Session 23: Approach To Common Paediatric Neurological And Neurodevelopmental Problems

Question 1

Seizure and Epilepsy (+ SpC Paed Sophelia Chan)

Answer 1

Seizure:
- A transient clinical event due to abnormal or excessive neuronal discharge in brain

Epilepsy definition:
- A disease of the brain, a symptom of many diseases rather than disease on its own
- Tendency (>=2) to have recurrent, unprovoked, epileptic seizure
- >=2 unprovoked seizures, occurring more than 24 hours apart
or
- 1 unprovoked seizure + probability of further seizures similar to the general recurrence risk (>=60%) after 2 unprovoked seizures, occurring over the next 10 years
or
- Diagnosis of an epilepsy syndrome

Seizure vs Convulsion:
- Convulsion: Substantial motor activity during a seizure: Tonic / Clonic / Myoclonic / Tonic-clonic

ILAE classification: 3 levels:
1. Seizure types (Focal / Generalised / Unknown)
—> 2. Epilepsy types (Focal / Generalised / Focal + Generalised / Unknown)
—> 3. Epilepsy syndrome
- Pay attention to Co-morbidities (e.g. learning disability, ADHD, neuropsychiatric problems), Etiology (Structural, Genetic, Infectious, Metabolic, Immune, Unknown)

Focal onset seizure:
- Aware (Simple) / Impaired awareness (Complex)
- Motor onset / Non-motor onset

Generalised onset seizure:
- Motor onset (e.g. Tonic-clonic, other motor) / Non-motor onset (e.g. Absence)

Epilepsy syndrome:
- Epilepsies can be organised into epilepsy syndromes by reliably identified common clinical + electrical characteristics
- Such syndromes have typical age of seizure onset, specific seizure types and EEG characteristics and often other features which when taken together allow the specific epilepsy syndrome diagnosis
- The identification of an epilepsy syndrome is useful as it provides information on which underlying etiologies should be considered, which anti-seizure medication(s) might be most useful and prognosis
- Several epilepsy syndromes demonstrate seizure aggravation with particular anti-seizure medications, which can be avoided through appropriate early diagnosis of the epilepsy syndrome

Generalised epilepsy syndrome examples:
1. Activity arising from both hemispheres
- Symmetrical: bilateral discharge on EEG
- LOC

2. Infantile spasms (Symptomatic / Genetic)
   - Spasm-like motor seizure, come in clusters (a number of spasms within a cluster, can have several clusters within same time)
   - Always occur in infant (i.e. <12 months, rarely >18 months)
   - West syndrome: Infantile spasm + Developmental delay + Hypsarrhythmia on EEG, associated with Tuberous sclerosis (self notes)
3. Juvenile myoclonic epilepsy (Genetic)
   - Repetitive jerking movement involving whole extremity / body part on wakening / early morning
   - Upper > Lower body
   - Peak onset 12-18 yo
   - EEG: 4-6Hz bilateral polyspike + slow wave discharges with frontal predominance
   - Carbamazepine may exacerbate
   - Treatment: Valproate lifelong (due to high risk of recurrence esp. deprived of sleep / after alcohol (SpC Paed)
   (From JC029:
   - Myoclonic seizures, GTCS, Absence seizures (less frequently) in adolescents
   - Normal intellectual function
   - EEG: Rapid, Generalised spike-wave + Polyspike-wave discharges)
4. Absence epilepsy
   - Abrupt onset: eye staring, frequently with automatism (blinking, chewing), abrupt stop, brief (in seconds), aggravated / triggered by hyperventilation, can occur many times per day
   - EEG: 3Hz spike and wave discharges

SpC Paed Senior tutorial:
Generalised epilepsy syndromes:
1. Infantile spasm
2. Juvenile myoclonic epilepsy
3. Lennox-Gastaut syndrome

Partial epilepsy syndromes:
1. Benign rolandic epilepsy

Question 2

History taking in Epilepsy (SpC Paed Senior Tutorial) + SpC Paed Sophelia Chan + Spotting The Sick Child Online Module

Answer 2

• Onset
• Duration

Pre-ictal:
- Aura
- Febrile symptoms
- Provocative factors (e.g. flashing lights)
- Prodromes (e.g. abnormal sounds, mood disturbance, confusion)
- Automatism
1. Fever?
2. Unwell recently?
3. Past medical history
4. Birth history
5. Developmental history
6. Did the child complain of anything prior to the fit?
7. Were they exercising? (cardiac syncope)

Ictal: (Head to toe)
- Types of seizure
- LOC / Response
- Cyanosis (breathing stop during tonic seizure)
- Pallor
- Eye uprolling
- Facial twitching
- Tongue biting
- Teeth clenching
- Limb stiffness / twitching
- Urine incontinence
- Witness
1. What were they doing when the fit started?
2. How did the fit start?
3. LOC
4. Incontinence
5. Movements in body parts
6. Eye rolling
7. Tongue biting
8. Tone
9. Colour
10. Duration
11. Self resolving / Alleviating factors

Post-ictal:
- Drowsiness
- Disorientation, Retrograde amnesia
- Paralysis (Todd’s paralysis)
- Drooling / Vomiting
- Injury
1. Drowsiness
2. Headache afterwards
3. Any injury

Common causes of fits:
1. Epilepsy
2. Febrile convulsion
3. Encephalitis / Meningitis
4. Head injury
5. Hypoglycaemia
6. Electrolyte disturbance (esp. Na, Ca)
7. Reflex anoxic seizure

Red flags:
1. Fits in babies
2. Aspiration
3. Hypoglycaemia
4. Status epilepticus
5. Pseudoseizures

Question 3

Investigations of Epilepsy (+ Senior tutorial)

Answer 3

1. Blood
   - CBC (exclude infection)
   - Glucose (exclude Hypoglycaemia)
   - Na, Ca, Mg (exclude HypoNa, HypoCa, HypoMg)
   - NH3, serum amino acid, urine metabolic screening, urine organic acid (if suspect metabolic causes)
   - Blood culture, Urinalysis, LP (if suspect infection)
   - HLA-B*1502 (if recurrent episodes for initiation of AED)
2. EEG (look for epileptiform discharge)
   - Standard EEG including photic stimulation + HV
   - +/- Sleep EEG
   - +/- 24 hours EEG
3. ECG (exclude arrhythmia causing anoxic seizure)
4. Neuroimaging
   - MRI (preferred)
   - CT (for gross pathology / when MRI N/A)
5. Genetics (Epilepsy panel, Whole exon sequencing (for epilepsy-related mutations))
6. Home videos
7. Developmental + Psychological assessment
   - in children with developmental delay + learning disabilities
   - in children with developmental regression / cognitive decline

Question 4

Antiepileptic drugs (AED)

Answer 4

1st Generation:
- Valproic acid (Epilim) (Good for generalised seizure) (Avoid in girl due to teratogenicity)
- Carbamazepine (Tegretol) (Good for focal seizure) —> HLA-B*1502 (15-30% of SJS)
- Clobazam (Frisium)
- Clonazepam (Klonopin)
- Ethosuximide (Zarontin)
- Phenobarbitone
- Phenytoin (Dilantin)
- Primidone (Mysoline)

2nd Generation:
- Felbamate (Felbatol)
- Gabapentin (Neurontin)
- Lamotrigine (Lamictal)
- Levetiracetam (Keppra)
- Oxcarbazepine (Trileptal)
- Pregabalin (Lyrica)
- Tiagabine (Gabitril)
- Topiramate (Topamax)
- Zonisamide (Zonegran)
- Ongoing expanding

Unconventional:
- Adrenocorticotropic hormone (ACTH)
- Acetazolamide (Diamox)
- Amantadine (Symmetrel)
- Bromides
- Clomiphene (Clomid)
- Ethotoin (Peganone)
- Mephenytoin (Mesantoin)
- Mephobarbital (Mebaral)
- Methsuximide (Celontin)
- Trimethadione (Tridione)

Question 5

Management of Epilepsy

Answer 5

Treatment:
1st line: Antiepileptic Drugs (AEDs)
2nd line (intractable epilepsy):
1. Ketogenic diet
2. Steroid
3. Epilepsy surgery
4. Vagus nerve stimulation (Implantable vagus nerve stimulator)
5. Experimental therapy

Psychosocial issues:
1. Parents and patients have many fear
- Reassurance + Explain
—> What is epilepsy
—> Epilepsy =/ intellectual disability
—> Epilepsy =/ psychiatric disorder
—> Death from seizure is rare
—> What to do when child has a seizure

2. Engaging in physical activities and sports for patients with Epilepsy
   - Activities of patients with seizures should be restricted as little as possible in a safe environment
   - Depend on seizure control
   —> Avoid high risk activities: Climbing, Diving, Aviation
   —> Caution about contact sports with potential injury (e.g. boxing, Karate)
   —> Biking with helmet
   —> Have company when go swimming

Question 6

Status epilepticus

Answer 6

Stage 1 (Early phase, 5-10 mins)
- Premonitory SE / Impending SE
- Without IV access: Rectal Diazepam / IM/Intranasal/Buccal Midazolam
- With IV access: IV Diazepam / Lorazepam

Stage 2 (Established SE, 10-30 mins)
- IV single dose Phenytoin / Phenobarbitone / Valproate / Levetiracetam

Stage 3 (Refractory SE, 30-60 mins)
- SE that continues despite stage 1 / 2 treatment (subtle SE, stuporous SE)
- Need ICU admission + EEG monitoring
- Infusion Midazolam / Propofol / Thiopentone
- Watch out for respiratory (all) / cardiac depression (thiopentone) —> close monitoring of vitals

Stage 4 (Super-refractory SE, >24 hours)
- SE that continues despite treatment with anaesthetic >24 hours
- Find out underlying causes that lead to refractoriness to treatment
- Immunomodulatory treatment (if cause is immune-mediated insult to brain e.g. immune-mediated encephalitis) —> Methylprednisolone / IVIG / Plasma exchange
- Ketamine infusion
- Magnesium infusion
- Pyridoxine in young children
- Non-pharmacological: Ketogenic diet, Hypothermia, Electroconvulsive therapy, Epilepsy surgery

Question 7

Febrile seizures

Answer 7

NOT considered a form of epilepsy (recurrent nonfebrile seizures)

Definition (UpToDate):
- A convulsion associated with an elevated temperature >38oC
- A child >6 months - <5 yo
- Absence of CNS infection / inflammation
- Absence of acute systemic metabolic abnormality that may produce convulsions
- No history of previous afebrile seizures

1. Simple (Typical) Febrile seizure
   - Short primary generalised seizure lasting <15 mins + not recurring within 24 hours at the typical age of 6 months - 5 years
   - Associated with high fever with rectal temp >38.9oC
   - Most febrile seizures occur during 1st day of onset of fever

Age of Occurrence:
- Most common childhood seizure
- Usually 6 months - 5 years
- Almost all first febrile seizures occur by age 3y
- Median age 18-22 months
- A benign + self-limiting condition
—> ALL children MUST have normal development (i.e. not other problems causing the seizure)

2. Complex (Atypical) Febrile seizure
   - Encompass seizures that are prolonged in nature (>15 minutes)
   - Have any focal features / recur within 24 hour period

Risk factors for developing Epilepsy after Febrile seizures:
- Risk of unprovoked seizure 2-4% after febrile seizures
1. Epilepsy in a first degree relative
2. Complex febrile seizure
3. Baseline neurodevelopment abnormalities

Red flags:
- Febrile seizure associated with meningeal signs are not considered febrile seizures —> must consider infectious process
- Frequent episodes of febrile status epilepticus (>30 mins) under 1 yo suggest an SCN1A channelopathy (Dravet syndrome)

Workup for Febrile seizure:
1. History + P/E
- Primary goal is to determine source of fever

2. Blood
   - CBC
   - Na, Mg, Ca, PO4
   - Glucose
   - NH3
3. Appropriate infection evaluation (seizure with fever =/ febrile seizure) (if indicated)
   - Blood culture
   - Stool culture
   - LP
   (many children may have HHV6, but not clinically indicated to test)
4. Imaging only indicated if
   - History of head trauma
   - Acute deterioration
   - Abnormal exam (e.g. focal neurological sign, altered conscious state)
   - Evidence of increased ICP
5. EEG
   - NOT helpful unless it is unclear if event was seizure or not
   - then should be done in first 7 days, if abnormal repeat to see if abnormalities resolve

Question 8

Tuberous sclerosis (TS)

Answer 8

• Autosomal dominant inheritance
• Prevalence 1:6000 to 1:10000 live births
• Variable phenotypic presentation
• Gene mutation testing available
• TSC1 (9q24, encode harmatin) / TSC2 (16p13.3, encode tuberin) gene mutation in ~85% patients
• Harmatin-tuberin complex downregulates mTOR C1
• Seizures occur in 80% of patients, many present with infantile spasms, though all seizure types can be encountered as they grow older
• Vigabatrin is 1st treatment of choice for infantile spasms associated with TSC
• Diagnosis: Clinical criteria

Diagnosis:
- Definite TSC: 2 major / 1 major + 2 minor / Positive genetic testing
- Probable TSC: 1 major + 1 minor
- Possible TSC: 1 major/ >=2 minor features

Major features:
- Facial angiofibromas or forehead plaque
- Nontraumatic ungual or periungual fibroma
- Hypomelanotic macules (>=3) (Ashleaf spots)
- Shagreen patch (connective tissue nevus)
- Multiple retinal nodular hamartomas
- Cortical tubers
- Subependymal nodule (SEN)
- Subependymal giant cell astrocytoma (SEGA)
- Cardiac rhabdomyoma
- Lymphangioleiomyomatosis (LAM)
- Renal angiomyolipoma

Minor features:
- Nonrenal hamartoma
- Retinal achromic patch
- “Confetti” skin lesions
- Multiple renal cysts
- Multiple, randomly distributed pits in dental enamel
- Hamartomatous rectal polyps
- Bone cysts
- Cerebral white matter radial migration lines
- Gingival fibromas

Evaluation:
1. Skin, Teeth, Eyes: Clinical examination
2. Brain: MRI, EEG, TAND
3. CVS: Echo, ECG
4. Kidney: USG, MRI, Hypertension screen, eGFR
5. Lungs: HRCT, Lung function
6. Genetics: 3 generation family history, Genetic testing

Surveillance:
1. Skin, Eyes: Annual
2. Teeth: Biannual
3. Brain: MRI every 1-3 years until 25, EEG based on clinical need, TAND annually
4. CVS: Echo every 1-3 years until rhabdomyoma regress, ECG every 3-5 years
5. Kidneys: MRI every 1-3 years, Annual BP, eGFR
6. Lungs: HRCT every 5-10 years, Lung function annually

From Vinson Cheng:
- Adenoma Sebaceum (Angiofibromas)
- Periungal Fibromas
- Hypomelanic macules (Ashleaf spots)
- Shagreen patches: Lower back
- Coloboma
- Mental retardation, epilepsy and developmental delay
- TSC1/2 mutation —> too much mTOR activation —> abnormal cell growth/proliferation
- Rare multisystem AD genetic condition
- non-cancerous tumours in brain / other vital organ

From Felix Lai:
- Vogt triad = Facial angiofibroma + Seizure + Intellectual disability (mental retardation)
- Mutation in either TSC1 / TSC2 gene (tumour suppressor genes)
- De novo mutation (80%) / Autosomal dominant (20%)

Clinical features:
1. Dermatological
- Angiofibroma
- Ashleaf spots (Hypopigmented macules / Confetti skin lesions)
- Shagreen patches
- Distinctive brown plaque on forehead
- Ungual fibroma

2. CNS manifestation
   - Glioneuronal hamartoma (Cortical dysplasia (tuber))
   - Subependymal nodules (SEN)
   - Subependymal giant cell tumours (SGCT) (aka Subependymal giant cell astrocytoma (SEGA))
   - Epilepsy
   - TSC-associated neuropsychiatric disorders (TAND) (90%)
3. CVS
   - Cardiac rhabdomyomas
4. Respiratory
   - Lymphangioleiomyomatosis (LAM)
5. Renal
   - Angiomyolipoma
   - RCC
   - Renal cysts
6. Ophthalmic
   - Retinal hamartoma
   - Chorioretinal depigmentation (Retinal achromic patches)

From ERS27:
Clinical features:
ASHLEAF
1. Ashleaf spots (Hypopigmented macules)
2. Shagreen patches (鯊魚皮斑病變)
3. Heart rhabdomyosarcoma
4. Lung hamartoma
5. Epilepsy due to cortical tubers
6. Angiomyolipoma in kidney
7. Facial angiofibroma (acne-like)

Treatment:
Rapamycin (Sirolimus) / Everolimus (2nd gen rapamycin derivative)
—> suppress mTOR pathway

Question 9

TSC-associated neuropsychiatric disorders (TAND)

Answer 9

• Aggressive behaviour
• Autism spectrum disorders
• Intellectual disabilities
• Psychiatric disorders and neuropsychological deficits
• School and occupational difficulties

Question 10

Neurofibromatosis type 1 (NF1)

Answer 10

Pathology:
- Germline mutation in 1 of 2 alleles of tumour suppressor gene NF1 on chromosome 17q11.2
- Autosomal dominant
- Although this heterozygous germline mutation is sufficient to cause NF1, somatic loss of function in the second allele is required for tumour formation.
- Neurofibromin (protein product), is important in regulating Ras, a proto-oncogene that plays a prominent role in cell growth and differentiation and is mutated in many common cancers
- Neurofibromin is expressed in most tissues but at particularly high levels in the nervous system (including Schwann cells along peripheral nerve trunks, glial cells, and neurons), which partially explains the predilection for peripheral nerve sheath tumors and gliomas

Mosaic NF1:
- Mosaic NF1 occurs when there is a somatic mutation later in embryonic development (as opposed to a germline mutation in generalised NF1). Mutations that occur very early in embryonic development can present with a phenotype similar to generalised NF1, whereas mutations in terminally differentiated cells typically manifest with isolated areas of involvement. Clinically, the area of involvement may vary from a narrow strip to one-half of the body; although often unilateral, it sometimes involves both sides
- In individuals with suspected mosaic NF1, genetic testing should be performed on blood as well as on the affected tissue (e.g. melanocytes from a CALM)

Clinical features (SpC Revision + Felix Lai):
1. Cafe au lait spots
2. Axillary Freckling
3. Lisch nodules
4. Neurofibromas and Plexiform Neurofibroma
5. CNS tumours (Gliomas)
- Astrocytoma
- Brainstem glioma
- Optic pathway gliomas (OPG) (affect vision / lead to blindness)
6. Soft tissue sarcomas
- Malignant peripheral nerve sheath tumour (MPNSTs)
- Rhabdomyosarcoma
- GISTs
- Glomus tumours
- Phaeochromocytoma
- Wilms tumour
- Juvenile myelomonocytic leukaemia
- Breast cancer
7. Bone abnormalities
- Long bone dysplasia
- Pseudoarthrosis
- Sphenoid wing dysplasia
- Non-ossifying fibroma within long bones
- Short stature
- Scoliosis
- Osteoporosis
8. Neurological abnormalities
- Cognitive deficits and learning disabilities
- Seizures
- Cerebrovascular abnormalities (Aneurysms, Stenosis, TIA)
- Peripheral neuropathy
- Macrocephaly
9. Hypertension
- Essential
- Renovascular

DDx of cafe au lait spots:
1. NF2
2. Schwannomatosis
3. Legius syndrome
4. McCune-Albright syndrome
5. Noonan syndrome
6. Russell–Silver syndrome

Diagnostic criteria:
Revised 2021 NF1 Diagnostic criteria
>=2 of following:
1. >=6 Cafe au lait spots of >5mm in size (before puberty) / 15mm in size (after puberty)
2. Freckling in axillary / groin (inguinal) regions
3. >=2 Neurofibromas of any type / 1 Plexiform neurofibroma
4. >=2 Lisch nodules (abnormal clumps of pigment on coloured portion of eye / >=2 Choroidal abnormalities
5. Optic pathway glioma
6. Certain abnormalities of bone development in the head (∵ thinning of cortex) (Sphenoid wing dysplasia) / abnormal bowing of bones (Pseudoarthrosis) / anterolateral bowing of tibia (Tibial dysplasia)
7. A parent with confirmed NF1
8. A pathogenic NF1 gene variant

Only Cafe au lait spots, Neurofibroma appear at birth, followed by tibial dysplasia, others develop later

SpC Revision:
Cutaneous NFs:
- Within dermis and epidermis
- Initially sessile, later pedunculated
- Red-blue-violaceous -fleshy and soft
- Not painful

Subcutaneous NFs:
- Deep to the dermis
- Skin moves over
- Discrete spherical or ovoid
- Firm, tender or painful

Plexiform NFs:
- Extensive interdigitating network
- Numerous fingerlike fronds that insinuate extensively into adjacent normal tissues
- Surgical removal impossible
- Superficial or deep
- +/- Overlying hyperpigmentation or hypertrichosis
- Usually present at birth

Treatment principles:
- NO specific medical treatment for neurofibromas exists
1. Genetic counselling
2. Treatment of various tumours
- Depends upon type of tumour, its effect on adjacent tissues and related complications
- Surgical treatment + Pain management of plexiform neurofibromas
3. Neurologic disorders that may require specific management
- Include cognitive deficits, learning disabilities, seizures, and peripheral neuropathy
4. Orthopedic intervention may be needed for long bone dysplasia and scoliosis

New drug:
- Selumetinib (MEK inhibitor (inhibit cell proliferation)) (SpC Paed)

Question 11

West syndrome

Answer 11

West syndrome:
1. Infantile spasm
2. Developmental delay
3. Hypsarrhythmia on EEG (bizarre, chaotic, high amplitude, spiky with no pattern)

• Age of onset: 4-9 months of age
• Seizure types: Epileptic spasms
• Associated EEG patterns: Hypsarrhythmia

Causes:
1. Tuberous sclerosis (10-30%)
2. Perinatal (15-25%)
- Fetal infections
- Hypoxic ischaemic encephalopathy (HIE) / Perinatal brain injury
- Hypoglycemia
3. Brain malformations
4. Metabolic abnormalities
5. Pyridoxine deficiency
6. Chromosomal abnormalities (Trisomy 21, ARX, TSC1, TSC2, RDXP2, ALDH7A1, POLG, CDKL5, STXBP1, SCN2A, FOXG1, PCDH19, SLC2A1, MeCP2)

Treatment:
1. Vigabatrin (if related to Tuberous sclerosis)
2. Prednisolone (ACTH in the past)

Prognosis:
- Developmental delay
- Many will have seizures later in life, can evolve to Lennox-Gastaut Syndrome (refractory epilepsies)

Question 12

Comorbidities of Epilepsy (SpC Paed Sophelia Chan)

Answer 12

1. Learning difficulty / Developmental delay / Intellectual disability
2. Psychiatric conditions e.g. ASD
3. Cerebral palsy / movement disorder
4. Feeding dysfunction
5. Visual / Hearing impairment
   Etc.