Alzheimer Disease

Alzheimer disease (AD) is the most common cause of dementia in the elderly. The disease usually becomes clinically apparent as insidious impairment of higher intellectual function, with alterations in mood and behavior. Later, progressive disorientation, memory loss, and aphasia become manifest, indicating severe cortical dysfunction. Eventually, in 5 to 10 years, the affected individual becomes profoundly disabled, mute, and immobile. Patients rarely become symptomatic before 50 years of age, but the incidence of the disease rises with age, and the prevalence roughly doubles every 5 years, starting from a level of 1% for the 60- to 64-year-old population and reaching 40% or more for the 85- to 89-year-old cohort. This progressive increase in the incidence of the disease with age has given rise to major medical, social, and economic problems in countries with a growing number of elderly individuals. Most cases are sporadic, and although 5% to 10% are familial, the study of such familial cases has provided important insight into the pathogenesis of the more common sporadic form. While pathologic examination of brain tissue remains necessary for the definitive diagnosis of Alzheimer disease, the combination of clinical assessment and modern radiologic methods allows accurate diagnosis in 80% to 90% of cases.

Morphology. Grossly, the brain shows a variable degree of cortical atrophy marked by widening of the cerebral sulci that is most pronounced in the frontal, temporal, and parietal lobes (Fig. 28-36). With significant atrophy, there is compensatory ventricular enlargement (hydrocephalus ex vacuo) secondary to loss of parenchyma and reduced brain volume. Structures of the medial temporal lobe, including hippocampus, entorhinal cortex and amygdala, are involved early in the course and are usually severely atrophied in the later stages. The major microscopic abnormalities of AD, which form the basis of the histologic diagnosis, are neuritic (senile) plaques and neurofibrillary tangles. There is progressive and eventually severe neuronal loss and reactive gliosis in the same regions that bear the burden of plaques and tangles.

FIGURE 28-36 Alzheimer disease with cortical atrophy most evident on the right, where meninges have been removed.

(Courtesy of the late Dr. E.P. Richardson, Jr., Massachusetts General Hospital, Boston, MA.)

Neuritic plaques are focal, spherical collections of dilated, tortuous, neuritic processes (dystrophic neurites) often around a central amyloid core, which may be surrounded by clear halo (Fig. 28-37A). Neuritic plaques range in size from 20 to 200 μm in diameter; microglial cells and reactive astrocytes are present at their periphery. Plaques are found in the hippocampus, amygdala, and neocortex, although there is usually relative sparing of primary motor and sensory cortices (this also applies to neurofibrillary tangles). The amyloid core, which can be stained by Congo Red, contains several abnormal proteins. The dominant component of the amyloid plaque core is Aβ, a peptide derived through specific processing events from a larger molecule, amyloid precursor protein (APP) (Figs. 28-37 and 28-38). The two dominant species of Aβ, called Aβ₄₀ and Aβ₄₂, share an Nterminus and differ in length by two amino acids at the C-terminus. Other proteins are present in plaques in lesser abundance, including components of the complement cascade, pro-inflammatory cytokines, α₁-antichymotrypsin, and apolipoproteins. In some cases, there is deposition of Aβ peptides with staining characteristics of amyloid in the absence of the surrounding neuritic reaction. These lesions, termed diffuse plaques, are found in superficial portions of cerebral cortex as well as in basal ganglia and cerebellar cortex. Diffuse plaques appear to represent an early stage of plaque development. This conclusion is based primarily on studies of brains from individuals with trisomy 21. Recall that in patients with trisomy 21 (Down syndrome), early onset of Alzheimer disease is common (Chapter 5). In some brain regions (cerebellar cortex and striatum) these diffuse plaques represent a major manifestation of the disease, with other clear-cut findings of Alzheimer disease, or in isolation. While neuritic plaques contain both Aβ₄₀ and Aβ₄₂, diffuse plaques are predominantly made up of Aβ₄₂.

FIGURE 28-37 Alzheimer disease. A, Plaques with dystrophic neurites surrounding amyloid cores are visible (arrows). B, Plaque core and surrounding neuropil are immunoreactive for Aβ. C, Neurofibrillary tangle is present within one neuron, and several extracellular tangles are also present (arrows). D, Silver stain showing a neurofibrillary tangle within the neuronal cytoplasm. E, Tangle (upper left) and neurites around a plaque (lower right) contain tau, demonstrated by immunohistochemistry.

FIGURE 28-38 Mechanisms of processing of amyloid precursor protein (APP). APP can be processed by two pathways; sequential cleavage by β-secretase and γ-secretase is the pathway that results in the generation of Aβ and the formation of amyloid fibrils.

Neurofibrillary tangles are bundles of filaments in the cytoplasm of the neurons that displace or encircle the nucleus. In pyramidal neurons, they often have an elongated “flame” shape; in rounder cells, the basket weave of fibers around the nucleus takes on a rounded contour (“globose” tangles). Neurofibrillary tangles are visible as basophilic fibrillary structures with H&E staining (Fig. 28-37C) but are dramatically demonstrated by silver (Bielschowsky) staining (Fig. 28-37D). They are commonly found in cortical neurons, especially in the entorhinal cortex, as well as in other sites such as pyramidal cells of the hippocampus, the amygdala, the basal forebrain, and the raphe nuclei. Neurofibrillary tangles are insoluble and apparently resistant to clearance in vivo, thus remaining visible in tissue sections as “ghost” or “tombstone” tangles long after the death of the parent neuron. Ultrastructurally, neurofibrillary tangles are composed predominantly of paired helical filaments along with some straight filaments that appear to have a comparable composition. A major component of paired helical filaments is abnormally hyperphosphorylated forms of the protein tau, an axonal microtubule-associated protein that enhances microtubule assembly (Fig. 28-37E). Other components include MAP2 (another microtubule-associated protein) and ubiquitin. Paired helical filaments are also found in the dystrophic neurites that form the outer portions of neuritic plaques and in axons coursing through the affected gray matter as neuropil threads. Tangles are not specific to AD, being found in other diseases as well.

In addition to the diagnostic features of plaques and tangles, several other pathologic findings are seen in the setting of AD. Cerebral amyloid angiopathy (CAA) is an almost invariable accompaniment of Alzheimer disease; however, it can also be found in brains of individuals without AD (see Fig. 28-18B). Vascular amyloid is predominantly Aβ₄₀, as is also the case when CAA occurs without AD. Granulovacuolar degeneration is the formation of small (∼5 μm in diameter), clear intraneuronal cytoplasmic vacuoles, each of which contains an argyrophilic granule. While it occurs with normal aging, it is most commonly found in great abundance in hippocampus and olfactory bulb in AD. Hirano bodies, found especially in AD, are elongated, glassy, eosinophilic bodies consisting of paracrystalline arrays of beaded filaments, with actin as their major component. They are found most commonly within hippocampal pyramidal cells.

Since both plaques and tangles may be present in low abundance in nondemented individuals, the diagnosis of Alzheimer disease is based on a combination of clinical and pathologic features. The progression of changes is fairly constant. Pathologic changes (specifically plaques, tangles, and the associated neuronal loss and glial reaction) are evident earliest in the entorhinal cortex, then spread through the hippocampal formation and isocortex, and then extend into the neocortex. Plaques are assessed semiquantitatively (absent, sparse, moderate, abundant) in each cortical area, while tangles are assessed based on how widespread they are in the brain.^38,39 These assessments are combined in the current NIA-Reagan criteria to provide an estimate of the likelihood that AD pathology caused a particular patient’s dementia.^40,41

Frontotemporal Dementias

Frontotemporal dementias (FTDs) are a group of disorders that were first classified together because they shared clinical features (progressive deterioration of language and changes in personality) corresponding to degeneration and atrophy of temporal and frontal lobes.⁴⁹ These entities have recently been better understood through a combination of immunohistochemical and biochemical, and genetic approaches. Several of the disorders to be considered share the accumulation of tau-containing deposits as their characteristic finding, giving rise to the term tauopathy.

Pick Disease

Pick disease (lobar atrophy) is a rare, distinct, progressive dementia characterized clinically by early onset of behavioral changes together with alterations in personality (frontal lobe signs) and language disturbances (temporal lobe signs). While most cases of Pick disease are sporadic, there have been some familial forms identified and linked to mutated tau protein.

Morphology. The brain invariably shows a pronounced, frequently asymmetric, atrophy of the frontal and temporal lobes with conspicuous sparing of the posterior two thirds of the superior temporal gyrus and only rare involvement of either the parietal or occipital lobe. The atrophy can be severe, reducing the gyri to a wafer-thin (“knife-edge”) appearance. This pattern of lobar atrophy is often prominent enough to distinguish Pick disease from AD on gross examination. In addition to the localized cortical atrophy there may also be bilateral atrophy of the caudate nucleus and putamen.

Microscopically, neuronal loss is most severe in the outer three layers of the cortex. Some of the surviving neurons show a characteristic swelling (Pick cells), while others contain Pick bodies, which are cytoplasmic, round to oval, filamentous inclusions that are only weakly basophilic but stain strongly with silver methods (Fig. 28-39). Ultrastructurally, these are composed of straight filaments, vesiculated endoplasmic reticulum, and paired helical filaments that are immunocytochemically similar to those found in AD, and contain 3R tau. Unlike the neurofibrillary tangles of AD, Pick bodies do not survive the death of their host neuron and do not remain as markers of the disease.

FIGURE 28-39 Pick disease. Pick bodies are round homogeneous neuronal cytoplasmic inclusions that stain intensely with silver stains.

Vascular Dementia

While some individuals with cognitive decline due to vasculitis show improvement with treatment, there is also an irreversible and progressive cognitive disorder associated with vascular injury to the brain.⁵² Various etiologies include widespread areas of infarction (abundant cortical microinfarcts, multiple lacunar infarcts, cortical laminar necrosis associated with reduced perfusion/oxygenation), and diffuse white-matter injury (hypertension, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). Additionally, dementia has been associated with so-called strategic infarcts, which are usually embolic and involve brain regions such as the hippocampus, dorsomedial thalamus, or the cingulate gyrus of the frontal cortex. Many individuals, in fact, demonstrate a combination of pathologic changes. There is also a relationship between vascular injury and other dementing disorders, such as AD. It has been found that individuals with vascular changes above a certain threshold have a lower burden of plaques and tangles for their level of cognitive impairment than do those without vascular-based cerebral pathology.

Parkinsonism

Parkinsonism is a clinical syndrome characterized by diminished facial expression, stooped posture, slowness of voluntary movement, festinating gait (progressively shortened, accelerated steps), rigidity, and a “pill-rolling” tremor. This type of motor disturbance is seen in a number of conditions that have in common damage to the nigrostriatal dopaminergic system. Parkinsonism may also be induced by drugs that affect this system, particularly dopamine antagonists and toxins. The principal diseases that involve the nigrostriatal system are as follows:

Parkinson Disease

This diagnosis is made in individuals with progressive L-DOPA-responsive signs of parkinsonism (tremor, rigidity, and bradykinesia) in the absence of a toxic or other known underlying etiology. Familial forms of PD with autosomal dominant or autosomal recessive inheritance exist. Although these make up a limited number of cases, they have contributed to our understanding of the pathogenesis of the disease.

Morphology. The typical macroscopic findings are pallor of the substantia nigra (compare Fig. 28-40A and B) and locus ceruleus. On microscopic examination, there is loss of the pigmented, catecholaminergic neurons in these regions, associated with gliosis. Lewy bodies (Fig. 28-40C) may be found in some of the remaining neurons. These are single or multiple, cytoplasmic, eosinophilic, round to elongated inclusions that often have a dense core surrounded by a pale halo. Ultrastructurally, Lewy bodies are composed of fine filaments, densely packed in the core but loose at the rim; these filaments are composed of α-synuclein. Lewy bodies may also be found in the cholinergic cells of the basal nucleus of Meynert, which is depleted of neurons (particularly in patients with abnormal mental function), as well as in other brainstem nuclei including the locus ceruleus and the dorsal motor nucleus of the vagus.

FIGURE 28-40 Parkinson disease. A, Normal substantia nigra. B, Depigmented substantia nigra in idiopathic Parkinson disease. C, Lewy body in a substantia nigra neuron, staining bright pink (arrow).

Dementia with Lewy Bodies

About 10% to 15% of individuals with PD develop dementia, with increasing incidence with advancing age. Characteristic features of this disorder include a fluctuating course, hallucinations, and prominent frontal signs. While some affected individuals have pathologic evidence of AD (or, less frequently, other degenerative diseases associated with cognitive changes) in combination with the findings of PD, in others the most prominent histologic correlate appears to be the presence of Lewy bodies in a wide range of cortical locations.^57,58 These inclusions are less distinct than those observed in the brainstem but similarly contain predominantly α-synuclein. Immunohistochemical staining for α-synuclein also reveals the presence of abnormal neurites, which contain aggregated protein—called Lewy neurites even though he never saw them! In this setting, the gross pathologic findings typically include depigmentation of the substantia nigra and locus ceruleus, paired with relative preservation of the cortex, hippocampus, and amygdala. The burden of cortical Lewy bodies is usually extremely low, and the mechanism by which this disease wreaks havoc on cognitive functioning is not clear. It has been suggested that Lewy body diseases represent a continuum; there is evidence that Lewy bodies and Lewy neurites are found first in the medulla, progress over time to reach the midbrain (when it becomes manifest as PD), and can eventually progress across the nervous system to reach the cortex (and manifest as dementia with Lewy bodies).⁵⁹

Multiple System Atrophy

The designation multiple system atrophy (MSA) describes a group of disorders characterized by the presence of glial cytoplasmic inclusions, typically within the cytoplasm of oligodendrocytes, that can have different patterns of clinical presentation.⁶⁰ The dominant symptoms can be parkinsonism (MSA-P, historically known as striatonigral degeneration), or cerebellar dysfunction (MSA-C, previously known as olivopontocerebellar atrophy), or autonomic dysfunction (MSA-A, once known as Shy-Drager syndrome). Of these, MSA-C is the least frequently observed pure syndrome. These variants appear to stem from a single disease mechanism, and many affected individuals develop symptoms during the course of the illness that fall into more than one clinical pattern.

Huntington Disease

Huntington disease (HD) is an autosomal dominant disease characterized clinically by progressive movement disorders and dementia, and histologically by degeneration of striatal neurons. Jerky, hyperkinetic, sometimes dystonic movements involving all parts of the body (chorea) are characteristic; affected individuals may later develop parkinsonism with bradykinesia and rigidity. The disease is relentlessly progressive, with an average course of about 15 years to death.

Molecular Genetics.

Huntington disease is the prototype of the polyglutamine trinucleotide repeat expansion diseases (see Chapter 5).^62,63 The HD gene, located on chromosome 4p16.3, encodes a 348-kD protein known as huntingtin. In the first exon of the gene there is a stretch of CAG repeats, which encodes a polyglutamine region near the N terminus of the protein. Normal HD genes contain 6 to 35 copies of the repeat; when the number of repeats is increased beyond this level it is associated with disease. There is an inverse relationship between repeat number and age of onset, such that longer repeats are associated with earlier onset. Because other factors modify the effect of the repeats, determination of repeat length is not an accurate predictor of age of onset. Repeat expansions occur during spermatogenesis, so that paternal transmission is associated with early onset in the next generation, the phenomenon of anticipation. Newly occurring mutations are uncommon; most apparently sporadic cases can be related to non-paternity, the death of a parent before expression of the disease, or a father as yet unaffected but with a mild repeat expansion that further enlarged during spermatogenesis.

Morphology. Macroscopically, the brain is small and shows striking atrophy of the caudate nucleus and, less markedly at early stages, the putamen (Fig. 28-41). The globus pallidus may be atrophied secondarily, and the lateral and third ventricles are dilated. Atrophy is frequently also seen in the frontal lobe, less often in the parietal lobe, and occasional in the entire cortex. On microscopic examination, there is severe loss of striatal neurons; the most marked changes are found in the caudate nucleus, especially in the tail and portions nearer the ventricle. The putamen is involved in the later stages of disease. Pathologic changes develop in a medial-to-lateral direction in the caudate and from dorsal to ventral in the putamen. The nucleus accumbens is the best preserved portion of the striatum. Both the large and small neurons are affected, but loss of the small neurons generally occurs first. The medium-sized, spiny neurons that use γ-aminobutyric acid as theirneurotransmitter, along with enkephalin, dynorphin, and substance P, are especially affected. Two populations of neurons are relatively spared, the diaphorasepositive neurons that contain nitric oxide synthase and the large cholinesterase-positive neurons; both appear to serve as local interneurons. There is also fibrillary gliosis that is more extensive than in the usual reaction to neuronal loss. There is a direct relationship between the degree of degeneration in the striatum and the severity of clinical symptoms. Protein aggregates containing huntingtin can be found in neurons in the striatum and cerebral cortex (Fig. 28-41, inset).

FIGURE 28-41 Huntington disease. Normal hemisphere on the left, compared with the hemisphere with Huntington disease on the right showing atrophy of the striatum and ventricular dilation.Inset, Intranuclear inclusions in neurons are highlighted by immunohistochemistry against ubiquitin.

(Courtesy of Dr. J.-P. Vonsattel, Columbia University, New York, NY.)

Pathogenesis.

The loss of medium spiny striatal neurons leads to dysregulation of the basal ganglia circuitry that modulates motor output. These neurons normally function to dampen motor activity; thus, their degeneration in HD results in increased motor output, often manifested as choreoathetosis. The cognitive changes associated with the disease are probably related to the neuronal loss from cerebral cortex.

The biologic function of normal huntingtin remains unknown, but there is little evidence to suggest that the disease is caused by haploinsufficiency related to a mutated allele. Rather, the expansion of the polyglutamine region seems to bestow a toxic gain of function on huntingtin. While the expanded polyglutamine repeat results in protein aggregation and formation of intranuclear inclusions as described above, it is not established that this is a direct pathway to cellular injury. Transcriptional dysregulation has been implicated in HD, with mutant forms of huntingtin binding important transcriptional regulators such as Sp1 and CBP (cyclic adenosine monophosphate response-element binding protein). A proposed consequence of this sequestration of critical transcription factors is the down-regulation of PGC-1α, itself a transcription factor involved in mitochondrial biogenesis and protection against oxidative injury.

Clinical Features.

The age at onset is most commonly in the fourth and fifth decades and is related to the length of the CAG repeat in the HD gene. Motor symptoms often precede the cognitive impairment. The movement disorder of HD is choreiform, with increased and involuntary jerky movements of all parts of the body; writhing movements of the extremities are typical. Early symptoms of higher cortical dysfunction include forgetfulness and thought and affective disorders, but there is progression to a severe dementia. Although individuals with HD have an increased risk of suicide, intercurrent infection is the most common natural cause of death. Given the ability to screen for disease-causing mutations and the devastating nature of the disease, HD is often the focal point of discussion of ethical issues in genetic diagnosis.

Spinocerebellar Ataxias

This is a group of genetically distinct diseases characterized by signs and symptoms referable to the cerebellum (progressive ataxia), brainstem, spinal cord, and peripheral nerves, as well as other brain regions in different subtypes. Pathologically they are characterized by neuronal loss from the affected areas and secondary degeneration of white-matter tracts.

Amyotrophic Lateral Sclerosis (ALS; Motor Neuron Disease)

ALS is characterized by loss of lower motor neurons in spinal cord and brainstem and upper motor neurons that project in corticospinal tracts. This relatively rare disease (incidence of about 2 cases per 100,000 population) affects men slightly more frequently than women and becomes clinically manifest in the fifth decade or later. Five to 10% of cases are familial (fALS), mostly with autosomal dominant inheritance.

Molecular Genetics.

Close to a quarter of familial cases of ALS are caused by mutations in the gene encoding copper-zinc superoxide dismutase (SOD1) on chromosome 21.⁶⁷ A wide variety of mutations, nearly all missense mutations, have been identified throughout the gene; ALS seems to be caused by an adverse gain-of-function phenotype associated with mutant SOD1. A mutation resulting in an alanine to valine substitution in residue 4 is the most common in the United States; it is associated with a rapid course, and rarely has upper motor neuron signs. Other loci for ALS have been mapped, although none appears in linkage with as large a fraction of the patient population as SOD1. These mendelian loci include the genes encoding dynactin (a protein involved in retrograde axonal transport), VAMP-associated protein B (involved in regulation of vesicle transport), and alsin (containing guanine nucleotide exchange factor domains and associated with regulation of endosomal trafficking through interaction with Rab5b).

Pathogenesis.

The pathogenesis of ALS is still not understood despite the identification of numerous genetic associations. The discovery of SOD1 mutations initially suggested that a reduced capacity to detoxify free radicals (the physiologic function of SOD) may account for neuronal death in ALS. However, this hypothesis has not been proved, and currently a more accepted idea is that the mutated SOD1 protein is misfolded and triggers an injurious unfolded protein response.⁶⁸ Mutated SOD1 in non-neuronal (glial and smooth muscle) cells may also contribute to the disease.⁶⁹ Alterations in axonal transport, neurofilament abnormalities, toxicity mediated by increased levels of the neurotransmitter glutamate, and aggregation of other proteins (such as one called TDP-43 that is sometimes found in cytoplasmic inclusions in neurons in ALS)⁷⁰, have all been suggested as mechanisms contributing to the progressive loss of motor neurons.

Morphology. On gross examination, the anterior roots of the spinal cord are thin (Fig. 28-42A). The precentral gyrus may be atrophic in especially severe cases. Microscopic examination demonstrates a reduction in the number of anterior-horn neurons throughout the length of the spinal cord with associated reactive gliosis and loss of anterior-root myelinated fibers. Similar findings are seen in the hypoglossal, ambiguus, and motor trigeminal cranial nerve nuclei. Remaining neurons often contain PAS-positive cytoplasmic inclusions, called Bunina bodies, that appear to be remnants of autophagic vacuoles. Skeletal muscles innervated by the degenerated lower motor neurons show neurogenic atrophy. Loss of the upper motor neurons leads to degeneration of the corticospinal tracts, resulting in volume loss and absence of myelinated fibers, which may be particularly evident at the lower segmental levels (Fig. 28-42B).

FIGURE 28-42 Amyotrophic lateral sclerosis. A, Segment of spinal cord viewed from anterior (upper) and posterior (lower) surfaces showing attenuation of anterior (motor) roots compared to posterior (sensory) roots. B, Spinal cord showing loss of myelinated fibers (lack of stain) in corticospinal tracts as well as degeneration of anterior roots.

Clinical Features.

Early symptoms include asymmetric weakness of the hands, manifested as dropping objects and difficulty in performing fine motor tasks, and cramping and spasticity of the arms and legs. As the disease progresses, muscle strength and bulk diminish, and involuntary contractions of individual motor units, termed fasciculations, occur. The disease eventually involves the respiratory muscles, leading to recurrent bouts of pulmonary infection. The severity of involvement of the upper and lower motor neurons is variable; the term progressive muscular atrophy applies to those relatively uncommon cases in which lower motor neuron involvement predominates. In some affected individuals, degeneration of the lower brainstem cranial motor nuclei occurs early and progresses rapidly, a pattern referred to as progressive bulbar palsy or bulbar ALS. In these individuals, abnormalities of deglutition and phonation dominate, and the clinical course is inexorable during a 1- or 2-year period; when bulbar involvement is less severe, about half of affected individuals are alive 2 years after diagnosis. Although it has been suggested that the motor neurons innervating extra-ocular muscles were spared in ALS, it is now clear that these cells are susceptible to the disease process when individuals survive longer. Familial cases develop symptoms earlier than most sporadic cases, but the clinical course is comparable.

Bulbospinal Atrophy (Kennedy Syndrome)

This X-linked adult-onset disease is characterized by distal limb amyotrophy and bulbar signs such as atrophy and fasciculations of the tongue and dysphagia. Affected individuals manifest androgen insensitivity, gynecomastia, testicular atrophy, and oligospermia. On microscopic examination there is degeneration of lower motor neurons in the spinal cord and brainstem. The gene defect is expansion of a CAG/polyglutamine repeat in the androgen receptor (40 to 60 for affected males as opposed to 11 to 33 for normals); nuclear inclusions containing aggregated androgen receptor can be found, although it remains unclear whether these inclusions are critical to cellular injury.⁷¹

Spinal Muscular Atrophy

This group of diseases affects mainly the lower motor neurons in children. As in ALS, there is a selective loss of anterior-horn cells and atrophy of anterior spinal roots. It includes several entities with distinct clinical courses (Chapter 27).

Neuronal Ceroid Lipofuscinoses

These are a set of inherited lysosomal storage diseases that are grouped because they share the accumulation of lipofuscin—an autofluorescent substance with a variety of ultrastructural appearances—in neurons. Neuronal dysfunction typically leads to a combination of blindness, mental and motor deterioration, and seizures. These disorders are classified based on age of onset into infantile (INCL), late infantile (LINCL), juvenile (JNCL), and adult neuronal ceroid lipofuscinoses (ANCL; Kuf disease), or on the pattern of inclusions by electron microscopy. Genetic studies indicate that there are likely eight causative loci, which encode a variety of proteins involved in the modification and degradation of proteins.⁷² The CLN1 locus, a common cause of INCL, encodes palmitoyl protein thioesterase 1 (PPT1), which removes palmitate residues from proteins; this is similar to CLN3, implicated in most cases of JNCL (also known as Batten disease), which encodes palmitoyl-protein Δ-9 desaturase, another enzyme related to regulation of membrane-associated palmitoylated proteins. How the abnormalities in protein modification lead to the accumulation of lipofuscin or the neuronal dysfunction is not understood.

Tay-Sachs Disease

This disease begins in early infancy with developmental delay, followed by paralysis and loss of neurologic function, and death after several years. It is discussed in Chapter 5 along with other lysosomal storage diseases.

Krabbe Disease

This disease is an autosomal recessive leukodystrophy resulting from a deficiency of galactocerebroside β-galactosidase (galactosylceramidase), the enzyme required for the catabolism of galactocerebroside to ceramide and galactose. More than 40 different mutations have been found in the gene encoding this enzyme, which is located on chromosome 14q31. While accumulation of galactocerebroside occurs, this is not the direct toxic agent in this disease. Instead, it seems that an alternative catabolic pathway removes a fatty acid from this molecule, generating galactosylsphingosine, which is a cytotoxic compound that may cause oligodendrocyte injury.

The clinical course is rapidly progressive, with onset of symptoms often between the ages of 3 and 6 months. Survival beyond 2 years of age is uncommon. The clinical symptoms are dominated by motor signs, including stiffness and weakness, with gradually worsening difficulties in feeding. The brain shows loss of myelin and oligodendrocytes in the CNS and a similar process in peripheral nerves (Fig. 28-43). Neurons and axons are relatively spared. A unique and diagnostic feature of Krabbe disease is the aggregation of engorgedmacrophages (globoid cells) in the parenchyma and around blood vessels (Fig. 28-43, inset). The potential exists for treatment with cord blood transplantation in the pre-symptomatic state.⁷³

FIGURE 28-43 Krabbe disease. Much of the white matter is gray/yellow because of the loss of myelin. Inset, “Globoid” cells are the hallmark of the disease.

Metachromatic Leukodystrophy

This disorder is transmitted in an autosomal recessive pattern and results from a deficiency of the lysosomal enzyme arylsulfatase A. This enzyme, present in a variety of tissues, cleaves the sulfate from sulfate-containing lipids (sulfatides), the first step in their degradation. Enzyme deficiency leads to an accumulation of the sulfatides, especially cerebroside sulfate; how this leads to myelin breakdown is not known, although sulfatides are reported to inhibit differentiation of oligodendrocytes. The gene encoding arylsulfatase A has been localized to the distal end of chromosome 22q, and a wide range of mutations have been described. Recognized clinical subtypes of the disorder include a late infantile form (the most common), a juvenile form, and an adult form. The two forms with childhood onset often present with motor symptoms and progress gradually, leading to death in 5 to 10 years. In the adult form psychiatric or cognitive symptoms are the usual initial complaint, with motor symptoms coming later. Approaches using various types of bone marrow stem cell transplantation have been shown to provide benefit, most commonly when performed before the neurologic deficits appear.⁷⁴

The most striking histologic finding is demyelination with resulting gliosis. Macrophages with vacuolated cytoplasm are scattered throughout the white matter. The membrane-bound vacuoles contain complex crystalloid structures composed of sulfatides; when bound to certain dyes such as toluidine blue, sulfatides shift the absorbance spectrum of the dye, a property called metachromasia. Similar changes in peripheral nerves are observed. The detection of metachromatic material in the urine is also a sensitive method of establishing the diagnosis.

Adrenoleukodystrophy

This disorder, which has several clinically and genetically distinct forms, is a progressive disease with symptoms referable to myelin loss from the CNS and peripheral nerves as well as adrenal insufficiency. In general, forms with earlier onset have a more rapid course. The X-linked form usually presents in the early school years with neurologic symptoms and adrenal insufficiency and is rapidly progressive and fatal. In individuals with later onset the course is more protracted; when it develops in adults it is usually a slowly progressive disorder with predominantly peripheral nerve involvement developing over a period of decades. The disease is associated with mutations in the ALD gene on chromosome Xq28, which encodes a member of the ATP-binding cassette transporter family of proteins, ABCD1. However, there is little correlation between clinical course and the underlying mutations. The disease is characterized by the inability to properly catabolize very-long-chain fatty acids (VLCFAs) within peroxisomes, with elevated levels of VLCFAs in serum. There is loss of myelin, accompanied by gliosis and extensive lymphocytic infiltration. Atrophy of the adrenal cortex is present, and VLCFA accumulation can be seen in remaining cells.

Pelizaeus-Merzbacher Disease

This is an X-linked, invariably fatal leukodystrophy beginning either in early childhood or just after birth, and characterized by slowly progressive signs and symptoms resulting from widespread white-matter dysfunction. Affected individuals present with pendular eye movements, hypotonia, choreoathetosis, and pyramidal signs early in the disease, followed later by spasticity, dementia, and ataxia. Although myelin is nearly completely lost in the cerebral hemispheres, patches may remain, giving a “tigroid” appearance to tissue sections stained for myelin. The disease has been shown to arise in most cases from mutations in a gene on the X chromosome that encodes two distinct myelin proteins, distinguished by alternative splicing: proteolipid protein (PLP) and DM20. Gene duplications are the most common mutation observed, although point mutations giving rise to null alleles are also observed; it remains unclear how these distinct mutations cause the disease.⁷⁵ This same genetic locus is also the site of one form of spastic paraplegia (SPG2).

Canavan Disease

This disease is characterized by megalocephaly, severe mental deficits, blindness, and signs and symptoms of white matter injury beginning in early infancy and relentlessly progressing to death within a few years of onset. Autopsy studies show spongy degeneration of the white matter. There is accumulation of N-acetylaspartic acid in this disorder as a consequence of loss-of-function mutations in the gene encoding the deactylating enzyme aspartoacylase, located on chromosome 17. The mechanisms of myelin injury remain uncertain.⁷⁶

Alexander Disease

This disease is characterized by megalencephaly, seizures, and progressive psychomotor retardation. There is white-matter loss, typically with a frontal-to-occipital gradient. The characteristic pathologic finding is the exuberant accumulation of Rosenthal fibers around blood vessels, in the subpial and subependymal zones and in the brain parenchyma. Even though Rosenthal fibers are primarily composed of various heat-shock proteins, including αB-crystallin, the basis of Alexander disease lies in mutations in the gene encoding glial fibrillary acid protein (GFAP).⁷⁷ The disease is believed to be caused by dominant gain-of-function mutations associated with decreased capacity to form filaments as well as induction of stress responses.

Vanishing-White-Matter Leukodystrophy

Vanishing-white-matter leukodystrophy, named for the characteristic progression of the disorder as revealed by imaging studies, is associated with mutations in the genes encoding any of the five subunits of eukaryotic initiation factor 2B (eIF2B).^78,79 The disease usually begins insidiously during the first few years of life, with ataxia and seizures as common symptoms. With a relentless downward course, sometimes exacerbated by intercurrent illnesses, affected individuals typically survive for a few years after onset of symptoms. Levels of eIF2B are reduced throughout the body; the basis for selective injury to the brain, with the primary burden falling on white matter, is not known.

Mitochondrial Encephalomyopathy, Lactic Acidosis, and Strokelike Episodes

Mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) is the most common neurologic syndrome caused by mitochondrial abnormalities. The syndrome is characterized by recurrent episodes of acute neurologic dysfunction, cognitive changes, and evidence of muscle involvement with weakness and lactic acidosis. The stroke-like episodes are often associated with reversible deficits that do not correspond well to specific vascular territories. Pathologically, areas of infarction are observed, often with vascular proliferation and focal calcification. The most prevalent mutations associated with MELAS occurs in tRNAs; coding-gene mutations have also been reported.

Myoclonic Epilepsy and Ragged Red Fibers

Myoclonic epilepsy and ragged red fibers (MERRF) is a maternally transmitted disease in which affected individuals have myoclonus, a seizure disorder, and evidence of a myopathy. Ataxia, associated with neuronal loss from the cerebellar system (including the inferior olive in the medulla, cerebellar cortex, and deep nuclei), is also a common component. Most cases of MERRF are associated with mutations in tRNA that are distinct from those in MELAS. In some affected individuals there seems to be an overlap between MERRF and MELAS.

Leigh Syndrome (Subacute Necrotizing Encephalopathy)

This disease of early childhood is characterized by lactic acidemia, arrest of psychomotor development, feeding problems, seizures, extra-ocular palsies, and weakness with hypotonia. Death usually occurs within 1 to 2 years. On histologic examination there are multifocal, moderately symmetric regions of destruction of brain tissue with a spongiform appearance and proliferation of blood vessels. The areas that are most commonly affected include the periventricular gray matter of the midbrain, the tegmentum of the pons, and the periventricular regions of the thalamus and hypothalamus. A wide spectrum of mutations has been identified as causing Leigh syndrome, including both nuclear and mitochondrial DNA mutations. Diverse mutations affecting mitochondrial genome–encoded components of oxidative phosphorylation complexes, as well as mitochondrial tRNA mutations, have been found; there does not seem to be a genotype-phenotype relationship. Interestingly, a point mutation in the mitochondrial gene for an ATPase subunit of complex V causes a maternally inherited form of Leigh syndrome when the cells contain a large proportion of the mutated mitochondrial DNA. However, when there is a higher fraction of normal mitochondria, the disease takes on a different clinical and pathologic appearance, as neuropathy, ataxia, and retinitis pigmentosa (NARP). Such unequal distribution of mitochondrial DNA among cells is called heteroplasmy (Chapter 5).

Kearn-Sayre Syndrome

Kearns-Sayre syndrome (“ophthalmoplegia plus”) is a sporadic disorder most often associated with a large mitochondrial DNA deletion/rearrangement. The disorder presents with cerebellar ataxia, progressive external ophthalmoplegia, pigmentary retinopathy, and cardiac conduction defects. Pathologically, there is spongiform change in gray and white matter, with neuronal loss most evident in the cerebellum. The basis of the disease is large defects in the mitochondrial genome.

Alpers Disease

This disorder combines neurologic symptoms with evidence of hepatic dysfunction and pathologic findings including hepatitis and bile duct proliferation.⁸² Alpers disease typically begins in the first few years of life with severe intractable seizures, followed by developmental delay, hypotonia, ataxia, and cortical blindness. There is neuronal loss in cerebral cortex and throughout deeper structures, and spongiform degeneration of gray matter. Mutations in the nuclear gene encoding DNA polymerase γ—the isoform of DNA polymerase responsible for replication of the mitochondrial genome—have been identified in Alpers disease.⁸³

Thiamine (Vitamin B₁) Deficiency

As was discussed in Chapter 9, thiamine deficiency may result in the slowly evolving clinical disorder beriberi, which is associated with cardiac failure. In certain affected individuals, thiamine deficiency may also lead to the development of psychotic symptoms or ophthalmoplegia that begin abruptly, a syndrome termed Wernicke encephalopathy. The acute stages, if unrecognized and untreated, may be followed by a prolonged and largely irreversible condition, Korsakoff syndrome, characterized clinically by memory disturbances and confabulation. Because the two syndromes are closely linked, the term Wernicke-Korsakoff syndrome is often applied. The syndrome is particularly common in the setting of chronic alcoholism, but it may also be encountered in individuals with thiamine deficiency resulting from gastric disorders, including carcinoma, chronic gastritis, or persistent vomiting. Treatment with thiamine may reverse the manifestations of Wernicke syndrome.

Vitamin B₁₂ Deficiency

Deficiency of vitamin B₁₂ often causes anemia (Chapter 14) but can also have severe and potentially irreversible effects on the nervous system. The neurologic symptoms may present in the course of a few weeks, initially with numbness, tingling, and slight ataxia in the lower extremities, but may progress rapidly to include spastic weakness of the lower extremities. Complete paraplegia may occur, usually only later in the course. With prompt vitamin replacement therapy, clinical improvement occurs; however, if complete paraplegia has developed, recovery is poor. On microscopic examination vitamin B₁₂ deficiency is associated with a swelling of myelin layers, producing vacuoles. This begins segmentally at the midthoracic level of the spinal cord in the early stages. With time, axons in both the ascending tracts of the posterior columns and the descending pyramidal tracts degenerate. While isolated involvement of descending or ascending tracts may be observed in a variety of spinal cord diseases, the combined degeneration of both ascending and descending tracts of the spinal cord is characteristic of vitamin B₁₂ deficiency and has led to the designation subacute combined degeneration of the spinal cord.

Hypoglycemia

Since the brain requires glucose and oxygen for its energy production, the cellular effects of diminished glucose resemble those of oxygen deprivation, as described earlier. Some regions of the brain are more sensitive to hypoglycemia than are others. Glucose deprivation initially leads to selective injury to large pyramidal neurons of the cerebral cortex, which, if severe, may result in pseudolaminar necrosis of the cortex, predominantly involving deep layers. The hippocampus is also vulnerable to glucose depletion and may show a marked loss of pyramidal neurons in Sommer sector (area CA1 of the hippocampus). Purkinje cells of the cerebellum are also sensitive to hypoglycemia, although to a lesser extent than to hypoxia. If the level and duration of hypoglycemia are of sufficient severity, there may be widespread injury to many areas of the brain.

Hyperglycemia

Hyperglycemia is most commonly found in the setting of inadequately controlled diabetes mellitus and can be associated with either ketoacidosis or hyperosmolar coma. The affected individual becomes dehydrated and develops confusion, stupor, and eventually coma. The fluid depletion must be corrected gradually; otherwise, severe cerebral edema may follow.

Hepatic Encephalopathy

The pathogenesis of hepatic encephalopathy is discussed in Chapter 18. The cellular response in the CNS is predominantly glial. Alzheimer type II cells are evident in the cortex and basal ganglia and other subcortical gray matter regions.

Carbon Monoxide

Many of the pathologic findings that follow acute carbon monoxide exposure are the result of hypoxia from altered oxygen-carrying capacity of hemoglobin. Selective injury of the neurons of layers III and V of the cerebral cortex, Sommer sector of the hippocampus, and Purkinje cells is characteristic. Bilateral necrosis of the globus pallidus may also occur; it is more common in carbon monoxide–induced hypoxia than in hypoxia from other causes. Demyelination of white matter tracts may be a later event.

Methanol

Methanol toxicity preferentially affects the retina, where degeneration of retinal ganglion cells may cause blindness. Selective bilateral putamenal necrosis and focal white-matter necrosis also occur when the exposure is severe. Formate, a major metabolite of methanol, may have a role in the retinal toxicity.

Ethanol

Experience tells us that the effects of acute ethanol intoxication are reversible, but chronic alcohol abuse is associated with a variety of neurologic sequelae, including Wernicke-Korsakoff syndrome, considered above. The toxic effects of chronic alcohol intake may be either direct or secondary to nutritional deficits. Cerebellar dysfunction occurs in about 1% of chronic alcoholics, associated with a clinical syndrome of truncal ataxia, unsteady gait, and nystagmus. The histologic changes are atrophy and loss of granule cells predominantly in the anterior vermis (Fig. 28-44). In advanced cases there is loss of Purkinje cells and proliferation of the adjacent astrocytes (Bergmann gliosis) between the depleted granular cell layer and the molecular layer of the cerebellum. The fetal alcohol syndrome is discussed in Chapter 10.

FIGURE 28-44 Alcoholic cerebellar degeneration. The anterior portion of the vermis (upper portion of figure) is atrophic with widened spaces between the folia.

Radiation

As discussed in Chapter 9, exposure to very high doses of radiation (>1000 rems) can cause intractable nausea, confusion, convulsions, and rapid onset of coma, followed by death. Delayed effects of radiation can also present with rapidly evolving symptoms, including headaches, nausea, vomiting, and papilledema that may appear months to years after irradiation. The pathologic findings consist of large areas of coagulative necrosis and adjacent edema. The typical lesion is restricted to white matter, and all elements within the area undergo necrosis, including astrocytes, axons, oligodendrocytes, and blood vessels. Adjacent to the area of coagulative necrosis, proteinaceous spheroids may be identified, and blood vessels show thickened walls with intramural fibrin-like material. Radiation can also induce tumors, which usually develop years after radiation therapy and include sarcomas, gliomas, and meningiomas.

Combined Methotrexate and Radiation-Induced Injury

Methotrexate toxicity most commonly develops when the drug has been administered in association with radiation therapy, either together or at separate times. The interval between the inciting events and the onset of symptoms varies considerably but may be as long as months. Symptoms often begin with drowsiness, ataxia, and confusion, and may progress rapidly. While some affected individuals recover function, others may become comatose; rarely, methotrexate neurotoxicity may be responsible for the patient’s death. The mechanisms of these delayed effects of methotrexate are unclear.

The pathologic basis of the symptoms are focal areas of coagulative necrosis within white matter, often adjacent to the lateral ventricles but at times distributed throughout the white matter or in the brainstem. Surrounding axons are often dilated and form axonal spheroids. Axons and cell bodies in the vicinity of the lesions undergo dystrophic mineralization, and there is adjacent gliosis.

Astrocytoma

The two major categories of astrocytic tumors are infiltrating astrocytomas and non-infiltrating neoplasms, of which the most common are the pilocytic astrocytomas. These tumor types have characteristic histologic features, distribution within the brain, age groups typically affected, and clinical course.

Infiltrating Astrocytomas

These account for about 80% of adult primary brain tumors in adults. Usually found in the cerebral hemispheres, they may also occur in the cerebellum, brainstem, or spinal cord, most often in the fourth through sixth decades. The most common presenting signs and symptoms are seizures, headaches, and focal neurologic deficits related to the anatomic site of involvement. Infiltrating astrocytomas show a spectrum of histologic differentiation that correlates well with clinical course and outcome; within this spectrum, tumors range from diffuse astrocytoma (grade II/IV) through anaplastic astrocytoma (grade III/IV) to glioblastoma (grade IV/IV). (The grade I/IV category is limited to pilocytic astrocytoma.)

Morphology. The gross appearance of diffuse astrocytoma is that of a poorly defined, gray, infiltrative tumor that expands and distorts the invaded brain (Fig. 28-45). These tumors range in size from a few centimeters to enormous lesions that replace an entire hemisphere. The cut surface of the tumor is either firm or soft and gelatinous; cystic degeneration may be seen. The tumor may appear well demarcated from the surrounding brain tissue, but infiltration beyond the outer margins is always present.

FIGURE 28-45 Diffuse astrocytoma. A, The right frontal tumor has expanded gyri, which led to flattening (arrows). B, There is bilateral expansion of the septum pellucidum by gray, glassy tumor.

On microscopic examination, diffuse astrocytomas are characterized by a mild to moderate increase in glial cellularity, variable nuclear pleomorphism, and an intervening feltwork of fine, GFAP-positive astrocytic processes that give the background a fibrillary appearance. The transition between neoplastic and normal tissue is indistinct, and tumor cells can be seen infiltrating normal tissue at some distance from the main lesion.

Anaplastic astrocytomas show regions that are more densely cellular and have greater nuclear pleomorphism; mitotic figures are often observed. The term gemistocytic astrocytoma is used for tumors in which the predominant neoplastic astrocyte shows a brightly eosinophilic cell body from which emanate abundant, stout processes.

In glioblastoma (previously called glioblastoma multiforme) variation in the gross appearance of the tumor from region to region is characteristic (Fig. 28-46). Some areas are firm and white, others are soft and yellow due to necrosis, and yet others show regions of cystic degeneration and hemorrhage. The histologic appearance of glioblastoma is similar to anaplastic astrocytoma with the additional features of necrosis and vascular or endothelial cell proliferation. Necrosis in glioblastoma often occurs in a serpentine pattern in areas of hypercellularity. Tumor cells collect along the edges of the necrotic regions, producing a histologic pattern referred to as pseudo-palisading (Fig. 28-47). Vascular cell proliferation is characterized by tufts of piled-up cells that bulge into the lumen; the minimal criterion for this feature is a double layer of endothelial cells. With marked vascular cell proliferation the tuft forms a ball-like structure, the glomeruloid body (see Fig. 28-47). VEGF, produced by malignant astrocytes in response to hypoxia, contributes to this distinctive vascular change. Since histologic features can be extremely variable from one region of the neoplasm to another, a single small biopsy specimen might not be representative of the worst aspects of a tumor.

FIGURE 28-46 A, Post-contrast T1-weighted coronal MRI shows a large mass in the right parietal lobe with “ring” enhancement. B, Glioblastoma appearing as a necrotic, hemorrhagic, infiltrating mass.

FIGURE 28-47 Glioblastoma. Foci of necrosis with pseudopalisading of malignant nuclei and endothelial cell proliferation.

In the condition called gliomatosis cerebri, multiple regions of the brain, in some cases the entire brain, are infiltrated by neoplastic astrocytes. Because of the widespread infiltration, this process follows an aggressive course and is considered to be a grade III/IV lesion—independent of the appearance of the individual tumor cells.

Molecular Genetics.

Certain genetic alterations correlate with the progression of infiltrating astrocytomas from low to high grade, which is part of the natural course of the disease in many patients.^86,88 Among the alterations that are most common in the low-grade astrocytomas are mutations affecting p53 and overexpression of platelet-derived growth factor α (PDGF-A) and its receptor. The transition to higher grade astrocytoma is associated with disruption of two well-known tumor suppressor genes, RB and p16/CDKNaA, and an unknown putative tumor suppressor on chromosome 19q.

It was recognized well before advances in genetic analyses that glioblastoma tends to occur in one of two clinical settings: most commonly as new onset disease, typically in older individuals (primary glioblastoma), and in younger patients with a past history of lower-grade astrocytoma (secondary glioblastoma). While primary and secondary glioblastomas show some molecular distinctions, the molecular lesions found in the two types of glioblastoma tend to impinge on the same pathways. For example, whereas secondary glioblastomas usually have p53 mutations, primary astrocytomas more commonly have amplification of MDM2, a gene that encodes an inhibitor of p53. Similarly, while secondary glioblastomas have increased signaling through the PDGF-A receptor, primary glioblastomas often have amplified, mutated epidermal growth factor receptor (EGFR) genes, which encode aberrant forms of EGFR known as EGFRvIII. Both types of mutations lead to increased receptor tyrosine kinase activity and the activation of the RAS and PI-3 kinase pathways, whichstimulate the growth and survival of tumor cells (Chapter 7). Based on whole genome sequencing, it is estimated that combinations of mutations that activate RAS and PI-3 kinase and inactivate p53 and RB are present in 80% to 90% of primary glioblastomas.⁹⁰

Clinical Features.

The presenting symptoms of infiltrating astrocytomas depend, in part, on the location and growth rate of the tumor. Well-differentiated diffuse astrocytomas may remain static or progress only slowly over a number of years; the mean survival is more than 5 years. Eventually, however, clinical deterioration occurs that is usually due to the appearance of a more rapidly growing tumor of higher histologic grade. Radiologic studies show mass effect as well as changes in the brain adjacent to the tumor, such as edema. High-grade astrocytomas have abnormal vessels that are “leaky” and therefore demonstrate contrast enhancement on imaging studies. The prognosis for individuals with glioblastoma is very poor, although the use of newer chemotherapeutic agents has provided some benefit.⁹² Methylation of the promoter for the gene encoding the DNA repair enzyme MGMT predicts responsiveness to DNA alkylating drugs—as would be expected since MGMT is critical for the repair of the chemotherapeutically induced DNA modification.⁹¹ Treatment of primary glioblastoma patients with tyrosine kinase inhibitors that target EGFR has produced some encouraging results.⁸⁹ With current optimal treatment, consisting of resection followed by radiation therapy and chemotherapy, the mean length of survival after diagnosis has increased to 15 months; 25% of such patients are alive after 2 years. Survival is substantially shorter in older patients, for those with lower performance status, and for large unresectable lesions.

Pilocytic Astrocytoma

Pilocytic astrocytomas (grade I/IV) are distinguished from the other types by their pathologic appearance and relatively benign behavior. They typically occur in children and young adults, and are usually located in the cerebellum but may also appear in the floor and walls of the third ventricle, the optic nerves, and occasionally the cerebral hemispheres.

Morphology. On macroscopic examination, a pilocytic astrocytoma is often cystic (Fig. 28-48); if solid, it may be well circumscribed or, less frequently, infiltrative. On microscopic examination the tumor is composed of bipolar cells with long, thin “hairlike” processes that are GFAP-positive and form dense fibrillary meshworks; Rosenthal fibers and eosinophilic granular bodies, are often present. Tumors are often biphasic with a loose microcystic pattern in addition to the fibrillary areas. An increase in the number of blood vessels, often with thickened walls or vascular cell proliferation, is seen but does not imply an unfavorable prognosis; necrosis and mitoses are uncommon. Unlike diffuse fibrillary astrocytomas of any grade, pilocytic astrocytomas have a narrow infiltrative border with the surrounding brain.

FIGURE 28-48 Pilocytic astrocytoma in the cerebellum with a nodule of tumor in a cyst.

These tumors grow very slowly, and, in the cerebellum particularly, may be treated by resection. Symptomatic recurrence of incompletely resected lesions is often associated with cyst enlargement rather than growth of the solid component. Tumors that extend into the hypothalamic region from the optic tract can have a more ominous clinical course because of their location. The histologic separation of these tumors from other astrocytomas is supported by the rarity of p53 mutations or other genetic changes that are found in infiltrating astrocytomas. Those pilocytic astrocytomas that occur in the setting of NF1 show functional loss of neurofibromin; this genetic alteration is not observed in sporadic forms.

Oligodendroglioma

These tumors constitute 5% to 15% of gliomas and are most common in the fourth and fifth decades. Patients may have had several years of neurologic complaints, often including seizures. The lesions are found mostly in the cerebral hemispheres, with a predilection for white matter.

Morphology. On gross examination, oligodendrogliomas are well-circumscribed, gelatinous, gray masses, often with cysts, focal hemorrhage, and calcification. On microscopic examination, the tumors are composed of sheets of regular cells with spherical nuclei containing finely granular chromatin (similar to normal oligodendrocytes) surrounded by a clear halo of cytoplasm (Fig. 28-49). The tumor typically contains a delicate network of anastomosing capillaries. Calcification, present in as many as 90% of these tumors, ranges from microscopic foci to massive depositions. As the tumor cells infiltrate cerebral cortex, there is often formation of secondary structures, often with tumor cells arrayed around neurons (perineuronal satellitosis). Mitotic activity is usually very difficult to detect, and proliferation indices are low. Oligodendrogliomas are considered to be WHO grade II/IV lesions.

FIGURE 28-49 Oligodendroglioma. Tumor nuclei are round, with cleared cytoplasm forming “halos” and vasculature composed of thin-walled capillaries.

Anaplastic oligodendrogliomas (WHO grade III/IV) are characterized by increased cell density, nuclear anaplasia, increased mitotic activity, and necrosis. These changes can often be found in nodules within an otherwise grade II/IV oligodendroglioma. Also often present in these higher grade lesions are discrete round cells with cytoplasmic GFAP and nuclei that resemble the other elements of the tumor. These microgemistocytes differ from gemistocytic astro cytes in that they lack abundant processes; the intermediate filaments are restricted to a small lump of cytoplasm. Some of these high-grade oligodendroglial tumors also show patterns that are indistinguishable from glioblastoma. Because several studies have shown that such appearance correlates with worse behavior, these tumors are grouped with glioblastoma.

Ependymoma and Related Paraventricular Mass Lesions

Ependymomas, as would be expected, most often arise next to the ependyma-lined ventricular system, including the oft-obliterated central canal of the spinal cord. In the first two decades of life they typically occur near the fourth ventricle and constitute 5% to 10% of the primary brain tumors in this age group. In adults the spinal cord is the most common location; tumors in this site are particularly frequent in the setting of neurofibromatosis type 2 (NF2).

Morphology.In the fourth ventricle, ependymomas are typically solid or papillary masses extending from the floor of the ventricle (Fig. 28-50A). Although ependymomas are moderately well demarcated from adjacent brain, the proximity of vital pontine and medullary nuclei usually makes complete extirpation impossible. In the intra-spinal tumors this sharp demarcation sometimes makes total removal feasible. On microscopic examination ependymomas are composed of cells with regular, round to oval nuclei and abundant granular chromatin. Between the nuclei there is a variably dense fibrillary background. Tumor cells may form glandlike round or elongated structures (rosettes, canals) that resemble the embryologic ependymal canal, with long, delicate processes extending into a lumen (Fig. 28-50B); more frequently present are perivascular pseudorosettes (Fig. 28-50B), in which tumor cells are arranged around vessels with an intervening zone consisting of thin ependymal processes directed toward the wall of the vessel. GFAP expression is found in most ependymomas. While most ependymomas are well differentiated and behave as WHO grade II/IV lesions, anaplastic ependymomas (WHO grade III/IV) reveal increased cell density, high mitotic rates, areas of necrosis, and less evident ependymal differentiation.

FIGURE 28-50 Ependymoma. A, Tumor growing into the fourth ventricle, distorting, compressing, and infiltrating surrounding structures. B, Microscopic appearance of ependymoma.

Myxopapillary ependymomas are distinct but related lesions that occur in the filum terminale of the spinal cord and contain papillary elements in a myxoid background, admixed with ependymoma-like cells. Cuboidal cells, sometimes with clear cytoplasm, are arranged around papillary cores containing connective tissue and blood vessels. The myxoid areas contain neutral and acidic mucopolysaccharides. Prognosis depends on completeness of surgical resection; if the tumor has extended into the subarachnoid space and surrounded the roots of the cauda equina, recurrence is likely.

Medulloblastoma

This tumor occurs predominantly in children and exclusively in the cerebellum (by definition). Neuronal and glial markers may be expressed, but the tumor is often largely undifferentiated.

Morphology. In children, medulloblastomas are located in the midline of the cerebellum, but lateral locations are more often found in adults. Rapid growth may occlude the flow of CSF, leading to hydrocephalus. The tumor is often well circumscribed, gray, and friable, and may be seen extending to the surface of the cerebellar folia and involving the leptomeninges (Fig. 28-51A). On microscopic examination medulloblastoma is extremely cellular, with sheets of anaplastic cells (Fig. 28-51B). Individual tumor cells are small, with scant cytoplasm and hyperchromatic nuclei that are frequently elongated or crescent shaped. Mitoses are abundant, and markers of cellular proliferation, such as Ki-67, are detected in a high percentage of the cells. The tumor may express neuronal (neurosecretory granules or Homer Wright rosettes, as occur in neuroblastoma; Chapter 10) and glial (GFAP+) phenotypes. The desmoplastic variant is characterized by areas of stromal response, marked by collagen and reticulin deposition and nodules of cells forming “pale islands” that have more neuropil and show greater expression of neuronal markers.

FIGURE 28-51 Medulloblastoma. A, Sagittal section of brain showing medulloblastoma destroying the superior midline cerebellum. B, Microscopic appearance of medulloblastoma.

At the edges of the main tumor mass, medulloblastoma cells have a propensity to form linear chains of cells infiltrating through cerebellar cortex to aggregate beneath the pia, penetrate the pia, and seed into the subarachnoid space. Dissemination through the CSF is a common complication, presenting as nodular masses elsewhere in the CNS, including metastases to the cauda equina that are sometimes termed drop metastases.

Atypical Teratoid/Rhabdoid Tumor

This highly malignant tumor of young children occurs in the posterior fossa and supratentorial compartments in nearly equal proportions. The presence of rhabdoid cells, resembling those of a rhabdomyosarcoma, is the defining characteristic of the lesion.

Primary CNS Lymphoma

Primary CNS lymphoma accounts for 2% of extra-nodal lymphomas and 1% of intra-cranial tumors. It is the most common CNS neoplasm in immunosuppressed individuals, including those with AIDS and immunosuppression after transplantation. In non-immunosuppressed populations, the age spectrum is relatively wide, and the frequency increases after 60 years of age.

The term primary emphasizes the distinction between these lesions and secondary involvement of the CNS by lymphoma arising elsewhere in the body (Chapter 13). Primary brain lymphoma is often multifocal within the brain parenchyma, yet nodal, bone marrow, or extra-nodal involvement outside of the CNS is a rare and late complication. Conversely, lymphoma arising outside the CNS rarely involves the brain parenchyma; involvement of the nervous system, when it occurs in lymphoma, is usually manifested by the presence of malignant cells within the CSF and around intradural nerve roots, and occasionally by the infiltration of superficial areas of the cerebrum or spinal cord by malignant cells.

Most primary brain lymphomas are of B-cell origin. In the setting of immunosuppression, the cells in nearly all such tumors are latently infected by Epstein-Barr virus. Overall, primary lymphomas of the CNS are aggressive, with relatively poor response to chemotherapy compared with peripheral lymphomas.

Intravascular lymphoma, an unusual lymphoid malignancy in which the tumor cells grow intraluminally within small vessels, often involves the brain along with other regions of the body.⁹³ Instead of presenting as a mass lesion, the occlusion of vessels by malignant cells can result in widespread microscopic infarcts. Affected individuals present with evidence of multifocal lesions, with the differential diagnosis usually including processes such as vasculitis and showers of emboli.

Germ Cell Tumors

Primary brain germ cell tumors occur along the midline, most commonly in the pineal and the suprasellar regions. They account for 0.2% to 1% of brain tumors in people of European descent but up to 10% in Japanese people. They are tumors of the young, with 90% occurring during the first two decades. Germ cell tumors, particularly teratomas, are among the more common congenital tumors. Germ cell tumors in the pineal region show a strong male predominance, which is not seen in suprasellar lesions.

The source of germ cells in the CNS is not clear; they may be “rests” that remain in the CNS or perhaps migrate there from other sites late in development. Germ cell tumors share many features with their counterparts in the gonads. In contrast to lymphomas, however, metastasis of a gonadal germ cell tumor to the CNS is not uncommon; thus, the presence of a non-CNS primary tumor must be excluded before a diagnosis of primary germ cell tumor is made. The histologic classification of brain germ cell tumors is similar to that used in the testis (Chapter 21), but the tumor that is histologically similar to the seminoma in the testis is referred to as germinoma in the CNS. The responses to radiation therapy and chemotherapy roughly parallel those of similar histologic lesions at other sites. As in the periphery, CSF levels of tumor markers including α-fetoprotein and β-human chorionic gonadotropin can be used to aid in diagnosis and track response to therapy.

Pineal Parenchymal Tumors

These lesions arise from specialized cells of the pineal gland (pineocytes) that have features of neuronal differentiation. The tumors range from well-differentiated lesions (pineocytomas, with areas of neuropil, cells with small, round nuclei, and no evidence of mitoses or necrosis) to high-grade tumors (pineoblastomas, with little evidence of neuronal differentiation, densely packed small cells with necrosis, and frequent mitotic figures). High-grade pineal tumors tend to affect children, while lower-grade lesions are found more often in adults. The highly aggressive pineoblastoma commonly spreads throughout the CSF space. It occurs with increased frequency in individuals with germline mutations in RB (so-called trilateral retinoblastoma). Gliomas are also found in the pineal region, arising from the glial stroma of the gland. Often low grade, these gliomas can be difficult to distinguish from the glial reaction that can accompany non-neoplastic pineal region cysts.

Schwannoma

These benign tumors arise from the neural crest–derived Schwann cell and cause symptoms by local compression of the involved nerve or adjacent structures (such as brainstem or spinal cord). Schwannomas are a component of NF2, and even sporadic schwannomas are commonly associated with inactivating mutations in the NF2 gene on chromosome 22. Loss of expression of the NF2 gene product, merlin, is a consistent finding in all schwannomas. Merlin normally restricts the cell-surface expression of growth factor receptors, such as EGFR, through interactions involving the actin cytoskeleton; in its absence, cells hyperproliferate in response to growth factors.

Morphology. Schwannomas are well-circumscribed, encapsulated masses that are attached to the nerve but can be separated from it (Fig. 28-53A). Tumors form firm, gray masses that may have areas of cystic and xanthomatous change. On microscopic examination tumors show a mixture of two growth patterns (Fig. 28-53B). In the Antoni A pattern of growth, elongated cells with cytoplasmic processes are arranged in fascicles in areas of moderate to high cellularity and scant stromal matrix; the “nuclear-free zones” of processes that lie between the regions of nuclear palisading are termed Verocay bodies. In the Antoni B pattern of growth, the tumor is less densely cellular and consists of a loose meshwork of cells, microcysts and myxoid stroma. In both areas the individual cells have an elongated shape and regular oval nuclei. Electron microscopy shows basement membrane deposits encasing single cells and collagen fibers. Because the lesion displaces the nerve of origin as it grows, silver stains or immunostains for neurofilament proteins demonstrate that axons are largely excluded from the tumor, although they may become entrapped in the capsule. The Schwann cell origin of these tumors is borne out by their S-100 immunoreactivity. A variety of degenerative changes may be found in schwannomas, including nuclear pleomorphism, xanthomatous change, and vascular hyalinization. Malignant change is extremely rare, but local recurrence can follow incomplete resection.

FIGURE 28-53 Schwannoma. A, Bilateral eighth-nerve schwannomas. B, Tumor showing cellular areas (Antoni A), including Verocay bodies (far right), as well as looser, myxoid regions (Antoni B, center).

(A, Courtesy of the late Dr. K.M. Earle.)

Neurofibroma

Neurofibromas can present as discrete localized masses—most commonly as a cutaneous neurofibroma or in peripheral nerve as a solitary neurofibroma—or as an infiltrative lesion growing within and expanding a peripheral nerve (plexiform neurofibroma). The presence of either multiple neurofibromas or plexiform neurofibromas strongly suggests the diagnosis of neurofibromatosis type 1 (NF1). Skin lesions grow as nodules, sometimes with overlying hyperpigmentation; they may become large and pedunculated. The risk of malignant transformation of these tumors is extremely small, and they are mostly of cosmetic concern. In contrast, plexiform tumors may result in significant neurologic deficits when they involve major nerve trunks, are difficult to remove because of their intraneural spread, and have a significant potential for malignant transformation.

Alterations in both copies of the NF1 gene have been consistently observed in the Schwann cell components of plexiform neurofibromas, supporting a critical role for loss of NF1 function in the genesis of this tumor. The product of the NF1 gene (neurofibromin) stimulates the activity of a GTPase that inhibits RAS activity (recall that RAS is active only when bound to GTP).

Malignant Peripheral Nerve Sheath Tumor

Malignant peripheral nerve sheath tumors are highly malignant tumors that are locally invasive, frequently with multiple recurrences and eventual metastatic spread. They are most commonly associated with medium to large nerves, rather than either cranial nerves or distal small nerves. While many occur sporadically, close to 50% of cases arise in the setting of NF1—either from transformation of a plexiform neurofibroma or following radiation therapy. NF1 function is lost at an early stage of development of malignant peripheral nerve sheath tumors; subsequent alterations often disrupt both the p53- and RB-dependent pathways for regulation of cell proliferation.

Neurofibromatosis Type 1

This autosomal dominant disorder, one of the more common genetic disorders, having a frequency of 1 in 3000, is characterized by neurofibromas (plexiform and solitary), gliomas of the optic nerve, pigmented nodules of the iris (Lisch nodules), and cutaneous hyperpigmented macules (café au lait spots). In individuals with NF1 there is a propensity for the neurofibromas, particularly plexiform neurofibromas, to undergo malignant degeneration at a higher rate than that observed for comparable tumors in the general population. As described earlier under “Neurofibroma”, the NF1 gene, located at 17q11.2, encodes neurofibromin—a large protein with a GTPase-activating domain that inhibits RAS. The tumor cells in NF1-related tumors lack NF1 expression due to biallelic inactivation of the gene.

The course of the disease is highly variable; some individuals who carry a mutated gene have no symptoms, while others develop progressive disease with spinal deformities, disfiguring lesions, and compression of vital structures, including the spinal cord.

Neurofibromatosis Type 2 (NF2)

This is an autosomal dominant disorder resulting in a range of tumors, most commonly bilateral eighth-nerve schwannomas and multiple meningiomas. Gliomas, typically ependymomas of the spinal cord, also occur in these patients. Many individuals with NF2 also have non-neoplastic lesions, which include nodular ingrowth of Schwann cells into the spinal cord (schwannosis), meningioangiomatosis (a proliferation of meningeal cells and blood vessels that grows into the brain), and glial hamartia (microscopic nodular collections of glial cells at abnormal locations, often in the superficial and deep layers of cerebral cortex). This disorder is much less common than NF1, having a frequency of 1 in 40,000 to 50,000.

The NF2 gene is located on chromosome 22q12, and the gene product, merlin, shows structural similarity to a series of cytoskeletal proteins; the NF2 gene is also commonly mutated in sporadic meningiomas and schwannomas. The protein is believed to regulate membrane receptor signaling, including contact growth inhibition.⁹⁸ There is some correlation between the type of mutation and clinical symptoms, with nonsense and frameshift mutations causing a more severe phenotype than missense mutations.

Tuberous Sclerosis Complex

Tuberous sclerosis is an autosomal dominant syndrome, occurring at a frequency of approximately 1 in 6000 births. It is characterized by the development of hamartomas and benign neoplasms involving the brain and other tissues. Hamartomas within the CNS take the form of cortical tubers and subependymal nodules; subependymal giant-cell astrocytomas are low grade neoplasms that appear to develop from the hamartomatous nodules in the same location. Cortical tubers are often epileptogenic, and surgical resection can be beneficial when medical management of the seizures is difficult. Elsewhere in the body, lesions include renal angiomyolipomas, retinal glial hamartomas, pulmonary lymphangioleiomyomatosis and cardiac rhabdomyomas. Cysts may be found at various sites, including the liver, kidneys, and pancreas. Cutaneous lesions include angiofibromas, localized leathery thickenings (shagreen patches), hypopigmented areas (ash-leaf patches), and subungual fibromas.

One tuberous sclerosis locus (TSC1) is found on chromosome 9q34, and it encodes a protein known as hamartin; the more commonly mutated tuberous sclerosis locus (TSC2) is at 16p13.3 and encodes tuberin. These two proteins bind, forming a complex that inhibits the kinase mTOR, which is a key regulator of protein synthesis and other aspects of anabolic metabolism. Of note, mTOR is well-known to control cell size, and the tumors associated with tuberous sclerosis are remarkable for having voluminous amounts of cytoplasm, particularly giant-cell astrocytomas in the CNS, and cardiac rhabdomyomas. Cortical and subependymal tubers are associated with an intact copy of the wild-type allele, while in subependymal giant-cell astrocytomas there is biallelic loss. Treatment is symptomatic, including anticonvulsant therapy for control of seizures.

Von Hippel–Lindau Disease

This is an autosomal dominant disease in which affected individuals develop hemangioblastomas and cysts involving the pancreas, liver, and kidneys, and have a propensity to develop renal cell carcinoma and pheochromocytoma. Hemangioblastomas are most common in the cerebellum and retina. The disease frequency is 1 in 30,000 to 40,000.

The gene associated with von Hippel–Lindau disease (VHL), a tumor suppressor gene, is located on chromosome 3p25–p26 and encodes a protein (pVHL) that, among its other functions, is a component of a ubiquitin ligase complex that down-regulates hypoxia-induced factor 1 (HIF-1), a transcription factor involved in regulating expression of vascular endothelial growth factor, erythropoietin, and other growth factors.⁹⁹ It is the dysregulation of erythropoietin that is responsible for the polycythemia observed in association with hemangioblastomas in about 10% of cases. There may be other targets of this ubiquitin ligase complex whose normal degradation is disrupted by loss of pVHL, explaining the other tumors associated with this syndrome. Missense mutations in VHL, but not other types of mutations, are highly likely to be associated with pheochromocytomas.

Therapy is directed at the symptomatic neoplasms, including resection of the cerebellar hemangioblastomas and laser therapy for retinal hemangioblastomas.