Keywords
sarcoidosis, neurosarcoidosis, inflammation, immunosuppression, CSF, MRI, systemic disease, cranial neuropathies
Sarcoidosis was first described in 1877 by Sir Jonathan Hutchinson as a disease of the skin. At the turn of the century, Caesar Boeck termed the disease multiple benign sarkoid , because of its histologic similarity to sarcoma, and from this is derived the modern term sarcoidosis. Boeck also demonstrated the unifying pathologic feature of sarcoidosis as epithelioid cell granulomas that could involve different organs. Sarcoidosis is today recognized as a multisystem granulomatous disorder of unknown etiology. Typical presentations include bilateral hilar adenopathy, pulmonary infiltration, and skin and eye lesions.
Neurologic involvement in sarcoidosis was first reported in the early 1900s by Heerfordt, who described patients with cranial nerve palsies. Varied neurologic manifestations of sarcoidosis are now recognized to occur in 5 to 15 percent of patients. Neurosarcoidosis manifests in diverse ways, including with cranial neuropathies, aseptic meningitis, mass lesions, encephalopathy-vasculopathy, seizures, hypothalamic–pituitary disorders, hydrocephalus, myelopathy, peripheral neuropathy, and myopathy. Because its neurologic manifestations are so diverse, its etiology is unknown, and confirmative laboratory tests are lacking, neurosarcoidosis poses a clinical challenge. The diagnosis of neurosarcoidosis is usually based on the identification of a characteristic neurologic presentation in an individual with systemic sarcoidosis; however, neurologic manifestations are the presenting feature for approximately 50 percent of patients with sarcoidosis. Optimal management of patients with neurosarcoidosis requires an understanding of the broad clinical spectrum of the disorder, the best methods of confirming the diagnosis, and the full range of treatment options.
Sarcoidosis
The first internationally accepted definition of sarcoidosis remains of value today: “sarcoidosis is a multisystem granulomatous disorder of unknown etiology, most commonly affecting young adults and presenting most frequently with bilateral hilar adenopathy, pulmonary infiltration, skin or eye lesions. The diagnosis is established most securely when clinical and radiographic findings are supported by histologic evidence of widespread noncaseating epithelioid-cell granulomas in more than one organ.” Sarcoidosis usually presents between the ages of 20 and 40 years but can occur in children as well as in older populations. Its clinical manifestations are similar in all age groups. Intrathoracic structures are most commonly affected, followed by lymph node, skin, and ocular disease ( Table 49-1 ). Although a diagnosis of sarcoidosis is most secure when it is based on histologic confirmation, in around 30 percent of patients the diagnosis is based solely on clinical and radiologic findings.
| Manifestation | Frequency (%) |
|---|---|
| Intrathoracic | 87 |
| Hilar nodes | 72 |
| Lung parenchyma | 46 |
| Upper respiratory tract | 6 |
| Dermatologic | |
| Skin | 18 |
| Erythema nodosum | 15 |
| Ocular | 15 |
| Lacrimal gland | 3 |
| Parotid gland | 6 |
| Splenomegaly | 10 |
| Peripheral lymphadenopathy | 28 |
| Bone | 3 |
| Cardiac | 3 |
| Hepatomegaly | 10 |
| Hypercalcemia | 13 |
| Neurologic | 5–15 |
| Hematologic, endocrinologic, gastrointestinal, and genitourinary | Rare |
Involvement of any organ by sarcoidosis is possible and may occur with or without symptoms. It is estimated that 20 to 40 percent of patients are asymptomatic at presentation, their disease being discovered by routine chest radiography. In fewer than 10 percent of patients, the onset of symptoms is neither systemic nor pulmonary. Neurologic presentations of sarcoidosis are in this category.
Many laboratory abnormalities have been described in sarcoidosis, but no specific or highly sensitive diagnostic test is available. Active sarcoidosis may cause an elevation in serum angiotensin-converting enzyme (ACE), which can then serve as a marker of systemic disease activity, but serum ACE is nonspecific, and often elevated in patients with other conditions such as liver disease, diabetes mellitus, hyperthyroidism, systemic infection, malignancy, and Gaucher disease.
Most patients with systemic sarcoidosis have a good prognosis. For approximately two-thirds, the disease resolves spontaneously without major difficulties. This benign course is most common in asymptomatic patients with only hilar adenopathy on chest radiographs, who have a 70 to 80 percent chance of spontaneous remission. However, for one-third of patients, symptoms persist or the disease progressively worsens. Pulmonary dysfunction is the major issue for most patients with a persistent or progressive clinical course. Mortality in systemic sarcoidosis is reported as below 5 percent. Deaths are most often due to respiratory failure; neurologic and cardiac involvement is also associated with a relatively high risk of death.
The basis of therapy for all forms of sarcoidosis is corticosteroids. However, debate continues as to the precise indications for treatment, because many patients are asymptomatic at the time of presentation and the rate of spontaneous resolution of sarcoidosis is high. In addition, the clinical presentations and course are so varied that treatment studies—particularly large, well-controlled studies— are not available. Corticosteroid treatment seems most clearly indicated for patients with significant functional impairment in any organ system, particularly with major pulmonary, cardiac, ocular, or central nervous system (CNS) involvement. Alternative immunosuppressive treatment options are discussed in detail later.
Pathophysiology
Although the precise etiology of sarcoidosis remains unknown, major strides have been made in understanding its pathogenesis. There is strong evidence that sarcoidosis is caused by heightened immune processes at sites of disease activity. This contrasts sharply with earlier concepts that had related sarcoidosis to impaired immunity and to generalized anergy.
Current understanding of the immunopathology of sarcoidosis derives largely from studies of pulmonary sarcoidosis. The initial lesion in pulmonary sarcoidosis is an alveolitis, an inflammation of the alveolar structures of the lung ( Fig. 49-1 ). Undoubtedly, processes similar to those in the lung underlie the pathogenesis of other forms of sarcoidosis, including neurosarcoidosis ( Fig. 49-2 ).
Sarcoidosis can be thought of as an inflammatory response to an as yet unidentified foreign antigen. The central pathologic hallmark of sarcoidosis, the granuloma, consists of macrophages, macrophage-derived epithelioid cells, and multinucleated giant cells that secrete cytokines ( Fig. 49-3 ). Surrounding this central core are CD4 + and CD8 + T lymphocytes, B lymphocytes, plasma cells, and fibroblasts .
Unfortunately, the inciting antigen or antigens remain unknown. Among the suspected causes have been infectious agents, organic agents such as pine pollen, and inorganic substances. Of the various possible infectious causes, mycobacterial infections have received the most attention. More recently, Propionibacterium species have also been implicated.
In reaction to an antigen, monocytes and macrophages form granulomas, and ultimately irreversible obliterative fibrosis can develop. Small foci of ischemic necrosis occur, probably as a consequence of in situ thrombosis due to perivascular inflammation. Importantly, granulomas are not specific for sarcoidosis, and nearly identical lesions occur in a variety of other conditions that must be excluded before a diagnosis of sarcoidosis can be made.
The pathology of neurosarcodosis is characterized by noncaseating granulomas and the accompanying diffuse mononuclear cell infiltrates that can be found in any part of the neuraxis, including peripheral nerve or muscle. The most common site of inflammation is the meninges, especially in the basal region of the brain ( Figs. 49-4 and 49-5 ). Sarcoid granulomas may be widely distributed or concentrated in one or more areas to form a mass lesion. Although sarcoidosis is not usually considered to be a primary vasculitis, arteriolar and venous infiltration can occur and may lead to infarction. The granulomatous inflammation found pathologically may correlate directly with clinical deficits or may be subclinical.
Inflammation affecting primarily the leptomeninges may spread along Virchow–Robin perivascular spaces to invade the brain or spinal cord, or it may remain more localized, involving the cranial nerves. Inflammation can also extend to the cerebrospinal fluid (CSF)-containing spaces, leading to hydrocephalus. Brain or spinal cord disease may appear as discrete granulomatous mass lesions or a diffuse encephalopathy-vasculopathy. The hypothalamic region is the most common site of parenchymal disease.
Granulomas can also be found in the epineurium and perineurium of peripheral nerves. The endoneurium may contain a mononuclear cell infiltrate. Perivascular and vascular inflammation may be seen in the epineurial and perineurial vessels. Nerve fibers of all sizes can be affected; a predominantly axonal neuropathy is usual, with only minor segmental demyelination.
Muscle pathology is common in sarcoidosis. Muscle biopsy of symptomatic patients reveals typical noncaseating granulomas. More diffuse inflammation can occur, with muscle fiber degeneration along with regeneration and fibrosis. Asymptomatic noncaseating granulomas are found in as many as one-half of all patients with systemic sarcoidosis undergoing muscle biopsy.
Epidemiology
The prevalence of sarcoidosis is estimated to be on the order of 60 per 100,000 population, with an annual incidence of approximately 11 per 100,000 population. However, the exact prevalence and incidence are difficult to validate because there is no single confirmatory diagnostic test. Sarcoidosis can occur at any age, although its peak is found in the third and fourth decades.
Population differences for sarcoidosis have been described. In the United States, its incidence is increased in blacks compared with whites; the disease also seems to be more severe in blacks. Certain areas of the world, such as Sweden, have a higher incidence of sarcoidosis, whereas it is quite rare in other areas, such as China or Southeast Asia. These observations raise the possibility of a genetic predisposition to the development of sarcoidosis, which does seem to occur with greater likelihood in some families. As yet, no well-defined genetic pattern has emerged and no consistent mode of inheritance is recognized. An increasing number of studies address candidate genes that may predispose to the development of sarcoidosis.
Neurologic Manifestations
Neurologic symptoms are the presenting feature of sarcoidosis in around 50 percent of individuals with neurosarcoidosis. Some three-fourths of patients with neurologic disease present within 2 years of developing symptomatic systemic sarcoidosis. The approximate frequency of the various neurologic complications is presented in Table 49-2 . Only rarely do patients with neurosarcoidosis have no evidence of even asymptomatic disease in other organ systems, such as the lungs. One-third to one-half of patients with neurosarcoidosis will develop more than one neurologic manifestation of their disease.
| Clinical Manifestation | Approximate Frequency (%) |
|---|---|
| Cranial neuropathy | 50–75 |
| Facial palsy | 25–50 |
| Aseptic meningitis | 10–20 |
| Hydrocephalus | 10 |
| Parenchymal disease | |
| Endocrinopathy | 10–15 |
| Mass lesion(s) | 5–10 |
| Encephalopathy-vasculopathy | 5–10 |
| Seizures | 5–10 |
| Myelopathy | 5 |
| Neuropathy | 5–10 |
| Myopathy | 10 |
Cranial Neuropathy
The most frequent neurologic complication of sarcoidosis is cranial neuropathy, occurring in approximately three-quarters of patients with neurosarcoidosis. Any cranial nerve can be affected. More than one-half of patients will have involvement of multiple cranial nerves.
Olfactory nerve dysfunction may occur secondary to meningeal sarcoidosis involving the subfrontal region. However, anosmia or hyposmia may also result from local nasosinus granulomatous invasion. Optic nerve involvement is much less frequent than other ocular manifestations of sarcoidosis such as uveitis. Optic neuropathy can present with visual loss that is acute, subacute, or chronic and can be painful or painless. The visual loss may be due to bulbar or retrobulbar invasion of the optic nerve by granulomas, compression of the optic nerve by a granulomatous mass, or optic atrophy. Optic disc edema may be secondary to papilledema from sarcoidosis-induced increased intracranial pressure or result from direct local invasion by sarcoid. A chiasmal syndrome also has been reported.
Disorders of ocular motility may follow involvement of the oculomotor , trochlear , or abducens nerves . Typically, these nerves are damaged in their extra-axial course in the subarachnoid space as they traverse the meninges. However, they may also be involved in local orbital disease, and rarely the brainstem nuclei and eye movement pathways can be affected. Occasionally, pupillary dysfunction is seen. Uncommonly, disordered ocular motility is due to sarcoidosis involving the extraocular muscles themselves.
Trigeminal nerve disease may present as facial numbness or, rarely, trigeminal neuralgia. Headache may also represent trigeminal nerve dysfunction intracranially. Involvement of the muscles of mastication is unusual.
Of the cranial nerve syndromes, peripheral facial nerve palsy is the most common, and it is also the single most frequent neurologic manifestation of sarcoidosis. It develops in 25 to 50 percent of all patients with neurosarcoidosis. Although the condition is usually unilateral, bilateral facial palsy can occur, presenting with either simultaneous or sequential paralysis. More than half of all patients with facial palsy also have other forms of nervous system involvement. In patients with an isolated facial palsy, the spinal fluid typically is normal, but when other manifestations of neurosarcoidosis are present, the CSF is abnormal in 80 percent of patients. The specific cause of facial nerve palsy in sarcoidosis is variable. Rarely, the facial palsy is caused by parotid inflammation. More commonly, the nerve is compromised as it traverses the meninges and subarachnoid space, or facial paresis is due to intra-axial inflammation of the facial nerve. In general, the prognosis for the facial palsy is good, with more than 80 percent of patients having recovery of function.
Eighth cranial nerve involvement is the second most common cranial neuropathy occurring in sarcoidosis. Inflammation may involve the auditory or vestibular portions of the nerve. Loss of hearing or vestibular dysfunction may be sudden or insidious and often fluctuates over time. If hearing loss occurs, it is typically of the sensorineural type. As with facial nerve palsy, bilateral eighth nerve disease may occur, and either bilateral seventh or eighth nerve dysfunction is suggestive of neurosarcoidosis.
Glossopharyngeal and vagus nerve involvement causes dysphagia and dysphonia. Hoarseness is more commonly due to laryngeal nerve dysfunction from intrathoracic disease than CNS inflammation involving the vagus nerve.
Eleventh and twelfth cranial nerve disease may occur but seems to be rare.
Meningeal Disease
Meningeal disease occurs in approximately 10 to 20 percent of patients with neurosarcoidosis and can present as aseptic meningitis or, less commonly, as a meningeal or dural-based mass lesion. Aseptic meningitis is characterized by headache, meningismus, and sterile CSF with usually a mononuclear pleocytosis that can be recurrent. Hypoglycorrhachia, or low CSF glucose concentration, is occasionally found, and there is often an elevation of the CSF protein concentration. It is not uncommon for there to be asymptomatic chronic meningitis within the context of other CNS manifestations of sarcoidosis. When meningeal sarcoid mass lesions occur, they may mimic intracranial tumors, such as meningiomas ( Fig. 49-6 ).
Hydrocephalus
Hydrocephalus is noted in about 10 percent of neurosarcoidosis patients and may have fatal consequences. Patients with acute hydrocephalus may die suddenly of increased intracranial pressure, and even patients with chronic hydrocephalus have the potential for acute decompensation. Patients with hydrocephalus characteristically present with headache, altered mentation or consciousness, and impaired gait. On examination, papilledema or other signs of raised intracranial pressure may be found. Acute decompensating hydrocephalus is a medical emergency that necessitates prompt diagnosis and treatment. Once clinically suspected, the diagnosis of hydrocephalus is best substantiated with imaging studies, such as cranial computed tomography (CT) or magnetic resonance imaging (MRI). A diagnostic lumbar puncture has been associated with sudden neurologic deterioration in some patients with hydrocephalus.
Chronic basilar meningitis with obliteration of subarachnoid CSF flow is a major cause of communicating hydrocephalus. In addition, infiltration of the ventricular system by granulomas, granulomatous compression of the aqueduct, or outlet obstruction of the fourth ventricle by granulomas may cause noncommunicating hydrocephalus.
Parenchymal Disease
Parenchymal brain disease is reported in about 50 percent of patients with neurosarcoidosis and can present in several forms. Hypothalamic dysfunction is the most common manifestation of CNS parenchymal disease.
Endocrine Disorders
Any of the neuroendocrinologic systems can be affected by sarcoidosis due to either a hypothalamic or pituitary granulomatous mass or a more diffuse local encephalopathy. Given the predilection of sarcoidosis for the basal meninges ( Fig. 49-7 ), the relative frequency of such endocrinologic disturbances is not surprising. Potential endocrinologic manifestations include thyroid disorders, disorders of cortisol metabolism, and sexual dysfunction. An elevated serum prolactin level, found in 3 to 32 percent of patients with sarcoidosis, may be an indication of hypothalamic dysfunction. Because neuroendocrinologic involvement is relatively common in individuals with CNS neurosarcoidosis, patients with more than just an isolated facial palsy probably merit a thorough evaluation with specific attention to hypothalamic hypothyroidism, hypocortisolism, and hypogonadism.
Hypothalamic disorders vary in their effect on vegetative functions. A disorder of thirst is the most common hypothalamic disorder related to neurosarcoidosis and is attributed to a change in the hypothalamic osmostat. More rarely, the syndrome of inappropriate secretion of antidiuretic hormone or diabetes insipidus occurs. Neurosarcoidosis-induced disruptions of hypothalamic function can also cause disorders of appetite, libido, temperature control, weight regulation, and sleep. Similar manifestations may occur from pituitary involvement.
Mass Lesions
An intraparenchymal lesion due to sarcoidosis may present as an isolated mass ( Fig. 49-8 ) or masses in any cerebral area or as multiple cerebral nodules. Such nodules may represent an inflammatory reaction in the Virchow–Robin spaces. Subdural plaque-like masses may also occur and are discussed later. Calcifications may be seen, mimicking infection or tumor. Although intraparenchymal mass lesions were historically considered rare, CT and MRI have shown parenchymal disease to be more frequent. The symptoms and signs in individual cases depend on the location of the lesion.
Encephalopathy-Vasculopathy
The diffuse encephalopathy and vasculopathy associated with neurosarcoidosis are not well understood. It is often difficult, both clinically and pathologically, to differentiate clearly between these entities and they frequently coexist. It is best therefore to consider them as a single overlapping entity, while recognizing that in individual patients, one form or the other may predominate.
The diffuse encephalopathy-vasculopathy found in neurosarcoidosis can involve the cerebral hemispheres or posterior fossa. Patients may experience delirium, personality change, or isolated memory disturbance as a result of focal or diffuse parenchymal inflammation ( Fig. 49-9 ). Clinical findings correlate with the extent of enhancement on imaging studies including hyperintensity on T2-weighted or fluid-attenuated inversion recovery (FLAIR) MRI sequences.
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