Neurosarcoidosis Imaging

Sarcoidosis is an idiopathic multisystem granulomatous disease characterized pathologically by the presence of noncaseating granulomas, and involvement of the central nervous system with or without systemic disease is referred to as neurosarcoidosis. Most cases of neurologic involvement occur in patients with active systemic disease, and neurologic symptoms usually occur within 2 years after the onset of systemic disease. Isolated central nervous system involvement is rare, being present in less than 3% of cases. ^{[1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12]}

Sarcoidosis is an uncommon disease, with an incidence of 30 cases per 100,000 population in the United States. Neurosarcoidosis occurs in 3-10% of patients with sarcoidosis. Although autopsy series have demonstrated involvement of the central nervous system in 25% of cases, symptomatic involvement of the CNS has been reported in only 5-10% of patients. Sarcoidosis can be self-limited or chronic. Many cases are diagnosed incidentally on routine chest radiography. Sarcoidosis most commonly involves the lungs and thoracic lymph nodes. ^{[10, 11, 13]}

Neurosarcoidosis may involve any portion of the central nervous system, including the brain, meninges, intracranial blood vessels, and spinal cord. Noncaseating granulomas of sarcoidosis are found in the adventitia of small and medium-size blood vessels, usually sparing the intima and media. However, mass compression of granulomas may cause the vessel lumen to become narrowed or obstructed, thereby resulting in infarction. Cranial nerves, including the optic nerve, can be affected by direct granuloma compression or by infiltration of the meninges or the nerve itself. The cervical and thoracic regions are the most common sites of spinal involvement.

In a review of the Optum health care database, which includes 15% of the US population, Baughman found that the incidence and prevalence rates of neurosarcoidosis were higher for African Americans (17.8 and 141.4 per 100,000, respectively) than for white individuals (8.1 and 49.8), Hispanics (4.3 and 21.7), or Asians (3.2 and 18.9). Women were 2 times more likely to have sarcoidosis, with the highest prevalence in African American women (178.5). ^[14]  

Conditions that may mimic neurosarcoidosis include tuberculosis, fungal infection, vasculitis, IgG4-related disease, and lymphoma. Findings on imaging include meningitis, parenchymal granulomas, white-matter signal abnormalities, ventriculitis, hydrocephalus, and spinal involvement. ^{[15, 16, 17, 18]}

Imaging modalities

Diagnosis is challenging, since clinical symptoms and imaging findings of neurosarcoidosis may mimic other infectious, demyelinating, granulomatous, neoplastic, and connective tissue disorders. ^{[19, 20, 21, 22, 23, 24]} Although histology is required for definitive diagnosis of neurosarcoidosis, imaging findings in the presence of systemic symptoms are highly suggestive of the diagnosis. The preferred imaging study is a contrast-enhanced MRI, including fat-suppressed T1 and FLAIR (fluid-attenuated inversion recovery) images of the orbits. A whole-body gallium scan or FDG-PET scan can help identify biopsy sites to confirm the diagnosis. ^[12]  Neurosarcoidosis lesions have been shown to be avascular in studies in which angiography has been utilized. Angiography may be useful in revealing vasculitic lesions. Definitive diagnosis of neurosarcoidosis can be made only by biopsy. ^{[12, 23, 25, 26, 27, 28]}

A chest radiograph may be helpful in providing support for the diagnosis of systemic sarcoidosis, with 90% of chest radiographs revealing hilar lymphadenopathy, lung parenchyma involvement, or both. However, patients may have completely normal images despite neurologic symptoms. Lymphoma may also demonstrate hilar lymphadenopathy on chest radiography. Multiple myeloma, hemangiomas, metastatic disease, and various lytic benign bone lesions also produce lytic calvarial lesions with nonsclerotic borders. A skull radiograph may incidentally demonstrate osteolytic calvarial lesions, although such a radiograph is not done routinely.

(Neurosarcoidosis is displayed in the images below.)

 

Anatomy

Symptoms of neurosarcoidosis depend on the location of involvement and the size of the granuloma. Cranial nerve palsy has been reported to occur in 73% of patients; aseptic meningitis, in 18%; focal cerebral parenchymal disease, in 15%; and hydrocephalus, in 6%.  In a study of 56 patients who were diagnosed with definite, probable, or possible neurosarcoidosis, 14 (27%) exhibited peripheral nervous system (PNS) involvement only. ^[29]

Cranial nerves

The facial nerve (CN VII) is the most common site affected, and 75% of cases are bilateral. Facial nerve palsies often occur rapidly and then resolve spontaneously. When facial nerve palsy is associated with parotiditis, anterior uveitis, and fever, it is termed Heerfordt syndrome.

The optic nerve is the second most commonly involved cranial nerve. ^[30] The clinical symptoms include visual-field deficits, blurry vision, optic neovascularization, and papillary edema. Patients with involvement of CN VIII may present with vertigo and hearing loss, ^[31] while patients with involvement of the glossopharyngeal and vagus nerves can present with dysphagia and dysphonia.

Meninges

The hallmark of neurosarcoidosis on CT and MRI is basal leptomeningeal involvement. Leptomeningeal involvement and granulomatous infiltration of the subependyma are the 2 primary causes of hydrocephalus resulting in intrinsic obstruction. ^{[32, 33]} Clinically, neurosarcoidosis may present as meningitis.

There is no definitive lab test to make the diagnosis; however, CSF examination may be helpful. The spinal fluid examination reveals mild to moderate pleocytosis, especially lymphocytic, and the protein level is usually elevated. There is an elevated angiotensin converting enzyme (ACE) level in 50% of patients.

Parenchyma

Patients with parenchymal involvement most commonly present with encephalopathy, including seizures, mood disturbances, cognitive impairment, psychosis, and personality changes. Other symptoms include headache, fatigue, seizures, multiple sclerosis–type symptoms, amnesia, intractable hiccoughs, schizophreniform symptoms, and acute stroke. Granulomatous involvement of the hypothalamus may result in diabetes insipidus, hypersomnolence, and impaired thermoregulatory mechanism.

Vascular structures

Involvement of the intracranial vascular structures resembles the involvement in other vasculitides, presenting as subarachnoid hemorrhage, stroke, dementia, psychosis, and epileptic seizures.

In a series of 32 patients with neurologic signs suggestive of neurosarcoidosis, the presence of medullary vein engorgement on susceptibility-weighted imaging (SWI) was found to have a sensitivity of 71.4% and a specificity of 92.3% for the diagnosis of neurosarcoidosis. ^[34]

Spine

There is spinal involvement in less than 1% of cases; such involvement may include cauda equina syndrome, back pain, and polyradiculopathies.

Treatment

The goal of treatment for neurosarcoidosis is to reduce or prevent organ system damage from harmful effects of granulomatous inflammation. Glucocorticoids are standard first-line treatment. Steroid-sparing agents should generally be given to patients with moderate to severe disease or to patients who are at risk from oral steroids. Steroid-sparing agents include azathioprine, methotrexate, mycophenolate mofetil, hydroxychloroquine, cyclophosphamide, and TNF inhibitors. ^[35]

Hydrocephalus is a common abnormality of neurosarcoidosis visible on CT scans. Granulomatous masses are seen as hyperdense nodules or calcification. After contrast administration, leptomeningeal enhancement is typically seen as linear and nodular meningeal enhancement, with a predilection for the basal cisterns; it can cause noncommunicating hydrocephalus. Periventricular enhancement suggests ependymal inflammation and results in communicating, rather than obstructive, hydrocephalus. Enhancement may extend deep into the cerebral parenchyma. (See the images below.)

Other findings include enhancing parenchymal masses with adjacent white-matter edema, optic nerve and chiasma enlargement and enhancement, and enlargement of the parotid, salivary, and lacrimal glands.

CT is neither specific nor sensitive; only 25-63% of patients with neurosarcoidosis have abnormal CT findings. Meningioma, leptomeningeal carcinomatosis, metastatic disease, and primary neoplasms can all present similar CT findings.

 

In 40% of cases of neurosarcoidosis, there are isointense T1-weighted and T2-weighted leptomeningeal nodules or plaques with focal or diffuse leptomeningeal thickening. ^{[36, 37]} The areas homogeneously enhance on postgadolinium T1-weighted sequences. The findings are most often seen at the base of the brain. Leptomeningeal disease can also appear as a dural-based mass with homogeneous enhancement, with T1-weighted and T2-weighted signal characteristics mimicking a meningioma.

(See the images below.)

Parenchyma

The most commonly visualized lesions of neurosarcoidosis on MRI are multiple, nonenhancing periventricular and deep white-matter lesions with high signal intensity on FLAIR and T2-weighted images. The parenchymal involvement is hypothesized to be secondary to a vasculitis–meningovascular sarcoidosis resulting in subclinical infarcts and transient ischemic attacks (TIAs). A less likely etiology is that the periventricular lesions represent progressive multifocal leukoencephalopathy, because long-term imaging demonstrates little or no change in lesion appearance. ^[38]

Solitary or multifocal ringlike, enhancing white-matter lesions are the second most common cerebral parenchymal finding.

(See the image below.)

The lesions are isointense on T1-weighted images and are usually hypointense on T2-weighted images, which is thought to be related to fibrocollagenous build-up. These lesions enhance homogeneously with contrast and are often associated with adjacent leptomeningeal lesions; therefore, they are believed to be secondary to leptomeningeal spread along perivascular spaces, presenting at a later disease stage and correlating with a poor prognosis. After treatment, the lesions decrease in signal intensity and do not enhance with contrast.

On T1-weighted and T2-weighted images, involvement of the hypothalamus or the pituitary stalk may present as a hypointense to isointense thickening, with nodular or heterogeneous enhancement.

Uveitis is the most common form of ocular involvement, occurring in 80% of patients. The process is usually bilateral, as is lacrimal gland involvement. There is parotid gland involvement in 6% of patients, often associated with widespread systemic disease.

Optic nerve or optic chiasm enhancement, or both, is present in 70% of patients (see the images below); an increased FLAIR signal without morphologic change is the predominant finding in optic nerve sarcoidosis. There is often contiguous involvement from the optic chiasm to the intracranial optic nerve, or there is nodular noncontiguous involvement of the contralateral optic nerve, which is considered to be a “stem-to-stem” appearance. ^[39] Neurosarcoidosis can also involve the retrobulbar fat, extraocular muscles, and globe in a diffuse, enhancing, infiltrative pattern that is indistinguishable from orbital pseudotumor.

Cranial nerve involvement may present as isointense on T1-weighted images and as enlargement of the cranial nerves on T2-weighted images, with enhancement on postcontrast T1-weighted images. Involvement of CN VIII (10-20% of cases) is often seen as a retrocochlear mass or an enlarged internal auditory canal, which is bilateral in 75% of cases. Nerve involvement is thought to occur because of perivascular and intraneural lymphocytic infiltration.

Hydrocephalus occurs in 5-12% of patients and may be communicating or obstructive.

Spine

The affected area of the spinal cord is enlarged. The first phase involves leptomeningeal enhancement, followed by leptomeningeal spread, resulting in patchy, peripherally located lesions in the spinal cord. The lesions are isointense on T1-weighted images and hypointense on T2-weighted images. These lesions then coalesce and consolidate. There may be chronic ischemia and direct disruption of neural pathways, resulting in spinal cord atrophy (see the image below).

Intradural extramedullary findings include pial enhancement; isointense enhancing root nodules; clumping of nerve roots; and isointense (possibly hypointense on T2-weighted images) enhancing cauda equina masses.

Extradural findings may involve paraspinal masses, spondylodiskitis, and enlarged cervical nerve roots on myelography.

Wegener et al, in a study of 13 patients with neurosarcoidosis, proposed a diagnostic path with spinal MRI as a mandatory and early step during diagnostic workup. In 6 of the 13 patients, clinically isolated neurosarcoidosis was present without signs or symptoms of systemic disease. Spinal cord involvement was associated with older age at diagnosis and a less favorable response to therapy. ^[40]

Skull

Osteolytic, well-circumscribed lesions, with nonsclerotic margins, are present. Bone scans may show increased radiotracer uptake.

Sensitivity

MRI is the most sensitive (82-97%) imaging study for neurosarcoidosis. Use of fat suppression for orbital images increases sensitivity. ^{[7, 41, 42, 43, 44, 45]}

MRI findings of bacterial, viral, fungal, lymphomatous, plasmacytoma, or carcinomatous meningitis may appear similar to those of leptomeningeal sarcoidosis.

The discrete intraparenchymal lesions of sarcoidosis may mimic the findings of astrocytoma, meningioma, tumefactive demyelination, and metastatic disease.

Findings of optic neuritis, multiple sclerosis, syphilis, cryptococcosis, and radiation-induced optic neuritis can look identical to findings of optic sarcoidosis.

MRI findings of histiocytosis and tuberculosis are similar to the MRI findings of pituitary sarcoidosis.

Gallium-67 citrate scans demonstrate increased uptake in sites of active sarcoidosis and other inflammatory and neoplastic processes. Less than 5% of patients have increased central nervous system uptake, but almost 50% demonstrate systemic uptake. Gallium demonstrates a lambda pattern of mediastinal lymphadenopathy uptake and a panda pattern (see the image below) of lacrimal, parotid, and nasal uptake. Gallium scanning lacks specificity. ^[46]

Fluorodeoxyglucose positron emission tomography (FDG-PET) demonstrates increased uptake in active granulomatous processes, including neurosarcoidosis (see the image below). One study indicated that FDG uptake greater than carbon-11–methionine (C11-Met) uptake suggests brain lesions secondary to inflammatory processes rather than malignancy. Reports of FDG uptake in the pituitary gland has also been reported. ^{[47, 48, 49, 50]}

Single-photon emission computed tomography (SPECT) may show asymmetric hyperfixation of technetium-99m (^99mTc) hexamethylpropyleneamine oxime (HMPAO) in areas affected acutely, possibly representing hyperperfusion of these areas secondary to active inflammation.

Whole-body PET imaging for sarcoidosis is up to 97% sensitive for pulmonary and lymphatic findings. Gallium uptake in sarcoidosis is similar to that in Sjogren disease, rheumatoid arthritis, and cytomegalovirus infection. Pulmonary PET findings for sarcoidosis cannot be distinguished from those for lymphoma.