Brain (1986), 109, 181-206 PROGRESSIVE NEURONAL DEGENERATION OF CHILDHOOD WITH LIVER DISEASE A PATHOLOGICAL STUDY by B. N. HARDING 1 , J. EGGER1, B. PORTMANN2, and M. ERDOHAZI1 SUMMARY A clinicopathological study of 10 cases of progressive neuronal degeneration of childhood is reported. In the typical clinical course early developmental delay is followed by intractable epilepsy leading rapidly to death, in some cases in liver failure. Diagnostically useful investigations include characteristic EEG changes, evidence of progressive atrophy (particularly occipital) on CT scan, absent or reduced visual evoked responses, and biochemical evidence of abnormal liver function in many cases before commencement of anticonvulsant therapy. Siblings of 4 of the reported cases suffered a similar clinical disorder. Macroscopic appearances of the brain varied from virtual normality to severe atrophy. The cortical ribbon showed patchy lesions, but the calcarine cortex was characteristically involved, narrowed, granular and discoloured. Histological damage to the cerebral cortex was widespread but patchily accentuated. In milder lesions status spongiosus, astrocytosis and neuronal loss occurred only in the superficial cortex, in moderately affected areas deeper laminae were involved, and in the most severe lesions the entire cortex was reduced to a thin densely gliotic remnant. There was a pronounced tendency for the striate cortex to be the worst affected area. Of subcortical structures the thalamus, hippocampus and cerebellum were particularly severely involved. There was usually accompanying liver disease, particularly a subacute hepatitis comprising massive fatty degeneration, hepatocyte loss, bile duct proliferation and fibrous scarring, with or without cirrhosis. These pathological features are distinct from other combined degenerations of liver and brain and the cortical lesions differ significantly from the neuropathological sequelae of birth injury or severe epilepsy. Hepatic pathology is distinctive and does not appear to be related to drug therapy. It is concluded that these 10 cases of progressive neuronal degeneration of childhood with concomitant liver disease, together with a small number of previously reported cases, are a nosological entity which may result from an autosomal recessive inherited metabolic defect, the nature of which is at present obscure. INTRODUCTION In 1931 Alpers described diffuse cerebral cortical degeneration in a child who had suffered marked developmental delay and severe seizures. Subsequent cases have Correspondence to: Dr B. N. Harding, Department of Neuropathology, Hospital for Sick Children, Great Ormond Street, London WC1N 3JH. © Oxford University Press 1986 Downloaded from http://brain.oxfordjournals.org/ by guest on June 7, 2016 (From ' The Institute of Child Health and Hospital for Sick Children, Great Ormond Street, London WC1N 3JH and2 King's College Hospital and School of Medicine and Dentistry, Denmark Hill, London SE5 9RS) 182 B. N. H A R D I N G AND OTHERS MATERIAL AND METHODS In 2 cases a complete post-mortem examination was performed in our laboratory. In the other 8 cases post-mortem was performed elsewhere, but thefixedbrain and sections of liver were available for study, except in Case 3 (no liver sections were available) and Case 9 (neuropathological examination was limited to paraffin-embedded blocks of pons, cerebellar hemisphere, occipital lobe, and a coronal section of one hemisphere with frontal and temporal cortex, basal ganglia and midbrain). In general, blocks surveying the major regions of the cerebral cortex, white matter, basal ganglia, brainstem and cerebellum were taken for paraffin histology, and sections stained with routine histological stains as well as Luxol fast blue-cresyl violet, phosphotungstic acid-haematoxylin, and Holmes and Glees-Marsland silver impregnations. Frozen sections stained for fat were also examined. CASE HISTORIES AND PATHOLOGICAL FINDINGS Case 1 (NP 18.75) Clinical history. Pregnancy and delivery were normal; this boy sat at 11 months, crawled at 12 months and walked at 18 months. He was always clumsy and speech development was slow. When 3 years old he started having seizures, and after an episode of status epilepticus, at the age of 6, partial seizures and status occurred frequently. Response to phenobarbital, carbamazepine and chlormethiazole was poor. He was hypotonic and later developed pyramidal signs. Liver function tests were abnormal at 6.5 years (SGOT 121 IU/I (normal < 17 IU/1), SGPT 19 IU/I (normal < 17 IU/I). The EEG showed asymmetric slow activity of high amplitude and polyspikes, and visual evoked responses (VERs) were asymmetric. He died in liver failure aged 7.5 years. He had received sodium valproate for the last ten weeks, and it was thought that this had aggravated an already existing liver disorder. His brother also suffered from progressive neuronal degeneration with liver disease and died in liver failure aged 9.5 years. Autopsy (Dr A. G. Ackerley). This showed bronchopneumonia. The liver weighed 550 g (normal 700 g) and was intensely yellow. The brain (fixed weight 1248 g) was macroscopically normal. Downloaded from http://brain.oxfordjournals.org/ by guest on June 7, 2016 either been labelled eponymously or given descriptive titles such as poliodystrophia cerebri progressiva (Christensen and Krabbe, 1949), diffuse progressive cerebral cortical atrophy (Ford et al., 1951), spongy glioneuronal dystrophy (Jellinger and Seitelberger, 1970), or diffuse cerebral degeneration in infancy (Blackwood et al., 1963). Many heterogeneous cases have been placed in this category including examples of birth injury, postepileptic encephalopathy, and a miscellany of obscure grey matter degenerations in children, as well as a hard core of apparently idiopathic infantile cerebral degenerations, some with familial occurrence. In recent years, however, a number of cases of progressive neuronal degeneration of childhood (PNDC) with associated liver disease have been reported (Blackwood et al., 1963; Wefring and Lamvik 1967; Cameron et al., 1968; Jellinger and Seitelberger, 1970; Huttenlocher et al., 1976). Over the past decade we have had the opportunity to examine post-mortem 10 cases of PNDC with concomitant liver degeneration. In the present paper we report the pathological findings which have been found to be consistent and characteristic of these cases, and which are correlated with the clinical observations. PROGRESSIVE NEURONAL DEGENERATION OF CHILDHOOD 183 Case 2 (NP1.78) Clinical history. Pregnancy and delivery were normal. This boy had recurrent episodes of vomiting and was investigated for failure to thrive when 3 months old. At 5 months he was hypotonic and abnormal liver function (AST 51 IU/1 (normal 6-17 IU/1), ALT 62 IU/1 (normal 2-12 IU/1)) and raised CSF protein (3 g/l) were recorded. The EEG showed excess of slow waves and poor rhythmic activity. VERs were present but the initial components were ill-defined. A CT brain scan showed slight cortical and central atrophy. When 15 months old he started to have myoclonic attacks, which were treated with diazepam. He died aged 21 months. Autopsy (Dr F. E. Scott). This revealed bronchopneumonia. The small liver weighed 128 g (normal 370 g) and was finely nodular. Macroscopic neuropathologicalfindings. The fixed brain weighed 736 g (normal for age 1060 g), the hindbrain 129 g. The cerebellum appeared relatively large. On coronal sections, the ventricular system was enlarged while the centrum semiovale and corpus callosum were reduced in bulk. In both hemispheres the cerebral cortex over the vertex and medial surface of the frontal and parietal lobes from the level of the anterior commissure to the parieto-occipital fissure was greatly shrunken and dark brown (fig. 1A). A similar almost symmetric lesion affected the calcarine cortex extending to the occipital poles (fig. 1B). Elsewhere the cortex appeared normal. Both thalami and caudate nuclei were flattened, but the Ientiform nuclei were normal. The hindbrain and cord also appeared normal. Histological findings. CNS. A generalized neuronal loss affected all regions of the cerebral cortex, even macroscopically normal areas. In the least affected areas, such as temporal and insular cortex, there was moderate but patchy nerve cell loss from laminae II and III often with spongy degeneration in lamina II. Laminar architecture was retained; neurons in the deeper layers were preserved. There was also a considerable astrocytic proliferation and fibrillary gliosis in the molecular layer, and a large number of macrophages packed with sudanophilic lipid. Macroscopically abnormal areas, such as parietal and frontal cortex, showed more severe lesions (fig. 2A, B): spongy degeneration extended into Downloaded from http://brain.oxfordjournals.org/ by guest on June 7, 2016 Histologicalfindings. CNS. Throughout the cerebral cortex there was a general but variable increase in astrocyte numbers, least in temporal cortex and confined to superficial laminae, but more obvious in frontal and parietal areas where pairs and small groups of astrocytic nuclei, some with Alzheimer type II morphology, permeated laminae I-IV. There was an associated mild fibrous gJiosis, particularly in subpial and periventricular zones. Neuronal loss appeared very slight but many nerve cells were shrunken. In both hemispheres the occipital cortex was more severely affected. On the right, patches of sponginess in laminae II and III, moderate neuronal loss and astrocytic proliferation occurred. The right striate cortex showed complete loss of lamination, only few granule cells and shrunken pyramidal cells remained, with replacement by large astrocytes, many Alzheimer type II, others gemistocytic, forming a dense feltwork of stout glial fibres. On the left, the parastriate cortex and focal areas on the superior and lateral surfaces were as severely affected as the right striate cortex. The left striate cortex was only slightly better preserved. Frozen sections revealed abundant sudanophil lipid within phagocytes in the cortex. The white matter was gliotic, but myelin was normally stained. There was moderate neuronal loss and some gliosis in the Sommer sector of the hippocampus, in the putamen and claustrum and the lateral geniculate nucleus, but only astrocytosis in other thalamic nuclei and the caudate. In the cerebellum there was generalized severe loss of Purkinje cells and proliferation of Bergmann glia throughout the hemispheres. The vermis was less affected. Several minute old scars with Purkinje and granule cell loss and heavy fibrous gliosis were also present. The dentate nucleus showed nerve cell loss, sponginess and gliosis. The brainstem was rather gliotic, but the olives particularly showed neuronal loss and gliosis. There was also moderate loss of anterior horn cells from the cervical cord. Liver. An on-going hepatitic process was indicated by extensive hepatocyte degeneration, severe panlobular microvesicular fatty change, and both portal and lobular mixed inflammatory cell infiltration. Numerous ductule-like structures were present at the margins of the portal tracts. The process was of long-standing, for areas of previous liver cell loss were replaced by fibrous tissue. 184 B. N. HARDING AND OTHERS the deeper parts oflamina III, there was severe neuronal depletion but preservation of large pyramidal cells in lamina V, large numbers of microglial cells, prominent capillaries, and numerous swollen hypertrophic astrocytes producing a marked fibrous gliosis. Occipital regions were similar but the striate cortex was even more severely affected: thin and shrunken, it contained virtually no nerve cells, Downloaded from http://brain.oxfordjournals.org/ by guest on June 7, 2016 FIG. 1. Case 2. Coronal sections of the brain. A, midthalamic level; B, occipital lobes. There is bilateral and almost symmetric narrowing and discolouration of the posterior frontal cortex (arrowheads) and striate cortex (arrows). ' i* } '*. • * v s Downloaded from http://brain.oxfordjournals.org/ by guest on June 7, 2016 .^n 'i 'A,' »> •v '^*<:ir& o o m on t/5 < m Z m C 7> O z > r a m O m Z m 70 > 5 Z o -n o I tD X o o D FIG. 2. Case 2. Histology of frontal cortex. Moderately severe lesion withgliosis, spongy ch^BgBSlnd toss tffneilrons in superficial layers but preservation of neurons in deeper laminae. Haematoxylin and eosin. A, bar «= O^Bmm; B, Jsar = 0.1 mtn. Igfi B. N. HARDING AND OTHERS only many capillaries, plump astrocytes and lipid-laden macrophages, supported by a dense glial network. The white matter was generally well preservedj.slight pallor of myelin staining occurred beneath the grossly affected cortical areas and sudanophil material was present in perivascular macrophages in the centrum semiovale and internal capsule. The pyramidal layer of the hippocampus showed severe neuronal loss; h2 was the least affected sector. In the thalamus there was considerable nerve cell loss, especially in ventral and lateral nuclei where microglia formed neuronophagjc nodules around shrunken degenerate neurons. Astrocytic proliferation and Alzheimer type II glia were also present. Gliosis and a more moderate neuronal loss were noted in the lateral geniculate nucleus, and also in the caudate. In the cerebellum patches of slight Purkinje cell loss and Bergmann gliosis occurred, the dentate nucleus being more noticeably depleted of neurons. The inferior olives also showed some nerve cell loss. FIG. 3. Case 2. Liver, post-mortem specimen, showing annular postnecrotic fibrous septa and micronodular cirrhosis. Gordon and Sweet's silver impregnation for reticulin; bar = 0.1 mm. Liver. The lobular hepatic architecture was distorted by thin 'postnecrotic' type bridging septa of collagen and reticulin producing a micronodular cirrhotic pattern (fig. 3). Considerable microvesicular fatty change with large ballooned hepatocytes was particularly prevalent in the periportal and periseptal areas, often associated with chronic inflammation. There were also foci of on-going parenchymal necrosis. Downloaded from http://brain.oxfordjournals.org/ by guest on June 7, 2016 .'V PROGRESSIVE NEURONAL DEGENERATION OF CHILDHOOD 187 Downloaded from http://brain.oxfordjournals.org/ by guest on June 7, 2016 FIG. 4. Case 3. Coronal sections of the brain, A, midthalamic level; B, occipital lobes. All cortical regions show uniformly severe atrophy. There is ventricular dilatation and shrinkage of the white matter. 188 B. N. H A R D I N G A N D O T H E R S Case 3 (NP39.78) ,wFIG. 5. Case 3. The calcarine cortex {C) and white matter (W) are reduced to a thin gliotic strip. V = ventricular cavity; M = leptomeninges. Haematoxylin and eosin; bar = 0.25 mm. Downloaded from http://brain.oxfordjournals.org/ by guest on June 7, 2016 Clinical history. Pregnancy and delivery were uneventful, and this girl developed normally until she was 4 weeks old when she began to suffer focal seizures and ceased making developmental progress. On examination she was hypotonic and thought to be blind. Routine investigations, including amino acids, serial viral titres, immunoglobulins and liver function tests were normal at the age of 6 weeks. Liver function tests were not repeated. The EEG showed slow waves of high amplitude and polyspikes of lower amplitude. VERs were absent. CT scans showed rapidly progressive cortical atrophy and low density areas in the left occipital white matter. She died when 12 months old. Her younger sister suffers from a progressive disorder with intractable seizures, mental retardation and liver disease. Autopsy (Dr J. W. Nicholas). This showed bronchopneumonia. Macroscopic neuropathologicalfindings. The fixed brain weighed 340 g (normal for age 950 g), the brainstem and cerebellum 75 g. It was grossly shrunken with slender, hard convolutions and wide sulci. The hindbrain appeared better preserved. Coronal sections (fig. 4A, B) showed markedly dilated ventricles, greatly reduced white matter, and a thin severely gliotic cortical ribbon throughout the hemispheres, although the occipital cortex seemed the worst affected. The hippocampi were very small, the thalamus was shrunken, and the caudate nucleus flattened. Superior cerebellar folia appeared P R O G R E S S I V E N E U R O N A L D E G E N E R A T I O N OF C H I L D H O O D 189 gliotic; the outline of the dentate nucleus was indistinct. The cerebral peduncles were narrow and the medullary pyramids grey. Histological findings. CNS. All regions of the cerebral cortex showed severe neuronal loss. The orbital cortex was least affected, many nerve cells being preserved in laminae V and VI, some even in lamina III, and there was spongy change in lamina II. In most cortical areas only a minority of neurons in laminae V and VI remained; a heavy fibrillary gliosis, numerous capillaries and many lipid-laden macrophages were present. The occipital cortex, including the striate cortex, was worst affected: no neurons survived, only a residual thin gliomesodermal sheet (figs 5, 6). Downloaded from http://brain.oxfordjournals.org/ by guest on June 7, 2016 FIG. 6. c O z > r D m o m Z m > 5Z o o o a Fio. 8. Case 8. Histology of the striate cortex. The full thickness of the cortex is replaced by hypertrophicastrocytes, microglia and capillaries. Haematoxylin and eosin. A, bar •- 0.3 mm; B, bar — 0.1 mm. 196 B. N. H A R D I N G AND O T H E R S signs. There was cortical atrophy on CT scan and abnormal slow waves and polyspikes on EEC He died at 10 months after aspirating food when in status epilepticus. His younger brother also has a progressive neurological disease with seizures, hypotonia, developmental delay, blindness and abnormal liver function. Autopsy (Dr W. Scarratt). The liver weighed 250 g (normal 270 g) and was pale. The brain weighed 525 g (normal for age 809 g). Histologicalfindings.CNS. Consistently throughout all areas of the cerebral cortex there was sponginess in lamina II and superficially in lamina III, moderate neuronal loss in the upper half of the cortical ribbon, and astrocytic proliferation in the molecular layer and lamina II with accompanying fibrillary gliosis. Patchy accentuation with more severe changes in layer III occurred in the cingulate gyms, insular cortex and medial occipital cortex including the striate cortex. The white matter of the cerebral hemispheres appeared well myelinated. The hippocampi showed severe nerve cell loss in the Sommer sector and the endplate, with markedfibrillarygliosis particularly in the latter (fig. 10); the h2 sector and fascia dentata were less involved. Moderate gliosis and nerve cell loss occurred in the thalamus, but to a lesser degree in the lateral geniculate than other nuclei. The basal ganglia were unaffected. The nuclei pontis were slightly depleted as was the dentate ribbon, but the cerebellar cortex was normal. Liver. The only pathological feature was extensive panlobular microvesicular fatty change. Downloaded from http://brain.oxfordjournals.org/ by guest on June 7, 2016 FIG. 9. Case 5. Liver, post-mortem specimen, showing centrizonal cell loss with bridging collapse towards a portal tract. Note the presence of duct-like structures (arrow) surrounding the postnecrotic areas, and the microvesicular fatty infiltration of the hepatocytes. H = hepatic venule; P = portal tract. Haematoxylin and eosin; bar =• 0.1 mm. PROGRESSIVE NEURONAL DEGENERATION OF CHILDHOOD 197 Case 10 {NPI5.84) Clinical history. Pregnancy and delivery were normal and motor development was normal until the age of 11 months when his progress slowed. There were recurrent episodes of vomiting from 16 to 24 months and at 28 months he had a prolonged left-sided convulsion, and similar seizures at 36 and 37 months. Subsequently he had recurrent short-lived seizures, mainly left-sided, and drop attacks. Anticonvulsant therapy included phenobarbital, clonazepam, carbamazepine, ethosuximide, phenytoin, diazepam, chlormethiazole, paraldehyde, sodium valproate and a ketogenic diet with no effect, and at 39 months old he required ventilation for status epilepticus. When examined at 3 years of age he was hypotonic, ataxic and his liver was enlarged, but liver function tests and CT scan were normal. The EEG showed a gross excess of high amplitude slow activity mixed with polyspikes and multifocal discharges, maximal in the anterior half of the right hemisphere. Flash VERs were abnormal with a simple waveform and absent early components. By the age of39 months liver function tests had become abnormal (AST 47 U/l (normal 15-45 U/l), ALT 39 U/l (normal 10-35 U/l)) and CT scan showed generalized atrophy with excessive low density in the right occipital region. He died in liver failure aged 41 months. Autopsy (Dr J. Finch). There was jaundice and massive ascites. The liver (498 g) was shrunken and wrinkled. Macroscopic neuropathologicalfindings. The fixed brain weighed 1176 g. Large areas of the frontal, Downloaded from http://brain.oxfordjournals.org/ by guest on June 7, 2016 FIG. 10. Case 9. Section through hippocampus showing loss of pyramidal cells from the Sommer sector and endplate but preservation of h2. Luxol fast blue-cresyl violet; bar = 1 mm. Downloaded from http://brain.oxfordjournals.org/ by guest on June 7, 2016 V I. f . . V i • -.. • .»• i • •• 4*;. • • % '. • •vv ' • •• **' .« FIG. 11. Case 10. Histology of occipital cortex. Mild lesion with superficial gliosis and spongy change in lamina II but preservation of neurons. Haematoxylin and eosin. A, bar = 0.3 mm; B, bar = 0.1 mm. 03 PROGRESSIVE NEURONAL D E G E N E R A T I O N OF C H I L D H O O D 199 SUMMARY OF CLINICAL FINDINGS Clinical data of the 10 cases presented in this paper are summarized in Table 1. There were no significant perinatal problems. Presentation was between early infancy and 15 months with developmental delay and failure to thrive. Recurrent vomiting and hypotonia were also common. After a further variable period, usually several months, there was an explosive onset of epilepsy, often recurrent status epilepticus, intractable despite combination anticonvulsant therapy. Additional neurological findings included ataxia, pyramidal and extrapyramidal signs, deafness and blindness. Although the last was only detected in 3 cases, VERs were abnormal in 5 cases out of 7 investigated. The EEG showed unusual and characteristic changes (Boyd et al., 1986), and CT scans indicated rapidly progressive atrophy particularly in occipital areas. Abnormal liver function was detected in 5 cases before commencement of anticonvulsant therapy. After the onset of epilepsy progression of the illness was usually rapid and relentless. SUMMARY OF PATHOLOGICAL FINDINGS Brain Macroscopic. These comprised irregularity, narrowing, granularity and dark brown discolouration of the cortical ribbon, restricted to both calcarine fissures in Case 8, largely confined to the occipital lobes and particularly striate cortex in Cases Downloaded from http://brain.oxfordjournals.org/ by guest on June 7, 2016 parietal and medial occipital cortex were abnormal, with laminar dehiscencc in places. There was dilatation of the temporal horns of the lateral ventricles. In the cerebellum many folia were shrunken. Histological findings. CNS. Widespread although variable changes were present in the cerebral cortex. The mildest lesion, astrocytic proliferation in the molecular layer, was in the temporal lobe. Parietal and insular cortex showed marked sponginess in lamina II, and astrocytosis and nerve cell loss in the upper half of the cortical ribbon. Alzheimer type II glia were prominent, particularly in the insula. Similar changes were present in the left occipital lobe (fig. 11 A, B) including striate cortex, but the right side showed only astrocytosis. More pronounced changes were present in the frontal cortex: sponginess in laminae II and III, considerable nerve cell loss, proliferation of plump astrocytes and gliosis. Patchy but considerable accumulations of sudanophil lipid were present in superficial cortex. The white matter was moderately gliotic, but myelination was normal. The hippocampus showed severe nerve cell loss from h i and h3, with moderate depletion of h2 and the dentate fascia. Plump astrocytes abounded in the Sommer sector and an intense fibrous gliosis involved the endplate and dentate fascia. There was astrocytic proliferation throughout the basal ganglia with Alzheimer type II glia particularly numerous in the caudate and amygdala, and more obvious nerve cell loss from the claustrum. The thalamus was more severely involved, with widespread spongy degeneration and considerable neuronal loss. Microglia and neuronophagia were noted in places, as well as astrocytosis. The lateral geniculate nucleus was normal. Large areas of the cerebellar cortex showed total loss of Purkinje cells and granule cells with proliferation of Bergmann glia and isomorphous gliosis. The dentate nucleus was slightly depleted of neurons and gliotic. Moderate nerve cell loss, gliosis and microglial proliferation occurred in the olives. Liver. As well as massive fatty change, marked cholestasis and liver cell depletion, there was extensive bridging fibrosis with micronodular cirrhotic transformation. 200 B. N. HARDING AND OTHERS TABLE 1. SUMMARY OF CLINICAL FEATURES Case Sex Affected sibling Age* and manner of presentation Other features Age at onset of epilepsy* Abnormal liver function tests detected* Age at death* 1 M M (t9}yr) VPA 36 80 89 2 M VHB 15 4 21 3 F VH 1 4 F VHEA 17 16 19 5 M A 37 37 41 6 M VHBDE 8 6 24 7 8 M M VHB A VHPA 16 30 16 31 21 33 9 M HP 4 10 M 12, mental retardation 3, failure to thrive 1, retarded, seizures < 12, mental retardation, failure to thrive 12, mental retardation 2, mental retardation 4, failure to thrive 15, mental retardation Retarded from infancy 11, mental retardation VHA 28 F F 12 10 39 41 In months. V — vomiting; H « hypotonia; P — pyramidal signs; E =• cxtrapyramidal signs; B — blindness; D — deafness; A — ataxia. 6 and 7, more extensively involving frontal, parietal and occipital lobes in Cases 2, 5 and 10, and widespread throughout the cortical ribbon with some accentuation in the occipital lobes in Cases 3 and 4. Shrinkage of the thalamus, caudate nuclei, hippocampi and cerebellum were also features. Microscopic. There was extensive neocortical pathology with wide variations between and within cortical regions, unrelated to vascular territories or gyral topography. The mildest change was astrocytic proliferation in the molecular layer, the next spongy change in lamina II, and then more obvious neuronal loss and astrocytosis in lamina III. Severely affected areas showed marked nerve cell loss, astrocytic hyperplasia and hypertrophy, and sometimes a 'collapsed' critical ribbon, the remnant comprising large astrocytes, a dense glial fibrillary meshwork and numerous capillaries. Topographical analysis (Table 2) revealed a pronounced tendency for the striate cortex to be the most severely affected cortical region. Case 9 differed slightly in being only mildly affected. Case 10 was the exception: frontal rather than striate cortex was worst affected. The white matter was usually only mildly affected. Subcortical lesions (Table 3) most consistently involved the hippocampi, thalamus and cerebellum. Liver The pathology can be summarized in three groups. Group 1. Cases 1, 5, 7, 8 and 10 showed widespread severe microvesicular fatty change, on-going liver cell necrosis, and diffuse bile duct proliferation, together with heavy liver cell loss, collapse of plates and bridgingfibrosis.Case 5 showed end-stage Downloaded from http://brain.oxfordjournals.org/ by guest on June 7, 2016 M Valproale PROGRESSIVE NEURONAL TABLE 2. TOPOGRAPHICAL Case Frontal DEGENERATION OF CHILDHOOD ANALYSIS OF CORTICAL Parietal Insula 201 DESTRUCTION Occipital Slriate +++++ ++++ +++++ +++ + + +++ + +++++ R +++++ L++++ ++ + ++ + 1 2 3 + ++++ ++++ (Orbital + + +) + ++++ ++++ + ++ ++++ + ++ ++++ R+++ L+++++ ++++ +++++ 6 7 (Motor + + + + +) +++ ++ ++ ++ +++ ++ +++ ++ ++++ +++++ 8 9 10 + ++++ + ++ ++ + ++ + + ++ + ++ +++ +++ + = superficial astrocytosis; + + = spongiosis layer II; + + + = spongiosis including layer III, obvious neuron loss; + + + + = severe neuron loss including layers IV, V; + + + + + = subtotal neuron loss; — = not available. TABLE 3. SUMMARY OF SUBCORTICAL PATHOLOGY Case Hippocampus Thalamus LGN* Basal ganglia Cerebellum Brainstem 1 2 3 4 + + + + + + + + + + + + + + + + + + + + + + + + 5 6 7 8 9 10 0 + + + + + + + 0 + + + 0 0 + + + 0 + + + + + + + + + + + + + + 0 + 0 + * Lateral geniculate nucleus. + = affected. 0 = normal. destruction and fibrosis, and Cases 7 and 10 nodular regeneration and cirrhosis; Cases 1 and 8 were intermediate, neither strictly cirrhotic nor completely disorganized. Group 2. Cases 2 and 4 showed less acute damage than Group 1 but more scarring and repair with fatty change and focal necrosis. Cirrhosis was predominant in Case 2, perilobular scarring and periportal bridging in Case 4. Others. In Case 9 there was panlobular fatty degeneration and in Case 6, midzonal necrosis. DISCUSSION Our present clinical and neuropathological findings are indicative of a distinct clinicopathological entity. The familial incidence (Blackwood et ai, 1963; Wefring Downloaded from http://brain.oxfordjournals.org/ by guest on June 7, 2016 Temporal 202 B. N. HARDING AND OTHERS Downloaded from http://brain.oxfordjournals.org/ by guest on June 7, 2016 and Lamvik, 1967; Jellinger and Seitelberger, 1970; Huttenlocher et al., 1976) suggests autosomal recessive inheritance. Important diagnostic indicators are early visual impairment highlighted by VER abnormalities, characteristic waveforms on EEG, cortical atrophy with occipital predominance on CT scan, and hepatic dysfunction detectable biochemically. The neuropathological findings are in keeping with previous descriptions (Blackwood et al., 1963; Jellinger and Seitelberger, 1970; Huttenlocher et al., 1976) in that all regions of the cerebral cortex are usually involved, not necessarily symmetrically, and there is variable severity between and within cortical areas. Progression of the lesions has previously been demonstrated (Blackwood et al., 1963) by comparing consecutive biopsies and autopsies. And in our material there is a graded spectrum of pathological change in the cortex from superficial astrocytosis and spongy change in the mildest lesions, to gradual loss of neurons and gliosis spreading through the depth of the cortex, and to complete disorganization in the severest lesions. One observation which has not been described previously is the bias towards the visual cortex, which in our cases is generally the worst affected area (Table 2). This feature is most striking in Cases 1, 5, 7 and 8, where the abnormal striate cortex was easily picked out on naked eye examination; more widespread mild cortical damage was discernible only microscopically. The cause for the severe involvement of the visual cortex is obscure, one possibility being an increased metabolic requirement in view of the higher number of neurons in primate visual cortex (Rockel et al., 1980). Its importance lies in its diagnostic usefulness, for it is the structural correlate of the notable abnormalities of visual function. Arguments favouring the view that PNDC is a nosological entity have failed in the past for lack of specific pathological indicators. There are no characteristic histological changes in neurons, and large numbers of lipid-laden macrophages mostly confined to the cortex represent nonspecific breakdown products (Blackwood et al., 1963). The pathological process itself is not specific, but we would suggest that the topography of the cortical lesions (Table 2) is characteristic. Astrocytic overgrowth is an important feature of PNDC, but it remains unclear whether it is a secondary reaction or an intrinsic part of the pathological process, a 'glioneuronal dystrophy' similar to Creutzfeldt-Jacob disease (Klein and Dichgans, 1969; Jellinger and Seitelberger, 1970). Crompton (1968) and Janota (1974) have noted morphological similarities between PNDC and CreutzfeldtJakob disease. Ultrastructural studies are as yet unhelpful, for while vacuolated astrocytic and neuronal processes are well known in Creutzfeldt-Jakob disease, electron microscopy of brain biopsies in a few cases of PNDC have disclosed only swelling of postsynaptic dendrites (Kolkmann, 1969), or giant neuronal mitochondria (Suzuki and Rapin, 1969; Sandbank and Lerman, 1972), a nonspecific finding. Successful transmission experiments have so far not been reported. In severely affected cortex thin-walled capillaries are very numerous. Capillary proliferation may occur as a response to any cortical necrosis, but the increased density of capillaries is more likely to result from collapse of tissue (Blackwood PROGRESSIVE NEURONAL DEGENERATION OF CHILDHOOD 203 Downloaded from http://brain.oxfordjournals.org/ by guest on June 7, 2016 etal., 1963). These histological appearances differ from Leigh's disease (Egger etal., 1984) in topography, nerve cell destruction and lack of endothelial hypertrophy. In children with seizure disorders as severe and longstanding as in PNDC, the possible contribution of epileptic-hypoxic damage to the cerebral cortical destruction should be considered. Hypoxia complicating birth, and particularly following severe and serial convulsions has been canvassed (Wolf and Cowen, 1954; Greenhouse and Neubuerger, 1964) as the prime pathogenetic mechanism for the diffuse cerebral cortical damage, although one early case (Christensen and Krabbe, 1949) had no generalized seizures. This view of PNDC as resulting from repetitive seizures is based on the apparent histological similarity between PNDC and postepileptic encephalopathy. In our cases of PNDC there is no clinical or pathological evidence for birth injury. After a normal start neurological deficit clearly preceded the onset of seizures. Also there is no correlation between the duration of the convulsive disorder and the degree of histological abnormality: the more mildly affected brains were those from patients who presented later and survived longer. The severity of the pathological lesions reflects the velocity of the whole clinical process rather than the epileptic component. From a histopathological standpoint too, the cerebral cortical degeneration differs significantly from descriptions of postictal damage in children surviving for short periods following prolonged status epilepticus (Scholz, 1951; Norman 1964; Ounsted et al., 1966). In postictal damage there is widespread ischaemic cell change of cortical neurons, the process showing laminar intensification. In our cases there is no ischaemic cell change, and the lesion has a different pattern, spreading gradually deeper from superficial laminae to involve the whole cortical ribbon. Nor is there an accentuation of lesions in the depths of sulci or in vascular boundary zones, as occurs in hypoxic lesions. An early change in PNDC is sponginess of the superficial laminae, whereas spongy change occurs late in hypoxic lesions. A further difference between PNDC and postepileptic lesions concerns the calcarine cortex. Scholz (1951) and Norman (1964) emphasized that in postepileptic encephalopathy where the occipital lobe is diffusely involved, the calcarine cortex is often remarkably spared. In our cases the calcarine cortex is certainly never spared; as a rule it is the worst affected area. PNDC thus appears to be quite distinct, both clinically and pathologically, from complications of birth injury or postepileptic encephalopathy. In subcortical structures it is more difficult to distinguish primary disease processes from possible effects of epilepsy, hypoxia or secondary retrograde degeneration. Cerebellar cortical pathology most probably results from hypoxia due to epilepsy. Hippocampal lesions in general also follow the expected pattern for postepileptic damage, Ammon's horn sclerosis or endplate sclerosis (Margerison and Corsellis, 1966). Nonetheless, the severity of the destruction and spongy degeneration in Cases 3 and 4 argue for some contribution from the primary degenerative process, as do the spongy lesions in the amygdala, substantia nigra and thalamus in Cases 3, 4, 5, 8 and 10. The lateral geniculate nucleus is of particular interest with regard to retrograde thalamic degeneration in view of the preferential 204 B. N. HARDING AND OTHERS Downloaded from http://brain.oxfordjournals.org/ by guest on June 7, 2016 involvement of the striate cortex. In Cases 1, 7 and 8 where the clinical course was more protracted, neuronal loss, shrinkage and gliosis in the lateral geniculate were out of proportion to the rest of the thalamus; but in other cases the lateral geniculate was affected to a similar or lesser degree than other thalamic nuclei. Liver disease is an integral part of the pathology in PNDC. Five of our cases (Group 1) showed similar rather unusual hepatic involvement with severe fatty degeneration of hepatocytes, accompanied by extensive cell loss, profuse bile duct proliferation, heavyfibrosis,and nodular regeneration. Two further cases (Group 2) showed fatty change and focal necrosis, but rather more scarring and repair and less acute liver damage. Similar lesions were found on reexamination of two siblings from the series of Blackwood et al. (1963)—one reminiscent of our Group 1, and the other more like Group 2—making it highly likely that they are different stages of the same process. Our Case 9 may represent an earlier or milder version of the process; this is consistent with the particularly mild cerebral lesions in that patient. Hepatic lesions have also been noted by Huttenlocher et al. (1976), Wefring and Lamvik (1967), Cameron et al. (1968) and Jellinger and Seitelberger (1970). In view of the multiple drug therapy needed for the intractable epilepsy of these patients, one possibility to be considered is a toxic reaction producing liver failure. Although liver disease in previous cases is reported as manifesting late in the clinical course (if at all), in our patients there was biochemical evidence of significant liver involvement before or at the onset of seizures, and therefore before the institution of anticonvulsant therapy. Sodium valproate has been reported to produce toxic liver damage (Suchy et al., 1979). Seven of our patients were given this drug (Cases 1,3,4, 5, 6, 7, 10); similar hepatic lesions occurred whether or not it was used, while the previously reported cases of PNDC with liver lesions were not exposed to valproate. Thus it seems highly unlikely that valproate had an initiating role in the liver disease, but the possibility that it may exacerbate established hepatic damage cannot be excluded. The only patient (Case 6) to show acute midzonal necrosis, which has an association with drug toxicity, had not received sodium valproate. This particular hepatic lesion remains unexplained, particularly as significant abnormalities of liver function were detected at least eighteen months before death. Some Alzheimer type II astrocytes were present in 6 cases and probably represent an acute response to terminal liver failure and attendant hyperammonaemia (Victor et al., 1965; Cavanagh and Kyu, 1971). Gross hepatic dysfunction occurred too late to be a major causative factor in the cerebral disorder. There are also considerable morphological differences between PNDC and hepatic encephalopathy in which severe striatal damage occurs and cortical degeneration has a laminar distribution with microcavitation at the corticomedullary junction. Wilson's disease differs even more from PNDC; pathology is found mainly in the basal ganglia, with milder changes in the cortex (Smith, 1976), and the clinical course is quite dissimilar. Reye's syndrome also enters the differential diagnosis but the clinical course is more acute, the cerebral pathology is basically different, and there is no chronic hepatic degeneration (Reye et al., 1963). The present evidence, therefore, strongly supports PROGRESSIVE NEURONAL DEGENERATION OF CHILDHOOD 205 ACKNOWLEDGEMENTS We wish to thank the pathologists and neuropathologists who made material available to us, and particularly Professor W. Blackwood and Dr P. Buxton for allowing us to examine sections from their published cases. We are indebted to Dr James Leonard and Dr John Wilson for permission to publish clinical details of their patients. We gratefully acknowledge the skilled assistance of Mrs P. KelmanMcConnachie for the histological preparations, and Mr J. Mills for the macroscopic photography.. REFERENCES ALPERS B J (1931) Diffuse progressive degeneration of the gray matter of the cerebrum. Archives of Neurology and Psychiatry, Chicago, 25, 469-505. BLACKWOOD W, BUXTON P H, CUMINGS J N, ROBERTSON D J, TUCKER S M (1963) Diffuse cerebral degeneration in infancy (Alpers' disease). Archives of Disease in Childhood, 38, 193-204. BOYD S G, HARDEN A, EGGER J, PAMPIGLIONE G (1986) Progressive neuronal degeneration of child- hood ('Alpers disease') characteristic neurophysiological findings. Neuropediatrics. In press. CAMERON A H, JONES E L, SMITH W T, WOOD B S B (1968) Combined hepatic and cerebral degeneration in infancy. 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