Peter O.O. Julu

Characterisation of breathing and associated central autonomic dysfunction in the Rett disorder

AIM To investigate breathing rhythm and brain stem autonomic control in patients with Rett disorder. SETTING Two university teaching hospitals in the United Kingdom and the Rett Centre, Sweden. PATIENTS 56 female patients with Rett disorder, aged 2–35 years; 11 controls aged 5–28 years. DESIGN One hour recordings of breathing movement, blood pressure, ECG R-R interval, heart rate, transcutaneous blood gases, cardiac vagal tone, and cardiac sensitivity to baroreflex measured on-line with synchronous EEG and video. Breathing rhythms were analysed in 47 cases. RESULTS Respiratory rhythm was normal during sleep and abnormal in the waking state. Forced and apneustic breathing were prominent among 5–10 year olds, and Valsalva breathing in the over 18 year olds, who were also most likely to breathe normally. Inadequate breathing peaked among 10–18 year olds. Inadequate and exaggerated breathing was associated with vacant spells. Resting cardiac vagal tone and cardiac sensitivity to baroreflex were reduced. CONCLUSIONS Labile respiratory rhythms and poor integrative inhibition in Rett disorder suggest brain immaturity. Linking this to an early monoaminergic defect suggests possible targets for the MECP2 gene in clinical intervention. Exaggerated and inadequate autonomic responses may contribute to sudden death.

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.

Guidelines for reporting clinical features in cases with MECP2 mutations

An international group recommends that papers relating phenotypes to genotypes involving mutations in the X chromosome gene MECP2 should provide a minimum data set reporting the range of disturbances frequently encountered in Rett Syndrome. A simple scoring system is suggested which will facilitate comparison among the various clinical profiles. Features are described which should prompt screening for MECP2 mutations.

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.

Cardiovascular regulation in the period preceding vasovagal syncope in conscious humans

To study cardiovascular control in the period leading to vasovagal syncope we monitored beat‐to‐beat blood pressure, heart rate (HR) and forearm blood flow in 14 patients with posturally related syncope, from supine through to tilt‐induced pre‐syncope. Signals of arterial blood pressure (BP) from a Finapres photoplethysmograph and an electrocardiograph (ECG) were fed into a NeuroScope system for continuous analysis. Non‐invasive indices of cardiac vagal tone (CVT) and cardiac sensitivity to baroreflex (CSB) were derived on a beat‐to‐beat basis from these data. Brachial vascular resistance (VR) was assessed intermittently from brachial blood flow velocity (Doppler ultrasound) divided by mean arterial pressure (MAP). Patients underwent a progressive orthostatic stress test, which continued to pre‐syncope and consisted of 20 min head‐up tilt (HUT) at 60 deg, 10 min combined HUT and lower body suction (LBNP) at −20 mmHg followed by LBNP at −40 mmHg. Pre‐syncope was defined as a fall in BP to below 80 mmHg systolic accompanied by symptoms. Baseline supine values were: MAP (means ±s.e.m.) 84.9 ± 3.2 mmHg; HR, 63.9 ± 3.2 beats min−1; CVT, 10.8 ± 2.6 (arbitrary units) and CSB, 8.2 ± 1.6 ms mmHg−1. HUT alone provoked pre‐syncope in 30 % of the patients whilst the remaining 70 % required LBNP. The cardiovascular responses leading to pre‐syncope can be described in four phases. Phase 1, full compensation: where VR increased by 70.9 ± 0.9 %, MAP was 89.2 ± 3.8 mmHg and HR was 74.8 ± 3.2 beats min−1 but CVT decreased to 3.5 ± 0.5 units and CSB to 2.7 ± 0.4 ms mmHg−1. Phase 2, tachycardia: a progressive increase in heart rate peaking at 104.2 ± 5.1 beats min−1. Phase 3, instability: characterised by oscillations in BP and also often in HR; CVT and CSB also decreased to their lowest levels. Phase 4, pre‐syncope: characterised by sudden decreases in arterial blood pressure and heart rate associated with intensification of the symptoms of pre‐syncope. This study has given a clearer picture of the cardiovascular events leading up to pre‐syncope. However, the mechanisms behind what causes a fully compensated system suddenly to become unstable remain unknown.

Recent insights into hyperventilation from the study of Rett syndrome

The medical literature presents two major groups of disorder in which hyperventilation is a presenting feature. Disorders of mood, notably panic disorder, and disorders of brain stem function—developmental, vascular, traumatic, toxic, metabolic, degenerative or neoplastic. References to the underlying brain morphology leading to these conditions are few and imprecise, perhaps reflecting the inaccessibility of the brain stem to clinical medicine and the complexity of the neural basis of respiratory control. Even in Joubert’s syndrome, where hyperventilation is a major feature, hypoplasia of the cerebellar vermis and cyst of the fourth ventricle have been described but the exact pathophysiology is unclear.1 The clinical medical literature gives more space to discussing the effects of hyperventilation, including the well known respiratory alkalosis with reduction in plasma ionised calcium, tingling sensations, tetany, induction of epileptic seizures, and induction of interictal epileptogenic activities seen on the electroencephalogram (EEG). In healthy children, especially girls, voluntary hyperventilation produces slow EEG waves, usually generalised over the cerebral cortex. Hyperventilation reduces oxygen delivery to the brain,2 and cardiac repolarisation abnormalities including ST depression and T wave inversion have been described.3 From its delineation in 1937 to the 1980s, the “hyperventilation syndrome” was held responsible for much of the symptomatology of panic disorder4; however, with increased accuracy of measurements, this notion was replaced by the view that autonomic instability underlies both hyperventilation and panic disorder.5 Although there is a clear association between panic and hyperventilation, the neurological basis for this is still unresolved. Hyperventilation or overbreathing is variously defined, according to the measures available and familiar to each scientific discipline. There is agreement that the breathing exercise must ventilate the lungs in excess of metabolic requirements at that particular point in time and thus induce measurable changes, usually a reduction in arterial or alveolar …

A clinical neurological, neurophysiological, and neuropsychological study of sheep farmers and dippers exposed to organophosphate pesticides

Objectives: To classify clinical diseases of the subjects with abnormal indices of peripheral neuropathy identified in field studies of sheep farmers and dippers exposed to organophosphate pesticides. To explore what neuropsychological profiles, if any, may be associated with neurophysiological damage in these subjects. Methods: A case-control study (79 subjects) nested within the cross sectional study (685 subjects) of sheep farmers from the field study. Three groups with no, possible, and probable or definite neuropathy according to field studies were recruited. Investigations comprised symptoms of neuropathy, neurologial signs, motor and sensory nerve conduction, electromyography, quantitative sensory testing, and neuropsychological tests. Results: The incidence of clinical neuropathy increased from 7% in the no neuropathy group to 52% in the probable or definite neuropathy group based on nerve conduction measurements or presence of neurological signs. Sensory abnormalities were found more often than motor deficits. Small diameter nerve fibres were also affected more than large fibres. Conclusions: The neuropathy is predominantly sensory and is characteristic of distal, chronic neuropathy with no acute features. Small fibre populations are affected more than large fibre populations. Increasing severity of neuropathy was associated with anxiety and depression as measured in the neuropsychological tests.

Cardiorespiratory challenges in Rett's syndrome

www.thelancet.com Vol 371 June 14, 2008 1981 Rett’s syndrome is a genetic neurodevelopmental disorder with brainstem immaturity that aff ects one in 10 000 women. The condition shows the importance of the brainstem in cardiorespiratory medicine. There is a lack of understanding of the cardiorespiratory disturbance in the disorder within the medical community, which makes management a challenge. Therefore an international group of experienced medical practitioners from various disciplines gathered in the Swedish National Rett Centre, Frösön, to collate their experience on Rett’s syndrome and provide a practical management strategy for all health-care tiers: the Frösö Declaration. The six cardinal features of Rett’s syndrome (table) are age-dependent. Abnormalities become evident during the fi rst or second year of life. A regression stage, characterised by an exacerbation of brainstem features, usually seems to take place in the second year. There is poor parasympathetic development, leading to a unique sympathovagal imbalance with the misleading impression of sympathetic overactivity. A lack of integrative inhibitions in the brainstem pre vents appropriate cardiovascular regulation during abnor mal breathing, causing an increased risk of adverse cardiorespiratory events. Brainstem disorders are the main reasons to seek urgent medical atten tion in Rett’s syndrome throughout life. Multiorgan involvement of in breathing-related metabolic disorders needs professional care and includes cardiologists, anaesthetists, respiratory physicians, endocrinologists, nutritionists, neurologists, paediatricians, and general practitioners. Early diagnosis to avoid long-term medical uncertainty is the primary aim. A search for mutations in the MECP2 gene in infants with unexplained developmental slurring is recommended. Then the cardiorespiratory phenotype should be established at the onset of brainstem disorders, because each of the three phenotypes is unique and needs a specifi cally tailored management strategy. Establishing the cardiorespiratory phenotype requires detailed neurophysiology. The primary pathophysiology is a defective control mechanism of carbon dioxide exhalation that leads to respiratory alkalosis or acidosis. Patients with phenotype 1 are forceful breathers who usually have fi xed low concentrations of partial pressure of carbon dixoide (pCO2), causing chronic respiratory alka losis. To interrupt an episode of forceful breathing, we recom mend fi rst re-breathing into a 5-L bag attached Cardiorespiratory challenges in Rett’s syndrome two-thirds of Tibetan people have not had access to iodised salt. Despite the overall poor coverage, the picture is not all bleak. In Tibet, there are 890 primary schools, 118 middle schools, and 1568 teaching. Of the 470 000 students attending these schools, three-quarters eat in school dining halls 5 days a week. Happily, all school dining halls in Tibet use iodised salt in accordance with a policy and schools health-promotion programme set out by the Education Bureau of Tibet in 2005. Since then, around 350 000 school children consume iodised salt at least 5 days a week, thus achieving the required intake of iodine for children.

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.

Real-time measurement of cardiac vagal tone in conscious dogs

Rapid changes in heart rate are caused by changes in parasympathetic tone. The NeuroScope is an electronic device designed to offer an objective real-time measure of instantaneous cardiac vagal tone by phase demodulation of a high-resolution time domain of R-R wave intervals. Data are displayed against an arbitrary but linear scale, the cardiac index of parasympathetic activity (CIPA). To validate this method, 10 conscious healthy dogs were each given six incremental doses of atropine (0.01 mg/kg) to a total dose of 0.06 mg/kg or equal volumes of saline. A dose-response curve was constructed. At the maximum dose of atropine, CIPA values fell to 1.3 ± 0.7% (SD) of baseline, whereas R-R intervals fell to 51.5 ± 11.5% of baseline, and standard deviation of the R-R wave interval fell to 10.6 ± 6.5% of baseline. These findings show that the NeuroScope can provide a specific real-time index of cardiac vagal tone in dogs without need for recourse to atropine.Rapid changes in heart rate are caused by changes in parasympathetic tone. The NeuroScope is an electronic device designed to offer an objective real-time measure of instantaneous cardiac vagal tone by phase demodulation of a high-resolution time domain of R-R wave intervals. Data are displayed against an arbitrary but linear scale, the cardiac index of parasympathetic activity (CIPA). To validate this method, 10 conscious healthy dogs were each given six incremental doses of atropine (0.01 mg/kg) to a total dose of 0.06 mg/kg or equal volumes of saline. A dose-response curve was constructed. At the maximum dose of atropine, CIPA values fell to 1. 3 +/- 0.7% (SD) of baseline, whereas R-R intervals fell to 51.5 +/- 11.5% of baseline, and standard deviation of the R-R wave interval fell to 10.6 +/- 6.5% of baseline. These findings show that the NeuroScope can provide a specific real-time index of cardiac vagal tone in dogs without need for recourse to atropine.