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Neurocognitive and Developmental Regression


The etiology of intellectual developmental disabilities includes a wide spectrum of disorders that may present at different periods of development (infantile, juvenile, adult) and with different trajectories ( Fig. 28.1 ). Some are static encephalopathies (cerebral palsy, hypoxic-ischemic encephalopathy), while others are progressive, resulting in intellectual, neurologic, and/or developmental regression ( Table 28.1 ).

Fig. 28.1
Potential developmental trajectories.

From Holland J, Brown R. Developmental regression: assessment and investigation. Paediatr Child Health. 2017;27[6]:253–259 [ Fig. 1 , p. 253].

TABLE 28.1
Criteria for Regression
Modified from Holland J, Brown R. Developmental regression: assessment and investigation. Paediatr Child Health . 2017;27(6):253–259 ( Box 1 , p. 254).
Any child who fulfills all the following three criteria:

  • Progressive deterioration for more than 3 mo with

  • Loss of already attained intellectual/developmental abilities and

  • Development of abnormal neurologic signs

Excluding: static intellectual loss, e.g., after encephalitis, head injury, or near drowning
Including:

  • Children who meet the case definition even if specific neurologic diagnoses have been made

  • Metabolic disorders leading to neurologic deterioration

  • Seizure syndromes (epileptic, encephalopathies) if associated with progressive deterioration

  • Pre-existing developmental delay with acute deterioration

Dominant etiologic categories include:

  • Storage diseases including leukoencephalopathies

  • Inborn errors of metabolism including mitochondrial disorders

  • Genetic and idiopathic epilepsy encephalopathies

  • Cerebrovascular diseases

  • Trauma

Progressive neurocognitive regression is an uncommon but important presentation to recognize, diagnose, and potentially treat. The cardinal feature is usually first stagnation and then loss of developmental milestones in young children or loss of abilities, especially cognitive, in older children. The deficits can be slow or rapidly progressive and may or may not be accompanied by other neurologic signs and symptoms. Early recognition and treatment, when possible, may prevent permanent neurologic deficits. Distinguishing delayed development from arrested development or loss of skills can be challenging, especially on first presentation when there are insufficient data to predict the overall trajectory. The recognition of subtle features depends on both parental reporting and careful developmental screening by primary care providers. Overt symptomatology or rapid decline is unlikely to go unnoticed and requires urgent evaluation in all cases. The differential diagnosis of neurodegenerative conditions is broad and includes genetic, neurologic, infectious, immunologic, endocrine, traumatic, and idiopathic conditions. Initial referral to multiple specialists may be needed.

Diagnostic Approach

Distinguishing delayed development from arrested development can be challenging, especially on first presentation when there are insufficient data to predict the overall trajectory. Normal development can include brief, transient plateaus or minor losses of skills that occur prior to a significant leap forward in overall development or during concurrent illness. In such cases careful observation and close follow-up will be reassuring. There are certain key elements to consider when taking a history or examining a patient that may trigger deeper exploration for the possibility of regression or intellectual disability (ID) ( Tables 28.2 and 28.3 ). Careful neurocognitive assessment is essential when there are subtle or ill-defined but concerning losses of skills or arrest of development. Referral for neuropsychologic evaluation is essential to correctly establish the specific areas of weakness or change and establish a baseline for the developmental diagnosis.

TABLE 28.2
Elements in History That Are Red Flags for Regression
General

  • Age at presentation: certain disorders present within specific age ranges

  • Trigger: some disorders manifest more symptoms during intercurrent illness

  • Nature of progression of symptoms (slow, sharp, or stepwise decline)

  • Other neurologic symptoms (movement disorders, gait disturbances, behavioral changes, ataxia, seizures, signs of increased intracranial pressure)

  • Seizures, if present: type, nature, frequency, and response to treatment

  • Endocrine disorders: adrenal dysfunction in peroxisomal disorders (Zellweger)

Developmental History

  • Milestones: rate achieved, change in progression

Family Health History

  • Family history of neurodegenerative disorders

  • Consanguinity

  • Ancestry (e.g., Tay-Sachs in Jewish and Amish communities)

TABLE 28.3
Elements on Physical Examination That Are Red Flags for Regression
Head Circumference

  • Macrocephaly (white matter disorders, hydrocephalus): especially if crossing centiles

  • Microcephaly (gray matter disorders)

Dysmorphic Features

  • Coarse facial features in mucopolysaccharidosis

  • Tall forehead, depressed nasal bridge, micrognathia in peroxisomal biogenesis disorders

Ophthalmology

  • Ptosis (mitochondrial disorders, myasthenia syndromes, Menkes syndrome)

  • Retinal degeneration (gray matter disease)

  • Optic atrophy (white matter disease)

  • Cherry-red spots (GM 1/2 [Tay-Sachs] gangliosidosis, Krabbe leukodystrophy, metachromatic leukodystrophy)

Neurology

  • Long tract signs in raised intracranial pressure

  • Abnormal tone (spasticity, dystonia, hypotonia)

  • Movement disorder (ataxia, chorea)

Skin

  • Café-au-lait spots in neurofibromatosis, Chediak-Higashi syndrome, Gaucher disease, Hunter syndrome

  • Hypopigmented macules and Shagreen patch in tuberous sclerosis

  • Abnormal “kinky” hair in Menkes syndrome

  • Severe, intractable eczema in biotinidase deficiency

Visceromegaly

  • Hepatosplenomegaly is a frequent manifestation of a number of storage disorders

Other

  • Skeletal manifestations: dysostosis multiplex in lysosomal disorders, stippling in peroxisomal disorders

  • Cardiac valvular disease in lysosomal storage disorders

Developmental regression should be considered as a separate diagnostic entity, unique from global developmental delay (GDD) or ID (see Chapter 27 ) even though there are overlapping conditions. Identifying true regression, rather than failure of development, may be challenging and require close follow-up over a period of time. Once regression is identified, evaluation is warranted.

If the arrest in development is more abrupt, global, or associated with other neurologic signs and symptoms, urgent evaluation is indicated. This may include referral to neurology and/or medical genetics, both basic labs (comprehensive metabolic panel, thyroid studies, blood counts) and specific laboratory studies based on accompanying symptoms, brain MRI, and EEG ( Table 28.4 and Figs. 28.2 and 28.3 ). A specific subset of metabolic disorders can present with regression and various treatment options are available; it is thus important to recognize and diagnose these potentially treatable disorders ( Tables 28.5 and 28.6 ). An exception to this rule is the loss of social and communication skills that precedes a diagnosis of autism in ∼30% of cases. Neuropsychologic evaluation is required to determine whether the regression is part of the autistic spectrum (see Chapter 32 ).

TABLE 28.4
Tiered Approach to Evaluating Regression ∗
Blood

  • Genetic testing: genomic approach—exome/genome or large gene panel on exome backbone if more targeted

  • Full blood count, urea and electrolytes, liver function test, bone profile, thyroid function test, ESR, ammonia, lactate, uric acid

  • Very long-chain fatty acids

  • Biotin

  • Copper and ceruloplasmin

  • Amino acids

  • Free carnitine and acylcarnitine profile

  • Lysosomal enzyme assay in leukocytes

  • Vitamin B 12 and E levels

  • Heavy metals: lead, mercury

Cerebrospinal Fluid

  • Amino acids (with plasma amino acids simultaneously)

  • Lactate and pyruvate

  • Glucose (with plasma levels simultaneously)

  • Neurotransmitters and neuroinflammatory markers (N-methyl-D-aspartate receptor antibodies)

Urine

  • Organic acids

  • Glycosaminoglycans and oligosaccharides through mass spectrometry

BRAIN MRI with consideration for targeted spectroscopy
TISSUE BIOPSY and analysis as indicated

  • Muscle for mitochondrial testing

  • Liver for assessment of copper, iron, or electron microscopy

∗ This evaluation is often coincident with the evaluation for intellectual disability (see Chapter 27 ).

Fig. 28.2, Evaluation of children with progressive cognitive, developmental, and neurologic deterioration. CDG, congenital disorders of glycosylation; CSF, cerebrospinal fluid; CTX, cerebrotendinous xanthomatosis.

Fig. 28.3, Bar graph depicting the yield of “metabolic screening tests.” For the mucopolysaccharidoses, enzyme activity should be measured as a next step: Hurler (iduronidase); Hunter syndrome (iduronate-2-sulfatase); Sanfilippo syndrome (IIIa = heparan-N-sulfatase, IIIb = N-acetyl-glucosaminidase, IIIc = acetyl CoA glucosamine N-acetyl transferase, IIId = N-acetyl-glucosamine-6-sulfatase); Sly syndrome (β-glucuronidase). ACP, plasma acylcarnitine profile; HHH, hyperornithinemia-hyperammonemia-homocitrullinuria; MPS, mucopolysaccharidosis; PAA, plasma amino acids; tHcy, total homocysteine; UOA, urine organic acids.

TABLE 28.5
Select “Intrinsic” Conditions Associated with Developmental Regression
Age at Onset (yr) Conditions Comments
<2, with hepatomegaly Fructose intolerance Vomiting, hypoglycemia, poor feeding, failure to thrive (when given fructose)
(see Chapter 17 )
Galactosemia Lethargy, hypotonia, icterus, cataract, hypoglycemia (when given lactose)
Glycogenosis (glycogen storage disease) types I–IV Hypoglycemia, cardiomegaly (type II)
Mucopolysaccharidosis types I and II Coarse facies, stiff joints
Niemann-Pick disease, infantile type Gray matter disease, failure to thrive
Tay-Sachs disease Seizures, cherry-red macula, edema, coarse facies
Zellweger (cerebrohepatorenal) syndrome Hypotonia, high forehead, flat facies
Gaucher disease type II Extensor posturing, irritability
Carbohydrate-deficient glycoprotein syndromes Dysmyelination, cerebellar hypoplasia
< 2, without hepatomegaly Krabbe disease Irritability, extensor posturing, optic atrophy, and blindness
Rett syndrome Females with deceleration of head growth, loss of hand skills, hand wringing, impaired language skills, gait apraxia
Maple syrup urine disease Poor feeding, tremors, myoclonus, opisthotonos
Phenylketonuria Light pigmentation, eczema, seizures
Menkes kinky hair disease Hypertonia, irritability, seizures, abnormal hair
Subacute necrotizing encephalopathy of Leigh White matter disease
Cerebro-oculofacioskeletal syndrome (of Pena and Shokeir) Reduced white matter, failure to thrive
Canavan disease White matter disease
Pelizaeus-Merzbacher disease White matter disease
2–5 Niemann-Pick disease types III and IV Hepatosplenomegaly, gait difficulty
Wilson disease Liver disease, Kayser-Fleischer ring; deterioration of cognition is late
Gangliosidosis type II Gray matter disease
Ceroid lipofuscinosis Gray matter disease
Mitochondrial encephalopathies (e.g., myoclonic epilepsy with ragged red fibers [MERRF]) Gray matter disease
Ataxia-telangiectasia Basal ganglia disease
Huntington disease (chorea) Basal ganglia disease
Hallervorden-Spatz syndrome Basal ganglia disease
Metachromatic leukodystrophy White matter disease
Adrenoleukodystrophy White matter disease, behavior problems, deteriorating school performance, quadriparesis
5–15 Adrenoleukodystrophy Same as for adrenoleukodystrophy in 2–5 yr olds
Multiple sclerosis White matter disease
Neuronal ceroid lipofuscinosis, juvenile and adult (Spielmeyer-Vogt and Kufs disease) Gray matter disease
Schilder disease White matter disease, focal neurologic symptoms
Refsum disease Peripheral neuropathy, ataxia, retinitis pigmentosa
Sialidosis type II, juvenile form Cherry-red macula, myoclonus, ataxia, coarse facies
Subacute sclerosing panencephalitis Diffuse encephalopathy, myoclonus; may occur years after measles

TABLE 28.6
Select “Extrinsic” Conditions Associated with Developmental Regression

  • Neoplasms and their therapy

  • Leukemia

  • Tumors

  • Langerhans cell histiocytosis

  • Hemophagocytic lymphohistiocytosis

  • Increased intracranial pressure

  • Hydrocephalus, including ventricular shunt malfunctions

  • Subdural hematoma or effusion

  • Infections

  • Encephalitis, including HIV infection, toxoplasmosis

  • Meningitis

  • Endocrine disorders

  • Vitamin B 12 and E deficiencies

  • Hypothyroidism

  • Chronic lead poisoning

  • Adrenocortical insufficiency

  • Autoimmune encephalitis (e.g., N-methyl-D-aspartate receptor [NMDAR] encephalitis)

  • Collagen vascular disease (e.g., systemic lupus erythematosus)

  • “Pseudo” regression

    • Child abuse

    • Behavioral disorders

    • Bullying

    • Medication, recreational drug effects

More than 300 neurodegenerative disorders have been described including genetic, neurologic, infectious, immunologic, endocrine, traumatic, and idiopathic conditions; additional classification based on progression and age is noted in Table 28.7 and in Figure 28.2 . Neurodegenerative disorders are often categorized as involving white matter, gray matter, basal ganglia, or the entire central nervous system. White matter diseases (e.g., adrenoleukodystrophy) affect long tracts and manifest with loss of motor skills, spasticity, disturbed gait, areflexia (if peripheral nerve is also involved), or ataxia, whereas gray matter diseases (e.g., ceroid lipofuscinoses) manifest with seizures and abnormalities of cognition, vision, and hearing. Many disorders commonly classified as “white matter” or “gray matter” manifest with a mixed picture of signs and symptoms. Diseases that involve primarily the basal ganglia (deep gray matter), such as Huntington disease, manifest with cognitive deterioration, behavioral changes, rigidity, dystonia, ataxia, dysarthria, seizures, and incoordination. When these diseases progress, neurologic signs and symptoms may become more widespread and less specific.

TABLE 28.7
Causes of Developmental Regression
Modified from Pina-Garza JE. Fenichel’s Clinical Pediatric Neurology: A Signs and Symptoms Approach . 7th ed. Philadelphia: Saunders; 2013.
Onset Before Age 2 yr
AIDS
Encephalopathy ∗
Autism Spectrum Disorder
Disorders of Amino Acid Metabolism

  • Guanidinoacetate methyltransferase deficiency ∗

  • Homocystinuria

  • Maple syrup urine disease (intermediate and thiamine response forms) ∗

  • Phenylketonuria

  • Hyperammonemic disorders

Disorders of Lysosomal Enzymes

  • Ganglioside storage disorders

    • GM 1 gangliosidosis

    • GM 2 gangliosidosis (Tay-Sachs disease, Sandhoff disease)

  • Gaucher disease type II (glucosylceramide lipidosis) ∗

  • Globoid cell leukodystrophy (Krabbe disease)

  • Glycoprotein degradation disorders

  • I-cell disease

    • Mucopolysaccharidoses ∗

    • Type I (Hurler syndrome) ∗

    • Type III (Sanfilippo disease)

  • Niemann-Pick disease type A (sphingomyelin lipidosis)

  • Sulfatase deficiency disorders

    • Metachromatic leukodystrophy (sulfatide lipidoses)

    • Multiple sulfatase deficiency

Carbohydrate-Deficient Glycoprotein Syndromes
Hypothyroidism ∗
Mitochondrial Disorders

  • Alexander disease

  • Mitochondrial myopathy, encephalopathy, lactic acidosis, stroke

  • Progressive infantile poliodystrophy (Alpers disease)

  • Subacute necrotizing encephalomyelopathy (Leigh disease)

  • Trichopoliodystrophy (Menkes disease)

Neurocutaneous Syndromes

  • Chediak-Higashi syndrome

  • Neurofibromatosis ∗

  • Tuberous sclerosis ∗

Other Disorders of Gray Matter

  • Infantile ceroid lipofuscinosis (Santavuori-Haltia disease)

  • Infantile neuroaxonal dystrophy

  • Lesch-Nyhan disease ∗

  • Progressive neuronal degeneration with liver disease

    • Infantile spasms (West, Lennox-Gastaut)

    • Epileptic encephalopathies (monogenetic, idiopathic)

  • Rett syndrome

    • Aicardi-Goutieres syndrome

Other Disorders of White Matter

  • Aspartoacylase deficiency (Canavan disease)

  • Galactosemia: transferase deficiency ∗

  • Neonatal adrenoleukodystrophy

  • Pelizaeus-Merzbacher disease

  • Progressive cavitating leukoencephalopathy

Progressive Hydrocephalus ∗
Onset After Age 2 yr
Disorders of Lysosomal Enzymes

  • Gaucher disease type III (glucosylceramide lipidosis)

  • Globoid cell leukodystrophy (late-onset Krabbe disease)

  • Glycoprotein degradation disorders

  • Aspartylglycosaminuria

  • Mannosidosis type II

  • GM 2 gangliosidosis (juvenile Tay-Sachs disease)

  • Metachromatic leukodystrophy (late-onset sulfatide lipidoses)

  • Mucopolysaccharidoses types II and VII

  • Niemann-Pick type C (sphingomyelin lipidosis)

Infectious Disease

  • AIDS encephalopathy ∗

  • Congenital syphilis ∗

  • Subacute sclerosing panencephalitis

Other Disorders of Gray Matter

  • Ceroid lipofuscinosis

    • Juvenile

    • Late infantile (Bielschowsky-Jansky disease)

  • Huntington disease

  • Biotin-thiamine-responsive basal ganglia disease

  • Mitochondrial disorders

    • Late-onset poliodystrophy

    • Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)

    • Myoclonic epilepsy and ragged-red fibers

  • Progressive neuronal degeneration with liver disease

  • Xeroderma pigmentosum

  • Wilson disease

  • Neurodegeneration with brain iron accumulation (NBIA)

  • Pantothenate kinase neurodegeneration

Other Disorders of White Matter

  • Adrenoleukodystrophy

  • Alexander disease

  • Cerebrotendinous xanthomatosis

  • Progressive cavitating leukoencephalopathy

  • Epileptic aphasia

    • Landau-Kleffner syndrome

    • Febrile infection-related epilepsy syndrome (FIRES)

∗ The most common conditions and the ones with disease-modifying treatments.

Progressive disorders may be the result of metabolic or storage diseases or due to a genetic syndrome (Rett syndrome). In contrast, static encephalopathies are usually the result of structural abnormalities due to abnormal development or trauma (see Tables 28.6 and 28.7 ).

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