EPILEPSY AND RETT SYNDROME Liisa Metsähonkala, Pediatric Neurologist Epilepsia-Helsinki, Helsinki University Hospital HUS Helsinki University Hospital RETT Epilepsy -syndrome Epilepsy in Epilepsy in Rett Rett syndrome syndrome Epilepsy may be a major or minor problem for people with Rett syndrome and their families 2 28.9.19 HUS Helsinki University Hospital EPILEPSY AND RETT SYNDROME - Some general aspects of epilepsy - Epilepsy in Rett syndrome (focus on children) - Diversity of epileptic seizures - Diversity of nonepileptic paroxysmal attacks - How to make the diagnosis? - Treatment of epilepsy 3 28.9.19 HUS Helsinki University Hospital WHAT IS EPILEPSY ? International - epilepsy is not one disease but a large group of different League disorders Against Epilepsy - an epileptic seizure is a transient occurrence of signs and/ or symptoms due to abnormal and certain kind of neuronal activity (excessive or synchronous) in the brain - versus nonepileptic symptoms - epilepsy is a disease characterized by an enduring predisposition to generate epileptic seizures – versus seizures that anyone can have because of an acute provoking factor 4 28.9.19 HUS Helsinki University Hospital Seizure types Etiology Focal Generalized Unknown onset onset onset Structural Genetic Epilepsy types Infectious Combined FocalFocal Generalized Unknown Generalized Metabolic & Focal Immune Co-morbidities Unknown Epilepsy Syndromes HUS Helsinki University Hospital Generalized seizures Focal seizures • Originate at some point within • Originate within networks and rapidly engage bilaterally limited to one hemisphere distributed networks HUS Helsinki University Hospital Generalized seizure 15 s 7 28.9.19 HUS Helsinki University Hospital Focal seizure 8 28.9.19 HUS Helsinki University Hospital 9 28.9.19 HUS Helsinki University Hospital DIFFERENT TYPES OF SEIZURES - the symptoms during a seizure depend on where does the seizure start and how does the epileptic activity spread in the brain - subjective feeling - focal or bilateral, simple motor movements like stiffening or jerks - intensive abnormal movements or normal movements without purpose - impared awareness or preserved awareness 10 28.9.19 HUS Helsinki University Hospital A simplified presentation – A seizure is initiated when a certain threshold has been reached - a lot of possible both provoking and inhibiting factors, both transient and long-lasting seizure threshold 11 28.9.19 HUS Helsinki University Hospital A lot of newly found gene defects and genetic factors causing or increasing the risk for epilepsy 12 28.9.19 HUS Helsinki University Hospital EPILEPSY IN RETT SYNDROME - epilepsy is a frequent problem in Rett syndrome - occurs in 60-80% of patients (an overestimate?) - typical start at 2-5 years of age - most frequent seizures at 7-14 years of age - epilepsy may be less drug resistant after adolescence - 20-30% drug resistant (Vignoli et al 2017) - 43% no epilepsy or a small seizure burden - occurrence of epilepsy is associated with several other symptoms (scoliosis, need of gastrostomy etc) - early onset of epilepsy is a risk factor for future difficult-to –treat epilepsy 13 28.9.19 HUS Helsinki University Hospital Dolce et al 2013, Tarquinio et al 2017 Tarquinio et al 2017 14 28.9.19 HUS Helsinki University Hospital FACTORS CONTRIBUTING TO EPILEPTIC Operto et la 2018 Tarquine et al 2017 ACTIVITY IN RETT SYNDROME Mouro et al 2019 - which gene mutation (MECP2, CDKL5 ,FOXG1, …) - early onset of epilepsy is typical for children with CDKL5- and FOXG1-mutations - what kind of mutation - the type of MECP2 mutation may influence epilepsy onset and severity - a lot of overlap: modifying genes, X inactivation - the basic underlying molecular mechanisms contribute also to the predisposition to epileptic activity - neuronal transmission via GABA system, cholesterol metabolism, neurosteroids, abnormal mitochondrial function - à optimal treatments of epilepsy? 15 28.9.19 HUS Helsinki University Hospital Frullanti et al 2019 16 28.9.19 HUS Helsinki University Hospital Precision medicine in epilepsies - identification of the specific gene mutation à identification of the functional defect à targetted therapy - identification of genetic risk for a side-effect à individual treatment choices 17 28.9.19 HUS Helsinki University Hospital EPILEPTIC SEIZURES IN RETT - very variable seizure types and epilepsy syndromes - most typical seizure types : focal seizures, convulsive seizures, myoclonic seizures, epileptic spasms - atonic seizures, absences - nonconvulsive status epilepticus, myoclonic status epilepticus - epilepsy syndromes: infantile spasms, Lennox-type epilepsy, continuous spike and wave during sleep (CSWS) 18 28.9.19 HUS Helsinki University Hospital NONEPILEPTIC ATTACKS AND SYMPTOMS - hand stereotypies - breathing patterns: breathholding - hyperventilation - staring spells/vacant spells with impared awareness - abnormal motor features: tremor, stiffness, abnormal movements, sudden falls - abnormal eye movements, blinking 19 28.9.19 HUS Helsinki University Hospital SEIZURES AND NONEPILEPTIC EVENTS Epileptic seizures can be Nonepileptic events can be misdiagnosed as nonepileptic misdiagnosed as epileptic - myoclonic seizures - nonepileptic myoclonias - tonic seizures - staring spells/poor - absences concentration - motor symptoms, dystonia, tremor, falls Risks of misdiagnosis: - epileptic seizures may cause traumas Risks of misdiagnosis: - frequent epileptic seizures - unnecessary medication or and epileptic activity may polytherapy with side effects worsen the daily performance 20 28.9.19 HUS Helsinki University Hospital EPILEPTIC AND NONEPILEPTIC SYMPTOMS MAY CONTRIBUTE TO EACH OTHER - breathing pattern has influence on the EEG - breathing pattern may influence proneness to seizures - epilepsy medication à tiredness à nonepileptic staring spells à more medication à more tiredness à more staring spells 21 28.9.19 HUS Helsinki University Hospital DIAGNOSIS OF EPILEPSY - the description of the symptoms is important - homevideos are very helpful - EEG is often abnormal, epileptic features may appear eventhough the patient does not have epilepsy - video-EEG (long term EEG ja video simultaneously) – used for confirmation of the nature of the symptoms if needed - video-EEG should also be performed - if arrupt changes in the performance and contact - in all patients with intractable epilepsy 22 28.9.19 HUS Helsinki University Hospital EVOLUTION OF EEG IN TYPICAL RETT SYNDROME Overall features – lots of individual patterns Stage 1 = EEG is usually normal Stage 2= focal spikes appear mostly in the motor cortex Stage 3= a lot of epileptic activity on a large area of brain, abnormal background activity Stage 4= less epileptic activity but abnormal back ground activity 23 28.9.19 HUS Helsinki University Hospital Abnormal Epileptic background activity = basic activity 24 28.9.19 HUS Helsinki University Hospital 10 year old girl –MECP2 -mutation 27 28.9.19 HUS Helsinki University Hospital A lot of individual variety 2 year old girl – intensive epileptic activity (=modified hypsarrythmia) already before diagnosis MECP2- mutation 28 28.9.19 HUS Helsinki University Hospital Nonepileptic motor symptom holding breath exhales+ arms extend parents suspect a seizure 29 28.9.19 HUS Helsinki University Hospital holding breath breathing An 8-year-old girl: motor seizures first considered as nonepileptic symptoms 30 28.9.19 Clear association between continuous hyperventilationà seizures HUS Helsinki University Hospital Continous irregular breathing à tonic seizure 31 28.9.19 HUS Helsinki University Hospital 6 year old girl seizures, during 6 months increased tiredness less active 32 28.9.19 HUS Helsinki University Hospital EPILEPSY IN THE EVERYDAY LIFE OF CHILDREN WITH RETT - epilepsy causes - increased need of surveillance - need of hospitalization - risk for traumas, falls etc - risk for side effects from medications - epilepsy and frequent seizures is an important factor worsening the quality of life of children with Rett and their families (Corchon et al 2018) - frequent seizures or epileptic activityà cognitive decline (epileptic and developmental encephalopathy) 33 28.9.19 HUS Helsinki University Hospital FACTORS CONTRIBUTING TO THE TREATMENT - the choice of medication is mostly dependent on: - seizure type and type of epilepsy syndrome - age of the patient - risk for side effects - risk for osteoporosis - risk for gastrointestinal problems (constipation) - risk for behavioral problems 34 28.9.19 HUS Helsinki University Hospital EPILEPSY MEDICATION AND TREATMENT CHOICES - medication should be started only when epileptic seizures exist - all antiepileptic medications on the market has been used in Rett syndrome - seizure type has influence on the choice of the medication - valproate was reported to be the most effective in young children and carbamazepine in > 15 years old patients (Vignoli et al 2017) - in the age group 10-14 years of age, polytherapy was most frequent (Vignoli et al 2017) - ketogenic diets and vagal nerve stimulation are also possibilities in severe epilepsy 35 28.9.19 HUS Helsinki University Hospital TAKE HOME MESSAGES 1. A question for the research: What is the reason for such high diversity of epileptic phenomena (both seizures and EEG findings) in Rett syndrome? 2. Correct diagnosis of epileptic and nonepileptic symptoms is important 3. Changes in behaviour and performance à EEG/video- EEG 36 28.9.19 HUS Helsinki University Hospital .