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Abstract: Gait dysfunction and postural instability represent a major therapeutic challenge in Parkinson's disease (PD). Gait disability in PD has been historically attributed to striato-nigral degeneration, however there is emerging evidence that multiple neurotransmitter deficits contribute to mobility impairment in PD. 4-aminopyridine (4-AP), a potent neurotransmitter modulator, has a wide range of favorable effects on gait in patients with neurological conditions including multiple sclerosis, spinal cord injury and cerebellar ataxia. In this Review we identify the neurobiological pathways involved in gait dysfunction in PD and discuss the mechanisms of action of 4-AP and its effect on gait related neuronal networks. The proposed mechanisms that may facilitate 4-AP favorable effect on gait in Parkinson's disease include 1) neurotransmitter release (dopamine, glutamate, acetylcholine and noradrenaline) 2) modulation of neuronal network oscillations and 3) increased cortical excitation. Recent clinical trials of 4-AP in neurological conditions associated with gait disorders will be highlighted and the importance of studying non-dopaminergic medications such as 4-AP in PD patients with gait impairment will be emphasized. [Copyright &y& Elsevier]

Abstract: Over the past two decades, several studies have aimed to quantify the kinetic properties of tremor with primary focus on the upper limbs. However, there is a lack of investigation into the properties of tremor in the lower limbs. The objective of this preliminary study was to investigate the properties of oscillatory movement, at rest and in posture, in both the upper and lower limbs of Parkinson’s disease (PD) patients with clinically undetectable to modest rest/postural tremor and healthy controls. PD patients (N=16) and controls (N=8) were examined clinically by a movement disorders specialist and oscillatory movements in all four extremities were evaluated using a portable biaxial accelerometer. While tremor intensity and frequency did not differ between groups, the intraindividual variability of rest and postural tremor frequency in the dexterity-dominant lower limb was lower in people living with PD than in healthy adults. Additionally, rest tremor frequency was discrepant between upper and lower limbs in PD. Our work introduces the possibility that minute variations in lower limb movements, which are imperceptible upon expert clinical exam, can be used to differentiate a diseased sample from a healthy one. These preliminary findings suggest that additional work using objective tremor measurement may improve our understanding of lower limb motor dysfunction in PD and lead to the refinement of current, and the development of new, metrics to enhance early diagnosis, differential diagnosis, and symptom quantification. [Copyright &y& Elsevier]

Abstract: Parkinson''s disease (PD) has classically been characterized by features of motor dysfunction, but these may manifest only after the nigrostriatal system has incurred significant damage. However, recent evidence suggests that cardiac sympathetic denervation occurs early on in PD. This may trigger a shift in physicians'' attention to features of cardiovascular dysautonomia and allow for the evolution of earlier screening techniques. MIBG and PET (6F-DA) scans have demonstrated the functional loss of postganglionic sympathetic cardiac neurons, while immunohistochemical stains have revealed signs of morphological degeneration. Given this information, various screening techniques have been proposed, though most are particular to PD patients with orthostatic hypotension (OH). This is a considerable drawback given that the prevalence of OH in PD patients is estimated to be 41%. We present the argument that a shift in focus is needed; investigators should look for other manners by which to screen patients that are not reliant upon blood pressure. In our point of view, the problem with using blood pressure as a measurement is that it can be affected by many other factors unrelated to cardiac denervation. This may be why many patients with PD cannot be detected using these techniques. In order to make further progress on this front, we believe that investigators should start looking for variables that are more purely dependent upon cardiac denervation. We give one possible example of such a variable in this paper using heart transplant patients as a model. [Copyright &y& Elsevier]

Abstract: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene, especially the G2019S mutation, have been identified as a common cause of Parkinson’s disease in southern European and other Mediterranean populations (Iberians, Ashkenazi Jews and North African Arabs). Owing to the geographic and historic vicinity of Greece with areas of high prevalence of LRRK2 mutations we studied the frequency of the G2019S mutation in a well characterized cohort of familial and sporadic Parkinson’s disease patients of Greek origin from mainland Greece. The prevalence of the LRRK2 R1441C mutation and the G2385R Asian polymorphism was also determined. We identified no patients with any of the studied mutations/polymorphisms. Very low prevalence of the LRRK2 G2019S mutation has been reported in other southern European populations. LRRK2 mutations appear to be limited in certain populations and differing ancestry and founder effects may explain the reported variability. Accurate estimations of the frequency and penetrance of different LRRK2 mutations are essential for correct and cost-efficient use of genetic testing and proper genetic counseling of patients with Parkinson’s disease. [Copyright &y& Elsevier]

Abstract: Oromandibular dystonia (OMD) is a form of focal dystonia that affects masticatory, lower facial, and lingual muscles. We compared the clinical variables and response to treatment between patients with idiopathic jaw-closure C-OMD (n=11) and jaw-opening dystonia O-OMD (n=12) seen in our Movement Disorders clinic over the last 10 years. The co-existence of dystonia in other regions and sensory tricks were significantly more prevalent in O-OMD (P=0.049 and 0.03, respectively). Male gender, orobuccolingual dyskinesias (facial grimacing, lip biting, tongue dyskinesias, platysma contractions and bruxism) and better response to botulinum toxin injections were more frequent in C-OMD but remained a trend. [Copyright &y& Elsevier]

Abstract: Although primary focal hand dystonia has been well characterized, primary focal foot dystonia in adults has rarely been reported. Our objective was to describe the clinical phenotype and treatment outcomes in patients with primary, adult-onset focal foot dystonia. To this end we conducted a retrospective study of four consecutive patients (59.5±13.5 years, range 44–67) diagnosed over a period of 6 years and followed-up for at least 5 years. Focal foot dystonia resulted in variable physical impairment. Anti-dystonic agents were mildly effective whereas botulinum toxin injections provided substantial benefit when used. Focal primary focal foot dystonia seems to be a rare form of focal dystonia with distinct clinical features that may benefit from treatment with botulinum toxin. [Copyright &y& Elsevier]

Abstract: The aim of this study was to investigate the causes and seasonality of death and co-morbid conditions among progressive supranuclear palsy (PSP) patients. 22 consecutive clinicopathologically confirmed PSP patients were compared with 22 gender and age-matched Parkinson''s disease (PD) patients and 26 non-neurological controls. All subjects consented during life to donate their brains to the University of Miami Brain Endowment Bank™. Respiratory-related deaths were significantly more frequent in PSP when compared to PD patients. Recurrent respiratory infections were also very frequent in PSP patients and were commonly associated with respiratory-related deaths. Deaths that occurred during winter and spring months accounted for about 70% of deaths among PSP patients. The most common co-morbid condition in PSP was hypertension, present in 50% of cases. [Copyright &y& Elsevier]

Hemifacial spasm is a disorder characterized by involuntary contractions of muscles innervated by the ipsilateral facial nerve. The majority of cases are of adult-onset. However, a few cases have been described in children. Detectable causes of pediatric hemifacial spasm include facial nerve compression by vasculature and brainstem masses. In the treatment of hemifacial spasm, surgical decompression of the facial nerve has been used with good results in both adults and children. However, surgical procedures have serious risks and should be used only in selected cases. Although injections of botulinum toxin type A have been successfully used in adult hemifacial spasm patients, to our knowledge there is no report of use of this indication in children. This report presents the first case of a pediatric patient with childhood-onset hemifacial spasm successfully treated with periorbital botulinum toxin injections. The literature on the subject is also reviewed. [Copyright &y& Elsevier]

Abstract: Painless arms/moving fingers is a rare variant of the painful limbs/moving extremities syndrome (PLME) characterized by slow involuntary movements of the toes or fingers. Its typical form is associated with limb pain. We report the first case of painless arms/moving fingers and describe its favorable response to botulinum toxin A injections. The presence of dystonic symptoms in our case argues in favor of a possible implication of a dystonic mechanism in at least some cases of PLME. [Copyright &y& Elsevier]

Abstract: The objective of this study was to determine if Parkinson''s disease (PD) patients with dyskinesia have a lower pain pressure threshold (PPT) than patients without dyskinesia and healthy controls. This was an outpatient, controlled study. We studied 25 healthy controls, 25 PD patients without dyskinesia and 25 PD patients with dyskinesia. A J Tech Pain Track algometer was used to measure PPT. No differences were found in PPT between controls and PD patients with or without dyskinesia. Patients and control women had a lower PPT than men. In conclusion, the presence of dyskinesia in PD patients does not appear to decrease PPT. [Copyright &y& Elsevier]

There is evidence that glycemic fluctuations trigger vascular-mediated dysfunction in both the retina and the striatopallidal regions in patients with diabetes. The latter is associated with a variety of hyperkinetic disorders that are rare but disabling and potentially preventable. We conducted a systematic review of the potential association between diabetic retinopathy and the risk and prognosis of hyperkinetic disorders in patients with diabetes. We identified a total of 461 articles and 147 were eligible for review. Nine out of 147 articles (6.12%) reported 13 patients with information on diabetic retinopathy. Glycemic fluctuations were present at onset in 10 patients (77%) and retinopathy was present in nine of them (69.23%). The degree of retinopathy was reported in four patients. Two had severe, bilateral proliferative retinopathy, one had moderate-to-severe non-proliferative retinopathy and one had non-proliferative retinopathy. In the nine patients with retinopathy, hyperkinesia persisted, required higher doses of dopamine receptor antagonists or deep brain stimulation. Retinopathy was absent in four cases (30.77%). In these patients, hyperkinesia resolved spontaneously or with lower doses of dopamine receptor antagonists. Diabetic retinopathy could be an indirect marker of striatopallidal microangiopathy in patients with diabetes. The severity of retinopathy may be associated with increased risk or worse prognosis for patients who develop hyperkinetic disorders of the diabetic striatopathy spectrum. Early detection of retinopathy could identify patients in which avoiding glycemic fluctuations may prevent the development of striatopathy and hyperkinetic disorders. [ABSTRACT FROM AUTHOR]

Introduction: Palliative care in Parkinson's Disease (PD) is an effective intervention to improve quality of life, although historically, access and availability have been very restricted.Methods: We performed a retrospective cohort study using the National Inpatient Sample (NIS) data from 2007 to 2014. Diagnostic codes were used to identify patients with PD and palliative care referral. Trends were calculated and logistic analysis performed to identify predictors of palliative care use.Results: We identified 397,963 hospitalizations from 2007 to 2014 for patients with PD. Of these, 10,639 (2.67%) were referred to palliative care. The rate of consultation increased from 0.85% in 2007 to 4.49% in 2014. For 1 unit in year increase, there was 1.23 time the odds of receiving palliative consultation (OR 1.23, CI 1.21-1.25, p < 0.0001). Hispanics (OR 0.90, CI 0.81-1.01, p = 0.0550), Black (OR 0.90, CI 0.81-1.01, p = 0.0747) and White patients had similar rates of referral after adjustment. Women were less likely to be referred to palliative care (OR 0.90, CI 0.87-0.94, p < 0.0001). Other factors strongly associated with a higher rate of referrals included private insurance when compared to Medicare (OR 2.14, CI 1.89-2.41, p < 0.0001) and higher income (OR 1.41, CI 1.30-1.53, p < 0.0001).Conclusion: There has been a significant increase in palliative care referrals among hospitalized patients with PD in the US, although the overall rate remains low. After controlling for confounders, racial and ethnic disparities were not found. Women, patients with Medicare/Medicaid, and those with lower income were less likely to be referred to palliative care. [ABSTRACT FROM AUTHOR]

Introduction: We report the prevalence of abnormal tandem gait (TG) in patients with idiopathic Parkinson disease (PD) and its association with symptoms of subjective unsteadiness, falls, freezing of gait, and cognitive impairment.Methods: We assessed subjective balance impairment, fall history, antero-posterior postural instability, and TG in PD patients (Hoehn and Yahr (HY) stage 0-4). We recorded the age, sex, current medications, HY stage, Schwab and England (S&E) scale score, and MOCA score for each patient. Logistic regression was used to evaluate age-adjusted associations between TG and other demographic and clinical factors.Results: A total of 102 patients with PD were assessed. Of those, 63.5% of HY 2 patients and 100% of HY 2.5 and 3 patients had a TG abnormality. The presence of TG abnormality was associated with subjective imbalance, falls, freezing of gait, S&E < 80, and MOCA score <24 after adjustment for age.Conclusions: TG abnormality is common in PD, precedes the development of antero-posterior postural instability, is associated with cognitive impairment, and may predict fall risk. A longitudinal study will help determine if TG is a predictor of impending progression from HY 2 to HY 3. [ABSTRACT FROM AUTHOR]

Introduction: Anxiety and depression are common in PD, occurring in an estimated 30%-40% of PD patients. However, the extent to which these emotional symptoms interfere with Deep Brain Stimulation (DBS) outcomes is not well established. This study examined the association between pre-operative emotional well-being and postsurgical cognitive, emotional, and motor performance in PD.Methods: Forty-nine PD patients underwent neurological, neuropsychological (global cognition, processing speed, language, visuospatial, memory), and emotional assessments pre- and post-DBS. Fifteen patients were administered the UPDRS. Patients were divided into Anxious (Anx; n = 21), Comorbid Anxious and Depressed (Anx + Dep; n = 15), and Emotionally Asymptomatic (EA; n = 13) based on BAI and BDI-II cutoffs, and compared on pre-post changes in neurocognitive, mood, and motor scores using analyses of covariance (ANCOVA), controlling for education, ethnicity, and disease duration.Results: Pre-DBS, there were no significant differences between the three groups on any neuropsychological measure. Overall change from pre-to post-DBS revealed declines on multiple cognitive measures and lower symptom endorsement on the BAI among all participants. No group differences were observed on neurocognitive measures, mood, or UPDRS.Conclusions: PD patients with mild-moderate anxiety or comorbid anxiety/depression pre-DBS do not show greater cognitive, emotional, and motor changes post-DBS compared to emotionally asymptomatic patients. These data emphasize the importance of discussing potential DBS outcomes, while keeping in mind that psychiatric comorbidity should not necessarily exclude patients from DBS. The notion that premorbid mood symptoms could disqualify a candidate for surgery would be a disservice, as this group performs comparably to asymptomatic peers. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy of solifenacin succinate in Parkinson's disease (PD) patients suffering from overactive bladder (OAB).Background: Urinary dysfunction is a commonly encountered non-motor feature in PD that significantly impacts patient quality of life.Design/methods: This was a double-blind, randomized, placebo-controlled, 3-site study with an open label extension phase to determine the efficacy of solifenacin succinate in idiopathic PD patients with OAB. Patients were randomized to receive solifenacin succinate 5-10 mg daily or placebo for 12 weeks followed by an 8-week open label extension. The primary outcome measure was the change in the mean number of micturitions per 24 h period. Secondary outcome measures included the change in the mean number of urinary incontinence episodes and the mean number of nocturia episodes.Results: Twenty-three patients were randomized in the study. There was no significant improvement in the primary outcome measure in the double-blind phase, but there was an improvement in the number of micturitions per 24 h period in the solifenacin succinate group compared to placebo at a mean dose of 6 mg/day (p = 0.01). In the open label phase, the mean number of urinary incontinence episodes per 24 h period decreased (p = 0.03), as did the number of nocturia episodes per 24 h period (p = 0.01). Adverse events included constipation and xerostomia, which resolved after treatment was discontinued.Conclusions: In this pilot trial, solifenacin succinate treatment led to an improvement in urinary incontinence, despite persistence in other OAB symptoms. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To evaluate the motor experiences of daily living section of the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS M-EDL) for assessing disability in PD patients; to determine the association between disability and quality of life; and to identify cut-off score ranges for no, mild, moderate and severe disability with this measure. Methods: International, observational, cross-sectional study of 435 PD patients, assessed with: MDS-UPDRS, Hoehn and Yahr staging, Rapid Assessment of Disability Scale, Clinical Impression of Severity Index for PD, Parkinson's Disease Questionnaire-8 and EQ-5D. Descriptive statistics, Spearman's rank correlation coefficients, Kruskal–Wallis test for group comparisons, ordinal logistic regression analysis for setting cut-off values and a step-wise multiple linear regression model were calculated. Results: MDS-UPDRS M-EDL correlated 0.70–0.80 with other disability measures, and −0.46 to 0.74 with quality of life scales. Scores significantly increased with higher disease duration and severity (p < 0.001). Cut-off values for the M-EDL were: 0–2 points, no disability; 3–16, mild; 17–31, moderate; and 32 points or more, severe. Linear regression analysis identified the MDS-UPDRS nM-EDL section as the main determinant of M-EDL, followed by the rest of MDS-UPDRS sections (explained variance: 59%). Conclusions: MDS-UPDRS M-EDL proved to be useful for assessing disability in PD. [Copyright &y& Elsevier]

Abstract: Essential Tremor (ET) is characterized by a 4–12-Hz postural and kinetic tremor, most commonly affecting the upper limbs. Deep brain stimulation (DBS) of the thalamus (Vim) has been found to be highly effective in severe/refractory forms of ET. Intra-operative assessment of tremor is performed using clinical methods based on patient and physician perception of tremor intensity. We present for the first time the case of a patient whose tremor was objectively monitored/quantified pre- and intra-operatively using device-based tremor registration to supplement clinical measures. We present the case of a 76-year-old right-handed woman that received unilateral (left-sided) DBS of the ventrointermediate (Vim) nucleus of thalamus (Vim) for medically refractory ET. Tremor was monitored with an accelerometer-based Tremor Pen®, which is part of a simple portable device (CATSYS 2000 System®, Danish Product Development Ltd., DK, www.catsys.dk). The patient was asked to perform tasks for tremor evaluation before and during thalamic DBS. Tremor quantification revealed a significant improvement (34.7-fold) in the contralateral (right) limb following macro-stimulation. No significant improvement was registered in the ipsilateral (non-operated) side. Simple electronic tremor registration methods during DBS of the Vim nucleus of the thalamus may supplement the existing methodology that is solely based on subjective measures derived from clinical observations. [Copyright &y& Elsevier]

Acquired chronic hepatocerebral degeneration is a central nervous system disorder secondary to several conditions related to hepatic dysfunction. Clinical features of acquired chronic hepatocerebral degeneration include a hyperkinetic extrapyramidal syndrome, neuropsychiatric symptoms, or both. We present for the first time a pediatric case of acquired chronic hepatocerebral degeneration secondary to endstage biliary disease. The pediatric phenotype of acquired chronic hepatocerebral degeneration is presented, and the differential diagnosis in regard to Wilson’s disease and management alternatives are discussed. [Copyright &y& Elsevier]