Orthostatic stress response in pediatric Fontan patients and the effect of ACE inhibition.

BACKGROUND: Many cardiocirculatory mechanisms are involved in the adaptation to orthostatic stress. While these mechanisms may be impaired in Fontan patients. However, it is yet unclear how Fontan patients, who exhibit a critical fluid balance, respond to orthostatic stress. Angiotensin converting enzyme inhibitors are often prescribed to Fontan patients, but they may negatively influence orthostatic tolerance. Therefore, we evaluated the response to orthostatic stress in pediatric Fontan patients before and after treatment with enalapril. METHODS: Thirty-five Fontan patients (aged 14 years) with moderate-good systolic ventricular function without pre-existent enalapril treatment were included. Before and after a three-month enalapril treatment period, the hemodynamic response to head-up tilt test was evaluated by various parameters including cardiac index, blood pressure, cerebral blood flow, aortic stiffness and cardiac autonomous nervous activity. Thirty-four healthy subjects (aged 13 years) served as controls. RESULTS: Fontan patients had a decreased cerebral blood flow and increased aortic stiffness in the supine position compared to controls, while all other factors did not differ. Patients and controls showed a comparable response to head-up tilt test for most parameters. Twenty-seven patients completed the enalapril study with a mean dosage of 0.3±0.1mg/kg/day. Most parameters were unaffected by enalapril, only the percent decrease in cardiac index to tilt was higher after treatment, but the cardiac index during tilt was not lower (3.0L/min/m2 pre-enalapril versus 2.8L/min/m2 after treatment; P = 0.15). CONCLUSION: Pediatric Fontan patients adequately respond to orthostasis with maintenance of blood pressure and cerebral blood flow and sufficient autonomic response. Enalapril treatment did not alter the response. CLINICAL TRIAL INFORMATION: Scientific title: ACE inhibition in Fontan patients: its effect on body fluid regulation (sAFE-study). The Netherlands National Trial Register: Trail NL6415. Registered 2017-07-20. Trial information: https://www.trialregister.nl/trial/6415.

The prevalence of pain in Huntington's disease in a large worldwide cohort.

INTRODUCTION: Pain could be an unknown non-motor symptom in Huntington's Disease (HD). The aim is therefore, to study the prevalence of pain interference, painful conditions and analgesic use across the different stages of HD and compare these levels to non-HD gene mutation carriers. METHODS: A cross-sectional analysis of the Enroll-HD study was conducted in premanifest, manifest HD gene mutation carriers (n = 3989 and n = 7,485, respectively) and in non-HD gene mutation carriers (n = 3719). To investigate group differences, multivariable logistic regression analysis was performed with pairwise comparisons. RESULTS: In the HD mutation carriers, the overall prevalence of pain interference was 34% (95% CI 31%-35%), of painful conditions 17% (95% CI 15%-19%) and analgesic use 13% (95% CI 11%-15%). Compared to non-mutation carriers, the prevalence of pain interference was significantly higher in the middle stage of HD (33% [95% CI 31%-35%] vs 42% [95% CI 39%-45%], P = 0,02), whereas the prevalence of painful conditions was significant lower in the late and middle stage of HD (17% [95% CI 16%-18%] vs 12% [95% CI 10%-14%], 15% [95% CI 13%-17%], P < 0,01]. No significant group difference was present in analgesic use. CONCLUSIONS: The prevalence of pain interference increases as HD progresses, however, the prevalence of painful conditions and analgesics do not increase accordingly. Further studies are necessary to investigate the aetiology of pain in HD and the risk for undertreatment of pain.

New hemodynamic criteria to separate classical orthostatic hypotension from vasovagal syncope.

OBJECTIVE: To define and evaluate hemodynamic criteria to distinguish between classical orthostatic hypotension (cOH) and vasovagal syncope (VVS) in tilt table testing (TTT). METHODS: Inclusion criteria for VVS were a history of VVS and tilt-induced syncope defined as a blood pressure (BP) decrease and electroencephalographic changes during syncope with complaint recognition. Criteria for cOH were a history of cOH and a BP decrease meeting published criteria. Clinical diagnoses were established prior to TTT. We assessed (1) whether the decrease of systolic BP accelerated, "convex," or decelerated, "concave"; (2) the time from head-up tilt to when BP reached one-half its maximal decrease; (3) the difference between baseline heart rate (HR) and HR at BP nadir. We calculated the diagnostic yield of optimized thresholds of these features and their combinations. RESULTS: We included 82 VVS cases (40% men, median age 44 years) and 65 cOH cases (66% men, median age 70 years). BP decrease was concave in cOH in 79% and convex in VVS in 94% (p < 0.001). The time to reach half the BP decrease was shorter in cOH (median 34 sec, interquartile range (IQR) 19-98 sec) than in VVS (median 1571 sec, IQR 1381-1775 sec, p < 0.001). Mean HR increased by 11 ± 11 bpm in cOH and decreased by 20 ± 19 bpm in VVS (p < 0.001). When all three features pointed to VVS, sensitivity for VVS was 82% and specificity was 100%. When all three pointed to cOH, sensitivity for cOH was 71% and specificity was 100%. INTERPRETATION: These new hemodynamic criteria reliably differentiate cOH from VVS.

Progressive microstructural changes of the occipital cortex in Huntington's disease.

In this study we longitudinally investigated the rate of microstructural alterations in the occipital cortex in different stages of Huntington's disease (HD) by applying an automated atlas-based approach to diffusion MRI data. Twenty-two premanifest (preHD), 10 early manifest HD (early HD) and 24 healthy control subjects completed baseline and two year follow-up scans. The preHD group was stratified based on the predicted years to disease onset into a far (preHD-A) and near (preHD-B) to disease onset group. Clinical and behavioral measures were collected per assessment time point. An automated atlas-based DTI analysis approach was used to obtain the mean, axial and radial diffusivities of the occipital cortex. We found that the longitudinal rate of diffusivity change in the superior occipital gyrus (SOG), middle occipital gyrus (MOG), and inferior occipital gyrus (IOG) was significantly higher in early HD compared to both preHD and controls (all p's ≤ 0.005), which can be interpreted as an increased rate of microstructural degeneration. Furthermore, the change rate in the diffusivity of the MOG could significantly discriminate between preHD-B compared to preHD-A and the other groups (all p's ≤ 0.04). Finally, we found an inverse correlation between the Stroop Word Reading task and diffusivities in the SOG and MOG (all p's ≤ 0.01). These findings suggest that measures obtained from the occipital cortex can serve as sensitive longitudinal biomarkers for disease progression in preHD-B and early HD. These could in turn be used to assess potential effects of proposed disease modifying therapies.

Cognitive decline in Huntington's disease expansion gene carriers.

BACKGROUND: In Huntington's Disease (HD) cognitive decline can occur before unequivocal motor signs become apparent. As cognitive decline often starts early in the course of the disease and has a progressive nature over time, cognition can be regarded as a key target for symptomatic treatment. The specific progressive profile of cognitive decline over time is unknown. OBJECTIVE: The aim of this study is to quantify the progression of cognitive decline across all HD stages, from pre-motormanifest to advanced HD, and to investigate if CAG length mediates cognitive decline. METHODS: In the European REGISTRY study 2669 HD expansion gene carriers underwent annual cognitive assessment. General linear mixed models were used to model the cognitive decline for each cognitive task across all disease stages. Additionally, a model was developed to evaluate the cognitive decline based on CAG length and age rather than disease stage. RESULTS: There was significant cognitive decline on all administered tasks throughout pre-motormanifest (close to estimated disease onset) participants and the subsequent motormanifest participants from stage 1 to stage 4. Performance on the Stroop Word and Stroop Color tests additionally declined significantly across the two pre-motormanifest groups: far and close to estimated disease onset. The evaluation of cognition performance in relation to CAG length and age revealed a more rapid cognitive decline in participants with longer CAG length than participants with shorter CAG length over time. CONCLUSION: Cognitive performance already shows decline in pre-motormanifest HD gene expansion carriers and gradually worsens to late stage HD. HD gene expansion carriers with certain CAG length have their own cognitive profile, i.e., longer CAG length is associated with more rapid decline.

Core Body and Skin Temperature in Type 1 Narcolepsy in Daily Life; Effects of Sodium Oxybate and Prediction of Sleep Attacks.

STUDY OBJECTIVES: Previous laboratory studies in narcolepsy patients showed altered core body and skin temperatures, which are hypothesised to be related to a disturbed sleep wake regulation. In this ambulatory study we assessed temperature profiles in normal daily life, and whether sleep attacks are heralded by changes in skin temperature. Furthermore, the effects of three months of treatment with sodium oxybate (SXB) were investigated. METHODS: Twenty-five narcolepsy patients and 15 healthy controls were included. Core body, proximal and distal skin temperatures, and sleep-wake state were measured simultaneously for 24 hours in ambulatory patients. This procedure was repeated in 16 narcolepsy patients after at least 3 months of stable treatment with SXB. RESULTS: Increases in distal skin temperature and distal-to-proximal temperature gradient (DPG) strongly predicted daytime sleep attacks (P < 0.001). As compared to controls, patients had a higher proximal and distal skin temperature in the morning, and a lower distal skin temperature during the night (all P < 0.05). Furthermore, they had a higher core body temperature during the first part of the night (P < 0.05), which SXB decreased (F = 4.99, df = 1, P = 0.03) to a level similar to controls. SXB did not affect skin temperature. CONCLUSIONS: This ambulatory study demonstrates that daytime sleep attacks were preceded by clear changes in distal skin temperature and DPG. Furthermore, changes in core body and skin temperature in narcolepsy, previously only studied in laboratory settings, were partially confirmed. Treatment with SXB resulted in a normalisation of the core body temperature profile. Future studies should explore whether predictive temperature changes can be used to signal or even prevent sleep attacks.

The effects of sodium oxybate on core body and skin temperature regulation in narcolepsy.

Patients suffering from narcolepsy type 1 show altered skin temperatures, resembling the profile that is related to sleep onset in healthy controls. The aim of the present study is to investigate the effects of sodium oxybate, a widely used drug to treat narcolepsy, on the 24-h profiles of temperature and sleep-wakefulness in patients with narcolepsy and controls. Eight hypocretin-deficient male narcolepsy type 1 patients and eight healthy matched controls underwent temperature measurement of core body and proximal and distal skin twice, and the sleep-wake state for 24 h. After the baseline assessment, 2 × 3 g of sodium oxybate was administered for 5 nights, immediately followed by the second assessment. At baseline, daytime core body temperature and proximal skin temperature were significantly lower in patients with narcolepsy (core: 36.8 ± 0.05 °C versus 37.0 ± 0.05 °C, F = 8.31, P = 0.01; proximal: 33.4 ± 0.26 °C versus 34.3 ± 0.26 °C, F = 5.66, P = 0.03). In patients, sodium oxybate administration increased proximal skin temperature during the day (F = 6.46, P = 0.04) to a level similar as in controls, but did not affect core body temperature, distal temperature or distal-proximal temperature gradient. Sodium oxybate administration normalised the predictive value of distal skin temperature and distal-proximal temperature gradient for the onset of daytime naps (P < 0.01). In conclusion, sodium oxybate administration resulted in a partial normalisation of the skin temperature profile, by increasing daytime proximal skin temperature, and by strengthening the known relationship between skin temperature and daytime sleep propensity. These changes seem to be related to the clinical improvement induced by sodium oxybate treatment. A causal relationship is not proven.

Microstructural brain abnormalities in Huntington's disease: A two-year follow-up.

OBJECTIVES: To investigate both cross-sectional and time-related changes of striatal and whole-brain microstructural properties in different stages of Huntington's disease (HD) using diffusion tensor imaging. EXPERIMENTAL DESIGN: From the TRACK-HD study, premanifest gene carriers (preHD), early manifest HD and controls were scanned at baseline and 2-year follow-up. Stratification of the preHD group into a far (preHD-A) and near (preHD-B) to predicted disease onset was performed. Age-corrected histograms of whole-brain white matter (WM), gray matter (GM) and striatal diffusion measures were computed and normalised by the number of voxels in each subject's data set. PRINCIPLE OBSERVATIONS: Higher cross-sectional mean, axial and radial diffusivities were found in both WM (P ≤ 0.001) and GM (P ≤ 0.001) of the manifest HD compared to the preHD and control groups. In preHD, only WM axial diffusivity (AD) was higher than in controls (P ≤ 0.01). This finding remained valid only in preHD-B (P ≤ 0.001). AD was also higher in the striatum of preHD-B compared to controls and preHD-A (P ≤ 0.01). Fractional anisotropy (FA) lacked sensitivity in differentiating between the groups. Histogram peak heights were generally lower in manifest HD compared to the preHD and control groups. No longitudinal differences were found in the degree of diffusivity change between the groups in the two year follow-up. There was a significant relationship between diffusivity and neurocognitive measures. CONCLUSIONS: Alterations in cross-sectional diffusion profiles between manifest HD subjects and controls were evident, both in whole-brain and striatum. In the preHD stage, only AD alterations were found, a finding suggesting that this metric is a sensitive marker for early change in HD prior to disease manifestation. The individual diffusivities were superior to FA in revealing pathologic microstructural brain alterations. Diffusion measures were well related to clinical functioning and disease stage.

Time- and state-dependent analysis of autonomic control in narcolepsy: higher heart rate with normal heart rate variability independent of sleep fragmentation.

Narcolepsy with hypocretin deficiency is known to alter cardiovascular control during sleep, but its aetiology is disputed. As cardiovascular control differs between sleep states, and narcolepsy affects sleep architecture, controlling for both duration and transitions of sleep states is necessary. This study therefore aimed to assess heart rate and its variability in narcolepsy during sleep taking these factors into account. The study included 12 medication-naïve patients with narcolepsy with cataplexy and hypocretin deficiency (11 male, 16-53 years old), and 12 sex- and age-matched healthy controls (11 male, 19-55 years). All subjects underwent 1-night ambulatory polysomnography recording. Cardiovascular parameters were calculated for each 30-s epoch. Heart rate was significantly higher in patients with narcolepsy than in controls in all sleep states and during wakefulness prior to sleep. Groups did not differ in heart rate variability measures. The effects of sleep state duration on heart rate and its variability were similar between patients and controls. In conclusion, heart rate was consistently higher in patients with narcolepsy than controls, independent of sleep stage and sleep fragmentation. A direct effect of hypocretin deficiency therefore seems probable.

Sleep-mediated heart rate variability after bilateral carotid body tumor resection.

STUDY OBJECTIVES: The carotid bodies are thought to play an important role in sleep-dependent autonomic changes. Patients who underwent resection of bilateral carotid body tumors have chronically attenuated baroreflex sensitivity. These subjects provide a unique opportunity to investigate the role of the baroreflex during sleep. DESIGN: One-night ambulatory polysomnography (PSG) recording. SETTING: Participants' homes. PARTICIPANTS: Nine patients with bilateral carotid body tumor resection (bCBR) (four women, mean age 50.4 ± 7.2 years) and nine controls matched for age, gender, and body mass index. INTERVENTIONS: N/A. MEASUREMENTS: Sleep parameters were obtained from PSG. Heart rate (HR) and its variability were calculated using 30-s epochs. RESULTS: In bCBR patients, HR was slightly but not significantly increased during wake and all sleep stages. The effect of sleep on HR was similar for patients and controls. Low frequency (LF) power of the heart rate variability spectrum was significantly lower in bCBR patients in active wakefulness, sleep stage 1 and REM sleep. No differences were found between patients and controls for high frequency (HF) power and the LF/HF ratio. CONCLUSIONS: Bilateral carotid body tumor resection (bCBR) is associated with decreased low frequency power during sleep, suggesting impaired baroreflex function. Despite this, sleep-related heart rate changes were similar between bCBR patients and controls. These findings suggest that the effects of sleep on heart rate are predominantly generated through central, non-baroreflex mediated pathways.

The semiology of tilt-induced psychogenic pseudosyncope.

OBJECTIVES: To provide a detailed semiology to aid the clinical recognition of psychogenic pseudosyncope (PPS), which concerns episodes of apparent transient loss of consciousness (TLOC) that mimic syncope. METHODS: We analyzed all consecutive tilt-table tests from 2006 to 2012 showing proven PPS, i.e., apparent TLOC had occurred without EEG changes or a decrease in heart rate (HR) or blood pressure (BP). We analyzed baseline characteristics, video data, EEG, ECG, and continuous BP measurements on a 1-second time scale. Data were compared with those of 69 cases of tilt-induced vasovagal syncope (VVS). RESULTS: Of 800 tilt-table tests, 43 (5.4%) resulted in PPS. The majority (74%) were women. The median duration of apparent TLOC was longer in PPS (44 seconds) than in VVS (20 seconds, p < 0.05). During the event, the eyes were closed in 97% in PPS but in only 7% in VVS (p < 0.0001). A sudden head drop or moving down the tilt table was more common in PPS than in VVS (p < 0.01), but jerking movements occurred more frequently in VVS (p < 0.0001). In PPS, both HR and BP increased before and during apparent TLOC (p < 0.0001). CONCLUSIONS: PPS is clinically distinct from VVS and can be diagnosed accurately with tilt-table testing and simultaneous EEG monitoring. Compared with VVS, eye closure during the event, long periods of apparent TLOC, and high HR and BP are highly specific for PPS. Improved understanding of the semiology of PPS as a clinical entity is vital to ensure accurate diagnosis.

Electromyographic activity in the EEG in Alzheimer's disease: noise or signal?

Many efforts have been directed at negating the influence of electromyographic (EMG) activity on the EEG, especially in elderly demented patients. We wondered whether these "artifacts" might reflect cognitive and behavioural aspects of dementia. In this pilot study, 11 patients with probable Alzheimer's disease (AD), 13 with amnestic mild cognitive impairment (MCI) and 13 controls underwent EEG registration. As EMG measures, we used frontal and temporal 50-70 Hz activity. We found that the EEGs of AD patients displayed more theta activity, less alpha reactivity, and more frontal EMG than controls. Interestingly, increased EMG activity indicated more cognitive impairment and more depressive complaints. EEG variables on the whole distinguished better between groups than EMG variables, but an EMG variable was best for the distinction between MCI and controls. Our results suggest that EMG activity in the EEG could be more than noise; it differs systematically between groups and may reflect different cerebral functions than the EEG.

Contrasting effects of isocapnic and hypocapnic hyperventilation on orthostatic circulatory control.

The effects of hyperventilation (HV) on mean arterial pressure (MAP) are variable. To identify factors affecting the MAP response to HV, we dissected the effects of hypocapnic HV (HHV) and isocapnic HV (IHV) and evaluated the effects of acute vs. prolonged HHV. In 11 healthy subjects the cardio- and cerebrovascular effects of HHV and IHV vs. normal ventilation were examined for 15 min in the supine position and also for 15 min during 60 degrees head-up tilt. The end-tidal CO(2) of the HHV condition was set at 15-20 mmHg. With HHV in the supine position, mean cerebral blood flow velocity (mCBFV) declined [95% confidence interval (CI) -43 to -34%], heart rate (HR) increased (95% CI 7 to 16 beats/min), but MAP did not change (95% CI -1 to 6 mmHg). However, an augmentation of the supine MAP was observed in the last 10 min of HHV compared with the first 5 min of HHV (95% CI 2 to 12 mmHg). During HHV in the tilted position mCBFV declined (95% CI -28 to -12%) and MAP increased (95% CI 3 to 11 mmHg) without changes in HR. With supine IHV, mCBFV decreased (95% CI -14 to -4%) and MAP increased (95% CI 1 to 13 mmHg) without changes in HR. During IHV in the tilted position MAP was further augmented (95% CI 11 to 20 mmHg) without changes in CBFV or HR. Preventing hypocapnia during HV resulted in a higher MAP, suggesting two contrasting effects of HV on MAP: hypocapnia causing vasodepression and hyperpnea without hypocapnia acting as a vasopressor.

EEG markers of future cognitive performance in the elderly.

This exploratory follow-up study investigated whether EEG parameters can predict future cognitive performance. Forty elderly subjects, ranging from cognitively unimpaired to those with Alzheimer disease underwent EEG registration at baseline and neuropsychological examination at both baseline and follow-up. We assessed relations between EEG measures and future cognitive performance (i.e., global cognition, memory, language, and executive functioning) controlling for age, follow-up time, and baseline cognitive performance. Regression models were constructed to predict performance on the Cambridge Cognitive Examination, a widely used tool within dementia screenings. Baseline EEG measures, i.e., increased theta activity (4-8 Hz) during eyes closed and less alpha reactivity (8-13 Hz) during eyes open and memory activation, indicated lower global cognitive, language (trend significant), and executive performance at follow-up. A regression model combining baseline cognitive and EEG measures provided the best prediction of future Cambridge Cognitive Examination performance (93%). EEG and cognitive measures alone predicted, respectively, 43% and 92% of variance. EEG and cognitive measures combined provided the best prediction of future cognitive performance. Although the "cognition only" model showed similar predictive power, the EEG provided significant additional value. The added value of EEG registration in the diagnostic work-up of dementia should be further assessed in larger samples.

Memory activation reveals abnormal EEG in preclinical Huntington's disease.

The EEG is potentially useful as a marker of early Huntington's disease (HD). In dementia, the EEG during a memory activation challenge showed abnormalities where the resting EEG did not. We investigated whether memory activation also reveals EEG abnormalities in preclinical HD. Sixteen mutation carriers for HD and 13 nonmutation carriers underwent neurological, neuropsychological, MRI and EEG investigations. The EEG was registered during a rest condition, i.e. eyes closed, and a working memory task. In each condition we determined absolute power in the theta (4-8 Hz) and alpha (8-13 Hz) bands and subsequently calculated relative alpha power. The EEG during eyes closed did not differ between groups. The EEG during memory activation showed less relative alpha power in mutation carriers as compared to nonmutation carriers, even though memory performance was similar [F (1,27) = 10.87; P = 0.003]. Absolute powers also showed less alpha power [F (1,27) = 7.02; P = 0.013] but similar theta power. No correlations were found between absolute and relative alpha power on the one hand and neuropsychological scores, motor scores or number of CAG repeats on the other. In conclusion, memory activation reveals functional brain changes in Huntington's disease before clinical signs become overt.

Water drinking as a potential treatment for idiopathic exercise-related syncope: a case report.

We report a 20-year-old sportsman with frequent attacks of lightheadedness, chest pain, blurred vision and falls during and shortly after exercise. Cardiac and pulmonal evaluation and routine autonomic function tests were normal apart from a relatively high resting heart rate (70 bpm) compared to endurance-trained men. In view of the relation to exercise, the patient was asked to cycle with maximal effort on an ergometer with continuous blood pressure (BP), heart rate (HR) and electroencephalogram (EEG) registration. Immediately after cessation of exercise a brief hypotensive period (75/45 mmHg) occurred together with sinus tachycardia (180 bpm) during which the patient experienced his typical complaints. We hypothesized that our patient's symptoms were primary related to sympathetic failure. As water drinking has been demonstrated to raise sympathetic activity rapidly, we undertook a second cycling test after ingestion of 1000 mL tap water. Symptoms nor hypotension recurred. Because of the short lasting pressor effect and its minimal side effects, we suggest water drinking as simple and possible effective therapy for idiopathic exercise-related syncope.