Berlin Congress Report

Country update Berlin 2017 – by Stella Peckary

A poster walk of 27 posters with a country update of 25 Rett-Association took place on Friday, during lunch time. A representative of each country was invited to speak briefly about recent activities, National Centres for Rare Diseases and Rett specialist services in his their country. The wishes and aims for the future of each Association were a very important point. This was an opportunity to find out what is happening in the Rett-Associations throughout Europe. Are there common wishes, special difficulties and how a network can bring the Associations closer together?



World Café – by Stella Peckary

A very unique session was the so called “World Café”. It was organised by Dörte Maack, a blind facilitator, and Hans-Jürgen Christen, Mmaster of Mmedical Eeducation, Hannover. Approximately 150 participants split into six groups with about 25 people in each. Then each group was divided into four subgroups with 5 to 6 persons each to discuss one subject at one table. On each table was a moderator, who led the group through the discussion on a certain subject. These subjects were Epilepsy, Transition, Breathing disturbances and Sleeping problems, and Communication. The Cross-national discussion got sometimes quite emotional. Parents, siblings, carers of RS patients were also joining the group as well as tTherapists, researchers and clinicians. Sometimes it was overwhelming, sometimes all participants agreed with the experience one person told on the subject, sometimes questions arose because of medical issues. The meaning advice of experts, who sneaked moved between the groups, helped sometimes with their medical knowledge. After 12 minutes the participants switched to the next table and therefor to the next subject. As the moderator took shorthand notes of each group he hosted, after 70 minutes he summarized the notes and passed them to the experts of hisfor each subject. Experts of on Epilepsy were Thomas Bast and Bernd Wilken, experts for Transition were Helen Leonard and Leslie Malton, experts for Breathing disturbances and Sleeping problems were Jeremy Turk and Jan-Marino Ramirez, and experts for Communication were Gillian Townend, Helena Wandin and Theresa Bartolotta.

In the following subsequent plenary session the experts of for each section pointed out the multiple very personal aspects of coping with everyday life a family with a Rett-patient has to face. It seemed that even the clinicians were emotionally impressed by the difficult problems families have and how they are going to manage them for the happiness of their child.


Epilepsy – by Leen Vangroenweghe

Professor Doctor Thomas Bast (Germany) started the interesting session about epilepsy: in 60 to 80% of the Rett girls with classical Rett syndrome, epilepsy can be expected. However, it is not part of the diagnostic criteria for Rett syndrome, because it hardly ever starts before the age of two. The highest seizure activity typically occurs between the age of seven and twelve. Both focal or generalized seizures occur, but the typical absences and clonic seizures are not usually seen in Rett girls. For the girls who do have epilepsy, the seizures are often less severe (or even gone) once puberty has passed, they can become seizure free even after stopping their anti-epileptic drug.
However, even with the technology of EEG, it remains difficult to say if a seizure is epileptic or not. Many girls have a disturbed EEG, but that does not mean that the seizures are of an epileptic nature. Many seizures are misdiagnosed as epileptic while they are typical Rett behaviours like breathing or sleep abnormalities.
68% of the parents say that the epilepsy has a negative impact on quality of life, diminished level of alertness, problems in communications and walking are most mentioned, but also the fear of seizures and the problems finding help at home.
Professor Doctor Aglaiea Vignoli (Italy) continued the session to talk about the different anti-epileptic drugs. The most frequently prescribed drugs are carbamazepine, valproic acid and lamotrigine. Which drug works is age dependant. Studies show that valproic is more efficient in younger girls, carbamazepine and lamotrigine in older girls. The spectrum and rate of side effects of the drugs in Rett girls is comparable to what is seen in other patients with epilepsy. Side effects can be irritability, sedation or weight loss.
Sadly 30% of the girls do not respond to anti-epileptic drugs:, non-pharmacological treatments can be tried, like ketogenic diet (a high-fat, low-carbohydrate, adequate protein diet), but constipation is a well known side effect of this treatment. Vagal nerve stimulation is also an option, but here pain and coughing are the most common side effects. Experiments with cannabinoids are also done, but the lack of standardization and regulation, imprecise dosing and possible side effects pose risks on this treatment.

by Becky Jenner

Rise and Natural history Rett Syndrome: dr Dr Alan Percy by Rett UK

The first presentation was from Dr Alan Percy who has many years of experience as a Professor in Paediatrics, Neurology and Genetics at the University of Alabama, Birmingham, USA. Dr Percy has been very involved from the early days and worked closely with the International Rett Syndrome Foundation (now which formed in 1985 and the early projects that began in Americas in 1986.
The first conferences were held in Vienna in 1984, 1986 and 1988. The clinical criteria were developed in 1984 by Professors Hagberg, Goutieres, Hanefeld, Wilson and Rett. This was then revised in 2010 by Jeff Neul et al and is used today as the basis for diagnosing Rett syndrome. (
The Natural History Study (NHS) was started around 15 years ago by to collect longitudinal data about Rett syndrome and related disorders. It has around 1400 records of people with Classic Rett as well as 200 with a diagnosis of atypical Rett syndrome.
Of those with Classic Rett syndrome, 96% have a MECP2 mutation with 60% of these being one of the 8 point mutations which we are familiar with. These are mainly de novo (new mutations in the family) of paternal origin and the incidence of a second child in the family with Rett syndrome is much lower than 1%.
Some of the important findings from the Natural History Study are:
Epilepsy – occurrence very variable in published literature with incidence rates of anything from 20 to 80 %. However, in the NHS study the prevalence was 90% by age 20. We know thought though that with many different causes for seizure like episodes in Rett a correct diagnosis can normally only be made when validated by an EEG which can also help to distinguish the different types of seizures especially when done with video telemetry. Around 35-44% of people with Rett syndrome will be on medication at any given time. 6% have a vagal nerve stimulator or use a ketogenic diet.
Breathing – Hyperventilation/breath holding occurs in nearly 100% of people in the study over the lifespan. This is lower in the milder atypical cases at around 60-70%. Remission is common with around 15% of people have total remission later in life. Prevalence is also lower in those with a higher BMI (Body Mass Index) and more normal head circumference.
It would appear to be worse in those with poor motor function, frequent hand stereotypies and seizures, prolonged QT syndrome (more info xxxx) and care givers associate this with poorer physical heath and risk of other illness.
Scoliosis- has been seen in 8% of pre-school children with Rett syndrome, 53% by age 8 and 84% by age 16. Severity increases with age, particularly during puberty when growth spurts occur but slows down with maturity. Risk factors for severity and early onset are associated with inability to sit, walk or have any purposeful hand use. Bracing should be considered wen when the curve exceeds 25 degrees but there is very little evidence as to its effectiveness in Rett syndrome. Surgery is recommended when the curve exceeds 40 degrees (this seems to differ somewhat with the UK which is normally around 50 – 60 degrees). Around 18% of those in the study had surgical correction for scoliosis and all said it had improved the quality of life for the person with Rett syndrome.
Phenotype and Genotype Correlation
Some generalisations could be made but X chromosome inactivation and skewing account for marked differences in severity in the same genotype (mutation type). However, Mutations R133C, R294x, R306C were relatively less severe than R106W, R168X, R255X and R270X. Ambulation, hand use and age at onset of the disorder were all linked to severity. Environmental influences though could also be seen in the long-term prognosis in terms of severity.
Sexual Maturation
Premature puberty was seen in 25% of those in the study; prior to age 8 years.
The average age of survival was beyond 50 years but cardiorespiratory issues caused the greatest difficulties. Ambulation, good weight and effective seizure control were seen in those that survived the longest. The extreme frailty that was reported in the early 1990s is now rarely seen but the need for good diet and effective therapies is emphasised.
Quality of Life (QOL) – for the person with Rett syndrome, more behaviour problems were seen in the more able people. In terms of parental quality of life their physical quality of life declined over time (no surprises there!) but their mental QOL improved!
Changing Face of Diagnosis
The average age is 2.7 years with regression occurring in the first 12- 30 months for 90% of those affected. The critical clues which would help lead to an early diagnosis are declining head circumference in infancy, development abnormal prior to regression, inattentiveness or lack of response to parents and too passive or too good as a baby!
The Future!
‘The efforts of basic and clinical scientists is critical but insufficient alone! It requires the energies of the international community including funding agencies, pharmaceutical firms, patient advocacy groups and especially families. Above all this demands patience and courage, focus and understanding and the collective will to succeed.

By Caroline Lietaer

Sleepdisturbances In Rett Syndrome – profProf.drDr. Jeremy Turk

Individuals may be resistant to behavioural and other psychosocial interventions and it is frequent for clinicians to prescribe medication, given high levels of personal and family distress resulting from severe difficulties. This presentation examines these issues, focusing on important clinical concerns, and reviews evidence-based practical and rational treatments. Rett Syndrome is associated with a range of sleep difficulties as reduced sleep efficiency and quality, difficulties settling to sleep and short and fragmented sleep duration.
Initial treatments should always be psychological and social. Simple measures such as ensuring a darkened room, minimising noise, establish a predictable and consistent bedtime routine, and preventing daytime sleeping can be effective. Other behavioural approaches are based on incentives and rewards for desired sleep behaviours, ignoring of night time misbehaviour and noisiness and removing distressing aspects, as and a good temperature in the room.
However these measures are often not sufficient. Melantonine is therefore often considered. Melantonine is used at bedtime as a sleep inducer, and there is interest in the melantonin antagonist, acebutolol, given first thing in the morning. Other calming, mentally focusing and sedating agents such as the alpha 2 agonists clonidine and guanfacine may help.
Traditional sedatives such as barbiturates and benzodiazepines should be avoided because of frequent tolerance, addiction and respiratory suppression. Other medication such as tricyclic and SSRI antidepressants may have roles in the presence of mood disordersuch as carbamazepine, sodium valproate and lamotrigine

Dr Gillian S Townend , Rett Expertise Centre Netherlands – GKC, Maastricht presented an overview of research and practices in relation to communication and Rett syndrome, especially focusing on the past 20 years. This was also undertaken as part of a project funded by, together with a review of grey literature, which included clinical practice documents. The research literature is small but growing and signals in an increasing awareness of the influence of coexisting features such as apraxia on the communicative behaviours of individuals with Rett Syndrome. Eye gaze is acknowledged to offer the most reliable form of access for assessment of cognition and receptive and expressive language skills, and for developing functional and more complex communication.
In February 2016 an international consortium led by Rett Expertise Maastricht (with Dr Gillian Townend, Dr Theresa Bartolotta, USA, Helena Wandin, Swedish Rett Centre, Anna Urbanowicz, Australia, Leopold MG Curfs) began a two-year project to develop clinical guidelines for assessment, intervention and long-term management of communication in individuals with Rettsyndrome.
The guidelines needs to be flexible and responsive to variations between countries in culture and language, and economic and political situations which influence and shape societal attitudes towards individuals with rare diseases and which determine differing national healthcare and education policies.
Prof. Dr. Boenisch, Univerty of Cologne presented a very interesting study about core vocabulary. These studies showed that only 200 core words cover 80% of our daily speech – independent of the cognitive development. 100 core cords words cover 70% of the spoken words. These results can be used to rethink the vocubulary organization on our communication devices. We need to make fast access to these top 100 words, take notice of motorplanning and create a consistent linguistic system. My Core and Score communication systems have been based on this principle.
Dr Theresa E. Bartolotta, USA explaines about the importance of the environment and the engagement of the communication partner. In AAC the role of the communication partner is crucial for successful interaction.Partners can take on a number of roles in the communicative interactions , including supporting the operation of the device and providing faciliting cues that support the AAC user.

Communication – By Stella

A main part of the lectures, posters, exhibitions and workshops during the 5th European Rett-Syndrome Congress was about Communication skills of the Rett Syndrome patients. Because of Dyspraxia there is no ability of for their own writing and speaking skills. Rett girls need assisted augmentative Communication. Several lectures on this theme were held during this congress:
Rosa Angela Fabio, University of Messina, Italy, talked about her scientific studies of the cognitive ability and the capacity of recognition and imaging of words, by using an Eye Gaze Technology. She focused on the success of previous studies with TOBII which has shown a positive effect on cognitive strengthening behavioural and cerebral parameters in young girls. In the current study 29 Rett girls were trained and tested on an Eye Tracking Device. Another study on Eye Gaze used by Rett -girls was done by Lotta Lintula, Tampere Hospital, Finland. In this study three teenage Rett-G girls took part in a three year process to learn and use Eye Gaze technology as a Communication Device. Depending on the different distinct of dyspraxia way dyspraxia is manifested, as well as the alertness and motivation, the use of eye gaze technology will become more and more important for communication with Rett-patients. Helena Wandin, RettCenter, Sweden, and Gerna Scholte, Rett Expertise Centre, Netherlands, showed in their lectures video clips of Rett -girls, while working with them on an Eye Gaze computer. Wandin’s study was about the evaluation and development of visual attention in a study of nine Rett-Syndrome patients. In the special case, when the device did not work properly, it showed, that the girls proved their personal initiative to let the teacher/moderator know, that something was wrong. Scholte’s conclusion of her study of real time video registration about using Eye Gaze device for communication was, that more research is needed and parents/carers should be more inspired and taught by this technology.
Judy Wine, Rett Syndrome Center, Karkur, Israel, has been working with Rett-SyndromeRett syndrome patients for years. She underlined the necessity of communication, simple technology, in everyday life with the girls. AAC includes all forms of communication which can be used to express thoughts (facial expression, mimicry), needs (gestures, signs, direction of vision), questions (YES/NO – Cards) or any other replacement of speech. Eye Gaze might be the future of Communication for Rett-patients, but any other device will do as well, before becoming available of an Eye Gaze Computer becomes available. And even more important is the role of playing with aided communication tools.
These various communication devices in the case for just having fun with a practical orientation were shown in the workshops of Romana Malzer, Lifetool Linz, Austria, and Christiane Dieckman, Fürth, Germany, both mothers of Rett-girls. Under the headline CHAT (Communication – Hope – Again – Technology) Malzer and Dieckman talked in their PowerPoint supported workshops about the difficult “communication-road” of their daughters from the very beginning to an Eye Gaze technology. Both girls started with simple YES/NO cards, Big Mac, Step by Step, Battery Switch Adaptors’, and other devices. With so called Social scripts (Linda Burkhart) using symbols, multi modal communication is made possible for the patients. Like a time-table for daily routine, a script for hand-washing or setting the table, a description of the way to kindergarden/school/day care centercentre, how to feed the dog, etc. Herewith symbols are learned more easily and make fun. For learning action/reaction toys adapted with a battery interrupter and a switcher (Puppy Dog, Cha Cha Bear,) is great fun for little kids. A pPower link allows the user to control the switches. In short video clips the girls with their siblings were shown having immense fun! The conclusion of the workshops – “don’t therapy communication – just do it. It is never too early and never too late to start with it”.

by Danijela Szili

Prof. Dr. Jeffrey Lorenz Neul, Vanderbilt University Medical Centre, Nashville, USA
The title of his session was Characterization of autonomic dysfunction in Rett Syndrome.
The autonomic and physiological abnormalities in Rett individuals affect many organ systems and are clearly present in breathing abnormalities ( hyperventilation and apneasapnoeas/breath hold), cardiac rhythm changes (QTc prolongation and decreased beat to beat variability), gastrointestinal dysfunction (reflux, gastric emptying and constipation), vasomotor disturbances ( skin colour change and abnormal sweating) and urinary retention.
A number of mouse models have been developed and they reproduce many of the clinical features seen in people with Rett syndrome. The Neul lab has characterized a number of autonomic and physiological abnormalities in mouse models of Rett syndrome. This information can be helpful for our understanding of the pathology of these problems in Rett individuals and instructs the approach to therapy in Rett syndrome.
Conclusions from the Natural History Study are that more than 8 out of 37 deaths (21%) were sudden and unexpected. There are three possible causes: breathing abnormalities, seizures and cardiac abnormalities with the latest one being the most probable one. This is why understanding the pathology of cardiac dysfunction in Rett syndrome is very important and can save lives.
QTc prolongation can cause fatal arrhythmias.
In the Mecp2Null/Y mice QRS prolongation has been confirmed and this made them susceptible to arrhythmias. Sudden bursts of very low activity with blocks were also noticed. Ventricular tachycardia was blocked by atropine (Ach antagonist). This suggested that anticholinergic drugs might be helpful in the treatment of these cardiac abnormalities in Rett syndrome individuals.
Previously in the study from 2011 it was concluded that blocking Na+ channels by using phenytoin (antiepileptic and antiarrhythmic drug) rather than beta blockers would prevent lethal cardiac arrhythmias.
One of the conclusions of this study is that drugs that increase K+ activity should be tried instead.
In the clinical practice beta blockers like propranolol are still used to treat prolonged QTc.

Removing Mecp2 from the heart did not cause QTc prolongation but removing it from the nervous system did. Genetic deletion of MeCP2 function in only the nervous system was sufficient to cause long QTc and ventricular tachycardia in mice, implicating neuronally mediated changes to cardiac electrical conduction as a potential cause of ventricular tachycardia in Rett syndrome.
Sudden cardiac death in mice was caused by AV block.

Kidney and bladder function was monitored on a Rett male mouse model. Lots of abnormalities were observed: They did not expel urine well when sick, distended kidney caused by urine not flowing out, kidney failure.
Take home message would be to keep track of the urine output especially if the Rett individual is on the medication for excessive drooling (sialorrhea) like Robinul (glycopyrronium Br) since it can make urinary retention worse. Urinary retention can be a serious health risk.

Walter E. Kaufmann, Greenwood Genetic Center&Boston Children’s Hospital, Boston

The title of his session was Treatment Options in Rett syndrome: Opportunities and false hopes
Similar to other neurodevelopmental disorders, Rett syndrome (RTT) has begun a new era of treatment research based mainly on targeting neurobiological mechanisms underlying Mecp2 deficiency. A large body of work attempts to identify new therapeutic targets at the level of the gene (e.g., silent MeCP2 activation, gene therapy); however, most of the research focuses on abnormalities downstream of MeCP2 and those include modulators of the synaptic function, medications affective metabolic pathways, as well as drugs that influence specific neurotransmitter systems (most of which are abnormal in RTT). Several of these drugs have moved from the preclinical (on the animal model) to clinical trials like for example trofinetide, a modified form of IGF-1’s active peptide. Trofinetide demonstrated effectiveness in two phase 2 randomized clinical trials. In the 2018 the first ever phase 3 (pivotal for regulatory approval) will start, first in the RTT field.
A gene therapy trial using a non-replicating adeno-associated virus (AAV9) capsid system could also begin in 2018. The company AveXis has to complete preclinical (i.e. non-human) studies first that will form the basis of the scientific rationale to advance the treatment into patients. These studies may take 12-24 months to complete. The company must then submit this data to the FDA and request an Investigational New Drug application (IND). Once the FDA accepts the IND, the company can begin clinical studies.
The completed trials ( IGF-1, trofinetide, glatiramer acetate(Copaxone), dextromethorphan) in addition to several phase 2 clinical trials testing a variety of drugs that will announce results in the next few months, bring hope and opportunities for affected girls and women.
Two new clinical trials were also announced that should start in the next year.
Novel type of drug: Sigma 1(ER)/ muscarinic agonist (
NMDA receptor antagonist low-trapping (BHV-5000)

These trials are encouraging but not overwhelming. Some of the challenges previously experienced in trials for other neurodevelopmental disorders such as fragile X syndrome have also emerged in RTT intervention studies. The most important is the limited number of appropriately validated outcome measures and biomarkers. These are critical measures for adequate selection of cohorts and more importantly for detecting positive response to treatment in early stages of drug development (preclinical phase, animal models).
Another major concern in RTT is the evolution of the disorder, which suggests that targeting the developmental regression period (currently avoided for appropriate data interpretation), will probably modify more effectively the progression of symptoms. Until intervention studies target the earliest stages of RTT new treatments should realistically aim at modifying the course of RTT rather than curing it. Nonetheless, the potential availability of therapies in the near future that can substantially improve multiple symptoms represents an important achievement. Adequate planning of future intervention studies (clinical trials) will determine the magnitude of these improvements.
Building a research agenda and prioritizing trials (e.g., phase 3, gene therapy) could be also one of the ways that could bring us forward more rapidly in his opinion.
This is the reason why Dr Kaufman suggested the need of international collaboration and establishing a Clinical Trials Committee. establishment.

Dr. Kamal Gadalla, University of Glasgow, Great Britain
The title of his talk was: Gene therapy for Rett syndrome-An update

It is now ten years since it was first shown that restoration of MeCP2 in mice modelling RTT resulted in a profound reversal of established RTT-like phenotypes. Since then several groups have used a recombinant adeno-associated virus (AAV) to deliver a functional copy of MECP2 either systemically or locally into the brain of mice modelling RTT. These studies have shown therapeutic efficacy in terms of enhancing survival and ameliorating or reversing RTT-like symptoms. Despite encouraging findings, the efficacy of vector-derived MeCP2 has been limited by the relatively low levels of brain transduction achieved as well as toxicity associated with delivering too much MeCP2 to certain cells and tissues. Recent studies from Dr Kamal’s group have shown the importance of the vector design and route of administration in increasing efficacy and safety of the vector-derived MeCP2.
It is also showed that there are significant challenges to a gene transfer approach in RTT and his opinion is that gene therapy clinical trials should not start yet, it would be too risky. He hopes that the rapid evolution of a strong brain penetrant viral capsid together with the identification of possible mechanisms to control or limit the expression level of vector-derived MeCP2 will help develop safer and more efficacious MeCP2 delivery vectors.

Jim Selfridge, The University of Edinburgh, Edinburgh, Scotland
The title of his session was: Radically shortened MeCP2 reverses RTT-like neurological defects
Results of the study is that mice expressing truncated MeCP2 lacking both the N- and C-terminal regions are phenotypically normal; and those expressing a minimal MeCP2 survive for over one year with only mild symptoms. In the first study the ’’truncated gene’’ was reactivated in transgenic mice. In the second study the truncated gene was delivered to the mice brain by scAAV. This minimal protein that started to form after both interventions is able to prevent or reverse neurological symptoms. Despite evolutionary conservation of the entire MeCP2 protein sequence, the DNA and co-repressor binding domains alone are sufficient to prevent RTT and the shortened alleles may be of therapeutic potential.

Dr Paul Ross, Glasgow, Great Britain
The title of his talk: MECP2 expression and RTT-like phenotypes

To determine whether aspects of the RTT phenotype that originate in non-neuronal tissues might have been overlooked, they generated mice in which MeCP2 remains at near normal levels in the nervous system, but is severely depleted elsewhere. Comparison of these mice with wild type and globally MeCP2 deficient mice showed that the majority of RTT-associated behavioral, sensorimotor, gait and autonomic (respiratory and cardiac) phenotypes are absent. Specific peripheral phenotypes were observed, most notably hypo-activity, exercise fatigue and bone abnormalities. These results confirm that the brain should be the primary target for potential RTT therapies, but also strongly suggest that some less extreme but clinically significant aspects of the disorder arise independently of defects in the nervous system.

PD Dr Franco Laccone, Vienna, Austria
Update protein replacement therapy

The key to the success of protein replacement therapy lies in the efficient expression and purification of functional MECP2 and its proper transduction into mammalian cells using the eleven amino acid-residue transduction domain derived from the HIV-tat (TAT). Following intraperitoneal injection, the fusion proteins crossed the blood-brain barrier and translocated to neuronal cell nuclei. Administration of two isoforms of fusion protein significantly extended the lifespan of MeCP2-/y mice and lead to significant improvements in motoric and learning abilities following treatment in conditional mouse model.
These findings indicate that biologically active recombinant TAT-MeCP2 proteins can reach the brain after peripheral injection and ameliorate the phenotype of Rett mouse models. One major issue has been that the production of the protein in a small laboratory setting is not consistent and does not guarantee the same properties per batch (i.e. transduction efficiency, lack of toxicity, aggregation properties).

Dr. Aglaia Vignoli, Epilepsy Center, Child and Adolescent Neurology and Psychiatry, ASST Santi Paolo, Milano, Italy
Antiepileptic Drugs in Rett Syndrome

Epilepsy is one of the major issues for clinicians who follow girls with RTT and for the families too. A recent study with a very large number of patients confirmed the prevalence of epilepsy in patients with RTT, which is around 70% and also the drug resistance in this population of patients around 30%.
The study abstract can be found here
Dealing with girls with RTT, we have always to keep in mind that the group off refractory patients may include patients with non-epileptic paroxysmal events.
The most frequently prescribed antiepileptic drugs (AEDs) are classical AEDs like carbamazepine (CBZ) and valproic acid (VPA) according to local prescription habits. VPA is the most commonly used first AED but cause threefold increased risk of fractures in RTT when used for more than a year (Leonard 2010) and that is why there is a need for regular monitoring of bone density and appropriate nutritional support. There is also a need for regular blood checks since it can possibly cause decrease of platelets in blood and coagulation probblemsproblems.
Newer AEDs such as topiramate, levetiracetam and lamotrigine (LTG) are commonly used in drug refractory patients in western countries. LTG may have additional benefit for the common behavioural abnormalities (improvement in general well-being and alertness) but as side effect can have weight loss and nausea.
AEDs can work differently according to age dependent factors. VPA is more effective in younger patients, while LTG and CBZ in the older ones.
In proven refractory epilepsies, other options can be considered in patients with RTT. Newer drugs can be employed like levetiracetam (Keppra), topiramate (Topamax) and zonisamide but age related restrictions should be considered. The most common side effects experienced by the patients in the Italian study were irritability and mood and sleep disturbances for levetiracetam, sedation for topiramate and weight loss for zonisamide. Topiramate and zonisamide can also cause renal stones formation.
Benzodiazepines (clobazam-Frizium, clonazepam-Rivotril… ) are potentially effective for seizures and eventually sleep disorders but possibly making makes respiratory function worse mainly in patients with severe scoliosis (increased risk of aspiratory pneumonia), increasing somnolence during the day that causes reduced alertness and participation to in daily activities.
Cannabidiol is also used as an alternative treatment but further studies are necessary for more information about efficacy and appropriate dosage.
The cannabis plant contains approximately 80 cannabinoids, of which cannabidiol and THC are the two most abundant. Cannabidiol is not psychoactive and may potentially have promising efficacy. THC can be proconvulsive in predisposed brains.
Other options can be non-pharmacological treatments, such as ketogenic diet, or vagal nerve stimulation (VNS).
Ketogenic diet is a high-fat, low-carbohydrate, adequate protein diet developed in the 1920s. The classic diet consists of a ratio in grams of fat to non-fat (protein and carbohydrates) of 4:1 and 3:1. The modified ketogenic diet consists of ratios of 2:1 and 1:1.
VNS implant modulates neurotransmitters levels. It causes increase in GABAergic tone and reduction of excitatory tone ( rNMDA EEG desynchronization)

Non epileptic paroxismal events in RTT

Epileptic seizures in RTT maybe over-reported, if patients are not studied with Video-EEG monitoring.
Results of the Italian study that involved 120 patients followed at S. Paolo Hospital in Milan are as follows: mean age was 9.6 years (range 4-23), all patients evaluated carried MECP2 mutations, 10/13 had a history of seizures and were receiving AEDs. All had abnormal EEGs. From the analyses of the episodes paroxysmal events were identified triggered by breathing disturbances in 2 girls, movement disorders (tremors) in 3, tonic/ dystonic posturing related to different sensitive stimuli in 4, sleep related events in 3.
This study confirmed very broad spectrum of paroxysmal events in RTT patients, the challenge of making a diagnosis in these cases, the usefulness of home videos made by families and the need of for definitive information provided by Video/EEG monitoring.

Berlin Congress Report
Scroll to top