Subthalamic nucleus physiology is correlated with deep brain stimulation motor and non-motor outcomes.

Subthalamic nucleus deep brain stimulation is commonly indicated for symptomatic relief of idiopathic Parkinson's disease. Despite the known improvement in motor scores, affective, cognitive, voice and speech functions might deteriorate following this procedure. Recent studies have correlated motor outcomes with intraoperative microelectrode recordings. However, there are no microelectrode recording-based tools with predictive values relating to long-term outcomes of integrative motor and non-motor symptoms. We conducted a retrospective analysis of the outcomes of patients with idiopathic Parkinson's disease who had subthalamic nucleus deep brain stimulation at Tel Aviv Sourasky Medical Centre (Tel Aviv, Israel) during 2015-2016. Forty-eight patients (19 women, 29 men; mean age, 58 ± 8 years) who were implanted with a subthalamic nucleus deep brain stimulation device underwent pre- and postsurgical assessments of motor, neuropsychological, voice and speech symptoms. Significant improvements in all motor symptoms (except axial signs) and levodopa equivalent daily dose were noted in all patients. Mild improvements were observed in more posterior-related neuropsychological functions (verbal memory, visual memory and organization) while mild deterioration was observed in frontal functions (personality changes, executive functioning and verbal fluency). The concomitant decline in speech intelligibility was mild and only partial, probably in accordance with the neuropsychological verbal fluency results. Acoustic characteristics were the least affected and remained within normal values. Dimensionality reduction of motor, neuropsychological and voice scores rendered six principal components that reflect the main clinical aspects: the tremor-dominant versus the rigidity-bradykinesia-dominant motor symptoms, frontal versus posterior neuropsychological deficits and acoustic characteristics versus speech intelligibility abnormalities. Microelectrode recordings of subthalamic nucleus spiking activity were analysed off-line and correlated with the original scores and with the principal component results. Based on 198 microelectrode recording trajectories, we suggest an intraoperative subthalamic nucleus deep brain stimulation score, which is a simple sum of three microelectrode recording properties: normalized neuronal activity, the subthalamic nucleus width and the relative proportion of the subthalamic nucleus dorsolateral oscillatory region. A threshold subthalamic nucleus deep brain stimulation score >2.5 (preferentially composed of normalized root mean square >1.5, subthalamic nucleus width >3 mm and a dorsolateral oscillatory region/subthalamic nucleus width ratio >1/3) predicts better motor and non-motor long-term outcomes. The algorithm presented here optimizes intraoperative decision-making of deep brain stimulation contact localization based on microelectrode recording with the aim of improving long-term (>1 year) motor, neuropsychological and voice symptoms.

Is There Horizontal Transmission of Creutzfeldt-Jakob Disease?

BACKGROUND: Sporadic Creutzfeldt-Jakob disease (s-CJD) is a rare, fatal neurodegenerative disorder. Familial cases of Creutzfeldt-Jakob disease (f-CJD) due to mutations in the PRNP gene are even rarer around the world; however, in Israel there is a focus of f-CJD patients carrying the E200K mutation. As the number of CJD E200K carriers in Israel is high and increasing, transmission of CJD to normal people was suspected. If such transmission occurs, the incidence of s-CJD would be expected to increase as well, resulting in changes of the ratio of familial/sporadic cases. METHODS: Using data from the National CJD Registry and official statistics on the Israeli population, we studied incidence rates of f-CJD and s-CJD for the period from 1985 to 2018 applying the Surveillance Epidemiology and End Results (SEER) statistical packet developed in the US National Cancer Institute. RESULTS: In total, 621 CJD patients (405 f-CJD and 216 s-CJD) cases are included in the registry. In the cohort of f-CJD patients, the mean age-adjusted annual incidence rate over the abovementioned period was 1.88 ± 0.09 (95% CI: 1.7-2.08) per 1,000,000. In the cohort of s-CJD patients, the mean age-adjusted incidence rate over the same period was 0.93 ± 0.06 (95% CI: 0.81-1.06) per 1,000,000 people. No significant time trends were found over the observation period in either s-CJD or f-CJD. The ratio f-CJD/s-CJD decreases over the observation period from 2.2 to 1.80. CONCLUSION: Israel has a high predominance of f-CJD compared to s-CJD. The mean incidence rate of s-CJD in Israel is similar to most countries. Between 1985 and 2018, the annual age-adjusted incidence rates for both forms of CJD remained stable. Thus, there is no evidence that CJD is transmitted from affected individuals to others.

Frequency of hand movements as a possible diagnostic tool for parkinsonian bradykinesia. Proposal of a simple bedside test.

BACKGROUND: Bradykinesia, dysrhythmia, and decrement in hand movements (HM) are core symptoms of Parkinson's disease (PD). The maximal rate of repetitive rhythm-preserving HM can be a diagnostic tool for PD bradykinesia. OBJECTIVES: To improve the clinical diagnosis of bradykinesia by identifying the frequencies at which rhythmic HM become irregular in PD patients compared to healthy age-matched controls. METHOD: Forty PD patients and 16 controls were asked to alternately perform left and right hand movements following the rate of a metronome with sound stimulation beginning at 85 beats per minute (BPM) and increasing in increments of 15 BPM up to 355 BPM. The rhythm of the HM for each rate was assessed visually, and the threshold frequency at which the subject could no longer rhythmically continue HM was measured by the metronome. The increasing rates of HM until reaching that threshold were compared between patients with PD and controls. RESULTS: The mean rates of a metronome in PD vs. healthy subjects were 173.3 ± 42.0 vs. 248.8 ± 48.5 BPM (p < 0.001) and 164.8 ± 34.2 vs. 241.2 ± 40.1 BPM (p < 0.001) for the dominant and non-dominant hands, respectively. The areas under the ROC curve were 0.929 [95%CI: (0.86-0.99)] for the dominant hand and 0.947 [95%CI: (0.88-1.0)] for the non-dominant hand. The BMP score cut-off value was 208 (sensitivity 72.7%, specificity 100%) for the dominant hand and 206 (sensitivity 87.5%, specificity 95%) for the non-dominant hand. CONCLUSIONS: The proposed test quantified the frequencies of rhythmic HMs in PD patients vs. controls and improved the diagnosis of bradykinesia in PD patients.

Creutzfeldt-Jakob and Vascular Brain Diseases: Their Overlap and Relationships.

Only a few case reports of stroke-like onset of Creutzfeldt-Jakob disease (CJD) have previously been published. We aimed to analyze the neurological, imaging, electroencephalographic (EEG), and laboratory features of patients with this very rare phenomenon. Here, we review the clinical characteristics, onset features, and clinical course variants of stroke-like CJD in 23 such patients. The median age of the patients was 71 years (range: 56-84 years); 12 were women. In 20 patients, CJD was sporadic. Thirteen patients developed apoplexy-like onset of symptoms, whereas the others had prodromal non-specific complaints. Most often the patients manifested with pyramidal signs (n = 13), ataxia (n = 9), and aphasia (n = 8). On MRI DWI sequence, all subjects had abnormal hyperintensities in various parts of the cerebral cortex, striatum, or thalamus, while EEG detected periodic triphasic waves only in 11. CSF 14-3-3 protein and total τ-protein were abnormal in 17 of 23 cases. All patients died, median lifespan being 2 months (range: 19 days-14 months). In conclusion, a complex of clinical, radiological, and laboratory manifestations of stroke-like onset of CJD is outlined. The clinical relationships between CJD and stroke are considered, in an attempt to highlight this rare presentation of an uncommon disease.

Quality of life in Parkinson's disease: A gender-specific perspective.

OBJECTIVES: The epidemiology, manifestations, and course of Parkinson's disease (PD) may differ in men and women. Assessments of severity of the illness and quality of life (QoL), and the burden on their caregivers (CG) may change as the disease advances. We determined gender differences in assessment by patients with PD themselves and by their CGs. METHODS: Married couples in whom one of the partners was a PD patient and his/her spouse served as CG were separately evaluated. The patient completed the PD QoL Questionnaire (PDQ-39), and the spouse completed the Multidimensional Caregiver Strain Index (MCSI). Comparisons were performed using statistical tests. RESULTS: We studied 122 patient-CG pairs consisting of 86 (70.5%) male patients. Female patients reported reduced QoL due to depression and pain. Worsening of QoL in advanced PD was reported only by male patients. Female CGs felt exhaustion and damage to their health resulting from care twice as often as male CG. Social constraint and time limitations were more frequent in female CGs, whereas in male CGs it remained the same. With increasing disease severity female CGs reported that manipulations and excessive demands from their male spouses increased, while male CGs reported the same level in female patients. Male CGs, unexpectedly considered themselves more free as PD advanced in their spouses. CONCLUSIONS: Male and female PD patients and CGs assess differently the severity and burden of the disease. Clinicians and social workers should be aware of these factors in attempting to improve QoL of PD patients and CGs.

Medical Cannabis in Parkinson Disease: Real-Life Patients' Experience.

BACKGROUND: The use of medical cannabis (MC) is controversial. Support for its benefits is based on small clinical series. OBJECTIVE: The aim of this study was to report the results of a standardized interview study that retrospectively assessed the effects of MC on symptoms of Parkinson disease (PD) and its adverse effects in patients treated for at least 3 months. METHODS: The survey used telephone interviews using a structured questionnaire based on subjective global impressions of change for various parkinsonian symptoms and yes/no questions on adverse effects. RESULTS: Forty-seven nondemented patients with PD (40 men) participated. Their mean age was 64.2 ± 10.8 years, mean disease duration was 10.8 ± 8.3 years, median Hoehn and Yahr (H&Y) was stage III. The duration of MC use was 19.1 ± 17.0 months, and the mean daily dose was 0.9 ± 0.5 g. The delivery of MC was mainly by smoking cigarettes (38 cases, 80.9%). Effect size (r) improvement for falls was 0.89, 0.73 for pain relief, 0.64 for depression, 0.64 for tremor, 0.62 for muscle stiffness, and 0.60 for sleep. The most frequently reported adverse effects from MC were cough (34.9%) in those who used MC by smoking and confusion and hallucinations (reported by 17% each) causing 5 patients (10.6%) to stop treatment. CONCLUSIONS: Medical cannabis was found to improve symptoms of PD in the initial stages of treatment and did not cause major adverse effects in this pilot, 2-center, retrospective survey. The extent of use and the reported effects lend support to further development of safer and more effective drugs derived from Cannabis sativa.

Clinical Practice: Evidence-Based Recommendations for the Treatment of Cervical Dystonia with Botulinum Toxin.

Cervical dystonia (CD) is the most frequent form of focal dystonia. Symptoms often result in pain and functional disability. Local injections of botulinum neurotoxin are currently the treatment of choice for CD. Although this treatment has proven effective and is widely applied worldwide, many issues still remain open in the clinical practice. We performed a systematic review of the literature on botulinum toxin treatment for CD based on a question-oriented approach, with the aim to provide practical recommendations for the treating clinicians. Key questions from the clinical practice were explored. Results suggest that while the beneficial effect of botulinum toxin treatment on different aspects of CD is well established, robust evidence is still missing concerning some practical aspects, such as dose equivalence between different formulations, optimal treatment intervals, treatment approaches, and the use of supportive techniques including electromyography or ultrasounds. Established strategies to prevent or manage common side effects (including excessive muscle weakness, pain at injection site, dysphagia) and potential contraindications to this treatment (pregnancy and lactation, use of anticoagulants, neurological comorbidities) should also be further explored.

Disorders of the oral cavity in Parkinson's disease and parkinsonian syndromes.

Awareness of nonmotor symptoms of Parkinson's disease is growing during the last decade. Among these, oral cavity disorders are, although prevalent, often neglected by the patients, their caregivers, and physicians. Some of these disorders include increased prevalence of caries and periodontal disease, sialorrhea and drooling, xerostomia, orofacial pain, bruxism, and taste impairment. Though many of these disorders are not fully understood yet and relatively few controlled trials have been published regarding their treatment, physicians should be aware of the body of evidence that does exist on these topics. This paper reviews current knowledge regarding the epidemiology, pathophysiology, and treatment options of disorders of the oral cavity in Parkinson's disease patients.

Effect of rivastigmine on mobility of patients with higher-level gait disorder: a pilot exploratory study.

BACKGROUND: Higher-level gait disorder (HLGD) in older adults is characterized by postural instability, stepping dysrhythmicity, recurrent falls and progressive immobility. Cognitive impairments are frequently associated with HLGD. OBJECTIVES: The aim of this study was to compare gait and cognitive performance before and after the use of rivastigmine in patients with HLGD, free from cognitive impairment or Parkinsonism. METHODS: Fifteen non-demented patients with HLGD (age 79.2 ± 5.9 years; 11 women; Mini-Mental State Examination [MMSE] 28.3 ± 1.4) received escalating doses of rivastigmine for 12 weeks in an open-label, pilot study. They were assessed before and after treatment (week 0 and week 12), and after a 4-week washout period (week 16). Assessments included the Mindstreams computerized neuropsychological battery, Activities-specific Balance Confidence Scale, State-Trait Anxiety Inventory, Geriatric Depression Scale, Timed Up and Go (TUG) test, gait speed and stride time variability. One-way multiple analysis of variance tests for repeated measures were used, and Pillai's trace test was considered as robust to investigate significant differences. RESULTS: The mean dose of rivastigmine during the 8-12 week period was 5.1 ± 2.3 mg/day. A positive effect was observed on the Mindstreams memory subscale and anxiety scores [Pillai's trace: F(6,724) = 0.508, p = 0.010; and F(7,792) = 0.545, p = 0.006, respectively, over the course of the study] as well as on mobility (TUG test) [Pillai's trace: F(4,863) = 0.448; p = 0.028], whereas gait speed and stride time variability did not change. CONCLUSIONS: The use of relatively low-dose rivastigmine did not affect gait speed and stride time variability; however, the general mobility and anxiety were improved. These preliminary results warrant a larger, randomized, placebo-controlled study.

Cognition in multiple system atrophy: neuropsychological profile and interaction with mood.

We evaluated cognitive functions and mood in two groups of patients with multiple system atrophy (MSA) in order to determine the influence of mood on cognitive performance. Our aim was to differentiate between parkinsonism-predominant (MSA-P) and cerebellar-predominant (MSA-C) MSA based on those parameters. Fifteen MSA-P and 10 MSA-C patients underwent neuropsychological tests that examined executive functions (working memory, response inhibition, and verbal reproduction), verbal learning and memory, verbal and visual reasoning, and processing speed. Anxiety and depression were also assessed. The findings on their cognitive performance and mood were compared to those of healthy controls and also discussed in relation to a group of Parkinson's disease (PD) patients. The results showed that cognitive and mood characteristics could distinguish MSA-P from MSA-C and that anxiety and depression are related to cognitive decline. Compared with healthy controls, MSA-P patients showed reduced verbal retrieval (immediate, P < 0.019; long-term, P < 0.018) while MSA-C patients had difficulties in learning new verbal information (P < 0.022) and in controlling attention (P < 0.023). These data indicate that MSA-P and MSA-C appear to have, at least in part, different cognitive and mood profiles. The neuropsychological assessments of MSA patients should test for and then take into account their level of anxiety and depression, insofar as it might have an adverse effect on their cognitive performance.

Suicidal thoughts in patients with Parkinson's disease treated by deep brain stimulation of the subthalamic nuclei: two case reports and review of the literature.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nuclei (STN) can result in depression despite the obvious motor improvement. CASE PRESENTATIONS: Two patients with serious life-threatening depressive episodes are described. In the first case, the trigger for depression was a slight adjustment of the left stimulating electrode's contact. In the second case, reducing both the dopaminergic therapy and the voltage of DBS resulted in the manifestation of depressive symptoms. CONCLUSIONS: DBS-induced depression possibly has pathogenetic differences from ordinary Parkinson's disease depression. The STN region seems to be a sensitive zone that influences emotions.

Striatal dopa and glucose metabolism in PD patients with freezing of gait.

In Parkinson's disease (PD), freezing suggests sudden and transient blocks of motor behavior during initiating or continuous repetitive movements. Its underlying pathophysiology remains unclear. The objective of this study is to compare striatal dopamine metabolism and cerebral glucose metabolism between PD patients with and without freezing of gait (FOG). A total of 10 PD patients with FOG at off and 7 PD patients without FOG underwent brain positron emission tomography with (18)[F]-6-fluoro-levodopa (FDOPA) and (18)[F]-fluordesoxyglucose (FDG). Striatum decarboxylase activity was expressed by metabolic influx constants of the striatum related to the occipital lobe (Kocc). FDG uptake in caudate and putamen was normalized to global FDG uptake. Region of interest (ROI) analysis of striatal regions was used, as well as voxel-based analysis by statistical parametric mapping (SPM). ROI analysis did not reveal differences in striatal FDOPA and FDG uptake between the groups. SPM showed lower putaminal FDOPA uptake (P = 0.05 uncorrected) with increased FDG uptake (P = 0.01 uncorrected) in freezing PD, whereas caudate uptake of the two tracers was reduced. Freezing-related cortical FDG decrease was found in (right) parietal regions. In conclusion, in freezing PD, caudate uptake of FDG and FDOPA was reduced, whereas putamen FDOPA decrease was associated with FDG increase. Right hemisphere circuitry seemed to be more affected in freezing patients.

Is freezing of gait in Parkinson's disease related to asymmetric motor function?

Freezing of gait (FOG) is a disabling phenomenon common in patients with advanced Parkinson's disease (PD). The cause of FOG is unclear. The objective of this study was to explore a novel hypothesis stating that FOG is related to asymmetric motor performance. We compared PD patients that experience FOG episodes (PD+FOG) with PD patients that do not (PD-FOG) and studied the relationship of FOG to asymmetry in gait and in rhythmic hand movement performance to determine whether potential FOG-related gait asymmetry is unique to walking or whether it is systemic. Subjects were tested in an "off" (unmedicated) and again in an "on" (medicated) state. Gait was more asymmetric in PD+FOG than in PD-FOG during "off" state (p = 0.005) and during "on" (p = 0.016). Rhythmicity of foot swing in one leg was correlated with the other leg in PD-FOG but not in PD+FOG. There was no difference in asymmetry in performance of rhythmic hand movements between the two groups. No correlation was found between asymmetry of clinical symptoms and gait asymmetry. Taken together, the results of this study suggest that bilateral uncoordinated gait and marked gait asymmetry, but not asymmetry in motor performance in general, are associated with FOG.

Gait dynamics in Parkinson's disease: relationship to Parkinsonian features, falls and response to levodopa.

OBJECTIVES: Patients with Parkinson's disease (PD) have an increased risk of falling that has yet to be fully explained. To better understand the gait disturbance in PD and the factors that contribute to falls, we quantitatively evaluated: (1) the relationship between gait variability (a marker of fall risk in other populations), fall history, and other parkinsonian features, and (2) the effects of levodopa on these relationships. METHODS: The average stride time and stride-to-stride variability were measured using force-sensitive insoles during comfortable walking. Fall frequency, motor control, function, and mental health were measured using the Unified Parkinson's Disease Rating Scale (UPDRS), the Mini-Mental State Exam (MMSE), and the timed motor tests of the Core Assessment Program for Intracerebral Transplantations (CAPIT) in 32 subjects with idiopathic PD, in an "off" (unmedicated) state and again in an "on" (medicated) state. RESULTS: Average stride time was not associated with any UPDRS or CAPIT measure and was similar in fallers and non-fallers in "off" and "on" states (p>0.27). Stride time variability was significantly associated with fall frequency as well as with total scores on the CAPIT and the UPDRS, ADL abilities, and motor function. Stride time variability and falls were not related to tremor, rigidity or bradykinesia in the "off" state. 41% of subjects reported one or more falls. Stride time variability was 8.8+/-7.9% in fallers and 4.2+/-1.3% in non-fallers (p<0.009). Stride time variability significantly improved in response to levodopa, both in fallers and non-fallers, but remained increased in fallers (vs. non-fallers). CONCLUSIONS: The patho-physiology responsible for impaired stride-to-stride regulation of gait timing is apparently independent of other cardinal features of PD, i.e., tremor, rigidity, or bradykinesia, but is responsive to levodopa. Stride-to-stride variability is especially impaired among PD subjects with a history of falls, suggesting, for the first time, the possibility of exaggerated impairment of internal clock function in PD fallers.