Neurophysiology versus clinical genetics in Rett syndrome: A multicenter study.

Many studies have attempted to establish the genotype-phenotype correlation in Rett syndrome (RTT). Cardiorespiratory measurements provide robust objective data, to correlate with each of the different clinical phenotypes. It has important implications for the management and treatment of this syndrome. The aim of this study was to correlate the genotype with the quantitative cardiorespiratory data obtained by neurophysiological measurement combined with a clinical severity score. This international multicenter study was conducted in four European countries from 1999 to 2012. The study cohort consisted of a group of 132 well-defined RTT females aged between 2 and 43 years with extended clinical, molecular, and neurophysiological assessments. Diagnosis of RTT was based on the consensus criteria for RTT and molecular confirmation. Genotype-phenotype analyses of clinical features and cardiorespiratory data were performed after grouping mutations by the same type and localization or having the same putative biological effect on the MeCP2 protein, and subsequently on eight single recurrent mutations. A less severe phenotype was seen in females with CTS, p.R133C, and p.R294X mutations. Autonomic disturbances were present in all females, and not restricted to nor influenced by one specific group or any single recurrent mutation. The objective information from non-invasive neurophysiological evaluation of the disturbed central autonomic control is of great importance in helping to organize the lifelong care for females with RTT. Further research is needed to provide insights into the pathogenesis of autonomic dysfunction, and to develop evidence-based management in RTT. © 2016 Wiley Periodicals, Inc.

Variant of Rett syndrome and CDKL5 gene: clinical and autonomic description of 10 cases.

UNLABELLED: Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting almost exclusively females. The Hanefeld variant, or early-onset seizure variant, has been associated with mutations in CDKL5 gene. AIMS: In recent years more than 60 patients with mutations in the CDKL5 gene have been described in the literature, but the cardiorespiratory phenotype has not been reported. Our aim is to describe clinical and autonomic features of these girls. METHODS: 10 girls with CDKL5 mutations and a diagnosis of Hanefeld variant have been evaluated on axiological and clinical aspects. In all subjects an evaluation of the autonomic system was performed using the Neuroscope. RESULTS: Common features were gaze avoidance, repetitive head movements and hand stereotypies. The autonomic evaluation disclosed eight cases with the Forceful breather cardiorespiratory phenotype and two cases with the Apneustic breather phenotype. CONCLUSIONS: The clinical picture remains within the RTT spectrum but some symptoms are more pronounced in addition to the very early onset of seizures. The cardiorespiratory phenotype was dominated by Forceful breathers, while Feeble breathers were not found, differently from the general Rett population, suggesting a specific behavioral and cardiorespiratory phenotype of the RTT the Hanefeld variant.

Dysautonomia Causing Severe Orthostatic Hypotension: An Important, Early Finding in Neurodegenerative Disorders.

Orthostatic hypotension is common and dangerous; it has neurogenic and nonneurogenic causes. We present the case of a 40-year-old man with severe neurogenic hypotension, caused by young-onset multiple system atrophy. In patients presenting with neurogenic orthostatic hypotension, underlying neurodegenerative diseases should always be considered. (Level of Difficulty: Advanced.).

Normal autonomic neurophysiology of postural orthostatic tachycardia and recommended physiological assessments in postural orthostatic tachycardia syndrome.

The current surge of interest in postural orthostatic tachycardia syndrome commonly known as POTS requires good knowledge of the very complex physiology involved, but this is currently lacking. The often overlooked normal physiology of orthostasis is reviewed including the definition of normal postural orthostatic tachycardia. An illustrated functional anatomy that embeds orthostatic tachycardia within the learned and skilful motor functions in the human population is presented. The four physiological phases of orthostasis and the role of tachycardia are described in a laboratory-controlled and progressive orthostatic stress in normal human volunteers. Standardized surrogate measures of autonomic control were used to quantify the trigger level for excessive tachycardia and the minimum autonomic control required to sustain viable arterial blood pressure during severe orthostatic stress in normal human volunteers. Tachycardia during orthostasis is part of a "democratic" contribution by four cardiovascular parameters of which the chronotropic function of the heart is just one of the parameters contributing toward cardiovascular compensation. It is adjusted during orthostasis in proportion to contributions from the other three parameters, namely inotropic function of the heart, windkessel vascular resistance and venous vascular capacitance. The physiological effects of the two stressors during orthostasis, gravity and isometric contraction of skeletal muscles are reviewed. A model of how the four cardiovascular parameters are regulated during orthostasis to achieve proportionate contributions is proposed emphasizing the necessity to quantify individual contributions from all these four parameters. Any one or more of these parameters may be compromised due to disease requiring disproportionate contribution of the prevailing magnitude of orthostatic tachycardia in an individual. It therefore requires neurophysiological assessment of the autonomic regulation of all the four cardiovascular parameters to assess the condition fully. We recommend here some current and novel neurophysiological methods that use modern medical technology to quantify laboratory standardized surrogate measures of some of these cardiovascular parameters including central parasympathetic regulation in postural orthostatic tachycardia syndrome.

Walking on treadmill with Rett syndrome-Effects on the autonomic nervous system.

People with Rett syndrome have deficient central autonomic control, which may interfere with walking. We have limited knowledge regarding the effects of exertion during physical activity in Rett syndrome. The aim was to investigate the autonomic responses during walking on a treadmill in Rett syndrome. Twenty-six females, 12 with Rett syndrome and 14 healthy females were included. All individuals started on the treadmill by standing still, followed by walking slowly with progressive speed until reaching maximum individual speed, which they kept for 6 min. Heart rate (HR), systolic (SBP), diastolic (DBP), mean arterial blood pressures (MAP), cardiac vagal tone (CVT), cardiac sensitivity to baroreflex (CSB), transcutaneous partial pressures of oxygen (pO2), carbon dioxide (pCO2), and breathing movements were recorded simultaneously and continuously. Autonomic responses were assessed by MAP, CSB and CVT during walking at 3 and 6 min. The changes in CSB and CVT in people with Rett syndrome compared to controls indicated more arousal, but only when the treadmill was started; as they continued walking, the arousal dropped to control level. People with Rett syndrome exhibited little changes in pCO2 whereas the controls showed increased values during walking. This suggests poor aerobic respiration in people with Rett syndrome during walking. Five people with Rett syndrome had Valsalva type of breathing at rest, three of those had normal breathing while walking on the treadmill while the remaining two started but soon stopped the Valsalva breathing during the walk. Our results show that individuals with Rett syndrome can walk for up to 6 min at their own maximum sustainable speed on a treadmill. Energy production may be low during walking in Rett syndrome, which could cause early tiredness. A treadmill can be used in people with Rett syndrome, but must be introduced slowly and should be individually tailored. We propose that walking promotes regular breathing in Rett syndrome.

Attenuation of Splanchnic Autotransfusion Following Noninvasive Ultrasound Renal Denervation: A Novel Marker of Procedural Success.

BACKGROUND: Renal denervation has no validated marker of procedural success. We hypothesized that successful renal denervation would reduce renal sympathetic nerve signaling demonstrated by attenuation of α-1-adrenoceptor-mediated autotransfusion during the Valsalva maneuver. METHODS AND RESULTS: In this substudy of the Wave IV Study: Phase II Randomized Sham Controlled Study of Renal Denervation for Subjects With Uncontrolled Hypertension, we enrolled 23 subjects with resistant hypertension. They were randomized either to bilateral renal denervation using therapeutic levels of ultrasound energy (n=12) or sham application of diagnostic ultrasound (n=11). Within-group changes in autonomic parameters, office and ambulatory blood pressure were compared between baseline and 6 months in a double-blind manner. There was significant office blood pressure reduction in both treatment (16.1±27.3 mm Hg, P<0.05) and sham groups (27.9±15.0 mm Hg, P<0.01) because of which the study was discontinued prematurely. However, during the late phase II (Iii) of Valsalva maneuver, renal denervation resulted in substantial and significant reduction in mean arterial pressure (21.8±25.2 mm Hg, P<0.05) with no significant changes in the sham group. Moreover, there were significant reductions in heart rate in the actively treated group at rest (6.0±11.5 beats per minute, P<0.05) and during postural changes (supine 7.2±8.4 beats per minute, P<0.05, sit up 12.7±16.7 beats per minute, P<0.05), which were not observed in the sham group. CONCLUSIONS: Blood pressure reduction per se is not necessarily a marker of successful renal nerve ablation. Reduction in splanchnic autotransfusion following renal denervation has not been previously demonstrated and denotes attenuation of (renal) sympathetic efferent activity and could serve as a marker of procedural success. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02029885.

Recovery from Cogwheel Rigidity and Akinesia and Improvement in Vibration Sense and Olfactory Perception following Removal of an Epoxy-Oleic Acid DNA Adduct.

The epoxy fatty acid cis-12,13-epoxy-oleic acid, which acts as a DNA adduct, may be generated during long-term storage of many seed oils, including those used in cooking, with frying oils and fried foods being a major source in the modern human diet. Removal of this epoxy fatty acid from the locus of the N-formyl peptide receptors was associated with recovery from cogwheel rigidity and akinesia as well as with improvement in vibration sense and olfactory perception.

Management of a severe forceful breather with Rett syndrome using carbogen.

We have used a novel neurophysiological technique in the NeuroScope system in combination with conventional electroencephalography (EEG) to monitor both brainstem and cortical activity simultaneously in real-time in a girl with Rett syndrome. The presenting clinical features in our patient were severe sleep disturbances, irregular breathing in the awake state dominated by Valsalva's type of breathing followed by tachypnoea and very frequent attacks of seizures and vacant spells. Our novel neurophysiological data showed that the patient was a Forceful Breather according to the breathing categories in Rett syndrome. She had frequent abnormal spontaneous brainstem activation (ASBA) preceded by severe attacks of hypocapnoea, which was caused by a combination of Valsalva's type of breathing and tachypnoea and all these together were responsible for the seizures and non-epileptic vacant spells. The ASBA was not detectable in conventional EEG and there were no epileptiform changes in the EEG during the seizures and vacant spells caused by the hypocapnic attacks, therefore these were pseudo-seizures. The record of brainstem activity confirmed that these were autonomic events, a kind of "brainstem epilepsy". We successfully treated the sleep disturbance with Pipamperone, a 5-hydroxytryptophan antagonist of receptor type 2 and we prevented the severe hypocapnoea during Valsalva's type of breathing and during tachypnoea using carbogen (a mixture of 5% carbon dioxide and 95% oxygen), which we gave by inhalation. Our treatment drastically reduced the autonomic events, promoted whole night sleep and significantly improved the quality of life in our patient. She can now participate in normal family activity which was previously impossible before treatment.

Respiratory and autonomic dysfunction in children with autism spectrum disorders.

INTRODUCTION: Cardiac parasympathetic hypofunction has been reported in autism spectrum disorders (ASD). This usually is linked to respiratory dysrhythmia which has been documented in some children with ASD. OBJECTIVES: This study evaluated the cardiorespiratory functions in ASD to elucidate the physiologic basis of behaviors. METHODS: Nineteen children with ASD and 18 age matched controls underwent autonomic function monitoring at a defined resting state using the NeuroScope. The non-invasive real time beat-to-beat blood pressure was measured by Portapres and fed into the NeuroScope where heart rate, cardiac vagal tone and cardiac sensitivity to baroreceptor were derived from the EKG and blood pressure waveforms using the Vagosoft software; and respiratory rate and rhythm were measured simultaneously by plethysmograph. Respiration was analyzed breath by breath using our prior published methods. RESULTS: Various respiratory dysrhythmias, particularly Biot's and Cheyne-Stokes respiration, were detected in children with ASD, who also exhibited greater variability in respiratory rhythm and amplitudes than controls. The respiratory dysrhythmia in children with ASD was associated with a lower cardiac vagal activity. CONCLUSION: The Biot's breathing and Cheyne-Stokes respiration coupled with cardiac vagal hypofunction in ASD suggest a brainstem dysfunction consistent with our previous findings. The low parasympathetic activity could explain in part the chronic sensory hyperarousal state in children with ASD.

Assessment of the maturity-related brainstem functions reveals the heterogeneous phenotypes and facilitates clinical management of Rett syndrome.

We have investigated whether brainstem assessment using the Neuro Scope could be used for objective and quantitative monitoring of early development and later progress in Rett syndrome. Brainstem features can be seen on bedside examination of Rett patients and are included in the International Scoring system. The following cardiovascular vital signs were recorded simultaneously in real-time: cardiac vagal tone (CVT), cardiac sensitivity to baroreflex (CSB), heart rate (HR), and mean arterial blood pressure (MAP) and respiratory vital signs: breathing rate and pattern, transcutaneous partial pressures of oxygen (pO(2)) and carbon dioxide (pCO(2)). We assessed the occipito-frontal head circumference (OFHC), height and body mass index (BMI). Results are from 72 patients with classical Rett syndrome studied at the Swedish National Rett Centre. Three cardiorespiratory phenotypes, designated Forceful, Feeble and Apneustic breathers were present in similar proportions in the Rett population but early development measured by OFHC and BMI differed. Height was not affected. Baseline levels of CVT and CSB also differed within the phenotypes indicating differences in parasympathetic activities. However, parasympathetic activity in the whole population was similar to that previously reported in Rett. Baseline levels of MAP and HR were similar across the phenotypes, consistent with previous reports of little effect of Rett disorder on baseline sympathetic tone. Adverse responses to opiate analgesics and hypocapnoeic attacks were unique to specific phenotypes. We recommend early characterisation of these phenotypes in the management of Rett syndrome. We conclude that classical Rett syndrome consists of heterogeneous clinical phenotypes with distinct cardiorespiratory states. Brainstem functions can be used to identify these and to monitor development and treatment, thereby facilitating clinical management.

Reduced cardiac parasympathetic activity in children with autism.

Many of the clinical symptoms of autism suggest autonomic dysfunction. The aim of this study was to measure baseline cardiovascular autonomic function in children with autism using the NeuroScope, a device that can measure this brainstem function in real-time. Resting cardiac vagal tone (CVT), cardiac sensitivity to baroreflex (CSB), mean arterial blood pressure (MAP), diastolic blood pressure (DBP), systolic blood pressure (SBP) and heart rate (HR) were recorded in three different groups of children. The symptomatic group (n = 15) consisted of those with autism who exhibited symptoms or signs of autonomic dysfunction. The asymptomatic group (n = 13) consisted of children with autism but without symptoms or signs of autonomic dysfunction and the healthy children were in the control group (n = 17) [corrected]. The CVT and CSB were significantly lower in association with a significant elevation in HR, MAP and DBP in all children with autism compared with the healthy controls. Further more, the levels of CVT and CSB were lower in the symptomatic than in the asymptomatic group. The levels of CVT and CSB were not related to age in all the three groups. These results suggest that there is low baseline cardiac parasympathetic activity with evidence of elevated sympathetic tone in children with autism whether or not they have symptoms or signs of autonomic abnormalities.

Low level exposures to organophosphorus esters may cause neurotoxicity.

A large number of published studies support the notion that long term, low level (LTLL) exposure to organophosphorus (OP) esters may cause neurological and neurobehavioral effects. In order to differentiate these from other effects of OP such as the acute cholinergic episodes, intermediate syndrome and organophosphate induced delayed neuropathy (OPIDN), the term Chronic Organophosphate Induced Neuropsychiatric Disorder (COPIND) will be used purely for the ease of reference. The question addressed in this particular review is whether LTLL exposure to OP may produce neurotoxicity. The profile and the degree of overlap of the various components of COPIND have been addressed elsewhere and description of the possible mechanisms for COPIND is outside the scope of this article. COPIND can be classified under two headings; those produced following one or more acute clinical cholinergic episodes, and those produced without such preceding attacks. With regards to the first group, there are a total of 11 studies, all of which support the existence of a positive link between exposure to OP and neurotoxicity; six of these studies comprise descriptions of large numbers of cases without controls while five additional studies employ controls. Appearance of neurotoxicity does not seem to be related to the number or the intensity of acute cholinergic attacks. With regards to the second group, three types of studies can be identified. Firstly, there are five studies using experimental animals, all of which showed a positive link between OP and neurotoxicity. Secondly, a total of seven case studies without controls, some involving large numbers of patients, concluded that there is a positive link between OP and neurotoxicity. Thirdly, 19 studies investigated such a link using cases and control groups. Of these, 15 studies (about 80%) showed a positive link and only four failed to identify any link between OP and neurotoxicity. Annotation of all the 19 studies according to ideal set of criteria showed that only a few of these comply with the rules of excellence and all of these few showed a positive link. Furthermore, the only study carried out blind without the identification of subjects or controls, showed a positive link between OP and neurotoxicity. This blind study estimated the overall incidence of a form of neurotoxicity in people exposed to OP to be about 40 times higher than in the general population. The type of neurological involvement was unique and different from OP induced syndromes previously described. The profile of the neurological involvement was similar to that in COPIND whether or not preceded by acute cholinergic episodes, thus providing further evidence that these two neuropathies probably share a similar mechanism. There is a characteristic pattern of involvement of 15 functional indices of the autonomic nervous system examined in our laboratory. There are, in addition, preferential anatomical sites of target organs affected, selective preservation of cholinergic function within the same neuropathy-positive site, and evidence of mal-function of cardiac chemoreceptors in patients exposed to OP. The peripheral nerve involvement in OP exposure is predominantly sensory in nature affecting both small and large fibre populations. Neurobehavioral involvement of mainly cognitive dysfunction and other features are also described in other studies. The weight of current evidence is therefore very much in favor of the motion that chronic low-level exposure to OP produces neurotoxicity. Criticisms levelled against this motion are unfounded and probably misconceived.

Discordant mental and physical efforts in an autistic patient.

We investigated whether there was mental effort in response to verbal commands in a 16-year old girl with autism, a high degree of non-compliance with commands and symptoms of autonomic dysfunction by monitoring the brainstem autonomic tone during an attempt to perform isometric exercise. An index of cardiac vagal tone (CVT), cardiac sensitivity to baroreflex (CSB), heart rate (HR) and mean arterial blood pressure (MAP) were measured simultaneously. Physical non-compliance with our commands meant there was no force applied by the patient during the attempted exercise, but CVT and CSB were both reduced and sustained at very low levels throughout the attempt, while MAP and HR were increased concurrently to higher levels in the same period. This vagal withdrawal to allow concurrent increases in HR and MAP is an arousal response appropriate for isometric exercise, which is a sign of a positive mental effort to comply with our commands. These results demonstrate discordant mental and physical efforts in our patient. In this particular case, the physical inabilities in some instances could have been mislabelled as mental non-compliance due to autism. It would be worthwhile to investigate the prevalence of discordant mental and physical efforts in autism.

Hyperosmia in Lyme disease.

Neurological involvement in Lyme disease has been reported to include meningitis, cranial neuropathy and radiculoneuritis. While it is known that in some cases of asceptic meningitis patients may develop hyperosmia, the association between hyperosmia and Lyme disease has not previously been studied. Objective To carry out the first systematic study to ascertain whether hyperosmia is also a feature of Lyme disease. Method A questionnaire regarding abnormal sensory sensitivity in respect of the sense of smell was administered to 16 serologically positive Lyme disease patients and to 18 control subjects. Results The two groups were matched in respect of age, sex and body mass. None of the 34 subjects was suffering from migraine. Eight (50%) of the Lyme patients and none (0%) of the controls suffered from hyperosmia (p=0.0007). Conclusion This first systematic controlled study showed that Lyme disease is associated with hyperosmia.

Respiratory modulation of cardiac vagal tone in Lyme disease.

AIM: To conduct the first systematic test of the hypothesis that modulation of cardiac vagal tone is impaired in Lyme disease. METHODS: The response of cardiac vagal tone to respiratory modulation was measured in 18 serologically positive Lyme disease patients and in 18 controls. RESULTS: The two groups were matched in respect of age, sex, body mass, mean arterial blood pressure, mean resting heart rate and mean resting cardiac vagal tone. The mean maximum cardiac vagal tone during deep breathing in the Lyme disease patients [11.2 (standard error 1.3)] was lower than in the matched controls [16.5 (standard error 1.7); P = 0.02]. CONCLUSION: Respiratory modulation of cardiac vagal tone is impaired in Lyme disease, which suggests that Lyme disease may directly affect the vagus nerve or the brainstem.

The association of lyme disease with loss of sexual libido and the role of urinary bladder detrusor dysfunction.

PURPOSE: The primary aim was to carry out a pilot study to compare the loss of sexual libido between a group of Lyme disease patients and a group of matched controls. The secondary aim was to evaluate whether loss of libido in Lyme disease patients is associated with urinary bladder detrusor dysfunction. METHODS: A group of 16 serologically positive Lyme disease patients and 18 controls were queried directly about loss of libido. RESULTS: The 2 groups were matched with respect to age, sex, body mass index, and mean arterial blood pressure. None of the 34 subjects was taking medication that might affect sexual libido or had undergone a previous operative procedure involving the genitourinary tract. Of the 16 Lyme disease patients, 8 (50%) had no loss of libido, and of the 18 controls, none had loss of libido (P<0.001). In the Lyme disease patient group, there was no statistically significant relationship between loss of libido and urinary bladder detrusor dysfunction (P=0.61). CONCLUSIONS: This pilot study suggested an association between Lyme disease and loss of libido. Moreover, this loss of libido did not seem to be associated with urinary bladder detrusor dysfunction. Given these results, we recommend further studies to confirm the association.

Treating hypoxia in a feeble breather with Rett syndrome.

Rett syndrome (RS) is a unique X-linked dominant neurodevelopmental disorder affecting 1 in 10,000 females. Mutations in the MECP2 gene located on Xq28 have been identified. Many of the characteristic features evolve due to immaturity of the brain in RS. Cardiorespiratory function should be investigated early to characterise the clinical phenotype of the person with RS because each of the three cardiorespiratory phenotypes; apneustic, feeble and forceful breathers have unique and different management strategies. We report a case of a feeble breather showing a correlation between cortical function and tissue pO(2) and pCO(2). We conclude that subtle changes in the levels of blood gases significantly affect cortical function in RS.

Normal reactions to orthostatic stress in Rett syndrome.

The aim of this study was to investigate orthostatic reactions in females with Rett syndrome (RTT), and also whether the severity of the syndrome had an impact on autonomic reactions. Based on signs of impaired function of the central autonomic system found in RTT, it could be suspected that orthostatic reactions were affected. The orthostatic reactions in 21 females with RTT and 14 normally developed females matched by age were investigated when they rose from a sitting position, and during standing for 3 min. Reactions of the heart, the blood pressure and the time for recovery of systolic blood pressure, were studied in real time, heartbeat by heartbeat, simultaneously. There was no difference between participants with RTT and the normally developed controls regarding general orthostatic reactions (heart rate, systolic and diastolic blood pressure, and mean arterial pressure) when getting up from a sitting position, and when standing erect for 3 min. In the specific immediate response by the heart to standing up, the 30:15 ratio, significantly lower values were found for females with RTT. In the RTT group, the maximum fall of systolic blood pressure showed a tendency to a larger decrease, and the initial decrease in systolic blood pressure was significantly faster. The time for recovery of systolic blood pressure from standing erect did not differ between groups. At baseline the females with RTT had significantly lower systolic blood pressure and a tendency to a higher heart rate. The results do not indicate any autonomic limitations for people with RTT in getting up from a sitting position and standing. The participants with RTT had normal orthostatic reactions indicated by the heart and blood pressure responses when standing erect for 3min. A faster initial drop in systolic blood pressure in people with RTT was notable.

Urinary bladder detrusor dysfunction symptoms in lyme disease.

PURPOSE: Symptoms of urinary bladder detrusor dysfunction have been rarely reported in Lyme disease. The aim was to carry out the first systematic study to compare the prevalence of such symptoms in a group of Lyme disease patients and a group of matched controls. METHODS: A questionnaire relating to detrusor function was administered to 17 serologically positive Lyme disease patients and to 18 control subjects. RESULTS: The two groups were matched in respect of age, sex, body mass, and mean arterial blood pressure. None of the 35 subjects was taking medication which might affect urinary function and none had undergone a previous operative procedure on the lower urinary tract. Six of the Lyme patients (35%) and none of the controls (0%) had symptoms of detrusor dysfunction (P<0.01). CONCLUSIONS: This first systematic controlled study confirms that Lyme disease is associated with urinary bladder detrusor dysfunction. Further evaluation of detrusor function is warranted in this disease.