Facilitatory rTMS over the Supplementary Motor Cortex Impedes Gait Performance in Parkinson Patients with Freezing of Gait.

Freezing of gait (FOG) in Parkinson's disease (PD) occurs frequently in situations with high environmental complexity. The supplementary motor cortex (SMC) is regarded as a major network node that exerts cortical input for motor control in these situations. We aimed at assessing the impact of single-session (excitatory) intermittent theta burst stimulation (iTBS) of the SMC on established walking during FOG provoking situations such as passing through narrow spaces and turning for directional changes. Twelve PD patients with FOG underwent two visits in the off-medication state with either iTBS or sham stimulation. At each visit, spatiotemporal gait parameters were measured during walking without obstacles and in FOG-provoking situations before and after stimulation. When patients passed through narrow spaces, decreased stride time along with increased stride length and walking speed (i.e., improved gait) was observed after both sham stimulation and iTBS. These effects, particularly on stride time, were attenuated by real iTBS. During turning, iTBS resulted in decreased stride time along with unchanged stride length, a constellation compatible with increased stepping frequency. The observed iTBS effects are regarded as relative gait deterioration. We conclude that iTBS over the SMC increases stepping frequency in PD patients with FOG, particularly in FOG provoking situations.

The Parkinson disease pain classification system: results from an international mechanism-based classification approach.

ABSTRACT: Pain is a common nonmotor symptom in patients with Parkinson disease (PD) but the correct diagnosis of the respective cause remains difficult because suitable tools are lacking, so far. We developed a framework to differentiate PD- from non-PD-related pain and classify PD-related pain into 3 groups based on validated mechanistic pain descriptors (nociceptive, neuropathic, or nociplastic), which encompass all the previously described PD pain types. Severity of PD-related pain syndromes was scored by ratings of intensity, frequency, and interference with daily living activities. The PD-Pain Classification System (PD-PCS) was compared with classic pain measures (ie, brief pain inventory and McGill pain questionnaire [MPQ], PDQ-8 quality of life score, MDS-UPDRS scores, and nonmotor symptoms). 159 nondemented PD patients (disease duration 10.2 ± 7.6 years) and 37 healthy controls were recruited in 4 centers. PD-related pain was present in 122 patients (77%), with 24 (15%) suffering one or more syndromes at the same time. PD-related nociceptive, neuropathic, or nociplastic pain was diagnosed in 87 (55%), 25 (16%), or 35 (22%), respectively. Pain unrelated to PD was present in 35 (22%) patients. Overall, PD-PCS severity score significantly correlated with pain's Brief Pain Inventory and MPQ ratings, presence of dyskinesia and motor fluctuations, PDQ-8 scores, depression, and anxiety measures. Moderate intrarater and interrater reliability was observed. The PD-PCS is a valid and reliable tool for differentiating PD-related pain from PD-unrelated pain. It detects and scores mechanistic pain subtypes in a pragmatic and treatment-oriented approach, unifying previous classifications of PD-pain.

Altered activation and connectivity of the supplementary motor cortex at motor initiation in Parkinson's disease patients with freezing.

OBJECTIVE: Motor initiation failure is a key feature of freezing of gait (FOG) due to Parkinson's disease (PD). The supplementary motor cortex (SMC) plays a central role in its pathophysiology. We aimed at investigating SMC activation, connectivity and plasticity with regard to motor initiation in FOG. METHODS: Twelve patients with FOG and eleven without FOG underwent a multimodal electrophysiological evaluation of SMC functioning including the Bereitschaftspotential and movement-related desynchronisation of cortical beta oscillations. SMC plasticity was modulated by intermittent theta burst stimulation (iTBS) and its impact on gait initiation was assessed by a three-dimensional gait analysis. RESULTS: Prior to volitional movements the Bereitschaftspotential was smaller and beta power was less strongly attenuated over the SMC in patients with FOG compared to those without. Pre-motor coherence between the SMC and the primary motor cortex in the beta frequency range was also stronger in patients with FOG. iTBS resulted in a relative deterioration of gait initiation. CONCLUSIONS: Reduced activation of the SMC along with increased SMC connectivity in the beta frequency range hinder a flexible shift of the motor set as it is required for gait initiation. SIGNIFICANCE: Altered SMC functioning plays an important role for motor initiation failure in PD-related FOG.

Decreased grey matter in the postural control network is associated with lateral flexion of the trunk in Parkinson's disease.

BACKGROUND: Disruption of central networks, particularly of those responsible for integrating multimodal afferents in a spatial reference frame, were proposed in the pathophysiology of lateral trunk flexion in Parkinson's disease (PD). Knowledge about the underlying neuroanatomical structures is limited. OBJECTIVE: To investigate if decreased focal grey matter (GM) is associated with trunk flexion to the side and if the revealed GM clusters correlate with a disturbed perception of verticality in PD. METHODS: 37 PD patients with and without lateral trunk flexion were recruited. Standardized photos were taken from each patient and trunk orientation was measured by a blinded rater. Voxel-based morphometry (VBM) was used to detect associated clusters of decreased GM. The subjective visual vertical (SVV) was assessed as a marker for perception of verticality and SVV estimates were correlated with GM clusters. RESULTS: VBM revealed clusters of decreased GM in the right posterior parietal cortex and in the right thalamus were associated with lateral trunk flexion. The SVV correlated with the extent of trunk flexion, and the side of the SVV tilt correlated with the side of trunk flexion. GM values from the thalamus correlated with the SVV estimates. CONCLUSIONS: We report an association between neurodegenerative changes within the posterior parietal cortex and the thalamus and lateral trunk flexion in PD. These brain structures are part of a network proposed to be engaged in postural control and spatial self-perception. Disturbed perception of verticality points to a shifted egocentric spatial reference as an important pathophysiological feature.

The Phenotypic Variation of a Parkin-Related Parkinson's Disease Family and the Role of Heterozygosity.

BACKGROUND: Parkinson's disease (PD) is a common neurodegenerative disorder with both sporadic occurrence and Mendelian heredity, as it is true for autosomal recessive parkin-related PD (PARK-parkin). Parkin-related PD is characterized by early onset, slow progression, frequent lower limb dystonia, and a robust response to levodopa. Clinicians are increasingly confronted with heterozygous PD patients mimicking dominant inheritance. Nevertheless, the exact clinical implications of heterozygosity are not fully understood. CASES: We present an illustrative PARK-parkin family with 2 affected sisters (compound heterozygous) and their father (heterozygous). One sister expresses the classical phenotype, whereas the other has isolated jerky tremor. The father has left-sided action tremor of the hand with some dystonic posturing without clear bradykinesia and normal DaTSCAN. CONCLUSION: This case series illustrates the phenotypic variability in parkin-related PD with 1 classical phenotype and 1 patient with isolated jerky tremor. Unilateral hand tremor of the heterozygous father could mislead genetic testing by mimicking dominant inheritance.

Radiation-induced cavernoma after total body irradiation and haematopoietic stem cell transplantation in an adult patient suffering from acute myeloid leukaemia.

Cerebral cavernomas are thin-walled vascular lesions composed of dilated capillary spaces. De novo formation of cavernomas after cerebral radiotherapy has been suspected since 1994. They are mostly seen in children after irradiation of brain tumours. Radiation dose and the developing juvenile brain are predisposing factors causing cavernomas. However, the underlying mechanisms are still far from being understood. In adults, radiation-induced cavernomas (RICs) usually occur 10 years after a high cumulative radiation dosage of >30 Gy. Here, we report a 45-year-old man with new-onset focal epileptic seizures caused by a haemorrhagic lesion noted on cerebral computed tomography scan. Brain MRI showed the typical appearance of a ruptured cavernoma. Of note, a cerebral MRI scan 5 years earlier showed no corresponding lesion. The patient had been treated with haematopoietic stem cell transplantation for acute myeloid leukaemia (AML) 16 years before. As part of this procedure, total body irradiation (TBI) consisting of 12 Gy was administered. According to the data from the literature, the typical delay from irradiation and a former normal brain MRI scan, we assume that our patient suffers from a RIC. To our knowledge, this is the first documented adult AML patient with a RIC treated with TBI. We aim to increase awareness among neurologists for the association of cranial irradiation or TBI and de novo cavernomas in patients suffering from malignant diseases.

The impact of a multidisciplinary educational intervention to reduce PEG tube placement in patients with terminal-stage dementia: a translation of research into practice.

The purpose of this translation of research into practice (TRIP) project was to to determine the impact of a multidisciplinary education-consultation intervention to reduce percutaneous endoscopic gastrostomy (PEG) tube placement in patients with terminal-stage dementia at a single urban hospital in a city characterized by numerous health care transitions. We attempted a "just-in-time" approach to educate busy clinicians through explicit recommendations offered during routine and requested consultation. The project results showed that the intervention had a modest positive clinical impact.

A Respiratory Distress Observation Scale for patients unable to self-report dyspnea.

BACKGROUND: Standard measures of dyspnea rely on self-report. Cognitive impairment and nearness to death may interfere with symptom distress reporting leading to underrecognition and overtreatment or undertreatment. Previous psychometric testing of the Respiratory Distress Observation Scale (RDOS) demonstrated internal consistency and convergent validity with dyspnea self-report and discriminant validity with pain and no dyspnea. Additional testing was needed with patients unable to self-report. The aim of this study was to establish further the reliability and construct validity of a revised RDOS. METHODS: An observational design was used with 89 consecutive patients referred for inpatient palliative care consultation and at risk for dyspnea who had one or more of lung cancer, chronic obstructive pulmonary disease (COPD), heart failure, or pneumonia. Patients were observed and the RDOS scored once each day for up to three days after the initial consultation. Other measures included: dyspnea self-report, neurologic diagnoses, opioid or benzodiazepine use, peripheral oxygen saturation, end-tidal carbon dioxide level, consciousness, cognitive state, nearness to death, and patient demographics. RESULTS: Perfect interrater reliability across data collectors was achieved. No differences in RDOS scoring were found by patient demographics. RDOS was associated with use of oxygen (p < 0.01), oxygen saturation (p < 0.01) and nearness to death (p < 0.01). A significant decrease in RDOS was found over time corresponding with treatment (p < 0.01). The reliability of this 8-item scale using Cronbach alpha is 0.64. CONCLUSIONS: Declining consciousness and/or cognition are expected when patients are near death. The RDOS performed well when tested with terminally ill patients who were at risk for respiratory distress, most of whom could not self-report dyspnea. The tool is sensitive to detect changes over time and measure response to treatment. The RDOS is simple to use; scoring takes less than 5 minutes. The RDOS has clinical and research utility to measure and trend respiratory distress and response to treatment.

Patients who are near death are frequently unable to self-report dyspnea.

BACKGROUND: Standard measures of dyspnea rely on the patient's self-report. Declining consciousness and/or cognitive function and nearness to death may interfere with dyspnea reporting making the patient vulnerable to undertreatment or overtreatment. METHODS: An observational design was used with 89 consecutive patients referred for inpatient palliative care consultation. Patients were included if they were at risk for dyspnea because of one or more of the following: lung cancer, chronic obstructive pulmonary disease (COPD), heart failure, or pneumonia. Patients were asked "Are you short of breath?" and asked to quantify any distress by pointing to a visual analogue scale (VAS). Other measures included: consciousness, cognitive state, terminal illness severity, and patient demographics. RESULTS: More than half of the patients (54%) were unable to provide a yes or no response. Only 20 of 41 (49%) able to respond with yes or no were able to quantify any distress with the VAS. Ability to self-report was positively associated with consciousness (p < 0.01), cognitive state (p < 0.01), and terminal illness severity (p < 0.01). A significant inverse relationship was found between consciousness and terminal illness severity (p < 0.01). Declines in consciousness and cognitive state were strongly correlated with nearness to death (p < 0.01). CONCLUSIONS: Declining consciousness and/or cognitive state are expected when patients are near death. The ability to give even the simplest self-report (yes or no) about dyspnea is lost in the near-death phase of terminal illness, yet the ability to experience distress may persist and may be overlooked and undertreated or overtreated. Other methods for symptom assessment are needed in this context.

Cardiovascular effects of sibutramine in the treatment of obese adolescents: results of a randomized, double-blind, placebo-controlled study.

BACKGROUND: Adolescent obesity is a major public health problem. Treatment options in addition to behavioral therapy could include pharmacotherapy with sibutramine. OBJECTIVES: Concerns regarding increases in blood pressure and heart rate after sibutramine treatment in some adult patients precipitated the present analysis, which evaluated the cardiovascular safety of sibutramine plus a behavioral therapy program in obese adolescents. PATIENTS AND METHODS: With this 12-month, randomized, double-blind, placebo-controlled trial in 33 US clinics we studied 498 adolescents aged 12 to 16 years with multiethnic backgrounds and BMIs of 28.1 to 46.3 kg/m2. RESULTS: The subjects were randomly assigned to behavioral therapy plus 10 mg of sibutramine or behavioral therapy plus placebo daily. At the end point, there was a mean treatment group difference in BMI of 2.6 kg/m2 in favor of sibutramine. Small mean decreases in blood pressure and pulse rate were seen in both sibutramine and placebo groups at the end point (systolic blood pressure: -2.1 vs -2.1 mmHg; diastolic blood pressure: -0.1 vs -1.1 mmHg; pulse rate: -0.2 vs -1.8 bpm). In both treatment groups, these reductions in vital signs were greater at the end point when BMI reduction was > or = 5% compared with < 5%. CONCLUSIONS: Sibutramine may have some direct cardiovascular effects on obese adolescents. These cardiovascular effects may be balanced by a reduction in BMI, which, in adolescents, seems to be greater than that observed in adults.

Sibutramine plus meal replacement therapy for body weight loss and maintenance in obese patients.

OBJECTIVE: Our objective was to assess the efficacy and safety of sibutramine with a low-calorie diet (LCD) and commercial meal-replacement product in achieving weight loss and weight-loss maintenance in obese patients. RESEARCH METHODS AND PROCEDURES: Eight U.S. centers recruited 148 obese patients for a 3-month comprehensive weight-loss therapy (Phase I) comprising daily sibutramine 10 mg + LCD (two Slim-Fast meal-replacement shakes, one low-calorie meal; total kcal/d = 1200-1500). Patients (N = 113) who lost > or =5% of initial body weight during Phase I were randomized for a 9-month period (Phase II) to daily sibutramine 15 mg + LCD (one meal-replacement shake; two low-calorie meals: total kcal/d approximately 1200-1500) or daily placebo + three low-calorie meals (total kcal/d approximately 1200-1500). Both phases included behavior modification. Efficacy was assessed by body weight change during each phase and by the number of patients at endpoint maintaining > or =80% of the weight they had lost by the end of Phase I. Other outcomes included changes in cardiovascular and metabolic risk factors, adverse events, and vital signs. RESULTS: Mean body weight change during Phase I was -8.3 kg (p < 0.001). Patients randomized to sibutramine in Phase II had an additional -2.5 kg mean weight loss vs. a 2.8-kg increase in the placebo group (p < 0.001). More sibutramine patients maintained > or =80% of their Phase I weight loss at the end of Phase II (85.5% vs. placebo 36.7%, p < 0.001). Most adverse events were mild or moderate in severity, and all serious adverse events were unrelated to sibutramine. DISCUSSION: Sibutramine plus LCD with meal replacements and behavior modification is a safe and effective strategy for achieving and sustaining weight loss in obese patients.

Effects of sibutramine treatment in obese adolescents: a randomized trial.

BACKGROUND: Increased prevalence of adolescent obesity requires effective treatment options beyond behavior therapy. OBJECTIVE: To see whether sibutramine reduced weight more than placebo in obese adolescents who were receiving a behavior therapy program. DESIGN: 12-month, 3:1 randomized, double-blind trial conducted from July 2000 to February 2002. SETTING: 33 U.S. outpatient clinics. PARTICIPANTS: 498 participants 12 to 16 years of age with a body mass index (BMI) that was at least 2 units more than the U.S. weighted mean of the 95th percentile based on age and sex, to the upper limit of 44 kg/m2. INTERVENTIONS: Site-specific behavior therapy plus 10 mg of sibutramine or placebo. Blinded study medication dose was uptitrated to 15 mg or placebo at month 6 if initial BMI was not reduced by 10%. MEASUREMENTS: Body mass index, waist circumference, body weight, fasting lipid and glycemic variables, safety, and tolerability. RESULTS: Seventy-six percent of patients in the sibutramine group and 62% of patients in the placebo group completed the study. The estimated mean treatment group difference at month 12 (linear mixed-effects model) favored sibutramine for change from baseline in BMI (-2.9 kg/m2 [95% CI, -3.5 to -2.2 kg/m2]) and body weight (-8.4 kg [CI, -9.7 to -7.2 kg]) (P < 0.001 for both). The sibutramine group had greater improvements in triglyceride levels, high-density lipoprotein cholesterol levels, insulin levels, and insulin sensitivity (P < or = 0.001 for all). The rate of tachycardia was greater with sibutramine vs. placebo (12.5% vs. 6.2%; difference, 6.3 percentage points [CI, 1.0 to 11.7 percentage points]) but did not lead to increased withdrawal (2.4% vs. 1.5%; difference, 0.9 percentage point [CI, -1.7 to 3.5 percentage points]). LIMITATIONS: The 1-year study duration precluded assessment of long-term weight maintenance and putative health benefits and harms, and 24% and 38% of the sibutramine and placebo groups, respectively, did not complete follow-up. CONCLUSIONS: Sibutramine added to a behavior therapy program reduced BMI and body weight more than placebo and improved the profile of several metabolic risk factors in obese adolescents.

Valproate unbound fraction and distribution volume following rapid infusions in patients with epilepsy.

The availability of an intravenous formulation now makes possible rapid administration of valproate (VPA) loading doses, but estimates of key VPA pharmacokinetic parameters in patients have limited the use of this approach. VPA disposition was characterized in 112 epilepsy patients, with or without enzyme inducing comedications, randomized to either 3.0 or 1.5mg/kg/min infusions of valproate sodium injection. Maximum dose was