NS can occur in the subfrontal region and cause an olfactory neuropathy and anosmia. Involvement of the optic nerve is relatively common and is seen in as many as 5% of patients.⁸ Funduscopic examination can demonstrate optic atrophy, optic disc swelling or papilledema, or retrobulbar optic neuritis.⁹ In patients with visual or optic abnormalities, however, it must be remembered that sarcoidosis affects the eye as a uveitis far more often than the optic nerve.

Dysfunction of eye movements because of involvement of cranial nerves III, IV, or VI is seen infrequently in NS. Trigeminal neuropathy causing facial numbness or pain is also quite rare. In contrast, cranial nerve VIII dysfunction causing deafness or vestibular symptoms can occur in as many as 20% of patients, thus making it the second most common cranial neuropathy associated with NS. In fact, the presence of bilateral seventh and eighth nerve abnormalities in a patient without any obvious mass lesions is highly suggestive of NS. Dysphagia or dysphonia secondary to glossopharyngeal or vagal nerve involvement, respectively, occasionally develops.

Symptoms of meningeal irritation, including headache, nuchal rigidity, nausea, and rarely, fever, have been reported to occur in 3% to 26% of patients with NS.⁸ Symptomatic meningeal involvement can take the form of either acute aseptic meningitis or chronic meningitis. Cerebrospinal fluid (CSF) studies generally reveal a mild mononuclear pleocytosis with increased protein. Glucose may be normal or decreased, with no evidence of bacteria. Given the extent of meningeal involvement seen in most patients with NS, symptomatic meningitis is relatively rare. Occasionally, meningeal-based granulomatous mass lesions can develop.

Pituitary and Hypothalamic Sarcoidosis

When sarcoidosis involves the CNS parenchyma, it most commonly affects the hypothalamus and parasellar region.¹⁰ This can result in vegetative alterations and neuroendocrinologic dysfunction. Symptoms include disturbances in sleep, appetite, thirst, temperature, and libido. Hypothalamic and pituitary lesions can also cause thyroid, gonadal, and adrenal abnormalities. Altered thirst, antidiuretic hormone deficiency or excess, and hyperprolactinemia have been reported.

Space-Occupying Lesions

Granulomatous masses forming localized space-occupying lesions can occur throughout the CNS but are most frequently found in the cerebral hemispheres.⁶ They can be manifested as a large, solitary mass mimicking either a primary or metastatic brain tumor.^11,¹² Alternatively, they can appear as multiple nodules.⁸ Finally, they can take the form of a dural-based plaque-like mass resembling a meningioma.¹³^–¹⁶

Seizures

Generalized or partial seizures have been reported in as many as 22% of patients with NS.¹⁷ They are thought to be caused by supratentorial parenchymal involvement in which the granulomatous inflammation is often found in a perivascular distribution.

Hydrocephalus

Hydrocephalus secondary to obstruction of normal CSF flow is a relatively common and potentially lethal clinical feature of NS.¹⁸^–²⁰ Communicating hydrocephalus can result from extensive meningeal involvement causing decreased CSF resorption through the arachnoid villi. Obstructive hydrocephalus can develop secondary to an intracranial mass or inflammation preventing the flow of CSF through the foramen of Monro, aqueduct of Sylvius, or foramen of Luschka or Magendie.^21,²²

Spinal Cord Sarcoidosis

Sarcoidosis of the spinal cord is relatively rare. It can occur at any segment of the spinal cord, as well as at the cauda equina, and the granulomatous lesions may be intramedullary or extramedullary.²³^–³⁰

Peripheral Neuropathy

Peripheral neuropathic manifestations include mononeuropathy, mononeuritis multiplex, and generalized sensory, sensorimotor, and motor neuropathies.^31,³² Patients can have a small-fiber sensory or autonomic neuropathy.³³ Clinical features resembling Guillain-Barré syndrome have also been described. Nerve biopsy shows granuloma formation in both the epineurial and perineurial spaces, as well as axonal degeneration. There can be associated vascular inflammation, thus suggesting that ischemia may play a role in the nerve damage.

Myopathy

Involvement of the skeletal muscles in sarcoidosis is relatively common. Initial features can range from asymptomatic nodules to acute or chronic myopathy with resultant atrophy.^34,³⁵

Diagnostic and Imaging Studies

The diagnosis of sarcoidosis is firmly established only when the clinical and paraclinical findings are supported by histologic evidence of widespread noncaseating granulomas.^1,² When neurological findings develop in a patient with sarcoidosis, NS should be considered, although an intercurrent infection or malignancy must be excluded. The following diagnostic criteria for NS are adapted from Zajicek and colleagues³⁶:

1 Possible: The clinical syndrome and neurodiagnostic evaluation are suggestive of NS. Infection and malignancy have not been rigorously excluded or there is no pathologic confirmation of systemic sarcoidosis.

2 Probable: The clinical syndrome and neurodiagnostic evaluation are suggestive of NS and alternative diagnoses have been excluded, especially infection and malignancy. There is pathologic evidence of systemic sarcoidosis.

3 Definite: (a) The clinical findings are suggestive of NS, other possible diagnoses have been excluded, and supportive nervous system pathology is present; or (b) the criteria for a “probable” diagnosis are met and the patient has had a beneficial response to therapy for NS over a 1-year observation period.

When NS is suspected, the patient should be evaluated for evidence of systemic disease and a search for a site suitable for biopsy undertaken. Because corticosteroids can eliminate evidence of systemic inflammation, they should be withheld until the diagnostic evaluation is completed unless severe illness requires their use. The search for systemic sarcoidosis should begin with an examination of the skin and lymph nodes.^1,² Chest radiographs are abnormal in approximately 90% of patients with sarcoidosis, but frequently, additional diagnostic information can be obtained from a computed tomography (CT) scan of the thorax. Serum angiotensin-converting enzyme (ACE) levels can be elevated in patients with sarcoidosis. However, infection or malignancy can cause serum ACE levels to be high, and in patients with isolated NS, serum ACE levels may be normal.^37,³⁸ Ophthalmologic examination can reveal uveitis or retinal vasculopathy, as well as conjunctival nodules. Endoscopic nasal and sinus examination can show evidence of mucosal inflammation.

CSF abnormalities occur in NS, but they tend to be nonspecific and thus are not a reliable marker of the disease. CSF opening pressure is elevated in approximately 10% of patients, and protein is increased in two thirds of patients. CSF glucose can be normal or low. Approximately 50% of patients have a predominantly mononuclear pleocytosis. The immunoglobulin G index may be elevated, and oligoclonal bands may be present.^6,^8,³⁹ The concentration of ACE in CSF may be elevated, but this finding is not specific to NS.⁴⁰ There are reports of patients deteriorating after lumbar puncture.²⁰

Gallium scanning can be informative; uptake in the lungs and salivary, parotid, and lacrimal glands is suggestive of sarcoidosis and, when a distinctive pattern is found in combination with elevated serum ACE levels, may be highly specific (>95%) for sarcoidosis.⁴¹ Whole-body fluorodeoxyglucose positron emission tomography (FDG-PET) is a sensitive technique for highlighting areas of inflammation.⁴²

CT and magnetic resonance imaging (MRI) enhance detection of meningeal (Figs. 151-1 and 151-2) and parenchymal disease (Figs. 151-3 and 151-4), even in patients without any neurological findings.

FIGURE 151-1 Gadolinium-enhanced, T1-weighted magnetic resonance image demonstrating diffuse leptomeningeal enhancement (arrowhead) in a patient with neurosarcoidosis.

(Modified from Sampath P, Clatterbuck RE, Rigamonti D, et al. Neurosarcoidosis. In: Osenbach RK, Zeidman SM, eds. Infections in Neurological Surgery—Diagnosis and Management. Philadelphia: Lippincott Raven; 1999:41-47.)

FIGURE 151-2 Contrast-enhanced computed tomography scans in a 32-year-old African American man demonstrating an enhancing, dural-based mass along the right convexity (arrowheads). The patient was evaluated for generalized seizures. He was taken to surgery for what was believed to be an en plaque meningioma. Frozen section of a biopsy sample of this lesion (which was densely adherent to cortex) revealed granulomatous disease consistent with neurosarcoidosis. The lesion resolved completely with steroid therapy. Sarcoidosis had not previously been diagnosed in the patient.

FIGURE 151-3 Contrast-enhanced computed tomography scan demonstrating a ring-enhancing, intraparenchymal lesion with significant surrounding edema. The patient had no history of sarcoidosis and was initially seen with symptoms and signs of an intracranial mass. The lesion was found to be a sarcoid granuloma at the time of surgery.

FIGURE 151-4 T2-weighted magnetic resonance image of the cervical spine demonstrating intramedullary neurosarcoidosis (arrowheads). This patient’s disease proved refractory to standard medical management and radiotherapy.

On CT, the granulomatous lesions of NS are usually isodense or hyperdense on non–contrast-enhanced studies and uniformly enhancing after the administration of contrast medium.^8,⁴³ CT can reveal bony erosion of the skull base caused by NS lesions. The orbital contents, including the optic nerve and extraocular muscles, can also be visualized, particularly with sagittal and coronal reconstructions.

The imaging procedure of choice for NS is MRI with gadolinium enhancement.⁴⁴^–⁴⁷ This test is particularly sensitive for detecting disease of the parasellar region, basal cisterns, and spinal cord. On T1-weighted images, NS lesions are usually hyperintense in relation to normal brain parenchyma, and they enhance after the administration of gadolinium. T2-weighted images often show minimal edema surrounding the lesions, although this finding can be variable and may be related to disease activity. A wide spectrum of NS abnormalities can be seen on MRI and can mimic other neurological diseases. Gadolinium-enhanced MRI can reveal both diffuse (see Fig. 151-1) and local (see Fig. 151-2) leptomeningeal involvement.^47,⁴⁸ The dura often shows marked thickening along with evidence of inflammation (pachymeningitis). Parasellar lesions and intraparenchymal masses (see Fig. 151-3) can also be readily identified, but the latter can easily be mistaken for a neoplasm.⁴⁹ Involvement of the optic nerves or other cranial nerves can likewise be documented. MRI can identify hydrocephalus, and the presence of transependymal edema on T2-weighted images can be a useful indicator of increased intracranial pressure secondary to obstruction of CSF flow. Finally, MRI can be valuable in the detection of sarcoidosis involving the spinal cord (see Fig. 151-4) and cauda equina.⁵⁰

In addition to its utility in identifying lesions consistent with NS, gadolinium-enhanced MRI can be used to monitor the efficacy of NS treatment.⁵¹ Decreased enhancement and regression of the size of lesions suggest therapeutic efficacy.

Biopsy of the brain, spinal cord, meninges, nerve, or muscle is occasionally performed to confirm a diagnosis of NS in patients with known sarcoidosis who have a neurological problem consistent with NS. Biopsy should also be considered in patients with known systemic sarcoidosis and neurological disease who are progressively deteriorating despite “optimal” treatment to uncover an alternative diagnosis.⁵² Importantly, biopsy can support a diagnosis of NS in patients in whom the diagnosis is suspected but for which there is no confirmatory systemic documentation. Occasionally, NS is the unexpected consequence of a CNS biopsy, for instance, in a patient with a dural-based mass thought to be a meningioma but on biopsy granulomatous inflammation is found.

Treatment

Because of the relative rarity of NS, there have been no rigorous clinical trials to determine optimal treatment. Given the pathophysiology of sarcoidosis, however, immunosuppressive therapy has been the cornerstone of therapy.^6,⁸

Corticosteroids are the first-line agents for the treatment of NS. The site of neurological involvement, disease severity, and response to treatment generally dictate the dose and duration of corticosteroid therapy. For example, patients with facial nerve palsy or aseptic meningitis are often treated with prednisone, 0.5 mg/kg per day for 2 weeks; patients with myopathy or neuropathy are generally treated with prednisone, 0.5 mg/kg per day for 4 weeks, and then reassessed, with most patients requiring chronic therapy; and patients with a meningeal or parenchymal mass lesion, encephalopathy, or symptomatic hydrocephalus usually require prednisone, 0.5 to 1 mg/kg per day for 4 weeks, before any improvement is appreciated, and most require chronic therapy. Once the acute exacerbation is under control, corticosteroid administration can usually be slowly tapered. Frequent clinical evaluation and, for CNS disease, periodic MRI to assess the extent of enhancement can be helpful in guiding therapy.^51,⁵³

Patients who deteriorate despite aggressive corticosteroid therapy, who cannot tolerate corticosteroids, or who have a contraindication to corticosteroids may benefit from alternative therapeutic agents.⁵⁴^–⁵⁶ Mycophenolate mofetil, cyclosporine,⁵⁷ azathioprine, methotrexate,^58,⁵⁹ chlorambucil, cyclophosphamide,⁵⁵ hydroxychloroquine,⁶⁰ pentoxifylline,^61,⁶² thalidomide,^63,⁶⁴ and infliximab and adalimumab⁶⁵^–⁶⁸ have all been used to treat NS. There are no studies comparing the efficacy of these alternative treatments in patients with NS. Consequently, selection of agents is often based on ease of use, cost, and desire to avoid the complications of a particular drug. Because a patient’s response to a specific agent cannot be predicted, two or three different agents should be tried before concluding that the patient’s disease is refractory.

Cranial or spinal irradiation has been used for refractory NS and should be considered in patients who fail corticosteroid therapy and trials of alternative agents.^69,⁷⁰ Radiotherapy has also been used in patients with acute, life-threatening disease.

Intracranial and intraspinal mass lesions generally respond well to corticosteroids or alternative agents if the disease has been caught early, before the development of significant ischemia or fibrosis.^6,⁸ Thus, in patients with known systemic sarcoidosis in whom a mass lesion develops, corticosteroid therapy should be initiated promptly as long as there are no significant contraindications and infection and malignancy have been reasonably excluded as diagnoses. In patients without extensive systemic disease, treatment of an intracranial or intraspinal mass can be complicated by the imaging similarities of sarcoidosis, tuberculosis, fungal disease, and neoplasm.⁴³ In patients without known sarcoidosis, it may be necessary to perform a biopsy at the primary site of involvement to determine the nature of a mass lesion. During surgery, effort should be made to minimize disruption of the surrounding parenchyma because NS can be infiltrative and patients can deteriorate after surgical intervention. If the biopsy reveals noncaseating granulomas, further resection should be deferred while appropriate medical management is pursued. Only in highly refractory cases in which a mass lesion persists or enlarges despite optimal immunosuppressive therapy should surgical debulking or resection be considered. The results of these aggressive surgical interventions are often unsatisfactory.⁷¹

In patients with hydrocephalus secondary to NS, the need for surgical intervention is more common. Placement of a ventricular drain can be a lifesaving maneuver in a patient with acute hydrocephalus. Once the appropriate CSF studies have been performed and cultures and cytology are deemed negative, a ventriculoperitoneal shunt is indicated in patients with symptomatic hydrocephalus. Chronically elevated protein and granulomatous debris in CSF can lead to shunt malfunction and result in the need for frequent shunt revisions. The use of high-protein shunt devices and targeted placement of ventricular catheters may help minimize this problem. In addition, the presence of an implanted foreign body in an immunosuppressed patient can increase the risk for infection.

Patients with chronic, asymptomatic hydrocephalus can be observed clinically, and surgical intervention can be offered if the hydrocephalus worsens or if the patient deteriorates despite medical therapy. These patients must be watched closely, however, because abrupt, life-threatening deterioration can occur. In patients who respond to medical therapy, improvement in CSF flow can occur over time.⁷²