MACROSCOPIC APPEARANCES

Arthrogryposis, pterygia, muscular hypoplasia, and pulmonary hypoplasia are found at necropsy (Fig. 7.1a). Bubble-like hemispheres that are macroscopically indistinguishable from those seen in encephaloclastic hydranencephaly have a diaphanous pallium studded with calcifications (Fig. 7.1b).

MICROSCOPIC APPEARANCES

The thin, disorganized pallium has a narrow immature cortical plate. Glomeruloid endothelial vasculopathy, which is unique to this disorder, is prominent throughout the CNS (Fig. 7.2). Endothelial cells in the glomeruloid structures have PAS-positive intracytoplasmic inclusions, which appear on electron microscopy as homogeneous granular material surrounded by rough endoplasmic reticulum (Fig. 7.3).

MACROSCOPIC APPEARANCES

Potter’s facies, contraction deformities of the limbs, pulmonary hypoplasia, and bilateral renal agenesis are found at necropsy, but there are no cutaneous vascular nevi.

The leptomeninges are extremely vascular, and in some cases there is subarachnoid hemorrhage. The circle of Willis is normal. The brain is small and gyral atrophy is evident. In the cerebrum, there is cortical and white matter necrosis, with or without hemorrhage and calcification.

MICROSCOPIC APPEARANCES

There is diffuse angiodysplasia, consisting of ectatic capillaries and veins. These are present in the leptomeninges, cerebral cortex, cerebellum, and brain stem. The angiodysplasia is complicated by thrombosis, infarction, hemorrhage, hemosiderin-laden macrophages, gliosis and calcification in the cerebral cortex and white matter (Fig. 7.4).

MACROSCOPIC AND MICROSCOPIC APPEARANCES

The vascular malformation is fed by one or both of the posterior cerebral arteries or their branches resulting in dilatation of the vein of Galen and enlargement of the cerebral venous system and sinuses (Fig. 7.5). The enlarging vascular mass may compress the aqueduct causing hydrocephalus, or may undergo calcification or thrombosis. Microscopically, veins show the typical changes of ‘arterialization’, e.g. hyperplasia and hypertrophy of the intima and muscularis, that result from increased intraluminal pressure.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Lymphocytic infiltration of the media and destruction of the elastica of affected vessels are associated with giant cells and followed by fibrosis and thickening. The blood vessels are further narrowed by superimposed intimal proliferation and atheroma. Thromboembolic disease leads to cerebral ischemia. Only rarely does the arteritic process directly involve cerebral vessels (Fig. 7.6).

MACROSCOPIC AND MICROSCOPIC APPEARANCES

In fatal cases, there is coronary arteritis with thrombosis and aneurysm formation, interstitial myocarditis, and myocardial infarction. Various medium-sized arteries can be involved, including cerebral vessels (Fig. 7.7).

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Hyaline eosinophilic platelet thrombi occlude small arteries and arterioles, which also show striking endothelial swelling. Multiple microinfarcts are present in cerebral and cerebellar gray matter (Fig. 7.8).

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Cerebral edema is common, and the consequences of profound cerebral hypoperfusion, particularly boundary zone infarction, are sometimes seen (Fig. 7.9).

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Macroscopic changes may be minimal, but in longstanding cases there is severe and extensive unilateral atrophy with ventricular dilatation.

Histologic changes (Fig. 7.11) are usually much more widespread than suspected macroscopically and include patchy chronic leptomeningitis and chronic inflammatory changes in the neocortex and hippocampus, subjacent white matter, and sometimes the basal ganglia. The principal features are:

In nearly all cases these changes are unilateral (Fig. 7.12). Progressive neuronal loss can lead to an end-stage appearance of a spongy gliotic and cystic cortical remnant devoid of nerve cells.

LAFORA BODY DISEASE (EPM2A; EPILEPSY, PROGRESSIVE MYOCLONIC 2)

This is an autosomal recessive, rapidly progressive form of myoclonic epilepsy, characterized by the accumulation of Lafora bodies within the brain and several other tissues.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

The brain usually appears macroscopically normal. Histology reveals numerous Lafora bodies in the cytoplasm of neurons and astrocytes in the cerebral cortex (Fig. 7.14), basal ganglia (especially the globus pallidus), thalamus, substantia nigra, cerebellar cortex, and dentate nucleus. Fewer inclusions are present in the brain stem and they are sparse in the spinal cord.

The Lafora bodies are composed of polyglucosans (polymers of sulphated polysaccharides) and are similar to corpora amylacea in composition and staining characteristics. The inclusions are round, measuring up to about 30 μm in diameter. They stain strongly with hematoxylin, and with PAS, and metachromatically with methyl violet. Most Lafora bodies contain a deeply hematoxyphilic, PAS-positive central core with a spiculated outline and a surrounding zone of less intensely staining material. The polyglucosans are resistant to diastase digestion. Ultrastructurally, Lafora bodies comprise of aggregates of 6–7 nm filaments. The aggregates are not membrane bound and are admixed with amorphous granular material.

There is usually mild to moderate gliosis and neuronal loss in those regions of the CNS that contain the most numerous Lafora bodies. These changes are most pronounced in the dentate nucleus.

Lafora bodies are present in liver, skeletal, and cardiac muscle. An axillary biopsy is useful for confirmation of the diagnosis in life since Lafora bodies occur in myoepithelial cells of the apocrine glands, and in the cells that form the eccrine sweat ducts.

UNVERRICHT–LUNDBORG DISEASE (BALTIC MYOCLONUS) (EPM1; EPILEPSY, PROGRESSIVE MYOCLONIC 1)

This is an autosomal recessive form of progressive myoclonic epilepsy that is most prevalent in the Baltic region of Estonia, eastern Sweden, and Finland. Several affected families in the USA have been reported. The onset of symptoms is usually earlier than in Lafora body disease but the progression is less rapid.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

The brain usually appears macroscopically normal. Histology reveals swelling, vacuolation and severe loss of Purkinje cells, with associated Bergmann cell astrocytosis. The most consistently observed additional histologic abnormalities are neuronal loss and gliosis in the medial thalamic nuclei.

Systemic examination is largely non-contributory but clear membrane-bound vacuoles have recently been reported to be present in the eccrine sweat gland cells of some patients.