Pediatric Disorders

Neurological Disorder Part 3 - Pediatric Disorders

CDKL5 Disorder

• Characteristics: • Rare x-linked genetic disorder • CDLK5 mutations cause deficiencies in the protein needed for normal brain development

• More common in females; however males with the disorder are affected much more severely than females

• Characteristics • CDKL5D mutations can be found in children who have been diagnosed with infantile spasms, Lennox Gastaut syndrome, Rett Syndrome, West Syndrome and autism

CDKL5 Disorder

• Symptoms: • Infantile spasms beginning the first 3 - 6 months of life • Neurodevelopmental impairment • Patients cannot walk, talk, or feed themselves • Repetitive hand movements (stereotypies)

• Seizures: • Early onset • Infantile spasms, myoclonic, tonic, tonic-clonic seizures • Status epilepticus and non convulsive status epilepticus can occur

CDKL5 Disorder

• Diagnosis: • Genetic blood testing to confirm the change or mutation on the CDKL5 gene

• EEG

• EEG Findings:

• Early in the disorder

• EEG may be normal or slightly abnormal

• During progression of the disorder

• Some background activity is slow and epileptic discharges can be seen in one or more areas

• Burst Suppression

• Atypical hypsarrhythmia

CDKL5 Disorder

• Treatment:

• Seizures are very difficult to treat

• Some patients are treated with monotherapy or adjective therapy

• Steroid treatments

• Ketogenic diets

• Vagus nerve stimulation

• Surgery

Ohtahara Syndrome Early Infantile Epileptic Encephalopathy

• Characteristics: • Rare epilepsy syndrome seen in neonates and infants • First seizure can be felt in the mother’s womb in the last trimester or seen within the first 10 days of life

• Equally affects males and females

• Characteristics: • No known cause • It is common for patients suffering from OS to have part or all of the cerebral hemispheres not fully developed and changes in their brainstem

Ohtahara Syndrome (OS) Early Infantile Epileptic Encephalopathy

• Symptoms: • First seizure can be felt in the mother’s womb in the last trimester or seen within the first 10 days of life

• Motor and cognitive problems deteriorate with age

• Seizures:

• Tonic seizures are the most common and occur singly or in clusters

• Partial or focal seizures

• Atonic

• Myoclonic

• Generalized tonic-clonic seizures

• Infantile spasms

Ohtahara Syndrome (OS) Early Infantile Epileptic Encephalopathy

• Diagnosis: • Physical exam • EEG • MRI of the brain to look for structural changes • Blood work

• EEG Findings: • Burst suppression when awake or asleep

Ohtahara Syndrome (OS) Early Infantile Epileptic Encephalopathy

• Treatment: • Valproate • Anti-seizure medication • Felbatol (felbamate) • Onfi (clobazam) • ACTH or prednisone • Klonopin (clonazepam) • Surgery • Sabril (vigabatrin) • Focal resection • Topamax (topiramate) • Hemispherectomy • Zonegran (zonisamide) • Ketogenic diet • Phenobaribital • Vagus nerve stimulator

• Characteristics: • Children with SCN8A gene mutation can present with • Early Infantile Epileptic Encephalopathy - 13 (EIEE13) (AKA Ohtahara syndrome)

• Benign Familial Infantile Seizures - 5 (BFIS5) • Paroxysmal Dsykinesia

SCN8A-Related Epilepsy

• Symptoms:

• Seizures multiple times a day

• Muscle spasms

• Abnormal movements

• Low or high muscle tone

• Ataxia

• Developmental and cognitive disabilities

• Seizures: • Generalized tonic-clonic • Tonic • Myoclonic • Atypical absence • Infantile spasms

SCN8A-Related Epilepsy

• Diagnosis: • Physical exam • EEG • Genetic testing • EKG • MRI

• EEG Findings: • May be normal at the onset of epilepsy but often comprises moderate to severe background slowing with focal or multifocal epileptiform discharges after onset

SCN8A-Related Epilepsy

• Treatments:

• Anti-seizure medication • Lamictal (lamotrigine)

• Depakote (valproate) • Banzel (rufinamide) Ketogenic diet • Tegretol (carbamazepin) • Steroids • Tripeptal (oxcarbazepine) • • Immunoglobulins • Dilantin (phenytoin) • Cannabinoids • Vimpat (lacosamide) • Vagus nerve stimulation © Trusted Neurodiagnostics Academy

Sturge-Weber Syndrome

• Characteristics: • Rare neurological condition that is present at birth • Is not hereditary • Mutation of the GNAQ gene • Port-wine birthmark on the child’s face

• Symptoms: • Abnormal brain functioning • Seizures • Hemiparesis • Varying degree of developmental delay • Glaucoma

Sturge-Weber Syndrome

• Seizures: • Focal seizures • Focal to bilateral tonic-clonic seizures • Epileptic spasms • Status epilepticus

• Diagnosis: • Physical exam • CT • MRI • EEG • Complete ophthalmologic exam

Sturge-Weber Syndrome

• EEG Findings: • Background may be normal or may show focal slowing over the region of the leptomeningeal angioma

• In generalized seizure types the background may show widespread slowing or hypsarrhythmia

• Focal rhythmic epileptiform discharges

Sturge-Weber Syndrome

• Treatment: • Anti-seizure medications • Vagus nerve stimulation • Surgery • Hemispherectomy • Focal resection

• First seizure can be felt in the mother’s womb • Severe early encephalopathy • Microcephaly may develop overtime • Reduced life expectancy

Early Myoclonic Encephalopathy

• Symptoms:

• Many seizure types may occur

• Myoclonic seizures

• Very frequent

• Brief

• Single

• Repetitive

• Erratic

• Nearly continuous body jerks

• Seizures: • Myoclonic • Focal motor • Tonic • Tonic spasms - rarely

Early Myoclonic Encephalopathy

• Diagnosis: • EEG • MRI • Blood work

• EEG Findings: • Background EEG is abnormal in all states with burst suppression pattern

• EEG may evolve to hypsarrhythmia pattern in children who evolve to have West Syndrome

Early Myoclonic Encephalopathy

• Treatment:

• Anti-seizure medications:

• Onfi (clobazam) • Vagus nerve stimulator • Klonopin (clonazepam) • Ketogenic diet • Topamax (topiramate) • Surgery • Zonegran (zonisamide) Focal resection • Phenobarbital •

• Valpoate • Hemispherectomy

• Felbatol (felbamate)

Rett Syndrome

• Characteristics:

• Progressive neurodevelopment disorder

• Almost exclusively affects females

• Infants with Rett syndrome develop normally for 7-18 months until they begin to have developmental regression

• Mutations of MECP2 gene suspected to be the cause

• More than 200 different mutations in the MECP2 gene

• Symptoms: • The symptoms, progression, and severity can greatly vary from one child to another

• Classic Rett Syndrome • Variant Rett syndrome • Additional MECP2 - Related Disorders

Rett Syndrome

Loss of eye contact, irritability Classic Rett Syndrome: • • and restlessness Infants are often placid and • Between 1-4 years of age have poor sucking ability • patients begin to lose previously acquired skills as Hypotonia is common • well as a decline in intellectual before 6 months of age function • Microcephaly can occur • Patients will lose the ability to make purposeful hand and • Between 6-18 months of age patients are finger movements but will developmentally stagnant develop stereotypic hand movements(wringing/clapping)

• Classic Rett Syndrome:

• Autistic-like features • Seizures are common • Panic attacks • Gait ataxia • Bruxism • Breathing difficulties leading to aerophagia • Tremors • Apraxia

Rett Syndrome

• Classic Rett Syndrome: • Some patients with Rett Following rapid Syndrome may lose their • ability to walk deterioration, neurological features Growth failure and muscle stabilize • wasting that worsens with age • Some patients show an overall • Bowel dysmotility improvement with behavior and social • Functional megacolon interactions

• Classic Rett Syndrome: • Vasomotor abnormalities

• Esotropia • Scoliosis • Osteopenia • Gallbladder • Sudden death which dysfunction and may be due to heart gallstones irregularities

Rett Syndrome

• MECP2-Related Disorders:

• Rarely, males can develop symptoms associated with a mutation of the MECP2 gene • Involuntary movements • Neonatal encephalopathy • Severe seizures

• Microcephaly • Breathing irregularities

• Abnormal muscle tone • Can be fatal by 2 yrs old

• MECP2-Related Disorders: • Males also develop PPM- • MECP2 mutations that X Syndrome: develop X-linked intellectual disabilities • Manic depressive (P)sychosis • Females have a mild, non-progressive • (P)yramidial signs intellectual disability • (P)arkinsonism • Males develop mild to severe intellectual (M)acro-orchidism disability •

Rett Syndrome

• Seizures:

• Generalized tonic-clonic

• Absence

• Myoclonic

• Tonic

• Focal seizures

• Infantile spasms

• Diagnosis: • Physical examination • Blood testing • MRI • EEG

Rett Syndrome

• EEG Findings: • Background slowing • Centrally located short-duration spikes and increased epileptiform activity during sleep

Rett Syndrome

• Treatment: • Anti-epileptic medication: • Valproate • Lamotrigine • Carbamazepine

• Gelastic - laughing seizures

• Dacrystic - Crying seizures

• Onset age is infancy with an average onset age of 10 months

• The first types of seizures seen in patients with hypothalamic hamartoma (HH)

• Rare, benign brain tumor or lesion of the hypothalamus

Gelastic & Dacrystic Seizures • Symptoms: • Gelastic seizures - uncontrollable laughing or giggling • Dacrystic seizures - uncontrollable crying • The emotions are forced and the patient has no control • Seizure onset is typically when falling asleep • The patient is aware during the seizure

• Parents report that seizures can be trigged by a loud noise • Seizures can occur multiple times a day

Gelastic & Dacrystic Seizures

• Seizures: • Focal seizures • Absence seizures • Atonic seizures • Tonic seizures • Tonic-clonic seizures

• Diagnosis: • Physical exam • EEG • MRI • CT

Gelastic & Dacrystic Seizures

• EEG Findings: • Ictal and interictal EEGs are non-specific • Both focal spikes and generalized spike-and-wave discharges can be seen

Gelastic & Dacrystic Seizures

• Treatment: • Trileptal (oxcarbazepine)

• Anti-seizure medication: • Topamax (topiramate) • Vagus nerve stimulation • Tegretol (carbamazepine) • Surgery: • Frisium (clobazam • Transcallosal anterior • Lamictal (lamotrigine) interforniceal surgery • Gamma knife radio surgery • Vimpat (lacosamide) • MR-guided stereotactic laser • Keppra (levetiracetam) thermoablation

• Characteristics

• Any disorder that can lead to brain damage can be an underlying cause of West Syndrome

• If spasms start shortly after birth = infantile spasms

• If spasms start in an older child = epileptic spasms

• Though, these terms are sometimes used interchangeably

Infantile Spasms/Epileptic Spasms (West Syndrome)

• Characteristics • Most babies are affected by age 1 year and usually stop between 2 - 4 years old

• Males and females affected equally

• Tuberous sclerosis complex (TSC) is the most common disorder for West Syndrome

• Autosomal dominant genetic condition associated with seizures, eye, heart and kidney tumors, and skin findings

Infantile Spasms/Epileptic Spasms (West Syndrome)

• Symptoms:

• Spasms may range from a violent jackknife-like seizure or can be more subtle and confined to another body part

• Each seizure last for a second or two and occur close together in a series

• Infantile spasms usually occur just after waking up

• Babies seem to stop developing and may lose skills like sitting or rolling over

• Diagnosis: • Physical and neurological exam • EEG • MRI of the brain • Blood and urine tests

Infantile Spasms/Epileptic Spasms (West Syndrome)

• EEG Findings: • Hypsarrhythmia when seizures are not occurring

• Treatment:

• ACTH injections • Klonopin (clonazepam)

• Anti-seizure medication • Onfi (clobazan)

• Depakote (valproate) • Seizure medication

• Topamax (topiramate) • Sabril (effective for children with TSC) • Pyridoxine (vitamin B6) • Ketogenic diet • Zonegran (zonisamide)

Dravet Syndrome

• Characteristics: • Rare, drug resistant form of epilepsy that begins the first year of life in an otherwise healthy infant

• Most cases are due to a severe SCN1A gene mutation • Typical onset between 1-18 months (<12 months on average)

• Symptoms: • The first seizure often presents with a prolonged focal febrile seizure

• Most children develop varying degrees of developmental disability

• Low muscle tone • Unsteady walking

Dravet Syndrome

• Seizures:

• Tonic-clonic seizures

• Clonic seizures • Tonic seizures

• Myoclonic seizures • Non-convulsive status epilepticus • Atypical absence seizures • Status Epilepticus • Atonic seizures

• Focal aware or impaired awareness seizures

• Diagnosis: • Physical and neurological exam • Genetic testing • MRI • EEG

Dravet Syndrome

• EEG Findings:

• The background EEG is usually normal in the first year of life. Postictal slowing can be seen

• Between ages 2 - 5 yrs, generalized spike-and-wave and multifocal discharges

• Photic stimulation can precipitate generalized spike-and- wave

• EEG abnormalities can be enhanced by sleep deprivation and by sleep

Dravet Syndrome • Treatment: • Anti-seizure medication: • Onfi (clobazam) • Depakote (valproic acid) • In 2018 Epidiolex was approved to treat the seizures associated with Dravet Syndrome patients >2 yrs old • Ketogenic diet • Vagus nerve stimulator • DO NOT TREAT WITH: Sodium channel blockers

• Characteristics: • Congenital abnormality of brain development • A common cause of intractable focal epilepsy in children

• Frequent cause of epilepsy in adults • Present at birth

Focal Cortical Dysplasia

• Symptoms: • Seizures • Focal seizures • Secondarily generalized tonic-clonic seizures

• Diagnosis: • Physical exam • EEG

Focal Cortical Dysplasia

• EEG Findings: • Background EEG may be normal or show focal slowing • EEG abnormality is enhanced by sleep deprivation and sleep

• Focal, rhythmic epileptiform discharges are the most characteristic feature

Focal Cortical Dysplasia

• Treatment: • Anti-seizure medications • Surgery: • Hemispherectomy • Small lesionectomy • Multiple subpial transections

• Bradley’s Neurology in Clinical Practice – 2 Volume Set • Merritt’s Neurology