Neurosarcoidosis Workup

Definitive diagnosis of neurosarcoidosis requires the exclusion of other causes of neuropathy and the identification of noncaseating sarcoid granulomas by histologic analysis of nerve and muscle biopsy specimens. Other studies and diagnostic procedures may include the following:

• Blood studies

• Serum protein immune electrophoresis

• Lumbar puncture with cerebrospinal fluid (CSF) analysis

• Chest radiography

• Magnetic resonance imaging (MRI)

• Fluorodeoxyglucose positron emission tomography (FDG-PET)

• Electromyography/nerve conduction studies (EMG/NCS)

• Evoked potential (EP) studies

• Optical coherence tomography (OCT)

The diagnosis of peripheral neuropathy as a result of sarcoidosis is determined by establishing, in the first instance, the presence of a peripheral neuropathy; excluding the common causes of peripheral neuropathy, such as hyperglycemic states, deficiencies of vitamins, and presence of toxins such as heavy metals; and establishing a pathologic diagnosis of noncaseating granulomas in neural or extraneural sites.

Findings of cerebrospinal fluid analysis are normal in 30% of cases, specifically in patients with cranial nerve and peripheral nerve involvement. When CSF analysis findings are abnormal, they reflect a nonspecific pattern. Serial CSF analyses may be necessary in some cases.

On skin testing, cutaneous anergy can be seen in systemic or active pulmonary sarcoidosis. However, it almost never occurs in pure neurosarcoidosis.

Small-fiber neuropathy may be evaluated by thermal threshold testing (TTT). On the other hand, sympathetic skin responses and cardiac autonomic testing (by Ewing test and iodine-123 meta-iodobenzylguanidine [¹²³ I-MIBG] myocardial scanning) have been reported to have limited diagnostic value for evaluation of small- fiber neuropathy.

A complete blood count (CBC) with differential may show a variety of changes, as follows.

• Normochromic normocytic anemia

• Megaloblastic changes

• Basophilic stippling

• Other dyshematopoietic states

• Lymphopenia

The erythrocyte sedimentation rate (ESR) may be elevated in systemic sarcoidosis. Creatine kinase, ESR, and aldolase may be useful in cases of myopathy.

Tests for hyperglycemic states should be performed, including fasting glucose and glycosylated hemoglobin levels to exclude diabetes mellitus. If those results are normal, a 2-hour oral glucose tolerance test is needed.

A serum vitamin B-12 level should be measured to exclude deficiency. If the level is on the low side, the diagnosis should be pursued by measuring serum homocysteine and methylmalonic acid levels, which are expected to be high in B-12 deficiency.

Blood urea nitrogen (BUN), creatinine, and serum calcium should be checked to rule out long-standing metabolic derangements, which can result in neuropathy. Hypercalcemia is a known feature of systemic sarcoidosis, and abnormalities of renal functions may reflect a wider involvement of the primary disease process.

Liver function tests (eg, alanine aminotransferase, aspartate aminotransferase, bilirubin, alkaline phosphatase, gamma glutamyl transpeptidase), if abnormal, may reflect systemic involvement by either sarcoidosis or other diseases. Antineutrophil cytoplasmic antibody (C-ANCA) titers may be needed to differentiate neurosarcoidosis from Wegener granulomatosis.

Endocrine studies should be performed whenever involvement of the pituitary-hypothalamic axis is suspected. This includes tests of the following:

• Thyroid function

• Prolactin

• Testosterone

• Growth hormone

• Luteinizing hormone

• Follicle-stimulating hormone

• Corticotropin-releasing hormone

• Estradiol

• Urine osmolality

• Insulinlike growth factor

Chest radiography often demonstrates perihilar lymphadenopathy or the interstitial lung disease of sarcoidosis. These abnormalities also may suggest lymphoma or other systemic diseases. See the images below.

Early chest radiograph findings in sarcoidosis.

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Advanced chest radiograph findings in sarcoidosis.

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MRI scans of the brain and spine are indispensable in assessing nervous system involvement. Imaging studies of specific regions or organ systems may be appropriate if clinically indicated or if laboratory testing suggests involvement of that organ system. Although computed tomography may also be used, MRI has become the modality of choice because of the superior images obtained.

The use of gadolinium and fluid-attenuated inversion recovery (FLAIR) has increased the sensitivity of an MRI, helping identify T2 enhancement of nerve roots, plexuses, and limb nerves. MRI of peripheral nerves may occasionally show a diffusely enlarged nerve as a soft tissue mass.

Some series have shown that gadolinium enhancement demonstrated leptomeningeal involvement in cases that unenhanced images might have missed. The enhancement can follow the contour of the brain, extending into the cortical sulci. Gadolinium also can leak into the contiguous CSF because of disruption of capillary endothelial tight junctions of the arachnoid matter.

A thick and ragged pial enhancement is indicative of invasion along perivascular spaces, leading to a meningoencephalovasculopathy. Enhancement of linear and nodular areas from the pial surface into the white matter indicates infiltration along Virchow-Robin spaces.

In the FLAIR technique, the signal from the CSF is suppressed, and mild or heavy T2 weighting (long TE) is used to detect lesions. This technique is of value in detecting low-contrast lesions. It also can be used to improve the accuracy of detecting T2 prolongation in the temporal lobe in cases of mesial temporal sclerosis.

The nulling of the CSF signal maximizes the sensitivity of the sequence to changes in the T1 of the CSF. The FLAIR technique is valuable in diffusion weighting and is especially sensitive to contrast enhancement. It also can be combined with fat suppression.

An MRI may demonstrate the following:

• Periventricular high-signal lesions on T2-weighted images

• Multiple supratentorial and infratentorial brain lesions

• Solitary intra-axial mass

• Solitary extra-axial mass

• Leptomeningeal enhancement

• Optic nerve enhancement (see the images below)

• Spinal cord intramedullary mass resembling demyelinating disease

  MRI of the brain in a 37-year-old man with neurosarcoidosis who had complete loss of vision in the right eye for 2 months and occasional blurry vision in the left. T1-weighted sagittal image shows intact optic nerves.

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  MRI of the brain in a 37-year-old man with neurosarcoidosis who had complete loss of vision in the right eye and mild left eye blurriness. This fluid-attenuated inversion recovery (FLAIR) axial image shows a wedge-shaped area of infarction in the right temporo-occipital area. The optic nerves exhibit abnormal signal.

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  MRI of the brain in a 37-year-old patient with sarcoidosis who had right eye blindness and mild blurry vision in the left eye. This postgadolinium, T1-weighted axial image shows right optic nerve enhancement along almost the entire intraorbital portion and a small amount in the prechiasmatic portion. The left optic nerve enhances from the level of the optic chiasm to the distal intraorbital portion. The right temporo-occipital infarct is seen as a faint hypodensity; it does not enhance after gadolinium administration.

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  MRI of the brain in a 37-year-old man with sarcoidosis who had loss of vision in the right eye and blurry vision in the left. This postgadolinium, T1-weighted axial image shows abnormal enhancement of both optic nerves, with the left optic nerve appearing worse on this study than in the study shown as Picture 5, which was done 6 months earlier. The right temporo-occipital hypodensity represents the old infarction.

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Fluorodeoxyglucose positron emission tomography (FDG-PET) imaging may show areas of hypermetabolism or hypometabolism in the central nervous system, and this information may be compared to a systemic PET scan in patients with systemic sarcoidosis, thus establishing a firmer diagnosis. However, because the brain has high metabolic activity, it may be difficult to interpret PET imaging in the evaluation of neurosarcoidosis. Whole-body FDG-PET was fojnd to be more sensitive than gallium scanning for assessing activity of sarcoidosis. ^[27] It has proven of great value in detecting occult diagnostic biopsy sites and in assessing residual activity in fibrotic pulmonary sarcoidosis and may help in making therapeutic decisions.

Whole-body FDG-PET scanning may reveal otherwise occult/subclinical areas of involvement, demonstrate the extent of disease, and suggest possible biopsy sites.

The combination of FDG- and F-18 fluorothymidine (FLT) PET/CT scanning can help in differentiating neurosarcoidosis from malignancy and in localizing biopsy sites. ^[28]

Electromyography/nerve conduction studies (EMG/NCS) can be used to confirm neuropathy. Findings include slowing of motor nerve conduction velocities, as well as abnormal sensory nerve conduction consisting of absent potentials, reduced amplitude, and mild slowing. Mixed compound nerve action potentials may be seen as well.

The most characteristic electrodiagnostic finding is mononeuropathy multiplex, showing axonal degeneration and segmental demyelination. In cases of myopathy, the EMG shows myopathic potentials. With treatment and clinical improvement, motor, sensory, and mixed nerve conduction tend to improve.

Evoked potential studies may be of value in supporting the diagnosis and in monitoring the course of the disease. Visual evoked potentials (VEPs) and brainstem auditory evoked potentials (BAEPs) tend to be abnormal in about one third of the patients with neurosarcoidosis.

Somatosensory evoked potentials tend to show abnormalities less frequently. All 3 modalities of EPs can show abnormalities in patients before the appearance of clinical signs.

When the involvement is purely peripheral (eg, diffuse peripheral neuropathy or myopathy), the CSF findings are normal. CSF examination shows a nonspecific pattern of pleocytosis and elevated protein (>0.5 g/L) if the root sheaths or meninges are involved. Glucose levels may be normal or low. In one study of 68 patients, the CSF leukocyte count was in the range of 5-220 cells/µL. These CSF findings, coupled with negative cytology and culture results, support the diagnosis of neurosarcoidosis.

levels of angiotensin-converting enzyme (ACE), lysozyme, and beta2-microglobulin can be elevated in the CSF in more than half the patients; changes in these markers can parallel the clinical course. The ACE level is rarely elevated in isolated neuropathy but may be elevated in systemic sarcoidosis.

High IgG, Ig index, and oligoclonal bands have been reported in the CSF. Studies of subpopulations of T lymphocytes have shown a high T4/T8 ratio, which can help in differentiating sarcoidosis from multiple sclerosis.

A recent study reported elevated levels of soluble CSF interleukin 2 receptor (sIL2-R) in patients with neurosarcoidosis, suggesting this as a possible marker for the diagnosis of the disease and for treatment and follow up of disease activity. ^[29]

Optical coherence tomography (OCT) appears to be a better tool in discovering retinal abnormalities before they appear on ophthalmologic examination. In a study of patients with neurosarcoidosis, 75% demonstrated quantitative OCT abnormalities, compared with 25% who had detectable abnormalities on detailed ophthalmological assessment. In the same study, 33% of patients with no ophthalmologic symptoms showed detectable abnormalities on OCT, compared with 8% of such patients who had abnormalities upon ophthalmologic examination. ^[30] [#WorkupProcedures]

Biopsy of an enlarged lymph node or an active area on gallium scan may reveal noncaseating granulomas, which suggest sarcoidosis as the pathologic etiology. Biopsy of the sural nerve may reveal fiber loss with a combination of axonal injury and demyelination.

Biopsies show granulomas surrounded by normal muscle in 50-80% of asymptomatic patients. A case report of neurosarcoidosis (sarcoid brainstem encephalitis) demonstrated nemaline rods in every muscle examined. ^[31]

Because the granulomas can be scarce, a large sample should be taken. Granulomas are not specific for neurosarcoidosis and can be seen in patients with tuberculosis, fungal infections, collagen vascular disorders, or carcinoma.

In symptomatic patients, nodules are less frequent. In some cases, noncaseous granulomatous myositis or chronic myopathic changes can be seen. Peripheral nerve biopsies may show segmental demyelination, degenerating nerve roots with inflammatory cells, axonal degeneration, and mechanical destruction of nerves by granulomas.

Brain biopsy may be required in selected patients with isolated brain involvement. In other cases, the patient's history, MRI scans, and chest radiograph may be sufficient for arriving at the correct diagnosis. Blood vessel biopsies of both arteries and veins can show involvement of the vessel wall, most frequently in the perforating arteries.

The diagnostic hallmark of sarcoidosis is the presence of granulomas in the involved tissue (see the images below). Granulomas are predominantly noncaseating (or solid), discrete, and naked, with a relative paucity of lymphocytes and plasma cells in the periphery. Nerve biopsy reveals secondary axonal degeneration with atrophy of nerve fibers. Myelin ovoids, which suggest demyelination, are occasionally seen. ^[32]

Noncaseating granuloma surrounded by epithelioid cells, from the medulla oblongata. Also shown are nodular inflammatory infiltrates consisting of multinucleated giant cells, macrophages, and lymphocytes (hematoxylin and eosin, 40x).

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Noncaseating granuloma in medulla oblongata showing the granuloma surrounded by epithelioid cells and nodular inflammatory infiltrates (hematoxylin and eosin, 20x).

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In a review by Vital et al of neuropathologic findings in 38 cases of sarcoid neuropathy, the characteristic noncaseating granulomas were found on the nerve in 11 cases, on the muscle alone in 5 cases, on both muscle and nerve in 10 cases, and in the nerve and another parenchyma (mainly lung or lymph node) in 12 cases. These cases included chronic sensory motor neuropathy, mononeuropathy multiplex, painful neuropathy, and atypical chronic inflammatory demyelinating polyneuropathy (CIDP). ^[33]

Moreover, necrotizing vasculitis was present in nerve biopsies from 8 cases and microvasculitis without obvious necrosis in 2 cases. Vital et al concluded that nerve fiber lesions, which are mainly axonal, are probably related to mechanical compression by noncaseating granulomas and/or to an ischemic process due to vasculitis. Cytokines and immune factors may also play a role, especially in certain cases with a clinical presentation of CIDP. ^[33]

In a separate series, Said et al found epineurial granulomas and perineuritis in all nerve specimens in 11 patients. The inflammatory infiltrates invaded the endoneurium, following connective tissue septae and blood vessels, in 5 patients. Multinucleated giant cells were found in 8 patients, and necrotizing vasculitis was found in 7. Inflammatory lesions were associated with variable, asymmetrical involvement of nerve fascicles and axon loss. ^[34]

A muscle specimen sampled during the same sitting in 10 patients showed inflammatory infiltrates and granulomas in 9 patients and necrotizing vasculitis in 2. Immunolabeling showed a mixed inflammatory infiltrate of T cells (predominantly CD4⁺ cells) and macrophages, in keeping with a delayed hypersensitivity reaction. ^[34] A case report by Bos et al revealed that nemaline rods can be found on muscle biopsy in neurosarcoidosis. ^[31]