Chapter 44 Cognitive and Motor Regression
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.
Diagnosis | Number of Cases |
---|---|
POLIODYSTROPHIES* | 129 |
Lysosomal storage disorders | 39 |
Hypoxic poliodystrophy | 29 |
Idiopathic poliodystrophy | 24 |
West’s syndrome | 17 |
Lennox–Gastaut syndrome | 9 |
Metabolic poliodystrophy | 4 |
Toxoplasmosis | 3 |
Post-vaccine poliodystrophy | 3 |
Lowe’s syndrome | 1 |
LEUKODYSTROPHIES† | 71 |
SSPE | 26 |
ADEM and MS | 17 |
Adrenoleukodystrophy | 8 |
Metachromatic leukodystrophy | 5 |
Pelizaeus–Merzbacher disease | 4 |
Krabbe’s disease | 4 |
Phenylketonuria | 2 |
Cockayne’s syndrome | 2 |
Canavan’s disease | 1 |
Alexander’s disease | 1 |
Maple syrup urine disease | 1 |
CORENCEPHALOPATHIES‡ | 26 |
Idiopathic corencephalopathy | 8 |
Huntington’s disease | 5 |
Mitochondrial disorders | 4 |
Dystonia musculorum deformans | 2 |
Hallervorden–Spatz syndrome | 2 |
Ataxia-telangiectasia | 1 |
Congenital indifference to pain | 1 |
Infantile neuroaxonal dystrophy | 1 |
Riley–Day syndrome | 1 |
Wilson’s disease | 1 |
DIFFUSE ENCEPHALOPATHIES | 63 |
Tuberous sclerosis | 19 |
Idiopathic encephalopathy | 17 |
Hyperammonemic disorders | 6 |
Mitochondrial disorders | 4 |
Neurofibromatosis | 4 |
Achondroplasia | 2 |
Organic acidurias | 2 |
Letterer–Siwe disease | 2 |
Sturge–Weber syndrome | 2 |
Zellweger’s syndrome | 2 |
Homocystinuria | 1 |
Incontinentia pigmenti | 1 |
Sjögren–Larsson syndrome | 1 |
SPINOCEREBELLOPATHIES§ | 51 |
Spinal muscular atrophy | 19 |
Hereditary spastic paraplegia | 12 |
Acute cerebellar ataxia | 8 |
Infantile polymyoclonus | 4 |
Charcot–Marie–Tooth disease | 2 |
Friedreich’s ataxia | 2 |
Marinesco–Sjögren syndrome | 1 |
OPCA | 1 |
Spinocerebellar degeneration | 1 |
Refsum’s disease | 1 |
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.
Diagnosis | Number of Cases |
---|---|
LEUKOENCEPHALOPATHIES | 183 |
Metachromatic leukodystrophy | 59 |
Krabbe’s disease | 33 |
Pelizaeus–Merzbacher disease | 17 |
Canavan’s disease | 13 |
Vanishing white matter disease | 11 |
Aicardi–Goutières syndrome | 10 |
Alexander’s disease | 10 |
Other | 31 |
NEURONAL CEROID-LIPOFUSCINOSES | 141 |
NCL late infantile | 73 |
NCL juvenile | 44 |
NCL infantile | 22 |
Other | 2 |
MITOCHONDRIAL | 122 |
Leigh’s syndrome | 17 |
NARP (including NARP/MILS) | 17 |
Other | 88 |
MUCOPOLYSACCHARIDOSES | 102 |
Mucopolysaccharidosis IIIA (Sanfilippo’s syndrome) | 69 |
Mucopolysaccharidosis IIA (Hunter’s disease) | 15 |
Other | 18 |
GANGLIOSIDOSES | 100 |
GM2 gangliosidosis type 1 (Tay–Sachs disease) | 41 |
GM2 gangliosidosis type 2 (Sandhoff’s disease) | 33 |
GM1 gangliosidosis | 23 |
Other | 3 |
PEROXISOMAL | 69 |
Adrenoleukodystrophy | 56 |
Other | 13 |
OTHER METABOLIC | 95 |
Niemann–Pick disease type C | 38 |
PKAN/NBIA | 21 |
Menkes’ disease | 16 |
Glutaric aciduria type 1 | 10 |
Molybdenum co-factor deficiency |