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autism

Image : “Autism” by Nick Youngson. License: CC BY-SA 3.0


Definition of Neurologic Disorders in Children

Intellectual disability (now the preferred term for mental retardation): below average intellectual function (usually full-scale IQ <70) and below-average adaptive behavior.

Autism spectrum disorder: now encompasses the previously separate diagnoses of autism, Asperger disorder, Rett disorder, childhood disintegrative disorder, and pervasive developmental disorder-not otherwise specified (PDD-NOS). ASD is a developmental disorder where patients do not develop a theory of mind. It is a qualitative impairment in social interaction and communication. Also manifests as repetitive and stereotyped behaviors.

Developmental regression: loss of previously attained developmental milestones with almost always a bad prognosis.

Neurocutaneous syndromes: broad term for congenital disorders that mainly and characteristically affect organs of ectodermal origin, especially the skin, the central nervous system, and the eyes. These include:

von hippel lindau disease

Image: “Distribution of Hemangioblastomas in the Central Nervous Systems of Study Patients with Von Hippel-Lindau Disease.” License: CC BY 2.5

  • Tuberous sclerosis complex
  • Neurofibromatosis type 1 and type 2
  • Sturge-Weber syndrome
  • Familial telangiectasia
  • Von Hippel-Lindau disease
  • Incontinentia pigment
  • Ataxia-telangiectasia

Not all disorders are discussed in detail in this article.

Infantile hypotonia, also known as floppy infant syndrome: a generalized reduction in postural tone. Not necessarily associated with significant weakness.

Epidemiology of Neurologic Disorders in Children

Cerebral palsy: incidence of around 3 in 1000 live births in developed countries

Autism spectrum disorders: incidence and prevalence of autism have increased rapidly in recent years. Around 14 in every 1000 children are diagnosed with some form of autism spectrum disorder in the United States every year.

Neurocutaneous disorders:

  • Tuberous sclerosis – an autosomal dominant disease with an incidence of 1 in 6,000
  • Neurofibromatosis type 1 – an autosomal dominant disease with an incidence of 1 in 3,000
  • Neurofibromatosis type 2 – an autosomal dominant disease that is far less common than neurofibromatosis type 1 (1 in 30,000)

Etiology of Neurologic Disorders in Children

Brain tissue begins to differentiate from the ectoderm at around 3 weeks gestation. Between weeks 3 and 4, neurulation (the formation and closure of the neural tube) takes place. The anterior (rostral) neural tube closes at around 24 days. Failure of this process leads to anencephaly or encephalocele. Infants with anencephaly have no forebrain and as such have an open calvarium.

An illustration of an infant with spina bifida

Image: “An illustration of an infant with spina bifida.” by Centers for Disease Control and Prevention – Centers for Disease Control and Prevention. License: Public Domain

The posterior or caudal neural tube closes at around 27 days. Failure can lead to myelomeningocele, meningocele, or spina bifida. In spina bifida, the bony spinal canal fails to close. It can often be seen as a “tuft” of hair on the lower back of the patient with a minor deficit.  

A meningocele is when the meninges form an outpouching or herniate through the bony defect.

A meningomyelocele occurs when both the meninges and nervous system tissue bulge through the defect.

Around weeks 5-6, the vesicle forms. The prosencephalon forms the telencephalon and diencephalon. The mesencephalon remains undivided. The rhombencephalon forms the metencephalon and myelencephalon.

Holoprosencephaly can occur due to a failure of prosencephalon cleavage. Holoprosencephaly is associated with mutations in the “sonic the hedgehog” gene. In severe instances, patients will have cyclopia.

Between weeks 8 and 32, cellular proliferation and migration take place. The cerebral sulci and gyri form. Other possible malformations that can occur during this process include:

  • Lissencephaly is a smooth cortical surface due to poor migration.
  • Pachygyria is defined as large gyri.
  • Microgyria is defined as small gyri.
  • Schizencephaly is defined as a crack in the brain where a cleft exists due to defective morphogenesis (often caused by a stroke).

Etiology of intellectual disability

This can be caused by a number of factors including prenatal or postnatal trauma, hypoxic-ischemic encephalopathy, perinatal infections (e.g. TORCH, HIV), chromosomal abnormalities as in Down’s or Fragile X syndrome, metabolic disorders as in hypothyroidism or Tay-Sachs disease. Toxins (e.g. alcohol in fetal alcohol syndrome) and perinatal hypoxic-ischemic insult can also lead to intellectual disability.

Developmental regression (the loss of previously attained developmental milestones) usually has an onset before age 2. It is caused by a number of disorders including:

  • Mitochondrial disorders (e.g. MELAS – mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes)
  • Hypothyroidism
  • Neurocutaneous disorders, such as neurofibromatosis
  • Gray matter disorders
  • White matter disorders, such as metachromatic leukodystrophy
  • Amino acid metabolism disorders, such as phenylketonuria
  • Enzymatic disorders

There are a number of causes of cerebral palsy and as such the disorder has multiple etiologies. Antenatal factors like premature birth and thyroid disease can lead to cerebral palsy. Perinatal factors like asphyxia have also been linked to the development of the condition.

Neurocutaneous disorders are genetic disorders. Tuberous sclerosis is caused by an autosomal dominant mutation in 2 genetic loci; either TSC1 on chromosome 9 which codes for the protein hamartin or TSC2 on chromosome 16 which codes for tuberin.

Neurofibromatosis type 1 is an autosomal dominant disease caused by a mutation on chromosome 17 in the gene that codes for the protein neurofibromin. Neurofibromatosis type 2 is an autosomal dominant disease that is caused by a mutation of chromosome 22 that codes for the protein Merlin.

Sturge-Weber syndrome is a somatic non-inherited mutation that causes a developmental abnormality in the neural crest. This is caused by the activation of a gene called GNAQ. It affects small blood vessels, and patients typically present with a classic “port wine” stain on the face.

Various underlying conditions can cause hypotonia (floppy infant syndrome). These can either be congenital or acquired.

Risk Factors for Neurologic Disorders in Children

Risk factors are events associated with the development of a disease. The underlying etiology of how the risk factors cause the disorder is not always known. Below are a number of risk factors for common pediatric neurological conditions.

In cerebral palsy, risk factors include:

Chorioamnionitis

Image: “Intermediate magnification micrograph chorioamnionitis. H&E stain.” by Nephron – Own work. License: CC BY-SA 3.0

  • Prematurity
  • Low birth weight
  • Chorioamnionitis
  • Prenatal viral infection
  • Prenatal strokes
  • Perinatal hypoxic-ischemic insult

Risk factors for autism spectrum disorders include:

  • Being of the male sex
  • Positive family history
  • Some genetic variant
  • Chromosomal abnormalities

 

Pathophysiology of Neurologic Disorders in Children

Pathophysiology of cerebral palsy

Cerebral palsy has several underlying pathophysiological mechanisms dependent on the etiology of the condition. In the event of oxygen compromise during or just after birth, there is a hypoxic-ischemic encephalopathy that may cause damage to the periventricular white matter (particularly the internal capsule, leading to motor deficits).

As such, neural projections from the motor cortex are disrupted in the internal capsule and skeletal muscle response is hence affected. Fine motor control is often lost.

Pathophysiology of autism spectrum disorders

The complete pathophysiology of autism is not known. There are genetic factors, but their association is weak and defining pathophysiology has not been deciphered. We do know that the disorder is neurodevelopmental and much research has been done on the altered function of the hippocampal and amygdala brain structures (associated with emotions and empathy).

Diagnosis of Neurologic Disorders in Children

A clinical diagnosis of autism is not expected to be made in the USMLE step 1, but it is good to understand the general principles. Diagnosis is typically made clinically and by pediatricians. Most patients will have behavioral signs that affect their home and school life by the age of 2 years. Babies are either quiet and placid or irritable and throw frequent tantrums.

Diagnosis is difficult because the severity of the disorder varies and many children without autism spectrum disorders also display these types of symptoms. Many patients will fail or perform poorly on “theory of mind” tests (e.g. the Sally Anne test).

The diagnosis of cerebral palsy is typically clinical. The examination will look at the range of motion, the power of movement, and voluntary motor control. A thorough history should be taken and risk factors like teratogen exposure during pregnancy or asphyxiation during birth should be identified.

Patients with tuberous sclerosis typically present with the classic Vogt’s triad of symptoms. These are skin lesions, convulsive seizures, and intellectual disability. Patients with tuberous sclerosis will have adenoma sebaceum, ungual fibroma, cortical tubers, subependymal nodules, and multiple retinal astrocytomas. They then go on to develop infantile spasms, ash leaf spots (hypomelanotic macules), cardiac rhabdomyoma, and renal angiolipomas.

Patients with neurofibromatosis type 1 will have café au lait spots, axillary freckles, and Lisch nodules (iris hamartomas). On investigation, these patients also present with plexiform simple neurofibromas, optic gliomas, obstructive hydrocephalus, and pheochromocytomas. Patients with neurofibromatosis type 2 will have bilateral acoustic neuromas and can also develop multiple meningiomas.

Sturge-Weber CT

Image: “CT (without contrast) of the brain of a 20-month-old child with Sturge-Weber syndrome demonstrating prominent subcortical white matter calcification.” by Frank Gaillard – Own work. License: CC BY-SA 3.0

Sturge-Weber syndrome can often be noticed through the “port wine” stain, or “nevus flammeus” stain that typically has a cranial nerve V distribution. Patients develop leptomeningeal angiomas and will suffer from seizures and intellectual disability. They may develop early-onset glaucoma.

Remember – hypotonia is not a diagnosis of a disease but a syndrome.  When examining a patient with hypotonia, it is important to identify underlying causes. Central hypotonia is typically associated with other signs of CNS dysfunction like seizures, developmental delay, microcephaly, and dysmorphic features. Peripheral hypotonia has a lack of central signs; weakness is prominent.

Management of Neurologic Disorders in Children

Treatment of cerebral palsy is tailored for the individual patient. In children with cerebral palsy, current therapies include anticonvulsants, botulinum toxin, diazepam, fitness training, and goal-directed training among others.

There is no treatment for neurocutaneous disorders like neurofibromatosis and Von Hippel-Lindau syndrome. When tumors form, surgery is often the only option. Apart from surgery, most management options are based on support and general counseling.

There is no cure for autism, and therapy is based mainly on improving social communication.

Prognosis of Neurologic Disorders in Children

The prognosis of cerebral palsy is highly dependent on the level of motor deficit and the intellectual ability of the patient. In most cases, cerebral palsy patients survive into adulthood and live to senior age. Life expectancy has improved significantly in the last 10-20 years.

Autism spectrum disorders are lifelong and have a variable course, often dependent on the severity of the disease in childhood. Many (around 15 %) will live independent lives. Another 15 to 10 % will need community living support. The most prognostic factors for independent living are cognitive and verbal capacity.

Those with neurofibromatosis type 1 rarely live beyond 50. Poor prognostic factors include childhood learning difficulties and optic gliomas among others.

Prognosis in patients with spina bifida depends on the severity of the defect. The milder the symptoms, the better the prognosis. However, medications, physical rehabilitation, and surgical intervention can improve the quality of life to a greater extent.

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