Neurosarcoidosis

Surabhi Ranjan MBBS ( Dr. Ranjan of the National Cancer Institute has no relevant financial relationships to disclose. ) Amber J Giles PhD ( Dr. Giles of National Cancer Institute has no relevant financial relationships to disclose. ) Deric M Park MD ( Dr. Park of the National Cancer Institute has no relevant financial relationships to disclose. ) Anthony T Reder MD, editor. ( Dr. Reder of the University of Chicago served on advisory boards and as a consultant for Bayer, Biogen Idec, Caremark Rx, Genentech, Genzyme, Novartis, Malinkrodt, Serono, and Teva-Marion.) Originally released May 8, 1995; last updated August 25, 2017; expires August 25, 2020

Sarcoidosis is an inflammatory, multisystem disorder of unknown etiology that classically is characterized by formation of noncaseating granulomas. The disease can be self-limiting or chronic, with frequent episodes of relapse and remission. The lungs are affected most commonly, but the skin, eyes, liver, and lymph nodes also may be involved. Involvement of the central nervous system (CNS) is a less common but severe and potentially devastating manifestation of sarcoidosis. Nervous system involvement usually occurs in patients who have had significant systemic involvement and are known to have active disease. However, it is possible for patients to have isolated neurosarcoidosis. In these cases, patients may present to the neurosurgeon after diagnostic imaging has identified a lesion of the brain or spinal cord. These lesions can mimic brain and spinal cord neoplasms, pituitary adenoma, meningioma, and basal meningitis. The neurosurgeon must have a high degree of clinical suspicion to diagnose this disease, avoid delays in instituting appropriate therapy, and avoid the pitfall of unnecessary surgery when other diagnostic and therapeutic options exist.

Prevalence
Sarcoidosis affects people of all races, ages, sexes, and geographic locations. Most patients are diagnosed between 20 and 40 years of age. The disease is relatively common, with a prevalence of 10 to 40 cases per 100,000 population in the United States and Europe. In the United States, it is more common in African-Americans compared with Caucasians (ratio ranges from 10:1 to 17:1) and is mor common in individuals who live in the Southeast. There is a slight female predilection. Nervous system involvement is seen in 5% to 15% of all patients with sarcoidosis, but it is very likely that its prevalence is underestimated due to subclinical forms of the disease. Postmortem studies indicate that as many as 25% of patients with systemic sarcoidosis have subclinical CNS involvement.

Pathophysiology
The exact cause of sarcoidosis is unknown. The noncaseating granulomas that are the hallmark of the disease are composed of mononuclear inflammatory cells, including epithelioid macrophages, lymphocytes, monocytes, and fibroblasts. The currently available evidence suggests that sarcoidosis is the result of an exaggerated cellular immune response that causes a preferential activation of the Th1 T lymphocyte cell line. Three possible hypotheses for the overactivation of the Th1 cell line have been documented: (1) persistent antigens that trigger only the Th1 cell arm of the immune system; (2) inadequate suppression of the Th1 cell line; or (3) inherited or acquired differences in immune response genes that lead to an exaggerated Th1 response. Mycobacterium and Propionibacterium spp. have been implicated in the pathogenesis of disease, but there is no solid evidence linking them to the development of sarcoidosis. The initial event in the pathogenesis is T lymphocyte proliferation and activation of the Th1 cell line by interleukin-4 (IL-4) and CD28. These Th1 cells accumulate in the affected tissue and release mediators such as interferon-γ and other cytokines that attract macrophages. This cascade of events leads to the formation of granulomas, which distort the normal architecture of the tissue by their bulk presence, thereby causing organ dysfunction.

Clinical Manifestations
Patients with neurosarcoidosis usually develop signs and symptoms within 2 years of onset of systemic disease. However, in some patients, neurologic symptoms may be the presenting manifestation. The symptoms of neurosarcoidosis are caused by the formation of granulomas within the nervous tissue, and they depend, therefore, on the location of nervous system involvement. Most patients in whom nervous system involvement is the presenting sign also will have evidence of pulmonary involvement.

Cranial Neuropathies
Cranial nerve palsies are the most common presentation of neurosarcoidosis, with the facial nerve most likely to be involved. Peripheral facial nerve palsy can be unilateral or bilateral and can be associated with parotiditis. Heerfordt syndrome, which is associated with acute neurosarcoidosis, is characterized by facial nerve palsy, parotid gland enlargement, anterior uveitis, and fever. It is not known whether this syndrome is a manifestation of neurosarcoidosis or systemic sarcoidosis. The usual mechanism behind this syndrome is direct nerve compression by parotid gland swelling, although a few cases in which there was a lesion within the facial canal, with related taste disturbances, have been reported.
The optic nerve is the second most commonly involved cranial nerve. Symptoms result from either direct infiltration of the nerve or compression of a granuloma in sur-rounding tissues, either of which may lead to visual field deficits, blurry vision, or pupillary defects. Other cranial nerves are involved less commonly. Dysphagia and dysphonia can occur when the glossopharyngeal and vagus nerves are involved. Involvement of cranial nerve VIII can present with vertigo and hearing loss, which is bilateral in 75% of patients.

Hydrocephalus
Fortunately, hydrocephalus is uncommon in patients with neurosarcoidosis. When it does occur, it can be either communicating or noncommunicating. It can result from meningeal involvement, infiltration of the ependyma or choroid plexus, or intrinsic obstruction of the ventricular system. Typically, an increase in the protein content in the cerebrospinal fluid (CSF) causes obstruction of CSF flow secondary to decreased absorption in the arachnoid granulations. Signs and symptoms are typical of hydrocephalus of any etiology, and imaging studies show only nonspecific changes such as ventriculomegaly, transependymal flow, and capping of the frontal horns. In chronic cases, imaging may reveal irregular ventricular contour due to loculations. In some cases, septation of the ventricles can occur, and areas of the ventricular system can be isolated by adhesions. In these cases, imaging may reveal focal areas of increased ventricular size, even in the presence of a functioning shunt ( Figure 1).

Meningeal Disease
Involvement of the basal leptomeninges is fairly common in neurosarcoidosis and may present as aseptic meningitis or a mass lesion. Aseptic meningitis usually is asymptomatic, but it can have symptoms that mimic bacterial meningitis. CSF examination reveals mild to moderate pleocytosis (usually lymphomonocytic, up to 200 cells/µL) in 70% of patients, elevated protein content in 80% of patients, and, rarely, a reduced glucose ratio (10% of patients). It is important to rule out a medically treatable infectious cause. On imaging studies, the meninges often are thickened, resembling chronic meningitis. Cranial nerve involvement can occur in meningeal disease. Although mass lesions are uncommon, thickened, The continuing education activity in Contemporary Neurosurgery is intended for neurosurgeons, neurologists, neuroradiologists, and neuropathologists. Contemporary Neurosurgery is independent and not affiliated with any organization, vendor, or company. Opinions expressed do not necessarily reflect the views of the Publisher, Editor, or Editorial Board. A mention of products or services does not constitute endorsement. All comments are for general guidance only; professional counsel should be sought for specific situations. Indexed by Bio-Sciences Information Services. For information on CME accreditation, see back page. enhancing meninges can mimic an en plaque meningioma on imaging studies.

Intracranial Parenchymal Disease
The most common parenchymal manifestation of neurosarcoidosis is sarcoid encephalopathy, which causes a wide range of symptoms, including seizures, mood disturbances, cognitive impairment, psychosis, and personal-ity changes. Cerebral vasculitis has been documented, with presentation as subarachnoid hemorrhage being more common than stroke. Diffuse vasculopathy can cause dementia, psychosis, and epileptic seizures.
Parenchymal disease in neurosarcoidosis can be focal, multifocal, or diffuse, and it can involve the cerebrum, cerebellum, or brainstem. The clinical features of sarcoid lesions in these regions are similar to those of any other space-occupying intracranial mass. Multifocal white matter lesions can occur, resembling vascular changes on imaging studies. Presentation as an isolated intracerebral tumor-like mass can occur. Infratentorial lesions are less common, and they are more likely to occur in the cerebellum than in the brainstem.
The hypothalamus, infundibulum, and posterior lobe of the pituitary commonly are involved, due to either direct tissue involvement or changes related to adjacent basal meningeal disease, resulting in enlargement of these structures. Enhanced MRI can show the enlargement of these structures; the appearance may mimic a pituitary tumor or a glioma (Figure 2). Such a finding often triggers a neurosurgical referral for resection of a suspected pituitary adenoma. As with other pituitary lesions, symptoms include visual field defects and various endocrinopathies such as diabetes insipidus, hyperprolactinemia due to a stalk effect, and hypogonadism.

Spinal Cord Lesions
Spinal cord involvement can be extradural, intradural extramedullary, or intradural intramedullary. Cervical and thoracic intramedullary lesions are the most common. Lesions commonly mimic spinal cord neoplasms both clinically and radiologically. Imaging studies reveal enhancement of the lesions, enlargement of the cord, and surrounding edema. Sensory and motor disturbances progress over time and are clinically and radiographically indistinguishable from neoplasm. Great caution must be exercised in making the decision to approach these lesions surgically, because nonsurgical techniques can result in resolution. In exceptional cases, the neurosurgeon may be called upon to obtain biopsy specimens from these lesions.

Peripheral Neuropathies
Peripheral nerve involvement in neurosarcoidosis manifests as paresthesias and radiculopathy. All patterns of peripheral neuropathies have been observed in neurosarcoidosis, including mononeuropathy, mononeuropathy multiplex, polyneuropathy, and a Guillain-Barré-like syndrome. Neuropathies can be sensorimotor, motor, or sensory and can involve small or large fibers. Electromyelography (EMG) and nerve conduction studies can be used to confirm neuropathy, demonstrating slowing of the motor nerve conduction velocities and abnormal sensory nerve conduction. The diagnosis of small fiber neuropathy is easy to miss because few objective measures are available to identify and quantify the neuropathy. It may cause autonomic dysfunction and also has been suggested as a causative lesion in restless legs syndrome.

Skeletal Muscle Involvement
Muscle involvement in systemic sarcoidosis is extremely common and usually asymptomatic. Symptomatic patients (approximately 1% to 2% of these patients) may describe signs and symptoms that seem to indicate neurologic involvement, when in actuality the granulomas are in the muscle and connective tissue itself. Patients with muscular involvement typically present with weakness, pain, and tenderness of the involved muscles to palpation. However, some patients may exhibit firm, palpable nodules and cramps, with atrophy and contractures in advanced cases. Acute myositis is rare. EMG can be performed in suspected cases and may demonstrate myopathic potentials; however, in most cases, the EMG results are normal. Muscle biopsy can help confirm the diagnosis.

Diagnosis
Systemic sarcoidosis has a variable course. Two thirds of patients have a monophasic illness; the rest have a chronic form and progress with remissions and relapses. Patients with nervous system involvement tend not to have remissions of disease. Therefore, it is extremely important to recognize and diagnose neurosarcoidosis early in the course of the disease process, because early treatment can help prevent morbidity and mortality.
Zajicek et al. proposed diagnostic criteria for three categories of neurosarcoidosis: certain neurosarcoidosis; probable neurosarcoidosis; and possible neurosarcoidosis. In this system, certain neurosarcoidosis is diagnosed when biopsy of nervous tissue reveals positive histologic identification of sarcoidosis (noncaseating granulomas) and other possible diagnoses are excluded. Probable neurosarcoidosis is suspected when the clinical presentation suggests neurosarcoidosis, laboratory evidence demonstrates signs of CNS inflammation, other diagnoses are excluded, and there is evidence of systemic sarcoidosis. Signs of CNS inflammation were defined in this system as elevated CSF protein, presence of oligoclonal bands, or MRI evidence compatible with neurosarcoidosis. Evidence of systemic sarcoidosis was defined as positive histology or at least two indirect markers including gallium scan, chest radiography, and serum angiotensin-converting enzyme. Possible neurosarcoidosis is diagnosed when it is suspected by clinical presentation, other diagnoses are eliminated, but the criteria for certain or probable neurosarcoidosis are not met.
It is crucial to exclude other treatable causes of their symptoms, such as neoplasia or infection, in patients with known systemic sarcoidosis and clinical signs of neurological involvement. The diagnosis of neurosarcoidosis also should be questioned in patients who do not respond to therapy. In patients who have undiagnosed systemic sarcoid disease, neurosarcoidosis can be difficult to diagnose. In these cases, a work-up for sarcoidosis should be under-taken, because there is lower morbidity with biopsy of other sites than with biopsy of neural tissue. Up to 80% of patients with neurosarcoidosis have manifestations outside the nervous system, although it may not be clinically evident. A thorough history and review of systems should be performed, as well as physical examination including the skin, lymph nodes, and pulmonary evaluation.
Tests that can help in the diagnosis of systemic disease include chest and thoracic imaging with radiographs and CT, gallium-67 scan, and bronchoalveolar lavage. These tests, as well as organ function evaluation (e.g., pulmonary function tests, ophthalmologic evaluation, and imaging of suspected areas of involvement) can identity potential systemic sites for biopsy. Serum angiotensin-converting enzyme also is a useful indicator of systemic sarcoidosis. The Kveim test historically has been used to detect systemic sarcoidosis, but it is available only in limited institutions due to safety concerns. Other tests that are not specific for sarcoidosis, but may aid in its diagnosis, include MRI of the muscles, positron emission tomography to reveal changes in metabolism of the tissue, 24-hour urine calcium, visual evoked potentials, auditory evoked potentials, somatosensory evoked potentials, nerve conduction studies, and EMG.
CSF analysis in suspected neurosarcoidosis also can be performed as part of the initial work-up. Elevation of ACE in the CSF has a sensitivity of 50% for neurosarcoidosis. Other reported abnormalities include normal to low glucose, elevated immunoglobulin G, and presence of oligoclonal bands; elevation of lysozyme and β2-microglobulin also have been reported.
Imaging is important in both the diagnosis and followup care of patients with neurosarcoidosis. Imaging is never specific for neurosarcoidosis, and a normal imaging study does not exclude the diagnosis. MRI is the most sensitive imaging study for neurosarcoidosis. The typical imaging feature is irregular leptomeningeal thickening and enhancement, especially around the base of the brain, which can include the pituitary and infundibulum. Other common findings include periventricular abnormalities, white matter lesions, hydrocephalus, and cranial nerve enhancement. MRI findings in the spine vary depending on the stage of the lesion. An infiltrating lesion with meningeal and intramedullary enhancement should alert the radiologist to possible sarcoidosis or other granulomatous diseases.
When the systemic work-up of sarcoidosis is negative, direct biopsy of the nervous tissue may be necessary to make a definitive diagnosis. However, in no case should complete excision of the lesion be attempted. The histologic finding of noncaseating granulomas in neural tissue confirms the diagnosis of neurosarcoidosis.

Treatment
Most authors recommend initiating drug therapy in neurosarcoidosis as soon as possible to avoid irreversible damage to nervous tissue. However, no clear guidelines or indications for the initiation of drug therapy have been established. The goal of therapy is to decrease the damage caused by fibrosis and ischemia of the tissue. The first-line treatment in neurosarcoidosis is corticosteroids. This therapy has not been shown to change the course of disease or improve long-term outcomes, but it alleviates acute symptoms. Treatment selection and duration depends on the patient's clinical manifestations, clinical course, and adverse treatment effects. Typical treatment recommendations for facial palsy include 1 week of prednisone followed by a 1week taper. Parenchymal disease is treated with high-dose prednisone for 2 to 4 weeks, followed by a taper. Alternatively, severe acute neurological symptoms can be treated by IV methylprednisolone for 3 days, followed by 2 to 4 weeks of prednisone with taper. One third of patients are found to be refractory to corticosteroid therapy and require immunosuppressive or immunomodulatory therapy. These drugs can be used in conjunction with corticosteroids, or independently when corticosteroids are contraindicated or are not tolerated. Potential agents include azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetil, cyclosporine, chlorambucil, cladribine, hydroxychloroquine, pentoxyfillin, thalidomide, and infliximab. Drug selection should include consideration of safety, adverse affects, location of drug metabolism, and drug toxicity. The most widely used and reviewed drug for sarcoidosis has been methotrexate; reports on the efficacy of infliximab are increasing.
If medical treatment fails to induce remission of disease, radiation therapy may be considered. Several successful cases with minimal adverse sequelae have been reported. Endocrinopathies arising from involvement of the hypothalamic-pituitary axis also may require treatment.
Surgery typically is indicated for neurosarcoidosis for diagnostic purposes rather than therapeutic benefit. Therapeutic indications include hydrocephalus or life-threatening mass lesions causing increased intracranial pressure. Some patients with hydrocephalus may require placement  of a ventriculoperitoneal shunt. Use of stereotactic guidance may be required to optimize shunt placement. Often, multiple shunts are required. Endoscopic fenestration of intraventricular adhesions and septae can be used to re-establish communication within the ventricular system. Care must be taken when using the endoscope, because the inflammatory changes in the ventricle wall may obscure normal landmarks. Use of the stereotactic system, with either CT or preferably MRI guidance, can greatly enhance the safety of endoscopic fenestration. Shunt malfunction is common, and multiple revision procedures often are needed. In addition, shunt placement in patients with neurosarcoidosis can be associated with an increased infection rate due to immunosuppression from drug therapy. Third ventriculostomy usually is not indicated because impaired absorption of CSF, which is a major component of the hydrocephalus in these patients, is not addressed by this technique.

Conclusion
Neurosarcoidosis can present with a variety of signs and symptoms, depending on the location of nervous system involvement. A high index of suspicion and a search for sarcoidosis at sites outside the nervous system are required for an early diagnosis. An algorithm for the workup of neurosarcoidosis is provided in Figure 3. Direct biopsy of nervous tissue may be required for diagnostic purposes; however, biopsy should be performed only after extensive medical and laboratory testing. Aggressive surgical intervention rarely is indicated, because treatment with corticosteroids usually provides a favorable outcome. However, ventriculoperitoneal shunting may be appropriate in patients with hydrocephalus secondary to neurosarcoidosis. Large prospective studies are needed to devise a clearcut standard of care in these patients, as well as to determine appropriate long-term follow-up recommendations.