Cognitive and psychiatric outcome 3 years after globus pallidus pars interna or subthalamic nucleus deep brain stimulation for Parkinson's disease

BackgroundEffects on non-motor symptoms, mainly cognitive and psychiatric side effects, could influence the decision for either globus pallidus pars interna (GPi) or subthalamic nucleus (STN) deep brain stimulation (DBS) for patients with Parkinson's disease (PD).Objective1) To compare cognitive and psychiatric outcomes 3 years after GPi DBS versus STN DBS, and 2) to report on occurrence of suicidal ideation, psychiatric diagnoses, social functioning, and marital satisfaction 3 years after DBS.MethodsPatients were randomized to receive GPi DBS (n = 65) or STN DBS (n = 63). Standardized assessments were performed at baseline, 1 year, and 3 years. We used linear mixed model analyses to investigate between-group differences on the Mattis Dementia Rating Scale (MDRS), neuropsychological tests, and psychiatric questionnaires 3 years after DBS.ResultsEighty-seven patients (68%) completed at least one neuropsychological test after 3 years. No significant between-group differences were found on the MDRS (p = 0.61), neuropsychological tests (p-values between 0.17 and 0.87), and psychiatric questionnaires (p-values between 0.23 and 0.88) 3 years after DBS. The Mini International Neuropsychiatric Interview did not indicate a substantial number of psychiatric diagnoses after 3 years. Social functioning and marital satisfaction were comparable in both groups.ConclusionsThree years after GPi DBS and STN DBS no pronounced between-group differences on measures of cognitive and psychiatric functioning could be demonstrated. Overall, cognitive and psychiatric outcome 3 years after DBS do not provide a clear direction for clinicians when considering which of these two surgical targets to choose.     

Pallidal low β-low γ phase-amplitude coupling inversely correlates with Parkinson disease symptoms

ObjectiveRecent discoveries suggest that it is most likely the coupling of β oscillations (13–30 Hz) and not merely their power that relates to Parkinson disease (PD) pathophysiology.MethodsWe analyzed power and phase amplitude coupling (PAC) in local field potentials (LFP) recorded from Pallidum after placement of deep brain stimulation (DBS) leads in nineteen PD patients and three patients with dystonia.ResultsWithin GPi, we identified PAC between phase of β and amplitude of high frequency oscillations (200–300 Hz) and distinct β-low γ (40–80 Hz) PAC both modulated by contralateral movement. Resting β-low γ PAC, also present in dystonia patients, inversely correlated with severity of rigidity and bradykinesia (R = −0.44, P = 0.028). These findings were specific to the low β band, suggesting a differential role for the two β sub-bands.ConclusionsPAC is present across distinct frequency bands within the GPi. Given the presence of low β-low γ PAC in dystonia and the inverse correlation with symptom severity, we propose that this PAC may be a normal pallidal signal.SignificanceThis study provides new evidence on the pathophysiological contribution of local pallidal coupling and suggests similar and distinct patterns of coupling within GPi and STN in PD.     

Determinants of denervation-independent depletion of putamen dopamine in Parkinson's disease and multiple system atrophy

BackgroundSevere putamen dopamine depletion characterizes Parkinson's disease (PD) and multiple system atrophy (MSA). The extent of the depletion is greater than can be accounted for by loss of nigrostriatal dopaminergic terminals alone. We used putamen tissue levels and ratios of cysteinyl and parent catechols to explore possible denervation-independent abnormalities of dopamine synthesis and fate in PD and MSA. 5-S-Cysteinyldopa (Cys-DOPA) is produced from spontaneous oxidation of DOPA and 5-S-cysteinyldopamine (Cys-DA) from spontaneous oxidation of DA.MethodsPost-mortem putamen tissue samples from 17 PD and 25 MSA patients and 30 controls were assayed for endogenous catechols including DA, its cytoplasmic metabolites (Cys-DA, 3,4-dihydroxyphenylacetic acid, 3,4-dihydroxyphenylethanol, and 3,4-dihydroxyphenylacetaldehyde), and tyrosine hydroxylation products proximal to DA (DOPA and Cys-DOPA).ResultsThe PD and MSA groups did not differ in mean values of parent or cysteinyl catechols, and the data for the two groups were lumped. In the patients an index of vesicular storage of DA (the ratio of DA to the sum of its cytoplasmic metabolites) averaged 54% of control (p = 0.001), and an index of L-aromatic-amino-acid decarboxylase (LAAAD) activity (the ratio of DA and the sum of its cytoplasmic metabolites to the sum of DOPA + Cys-DOPA) averaged 21% of control (p < 0.0001). An index of innervation (the sum of DOPA + Cys-DOPA) averaged 63% of control (p = 0.01).InterpretationBased on patterns of parent and cysteinyl catechols in putamen, PD and MSA involve decreased vesicular uptake and decreased LAAAD activity in the residual dopaminergic terminals. The combination seems to contribute importantly to dopamine depletion in these diseases.     

Association between dopaminergic dysfunction and anxiety in de novo Parkinson's disease

ObjectivesTo explore the relationships between nigrostriatal dysfunction and neuropsychiatric symptoms (including anxiety, depression and apathy) in a large cohort of newly diagnosed, drug-naïve Parkinson disease (PD) patients compared to a cohort of healthy controls (HC).MethodsThis is a cross-sectional analysis of the Parkinson's Progression Markers Initiative (PPMI) cohort at baseline, including 405 PD patients and 187 HC. Nigrostriatal degeneration was evaluated by means of SPECT DAT scan. Relationships between neuropsychiatric symptoms and DAT uptakes were analysed by means of stepwise multiple regression analysis.ResultsIn the PD group, lower DAT uptake in the right caudate was associated with higher STAI trait subscore (β = −2.939, 95%CI: −4.634 to −1.254, p = 0.001). Depression and apathy scores were not related with DAT uptakes. No associations were found in the HC group.ConclusionsOur cross-sectional analysis of the PPMI data shows that lower caudate DAT uptake is associated with higher level of anxiety. The data strengthens the relationship between dopaminergic dysfunction and neuropsychiatric symptoms in early PD.     

Smartphone-based tactile cueing improves motor performance in Parkinson's disease

IntroductionVisual and auditory cueing improve functional performance in Parkinson's disease (PD) patients. However, audiovisual processing shares many cognitive resources used for attention-dependent tasks such as communication, spatial orientation, and balance. Conversely, tactile cues (TC) may be processed faster, with minimal attentional demand, and may be more efficient means for modulating motor-cognitive performance. In this study we aimed to investigate the efficacy and limitations of TC for modulating simple (heel tapping) and more complex (walking) motor tasks (1) over a range of cueing intervals, (2) with/without a secondary motor task (holding tray with cups of water).MethodsTen PD patients (71 ± 9 years) and 10 healthy controls (69 ± 7 years) participated in the study. TCs was delivered through a smart phone attached to subjects' dominant arm and were controlled by a custom-developed Android application.ResultsPD patients and healthy controls were able to use TC to modulate heel tapping (F(3.8,1866.1) = 1008.1, p < 0.001), and partially modulate walking (F(3.5,1448.7) = 187.5, p < 0.001) tasks. In the walking task, PD patients modulated performance over a narrower range of cueing intervals (R² = 0.56) than healthy controls (R² = 0.84; group difference F(3.5,1448.7) = 8.6, p < 0.001). TC diminished synchronization error associated with performance of secondary motor task during walking in PD patients and healthy controls (main effect of Task (F(1,494) = 0.4; p = 0.527), Task X Group interaction (F(1,494) = 0.5; p = 0.493)).ConclusionThis study expands modalities of TC usage for movement modulation and motor-cognitive integration in PD patients. The smartphone TC application was validated as a user-friendly movement modulation aid.     

Bradykinesia of posed smiling and voluntary movement of the lower face in Parkinson's disease

ObjectiveImpaired facial expression, including spontaneous and emotional movements such as smiling, has been often reported in Parkinson's disease (PD). There is a general consensus that spontaneous smiling is abnormal in PD. Investigations on posed smiling yield contrasting results. Moreover, no study has yet addressed the relationship between posed smiling and abnormalities of voluntary movements of the lower face, global motor impairment and the effects of dopaminergic medication.MethodsWe investigated the kinematics of posed smiling (mimicking a smile shown in a picture) and those of voluntary movements of the lower face (showing the teeth as fast as possible – voluntary grinning) in 15 patients with PD (ON and OFF therapy) and in 16 healthy controls. Facial movements were recorded using a 3D optoelectronic system and analyzed using dedicated software.ResultsSome kinematic parameters of both posed smiling and voluntary grinning were abnormally lower in PD patients in comparison to healthy subjects. The kinematics of posed smiling correlated with those of voluntary grinning in PD patients but not in healthy controls. Posed smiling and voluntary grinning abnormalities were related to global motor severity but did not significantly improve upon L-dopa administration.ConclusionsThese results suggest that posed smiling and voluntary grinning are both abnormal in PD patients and that they are likely mediated by a common pathophysiological mechanism.     

Diabetes mellitus is independently associated with more severe cognitive impairment in Parkinson disease

BackgroundThere is increasing interest in interactions between metabolic syndromes and neurodegeneration. Diabetes mellitus (DM) contributes to cognitive impairment in the elderly but its effect in Parkinson disease (PD) is not well studied.ObjectiveTo investigate effects of comorbid DM on cognition in PD independent from PD-specific primary neurodegenerations.MethodsCross-sectional study. Patients with PD (n = 148); age 65.6 ± 7.4 years, Hoehn and Yahr stage 2.4 ± 0.6, with (n = 15) and without (n = 133) comorbid type II DM, underwent [¹¹C]methyl-4-piperidinyl propionate (PMP) acetylcholinesterase (AChE) PET imaging to assess cortical cholinergic denervation, [¹¹C]dihydrotetrabenazine (DTBZ) PET imaging to assess nigrostriatal denervation, and neuropsychological assessments. A global cognitive Z-score was calculated based on normative data. Analysis of covariance was performed to determine cognitive differences between subjects with and without DM while controlling for nigrostriatal denervation, cortical cholinergic denervation, levodopa equivalent dose and education covariates.ResultsThere were no significant differences in age, gender, Hoehn and Yahr stage or duration of disease between diabetic and non-diabetic PD subjects. There was a non-significant trend toward lower years of education in the diabetic PD subjects compared with non-diabetic PD subjects. PD diabetics had significantly lower mean (±SD) global cognitive Z-scores (−0.98 ± 1.01) compared to the non-diabetics (−0.36 ± 0.91; F = 7.78, P = 0.006) when controlling for covariate effects of education, striatal dopaminergic denervation, and cortical cholinergic denervation (total model F = 8.39, P < 0.0001).ConclusionDiabetes mellitus is independently associated with more severe cognitive impairment in PD likely through mechanisms other than disease-specific neurodegenerations.     

Impaired contrast sensitivity is associated with more severe cognitive impairment in Parkinson disease

ObjectivesDopaminergic degeneration affects both nigrostriatal projection neurons and retinal amacrine cells in Parkinson disease (PD). Parkinsonian retinopathy is associated with impaired color discrimination and contrast sensitivity. Some prior studies described associations between color discrimination deficits and cognitive deficits in PD, suggesting that contrast discrimination deficits are due, at least in part, to cognitive deficits in PD. We investigated the relationship between cognitive deficits and impaired contrast sensitivity in PD.MethodsPD subjects, n = 43; 15F/28M; mean age 66.5 ± 8.2, Hoehn and Yahr stage 2.6 ± 0.6, and duration of disease of 6.2 ± 5.0 years underwent neuropsychological and Rabin contrast sensitivity testing.ResultsMean Rabin contrast sensitivity score was 1.34 ± 0.40. Bivariate analyses showed significant correlation between Rabin contrast sensitivity scores and global cognitive z-scores (R = 0.54, P = 0.0002). Cognitive domain Z-score post hoc analysis demonstrated most robust correlation between Rabin scores and executive functions (R = 0.49, P = 0.0009), followed by verbal learning (R = 0.44, P = 0.0028), visuospatial (R = 0.39, P = 0.001) and attention z-scores (R = 0.32, P = 0.036).ConclusionsImpaired contrast sensitivity in PD is robustly associated with cognitive deficits, particularly executive function deficits. These results suggest that contrast sensitivity may be a useful biomarker for cognitive changes in PD and may have implications for driving safety evaluations in PD.     

Characterizing the Mechanisms of Central and Peripheral Forms of Neurostimulation in Chronic Dysphagic Stroke Patients

BackgroundSwallowing problems following stroke may result in increased risk of aspiration pneumonia, malnutrition, and dehydration.Objective/hypothesisOur hypothesis was that three neurostimulation techniques would produce beneficial effects on chronic dysphagia following stroke through a common brain mechanism that would predict behavioral response.MethodsIn 18 dysphagic stroke patients (mean age: 66 ± 3 years, 3 female, time-post-stroke: 63 ± 15 weeks [±SD]), pharyngeal electromyographic responses were recorded after single-pulse transcranial magnetic stimulation (TMS) over the pharyngeal motor cortex, to measure corticobulbar excitability before, immediately, and 30 min, after real and sham applications of neurostimulation. Patients were randomized to a single session of either: pharyngeal electrical stimulation (PES), paired associative stimulation (PAS) or repetitive TMS (rTMS). Penetration-aspiration scores and bolus transfer timings were assessed before and after both real and sham interventions using videofluoroscopy.ResultsCorticobulbar excitability of pharyngeal motor cortex was beneficially modulated by PES, PAS and to a lesser extent by rTMS, with functionally relevant changes in the unaffected hemisphere. Following combining the results of real neurostimulation, an overall increase in corticobulbar excitability in the unaffected hemisphere (P = .005, F_1,17 = 10.6, ANOVA) with an associated 15% reduction in aspiration (P = .005, z = −2.79) was observed compared to sham.ConclusionsIn this mechanistic study, an increase in corticobulbar excitability the unaffected projection was correlated with the improvement in swallowing safety (P = .001, rho = −.732), but modality-specific differences were observed. Paradigms providing peripheral input favored change in neurophysiological and behavioral outcome measures in chronic dysphagia patients. Further larger cohort studies of neurostimulation in chronic dysphagic stroke are imperative.     

Cancer in Parkinson’s disease

INTRODUCTIONWe examined the prevalence of cancer in patients with Parkinson’s disease (PD) and controls evaluated at the Mayo Clinic in Jacksonville, Florida, between 2003 and 2014.METHODSWe retrospectively collected information regarding cancer diagnoses and diagnosis of PD from 971 unrelated PD patients and 478 controls, and all were white. For PD patients, we examined cancers diagnosed before and after PD diagnosis separately in addition to considering all cancer diagnoses.RESULTSTwenty different cancers were identified. In PD patients, the most common types of cancer were skin cancer (17.3% overall; 10.6% before PD), followed by nonmelanoma skin cancer (16.0% overall; 9.7% before PD), prostate cancer in men (12.8% overall; 9.2% before PD), breast cancer in women (10.6% overall; 6.3% before PD), and melanoma (2.4% overall; 1.1% before PD). Compared to controls, a significantly lower frequency of nonmelanoma skin cancer (odds ratio [OR]: 0.62, P = 0.0024) and any skin cancer (OR: 0.57, P = 0.0002) was observed in PD patients. These differences were greater when considering only cases with cancers that occurred before PD diagnosis (OR: 0.49, P < 0.0001; OR: 0.45, P < 0.0001, respectively), and there was a lower frequency of melanoma and any cancer preceding PD diagnosis compared to controls (OR: 0.31, P = 0.003; OR: 0.36, P < 0.0001). There was no evidence of a frequency difference for any other cancer.CONCLUSIONSPD patients had a lower frequency of skin cancers or any cancer prior to PD diagnosis compared to controls, suggesting that cancer may have a protective effect on PD risk.     

Levodopa/carbidopa intestinal gel can improve both motor and non-motor experiences of daily living in Parkinson’s disease: An open-label study

BackgroundLevodopa/carbidopa intestinal gel therapy (LCIG) can efficiently improve several motor and non-motor symptoms of advanced Parkinson's disease (PD). The recently developed Movement Disorder Society-sponsored Unified Parkinson's Disease Rating Scale (MDS-UPDRS) improved the original UPDRS making it a more robust tool to evaluate therapeutic changes. However, previous studies have not used the MDS-UPDRS and the Unified Dyskinesia Rating Scale (UDysRS) to assess the efficacy of LCIG.ObjectivesOur aim was to determine if the MDS-UPDRS and UDysRS could detect improvement in the experiences of daily living following 1-year LCIG treatment.MethodsIn this prospective, multicenter, open-label study, 34 consecutive patients undergoing LCIG treatment were enrolled. Patients were examined twice: prior to LCIG initiation and 12 months later. Impact of PD-related symptoms and dyskinesia was assessed by the MDS-UPDRS and UDysRS.ResultsNon-motor Experiences of Daily Living part of MDS-UPDRS improved from 20 (median, interquartile-range, IQR:14–23) to 16 points (median, IQR:12–20, p = 0.044) and the Motor Experiences of Daily Living ameliorated from 24 (median, IQR:20–29) to 18 points (median, IQR:13–25, p = 0.025). Health-related quality of life, measured by PDQ-39, also improved from 35.4 (median, IQR:26.9–50.3) to 27.0 (median, IQR:21.3–31.4) points (p = 0.003). The total score of UDysRS decreased from 47 (median, IQR:36–54) to 34 (median, IQR:21–45) points (p = 0.003).ConclusionsAs far as the authors are aware of, our paper is the first to evaluate the impact of LCIG on dyskinesia by the means of UDysRS. Changes in MDS-UPDRS and UDysRS confirm that LCIG treatment can efficiently improve experiences of daily living in advanced PD.     

Subclinical neurological involvement does not develop if Wilson's disease is treated early

Background & aimsWilson's disease (WD) is a genetic disorder of copper metabolism causing dysfunctions of various organs, mostly the liver and brain. If untreated, WD is fatal, but early treatment results in a good prognosis, although the long-term neurological outcome has not yet been clarified. To address this issue, we evaluated the neurological status of early-treated WD patients without overt nervous system impairment using neurophysiological, neuropsychological and neuroimaging procedures at least 10 years after treatment onset.MethodsThirty-eight WD patients (18 females, aged 24.47 ± 7.50 years), who received an early diagnosis (in presymptomatic or mild/moderate liver disease stages without neurological involvement) and prompt treatment, were clinically evaluated with the Global Assessment Scale. Presentation was hepatic in 36 subjects (95%), while 2 patients (5%) were presymptomatic. A neurophysiological study was performed to explore the central motor conduction time of the upper and lower limbs, and motor cortex excitability using single pulses and paired-pulse transcranial magnetic stimulation. Neuroimages were obtained with brain magnetic resonance scans. Cognitive abilities, and psychiatric and behavioral disturbances were evaluated with neuropsychological tests.ResultsPatients were undergoing treatment with penicillamine (7 patients) or zinc salts (31 patients) with good adherence. They did not present any neurological signs at clinical evaluation or at specific scale of impairment, the mean Global Assessment Scale score was 0.3 ± 0.7. Magnetic resonance imaging, transcranial magnetic stimulation studies and neuropsychological/neuropsychiatric assessment ruled out subclinical involvement.ConclusionsThis study suggests that early diagnosis and treatment of WD may prevent the onset of neurologic damage, even at subclinical level.     

Attention modulates step initiation postural adjustments in Parkinson freezers

BackgroundIn view of freezing of gait's circumstances of occurrence in Parkinson's disease, attentional resources appear to be involved in step initiation failure. Anticipatory postural adjustments (APAs) are essential because they allow unloading of the stepping leg and so create the conditions required for progression.Our main objective was to establish whether or not a change in attentional load during step initiation modulates APAs differently in patients with vs. without freezing of gait.MethodsThree groups of 15 subjects were recruited: elderly people and parkinsonian patients with or without freezing of gait. Attention was modulated before step execution by means of an auditory oddball discrimination task with event-related potential recording. The primary endpoint was the occurrence of inappropriate APAs following the attentional task, i.e. APAs not followed by a step after an intercurrent auditory stimulus.ResultsIn parkinsonian patients with freezing of gait, inappropriate APAs were recorded in 63% of the trials and were observed more frequently than in patients without freezing of gait (51%) and elderly controls (48%). Furthermore, inappropriate APAs in freezers were longer and more ample than in parkinsonian non-freezers and controls. Lastly, postural preparation was impaired in the parkinsonian patients.ConclusionOur results indicate that allocation of attentional resources during step preparation influences the release of APAs differently in freezers and non-freezers. Modulating attentional load is partly responsible for triggering an inappropriate motor program. This difficulty in focusing attention or resisting interference may contribute (at least in part) to the gait initiation failure observed in parkinsonian freezers.     

Distal muscle activity alterations during the stance phase of gait in restless leg syndrome (RLS) patients

ObjectiveTo assess if there is a circadian variation in electromyographical (EMG) muscle activity during gait in restless legs syndrome (RLS) patients and healthy control participants.MethodsGait assessment was done in 14 RLS patients and 13 healthy control participants in the evening (PM) and the morning (AM). Muscle activity was recorded bilaterally from the tibialis anterior (TA), lateral gastrocnemius (GL), rectus femoris (RF) and biceps femoris (BF) muscles.ResultsA circadian variation during the stance phase in only TA (PM > AM, p < 0.005) and BF (PM < AM, p = 0.008) activity was observed in control participants. Conversely no circadian variation was seen in any muscles in the RLS patients. RLS patients had an increased TA and GL activity (RLS > Controls, p < 0.05) during early stance and decreased GL activity (RLS < Controls, p < 0.01) during terminal stance in comparison to control participants in the evening. No other significant differences were noted between RLS patients and control participants. Activation of GL during the swing phase was noted in 79% of RLS patients and in 23% of control participants in the morning compared to 71% and 38% in the evening, respectively.ConclusionEMG muscle activity shows no circadian variation in RLS patients. Evening differences in gait muscle activation patterns between RLS patients and control participants are evident. These results extend our knowledge about alterations in spinal processing during gait in RLS. A possible explanation for these findings is central pattern generator sensitization caused by increased sensitivity in cutaneous afferents in RLS patients.     

Does α-synuclein have a dual and opposing effect in preclinical vs. clinical Parkinson's disease?

α-Synuclein gene (SNCA) multiplications cause familial parkinsonism and allele-length polymorphisms within the SNCA dinucleotide repeat REP1 increase the risk for developing Parkinson's disease (PD). Since SNCA multiplications increase SNCA expression, and REP1 genotypes that increase the risk of developing PD show increased SNCA expression in cell-culture systems, animal models, and human blood and brain, PD therapies seek to reduce SNCA expression. We conducted an observational study of 1098 PD cases to test the hypothesis that REP1 genotypes correlated with reduced SNCA expression are associated with better motor and cognitive outcomes. We evaluated the association of REP1 genotypes with survival free of Hoehn and Yahr stages 4 or 5 (motor outcome) and of Modified Telephone Interview for Cognitive Status score ≤27 or Alzheimer's Disease Dementia Screening Interview score ≥2 (cognitive outcome). Median disease duration at baseline was 3.3 years and median lag time from baseline to follow-up was 7.8 years. Paradoxically, REP1 genotypes associated with increased risk of developing PD and increased SNCA expression were associated with better motor (HR = 0.87, p = 0.046, covariate-adjusted age-scale analysis; HR = 0.85, p = 0.020, covariate-adjusted time-scale analysis) and cognitive outcomes (HR = 0.90, p = 0.12, covariate-adjusted age-scale analysis; HR = 0.85, p = 0.023, covariate-adjusted time-scale analysis). Our findings raise the possibility that SNCA has a dual, opposing, and time-dependent role. This may have implications for the development of therapies that target SNCA expression.     

Responses to voluntary hyperventilation in children with separation anxiety disorder: Implications for the link to panic disorder

BackgroundBiological theories on respiratory regulation have linked separation anxiety disorder (SAD) to panic disorder (PD). We tested if SAD children show similarly increased anxious and psychophysiological responding to voluntary hyperventilation and compromised recovery thereafter as has been observed in PD patients.MethodsParticipants were 49 children (5–14 years old) with SAD, 21 clinical controls with other anxiety disorders, and 39 healthy controls. We assessed cardiac sympathetic and parasympathetic, respiratory (including pCO₂), electrodermal, electromyographic, and self-report variables during baseline, paced hyperventilation, and recovery.ResultsSAD children did not react with increased anxiety or panic symptoms and did not show signs of slowed recovery. However, during hyperventilation they exhibited elevated reactivity in respiratory variability, heart rate, and musculus corrugator supercilii activity indicating difficulty with respiratory regulation.ConclusionsReactions to hyperventilation are much less pronounced in children with SAD than in PD patients. SAD children showed voluntary breathing regulation deficits.     

Impaired short-term plasticity in restless legs syndrome: a pilot rTMS study

BackgroundPrevious studies showed an impairment of the LTP-like plasticity to TMS in restless legs syndrome (RLS). Clinically, repetitive TMS (rTMS) was effective in alleviating the sensory-motor complaints of patients, although the effects induced by low-frequency (inhibitory) rTMS have not yet been investigated. An impaired LTD-like mechanism of cortical plasticity has been hypothesized, which we have directly assessed in this pilot study.MethodsMotor evoked potentials (MEPs) from the right first dorsal interosseus muscle were recorded at the stimulus intensity of 110% of the resting motor threshold (rMT) from 13 right-handed patients and ten age-matched right-handed healthy controls. Median peak-to-peak amplitudes were calculated in all participants at baseline (T₀), after the first train of a single evening session of low-frequency (1 Hz) rTMS over the left primary motor cortex (T₁), and after the whole rTMS procedure (T₂), which consists of 20 trains with 50 stimuli per train and intertrain interval of 30 s (1000 stimuli in total).ResultsNo differences were found for rMT and MEPs size between the two groups at T₀. Smaller MEPs amplitudes at both T₁ and T₂ were observed in all subjects, although this was significantly more pronounced in controls than in patients.ConclusionsCompared to normal individuals, patients exhibited an impairment of the LTD-like mechanisms induced by inhibitory rTMS, thus adding support to the involvement of GABA in RLS pathophysiology. Although future studies with a larger population are needed, TMS is confirmed to be effective in noninvasive probing of the neurophysiology and neurochemistry of RLS.     

The effects of continuous positive airway pressure therapy on Troponin-T and N-terminal pro B-type natriuretic peptide in patients with obstructive sleep apnoea: a randomised controlled trial

IntroductionUntreated obstructive sleep apnoea (OSA) is associated with increased risk of coronary artery disease (CAD) and heart failure. High-sensitivity cardiac troponin (hs Trop-T) and B-type natriuretic peptide (NT-pro-BNP) are sensitive biomarkers for myocardial injury and heart failure respectively. No randomised controlled trials have examined the treatment effect of continuous positive airway pressure (CPAP) in patients with OSA on these biomarkers.MethodPatients >21 years old with apnoea-hypopnoea index (AHI) ≥25/h by overnight polysomnography were recruited. Main exclusion criteria were previous CPAP use and any significant comorbidities including CAD and heart failure. Eligible subjects were randomised to receive CPAP or sham CPAP for eight weeks each in a crossover design with a wash out period of one month between the treatments. Blood samples were collected at 8pm, 3am, and 8am during sleep studies conducted at the end of each eight-week treatment period.ResultsOf the 37 patients who were randomised, 28 patients had stored frozen samples available for analysis. In comparison to sham treatment, CPAP significantly lowered the NT-pro-BNP level by 0.91 pmol/L (p = 0.0002). The reduction of 0.235 ng/L in hs Trop-T on CPAP therapy was not statistically significant (p = 0.052). There were no overnight changes, across the three time points, in either biomarker with either treatment.ConclusionOur study confirms CPAP therapy in patients with moderate-severe OSA reduces NT-pro-BNP, but we did not confirm a significant effect on hs Trop-T. Future larger studies of longer duration incorporating biomarkers and cardiac functional measures are needed to better establish the benefit of OSA treatment.     

The SERVE-HF safety notice in clinical practice – experiences of a tertiary sleep center

BackgroundIn May 2015, the results of the SERVE-HF trial – addressing adaptive servoventilation (ASV) in chronic congestive heart failure (CHF) patients with central sleep apnea (CSA) – prompted a field safety notice. It was recommended to identify CHF patients treated with ASV and to advise the discontinuation of the treatment. We aimed to analyze the identification process and effect of ASV discontinuation on affected patients.Methods126 patients treated with ASV on May 13th, 2015 at our institution were retrospectively analyzed. Treatment decisions, effect of ASV discontinuation and clinical course were followed for a year. Patients on ASV with CHF were compared to those without CHF.ResultsThe risk criteria of the safety notice were fulfilled by 10.3% of patients (13/126). Additional echocardiographies were performed in 38%. ASV was discontinued in 93% of patients without adverse events (emergency hospitalization in n = 1). CSA reappeared immediately. Day- or nighttime symptoms were reported by 61%. Symptomatic patients were started on alternative treatments. CHF and non-CHF patients differed in cardiac function and type of SDB. CHF patients had shorter overall treatment duration. Compliance to ASV was similar in both groups with a median usage of 412 min (269; 495)/night in the CHF group and 414.5 min (347; 480) in the non-CHF group.ConclusionIdentification of patients “at risk” is feasible but outcome of discontinuation of ASV cannot be evaluated based on these data. ASV withdrawal in patients with stable chronic CHF and CSA leads to an immediate return of sleep disordered breathing. Symptomatic patients may ask for alternative treatment options.     

Spontaneous improvement in both obstructive sleep apnea and cognitive impairment after stroke

BackgroundKnowledge available about the relationship between obstructive sleep apnea (OSA) and cognitive impairment after stroke is limited. The evolution of OSA and cognitive performance after stroke is not sufficiently described.MethodsWe prospectively enrolled and examined acute stroke patients without previously diagnosed OSA. The following information was collected: (1) demographics, (2) sleep cardio-respiratory polygraphy (PG) at 72 h, day seven, month three, and month 12 after stroke, (3) post-stroke functional disability tests at entry and at months three and 12, and (4) cognition (attention and orientation, memory, verbal fluency, language, and visual-spatial abilities) using the revised Addenbrooke's Cognitive Examination (ACE-R) at months three and 12.ResultsOf 68 patients completing the study, OSA was diagnosed in 42 (61.8%) patients. The mean apnea/hypopnea index (AHI) at study entry of 21.0 ± 13.7 spontaneously declined to 11.6 ± 11.2 at month 12 in the OSA group (p < 0.0005). The total ACE-R score was significantly reduced at months three (p = 0.005) and 12 (p = 0.004) in the OSA group. Poorer performance on the subtests of memory at months 3 (p = 0.039) and 12 (p = 0.040) and verbal fluency at months 3 (p < 0.005) and 12 (p < 0.005) were observed in the OSA group compared to non-OSA group. Visual-spatial abilities in both the OSA (p = 0.001) and non-OSA (p = 0.046) groups and the total ACE-R score in the OSA (p = 0.005) and non-OSA (p = 0.002) groups improved.ConclusionsA high prevalence of OSA and cognitive decline were present in patients after an acute stroke. Spontaneous improvements in both OSA and cognitive impairment were observed.