Articles

The Frösö Declaration

Clinical update: Addressing the cardiorespiratory challenges posed by Rett Syndrome in Medicine. The Frösö Declaration.

Peter O O Julu, Ingegerd Witt Engerström, Stig Hansen, Flora Apartopoulos, Bengt Engerström, Giorgio Pini, Robert S Delamont and Eric E J Smeets

The Wingate Institute of Neurogastroenterology, Queen Mary School of Medicine and Dentistry, London, UK (POOJ); Rett Center, Östersund Hospital, Sweden (IWE, BE and POOJ); Institute of Neurological Sciences, South Glasgow University Hospitals, Glasgow, UK (SH and AP); Child Neuropsychiatry and Centro Rett Versilia, Area Vasta Toscana, Nord-Occidentale, Italy (GP); Regional Neuroscience Centre, King’s College Hospital NHS Foundation Trust & King's College London, London, UK (RSD) and Department of Clinical Genetics, University Hospital Maastricht, Maastricht, The Netherlands (EEJS)

We are an international group of medical practitioners and specialists in various fields that all have had a minimum of ten years experience with Rett syndrome and have managed various medical emergencies involving these people. Our combined experience of clinical practice reveals a conspicuous absence of management strategy as a result of a lack of understanding of the cardiorespiratory turmoil in Rett syndrome. Gathered in the Swedish National Rett Centre in Frösön, we have collated our experience into a declaration for a practical management strategy that can be applied across all the tiers of health care.

Update of developmental physiology

Rett syndrome (RTT) is a unique X-linked dominant neurodevelopmental disorder that affects 1 in 10,000 females. Six cardinal features evolve due to immaturity of the brain in RTT. Two cortical features include severe mental retardation and epilepsy (1). The third feature is extra-pyramidal with dystonia, orthopaedic deformations of which scoliosis is the most common, secondary muscle wasting, incoordination of actions (1). The fourth is monoaminergic dysfunction in the brainstem with dyspraxia, sleep disturbance, frequent daytime sleeping, night awakening and agitation.(2). The fifth feature may be due to incompetence of the neuronal network of inhibitions in the brainstem secondary to immaturity with abnormal breathing rhythms in the awake-state (3). These resulting abnormal breathing rhythms and accompanying autonomic dysfunctions can explain the sudden deaths accounting for at least 25% of all deaths in RTT (4;5). Irregular breathing in RTT as a consequence of immature brainstem function has been described in detail elsewhere (6). The sixth feature recognised as part of brainstem dysfunction in RTT (6;7) is dysautonomia. In addition to previously known autonomic features like delayed nociception and cold, blue extremities, there is a unique sympatho-vagal imbalance in which the sympathetic tone is normal but the parasympathetic tone is very low and remains at the neonatal level throughout life (8).

The chronology of uncertainty in Rett syndrome

Babies with RTT are born apparently normal. Developmental slurring in the first or second year of life may catch medical attention, but without obvious physical signs, these children are often missed by General Practitioners and Paediatricians alike at the early stage of the disorder. Full descriptions of the clinical stages of Rett syndrome are given elsewhere (9;10). A regression stage generally appears in the second year of life but may appear as late as the fifth year and is characterised by exacerbation of the brainstem features. The unique sympatho-vagal imbalance gives a misleading clinical impression of a sympathetic hyperactivity in RTT. There is also a lack of integrative inhibitions that prevent appropriate cardiovascular regulations during abnormal breathing with increased risks of adverse cardiorespiratory events (4;6). As a result, brainstem features are one of the major reasons for seeking medical attention in RTT starting from childhood and continuing throughout life. There are also symptoms of multi-organ involvement due to metabolic, mostly acid-base imbalance caused by cardiorespiratory turmoil. This will draw in more medical specialties like cardiologists, anaesthetists, respiratory physicians, endocrinologists and nutritionists. By now it is evident that the care for people with RTT is multi-disciplinary and requires cross-professional collaboration.

Management strategy in Rett Syndrome

Early diagnosis to avoid prolonged medical uncertainty is the primary aim. A genetic search for mutation in the MECP2 gene in infants with unexplained developmental slurring is recommended. Routine tests for mutation analysis are now available in the National Health Service in the United Kingdom and other health services in Europe. This requires awareness by health visitors and Paediatricians in community practices. Characterisation of the clinical phenotypes of cardiorespiratory dysfunctions (11) is recommended at the beginning of the exacerbation of the brainstem features. This requires awareness by General Practitioners, Paediatricians or Child Neurologists who are likely to be confronted initially with this problem. Each of the three cardiorespiratory phenotypes; Apneustic, Feeble and Forceful breathers has a unique management strategy of the brainstem features.(11)

Management of the Breathing irregularity

The immediate clinical strategy is to establish the cardiorespiratory phenotype of the breathing dysrhythmia (11). Assessing this requires an appropriately set up neurophysiology department (11). It is very important to understand that there is predominantly a disorder of the control mechanisms of carbon dioxide exhalation in RTT including both respiratory alkalosis and respiratory acidosis.

The management strategies following identification of any of the three types of breathers are as follows: Forceful breathers tend to have fixed low levels of pCO2 (Chronic Respiratory alkalosis). To interrupt an episode of forceful breathing, we recommend first re-breathing in a 5L bag attached to a tightly fitting facial mask. Long-term weaning from the chronic respiratory alkalosis requires Carbogen treatment (5% CO2 in oxygen mixture) (12). Treatment by controlling the tidal volume with Bi-level Positive Airway Pressure (BiPAP system) is theoretically possible, but some people with RTT may not tolerate the masks used to administer this treatment. Treatments must be monitored continuously and we recommend transcutaneous measurement of blood gases. Levels of carbon dioxide determine the end-points of treatments. We emphasise that due to the reset of the central respiratory chemoreceptors, the operational levels of pCO2 for stable breathing is very variable in RTT and has to be establish by trial and error during treatment. The long-term aim is to move the operational pCO2 level towards normal between 39-44 mmHg. The nutritional implications of this cardiorespiratory phenotype are summarised below.

Feeble breathers tend to have fixed higher levels of pCO2 (Chronic Respiratory acidosis) due to long-term inadequate ventilation. Stimulation of breathing is important in these people. Physical activation during personal contact is useful, but is short-lived. We recommend Theophylline by mouth as a first choice respiratory stimulant in Feeble Breathers. The non-invasive BiPAP system should also be considered, although our clinical experience is limited. The rationale behind using BiPAP is to increase the tidal volume mechanically at night only and this should be sufficient for daytime maintenance. The end-point of treatment is established by monitoring breathing rate and rhythm and transcutaneous pCO2. The long-term aim is to achieve a normal breathing rhythm at or near normal operational level of pCO2. The RTT population with this cardiorespiratory phenotype often have idiosyncratic sensitivity to opiates and other respiratory depressants, all of which must be avoided. Idiosyncrasy to diazepam has also been reported in Feeble Breathers. Anaesthetists should be aware of the hypercapnoea and sensitivity to respiratory depressants in this population of RTT. The high operational pCO2 in these patients must be considered if spontaneous breathing fails during weaning from artificial ventilation in intensive care.

Apneustic breathers accumulate carbon dioxide due to the delayed and inadequate expirations. We recommend Buspirone by mouth as the drug of first choice and this was shown to be effective against apneusis (13). Treatment using the BiPAP system in spontaneous time mode with backup frequency is theoretically possible, but has the shortcomings mentioned above. The short and long-term treatment aims are as for Feeble Breathers. This is the only cardiorespiratory phenotype shown to respond to Buspirone. The chronic hypercapnoea and high operational pCO2 in this cardiorespiratory phenotype has implications in anaesthesia similar to Feeble Breathers.

Valsalva’s manoeuvre is a common complication of breathing dysrhythmia in RTT and has powerful excitatory effects on the autonomic nervous system and brainstem functions leading to recognisable clinical features. All three cardiorespiratory phenotypes are affected (11). This is not a bedside diagnosis. The typical and diagnostic heart rate and blood pressure changes can only be confirmed during autonomic monitoring in appropriate neurophysiological set up (11). This complication often leads to visible clinical deterioration of the well being of the person with RTT, particularly the Forceful Breathers. All medical and non-medical carers of persons with RTT should be aware of this. Autonomic disturbance caused by these manoeuvres mimic epileptic seizures. Therefore, early and correct diagnosis is essential to avoid unnecessary treatment with anti-epileptic drugs that are ineffective against the autonomic paroxysms. The nutritional implications of Valsalva’s manoeuvre are summarised below.

Management of Agitation

Agitation in RTT is largely a consequence of unrestrained sympathetic activity. Typical symptoms and behaviour include very short attention span, increased physical activity, dilated pupils, excessive perspiration and transpiration, sudden screams or rage. Management must include identification of the trigger event or situation. Treatment must start with the avoidance or removal of the likely trigger. Eventual use of time-out in sensory deprivation is reasonable. The drugs of choice are Risperidone or Pipamperon by mouth in low doses administered twice daily.

Management of Sleep Disturbance

Sleep problems and night awakening are common in RTT. Management must include evaluation of the circadian rhythm or identification of problems in the initiation of sleep. Arousals due to breathing dysrhythmia should also be considered. Drug treatments recommended are Melatonin and or Pipamperon/Risperidon to restore the circadian rhythm, pipamperon if agitation is a major factor in the sleep disturbance, L-tryptophan if there is difficulty in the initiation of sleep. The CPAP (Continuous Positive Airway Pressure) system should be considered in cases where defence arousals are the major cause of the sleep disturbance.

Management of Epileptic and non-epileptic paroxysms

Problematic epilepsy is common in the RTT population (14). However, autonomic events may simulate atypical seizures. Management must start with a clear clinical description of the fits, which is essential for the correct diagnosis of epilepsy. Signs of abnormal brainstem activity include blinking of the eyes and or facial twitching, non-epileptic vacant spells (atypical absence attacks without EEG evidence of epilepsy) with or without cyanosis and hypocapnic attacks with tetany. The abnormal brainstem activity can only be confirmed by monitoring both the brainstem and cortical activities synchronously and simultaneously in appropriate neurophysiological set up (6).

Treatment of epilepsy in RTT is aimed at reducing the excitability of neurones in the immature brain while at the same time trying to prevent the spread of seizures. We must not try to treat the EEG abnormalities in RTT, unless there is a clear clinical correlate. We have found a combination of Sodium Valproate (Epilim) and Lamotrigine useful for these purposes. There is a potential use of Gabapentin or Pregabalin for treatment of the very common abnormal brainstem autonomic paroxysms in RTT. The rationale of these drugs is neuronal membrane stabilisation. We also have limited experience with left vagus nerve stimulation using implanted stimulators. The two treatment regimes are promising but require further clinical evaluation.

Nutrition

Derangement of metabolic equilibrium is manifested in multiple organs in RTT. This often has a nutritional origin. There is very high-energy expenditure through increased motor activity, forceful breathing, Valsalva’s manoeuvre type of breathing, hyperventilation and perspiration. Daily energy and water requirements may be much higher than is often provided to persons with RTT. It is apparent that Forceful Breathers and the RTT population with the Valsalva’s manoeuvre type of breathing will require more than the normal amount of daily energy intake. It is also apparent that there is extra need for DNA and cell repair due to increased catabolism. This is usually carried out through the complex pathways of intracellular and extracellular membrane transport systems that are affected by the Reduction-oxidation (REDOX) status of the cell. The deranged carbon dioxide metabolism in RTT affects the REDOX status of the cell and therefore influences these cellular processes.

Nutritional management in RTT must include evaluation and calculation of daily intake of food and energy requirements by a dietician. Measurements of Body Mass Index (BMI) and skin folds are useful for monitoring the progress of treatment. Clinical monitoring of blood total protein, albumin, protein electrophoresis, urea, creatinin and electrolytes like Na+, K+, Cl¯, Ca2+ and PO4 are useful in the assessment of nutritional status in RTT. Nutritional treatment must include high and condensed calorie diets. Poor responders may eventually require Percutaneous Endoscopic Gastrotomy, later replaced by small Mickey button, for supplementary feeding. Food supplements and extra micronutrients like glycoproteins, glycolipids and essential fatty acids are required. Glyconutrients are necessary for cellular and nucleic acid repairs (15).

Conclusion

Comprehensive management has a significant impact on the health and longevity of RTT persons. Good management requires the involvement of many different specialists engaged in an individualised approach. The Frösö Declaration promotes the need to understand the nutritional and cardiorespiratory requirements of these patients in order for them to receive appropriate and effective treatment. Parents are asking for such treatment throughout their interactions with health care providers from primary through secondary to tertiary centres. We believe that some aspects of treatment in RTT are now beyond the anecdotic stage.

Acknowledgements

We thank Mr Torkel Segebladh, Medela Medical AB, Täby, Sweden for help and advice during trials with CPAP/BiPAP. We greatly acknowledge “Amelies Minne” (in Memory of Amelie) for important support.

No author has any conflict of interest to declare.

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