John C. M. Brust
Sarcoidosis is a multisystem, granulomatous disease of unknown cause. Sarcoid granulomas resemble those of tuberculosis but lack tubercle bacilli or caseation, although central necrosis is sometimes seen. Active lesions contain epithelioid and multinucleate giant cells; such lesions may resolve but more often become fibrotic.
Sarcoidosis occurs worldwide, with estimated incidence ranging from 3 to 50 cases per 100,000 population. Incidence is especially high among African-Americans, in whom the disease is more likely to be chronic and severe. Susceptibility to sarcoidosis is polygenetically influenced, and different polymorphisms involving the major histocompatibility complex predict the severity of disease. Onset is most often in the third or fourth decade, but the disease also affects children and the elderly. Sarcoid granulomas are attributed to heightened immune responses to unidentified exogenous antigens. An infectious cause remains elusive. Sarcoidosis is described in patients with HIV infection treated with highly active antiretroviral therapy (HAART), reflecting what is known as the immune reconstitution inflammatory syndrome. Sarcoidosis has also developed following interferon alpha therapy for hepatitis C.
The disorder is mediated primarily by CD4+ T-helper 1 (Th1) cells and mononuclear phagocytes, with participation of numerous cytokines and chemokines that include interleukins, adhesion molecules, interferon gamma, tumor necrosis factor (TNF)-alpha, and transforming growth factor-beta. Lesions may affect any organ, especially lungs, lymph nodes, skin, bones, eyes, and salivary glands. Although nearly 20% of patients with neurosarcoidosis lack systemic symptoms or signs, workup reveals systemic sarcoidosis in as many as 97%. When nervous system disease complicates systemic sarcoidosis, it usually does so within 2 years of onset.
In the central nervous system (CNS), sarcoid granulomas most often involve the meninges, especially at the base of the brain, with secondary infiltration of cranial nerves and obstruction of cerebrospinal fluid (CSF) flow. Lesions tend to be perivascular and thereby may spread intraparenchymally, frequently affecting the hypothalamus and, less often, other CNS structures, including the spinal cord. Granulomas also occur in peripheral nerves and muscle.
Given the unpredictable dispersal of lesions, sarcoidosis is a clinically protean disease systemically and neurologically. Nearly 50% of patients with neurosarcoidosis have more than one neurologic complication, with relative frequencies varying among different clinical series (Table 72.1).
TABLE 72.1 Symptoms and Signs in Neurosarcoidosis
Although any cranial nerve may be affected, the most frequently affected is the seventh, sometimes in association with uveitis and parotitis (uveoparotid fever) but usually alone, thus suggesting Bell palsy. Facial weakness may be bilateral and either simultaneous or sequential and may recur after recovery. Eighth nerve involvement, the second most common cranial neuropathy in sarcoidosis, causes deafness (often bilateral) and vestibular symptoms. Optic nerve involvement causes papillitis or retrobulbar neuritis and eventually optic atrophy. Trigeminal nerve involvement causes either sensory loss or neuralgia.
Granulomas involve the hypothalamus more often than the pituitary, thereby producing combinations of endocrinologic and nonendocrinologic symptoms that include diabetes insipidus, decreased libido, galactorrhea, amenorrhea, abnormal sleep patterns, altered appetite, temperature dysregulation, and abnormal behavior. Cerebral granulomas may be scattered diffusely, with some too small to be detected on computed tomography (CT) or magnetic resonance imaging (MRI), or they may consist of one or larger masses that mimic a brain neoplasm. Seizures are common in such patients. Cognitive and behavioral symptoms include dementia, depression, psychosis, hallucinations, and delirium. Rarely, sarcoid vasculitis causes cerebral infarction (or even intracranial hemorrhage) in a pattern clinically and pathologically indistinguishable from what is commonly called granulomatous angiitis of the nervous system. Autoantibodies to endothelial cells have been identified in patients with neurosarcoidosis.