Chapter 206 – Tumors, Infections, Inflammations, and Neurodegenerations
HOSSEIN G. SAADATI
ALFREDO A. SADUN
• Tumors are compressive lesions and may compromise the function of adjacent tissues.
• Infections are invasions of tissues by microorganisms (bacterial, fungal, or viral).
• Inflammations reflect intrinsic responses by various tissues related to the immune system and may compromise tissue function.
• Neurodegenerations of the central nervous system often involve premature dysfunction consequent to genetic factors.
• Tumors, infections, and inflammations of the central nervous system may involve the meninges, the brain substance (parenchyma), or the surface of the brain (extraparenchymal).
• Neurodegenerations may be specific for certain regions of the brain (such as Huntington’s chorea) or involve the brain diffusely (such as Alzheimer’s disease).
• Tumors may be benign or malignant; primary or metastatic.
• Inflammatory and infectious responses may be acute or chronic, according to the cadence of development.
Tumors of the brain may produce symptoms that arise from their size, location (abutment to critical structures), malignancy (which produces adjacent necrosis), or nonspecific mechanical effects (such as blockage of the cerebrospinal circulation). Tumors may present with signs and symptoms that are localizing (such as chiasmal visual field loss) or nonlocalizing (such as headaches, seizures). New-onset seizures are harbingers of an intracranial tumor in up to 33% of adults. Papilledema and sixth nerve palsies are important nonlocalizing signs of increased intracranial pressure and may indicate the presence of an intracranial tumor.
Although it is beyond the scope of this chapter to describe the characteristics of each tumor type, several tumors that mimic infections or inflammations at the base of the brain or are in the differential diagnosis of meningitis with neuro-ophthalmic symptoms are discussed.
EPIDEMIOLOGY AND PATHOGENESIS
Tumors tend to develop in the posterior fossa in children and in the cerebral hemispheres in adults. For example, medulloblastomas are seen most commonly in male children 4–8 years of age. Neuroblastomas and, to a lesser extent, ependymomas and papillomas of the choroid also are more common in the young.
Tumors produce signs and symptoms in accordance with their location. Additionally, many tumors are nonlocalizing. Papilledema and diplopia from sixth nerve palsies may be produced by tumors in any location.
Localizing tumors are likely to affect adjacent structures. Tumors of the optic nerve, such as meningiomas or gliomas, often produce a slowly progressive, painless visual loss; loss of optic nerve functions (dyschromatopsia, pupillary defects, and loss of brightness sense); visual field defects; and disc edema early in the course of the disease process (see Chapter 189 ). Eventually, optic atrophy develops. If the tumor is intraorbital, significant proptosis, increased resistance to retropulsion, signs of orbital congestion, and, uncommonly, diplopia from ophthalmoplegia may be seen.
Metastatic tumors, or malignant invasive tumors, may produce inflammation and necrosis in surrounding tissue and may even simulate orbital cellulitis.
Cavernous sinus involvement is likely to produce ophthalmoplegia with or without pain. The signs and symptoms may be quite similar to those of an orbital apex syndrome. Numbness or pain in the distribution of the first division of the fifth nerve is common.
Near the optic chiasm, a variety of tumors may produce a chiasmal syndrome (bitemporal visual field defects). The most common of these are pituitary adenomas, but gliomas, meningiomas, craniopharyngiomas, and tumors from the sphenoidal sinus and clivus all may involve the optic chiasm. Pituitary adenomas may expand suddenly when affected by necrosis and hemorrhage; this pituitary apoplexy is the exception to the rule that intracranial tumors develop and produce symptoms slowly.
Tumors in the parietal and temporal lobes may involve the posterior visual pathways and produce corresponding defects in the visual field. Occipital lobe tumors produce much more congruous visual field defects, which often spare visual fixation.
Each tumor type has its own histopathological features. Often, special stains, such as immunohistochemistry, are useful in the differentiation of subsets of tumor types. It may be useful, therefore, to preserve some tissues in standard fixative and set other specimens aside in the frozen state and, in certain cases, in mixed buffered aldehydes for possible electron microscopy.
Treatment of malignancies that produce a base-of-the-brain syndrome or a paraneoplastic syndrome depends on the type of
malignancy. In addition to addressing the primary tumor, consideration has to be given to malignant cells that might be in the cerebrospinal fluid (CSF) and to the immune response. At times, immunosuppressive therapy may be of temporary benefit (such as in the administration of corticosteroids for cancer-associated retinopathy or in CSF paraneoplastic disease). Often, central nervous system (CNS) irradiation (brain and spinal cord axis) may be necessary.
COURSE AND OUTCOME
Responses to chemotherapy or radiation therapy are extremely variable and depend largely on the type of neoplasm involved. However, the long-term visual prognosis is guarded.
Despite the advancements in control programs and powerful antibiotics, CNS infections in general are still a management problem. In this era of acquired immunodeficiency syndrome (AIDS) and other forms of immunosuppression, symptoms and signs that are not typical for a particular infection in non-AIDS or nonimmunosuppressed patients have to be recognized.
Infections of the CNS have a diverse presentation; however, most share four cardinal manifestations: headache, altered mental status, focal neurological signs, and fever. Because these features are nonspecific, other characteristics are important in the evaluation of these patients, such as the time course of the disease and its natural history. The syndrome of chronic meningitis is defined as meningitis that fails to improve or progresses over at least 4 weeks of observation. Infections at the base of the brain (“basilar meningitis”) usually run a subacute or chronic course, are gradual in onset, and may last for weeks or months; their mortality rate is moderate to high. Focal neurological findings are more common than in acute meningitis. Diagnosis with regard to the causative agent is of utmost importance.
EPIDEMIOLOGY AND PATHOGENESIS
Meningitis may present with a variety of clinical syndromes, and the clinical expression of meningitis depends on the underlying medical condition and the immune status of the patient. Meningococcus accounts for 20% of all cases of bacterial meningitis in the United States. Interestingly, serogroup B is present in 50% of such cases. In acute fulminant cases of infectious meningitis, a severe inflammatory reaction occurs in the meninges, primarily in the subarachnoid spaces over the convexity of the brain and around the cisterns at the base of the brain; the reaction rarely breaks into the parenchyma. As the inflammation continues, adhesions form that may interfere with CSF flow and cause fibrosis of the meninges along the roots of the cranial nerves. The toxic effect of the infectious organism also may contribute to the inflammatory process via the release of various cytokines.
The initial systemic symptoms of fever, chills, nausea, and vomiting are often accompanied by headache, stiffness of the neck, seizures, and cranial nerve palsies. These symptoms present more acutely in viral and bacterial infections and more insidiously in the basilar meningitis that results from fungus, tuberculosis, syphilis, or other similar causes.
The hallmark signs for most forms of meningitis are the meningeal signs of Kernig and Brudzinski, which are commonly present. Both maneuvers stretch the possibly inflamed spinal structures and, in cases of meningitis, lead to pain and a reflexive extension of the neck and flexion of the hips and knees.
Basilar meningitis, especially, may produce cranial nerve palsies. Involvement of the third, fourth, and sixth nerves produces binocular diplopia. More rarely, an optic neuritis or chiasmatis may develop, with a resultant loss of optic nerve function and visual acuity and with losses in the visual field. More often, increases in intracranial pressure result in papilledema and its associated signs and symptoms (see Chapter 189 ).
DIAGNOSIS AND TESTING
The key finding is an abnormal CSF analysis that shows increased intracranial pressure, increased white cell count, cloudy CSF, increased protein, decreased sugar level, and identification of the microorganism on Gram’s stain with growth on the appropriate culture media. However, patients whose bacterial meningitis is partially treated may continue to show signs and symptoms of acute meningitis with sterile CSF. Negative Gram’s stains or cultures and sensitivities also may reflect patients with fungal, tuberculous, and parameningeal infections.
Generally, infections are identified by Gram’s stain or culture and sensitivities. However, on occasion, histopathology may be helpful, particularly for fungal, protozoan, or atypical bacterial infections.
Appropriate antibiotic therapy to which the microorganism is sensitive is essential in bacterial meningitis; delay is life threatening. It is important that the antibiotic cross the blood-CSF barrier in sufficient concentrations to achieve therapeutic values in the CSF. Maintenance of adequate fluid and electrolyte balance is important to help control the cerebral edema. Corticosteroid administration concomitant with the use of antibiotics has been advocated by some investigators as being particularly beneficial in children to reduce the neurological sequelae. However, no prospective study has confirmed this advantage.
COURSE AND OUTCOME
If the infectious meningitis is responsive to therapy, the outcome may be only minimal neurological sequelae. About 20–25% of patients who recover are left with sequelae, which can vary from minimal facial weakness or hearing loss to severe intellectual or other physical ailments such as hemiplegia, paraplegia, seizures, cranial nerve palsies with diplopia, blindness, chronic increased intracranial pressure, syndrome of inappropriate antidiuretic hormone, and subdural effusion. In association with human immunodeficiency virus (HIV) epidemics, infectious meningitis may become more resistant to therapy, and the process may be chronic and indolent with a poorer response to treatment.
For the most part, inflammations of the brain involve blood vessels with or without vessel wall necrosis. Systemic vasculitis may be present with predominant CNS manifestations, as well as forms of vasculitis that are limited primarily to the CNS.
EPIDEMIOLOGY AND PATHOGENESIS
Inflammations of the brain and, in particular, vasculitis are more common in young adults. Vasculitis is an idiopathic disorder that involves the small and medium blood vessels of the brain and spinal cord and usually presents with multiple bilateral infarcts
of the cortex and subcortical white matter. The CNS may be injured by the ischemia that results from vasculitis or directly from the effects of inflammation. In the inflammatory process, granulocytes and macrophages directly destroy oligodendrocytes, as well as neurons and their axons, either through the release of cytotoxic agents or through phagocytosis.
The specific pathogenesis varies with the type of systemic vasculitis. Polyarteritis nodosa (PAN) is rare, with a male-female ratio of 2.5:1. In systemic lupus erythematosus, most cases begin in the age range of 20–40 years, and 95% of patients are women. Giant cell arteritis is a relatively common form of vasculitis, with a 5-year incidence as high as 24 per 100,000 in individuals of northern European ancestry who are older than 50 years. Wegener’s granulomatosis is a rare entity of unknown cause that affects adult men and women in a ratio of 2:1. The pathogenesis includes the evolution of necrotizing granulomas.
The prevalence of Sjögren’s syndrome in the general population is 2–3%. This chronic systemic condition is caused predominantly by lymphocytic infiltration of lacrimal and salivary glands. Although traditionally considered a disease of middle-aged to elderly women, several cases have been reported of young adults, adolescents, and even children affected by the disease. Behçet’s syndrome occurs more frequently in those of Middle Eastern, Mediterranean, or Japanese descent and has a male preponderance. Its pathogenesis remains elusive, but an association with the HLA-B5 antigen occurs in some geographical regions.
Since the initial report in 1956, 223 cases of Miller-Fisher syndrome have been described. The male-female ratio is 2:1, with a mean age of 43.6 years at disease onset. A viral infection precedes the neurological symptoms in more than 70% of cases. Vogt-Koyanagi-Harada syndrome is a granulomatous inflammatory disorder. It occurs more commonly in darkly pigmented races such as Asians, Hispanics, American Indians, and Asian Indians. It also is more common in Japan, where it accounts for 6.8–9.2% of all cases of uveitis. Most patients are in the second to fifth decades of life. The pathogenesis may be the selective damage of melanocytes as part of an autoimmune process.
Primary cerebral vasculitides include a variety of pathologies that mainly involve blood vessels of the brain and spinal cord. The clinical manifestations vary widely as diffuse or focal neurological dysfunction, which may affect different regions of the CNS. Further differences occur between diseases that affect primarily small versus larger blood vessels. Typical symptoms of diffuse involvement include headache, seizures, confusion, hallucination, and generalized lethargy. Focal involvement may manifest as a cerebrovascular accident; if the cranial nerves are affected, this may present as ophthalmoplegia or optic neuropathy; involvement of the posterior visual pathways produces characteristic visual field defects.
Systemic Necrotizing Vasculitides
Systemic necrotizing vasculitides are listed in Table 206-1 . In PAN, the visual loss may result from retinal vascular disease, retinal vasculitis, or cortical blindness, all of which are rare. The CNS becomes involved with variable frequency, usually after the initial diagnosis of PAN. Presentation is variable and may include diffuse encephalopathy or seizures. Focal neurological deficits appear to be secondary to cerebral infarction and hemorrhage involving one cerebral hemisphere. Peripheral neuropathy (mononeuritis multiplex) is frequently the presenting manifestation; seen less commonly is a diffuse, sensorimotor type. These forms of neuropathy are attributed to ischemia or arteritis of nutrient vessels. 
In systemic lupus erythematosus (SLE), visual sensory disturbances may result from optic nerve disease related to optic neuritis
TABLE 206-1 — PRIMARY CENTRAL NERVOUS SYSTEM AND SYSTEMIC VASCULITIDES
Central Nervous System Sign (Most Common)
Primary central nervous system
Granulomatous angiitis of the central nervous system
Acute posterior multifocal placoid pigment epitheliopathy
Microangiopathy of the brain
Giant cell arteritis
Systemic lupus erythematosus
Polymyositis and dermatomyositis
Lethal midline granuloma
(inflammatory or ischemic) or papilledema (pseudotumor cerebri or malignant hypertension). Retrochiasmatic pathway involvement may present as transient visual phenomena (which may be mistaken for migraine) or as permanent homonymous field defects, which may be acute or subacute and occasionally herald the diagnosis of SLE. Involvement of the CNS occurs in 35–60% of patients who have SLE. The neurological manifestations are divided into two types—diffuse and focal. The former includes major motor seizures, dementia, delirium, organic mood disorder, and organic psychosis. The focal types are cranial neuropathies, stroke, transverse myelitis, focal seizures, and chorea. The ocular motor pathway may be involved from the cerebral cortex to the extraocular muscles; the most common locus of involvement is a brainstem infarction.
Giant cell arteritis (GCA) is a common vasculitis in which the most serious clinical manifestations are largely ophthalmic. One of the most devastating is irreversible blindness, which occurs in 36% of cases. The incidence of second eye involvement is about 65% among untreated patients. The most common ocular presentation is anterior ischemic optic neuropathy, with severe visual loss to no light perception and a pale, swollen optic nerve. Visual loss also may result from posterior optic neuropathy, severe choroidal ischemia, central retinal artery or ophthalmic artery occlusion, anterior segment ischemia, and chiasmal or cortical ischemia. Other ocular manifestations are diplopia related to ophthalmoplegia that involves the third, fourth, or sixth cranial nerve.
In GCA, headache and pain often occur in the temples, occipital region, ear, or tongue. Jaw claudication pain, manifested upon chewing or talking, is a classic and highly specific symptom that, unfortunately, is not consistently present (found in 30% of patients). Other neurological manifestations occur in 30% of patients and include transient ischemic attacks that involve the posterior circulation and infarcts of the vertebrobasilar system that produce ataxia, lateral medullary syndrome, hemianopia, dementia, otological manifestations, loss of taste, and gangrene of the tongue.
In Wegener’s granulomatosis, orbital involvement occurs in 20% of patients and may simulate the appearance of orbital pseudotumor or lymphoma. Scleritis of the necrotizing variety and uveitis may be the initial manifestations. Involvement of the CNS occurs in 25–50% of cases and usually presents as cranial neuropathies, hypertensive encephalopathy, and cerebral vasculitis. 
In Sjögren’s syndrome, the cardinal ocular manifestation is keratitis sicca, or dry eyes, which may result in corneal ulceration and even perforation. Optic neuropathy may occur alone but more commonly is associated with multifocal CNS disease. Presentations include acute retrobulbar optic neuritis, ischemic optic neuropathy, and insidious visual loss with optic atrophy. Cranial neuropathies may be peripheral or central. The best recognized is a trigeminal sensory neuropathy. Facial nerve involvement may compromise autonomic secretory function and further exacerbate the sicca syndrome. Acute and chronic subarachnoid hemorrhages with microhemorrhages within the meninges are very common in CNS antibody-positive individuals (SS-A). Less common CNS manifestations are parkinsonism, cerebellar syndromes, and aseptic meningitis.
In Behçet’s syndrome, ocular involvement is seen in 83–95% of men and 67–73% of women. Bilaterality is the rule, although delayed and asymmetrical involvement of the fellow eye is common. Loss of vision is usually the most serious complication, which may result from chronic anterior segment inflammation, neovascular glaucoma, or occlusive vasculitis. Neovascularization, retinal detachment, and optic atrophy are common sequelae. Loss of vision is a late manifestation that occurs an average of 3 years after the onset of ocular Behçet’s syndrome. Among patients affected by ocular disease, 10–30% present with meningoencephalitis, brainstem syndrome, and organic brain syndrome. 
In sarcoidosis, the target organs commonly are the eyes, lacrimal glands, lungs, lymph nodes, and salivary glands. Ocular manifestations include granulomatous uveitis, inflammatory glaucoma, optic neuropathy ( Fig. 206-1 ), and lacrimal gland enlargement. About 5% of patients present with either central or peripheral nervous system disease within 2 years of onset. In the CNS, the meninges at the base of the brain are most affected; secondary infiltration of cranial nerves (37–73%) and obstruction of CSF flow (7%) also occur, and CNS parenchymal disease is common (8–40%).
Miller-Fisher syndrome consists of the triad of ataxia, ophthalmoplegia, and areflexia and is described as a variant of Guillain-Barré syndrome. The initial presentation is commonly diplopia (39% of cases). A complete external and internal ophthalmoplegia, which may be bilateral, is seen in about 50% of patients. Other manifestations are supranuclear gaze paresis with internuclear ophthalmoplegia, Parinaud’s syndrome, and occasional facial palsy. Ataxia (occurring in 21% of patients) is cerebellar in most cases. Areflexia was present in 81% of the 223 cases reviewed.
Vogt-Koyanagi-Harada (VKH) syndrome is a bilateral, diffuse, granulomatous uveitis associated with vitiligo, alopecia, poliosis, and CNS signs; it may be categorized clinically in four phases:
Prodromal, characterized by headache, nausea, vertigo, fever, meningismus, and orbital pain.
Uveitic, in which 70% of patients present with unilateral or bilateral posterior uveitis.
Convalescent, which follows after several weeks and is characterized by depigmentation of the skin (vitiligo) and choroid.
Chronic recurrent, which is characterized by smoldering panuveitis with exacerbations of acute episodes of granulomatous anterior uveitis.
Figure 206-1 Fundus view of optic nerve head in sarcoidosis. Note the sheathing of vessels and exudates, as well as pallid edema of the optic disc.
The neurological manifestations of VKH syndrome are more common during the prodromal phase. Focal neurological signs, such as cranial neuropathies, hemiparesis, aphasia, transverse myelitis, and ciliary ganglionitis, may be found but are uncommon. Lumbar puncture may reveal lymphocytic pleocytosis and elevated protein.
DIAGNOSIS AND TESTING
Angiography generally is not very sensitive for CNS vasculitis. The gold standard for such diagnosis is biopsy of the leptomeninges.
In PAN, the common but nonspecific laboratory findings include decreased serum complement and circulating immune complexes. The diagnosis often is established by biopsy of the sural nerve or muscle. In SLE, an important laboratory test is for antinuclear antibody titers (double stranded), which is also a good measure of the activity of the disease. For CNS lupus, the following laboratory tests are helpful:
• Elevated CSF immunoglobulin (Ig) index or oligoclonal band
• CSF antineuronal antibodies
• Serum antiribosomal antibodies
Together, these tests have a sensitivity of 100% and a specificity of 86%. Furthermore, patients who show focal presentations have evidence of antiphospholipid antibodies, abnormal brain magnetic resonance imaging (MRI) with multiple lesions, and peripheral vasculitis.
In GCA, the diagnosis is primarily clinical. However, more than 80% of patients have a markedly elevated Westergren erythrocyte sedimentation rate. Other helpful laboratory tests include a complete blood count (for anemia), serum fibrinogen levels, C-reactive protein, and plasma activating factor. Definitive diagnosis is histological proof of arterial involvement by biopsy of the temporal artery.
For Wegener’s granulomatosis, clinical diagnosis requires the finding of at least two of the following four criteria established by the American Academy of Rheumatology:
Oral ulcers or purulent bloody nasal discharge
Abnormal chest radiographs that show nodules, fixed infiltrates, or cavities
Microhematuria that signals kidney involvement
Biopsy evidence of granulomatous inflammation in the wall of an artery
For histological diagnosis, the nasal mucosa is the best biopsy source. Other laboratory tests that are useful for the diagnosis of
Wegener’s granulomatosis are those for antineutrophilic cytoplasmic antibodies type C, a specific marker found in 90% of patients who have systemic involvement.
In Sjögren’s syndrome, the electroencephalogram is abnormal in about 40% of patients. In 20% of patients, cerebral angiography shows changes consistent with vasculitis of small to medium vessels. Brain MRI is abnormal in about 80% of patients affected by progressive focal neurological symptoms, but these MRI changes are not differentiable from those found in multiple sclerosis. Studies of CSF show an elevated IgG index in 50% of cases, with oligoclonal bands present. Other laboratory tests include those for anti-Ro (SS-A) and anti-La (SS-B) antibodies; however, a definitive diagnosis may require a salivary gland biopsy.
In Behçet’s syndrome, fluorescein angiography is of major importance as an early diagnostic tool, because leakage from the vessels may be found even in the absence of funduscopic abnormalities. Ancillary tests for sarcoidosis include measurement of angiotensin-converting enzyme levels (elevated in 65% of cases) and gallium-67 scans of the head and chest. Biopsy may be definitive, as it may show noncaseating granulomas in the lacrimal glands, lymph nodes, conjunctiva nodules, or even the liver.
In CNS vasculitis, the small- and medium-size vessels are affected primarily. The cellular infiltrate is composed of lymphocytes, macrophages, and giant cells in all layers of the vessel wall. In PAN, a widespread panarteritis is found, with necrosis of the media and elastic membranes that results, in some cases, in the formation of small aneurysms, which may thrombose or rupture. In SLE, immune complex deposits develop in the walls of small blood vessels; the primary damage occurs in the subendothelial connective tissues of capillaries, small arteries, veins, and endocardium. In GCA, the pathological changes include granulomatous inflammation that results in vessel obstruction, embolism, or thrombosis ( Fig. 206-2 ). Also characteristic is the intimal proliferation and destruction of the internal elastic lamina.
In Wegener’s granulomatosis, the granuloma formation or vasculitis involves the small arteries and veins, and a fibrinoid necrosis of the vessel wall occurs with infiltration by neutrophils and histiocytes. In Sjögren’s syndrome, the inflammatory infiltrates are predominantly lymphocytes (T-cell type), macrophages, and plasma cells. Small blood vessels of the venous system are invariably involved, followed by those of the arterial system (small arteries or arterioles). In the CNS, blood vessels within the white
Figure 206-2 Temporal artery almost obliterated by vasculitis. In this case of giant cell arteritis, the media is filled with granulomatous infiltration (with giant cells and epithelioid cells). Also, note that the elastica has been fragmented (periodic acid–Schiff staining).
matter, in subcortical and periventricular locations, are mainly involved. In Behçet’s syndrome, the basic lesion is an occlusive, necrotizing, nongranulomatous vasculitis and perivasculitis found in the uvea and retina.
The treatment of CNS vasculitis with prednisone or cyclophosphamide may produce remission or cure. Certain specific inflammations require a more specified approach. For example, in Wegener’s granulomatosis, treatment involves cytotoxic therapy with cyclophosphamide and, less commonly, with methotrexate, azathioprine, and chlorambucil. The response to therapy is measured by clinical improvement and reduction of the antineutrophil cytoplasmic antibody titer over time. Sjögren’s syndrome requires pulse cyclophosphamide therapy in conjunction with corticosteroids for at least 12 months until disease stabilization or improvement occurs.
Therapy for sarcoidosis consists of treatment with corticosteroids for several weeks. If this fails, immunosuppressive agents such as azathioprine, methotrexate, cyclophosphamide, chlorambucil, and cyclosporine may be used.
COURSE AND OUTCOME
The chronic course for CNS vasculitis is usually characterized by cognitive deficits and focal findings. Without treatment, patients often suffer recurrent strokes and die within a few years. The prognosis in PAN is poor; patients die from lesions of the kidneys, heart, or other viscera. Cerebral SLE may be catastrophic and generally has a poor prognosis; death may result from renal failure, infection, or CNS involvement. Wegener’s granulomatosis was once regarded as uniformly fatal, but survival rates have increased with the use of cytotoxic drugs, predominantly cyclophosphamide.
The prognosis for Miller-Fisher syndrome is good, with complete recovery within 10 weeks of treatment, on average. Secondary infections, such as pneumonia or sepsis, may cause morbidity and mortality. In VKH syndrome, the prognosis is fair, but ocular complications are common. The most common complications include cataracts, glaucoma, and subretinal neovascular membranes. The major risk for the development of these complications is recurrence of the intraocular inflammation. 
Despite the specific denotation and vague negative connotation of “degeneration,” the term neurodegeneration continues to be used to imply a decline to a lower level of CNS function. We consider the term synonymous with heredodegeneration. This, and the older term abiotrophy, suggests a genetic cause for premature neuronal disease and death. Neuronal injury as a result of metabolic, toxic, or nutritional problems is dealt with in Chapter 192 ; however, not surprisingly, the clinical manifestations of these two categories of disease are quite similar. Recent advances in genetics and molecular biology have elucidated inborn errors in metabolism.
EPIDEMIOLOGY AND PATHOGENESIS
Each of the neurodegenerative diseases has a different epidemiology and pathogenesis. Alzheimer’s disease is the most common form of dementia, with a prevalence of 10.3% in people aged 65 years, which rises to 47% for those older than 80 years. A genetic basis is suspected strongly; however, a number of environmental risk factors and even viral infections have been implicated.
The pathology involves marked atrophy of the cerebral cortex. Histopathology reveals nonspecific plaques and tangles. Selective loss of large retinal ganglion cells and their axons that underlie the M-cell pathway may contribute to the visuospatial abnormalities.  
Each neurodegenerative syndrome has its own constellations of signs and symptoms. An outline of such degenerations is given in Box 206-1 , and a brief description of some of the more characteristic ophthalmic features follows.
Dystonic movements are sustained contractions or spasms that may be twisting or postural and tend to increase with action. In children who have dystonia, involvement of the arms and legs often occurs. Dystonic tremor includes features of both action and postural tremor. Dystonia tends to progress from focal to segmental to generalized. In advanced cases, the affected body part remains in a fixed dystonic posture. In adults, dystonia may begin with the arms (writer’s cramp), neck (torticollis), face (blepharospasm), jaw (oromandibular), tongue (lingual), or vocal cords (spastic).
Blepharospasm is a form of focal dystonia that commonly presents to the ophthalmologist. Caused by contraction of the orbicularis muscles, it begins with increased blinking followed by involuntary eyelid closure. If, in addition to blepharospasm, other cranial dystonias are present, the syndrome is called Meige’s syndrome. However, when the spasm involves all the branches of the facial nerve, it appears as hemifacial spasm, which is considered by Jankovic  to be a form of segmental (branchial) myoclonus.
Cerebellar Neurodegenerative Diseases
When the cerebellum and its connections are affected in a familial or hereditary pattern, the cardinal clinical feature seen is ataxia. The inherited ataxias may have an early onset; for example, Friedreich’s ataxia, an autosomal recessive disorder, starts
Ramsay Hunt syndrome
X-Linked inherited ataxia
Progressive supranuclear palsy
Hereditary nonprogressive chorea
• Sydenham’s chorea
• systemic lupus erythematosus
Metabolic and endocrine
• chorea gravidarum
• birth control pills
• hyperglycemic nonketotic encephalopathy
• hemichorea/hemiballismus with subthalamic nucleus lesion
• periarteritis nodosa
• Alzheimer’s disease
• Pick’s disease
• Creutzfeldt–Jakob disease
• Dyke–Davidoff–Masson disease
• Charles Bonnet disease
• mitochondrial encephalopathies—DNA related
• Leber’s hereditary optic atrophy
• mitochondrial diseases with mutations of nuclear DNA
before age 30 years. Patients present with progressive ataxia of gait and limbs, absent deep tendon reflexes, and extensor plantar responses. Patients also have dysarthria, clumsiness, and cardiopathy (75%). Less common features of Friedreich’s ataxia include nystagmus (25%), pes cavus (50%), diabetes (10–20%), deafness, and optic atrophy (25%), with a moderate reduction in vision. Posterior column disorder is seen in almost all patients. Loss of appreciation of vibration is an early sign. Computed tomography (CT) and MRI of the brain are usually normal, except with cerebellar atrophy. Cervical spinal cord atrophy is present, and the CSF is normal. The course is progressive, although variability exists. The mean age at death is 50 years, and there is no treatment other than palliative.
Ramsay Hunt syndrome is an early-onset ataxia that combines myoclonus and progressive ataxia. The most common cause is mitochondrial encephalomyopathy. Marinesco-Sjögren syndrome is another early-onset, recessive ataxia characterized by bilateral cataracts, mental retardation, and short stature.
Late-onset ataxias, under the rubric autosomal dominant cerebellar ataxia (ADCA), encompass all autosomal dominant ataxias that begin during adulthood. Late-onset ataxias are categorized according to clinical characteristics and gene loci, designated as SCA1, SCA2, and so on. The most common clinical form of ADCA is SCA1, which usually begins in patients between 20 and 40 years of age with gait ataxia, early hyperreflexia, abnormal evoked potentials, peripheral neuropathy, and pseudobulbar dysarthria. Early nystagmus and ophthalmoparesis are common. MRI shows cerebellar and brainstem atrophy, which particularly affects the pons and middle cerebellar peduncle.
Another form of ADCA is Azorean disease (SCA3). Patients present with gait and limb ataxia, leg spasticity, dysarthria, pyramidal signs, dystonia, rigidity, amyotrophy, and facial and lingual fasciculations. The ophthalmological manifestations are pseudoproptosis with lid retraction and decreased blinking and ophthalmoplegia, in which saccades are slow; also found are nystagmus and ocular dysmetria, followed by supranuclear ophthalmoplegia that spares downgaze. Ataxia SCA2 is characterized by slow saccades without nystagmus and early loss of tendon reflexes in the arms, in addition to ataxia. Other ADCAs are defined by different combinations of cerebellar ataxia and retinal degeneration.
Sporadic cerebellar ataxia of late onset often begins after age 40 years and is attended by parkinsonism, upper motor neuron signs, and dementia. Olivopontocerebellar atrophy is a common example of this category of degeneration. These patients may have autonomic dysfunction (neurogenic orthostatic hypotension).
Other types of ataxia include ataxia-telangiectasia, or Louis-Bar’s syndrome, which is an autosomal recessive disorder linked to a metabolic error. Patients present as children with truncal ataxia, delayed growth, and sexual and mental retardation. Oculomotor problems are prominent (pseudo-oculomotor apraxia). Telangiectasias of the skin and conjunctiva are often seen.
The parkinsonism symptom complex is characterized by six cardinal features:
Tremor at rest.
Bradykinesia-hypokinesia (slow and delayed movements).
Loss of postural reflexes.
Freezing phenomenon (motionlessness).
Two of these features, which must include either tremor or bradykinesia, are required for definitive diagnosis of parkinsonism. Tremor at rest with the “rolling pill sign” is common. In addition to the cardinal signs, these patients have decreased attention span and visuospatial impairments. Depression develops at
a rate of 2% of cases per year. Cognitive impairment may occur, but there are no memory problems.
Progressive Supranuclear Palsy
Progressive supranuclear palsy, or Steele-Richardson-Olszewski syndrome, is a neurodegenerative disease characterized by pseudobulbar palsy, supranuclear vertical gaze palsy (which affects primarily downgaze), extrapyramidal rigidity, gait ataxia, and dementia. The course is evolution to bed confinement in about 5 years and death a few years later.
Choreas may be hereditary, secondary (such as from SLE, phospholipids, or infections), drug-induced (such as from l-dopa, anticonvulsants, or anticholinergics), metabolic and endocrine, vascular, or miscellaneous (senile, or essential).
Huntington’s disease is a progressive hereditary disorder that becomes manifest only in adult life and is characterized by chorea, personality disorder, and dementia. Sydenham’s chorea is seen in children and is characterized by rapid, irregular, aimless, involuntary movements of the muscles of the limbs, face, and trunk. Patients also show emotional lability, hypotonia, and muscular weakness.
Dementias with Eye Findings
Alzheimer’s disease is a progressive neurological disorder that may present with visual disturbances such as anomalies of color vision, spatial contrast sensitivity disturbance, fixation instability, saccadic latency prolongation with hypometric saccades, and saccadic intrusions during smooth-pursuit eye movements.   The vestibular ocular reflex is normal in most patients. In addition to generalized cognitive problems, some patients may show disorders of higher cortical dysfunction of vision, such as visual agnosia and optic ataxia. Other dementias that accompany inherited metabolic disease with eye findings include Wilson’s disease, Fahr’s syndrome, metachromatic leukodystrophy, MELAS syndrome, MERRF syndrome, and Hallervorden-Spatz disease.
CHARLES BONNET SYNDROME.
Charles Bonnet syndrome is more than a type of dementia. Classically, however, it has been regarded as such because this condition is often an early marker for various dementias. This syndrome involves the onset of complex and vivid visual hallucinations in the absence of clouded consciousness, medical illness, psychopathology, or intellectual impairment. Classically, the patient has positive visual phenomena (hallucinations) that may be formed or unformed and probably represent a release phenomenon in the setting of deafferentation. It may occur after a stroke or other causes of diminished vision.
In addition to the focal deficit from stroke, an acquired intellectual impairment results from multiple small injuries to the brain caused by stroke, either hemorrhagic or ischemic. These patients have loss of memory and cognitive impairments that involve attention, orientation, visuospatial abilities, calculation, and motor control. Cortical syndrome is caused by repeated atherothrombotic or cardioembolic strokes and is characterized by more obvious, focal, sensorimotor signs and a more abrupt onset of cognitive failure. In contrast, subcortical syndrome is notable for pseudobulbar signs, isolated pyramidal signs, depression, emotional lability, frontal behavior, mild memory impairment, disorientation, inattention, and perseveration. 
DEMENTIA COMPLEX ASSOCIATED WITH HIV.
This sequela of autoimmune deficiency syndrome includes several CNS problems, such as apathy, cognitive slowing, and memory loss, as well as the more focal neurological abnormalities. The eye findings include subtle deficits of color vision and contrast sensitivity, especially in the midspatial frequencies. 
Originally thought to result from a slow virus, these spongiform encephalopathies are, indeed, transmissible. The prion diseases include kuru, Creutzfeldt-Jakob disease, fatal familial insomnia, and Gerstmann-Sträussler-Scheinker disease. These diseases cause rapidly progressive dementia that may include visual agnosias. 
DIAGNOSIS AND TESTING
In Huntington’s chorea, CT scans may be quite useful, as neuroimaging often shows enlarged ventricles with a butterfly appearance because of the selective degeneration of the caudate nucleus. Prenatal testing may be carried out for the Huntington’s disease gene near the tip of the short arm of chromosome 4.
In Alzheimer’s disease, the diagnosis may be challenging. Aside from the extensive neurological work-up, which includes psychometric testing, ophthalmological testing may be of some assistance. For example, a visual evoked potential recording may be of diagnostic significance, since these patients often show a normal-pattern visual evoked potential yet an abnormal flash visual evoked potential. Further, these patients have been found to have electroretinograms of a lower-amplitude pattern compared with normal flash electroretinograms. Ocular motility may also be abnormal.
In prion diseases, the electroencephalogram shows diffuse slowing, with pseudoperiodic, biphasic, and triphasic spike and wave complexes that are time locked to myoclonic jerks. Recently, it has become possible to look for a CSF marker, a protein designated 14-3-3 and detected by immunoassay. This test has about 96% sensitivity and specificity. However, brain biopsy with histopathology remains the diagnostic gold standard.
The pathophysiological problem of Parkinson’s disease relates to decreased dopaminergic neurotransmission in the basal ganglia with loss of dopamine receptors. The multiple causes for this include drug induced, postinfection, post-traumatic, tumor related, metabolic, hypoxic, postencephalitic, toxic, multi-infarct, and idiopathic. The pathological markers in Parkinson’s disease are the so-called Lewy bodies—neurons that contain eosinophilic cytoplasmic inclusions. In Alzheimer’s disease, in addition to the plaques and tangles in the cerebral hemispheres, direct injury occurs to the retinal ganglion cells and their axons ( Figs. 206-3 and 206-4 ).
Stereotaxic thalamotomy may be useful in unilateral dystonia, but bilateral ablations carry a 20% risk of dysarthria.
Treatment of hemifacial spasm has been attempted using high doses of anticholinergics (such as trihexyphenidyl [benzhexol]) and high doses of baclofen, benzodiazepines, and antidopaminergics (such as reserpine or dopamine receptor blockers), with limited success. More recently, botulinum toxin injections have been used with good success; however, this response does not last beyond 3 months.
Cerebellar neurodegenerative diseases with paroxysmal (or periodic) cerebellar ataxia may be amenable to treatment with acetazolamide in doses of 200–1000?mg/day, which reduces or abolishes the attacks.
The aim of treatment for Parkinson’s disease is to control symptoms. Options include dopamine precursors (such as levodopa), carbidopa, dopamine agonists (such as bromocriptine and pergolide), dopamine releasers (such as amantadine), anticholinergics, antidepressants, muscle relaxants, and surgery using techniques such as thalamotomy, pallidotomy (to target the
Figure 206-3 Degenerating axons in the human optic nerve in Alzheimer’s disease. Note several dark profiles, the largest of which has an extra myelin sheath about it (paraphenylene-diamine staining, epon embedded section).
Figure 206-4 Electron microscopy of the optic nerve in Alzheimer’s disease. Demonstrated are degenerating axons (D) and glial cells with lipofuscin (L), part of the process of degeneration. Normal myelinated axons (N) are also seen.
posterolateral part of the medial globus pallidus), subthalamic stimulation, or implants of embryonic tissues. Levodopa is the most widely used drug in Parkinson’s disease, but the response is variable, and after 5 years of therapy, up to 75% of patients have serious complications.
Huntington’s chorea may be treated with tricyclic antidepressants and antipsychotics. Attempts to replace the ?-aminobutyric acid deficiency in this disease have not been successful. No specific treatment exists for Sydenham’s chorea, but sedatives and antidopaminergic drugs may be used.
Agents under investigation for the treatment of Alzheimer’s disease are tetrahydroaminoacridine (cholinesterase inhibitor), acetyl levocarnitine, and physostigmine, as well as selegiline. However, none of these treatments shows as great a promise as the manipulation of hormones (estrogen) and nonsteroidal anti-inflammatory agents. Currently, no treatment for prion diseases exists; care must be taken to avoid iatrogenic spread from organ donation or accidental inoculation.
COURSE AND OUTCOME
Most neurodegenerative diseases have a long and relentless downward course. However, in many cases, the process may proceed very slowly (as in Alzheimer’s disease). In Parkinson’s disease the initial response to therapy is often excellent and may last 5–10 years. For hemifacial spasm or blepharospasm, newer modalities of treatment (such as injections of botulinum toxin) show excellent promise for control, but not cure, of the disorder.
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