Developmental regression

Developmental regression is the loss of previously acquired developmental skills (motor, language, social, cognitive or self care) after a period of normal or delayed progress. It differs from developmental delay, in which skills are not acquired, and from plateau, in which skills are not gained but not lost.

It is a neurological red flag that may signal:

• a progressive disease of the brain, spinal cord, nerves or muscles
• a treatable metabolic or inflammatory disorder
• an epileptic encephalopathy
• a structural lesion, infection or toxin exposure
• a psychosocial cause (trauma, abuse, severe stress)

It requires urgent, systematic evaluation because several causes are treatable. These are infantile spasms, Landau-Kleffner syndrome, hydrocephalus, tumour, hypothyroidism, vitamin B12 deficiency and Wilson disease.

Other treatable causes are biotinidase deficiency, glucose transporter deficiency, subacute sclerosing panencephalitis with early treatment, HIV encephalopathy, autoimmune encephalitis, lead poisoning, abusive head trauma, and neurotransmitter disorders.

Definitions.

• Regression is a loss of acquired skills that were previously established, in one or more domains, persisting for more than a few days.
• Plateau is a failure to progress without loss.
• Developmental stagnation is a prolonged plateau.
• Regression in language alone with preserved other domains occurs in acquired epileptic aphasia and some autism.
• Autistic regression is the loss of language or social skills, usually between 12 and 36 months, in children later diagnosed with autism spectrum disorder (15% to 40% of cases).
• Neurodegeneration is progressive loss of neurons and function, with continuing decline.
• Epileptic encephalopathy is a condition in which epileptic activity itself contributes to cognitive and behavioural decline (infantile epileptic spasms syndrome, Lennox-Gastaut syndrome, electrical status epilepticus in sleep, Landau-Kleffner syndrome).
• Leukodystrophy is a disease of white matter.
• Polioencephalopathy is a disease of grey matter.

Classification by cause

• Epileptic encephalopathies: infantile epileptic spasms syndrome (West syndrome), Lennox-Gastaut syndrome, Dravet syndrome, electrical status epilepticus in sleep, Landau-Kleffner syndrome (acquired epileptic aphasia), and other developmental and epileptic encephalopathies.
• Metabolic:
  • lysosomal storage disorders (Tay-Sachs and Sandhoff disease, Niemann-Pick disease type C, Gaucher type 2 and 3, metachromatic leukodystrophy, Krabbe disease, mucopolysaccharidoses, neuronal ceroid lipofuscinoses)
  • peroxisomal disorders (X-linked adrenoleukodystrophy)
  • mitochondrial disease (Leigh syndrome, MELAS)
  • organic acidaemias, urea cycle disorders, aminoacidopathies (untreated phenylketonuria, maple syrup urine disease)
  • biotinidase deficiency, glucose transporter 1 deficiency, creatine deficiency, cerebral folate deficiency, vitamin B12 deficiency, Wilson disease, congenital disorders of glycosylation, and neurotransmitter disorders
• Genetic neurodevelopmental disorders: Rett syndrome (girls, regression of hand use and speech at 6 to 18 months with hand stereotypies and deceleration of head growth), childhood disintegrative disorder, fragile X syndrome (rarely), CDKL5 deficiency disorder, and other syndromes.
• Infectious and post infectious: HIV encephalopathy, subacute sclerosing panencephalitis (measles), bacterial meningitis, herpes simplex encephalitis, cerebral malaria sequelae, neurosyphilis, tuberculous meningitis, congenital cytomegalovirus, progressive multifocal leukoencephalopathy, acute disseminated encephalomyelitis, and prion disease (rare).
• Autoimmune and inflammatory: anti-N-methyl-D-aspartate receptor encephalitis, other autoimmune encephalitis, opsoclonus myoclonus syndrome, Hashimoto encephalopathy, Rasmussen encephalitis, acute disseminated encephalomyelitis, multiple sclerosis, and paediatric autoimmune neuropsychiatric syndromes (controversial).
• Structural and acquired: hydrocephalus, shunt malfunction, brain tumour, subdural haematoma, abusive head trauma, hypoxic injury, stroke, and neurocutaneous disorders (tuberous sclerosis, Sturge-Weber syndrome).
• Endocrine and nutritional: acquired hypothyroidism, vitamin B12 deficiency, vitamin B6 deficiency, thiamine deficiency, severe malnutrition, and iodine deficiency.
• Toxic: lead poisoning, mercury, drugs (antiepileptics, sedatives), alcohol and cannabis in adolescents, and carbon monoxide.
• Neuromuscular: spinal muscular atrophy (late onset), muscular dystrophy, Charcot-Marie-Tooth disease, hereditary neuropathies, and juvenile myasthenia.
• Psychiatric and psychosocial: depression, trauma and posttraumatic stress disorder, abuse, neglect, severe anxiety, selective mutism, conversion disorder, schizophrenia (adolescents), autism spectrum disorder, and attachment disorders.

Epidemiology. Regression is uncommon but important. Neurodegenerative disorders collectively affect about 1 in 3,000 to 1 in 5,000 children, though each is rare.

• Infantile spasms affect about 1 in 2,000 to 4,000 infants, usually at 3 to 12 months, and early treatment improves outcome.
• Rett syndrome affects 1 in 10,000 girls.
• Autistic regression occurs in about 20% to 30% of children with autism.
• Lysosomal storage disorders affect 1 in 7,000 live births collectively.
• Subacute sclerosing panencephalitis occurs in about 1 in 10,000 to 25,000 measles cases (higher with infection under 1 year), 4 to 10 years after infection.
• HIV encephalopathy is common in children with untreated HIV in sub-Saharan Africa.
• Consanguinity increases the frequency of recessive metabolic conditions.

Mechanisms. Loss of skills reflects neuronal or white matter injury or dysfunction caused by accumulation of toxic metabolites, energy failure, demyelination, ongoing epileptiform activity, inflammation, raised intracranial pressure, structural damage, deficiency of an essential nutrient or hormone, or psychological stress. Loss of skills often follows the order of their acquisition in reverse, with the most recently acquired skills (language, social skills) lost first.

Key distinctions.

• Loss of vocalisation and eye contact with brief jerks of the trunk and arms in clusters in an infant 3 to 12 months points to infantile spasms.
• Loss of speech comprehension and expression in a previously normal child of 3 to 7 years with seizures and an abnormal sleep electroencephalogram points to Landau-Kleffner syndrome.
• Loss of hand skills and speech with hand wringing in a girl aged 6 to 18 months, with deceleration of head growth and breathing irregularities, points to Rett syndrome.
• Loss of social and language skills before 3 years without seizures, with repetitive behaviour, points to autistic regression.
• Myoclonic jerks, school decline and personality change several years after measles points to subacute sclerosing panencephalitis.
• Loss of vision, hyperacusis and a cherry red spot on the macula with progressive weakness in infancy points to Tay-Sachs disease.
• Progressive gait ataxia, vertical gaze palsy, splenomegaly, cataplexy and cognitive decline in a school age child points to Niemann-Pick disease type C.
• Loss of motor milestones with irritability, spasticity and abnormal white matter on imaging in infancy points to Krabbe disease.
• Boys aged 4 to 10 with school failure, behaviour change, visual problems and adrenal insufficiency point to X-linked adrenoleukodystrophy.
• Fluctuating deterioration with lactic acidosis during illness, brain stem signs, and basal ganglia lesions on imaging points to mitochondrial disease.
• Psychiatric symptoms, seizures, catatonia, movement disorder and autonomic instability in a young female point to anti-N-methyl-D-aspartate receptor encephalitis.
• Headache, vomiting, enlarging head, sunset eyes and falling school performance point to hydrocephalus.
• Regression after trauma with bruises and retinal haemorrhages points to abusive head trauma.
• Loss of skills with sadness, withdrawal and a history of adversity points to depression, posttraumatic stress disorder or abuse.

History

• Confirm the regression. Establish which skills were lost (specific words, motor tasks, social behaviours, toileting, play), the age at which they were acquired and at which they were lost, and how quickly (days, weeks, months). Establish whether the loss is continuing, partial or complete, and whether it is static or episodic.
• Use videos, nursery and school records, and developmental notes. Ask whether the child ever had a skill in an unreliable way ("once said a word").
• Pattern: sudden (after illness, injury, seizure, vaccine, fever), stepwise (strokes, metabolic crises), slowly progressive, or fluctuating.
• Domains: language (loss of words, comprehension), motor (walking, hand use, falls, clumsiness, tremor, stiffness, weakness), social and emotional (eye contact, interest, play, affect), cognition and school performance, vision, hearing, behaviour (aggression, personality change, hallucinations), sleep, feeding and swallowing, continence, and appetite.
• Neurological symptoms: seizures (type, frequency, infantile spasms), headache, vomiting, gait disturbance, abnormal movements, drooling, visual loss, deafness, and breathing irregularities.
• Systemic symptoms: fever, infection, weight loss, failure to thrive, recurrent vomiting, constipation, diarrhoea, rash, skin and hair changes, jaundice, abdominal distension, bone pain, and arthritis.
• Triggers and exposures: infection, vaccination, head injury, fall, sedatives, anticonvulsants, lead (pica, paint, battery recycling, contaminated cosmetics, cookware), mercury, solvents, drugs, alcohol and sexual abuse or trauma.
• Perinatal and developmental history: gestation, birth, early milestones (were they normal before regression), previous delay, vaccination, measles infection, and HIV status (mother and child).
• Family history: consanguinity, similar illness, early childhood deaths, neurodegeneration, metabolic disease, epilepsy, autism, psychiatric illness, and pedigree.
• Medicines and diet: antiepileptic drugs, vegetarian diet, breastfeeding by a mother with low B12, and restrictive diets.
• Social: home environment, bullying, abuse, bereavement, parental separation, domestic violence, school stress, and safeguarding concerns.

Examination

• Growth: weight, height, head circumference (microcephaly or deceleration in Rett syndrome and neurodegeneration, macrocephaly in hydrocephalus and some leukodystrophies and lysosomal disorders).
• General: dysmorphic features, coarse features, skin (café au lait macules, ash leaf macules, angiofibromas, hyperpigmentation in adrenoleukodystrophy, photosensitivity), hair (sparse or kinky), liver and spleen enlargement, corneal clouding, skeletal changes (dysostosis), cardiomyopathy, and signs of infection or abuse (bruises, fractures).
• Vital signs, including blood pressure and temperature.
• Neurological: mental state and developmental level, eye movements (nystagmus, opsoclonus, vertical gaze palsy), and fundus (cherry red spot, optic atrophy, papilloedema, retinitis pigmentosa, chorioretinitis).
• Also examine pupils, cranial nerves, tone (hypotonia, rigidity, spasticity), power, reflexes (increased or lost), and plantar responses. Look for ataxia, tremor, dystonia, chorea, myoclonus, and stereotypies. Assess gait and bulbar function.
• Hearing and vision testing, and speech and language assessment.
• Seizure observation, and examination of the spine.
• Mental state in older children: mood, anxiety, perceptual disturbance, thought disorder, and catatonic signs.
• Look for signs of raised intracranial pressure (bulging fontanelle, papilloedema, cranial nerve VI palsy, Cushing response).

Red flags

• Loss of previously acquired skills at any age (every case needs urgent specialist evaluation).
• Infantile spasms (clusters of jerks) or any new seizure type with regression.
• Features of raised intracranial pressure: headache, vomiting, bulging fontanelle, enlarging head, papilloedema, or falling consciousness.
• Acute onset after fever or head injury (encephalitis, encephalopathy, abuse).
• Focal neurological signs, ataxia, or loss of gait.
• Visual loss, optic atrophy, cherry red spot, or retinal pigmentary change.
• Hearing loss.
• Rapid head circumference deceleration or acquired microcephaly.
• Hepatosplenomegaly, coarse features, bone abnormalities, or corneal clouding.
• Vomiting, acidosis, hypoglycaemia, or lethargy during illness (metabolic decompensation).
• Movement disorder, catatonia, psychosis, or autonomic instability (autoimmune encephalitis).
• Myoclonus with cognitive decline (subacute sclerosing panencephalitis).
• Known or suspected HIV, tuberculosis contact, or exposure to lead.
• Bruising, retinal haemorrhages, fractures, or signs of neglect or abuse.
• Suicidal thoughts, self harm, hallucinations, or severe agitation in an adolescent.
• Consanguinity with an affected sibling.
• Dysphagia, aspiration, respiratory irregularity, or loss of airway reflexes.

Special groups

• Infants under 12 months: infantile spasms, metabolic disease, Krabbe disease, Tay-Sachs disease, neuronal ceroid lipofuscinosis (infantile type), congenital infection, abuse, and hypothyroidism.
• Toddlers (1 to 3 years): Rett syndrome, autistic regression, mitochondrial disease, Niemann-Pick disease, Landau-Kleffner syndrome (from 3 years), infection, and trauma.
• School age children: Landau-Kleffner syndrome, adrenoleukodystrophy, juvenile neuronal ceroid lipofuscinosis, subacute sclerosing panencephalitis, Wilson disease, tumour, autoimmune encephalitis, psychiatric illness, and electrical status epilepticus in sleep.
• Adolescents: psychiatric disorders, substance use, Wilson disease, autoimmune encephalitis, multiple sclerosis, adult onset forms of storage disease, HIV, and trauma.
• Children with known developmental disorders: regression is not part of the underlying condition and needs full evaluation.
• Region specific: HIV encephalopathy, measles associated subacute sclerosing panencephalitis, cerebral malaria sequelae, neurocysticercosis, tuberculous meningitis, lead poisoning, iodine and vitamin B12 deficiency, kernicterus, and consanguinity related metabolic disease.

Epileptic and electrical

• Infantile epileptic spasms syndrome, Lennox-Gastaut syndrome, Dravet syndrome, electrical status epilepticus in sleep, Landau-Kleffner syndrome, other developmental and epileptic encephalopathies, and the effects of antiepileptic drugs.

Genetic neurodevelopmental

• Rett syndrome, CDKL5 disorder, childhood disintegrative disorder, autism spectrum disorder with regression, fragile X syndrome, tuberous sclerosis complex.

Metabolic and neurodegenerative

• Lysosomal storage disorders: Tay-Sachs and Sandhoff disease, GM1 gangliosidosis, Niemann-Pick type C, metachromatic leukodystrophy, Krabbe disease, Gaucher disease types 2 and 3, mucopolysaccharidoses, neuronal ceroid lipofuscinoses, and Fabry disease.
• Peroxisomal: X-linked adrenoleukodystrophy, Zellweger spectrum disorders, and Refsum disease.
• Mitochondrial: Leigh syndrome, MELAS, MERRF, and other respiratory chain disorders.
• Others: organic acidaemias, urea cycle disorders, untreated phenylketonuria, biotinidase deficiency, glucose transporter 1 deficiency, creatine deficiency, congenital disorders of glycosylation, cerebrotendinous xanthomatosis, Wilson disease, and neurotransmitter disorders.
• Leukodystrophies (Pelizaeus-Merzbacher disease, Alexander disease, Canavan disease, vanishing white matter disease).
• Neurodegeneration with brain iron accumulation and Huntington disease (juvenile).

Infectious and post infectious

• HIV encephalopathy, subacute sclerosing panencephalitis, herpes simplex encephalitis and other encephalitis, bacterial and tuberculous meningitis, neurosyphilis, cerebral malaria sequelae, neurocysticercosis, congenital infections, and progressive multifocal leukoencephalopathy.
• Acute disseminated encephalomyelitis and post infectious cerebellitis.

Autoimmune

• Anti-N-methyl-D-aspartate receptor encephalitis, other autoimmune encephalitis (anti-leucine rich glioma inactivated 1, anti-contactin associated protein like 2, anti-myelin oligodendrocyte glycoprotein), opsoclonus myoclonus ataxia syndrome (often paraneoplastic neuroblastoma), Hashimoto encephalopathy, multiple sclerosis, systemic lupus erythematosus with neuropsychiatric involvement, and CNS vasculitis.

Structural and traumatic

• Hydrocephalus and shunt malfunction, brain tumour (posterior fossa, hypothalamic, thalamic), subdural haematoma, abusive head trauma, stroke, cerebral venous thrombosis, and arteriovenous malformation.

Endocrine, nutritional and toxic

• Acquired hypothyroidism, vitamin B12 deficiency, thiamine deficiency, vitamin B6 deficiency, pellagra, malnutrition, hypoglycaemia, hypocalcaemia, and diabetic complications.
• Lead poisoning, mercury, solvent inhalation, alcohol, cannabis, carbon monoxide, and drug effects.

Neuromuscular

• Spinal muscular atrophy, muscular dystrophy, hereditary motor sensory neuropathy, and Guillain-Barre syndrome (motor loss, not cognitive).

Psychiatric and psychosocial

• Depression, posttraumatic stress disorder, trauma, sexual or physical abuse, neglect, bereavement, severe anxiety, conversion disorder, selective mutism, schizophrenia, and catatonia.

Step 1. Resuscitate and stabilise. Assess airway, breathing, circulation, consciousness and glucose. Treat seizures, raised intracranial pressure, shock, and hypoglycaemia. Admit unwell children.

Step 2. Confirm and characterise the regression. Compare the history, records and videos with the current examination. Document domains lost, speed and pattern. Formal developmental or neuropsychological testing helps quantify the loss. Distinguish true regression from transient loss during illness, from unreliable observation, from behavioural refusal, and from delay.

Step 3. First line tests (all children with confirmed regression)

• Capillary glucose, full blood count and film (vacuolated lymphocytes, acanthocytes), C-reactive protein, urea, creatinine, electrolytes, calcium, phosphate, magnesium, liver tests, creatine kinase, lactate, ammonia (on ice, prompt analysis), venous gas, thyroid function, vitamin B12, folate, copper and caeruloplasmin, lead level, and ferritin.
• Urinalysis, urine organic acids, and plasma amino acids; acylcarnitine profile; very long chain fatty acids (for suspected peroxisomal disease in boys with white matter disease).
• Hearing test (audiology, auditory brainstem response) and ophthalmological examination (retinal changes, cherry red spot, optic atrophy, Kayser-Fleischer rings on slit lamp).
• HIV test, syphilis serology, measles antibodies, tuberculosis tests, and malaria test as relevant.
• Magnetic resonance imaging of the brain with contrast (and spine if indicated), under sedation or general anaesthesia if needed. Look for white matter changes (leukodystrophy), basal ganglia and thalamic lesions (mitochondrial disease, Wilson disease, neurodegeneration with brain iron accumulation), atrophy, tumours, hydrocephalus, subdural collections, cerebral oedema, and cortical malformation.
• Add magnetic resonance spectroscopy (lactate, N-acetylaspartate, creatine) and diffusion imaging.
• Electroencephalogram (including sleep recording): hypsarrhythmia in infantile spasms, continuous spike wave in sleep in electrical status epilepticus in sleep and Landau-Kleffner syndrome, periodic complexes in subacute sclerosing panencephalitis, and extreme delta brush in anti-N-methyl-D-aspartate receptor encephalitis.

Step 4. Targeted tests

• Lumbar puncture (after imaging) with cell count, protein, glucose with paired blood glucose, lactate, pyruvate, amino acids, neurotransmitter metabolites, 5-methyltetrahydrofolate, oligoclonal bands, and opening pressure.
• Cerebrospinal fluid tests also include measles antibody (subacute sclerosing panencephalitis), polymerase chain reaction for herpes simplex virus and others, and autoimmune antibodies (anti-N-methyl-D-aspartate receptor, others) in serum and cerebrospinal fluid.
• Lysosomal enzyme panel (white cell hexosaminidase A and B, beta-galactosidase, arylsulphatase A, galactocerebrosidase, glucocerebrosidase, sphingomyelinase, chitotriosidase, oxysterols and lyso-sphingomyelin for Niemann-Pick type C), urine glycosaminoglycans and oligosaccharides, and transferrin isoforms.
• Biotinidase activity, phytanic acid, pristanic acid, 7-dehydrocholesterol, creatine and guanidinoacetate, and 24 hour urine copper.
• Nerve conduction studies, electromyography, muscle biopsy (histology, respiratory chain enzymes), skin biopsy (neuronal ceroid lipofuscinosis, fibroblast enzyme studies), and bone marrow in selected cases.
• Genetic testing (chromosomal microarray, MECP2, CDKL5, SCN1A, TSC1 and TSC2, ABCD1, NPC1, epilepsy gene panels, and exome or genome sequencing), mitochondrial DNA analysis, and trio sequencing with counselling.
• Paraneoplastic and tumour screening for opsoclonus myoclonus (urine catecholamines, metaiodobenzylguanidine scan, magnetic resonance imaging of chest and abdomen), and pelvic imaging for ovarian teratoma in anti-N-methyl-D-aspartate receptor encephalitis.
• Skeletal survey, repeat retinal examination, and child protection assessment where abuse is suspected.
• Psychiatric and psychological assessment, and autism assessment, for suspected autistic or psychological regression.
• Brain biopsy only in carefully selected cases, under specialist neurology and neurosurgery.

Step 5. Interpretation. Match the pattern of regression, age at onset, examination findings and imaging to a short list, and test for the treatable causes first.

• Hypsarrhythmia with spasms establishes infantile epileptic spasms syndrome.
• Continuous spike wave activity in over 85% of slow sleep with cognitive or language regression establishes electrical status epilepticus in sleep.
• Raised cerebrospinal fluid measles antibody titres with periodic electroencephalogram complexes establishes subacute sclerosing panencephalitis.
• Low enzyme activity in white blood cells confirms most lysosomal disorders, but genetic confirmation is needed for counselling.
• Normal investigations with a history of adversity and psychological symptoms favour a psychosocial cause, but a full medical evaluation is still required.

Many children remain undiagnosed after first tier testing. Exome or genome sequencing and repeat neuroimaging improve yield.

Limits. Early in the disease imaging and enzyme tests can be normal. Heterogeneity is wide, so testing must follow the pattern. Genetic findings may be of uncertain significance. A diagnosis may not change treatment but remains important for prognosis and genetic counselling.

Immediate

• Admit most children with new regression for urgent investigation, unless the cause is clearly psychosocial and the child is safe.
• Stabilise airway, breathing and circulation; give oxygen to keep saturation 94% or over; check glucose.
• Hypoglycaemia: 10% dextrose 2 mL/kg intravenously, then infusion at 5 to 8 mg/kg/minute.
• Seizure: lorazepam 0.1 mg/kg intravenously (maximum 4 mg) or midazolam 0.3 mg/kg buccal (maximum 10 mg), repeated once after 5 to 10 minutes, then levetiracetam 40 to 60 mg/kg (maximum 4.5 g) or phenytoin 20 mg/kg intravenously (phenobarbital 20 mg/kg in infants under 1 month).
• Raised intracranial pressure: head up 30 degrees, 3% sodium chloride 3 to 5 mL/kg over 10 to 20 minutes, dexamethasone 0.25 to 0.5 mg/kg (maximum 10 mg) every 6 hours for tumour, and urgent neurosurgery for hydrocephalus (external ventricular drain or shunt revision) or mass.
• Suspected metabolic decompensation (vomiting, acidosis, hyperammonaemia, hypoglycaemia): stop protein intake, give 10% dextrose with electrolytes at 1.5 times maintenance, treat infection, and involve a metabolic specialist early.
• For ammonia over 150 micromoles/L give sodium benzoate 250 mg/kg, sodium phenylbutyrate 250 mg/kg and arginine 200 to 600 mg/kg as a loading dose over 90 to 120 minutes. Then give a maintenance infusion under specialist direction. Use renal replacement for ammonia over 400 micromoles/L or failure to respond.
• Suspected encephalitis: aciclovir 10 mg/kg intravenously every 8 hours (20 mg/kg in infants under 3 months), ceftriaxone 80 mg/kg once daily, and lumbar puncture as soon as safe.
• Suspected autoimmune encephalitis, after infection is excluded: methylprednisolone 30 mg/kg daily (maximum 1 g) intravenously for 3 to 5 days.
• Combine with intravenous immunoglobulin 0.4 g/kg daily for 5 days or 2 g/kg over 2 to 5 days, or plasma exchange (5 to 7 exchanges).
• Second line is rituximab 375 mg/m2 weekly for 4 doses or 750 mg/m2 (maximum 1 g) twice 2 weeks apart under neurology. Search for and remove an ovarian teratoma.
• Abusive head trauma or neglect: urgent child protection process, imaging, ophthalmology, and a safe place.

Treatment by cause

• Infantile epileptic spasms syndrome: treat within days.
  • Prednisolone 4 to 8 mg/kg daily (for example 10 mg four times daily, or 40 to 60 mg daily) for 14 days, then taper over 7 to 14 days.
  • Or vigabatrin 50 mg/kg daily in two doses, increased over 3 to 5 days to 100 to 150 mg/kg daily (maximum 200 mg/kg daily) for 4 to 6 months (preferred in tuberous sclerosis). Use visual field or electroretinogram monitoring and magnetic resonance imaging surveillance for signal changes.
  • Combined hormonal and vigabatrin therapy for faster response.
  • ACTH (tetracosactide) 0.5 to 1 mg intramuscularly on alternate days where available.
  • Ketogenic diet and epilepsy surgery for refractory cases.
  • Monitor blood pressure, glucose, infection, and electrolytes during steroids, and give proton pump inhibitor and calcium.
  • Consider a test dose of pyridoxine 100 mg intravenously and then 30 mg/kg daily for pyridoxine dependent epilepsy, and folinic acid 3 to 5 mg/kg daily for folinic acid responsive seizures.
• Electrical status epilepticus in sleep and Landau-Kleffner syndrome:
  • ethosuximide 20 to 30 mg/kg daily
  • sodium valproate 20 to 40 mg/kg daily (avoid in girls who may become pregnant, in mitochondrial disease, and in children under 2 years)
  • levetiracetam 20 to 60 mg/kg daily
  • clobazam 0.5 to 1 mg/kg daily
  • corticosteroids (prednisolone 1 to 2 mg/kg daily for 4 to 6 weeks and taper, or pulse methylprednisolone 20 to 30 mg/kg for 3 days monthly)
  • intravenous immunoglobulin 2 g/kg monthly
  • consideration of surgery
  Avoid carbamazepine, oxcarbazepine and phenytoin, which may worsen discharges.
• Rett syndrome: supportive and multidisciplinary (physiotherapy, occupational therapy, communication aids, seizure treatment with valproate or lamotrigine, treatment of scoliosis, constipation, reflux, osteopenia, and gastrostomy); trofinetide where available (weight band dosing, twice daily) under specialist care.
• Subacute sclerosing panencephalitis: isoprinosine (inosine pranobex) 100 mg/kg daily (maximum 3 to 4 g) with interferon alpha, and supportive care for myoclonus (valproate, clonazepam 0.01 to 0.05 mg/kg daily, carbamazepine); prevention by measles vaccination at 9 months and 15 to 18 months or by the national schedule.
• HIV encephalopathy: antiretroviral therapy (central nervous system penetrating regimen with dolutegravir, abacavir and lamivudine, with weight band dosing), cotrimoxazole prophylaxis 5 mg/kg of trimethoprim daily, treatment of opportunistic infection and tuberculosis.
• Tuberculous meningitis: isoniazid 15 to 20 mg/kg, rifampicin 15 to 20 mg/kg, pyrazinamide 35 mg/kg and ethionamide 20 mg/kg (or ethambutol or a fluoroquinolone) daily for 2 months, followed by isoniazid and rifampicin for 10 months, with dexamethasone 0.4 mg/kg daily tapering over 6 to 8 weeks and pyridoxine 10 to 20 mg daily.
• Bacterial meningitis: ceftriaxone 100 mg/kg once daily with dexamethasone 0.15 mg/kg every 6 hours for 4 days; neurosyphilis: benzylpenicillin 50,000 units/kg intravenously every 4 to 6 hours for 10 to 14 days.
• Congenital cytomegalovirus: valganciclovir 16 mg/kg twice daily for 6 months in symptomatic infants started in the first month, under specialist care.
• Hypothyroidism: levothyroxine 2 to 3 micrograms/kg daily (children 6 to 12 years), 4 micrograms/kg daily (1 to 5 years), 10 to 15 micrograms/kg daily (infants), titrated to thyroid stimulating hormone.
• Vitamin B12 deficiency: hydroxocobalamin 1 mg intramuscularly alternate days for 2 weeks (250 to 500 micrograms for infants), then 1 mg every 1 to 3 months, or 1 mg orally daily; folate must not be given alone.
• Biotinidase deficiency: biotin 5 to 20 mg daily.
• Glucose transporter 1 deficiency: ketogenic diet 3:1 or 4:1.
• Creatine transporter and synthesis defects: creatine monohydrate 300 to 400 mg/kg daily (with arginine restriction and ornithine in guanidinoacetate methyltransferase deficiency).
• Cerebrotendinous xanthomatosis: chenodeoxycholic acid 15 mg/kg daily.
• Cerebral folate deficiency: folinic acid 0.5 to 1 mg/kg daily.
• Responsive epilepsy: pyridoxine 30 mg/kg daily or pyridoxal phosphate 30 to 50 mg/kg daily in divided doses.
• Wilson disease: zinc acetate 25 to 50 mg three times daily (elemental zinc) or penicillamine 20 mg/kg daily in two or three divided doses on an empty stomach with pyridoxine 25 mg daily, or trientine 20 mg/kg daily, with a low copper diet and liver transplantation for acute liver failure.
• Phenylketonuria: low phenylalanine diet with amino acid formula and sapropterin 5 to 20 mg/kg daily (responders).
• Lysosomal storage disorders:
  • disease specific enzyme replacement (Gaucher disease: imiglucerase 60 units/kg every 2 weeks, but it does not cross the blood brain barrier; mucopolysaccharidosis types I, II, IVA, VI: weekly or fortnightly enzyme infusions)
  • substrate reduction (miglustat 200 mg three times daily in adults, 100 mg three times daily for children for Niemann-Pick type C, adjusted by surface area)
  • haematopoietic stem cell transplantation (early in Krabbe disease, metachromatic leukodystrophy, adrenoleukodystrophy and mucopolysaccharidosis type I before symptoms or at early stage)
  • gene therapy for selected conditions (metachromatic leukodystrophy, cerebral adrenoleukodystrophy)
  • symptomatic care
  • cerliponase alfa 300 mg intraventricularly every 2 weeks for neuronal ceroid lipofuscinosis type 2 in specialist centres
• X-linked adrenoleukodystrophy: adrenal replacement (hydrocortisone 8 to 10 mg/m2 daily in divided doses, fludrocortisone 0.05 to 0.1 mg daily) and screening of male relatives.
• Early stem cell transplantation or gene therapy for cerebral disease (Loes score under 9 with gadolinium enhancement). Glyceryl trioleate with glyceryl trierucate in presymptomatic cases (limited evidence).
• Mitochondrial disease: avoid valproate, aminoglycosides in some variants, prolonged fasting, and dehydration. Treat acute crises with glucose and supportive care, and treat lactic acidosis.
• Supplements have limited evidence (coenzyme Q10 5 to 15 mg/kg daily, riboflavin 50 to 400 mg daily, thiamine 100 to 300 mg daily, L-carnitine 50 to 100 mg/kg daily, alpha lipoic acid). Provide seizure management and multidisciplinary care.
• Brain tumour: neurosurgical resection, dexamethasone, and oncology.
• Hydrocephalus: shunt or endoscopic third ventriculostomy.
• Lead poisoning: remove source.
• Give succimer 10 mg/kg three times daily for 5 days then twice daily for 14 days (blood lead over 45 micrograms/dL).
• For lead over 70 micrograms/dL or encephalopathy, give calcium disodium edetate 1000 mg/m2 daily intravenously for 5 days (with dimercaprol 4 mg/kg every 4 hours).
• Provide nutrition (iron, calcium).
• Opsoclonus myoclonus syndrome: corticotropin or prednisolone, immunoglobulin, rituximab, and treatment of neuroblastoma.
• Psychiatric and psychosocial regression: psychological therapy (trauma focused cognitive behavioural therapy), family support, child protection, treatment of depression with fluoxetine 10 mg daily increased to 20 mg after specialist assessment, and restoring routine and safety.
• Autistic regression: early intensive behavioural and communication intervention, speech and language therapy, special education, and treatment of co-existing seizures, sleep disorder (melatonin 1 to 5 mg at night) and irritability (risperidone 0.25 mg daily, maximum 3 mg).

Supportive and palliative care

• Multidisciplinary team: physiotherapy, occupational therapy, speech and language therapy, dietitian, orthotist, social worker, psychologist, specialist nurse, and school liaison.
• Symptom management covers:
  • spasticity (baclofen 0.3 mg/kg daily in three divided doses, increased to a maximum of 2 mg/kg daily, botulinum toxin, trihexyphenidyl 0.1 mg/kg daily for dystonia)
  • seizures
  • drooling (glycopyrronium 20 micrograms/kg three times daily)
  • sleep (melatonin 2 to 5 mg)
  • feeding (gastrostomy)
  • reflux and constipation
  • respiratory care (airway clearance, ventilatory support)
  • pain (paracetamol, gabapentin 5 mg/kg three times daily increasing to 10 mg/kg)
  • irritability
• Palliative care referral at diagnosis of a life limiting condition, with advance care planning, family support, respite, bereavement support, and a home care plan.
• Genetic counselling: explain the mode of inheritance (25% recurrence risk in autosomal recessive conditions), offer carrier testing, prenatal diagnosis and pre-implantation options, and test at risk siblings (early treatment is vital in X-linked adrenoleukodystrophy and Krabbe disease).

Special populations

• Infants: early treatment of infantile spasms and metabolic disease changes outcome. Newborn screening for treatable conditions.
• Girls of reproductive age: avoid valproate and counsel about contraception with antiepileptic drugs.
• Kidney and liver impairment: adjust doses of antiseizure drugs and chelators.
• Low resource settings: prioritise treatable causes (infection, HIV, hypothyroidism, B12 deficiency, hydrocephalus, lead, epilepsy), measles vaccination, and community rehabilitation.

Monitoring. Monitor the following:

• neurological examination and developmental assessment at each visit
• head circumference and growth
• seizure diary and electroencephalogram
• feeding, swallowing and respiratory status
• laboratory monitoring for specific therapies (blood pressure and glucose on steroids, visual fields on vigabatrin, liver and kidney tests on valproate and chelators, thyroid function, ammonia)
• imaging at intervals
• mood and behaviour, and caregiver wellbeing

Referral and escalation. Urgent paediatric neurology (same day for infantile spasms, suspected encephalitis, raised intracranial pressure or rapid decline). Metabolic medicine, clinical genetics, neurosurgery, ophthalmology, audiology, infectious diseases, immunology, endocrinology, child and adolescent mental health services, palliative care, and child protection teams as indicated. Tertiary centres for stem cell transplantation, gene therapy and enzyme replacement.

Admission criteria. Rapid regression, infantile spasms, encephalitis or encephalopathy features, uncontrolled seizures, raised intracranial pressure, metabolic decompensation, loss of airway protection or feeding ability, suspected abuse, severe psychiatric symptoms with risk, and the need for urgent diagnostic work up.

Discharge and follow up. Discharge when the cause has been identified or a diagnostic plan is in place, treatment has started, and seizures and feeding are stable. The family needs a written plan, therapy appointments, and contacts.

Review in 1 to 2 weeks, then monthly during active treatment, and every 3 months once stable.

Safety net advice: return at once for:

• seizure that lasts over 5 minutes or clusters
• new loss of skills
• drowsiness or reduced responsiveness
• repeated vomiting
• severe headache
• rapid head enlargement
• choking or breathing difficulty
• refusal of feeds
• fever with deterioration
• distress that cannot be managed at home