Neurodegenerative disorders of gray matter in childhood
CEREBRAL CORTEX
ALPERS–HUTTENLOCHER SYNDROME OR PROGRESSIVE NEURONAL DEGENERATION OF CHILDHOOD (PNDC)
MACROSCOPIC APPEARANCES
Lesions may be minimal, patchy, or extensive (Fig. 6.1). In affected regions the cortical ribbon is thin, granular, and brown, and even dehiscent in some poorly fixed brains. The calcarine cortex is often picked out in a remarkably selective and characteristic way. Rarely, there is softening of the occipital white matter.
6.1 Alpers–Huttenlocher syndrome.
Selective involvement of the calcarine cortex is a helpful diagnostic pointer. (a) In this child, coronal sections of occipital lobe show the primary visual cortex in both hemispheres delineated by granularity and brown discoloration (arrow). (b) Similar discrete areas of cortical thinning and discoloration are present in the posterior frontal cortex at midthalamic level (arrow). (c) Although cortical lesions are usually patchy, in extreme cases the whole cortical ribbon may be diffusely and uniformly shrunken. In addition, there is ventricular dilatation, some thalamic atrophy, and marked shrinkage of Ammon’s horns.
MICROSCOPIC APPEARANCES
Histologic abnormalities are more widespread than expected from the macroscopic appearances. The patchy lesions do not conform to vascular territories or watershed zones and show a graded intensification and extension of the degenerative process through the depth of the cortical gray matter. Mild superficial spongiosis gives way to increasing sponginess, neuronal loss, and gliosis extending down through the cortex. In severe lesions, the whole ribbon is replaced by a narrow remnant of hypertrophic astrocytes devoid of nerve cells (Fig. 6.2). Neutral fat may be deposited in considerable amounts. Lesions may be symmetric or asymmetric, but there is a striking predilection for the striate cortex. Secondary changes are found in the white matter. Other variable findings include hippocampal sclerosis, cerebellar cortical infarcts, spinal cord tract degeneration, and spongiosis and gliosis in the thalamus (Fig. 6.3), amygdala, substantia nigra, and dentate nuclei.
6.2 Alpers–Huttenlocher syndrome.
(a) The mildest histologic changes consist of a fine spongiosis in the superficial cortical layers. (b) Neuronal loss and gliosis gradually extend more deeply through the cortical ribbon. (c) Eventually, the whole cortex is replaced by hypertrophic astrocytes. This shows the striate cortex, which is especially prone to such severe destruction. (d) The neurons and neuropil of the striate cortex are entirely replaced by a cystic meshwork of glial processes emanating from plump hypertrophic astrocytes. (e) Massive amounts of neutral fat can be deposited in the degenerating cortex. (f) The chronic end stage of this process is a thin, poorly cellular gliotic remnant. This shows striate cortex from the same case as in Fig. 6.1c.
HEPATIC PATHOLOGY
Nearly all patients show characteristic changes in the liver: the hepatocytes undergo severe microvesicular fatty or oncocytic change (Fig. 6.4). There are hepatocyte necrosis, diffuse haphazard bile duct proliferation, and bridging fibrosis, with disorganization and regeneration that amount to cirrhosis at one end of the histologic spectrum (Fig. 6.5), or end-stage collapse and fibrosis at the other.
6.4 Alpers–Huttenlocher syndrome: liver pathology.
Histologic changes in the liver are characteristic and essential for a confident diagnosis. (a) The principal features are hepatic steatosis and oncocytic change along with hepatocyte necrosis and a profuse and haphazard proliferation of bile ductules. (b) Fibrosis and nodular regeneration often give rise to a cirrhotic pattern. (c) Fat may be heavily deposited within the regenerative nodules. (d) In some patients, regeneration does not occur and the liver is replaced by dense fibrous tissue and irregular bile ductules. Note the bile retention.
6.5 Alpers–Huttenlocher syndrome.
Liver pathology in two brothers who died from PNDC. One of these brothers received valproate therapy, but both showed typical liver pathology. (a) Macroscopic appearance of the finely nodular cirrhotic liver of one brother. (b) Liver histology shows the typical changes of PNDC in the other brother. The role of drug therapy and in particular valproate toxicity in the pathogenesis of PNDC is controversial.
ALPERS–HUTTENLOCHER SYNDROME
DIFFERENTIAL DIAGNOSIS OF ALPERS–HUTTENLOCHER SYNDROME WITH EPILEPSY IN THE CONTEXT OF PROGRESSIVE CEREBRAL ATROPHYThe following discriminating features should be sought:
Hypoxic–ischemic encephalopathy: predilection for vascular boundary zones, relative preservation of gyral crests; striate cortex spared.
Hepatic encephalopathy: involvement of basal ganglia; cavitation of gray–white matter interface.
Neuronal storage disorders: neuronal abnormalities.
ETIOLOGY OF ALPERS–HUTTENLOCHER SYNDROME
Prominent spongiosis prompted speculation of a kinship with Creutzfeldt–Jakob disease but one apparently successful animal transmission experiment has not been duplicated.
Evidence of mitochondrial dysfunction in some patients includes cytochrome oxidase deficiency.
Most patients are compound heterozygotes with two mutations of the mtDNA polymerase gene POLG1.
BASAL GANGLIA
HOLOTOPISTIC STRIATAL NECROSIS (FAMILIAL STRIATAL DEGENERATION)
DIFFERENTIAL DIAGNOSIS OF BASAL GANGLIA DISORDERS IN CHILDHOOD
The following discriminating clinicopathological features should be sought.
Holotopistic striatal necrosis: acute necrosis or slow degeneration; recessive inheritance.
Wilson’s disease: striatal, retinal, and hepatic degeneration.
Juvenile Parkinson disease: degeneration of substantia nigra and locus ceruleus.
Glutaric acidemia: striatal degeneration; specific biochemical abnormality.
Propionic acidemia: striatal gliosis and/or marbling; specific biochemical abnormality.
Methylmalonic acidemia: infarcts; hemorrhages; specific biochemical abnormality.
MACROSCOPIC AND MICROSCOPIC APPEARANCES
Two patterns are observed (Fig. 6.6):
6.6 Holotopistic striatal necrosis.
(a) Histologic section demonstrating shrinkage and pallor of the dorsal halves of both caudate and putamen. (b) Marked neuronal loss and gliosis in the striatum. (c) In another patient the caudate nuclei are atrophic brown crescents and the putamina are replaced by cavities outlined by grayish membranes. Ventricular dilatation and cortical atrophy are pronounced. (d) In this child, there is also cerebellar cortical atrophy, seen here in the vermis.
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION-1 (HALLERVORDEN–SPATZ DISEASE)
HOLOTOPISTIC STRIATAL NECROSIS
Some cases are familial (usually autosomal recessive, but a similar disorder can occur in association with Leber’s hereditary optic neuropathy due to mitochondrial DNA mutations).
Onset may be acute (following a febrile illness) or insidious.
Symptoms include choreoathetosis, abnormal eye movements, seizures, and mental retardation.
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION-1
MACROSCOPIC AND MICROSCOPIC APPEARANCES
Yellow–brown discoloration of the globus pallidus and substantia nigra are evident (Fig. 6.7). Neuronal loss, gliosis, and deposition of iron pigment occur bilaterally in the internal segment of the globus pallidus and the pars reticularis of the substantia nigra. There is also a more widespread distribution of swollen axons (spheroids). Neurochemical studies indicate abnormal cysteine metabolism in the pallidum and it is suggested that cysteine chelates iron, which in turn induces tissue damage mediated by free radicals (see also neuroaxonal dystrophy, in Chapter 33).
6.7 Neurodegeneration with brain iron accumulation-1.
(a) Coronal sections at the level of the anterior thalamus demonstrate a remarkable yellow–brown pigmentation in both pallida. (b) Microscopically, there are hematoxyphilic mineralizations, eosinophil axonal spheroids, and deposits of brown pigment in the pallidum. (c) These deposits stain positively for iron. (d) Neuroaxonal spheroids demonstrated with antibody to phosphorylated neurofilaments, and mineral concretions (stained blue) within the pallidum. (e) Neuroaxonal spheroids, labeled here with an antibody to neurofilament protein, are also plentiful in the gray matter bridges between caudate and putamen.
CEREBELLUM
MACROSCOPIC AND MICROSCOPIC APPEARANCES
Microscopically there are neuronal loss and myelin deficiency in the temporal cortex and hippocampus. In the cerebellum marked depletion of the granular layer is combined with displacement of Purkinje cells, which show ‘torpedoes’, dendritic distortions, and somal sprouting (Fig. 6.8).
