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Develop. Med. Child Nrurol. 1974, 16, 228-241

Revision Article M. J . Noronha

Cerebral Degenerative Disorders of - Infancy and Childhood

Introduction The classification and terminology of the

progressive cerebral degenerative disorders present certain problems. It had been traditional to divide them into the neurolipidoses and the leucodystrophies, this having had the deceptive virtue of sim- plicity. However, recent advances consequent on newer histological and biochemical techniques have made the distinc- tion between the two groups and other associated disorders less certain. Two leucodystrophies. metachromatic and Krabbe’s globoid cell, are now known to be disorders of sphingolipid metabolism and are accordingly classified with the neurolipidoses. On the other hand, in Batten’s disease-which was previously classified with the amaurotic family idiocies -no abnormality of sphingolipid metabolism has so far been demonstrated. therefore it cannot be included with the sphingolipidoses. Further, it is now known that some of the mucopolysaccharide disorders, e.g, Hunter’s and Hurler’s disease, also show an excess of sphingolipid in the stored neuronal material as we11 as the accumulated mucopolysaccharide.

O’Brien (1970) has suggested that there are four levels of sophistication to be distinguished in the elucidation of inborn errors of metabolism.

( I ) The phenotypical delineation of the disorder from the clinical, pathological and genetic points of view. (2) The identification of the compounds of which metabolism is deranged. ( 3 ) The determination of the enzymic or structual protein defect which is the pathogenetic key-stone. (4) The determination of the nature of the enzymatic or structural protein abnormality, e.g. reduced hydrolytic activity, increased rate of degradation or depressed synthesis either because of operator gene mutation or because of activity change in a repressor gene.

From the clinician’s point of view, O’Brien suggests that the diagnosis should extend to levels 1 and 2, as the clinician is neither trained nor required to become fully conversant with the chemical and molecular biological complexities, i.e. levels 3 and 4.

Accordingly, on clinical and pathological grounds it is possible to divide cerebral degenerative disorders into two broad groups : those affecting primarily the neurone (grey matter), resulting in the accumulation within it of enlarged or numerically increased lysosomes--‘the neuronal storage diseases’: and those in which the metabolic defect affects predominantly the myelin sheath (white matter).

___

Royal Manchester Children’s Hospital and Booth Hall Children’s Hospital, Manchester.

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M. J. NORONHA

Grey-matter disease is usually characterised early on by impairment of neuronal function. This may manifest itself clinically in infancy and early childhood as a slowing and then arrest of the acquisition of skills, linguistic and physical, before there is obvious regression. In older children, deteriorating school performance-often associated with behaviour problems and dementia-is a common presenting feature. Epileptic seizures are almost invariable, but less common is progressive visual failure due to retinal involvement. Pyramidal tract signs usually occur as a late feature.

White-matter disease, on the other hand, is characterised by a different course, since the tracts are initially involved. Early symptoms are motor rather than intellectual deterioration, and they are characterised by spasticity, ataxia, hyper- reffexia and a positive Babinski sign. Epileptic seizures and dementia occur as a late feature, whilst visual disturbance is due to optic nerve or optic tract involvement.

Grey Matter or Neuronal Storage Diseases The vast majority of the recognised de-

generative diseases of grey matter involve the accumulation of material within neurones. In some, the material is a sphingolipid (gangliosides are highly com- plex sphingolipids), mucopolysaccharide, glycogen or other substance (Table I). The neuronal storage or abnormal material sooner or later results in many neurones perishing, and their loss is accompanied by atrophy and gliosis of the tissue. The intensity and extent of the involvement vary widely, but as a general rule, the earlier the onset, the more widespread the neuronal involvement and the more rapid the course of the disease.

GM, Gaizgliosidoses (Generalised Gangliosidosis)

In this disease there is a generalised storage of ganglioside GM, consequent on an enzyme deficiency of GM, J-galactosidase. Two clinical types are described. Type I, or Znfantile-generalised ganglio-

TABLE I Classification of neuronal storage diseases

Accumulation of ganglioside

Accumulation of other sphingolipids

~

Accumulation of other substances

Chemical name or eponym

Generalised Tay-Sachs Neurovisceral

Gaucher (acute infantile)

Niemann-Pick Metachromatic

leucodystrophy Krabbe’s globoid

cell leucodystrophy

Pompe Ceroid lipofuscinosis :

Bielschowsky Batten-Spielmeyer-

Kufs Mucopolysaccharidoses :

Hunter Hurler Sanfillipo

Mucolipidoses

Vogt

Stored material

GM, ganglioside GM, ganglioside GM, ganglioside

Glucocerebroside

Sphingomy elin Cerebroside sulphate

Galactocerebroside

Glycogen Ceroid and lipofuscin

MPS and ganglioside

Mucopolysaccharides and glycolipids

Enzyme deficiency

P-galactosidase A, B, C Hexosaminidase A, B P-galactosidase

Glucocerebrosidase

Sphingomy elinase Cerebroside sulphatase

(arylsulphatase A) Galactocerebroside

P-galactosidase

a-glucosidase ?

Lysosomal acid hydrolases, P-galactosidase

m-fucosidase a-mannosidase a-lysosomal hydrolases

G 229

DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY. 1974, 16

sidosis in which there is a total deficiency of J-galactosidase isoenzymes A, B and C. Onset is at birth or early infancy and con- sists of hypotonia and hypoactivity, with facial and peripheral oedema. Facial features and skeletal changes resemble those seen in Hurler’s syndrome. The corneas are clear and a cherry-red spot at the macula region occurs in 50 per cent of patients. Hepatosplenomegaly is usual Mental and motor retardation occur and death is usual between six months and two years. Tiyc I I , or Lare Il!fantilc-generalised gangliosidosis in which there is a total deficiency of J-galactosidase B and C. Onset is usually in the second or third year of life and is characterised by mental and motor retardation. Cerebellar and striatal signs may be present and seizures may develop. After the second year of the ill- ness, deterioration is rapid and leads to a severe decorticate state. Hepatospleno- megaly is absent and skeletal changes usually do not occur. Survival beyond five years of age is rare.

G M , Gangliosidoses (Tay-Sachs Disease) In this disease there is storage of

ganglioside GM, in neurones and in viscera, due usually to a total or partial deficiency of hexosaminadase A and/or B. Three clinical types have been described. I/?fatitile. Onset usually is within the first six months of life and the first sign is an abnormal and excessive startle reaction to sound. Retardation of growth and development occur first, followed later by motor regression and dementia. Seizures of various types occur. Muscle weakness and hypotonia are present initially but are later replaced by spasticity. hyperreflexia and contractures. A cherry-red spot at the macula is usual and optic atrophy leads to blindness. Megalencephaly is common. Death usually occurs by the fourth year. Lrrtc, I/$mti/e. Onset is between one and

two years of life. Epileptic seizures occur early and are associated with an excessive startle reaction, progressive motor loss and dementia. A cherry-red spot and optic atrophy may be seen. Death usually occurs between the ages of four and 10 years. Juvenile. Onset is between four and five years and is characterised by dementia, speech loss and fits of various types. There may also be pyramidal, cerebellar and striatal signs and optic atrophy is usual later. Death occurs in the mid-teens.

G M , Gangliosidosis This condition is extremely rare and very

few of the patients described have been studied in detail. Clinically, the patients have developed mental retardation and hepatosplenomegaly and examination of the cortex has shown an excess of GA,, GM, and GM, gangliosides (Pilz et al. 1966). The defect appears to be a deficiency of J-galactosidase (Raine 1970).

Gaudier’s Disease Cerebral involvement only occurs in the

acute or infantile variety, and is characterised by the storage of glucocerebroside in neurones and the reticulo-endothelial system. The enzyme deficiency is glucocerebrosidase.

Onset usually occurs by the fourth month and is characterised by failure to thrive, hepatosplenomegaly and anaemia. There is regression of development and the infant becomes apathetic and fretful. Pyramidal signs result in a spastic quadriparesis and in progressive bulbar palsy with swallowing difficulties. Fits are uncommon. Death usually occurs in the second year of life.

Sphirigoni~eliiiosis (Niemann-Pick Disease) This group is characterised by the accu-

mulation of sphingomyelin intracellularly and this may occur in most cells throughout

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the body. At least four types have been described and they can be distinguished into cases with and without cerebral involvement (visceral and cerebral forms).

The infantile form, with cerebral involvement, is the most common and typical expression of Niemann-Pick disease; it comprises approximately 85 per cent of all cases and is observed mainly among the Jewish population. During the first months of life hepatosplenomegaly and stunting of growth occur, together with neurological features of mental and motor retardation. In some cases a cherry- red spot of the fovea centralis can be observed. Death usually occurs in the second or third year of life.

A more chronic form of this disease, be- ginning predominantly in late infancy, may be distinguished by a milder enlargement of liver and spleen and later onset of cerebral and cerebellar signs. Death usually occurs in late childhood or teens.

Metachromatic Leucodystrophy This may occur at all ages but it is most

common in infancy or childhood. Accord- ing to Pilz (1970), the disease may be infantile, late infantile, juvenile or adult in type. In the childhood cases, the child develops normally until about 12 to 14 months of age, when gait disturbances and ataxia commonly first occur. Cortico- spinal tract involvement may be modified by peripheral nerve involvement, resulting in hypotonia and hyporeflexia rather than a spastic quadriparesis. In the later stages, loss of mental functions and epileptic seizures may occur and the final stages are characterised by rigidity, blindness, deafness, apathy and hyperpyrexia. In the adult form, dementia and psychological changes are an early feature.

The basic defect appears to be a deficiency or absence of cerebroside sulphatase (arylsulphatase A), resulting in the accumulation of brown metachromatic-

staining material (cerebroside sulphate) in neurones, glial cells, peripheral nerves, many somatic tissues and in the urine. It is thought that the primary disturbance is excessive storage of sulphatides, demyelination being a secondary feature (Crome and Stern 1972). The cerebrospinal fluid (CSF) protein may be raised, nerve conduction velocity is usually decreased and enzymatic activity of arylsulphatase A in leucocytes or cultured fibroblasts is reduced or absent (Percy and Brady 1968, Port et al. 1971).

Krabbe’s Globoid Cell Leucodystrophy This is usually a disease of early onset

and rapid progression. Many affected children are clearly not thriving by the fourth or fifth month of life, and are often noted to have persistent vomiting and failure to gain weight. It is only when the lack of motor and social development are recognised that the diagnosis of a cerebral degenerative disorder is suspected. Tendon reflexes are lost early due to peripheral nerve involvement. As the disease progresses, optic atrophy and eventually blindness occur; there is usually generalised increase in muscle tone, although occasionally hypotonia is present. Death usually occurs within the first two years of life.

The deficient enzyme has been shown to be galactocerebroside J-galactosidase, resulting in the storage of a galactocerebroside in the glial cells; a characteristic feature histologically is the presence of so- called globoid cells representing these over- grown glial cells. There is a diffuse, rapidly progressive degeneration of the white matter, with patchy demyelination. The CSF protein is elevated, nerve conduction velocity is decreased and low activity of galactocerebroside J-galactocerebrosidase in serum, leucocytes and cultured fibroblasts of patients has been demonstrated (Suzuki 1971).

23 1


Glycogen Storage Disease (Pompe’s Disease)

Although the majority of the forms of glycogen storage disease do not involve the central nervous system, one form (generalised glycogen disease or Pompe’s disease) may be associated with progressive neurological deterioration. This form is characterised by deposition of normal glycogen in brain, muscle and heart. J n early infancy, clinical features include feeding and respiratory difficulties, marked hypotonia and areflexia, macroglossia and progressive mental deterioration. Cardio- megaly, due to infiltration of the muscle with glycogen, produces cardiac failure, the usual cause of death which occurs within the first year of life. There is widespread neuronal and glial storage of glycogen and generalised gliosis of the white and grey matter (Crome et al. 1963). A deficiency of r-glucosidase has been demonstrated in the leucocytes of these patients (Hers 1963).

Ceroid Lipqfifirscitzosis (Batten’s Disease) The term ‘amaurotic family idiocy’ has

been used to designate a heterogenous group of entities, but recent biochemical and ultrastructural studies have demonstrated that they contain two distinctly different groups. The first is composed of diseases with abnormal ganglioside metabolism (e.g. Tay-Sachs disease) and generalised or neurovisceral gangliosidosis : the second group is much commoner and differs clinically, pathologically and biochemically from the first group (Zeman and Dyken 1969. Gordon et a/. 1972). The second group differs clinically by having a more protracted course, a more variable age of onset and usually by the presence of retinal abnormalities consisting of abnormal pigmentation and optic atrophy, and not the ‘cherry-red spot’ as seen in Tay-Sachs disease. Biochemically, the sphingolipid pattern of brain extract is normal and

pathologically there is severe neuronal loss in the retina and brain, with the remaining neurones swollen by auto-fluorescent yellow granules which have been shown to be ceroid and lipofuscin.

The term ‘amaurotic family idiocy’ has had various eponyms attached to it in the past, depending on age of onset- Bielschowsky-Jansky, Spielmeyer-Vogt, Batten-Mayou and the adult type or Kuf’s disease-and has included both some of the gangliosidoses and of this group. It is now suggested that the latter group should be called ceroid-lipofuscinosis or Batten’s disease (Zeman and Dyken 1969).

There are a number of clinical features that may suggest the condition. Visual complaints are common and there may be optic atrophy or macular degeneration with abnormal fundal pigmentation. Epi- leptic seizures are an integral part of the disease, often starting as generalised convulsions which are superseded by myo- clonus. Dementia usually appears and motor disturbances include dystonia, involuntary movements, ataxia and spastic quadriplegia. In some cases a period of remission may occur, but usually the course is progressive and death results commonly from intercurrent ailments secondary to the neurological disability.

Mt~copoli.saccharidoses The mucopolysaccharidoses (MPS) are a

group of systemic storage diseases, recently classified by McKusick et al. (1965) into six diseases on the basis of genetic pattern, clinical manifestations and the excretion of differing compounds in the urine (Table 11). The substances stored and excreted are macromolecules consisting of repeating units of hexuronic acid and hexosamine, these being important units of connective tissue in cartilage, cornea, vessel walls and subcutaneous tissue. Besides mucopolysaccharide accumulation, there is also cerebral accumulation of gangliosides

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M. J. NORONHA

TABLE I1 The mucopolysaccharidoses (Dorfman 1972)

I

Disease -_ Hurler

Hunter

Sanfillipo

Morquio

Scheie

Maroteaux-Lamy

Clinical characteristics

Severe mental retardation, skeletal deformities, marked corneal opacity, marked somatic changes.

Moderate mental retardation, marked skeletal deformities, no corneal clouding, marked somatic changes, early deafness. Severe mental retardation, mild skeletal changes, corneal clouding question- able.

No mental retardation, severe skeletal deformities, marked spondylepiphyseal dysplasia. Corneal opacities may occur. No mental retardation, mild skeletal changes, severe corneal opacity. No mental retardation, severe skeletal deformities, gross corneal opacity.

resulting in severe mental subnormality, this latter feature being present especially in Hurler’s, Hunter’s and Sanfillipo groups of MPS disorders and not in the other forms. Hurler’s Syndrome

The usual signs are dwarfism, short neck and a large dolichocephalic head with hypertelorism, corneal opacity, coarse hair, hirsutism, lumbar kyphosis, flexion contractures with limitation of joint-move- ment, hepatosplenomegaly, cardiac defects, persistent nasal discharge and some deafness.

Development may be normal in the first year or two and is then followed by severe and progressive mental deterioration. Progressive corneal clouding occurs. Death, usually due to heart failure consequent on valvular or coronary artery disease, commonly occurs before 10 years of age. Hunter’s Syndrome

Clinical features are similar to those of

Biochemical findings ~~~

Dermatan sulphate and heparan sulphate in mine and tissues. Increased gangliosides in brain. Absence of a-L-iduronidase. Dermatan sulphate and heparan sulphate in urine and tissues. Increased gangliosides in brain.

Type A: heparan sulphate in urine and tissues, ? decreased sulphamidase. Type B: heparan sulphate in urine and tissues. Absence of a-N-acet yl-hexosaminidase. Keratan sulphate and chondroitin sulphate in urine,

Dermatan sulphate in urine. Absence of a-L-iduronidase.

Dermatan sulphate in urine.

Genetics

Autosomal recessive

X-linked recessive

Autosomal recessive

Autosomal recessive

Autosomal recessive

Autosomal recessive

Hurler’s syndrome but the disease tends to run a milder course and mental deterioration progresses at a much slower rate. There is no corneal clouding. Death from heart disease usually occurs by the age of 20 years. Sanjillipo

Mental retardation is usually severe and progressive and evident before school age. Behaviour is often aggressive and makes management a problem. There is no corneal clouding and physical abnormalities are relatively mild, with only slight skeletal changes, dwarfism and hepatosplenomegaly. There are no heart abnormalities and patients often survive into their second or third decade. Recent studies indicate that there are two types of the disease, with diminished activity of differing enzymes (Dorfman 1972).

Mucolipidoses This group combines features of the

233


234

mucopolysaccharidoses with neuronal, visceral and mesenchymal storage of sphingolipids. Eight such disorders, differing widely in clinical and biochemical manifestations. were reviewed by Spranger and Wiedermann (1970) and in all but one the MPS secretion in the urine was normal.

White Matter Disease (Leucodystrophies) The leucodystrophies are characterised

by degeneration or abnormal formation of the white matter of the cerebrum and, often. the cerebellum. The brainstem, and more rarely the spinal cord. may be affected, while the peripheral nerves frequently show segmental demyelination. Involvement of the grey matter is usually secondary and relatively mild. The changes i n the white matter are as a rule diffuse, symmetrical and widespread : the arcuate fibres (U-fibres) are often spared, whilst the axis cylinders-being tougher than the myelin sheaths-are usually preserved for some time after the breakdown of myelin.

The myelin sheath is formed by the spiral winding of the external membrane of the Schwann cell or oligodendrocyte around the nerve axon. Myelin contains lipids and protein in the ratio of 4:1 and once formed it undergoes only very slow turnover. The diseases which affect myelin may be divided broadly into two groups. In one there is a defect in the metabolism of myelin which affects either its synthesis or maintenance. In the second group, by contrast, the synthesis and metabolism of myelin is normal but some exogenous process (e.,?. multiple sclerosis, Schilder's disease) leads to its breakdown.

P'i>li:(ieiis- Merzhacher Disease ( a d P a r i m t s )

This group has been reviewed by Stark (1972). In the classical form described by Pelizaeus and Merzbacher in 14 members of one family, gross nystagmus and head tremor appeared in the early months of

life. These were followed by delay in motor development, accompanied by features of cerebellar ataxia, choreo-athetosis and spasticity of the lower limbs. Fits were in- frequent and dementia mild. After the age of five o r six years deterioration was very slow and death occurred in early adult life. Most cases have been described in boys and inheritance is predominantly sex-linked recessive.

A lexat ider Type L eucodyst rophy This condition is rare, familial and is

characterised by slow progression. Onset is in early infancy and there is slow development followed by increasing spasticity and dementia. Enlargement of the brain (megalencephaly) is striking, and although the ventricles are dilated there are no signs of raised intracranial pressure. Patho- logically there is diffuse demyelination and the presence of many Rosenthal fibres is very striking and characteristic.

Canavail's Spongiforni Eiicephalopathy This is also a rare condition affecting

mainly individuals of Jewish ancestry. The disease occurs within the first few months of life, presenting initially with hypotonia which is succeeded by marked hypertonia with hyperextension of the trunk and lower limbs, involuntary movements and blindness due to optic atrophy. Megal- encephaly is a striking feature and is due t o enlargement of the brain and not t o obstructive hydrocephalus. I t is characterised by rarefaction, vacuolation and breakdown of neural tissue, these findings being most marked at the junction of the white matter and cortex. Chronic oedema has been suggested as the pathogenetic factor in this condition, and Adornato et al. ( I 972) have found that the neurometabolic disorder is most probably related to de- fective mitrochondrial metabolism and not to an enzyme defect in the cell-membrane ionic pump. Similar pathological findings

have been described in other types of cerebral degeneration, e.g. maple syrup urine disease (Crome and Stern 1972).

Schilder’s Disease (Sudanophilic Leucodystrophj?)

There has been considerable confusion concerning the term Schilder’s disease, as it has been used rather loosely to describe a number of demyelinating disorders, many of which have now been classified with greater precision. Poser (1970) discusses the problems of classification and suggests that diffuse cerebral sclerosis belongs to a group of demyelinating disorders which include diffuse-disseminated or transitional sclerosis. Poser also suggests that they might simply be a variant of multiple sclerosis, the difference in the clinical and pathological features resulting, perhaps, in the terrain, i.e. the age and maturity of the myelin sheath when it is involved in the pathological process. He terms these diseases ‘myelinoclastic’ demyelinating disorders and suggests they represent the breakdown of normally constituted myelin by exogenous factors, in contradistinction to the dysmelinating group, in which there is an inborn error of metabolism causing a defect of myelin anabolism.

In almost 50 per cent of cases the disease commences before the age of 10 years and usually runs a subchronic course over a period of two to three years. It can, however, start in acute fashion with fits. Poser quotes L’Hermitte as dividing the clinical features into several types. (1) Progressive form, the most common symptoms being psychic difficulties, pyramidal tract signs, and blindness and deafness from involvement of the optic and auditory tracts. The disease is progressive but advances gradually. (2) Polysclerotic form, progresses by suc- cessive bursts of symptoms and signs which are reminiscent of multiple sclerosis.

M. J. NORONHA

23 5

(3) Pseudotumoural form, presenting with features of raised intracranial pressure, papilloedema, etc. (4) Predominantly psychiatric symptoms ; the mental symptoms may predominate in the absence of definite neurological signs. The psychiatric manifestations may run the whole range of dementia, mania, melancholia and even schizophrenic epi- sodes.

Slow Virus Infections The classical concept of a viral infection

is that of an acute, self-limited disease in which the virus enters the body, proliferates in one or more tissues and then is elimin- ated by the host’s immune mechanisms. It had been known in animals that ‘slow- virus infections’ of the central nervous system occur, e.g. scrapie in sheep and mink encephalopathy. These diseases are caused by transmissible agents with a high degree of host specificity and a long incu- bation period of months to years, followed by a progressive and destructive disease process (Gajdusek 1967).

Interest in the possibility of man being similarly affected was raised in 1957 with the discovery of the pathological similarity between scrapie and kuru, a progressive central nervous system degenerative disease found only among the Fore group in- habitants of the eastern highlands of New Guinea. Since the discovery of kuru, about 2,000 cases have been reported. Clinically, patients show a progressive ataxia, tremor of head and extremities, increasing dys- arthia and emotional lability, but not dementia. Death usually occurs within about two years. The disease has been transmitted successfully to chimpanzees by jntra-cerebral innoculations of suspensions of brain from kuru patients (Gibbs et al. 1969). The mode of transmission of the virus was probably related to cannibalism of the bodies, including the brain, of their dead kinsmen. Since this practice has


stopped, no new cases have appeared. The possibility that other chronic central

nervous system diseases may also be related to slow virus infections has been in- vestigated and now is considered likely in subacute sclerosing panencephalitis (Chen et ul. 1969. Horta-Barbosa et a/. 1969, Lehrich et 01. 1970, Parker et al. 1970); spongiform-encephalopathy - -'Creutzfeld- Jakoh' disease (Gibbs and Gajdusek 1969); and progressive multifocal leucoencephalo- path) (Morecki and Porro 1970. Padgett et ul. 1971). The relationship between multiple sclerosis and previous measles \ irus infection is also being inbestigated.

Suhacwre Scleroshig Paiieiiceplialitis (SSPE) This has also been called Dawson's in-

clusion-body encephalitis. Most cases occur within the first two decades of life. although occasional adult cases have been described. The disease has conveniently been divided into four clinical stages (Jabbour et a/. 1969). Stage 1. Cerebral signs with insidious intellectual deterioration and changes of personality. This is seen as gradual de- crease in school performance, forgetfulness, disobedience or temper outbursts. Sleep- lessness. distractibility and visual or auditory hallucinations may occur. Stage 2. Convulsions and motor signs. The convulsions commonly are myoclonic jerks of the head, limbs or trunk. Inco- ordination of the trunk and limbs, dys- kinesias, choreo-athetoid postures, tremors and involuntary movements may all occur. Stage 3, Unresponsiveness to any stimulus, decerebrate rigidity and extensor hypertonus, irregular and stertorous respirations. Stage 4. The final stage usually appears between two and six months later. The sebere hypertonus diminishes. periods of pathological laughing and crying appear and the myoclonic jerks diminish in frequency. Blindness may be due to optic atrophy or cortical involvement. Termin-

ally, there are often signs of hypothalamic dysfunction with intermittent hyper- thermia, blotchy rashes and disturbances of pulse and blood pressure.

Although it is exceptional in SSPE for the disease to last for more than a year or so, remissions have occasionally been reported (Cobb and Morgan-Hughes 1968). Boys are affected much more commonly than girls. Brody and Detels (1970) have suggested that the measles infection might occur at an unusually early age when passive maternal antibody is still present. Although subsequent immunity is sufficient to prevent a second clinical attack of measles, the balance between host and virus is altered. They suggest that SSPE occurs among those individuals in whom this abnormal balance between measles virus and host immune mechanism exists, per- mitting measles virus to persist in the neurones. The balance is upset possibly by an infection with another virus; this second virus could be a papova-like agent which has been observed in tissue culture innoculated with SSPE brain material.

The diagnosis is confirmed by the CSF

examination showing a normal or slightly elevated protein level with a strongly first zone (paretic type) colloidal gold curve and negative tests for neurosyphilis; by elevated measles antibody titres in the serum and CSF; and by a characteristic EEG pattern consisting of stereotyped paroxysmal bursts of high-voltage synchronous diphasic waves, often associated with sharp waves occurring regularly every few seconds. Cerebral biopsy is usually not indicated as the diagnosis can be made on the pattern of clinical features and other investigations.

Progressive Multifocal Leucoeticeplialopatliy

PML commonly occurs as a terminal complication of chronic proliferative disorders of the lymphoid tissue (Lancet 1972). Pathologically, there are foci of demyelin-

( P M O

236

M. I. NORONHA

ation scattered through the cerebral hemispheres and brain stem. The symptoms and signs depend on where the lesions are situated, but dementia, fits and pyramidal signs commonly occur. The course of the disease is progressive and death occurs within a few months of onset. On electron- microscopy, virions resembling the papova virus have been seen and they have also been cultivated from the brain of a case of PML (Padgett el al. 1971).

Work-up of a Child with a Cerebral Degenerative Disorder

The most important aspect is the history, and perhaps the most important facet in the history is whether the neurological deficit has been progressive. This progression may be in many areas: loss of motor abilities; loss of intellectual or speech functions; behavioural difficulties; progressive weakness or progression of neurological signs. Two other important features in the history are (1) family history (details of similar involvement of other sibling or relatives) and (2) age of onset and the pattern and rate of progression of the disease. The physical examination may reveal that the disease process is primarily affecting the nervous system, but systemic involvement, e.g. the finding of hepatosplenomegaly, might suggest a systemic sphingolipidosis, like Gaucher’s disease, or a disorder of mucopolysaccharide metabolism.

A number of laboratory investigations may be required to establish the diagnosis. These have recently been reviewed by Wilson (1972) and are summarised in Table 111.

Recent advances in biochemical techniques have reduced the necessity for carry- ing out tissue biopsies. Enzyme assays on leucocytes can be carried out at certain laboratories and it is possible to detect deficiency of GM, J-galactosidase in GM, gangliosidoses, hexosaminadase A in Tay-

Sachs disease, J-glucocerebrosidase in Gaucher’s disease, sphingomyelinase in Niemann-Pick’s disease, arylsulphatase A in metachromatic leucodystrophy, galactocerebroside J-galactosidase in Krabbe’s disease and u-glucosidase in Pompe’s disease. A further feature of these biochemical enzyme assays is that they can be performed on cells obtained and cultured from amniotic fluid in the early weeks of pregnancy and thereby help in the prenatal diagnosis of some of these cerebral degenerative disorders (Matalon et al. 1970, Schneck et al. 1970, Adachi et al. 1971, O’Brien et al. 1971). I t may also be possible to do pedigree studies to detect heterozygotes (Bass et al. 1970, Kaback and Howell 1970, O’Brien et al. 1970, Suzuki et al. 1971).

Biopsy of a peripheral nerve, e.g. sural nerve, may be helpful in metachromatic and Krabbe leucodystrophies (Hogan et al. 1969), and the question of sural nerve biopsies in paediatric neurological disorders has been discussed by Appenzeller et al. (1970). Biopsy of the appendix or rectal mucosa and examination of the myenteric plexus and ganglion cells may be helpful in the splingolipidoses and Batten’s disease (Brett and Berry 1967, Adachi et al. 1969), especially if the techniques of leucocyte enzyme assays are not available.

With the newer techniques of biochemical investigations on leucocytes and peripheral nerve examination, it is hoped that fewer cerebral biopsies will be required. There are, however, a number of diffuse diseases of the nervous system where it is still extremely difficult, if not impossible, to reach an exact diagnosis without examining a portion of cerebral tissue. At present an exact diagnosis is seldom important with regard to therapy but it may be invaluable when genetic advice is requested by the parents, and in prognosis. It is imperative that the modern diagnostic possibilities be ex-

237


TABLE 111 Diagnostic tests for detection of cerebral degenerative disorders

Tissue Disense Teb t Result Coinnzenr

Serum SSPE Measles antibodies Elevated I Gaucher's Acid phosphatase Elevated

Leticocytes

Urine

~~

Sphingolipidoses, Specific degradative Pompe's disease enzymes

__________ _ _ _ Metachromatic Metachroniatic

leucod ystrophy staining

of MPS

Arylsulphatase A Mucopolysaccharides Total and patterns

Decreased May be useful for detecting heterozygotes

~~ ~

Positive Difficult to interpret

Decreased Elevations of MPS

with particular patterns

CSF MLD Protein Elevated Krabbe's Protein Elevated SSPE Colloidal gold First-zone rise

(paret ic) Measles antibodies Elevated

Peripliercrl t w r w MLD Nerve conduction, Decreased velocity, Krahbe's) biopsy pathological I changes

I Botre nintrou' Gaucher's Biopsy Gaucher's cells

Recinl tnucusa Sphingolipidoses Biopsy Batten's disease } I Myenteric plexus

ganglion cells involved.

Brriiti Various degenerative Biopsy Characteristic

SSPE EEG Characteristic disorders histology/chemistry

periodic complexes

Awniutic /f i t id Sphingolipidoses ) Specific degradative Decreased Prenatal M PS enzymes diagnosis I

ploited to the fullest in the examination of the material obtained, and this will include the many laboratory specialists who will want a share of the specimen: the histo- chemist, the virologist, the chemical patho- logist. the neuropathologist and the electron-microscopist (McMenemy 1968). Biemond (1966) has summarised his views on the moral aspects of cerebral biopsy, especially as cerebral tissue does not regenerate and therefore removal of a portion of it will always produce permanent damage, even though this damage may not be clinically apparent.

Blackwood (1970) discusses the value

and diagnostic yield in a large series of cerebral biopsies that have been reported. Of his own series of 178 cases (Blackwood and Cummings 1965) 43 per cent (72) were diagnostic, 37 per cent (66) were abnormal but not diagnostic and 20 per cent (35) were not abnormal. In a follow-up of this series of patients, a number of whom had died and come to autopsy, the ultimate findings indicated that a definitive diagnosis was usually accurate and that negative findings were rarely in error. Only in the 'abnormal but not diagnostic' group did the correct diagnosis sometimes remain undetected.

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Treatment Therapy for the cerebral degenerative

disorders has, until recent years, been con- fined to non-specific measures aimed at controlling epileptic seizures, and sup- porting parents and giving genetic advice.

Replacement of the specific enzyme or ‘corrective factor’ has been tried in some of these conditions, especially since the report of the successful treatment by plasma in- fusions in Fabry’s disease which is a glycosphinogolipid lipidosis resulting in the accumulation of ceramide in various tissues but not in the neurones or glial cells of the central nervous system (Mapes et al. 1970).

Plasma infusion or whole blood trans- fusions have been tried in the various mucopolysaccharidoses (Types I, I1 and 111) but so far without success (Crocker 1972, Dekaban et al. 1972, Erickson et al. 1972). In tissue culture, however, the ad- dition of the appropriate factor to either Hunter or Hurler cells results in the restoration of the normal turnover of mucopolysaccharides (Dorfman 1972).

Similarly, in metachromatic leucodystrophy, correction of the abnormal cerebroside sulphate in cultured fibroblasts has been achieved by incorporating arylsulphatase A in the culture medium (Porter et al. 1971), but the administration of arylsulphatase-A to a patient with MLD

was unsuccessful (Greene et al. 1969). Antiviral agents and corticosteroids have been tried in patients with SSPE, but they have been unsuccessful.

Despite the gloomy prospects concerning the successful treatment of these patients at the present time, it is hoped that in the future it may be possible to correct the dis- ordered neurometabolic activity. It is, therefore, important that an exact clinical and biochemical diagnosis should be obtained if further progress is to be made. The previous criticism that neurologists were interested only in the academic exer- cise of diagnosis should no longer be applicable.

Acknowledgement: I wish to thank Dr. N. S. Gordon for his advice and criticism during the preparation of this manuscript.

SUMMARY The article is a comprehensive review of the cerebral degenerative disorders in infancy and

childhood. The place of clinical and biochemical investigation and biopsy in the diagnosis of the disorders is discussed, and some of the more recent methods of treatment are briefly described.

R I ~ S U M I ~ Affections cPrPbrales diginiratives de la petite et seconde enfance

L’auteur fait une revue d’ensemble des affections ctrkbrales dkgtntratives de la petite et seconde enfance. La place des bilans cliniques et biochimiques et de la biopsie dans le diagnostic des affections est discutie et quelques unes des mithodes les plus ricentes d e traitement sont brihement dtcrites.

ZUSAMMENFASSUNG Degenerative Cerebralerkrankungen im Sauglings- und Kindesalter

Der Autor gibt einen umfassenden Uberblick uber die degenerativen Hirnerkrankungen im Sauglings- und Kindesalter. Die Bedeutung klinischer und biochemischer Unter- suchungen und der Biopsie bei der Diagnosestellung der Erkrankung wird diskutiert und einige der neueren Behandlungsmethoden werden kurz beschrieben.

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DEVELOPMENTAL MEDICINE A N D CHILD NEUROLOGY. 1974, 16

RESUMEN Alteracioties degetierativas cerebrales en la lactancia e illfaticia

El autor revisa las alteraciones degenerativas cerebrales en la lactancia e infancia. Se discute el lugar de la investigacion clinica y bioquimica y de la biopsia en el diagnbstico de las alteraciones, y se describen brevemente algunos de 10s mCtodos de tratamiento mas recientes.

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