Introduction

Diseases in which there is a gradual loss of cognitive function can be described as progressive encephalopathies (PE). A number of toxic, infectious, inflammatory, and neoplastic disorders of the central nervous system (CNS) can have subacute to chronic presentations, and must be considered in the differential diagnosis of patients initially presenting with PE, but this chapter is primarily focused on the diagnostic challenge posed by patients with genetic disorders that present with progressive neurological dysfunction.

One challenge posed by these disorders relates to their being individually rare and thus generally unfamiliar to clinicians. A second challenge relates to phenotypic variability, as many of the inborn errors of metabolism (IEMs) that had been known by one or more “classic” phenotypes are now known to vary greatly in presentation, based on the degree of the enzymatic defect. For example, neonatal encephalopathy and multi-organ failure may result from the complete deficiency of an enzyme, whose partial deficit may cause only nonspecific psychiatric symptoms in adulthood.

Pathophysiology

Most genetic causes of PE can be classified as an IEM or neurodegenerative disorder (ND). The IEMs are themselves frequently divided into three groups, based on pathophysiology. In the first group are those disorders in which symptoms of acute or chronic intoxication are caused by the intracellular and extracellular (and thus measurable in blood, urine, and cerebrospinal fluid) accumulation of the compounds proximal to the defective enzyme. This includes errors of amino acid catabolism (e.g., phenylketonuria and maple syrup urine disease), organic acid catabolism (e.g., methylmalonic aciduria and propionic acidemia), urea synthesis (e.g., ornithine transcarbamylase deficiency and argininemia), sugar catabolism (e.g., galactosemia and hereditary fructose intolerance), metal transport (e.g., Wilson’s disease and Menkes’ disease), and porphyrin metabolism. Because the placenta acts to maintain homeostasis, these disorders are unlikely to cause embryonic toxicity. Most patients develop symptoms in infancy and childhood, following a symptom-free period whose length depends in part on the degree of enzyme deficiency. Other circumstances, such as fever, illness, and diet changes, can also influence the timing and severity of symptoms.

The second group of IEMs are those in which symptoms are due, at least in part, to the inability of the brain and other organs to produce or utilize sufficient energy for normal function. Energy deficiency can result from defective function of the mitochondria, including defects of pyruvate transport and modification, the Krebs cycle enzymes, fatty acid oxidation enzymes, and the respiratory chain enzymes that allow for aerobic metabolism. Energy deficiency can also result from defects in cytoplasmic enzymes, such as those responsible for glycogen synthesis, glycolysis and gluconeogenesis, insulin secretion and responsiveness, creatine synthesis and transport, and the pentose phosphate pathway. It is not uncommon for children with IEMs causing energy defects to present with congenital dysmorphism or cerebral dysgenesis.

The third group of IEMs are typically thought of as storage disorders, in which incompletely catabolized complex molecules accumulate within neuronal and extraneuronal tissues and cause progressive neurologic symptoms and somatic changes. This would include the mucopolysaccharidoses, the oligosaccharidoses, and the lysosomal storage disorders. Some authors expand this third group to include disorders of complex molecule synthesis and catabolism that do not result in measurable storage, including the Peroxisomal disorders, congenital disorders of glycosylation, and disorders of cholesterol biosynthesis.

Genetic disorders causing PE, which are not known to have a specific metabolic basis but which result in the progressive loss of neurons, usually demonstrated as progressive atrophy on neuroimaging, are classified as neurodegenerative. While the diagnosis of a ND previously relied solely on clinical features and expert pattern recognition, the past decades have seen elucidation of the genetic basis for most and the pathophysiologic basis for many. Those NDs in which the pathophysiology remains unclear are often subdivided into those affecting the brain homogenously (diffuse encephalopathies) and those tending to affect the cerebral cortex (poliodystrophies), cerebral white matter (leukodystrophies), basal ganglia (CORENCEPHALOPATHIES), cerebellum, or to preferentially affect the brainstem.

Epidemiology

Although the causes of PE are individually rare, the combined incidence of PE has been estimated to be as high as 1 in 2000 live births [Surtees, 2002]. Much of what has been published regarding these disorders has been retrospective and focused on individual conditions, providing little basis for a discussion of their collective epidemiology. A few studies have been notable exceptions.

An early paper examining the experience with PE at two large academic centers in the United States found that, of 1218 admissions to their child neurology services over the course of 10 years, 341 patients were diagnosed with 1 of more than 50 disorders causing neurological dysfunction [Dyken and Krawiecki, 1983]. Table 44-1 shows the results of their analysis of the relative frequency of the various diagnoses. Although 72 percent of the cases studied had a genetic or metabolic disorder causing PE, the study also included a significant number of children with pure lower motor neuron syndromes and acquired injuries due to infection, immunologic disorders, refractory epilepsy, chronic environmental insults, nutritional deficiencies, and iatrogenic factors. A study from the Children’s Hospital of Lahore, Pakistan [Sultan et al., 2006], found that, of the 1273 children admitted to the neurology service from 2004 to 2005, 66 were diagnosed with PE and most received a specific diagnosis. The most common diagnoses, in descending order of frequency, were metachromatic leukodystrophy (14 cases), adrenoleukodystrophy (11), subacute sclerosing panencephalitis (8), Wilson’s disease (6), Friedreich’s ataxia (5), liposis (4), Gaucher’s disease (3), Alexander’s disease (2), and pantothenate kinase-associated neurodegeneration (PKAN) (2). More than half of the patients underwent funduscopic examination, electroencephalography, and cerebrospinal fluid examination as part of their diagnostic work-up.

Table 44-1 Diagnosis in 340 Cases of Developmental Regression

ADEM, acute disseminated encephalomyelitis; MS, multiple sclerosis; OPCA, olivopontocerebellar atrophy; SSPE, subacute sclerosing panencephalitis.

* Poliodystrophies = predominant cortical involvement.

† Leukodystrophies = predominant cerebral white-matter involvement.

‡ CORENCEPHALOPATHIES = predominant basal ganglia involvement.

§ Spinocerebellopathies = predominant spinal cord and cerebellar involvement.

(From Dyken P, Krawiecki N. Neurodegenerative diseases of infancy and childhood. Ann Neurol 1983;13:351–364.)

Following the initial description in 1996 of 10 cases of new variant Creutzfeldt–Jakob disease (nvCJD) affecting young adults in the United Kingdom [Will et al., 1996], several countries instituted prospective surveillance programs to collect data on patients with PE to better identify additional cases of nvCJD. Although these studies have relied on reports from pediatricians and have been unable to describe absolute incidence or prevalence figures, they have reported relative prevalences within their areas. The first report from the surveillance done in the UK [Devereux et al., 2004] collected and analyzed pediatric cases of progressive intellectual and neurological deterioration (PIND) over a 5-year span. The cases included children who had:

The study excluded children with intellectual and neurological deterioration after a nonprogressive insult, such as encephalitis, trauma, or global hypoxic-ischemic injury, but did include children with seizure disorders who otherwise met the case definition and children carrying diagnoses that could be expected to lead to progressive deterioration in the future. Of the 798 cases collected, 577 had a confirmed diagnosis, 6 had definite or probable nvCJD, and 211 had no clear etiologic diagnosis at the time of publication but did not have clinical features suggestive of nvCJD. There were nearly 100 different confirmed diagnoses, but more than one-quarter of the cases were explained by the five most common: mucopolysaccharidosis type III (Sanfilippo’s syndrome), adrenoleukodystrophy, late infantile neuronal ceroid-lipofuscinosis, mitochondrial diseases, and Rett’s syndrome. Higher rates of prevalence and of consanguinity were reported in families of South Asian origin. A follow-up of the UK study [Verity et al., 2010a] reported a confirmed etiologic diagnosis in 1047 of the 2493 cases of PIND that had been collected by 2008, with nearly one-quarter of cases again explained by the five most common diagnoses: neuronal ceroid-lipofuscinoses, mitochondrial diseases, mucopolysaccharidoses, GANGLIOSIDOSES, and Peroxisomal disorders. The most recent update of the study [Verity et al., 2010b] reported that, after 12 years, 147 different etiologies were found to explain 1114 of the 2636 cases of PIND collected. In total, only 6 children with confirmed or probable nvCJD had been identified. The 30 most common diagnoses identified in the study are presented in Table 44-2.

Table 44-2 Common Diagnoses in 1114 Cases of Progressive Encephalopathy

MILS, maternally inherited Leigh’s syndrome; NARP, neuropathy, ataxia, and retinitis pigmentosa; NBIA, neurodegeneration with brain iron accumulation; NCL, neuronal ceroid-lipofuscinosis; PE, progressive encephalopathy; PKAN, pantothenate kinase-associated neurodegeneration (previously Hallervorden–Spatz disease).

(From Verity et al., The epidemiology of progressive intellectual and neurological deterioration in childhood. Arch Dis Child 2010b.)

A survey-based study conducted in Australia [Nunn et al., 2002] identified 230 cases of childhood PE in a 2-year period, with 134 patients having Rett’s syndrome, 20 having a lysosomal storage disorder, 16 having a leukodystrophy, and 15 having a mitochondrial disease. A study done in Oslo, Norway, gathered cases of pediatric PE over an 18-year period from the area’s one children’s hospital and from the national diagnostic laboratory for metabolic diseases [Strømme et al., 2007]. The authors excluded patients with diseases in which cognitive impairment was either atypical (e.g., spinocerebellar ataxia and spinal muscular atrophy) or typically seen only late in the course (multiple sclerosis). Also, unlike the studies already discussed, this study excluded disorders, such as regressive autism and Rett’s syndrome, in which intellectual deterioration may be seen early in the course but typically stabilizes. They reported a total of 84 cases of PE, of which they classified two-thirds as metabolic, one-third as neurodegenerative, and 2, both due to HIV/AIDS, as infectious. The metabolic and neurodegenerative cases were further subcategorized as shown in Table 44-3.

Table 44-3 Diagnoses in 84 Cases of Progressive Encephalopathy in Oslo, Norway

(From Strømme P et al. Incidence rates of progressive childhood encephalopathy in Oslo, Norway: A population based study. BMC Pediatr 2007;7:25.)

There were 28 children with disorders of subcellular organelles (23 lysosomal, 3 mitochondrial, and 2 Peroxisomal) and 27 with disorders of intermediary metabolism (11 organic acidurias, 6 fatty acid oxidation disorders, 4 urea cycle disorders, 4 galactosemia, and 2 unspecified). The neurodegenerative cases included 10 children with a specific diagnosis (1 ataxia telangiectasia, 2 Cockayne’s syndrome, 1 megalencephalic leukoencephalopathy with subcortical cysts, 3 microphthalmia and brain atrophy, 1 pontocerebellar hypoplasia and infantile spinal muscular atrophy, and 2 Schinzel–Gideon syndrome) and 17 in which only the portion of the CNS most affected could be specified (8 cerebellum, 3 cerebral cortex, 3 cerebral white matter, 1 basal ganglia, 1 cerebellum and basal ganglia, and 1 cerebellum and brainstem). Analysis of the study data found that there was a 7-fold increase in risk of PE in children of Pakistani origin, due largely to the predominantly autosomal-recessive inheritance pattern for causes of PE and the much higher incidence of reported consanguinity in that community [Strømme et al., 2010]. It was estimated that 30 percent of all cases of PE, and at least 50 percent of the cases in children of Pakistani origin, would have been prevented if the practice of consanguinous marrage were avoided.

The same authors [Strømme et al., 2008] used local population data to calculate an overall incidence rate for PE of 6.43 per 100,000 person years (95 percent CI 5.15–7.97), with the age-specific rates being highest for infants <1 year old (79.9 per 100,000 person years) and lowest for children over 5 years (0.65 per 100,000 person years). They also found that the age at diagnosis averaged 0.5 years for patients with metabolic diseases and 4.5 years for patients with neurodegenerative diseases, and that children with neonatal onset and metabolic etiology had the highest risk of mortality.

Diagnostic Evaluation

Every child with a suspected developmental disorder should be subjected to a thorough clinical evaluation that includes a detailed medical and developmental history, family history, review of systems, and physical examination. The two features that most suggest a PE are:

These features are most readily observed when disorders have a later onset and more rapid deterioration, as is often seen in the cerebral forms of adrenoleukodystrophy [Moser et al., 2007]. PE may be difficult to recognize when disorders have a very early onset, develop very slowly, or prevent even initial development from being normal. A variety of metabolic and genetic conditions have been diagnosed in children initially thought to have cerebral palsy due to static encephalopathy [Gupta and Appleton, 2001], and those that have been reported in the literature are listed in Table 44-4. This experience suggests that children with a diagnosis of cerebral palsy should undergo further evaluation for neurodegenerative disorders when any of the following conditions is identified: no definite history of a preceding injury, a family history of neurologic symptoms, a history of parental consanguinity, or inadequately explained oculomotor abnormalities, involuntary movements, ataxia, muscle atrophy, or sensory loss. Children with recurrent, unexplained episodes of altered mental status, vomiting, or abnormal movements should be strongly suspected of having an IEM, such as a mitochondrial disease, aminoacidopathy, organic aciduria, or urea cycle enzyme defect.

Table 44-4 Progressive Encephalopathy Reported to Present as Cerebral Palsy

NARP, neuropathy, ataxia, and retinitis pigmentosa.

Conversely, children who do not have a progressive neurological disease can undergo clinical deterioration resulting from medication side effects, intercurrent medical or psychiatric illnesses, or the evolution of existing hydrocephalus, spasticity, dystonia, or seizures. Some epileptic and neurodevelopmental disorders are associated with loss of acquired skills or cognitive function, but the deterioration is not relentlessly progressive and there is often no discernible destructive process occurring in the CNS. This situation is seen in children with epileptic encephalopathies, such as Dravet’s syndrome, West’s syndrome, and Lennox–Gastaut syndrome, in which neurodevelopment plateaus or regresses at the onset of seizures but may progress again in the future. The regression in language and social skills seen in cases of idiopathic autism is also distinguishable in this way from PE due to metabolic and neurodegenerative disorders.

The critical elements of the clinical evaluation are no different from those discussed in the evaluation of children with nonprogressive neurodevelopmental disorders, which is discussed in detail in Chapter 43. To establish the progressive nature of the child’s symptoms or clinical findings, however, it can be particularly helpful to review any records of the child’s appearance and abilities to which the caregivers can provide access, including photographs, videotapes, and examples of the child’s writing and drawing. Repeated examinations over months or even years may be necessary to uncover subtle regression in some children.

Primary motor and sensory functions are readily assessed by the screening neurologic examination, even in uncooperative children, but higher cortical functions are far more difficult to evaluate. The collective observations of clinicians, parents, and teachers who suspect subtle cognitive decline should be supplemented by those of a child psychologist who is trained to administer age-specific tests and to give an appropriate assessment of the impact of potential confounders, such as primary sensory and motor deficits, inattentiveness, shyness, behavior problems, and cultural and language differences [Sparrow and Davis, 2000]. Children with PE generally have sufficiently impaired social and occupational functioning from loss of higher cortical function to be described as suffering dementia, although the term is rarely applied.

Disturbances of higher cortical function are well characterized and localized in adult patients with acquired and degenerative disorders, including amnesia (i.e., disturbed ability to form new memories or to recall previously learned information), aphasia (i.e., difficulty with the expression or comprehension of language), apraxia (i.e., difficulty carrying out learned motor tasks not caused by weakness or incoordination), agnosia (i.e., difficulty recognizing or identifying objects or sounds not caused by sensory loss), and disturbed executive functioning (i.e., poor planning, organizing, sequencing, and abstracting). The definitions and localizations of the most commonly encountered cognitive disturbances are listed in Table 44-5.

Table 44-5 Cortical Localization of Cognitive Impairments

Laboratory Testing

When PE is suspected, a timely evaluation that results in a specific diagnosis can be of great value. Although specific treatments are available for only a minority of diseases, an etiological diagnosis is helpful in relieving caregivers of anxiety and uncertainty; empowering caregivers to become involved in support and research networks; limiting further diagnostic testing, which may be costly or invasive; and improving understanding of:

In all cases, the diagnostic tests employed should be tailored to the presentation of the child should generally proceed from least to most invasive. Consideration should be given to the early identification or exclusion of all potentially treatable causes of the patient’s symptoms.

One approach to the laboratory evaluation of children with nonspecific PE is outlined in Table 44-6, which lists screening tests that might be applicable to all such children, as well as basic studies for infectious, toxic, endocrinologic, genetic, neoplastic, metabolic, autoimmune, and nutritional disorders that may be suspected on the basis of the history or the results of the initial screening tests. The results of these tests will often suggest the need for:

Table 44-6 Screening Diagnostic Tests for Nonspecific Progressive Encephalopathy

ACTH, adrenocorticotropic hormone; CSF, cerebrospinal fluid; CT, computed tomography; HIV, human immunodeficiency virus, HSV, herpes simplex virus, MRI, magnetic resonance imaging; REM, rapid eye movement; TSH, thyroid stimulating hormone.

Another approach to the evaluation of a patient who may have a rare disease with which the clinician is unfamiliar is to use an interactive database to generate a broad differential diagnosis [Segal, 2007]. Simulconsult (www.simulconsult.com) is a web-based program of this kind that is freely available to clinicians and students. As each piece of clinical information about a patient is entered, including the age of onset of symptoms and pertinent negatives, the program re-orders the diagnoses on its suggested differential and updates the suggestions it makes for what additional pieces of clinical and laboratory data would most help in distinguishing between them. Currently, the program has information on more than 2300 predominantly metabolic and genetic neurological disorders, including more than 120 that are suggested when the finding of “regression (loss or deterioration of milestones)” is entered. A broad differential can help clinicians to avoid cognitive pitfalls that commonly contribute to diagnostic error and delay [Norman and Eva, 2010], including the biases of availability and representativeness (favoring familiar diagnoses over less well-known diagnoses or disease variants) and those of framing and premature closure (favoring findings that confirm rather than question a pre-existing diagnosis).

The individual disorders causing PE in childhood are too numerous to discuss in detail in this chapter, but they are presented in the tables that follow, grouped by age of presentation, the presence or absence of associated somatic signs, and the neurological presentation itself. Treatable disorders are highlighted in boldface and the reader is directed to the appropriate chapter of this textbook for further details regarding clinical presentation, diagnostic testing, and disease management.

We begin with Table 44-7, which classifies the common metabolic disorders presenting in neonates based on clinical features, degree of acidosis and ketosis, and the results of tests for ammonia, lactate, glucose, calcium, and cell counts. For infants from 1–12 months old, disorders causing PE have been grouped into those associated with somatic abnormalities (Table 44-8), those with specific or suggestive neurological signs (Table 44-9), and those that typically cause slowly progressive developmental delays without more specific findings (Table 44-10). For children between the ages of 1 and 5 years, the disorders causing PE have been grouped into three different categories: those with somatic signs (Table 44-11), those with paraparesis (Table 44-12), and those with ataxia and incoordination (Table 44-13). The disorders causing PE in later childhood, between the ages of 5 and 15 years, have been divided into those that present with seizures and ataxia (Table 44-14), extrapyramidal signs, such as dystonia or choreoathetosis (Table 44-15), severe and diffuse CNS signs, including seizures and visual loss (Table 44-16), polymyoclonus (Table 44-17), cerebellar ataxia (Table 44-18), polyneuropathy (Table 44-19), and psychiatric symptoms (Table 44-20). Finally, disorders that may present with PE in late adolescence and adulthood are listed in Table 44-21.

Table 44-20 Progressive Encephalopathy in Middle to Late Childhood (5–15 Years) with Predominantly Psychiatric Symptoms

ACTH, adrenocorticotropic hormone; CSF, cerebrospinal fluid; MRI, magnetic resonance imaging.

* Disorders shown in bold type are treatable.

(Adapted from Scriver et al., The Metabolic and Molecular Basis of Inherited Disease, online edition.)

Up-to-date information about the sensitivity and availability of tests for specific genetic disorders is available through the Gene Tests website (www.genetests.org), maintained by the University of Washington at Seattle through funding from the National Institutes of Health. Some genetic tests can be performed on a research basis through direct communication and cooperation between the clinician and research laboratory.

Management

The specific cause of childhood PE can be difficult to uncover, with about half of the cases in large epidemiologic surveys having no etiologic diagnosis. Still, as a small number of disorders can be at least ameliorated by medical therapies, there is a sense of both hope and urgency to the diagnostic work-up. Caregivers can be expected to have a great number of questions and concerns that will require a large amount of time, patience, and sensitivity on the part of the clinician. Even when disease-specific treatments are not available, the clinician can be of great assistance in maintaining the child’s quality of life. Efforts should be made early in the course to direct the child to other sources of supportive care, including rehabilitation specialists, nutritionists, special education instructors, and speech, occupational, and physical therapists. When possible, the child’s caregivers should be referred to a social worker who can help them obtain financial support, nursing care, and social support networks.

References

The complete list of references for this chapter is available online at www.expertconsult.com.

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