MACROSCOPIC AND MICROSCOPIC APPEARANCES

In most cases, the brain appears macroscopically normal and scant abnormalities (mild cortical gliosis, slight prominence of microglia) are demonstrable by conventional staining. Use of appropriate silver impregnation techniques reveals argyrophilic material containing aluminum in the choroid epithelium and to a lesser extent in the glia and neurons, particularly in the brain stem nuclei.

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The peripheral neuropathy caused by chronic trivalent arsenical intoxication may be associated with chromatolysis and loss of anterior horn cells. In patients with acute hemorrhagic leukoencephalopathy complicating organic pentavalent arsenical administration, the brain is swollen and contains numerous small and occasional larger foci of hemorrhage (Fig. 25.1). Histology reveals fibrinoid necrosis of many parenchymal blood vessels and hemorrhage into the surrounding tissue (Fig. 25.1). Some of the blood vessels are surrounded by a fibrin exudate containing a mixed inflammatory infiltrate. The findings are described in more detail in Chapter 20.

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Descriptions of the neuropathologic findings of bismuth toxicity are sparse. Bismuth can be demonstrated histochemically in neurons, glia and the walls of blood vessels. However, most of the described abnormalities such as a loss of Purkinje cells and degeneration of pyramidal cells in the hippocampus are probably due to hypoxia.

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Changes reported in acute lead encephalopathy include brain swelling and congestion, and in some cases petechial hemorrhages or hydrocephalus.

Microscopically, endothelial swelling, and capillary necrosis and thrombosis have been reported, with a proteinaceous exudate in the perivascular spaces and extending into the adjacent brain tissue. Periodic acid–Schiff (PAS)-positive globules may be seen within the exudate and in astrocytes. Other reported findings include widespread gliosis, and, in some cases, foci of necrosis or spongiosis.

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In contrast to idiopathic Parkinson’s disease (see Chapter 28), the substantia nigra is preserved, but there is gliosis and a loss of neurons from the pallidum and subthalamic nucleus and, to a lesser extent, from the caudate and putamen.

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There are no reports of macroscopic abnormalities in the brain following exposure to inorganic mercury. Survivors of methylmercury intoxication develop moderate to marked brain atrophy, particularly of the calcarine cortex and cerebellum.

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There is preferential loss of small neurons, particularly from the granule cell layer of the cerebellum and the primary visual, auditory, and somatosensory regions of the cerebral cortex, in which small neurons predominate. In severe cases, particularly in children, neuronal loss is more extensive and there is spongiform cortical degeneration. Other features include an associated gliosis and, in acute lesions, infiltration by macrophages. Degeneration of dorsal root ganglion cells results in some loss of nerve fibers from the posterior columns of the spinal cord. Sprouting of Purkinje cell dendrites is a prominent feature in long-term survivors, in whom granular deposits of mercury are demonstrable in astrocytes, microglia, and neurons (Fig. 25.2).

Fetal intoxication can cause neuronal heterotopia and cortical dysplasia in addition to degenerative lesions. Extensive architectural disruption of neuronal elements can be observed within the cerebellum.

 chromatolysis of motor neurons

 degeneration of posterior column fibers.

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Triethyltin causes striking white matter edema in brain and spinal cord (Fig. 25.4) due to the accumulation of fluid in vacuoles within the myelin sheaths (Fig. 25.4). The vacuoles are formed by separation of myelin along intraperiod lines (Fig. 25.4). Trimethyltin does not cause intramyelinic edema, but is toxic to neurons in the hippocampus, basal ganglia, entorhinal cortex, and amygdala. It elicits specific apoptotic destruction of pyramidal neurons in the CA3 region of the hippocampus and in other limbic structures.

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The brain and spinal cord appear macroscopically normal. Histology reveals swelling and degeneration of the distal part of longer axons in peripheral nerves and the posterior spinal, spinocerebellar, and corticospinal tracts. The swellings contain accumulations of neurofilaments.

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The brain and spinal cord appear macroscopically normal, and histologic changes are sparsely documented. In the peripheral nervous system, carbon disulfide intoxication results in axonal swellings (Fig. 25.5), which contain abnormal accumulations of neurofilaments, and distal nerve fiber degeneration. Described CNS abnormalities include distal axonal spinocerebellar degeneration and increased cerebral atherosclerosis. Spinal long tracts contain neurofilamentous axonal swellings (Fig. 25.5). The distal axonopathy is probably secondary to progressive cross-linking and accumulation of neurofilaments during their anterograde transport in long axons.

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Published descriptions of the pathologic features of carbon tetrachloride toxicity are scarce. Brain edema, hemorrhages, focal vascular necrosis, venous thromboses, and hemorrhagic infarcts have been reported.

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Acute intoxication produces meningeal congestion and cerebral edema, and, occasionally, petechial hemorrhages. Microscopically, birefringent calcium oxalate deposits can usually be demonstrated by polarized light microscopy (Fig. 25.6) in and around vessels in the meninges, brain parenchyma, and choroid plexus. Neurons may show hypoxic change and there is often white matter edema. Scanty perivascular acute inflammatory infiltrates may be seen, but these are not consistently related to the calcium oxalate deposits and may be a reaction to hypoxic brain injury.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

The brain and spinal cord appear macroscopically normal. Histologic changes in the human CNS are sparsely documented, but there are many experimental studies demonstrating the formation of neurofilamentous axonal swellings (Fig. 25.7) and distal degeneration of nerve fibers in long ascending (spinocerebellar and posterior column) and descending (corticospinal) spinal tracts, as occur in the peripheral nerves. As in carbon disulfide intoxication, the changes are probably due to progressive cross-linking and accumulation of neurofilaments during their anterograde transport.

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In acute methanol intoxication the brain is usually edematous and shows features of global hypoxic injury (see Chapter 8). There may be scattered petechial hemorrhages and larger, symmetric foci of hemorrhagic infarction in the putamen. In severe cases, hemorrhagic necrosis of the putamen is accompanied by more widespread hypoxic damage to the cerebral cortex and extensive white matter necrosis (Figs 25.8–25.10). Survivors of the acute toxicity may show putaminal cavitation, with accumulation of macrophages and reactive astrocytosis (Fig. 25.11). Degeneration of retinal ganglion cells results in optic nerve atrophy and gliosis.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

The brain and spinal cord appear macroscopically normal. Histology reveals swelling and degeneration of the distal part of longer axons, particularly in peripheral nerves, but also in the posterior spinal, corticospinal, and spinocerebellar tracts.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Cerebellar atrophy has been demonstrated by computerized tomography and an increase in the water content of white matter is suggested by findings on magnetic resonance imaging. No information is available about the pathologic findings in humans. In rats, prenatal exposure to toluene results in abnormal neurogenesis and neuronal migration in the somatosensory cortex. Adult rats show neuronal loss in the hippocampus and it has been suggested that similar abnormalities may be the substrate of memory deficits after repeated exposure in man.

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No macroscopic changes have been reported. Striking inflammatory and vasculitic abnormalities affect peripheral nerves and skeletal muscle, but tend to spare the CNS. Large neurons in the spinal cord and brain stem may be chromatolytic or, in some cases, vacuolated and distended by argyrophilic masses composed of neurofilaments.

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During the first few hours, the brain is swollen, congested, and cherry-red in color, though this is less striking after prolonged formalin fixation. After 24–48 hours of survival, scattered petechial hemorrhages may be seen in the white matter and larger hemorrhages in the pallidum (Fig. 25.12). These usually involve the dorsal part of the inner segment of the pallidum, but may extend laterally into the outer segment or dorsomedially into the internal capsule. The pallidal lesions are often asymmetric (Fig. 25.12) and may be unilateral or absent. In some cases there are hemorrhages in the hippocampus and cerebral cortex. Following survival of several days or weeks, the lesions in the pallidum appear necrotic or cavitated (Fig. 25.12). Discrete or confluent foci of necrosis may also be evident in the white matter (Fig. 25.12). These tend to spare the arcuate fibers.

Although pallidal necrosis is typical of delayed death from carbon monoxide poisoning, it is not unique to this condition and can occur in other hypoxic states, methanol toxicity (see above), or cyanide toxicity (see below).

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In the acute stage there may be foci of necrosis and/or perivascular hemorrhage in the affected parts of the gray and white matter. Within days, these foci accumulate numerous lipid- or hemosiderin-laden macrophages. Lesions in longer-term survivors are cavitated (Fig. 25.13) or rarefied and gliotic. Typical changes of global brain hypoxia–ischemia of varying severity (see Chapter 8) are usually seen. The white matter lesions may be small and discrete, extensive, or even confluent. In some cases there is a loss of myelin, but relative preservation of axons in the deep white matter. This pattern tends to be associated with a delayed clinical deterioration. Arcuate fibers are usually spared (Fig. 25.14).

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After acute intoxication, the brain usually appears normal, but if death is delayed by a few hours, there may be edema and small subarachnoid and petechial parenchymal hemorrhages. Necrotic foci have been noted in the white matter and pallida in the rare cases that survive days or weeks. These lesions are similar to those associated with carbon monoxide poisoning (see above).

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Relevant data are sparse. Reported findings in patients surviving days or weeks include white matter and pallidal necrosis, gliosis of the cerebral cortex, and loss of cerebellar Purkinje cells.

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Human data are lacking, but administration of nitrous oxide to animals has produced neuropathologic changes resembling those of subacute combined degeneration (see Chapter 21).

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In experimental animals, amphotericin B produces a leukoencephalopathy with a loss of oligodendrocytes, axon swelling or fragmentation, gliosis, and an accumulation of lipid-laden macrophages. Data on human intoxication are sparse, but multifocal necrotizing leukoencephalopathy has been reported.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

The brain and spinal cord appear macroscopically normal. Histology reveals degeneration of the distal part of longer axons in:

Other abnormalities that may be seen include:

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Intoxication causes spongy degeneration of the white matter due to intramyelinic edema (see above), which is most marked in the brain stem (Fig. 25.15). Necrosis of the optic nerves, chiasm, and tracts has also been reported.

 Chloramphenicol may cause optic atrophy and peripheral neuropathy after prolonged high-dose administration.

 Cycloserine, ethionamide, and pyrazinamide may cause a pellagra-like syndrome similar to that associated with isoniazid toxicity (see below).

 Gentamicin is a rare cause of encephalopathy. Foci of white matter necrosis and calcification have been observed in the midbrain and pons after intrathecal administration. The aminoglycosides, including gentamicin, are all ototoxic.

 Overdosage is a particular risk in slow acetylators of the antituberculous drug isoniazid (isonicotinic acid hydrazide, INH), and especially in patients with impaired renal function. INH chelates pyridoxal phosphate and the resulting inhibition of pyridoxal phosphokinase and impaired conversion of tryptophan to niacin produces an acute pellagra-like syndrome, which responds to pyridoxine (vitamin B6) administration. The occurrence of seizures is thought to be due to inhibition of the synthesis of the inhibitory neurotransmitter γ-aminobutyric acid. Visual disturbances and optic atrophy have been reported.

 Ethambutol can cause visual disturbances and optic atrophy.

 Metronidazole can cause a reversible encephalopathy in high doses. The most common clinical manifestations are dysarthria, gait disturbance, weakness of the extremities, and confusion. On MR imaging, high T2 signal is often seen in the dentate nuclei in the cerebellum but may also involve the tectum, red nucleus, periaqueductal gray matter, and dorsal pons. The abnormalities are reversible on discontinuation of the drug.

 Nimorazole, an anti-protozoal drug that is also used to sensitize hypoxic tumor cells to radiotherapy, has been reported to cause foci of cerebral and cerebellar white matter necrosis, with a predilection for long fiber tracts, and lesions similar to Leigh’s disease in the brain stem and cerebellar dentate nuclei. Interference with mitochondrial function, with resulting energy deprivation, was the postulated mechanism.

 Penicillins can cause seizures, partly because the β-lactam ring binds to γ-aminobutyric acid receptors. Hydrophobic penicillins such as cloxacillin and dicloxacillin are most likely to be neurotoxic.

 Sulfonamides (USA)/sulphonamides (UK) very rarely cause acute psychosis, meningism, and myelitic symptoms. Neuropathologic examination of fatal cases has shown vascular endothelial swelling and necrosis, and scattered foci of necrosis with or without hemorrhage in the gray and white matter.

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There are few reports on the neuropathologic findings in human toxicity. The parieto-occipital white matter may be edematous. Electron microscopy in one case showed detachment of astrocytic foot-processes from blood vessels in the white matter. Vasculitis has also been reported. Rarely, there is also extensive axonal damage and degeneration, with loss of myelin and infiltration by macrophages (Fig. 25.16).

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Multiple discrete or confluent foci of necrosis may be evident in the cerebral and/or spinal white matter. The lesions may be periventricular in patients given intraventricular methotrexate. In longer-term survivors the white matter is gliotic and atrophic.

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There is a loss of myelin and swelling and fragmentation of axons within foci of coagulative necrosis in the white matter (Fig. 25.17). Multifocal axonal injury with accumulation of β-amyloid precursor protein may be demonstrable immunohistochemically. Lipid-laden macrophages are plentiful in the early stages. The axonal swellings and other cellular debris tend to calcify. In longer-term survivors the white matter may be reduced to an attenuated layer of gliotic, focally calcified tissue. Vascular abnormalities are present in some cases and include perivascular fibrin exudates, fibrinoid vascular necrosis, and a non-inflammatory mineralizing angiopathy, which is most severe in the lenticular nuclei. Intra-arterial methotrexate administration has caused multiple hemorrhagic infarcts due to fibrinoid necrosis and thrombosis of small blood vessels.

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Reported findings in cases of cytosine arabinoside toxicity include cerebellar cortical degeneration and karyorrhexis of brain stem tegmental and spinal motor neurons associated with perikaryal accumulation of masses of neurofilaments. White matter vacuolation and loss of nerve fibers have been noted in the spinal cord.

Experimentally, 5-fluorouracil and its derivatives cause intramyelinic edema and foci of gray matter softening and necrosis in the cerebellum and brain stem. Findings in human intoxication have included neuronal degeneration involving Purkinje cells and the dentate and inferior olivary nuclei, and an inflammatory cerebral demyelinating disease.

Autopsy examination of the brain in patients with fludarabine-associated neurotoxicity has shown a necrotizing leukoencephalopathy (Fig. 25.18) most severe in the occipital lobes, but also involving the medullary pyramids and posterior spinal columns. The subcortical white matter lesions may extend into the adjacent cerebral cortex.

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Neuropathologic findings in the CNS have included distension of neurons in the spinal cord and brain stem by abnormal aggregates of neurofilaments and, in one case, eosinophilic intracytoplasmic crystals, which may have been composed of microtubule proteins.

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Neuropathologic examination has shown neuronal loss and gliosis in the cerebellar cortex and dentate nuclei, and spongy vacuolation of the cerebellar white matter.

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Mononuclear inflammatory infiltrates around blood vessels in the periventricular region were noted in a patient who died after intraventricular instillation of metrizamide.

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There may be obvious atrophy of the cerebellar vermis and hemispheres (Fig. 25.19). Microscopic findings are relatively nonspecific, with severe loss of Purkinje, and usually, granule cells (Fig. 25.19). There is marked proliferation of Bergmann astrocytes, with associated isomorphic gliosis (Fig. 25.19). The cerebellar cortical degeneration is usually diffuse, but may be patchy.

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Neuropathologic complications include arterial or venous infarcts and subarachnoid or parenchymal hemorrhages. In a few cases histology has shown a necrotizing vasculitis, predominantly of small blood vessels, but larger arteries and veins may also be involved.

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Neuropathologic complications include arterial infarcts, and subarachnoid or parenchymal hemorrhages (Fig. 25.20):

The spinal cord may be affected.

Rupture of saccular (berry) aneurysms (see Chapter 10) is a well-documented complication of cocaine abuse in young adults and is thought to be due to the transient, but occasionally marked, hypertension.

The vasoconstrictive action of chronic intranasal cocaine can cause local soft tissue and bony erosion. Rarely this results in CSF rhinorrhea and secondary bacterial or fungal infection.

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Angiographic findings have been suggestive of a small vessel angiitis in some patients. However, the predominant findings have been watershed infarcts, laminar sclerosis, and bilateral infarcts of the globus pallidum, all presumably due to a combination of reduced cerebral perfusion and global hypoxia. The spinal cord may be affected. Refractile embolic particles of foreign material have been observed in the skin, and rarely in the spinal cord of heroin users, but not in the brain.

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Neuropathologic examination reveals nigrostriatal neuronal degeneration in a pattern closely resembling that of idiopathic Parkinson’s disease (see Chapter 29). Typical Lewy bodies are, however, not seen. In experimental studies:

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Fatal acute intoxication may produce cerebral congestion, edema, and diffuse petechial hemorrhages. Occasionally, a massive hemorrhage or infarct is encountered, usually in the context of pre-existing arteriosclerosis or hypertension.

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Post-mortem morphometric analysis has shown that the loss of volume predominantly involves the white matter. The neuropathologic findings, however, are non-specific and correlate poorly with the cognitive decline that tends to be associated with chronic alcoholism.

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Neuropathologic examination reveals atrophy of the superior part of the vermis and adjacent regions of the cerebellar hemispheres, with atrophy of the folia and widening of the sulci (Fig. 25.22). In contrast to the pattern of degeneration resulting from hypoxia, the crests of the folia tend to be more severely affected than the depths of the sulci. There is a loss of Purkinje cells, a patchy loss of granule cells with resulting atrophy of the molecular layer, and proliferation of Bergmann glia (Fig. 25.22). Neuronal loss and gliosis are usually evident in the dorsal layer of the inferior olivary nuclei (Fig. 25.22). The vestibular, fastigial, globose, and emboliform nuclei may show mild degenerative changes.

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Macroscopically, the central part of the corpus callosum appears shrunken, and dusky gray or yellow, depending on the age of the lesion (Fig. 25.23), and there may be cavitation. Similar lesions are occasionally seen in the optic chiasm, anterior and posterior commissures, and middle cerebellar peduncles. Striatal necrosis is an inconstant finding.

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Histologically, the disorder is characterized by variable combinations of necrosis and demyelination. These most consistently involve the genu and body of the corpus callosum and spare a thin layer of myelinated fibers along the dorsal and ventral surfaces (Fig. 25.23). Other white matter structures may be involved, as noted above. Macrophages are abundant in the early stages, but lymphocytic inflammation is not a feature. Oligodendrocytes are markedly reduced in number, and astrocytes generally show only modest reactive changes. A striking feature is the proliferation and hyaline thickening of small blood vessels.

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Histologic changes in the CNS are sparse if death occurs before the fifth day of the illness. Thereafter neurons in the cerebral cortex and brain stem in particular become swollen and chromatolytic. Brain edema, focal vascular necrosis, and perivascular hemorrhages have been reported. Tetanus toxin fragment C has been detected at autopsy in the perikarya and axons of large motor neurons in the ventral horn.

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Histology reveals symmetric degeneration of the corticospinal tracts in the lumbosacral and, to a lesser extent, thoracic regions of the cord. Posterior column degeneration and filamentous and paracrystalline inclusions in anterior horn cells have been noted in a patient who developed neurolathyrism 30 years earlier.

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There is little information on the neuropathological changes in man but affected marine mammals have been reported to show neuronal loss affecting the hippocampus and amygdala.