Flora Apartopoulos

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.

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.

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.

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.

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.

Peripheral Nerve Dysfunction in Farmers Using Organophosphate Sheep Dip

Purpose : To investigate the function of the peripheral and central nervous system in farmers regularly using organophosphate (OP) compounds either after acute intoxication or following low level repeated exposure. Design : Case control and cross-sectional studies. Materials and Methods : Two groups, each of sixteen farmers regularly involved in dipping sheep, were compared with a group of sixteen healthy controls of similar age range using clinical neurological and neurophysiological assessment. Farmers in group 1 had long-term ill health following episodes of mild to moderate acute OP poisoning while farmers in group 2 had none of the above. Clinical symptoms and signs of neuropathy were recorded. Motor and sensory nerve conduction, electromyography (EMG), quantitative sensory testing and visual, brainstem auditory and somatosensory evoked potentials were measured. Results : A similar pattern of significant abnormalities of distal sensory and motor peripheral nerve axonal dysfunction was found in both f...