1.81; 95% CI = 1.42 – 2.31; p = 1.51 × 10−6). The SNP rs6482992 in the CLRN3 gene had the smallest p-value in analyses of the cognitive outcome (HR = 2.03, 95% CI 1.47–2.79, p = 4.08 × 10−6). However, no SNP associations were significant after Bonferroni correction. The C8orf4 gene had small p-values for both motor and cognitive outcomes, highlighting inflammation as a possible pathogenesis mechanism for progression in PD.
This study suggests that common variants in several genes may be associated with motor and cognitive outcomes in PD, with biological plausibility.
Genome wide association studies; Parkinson’s disease; outcomes
Functional electrical stimulation; dystonia
Small case series suggest tremor occurs frequently in IgM-monoclonal gammopathy of undetermined significance (IgM-MGUS) neuropathy. Epidemiologic study to confirm this association is lacking. Whether the neuropathy or another remote IgM-effect is causal remains unsettled.
Materials and methods
An IgM-MGUS neuropathy case cohort (n=207) was compared to age, gender, and neuropathy impairment score (NIS) matched, other-cause neuropathy controls (n=414). Tremor details were extracted from structured neurologic evaluation. All patients underwent nerve conductions.
Tremor occurrence was significantly higher in IgM-MGUS case cohort (29%) than in control cohort (9.2%) (p=0.001). In IgM-MGUS cases, tremor was associated with worse NIS (p=0.025) and demyelinating nerve conductions (p=0.020), but 11 of 60 (18%) IgM-MGUS cases with tremor had axonal neuropathy. In other-cause neuropathy controls, tremor was associated with axonal nerve conductions (p=0.03) but not with NIS severity (p=0.57). Tremor occurrence associated with older age in controls, (p=0.004) but not in IgM-MGUS cases (p=0.272). Most IgM-MGUS tremor cases (49/60) had a postural-kinetic tremor, 8 had rest tremor, 3 had mixed rest-action. Alternative causes of tremor was identified in 42% of IgM-MGUS cases, the most common type is inherited essential tremor 6/60 (p=0.04).
This first epidemiologic case-control study validates association between IgM-MGUS neuropathy and tremor. Among IgM-MGUS neuropathy cases, severity as well as type of neuropathy (demyelinating over axonal) correlated with tremor occurrence. IgM-MGUS paraproteinemia may increase tremor expression in persons recognized with common other risk factors for tremor.
Tremor; Peripheral Neuropathy; IgM-MGUS
Difficulty switching between motor programs is a proposed cause of motor blocks in Parkinson disease (PD). Switching from one movement to another has been studied in the upper extremity and during postural control tasks, but not yetin the eyes and lower limb in PD. The purpose of this study was to compare movement orientation switching ability between people with PD and age-matched controls (CON) and to determine if switching ability is correlated between the eyes and lower limb. Twenty-six persons with PD and 19 age-matched controls participated. Movement orientation switching was studied in a seated position with the head fixed in a chinrest. In response to a randomly generated tone, participants switched from a continuous back-and-forth movement in either the horizontal or vertical orientation to the opposite orientation as quickly as possible. Lower limb movements were performed with the great toe pointing back and forth between targets positioned on a 45° angled floor platform. Eye movements were back and forth between the same targets. Eye and lower limb switch time was reduced in PD (p<0.01), but after normalizing switch time to movement velocity, no differences existed between PD and CON. Eye and lower limb switch times were correlated in PD (r=0.513, p<0.01) but not in CON. In PD, switch time and movement velocity of the lower limb, but not the eyes, correlated with bradykinesia and postural instability/gait. Our results suggest that individuals with PD experience movement switching deficits with both the eyes and lower limb, perhaps driven by overall bradykinesia.
Parkinson’s disease; eye movements; basal ganglia