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.

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.

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.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Two patterns are observed (Fig. 6.6):

Both patterns may occur in familial cases. Neocortical and cerebellar degeneration may also be found.

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).

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Macroscopic features include marked microcephaly, quite frequent subdural hematomas, and a variable degree of cerebellar atrophy with narrowed folia.

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).

MACROSCOPIC AND MICROSCOPIC APPEARANCES

There are cerebellar cortical atrophy with a severe loss of Purkinje and granule cells (Fig. 6.9) and posterior column degeneration in the spinal cord. Systemic features include hypoplasia of thymus, lymphoid tissue, and gonads (see also Chapter 29).

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Brain weight may be normal or slightly reduced, but the hindbrain accounts for 5% or less of the total weight because the cerebellum is

globally small with narrow, prominent, and hard folia (Fig. 6.10). The pontine base is flattened.

CDG1 is characterized microscopically by a subtotal loss of Purkinje and granule cells, extensive loss of cerebellar white matter, and gliosis, while the dentate nucleus and superior cerebellar peduncles appear well preserved. The pontine nuclei and inferior olives show marked neuronal depletion, and the middle and inferior cerebellar peduncles and transverse pontine fibers are extremely atrophic.

At necropsy, pleural and pericardial effusions and ascites are common. The liver shows macrovesicular fatty infiltration (Fig. 6.11), abnormal bile duct plates, and portal fibrosis. The kidneys show pronounced cystic dilatation of tubules and collecting ducts.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Microcephaly and marked cerebellar atrophy are seen macroscopically (Fig. 6.12). Histologic features are cerebellar cortical degeneration, severe Purkinje cell loss accompanied by ‘torpedo’ axonal swellings, asteroid dendritic expansions, and variable granule cell involvement. The inferior olivary nuclei are always involved, but the pontine nuclei are spared. Atrophy of the optic nerves, superior colliculi, lateral geniculate nuclei, and visual cortex can also occur.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Microcephaly, cerebellar atrophy, a shallow pons, and flat inferior olives are accompanied by a subtotal loss of Purkinje cells, lesser depletion of granule cells, Bergmann cell gliosis, severe olivary atrophy, and variable depletion of the nuclei pontis (Fig. 6.13).

 Brown–Vialetto–van Laere syndrome.

 Fazio–Londe disease.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

In both Brown–Vialetto–van Laere syndrome and Fazio–Londe disease the main histologic findings are degeneration of:

Additionally in Brown–Vialetto–van Laere syndrome there is degeneration of the sensory cochleovestibular nerves and ventral cochlear nuclei.

 Hallervorden–Spatz disease.

 Infantile neuro-axonal dystrophy (INAD).

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Apart from cerebellar atrophy, macroscopic abnormality in INAD is minimal. Axonal spheroids are widely distributed throughout the CNS (Fig. 6.15), but are most easily found in the cerebellum, brain stem, and spinal cord, notably among the long sensory tracts. They are also present in cerebellar and cerebral white matter, basal ganglia, thalamus, and in the cerebral cortex where their small size makes detection difficult with conventional histology.

The axonal spheroids have the appearance of eosinophilic ovoids that sometimes show a cleft. They are irregularly argyrophilic, and immunoreactive with neurofilament antibodies. The nonspecific esterase technique in frozen sections is particularly effective for detecting spheroids in cortical biopsies.

Myelin pallor or degeneration may be widespread in cerebral and cerebellar white matter. Other findings include cerebellar cortical degeneration, neurofibrillary tangles, and Lewy bodies.

Ultrastructurally, the axonal swellings are packed with tubulovesicular membranous material, often surrounding a central cleft.

MACROSCOPIC APPEARANCES

There are characteristic symmetric circumscribed brown patches or gray lesions, which are sometimes cavitated (Fig. 6.16). These lesions are present in the striatum, subthalamic nucleus, substantia nigra, inferior olives, and hindbrain tegmentum, and often run in a linear fashion below the ventricle.

MICROSCOPIC APPEARANCES

In typical cases there are many vasculonecrotic lesions distributed symmetrically through the CNS. These lesions take three histologic forms (Fig. 6.17), which probably reflect varying chronicity, but the different appearances are often contiguous, suggesting repetitive damage to the area. The oldest lesions are fibrous or cavitated gliotic scars, equivalent to old infarcts. The youngest and least frequent lesions are composed of poorly cellular edematous neuropil with activated macrophages and eosinophilic neurons. The most typical lesion is characterized by numerous foamy macrophages and variable astrocytosis, prominent congested and hypertrophic capillaries, and collapse of the neuropil, within which there are often some normal neurons. This recent lesion (probably several weeks old) resembles the lesions of Wernicke’s encephalopathy, but there is never any hemosiderin deposition.

Symmetric lesions, often confined to the same part of a nucleus, are found in many gray areas (Table 6.1). Lesions are nearly always present in the substantia nigra, but in only about 50% of patients in the striatum and inferior olives, notably in those patients dying after the first year.

Other features include spongy vacuolation or severe myelin loss in the optic nerves and tracts, spinal cord, centrum semiovale, and cerebellar white matter, and patchy loss of Purkinje cells associated with ‘torpedo’ formation.

 Type I: acute infantile SMA; Werdnig–Hoffman disease.

 Type II: intermediate SMA.

 Type III: chronic SMA; Kugelberg–Welander syndrome.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

At necropsy, there is a striking atrophy of anterior spinal nerve roots and motor nerves (Fig. 6.18). There is usually a profound loss of anterior horn cells and gliosis at many levels of the spinal cord. In the early stages there are acute degenerative changes such as chromatolysis and microglial nodules. The degenerative process may also extend to the bulbar cranial nerve nuclei and sometimes to the dorsal root sensory ganglion cells.

Muscle biopsy at first shows atrophy of all fiber types, and then compensatory hypertrophy due to collateral sprouting of residual intact nerve fibers, which produces grouping of large and small fibers. Groups of hypertrophic type I fibers are particularly common in SMA. Secondary myopathic changes, including endomysial fibrosis, may be prominent in chronic forms of SMA.

SMA VARIANTS

There are several similar clinical entities of diverse genetic background that cause anterior horn cell degeneration and these should be differentiated from the typical acute form of SMA. Table 6.2 places them in context alongside SMA and the progressive bulbar palsies of childhood.