(A shorter version was published in The Lancet: 2008; 371:1981-1983)

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)

Correspondence to:
Dr Peter O.O. Julu
The Wingate Institute of Neurogastroenterology
Queen Mary School of Medicine and Dentistry
26 Ashfield Street
Whitechapel
London E1 2AJ

Tel: 020 7882 2655

Fax: 020 7275 2103
e-mail: p.julu@imperial.ac.uk

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.

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