AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

In its most common form, the idiopathic multisystem disorder sarcoidosis is characterized by pulmonary, lymphoreticular system, and skin involvement. Histologically, noncaseating granulomas are prominent in biopsies from lymph nodes or affected organs. Neurological involvement occurs in 5-15% of cases. Among those with neurosarcoidosis, a subset has predominantly neuromuscular involvement.

Pathophysiology

Sarcoidosis is idiopathic, and the trigger antigen inciting granuloma formation is unknown. The prominent involvement of the pulmonary system has raised the possibility of inciting airborne agents, but to date no infectious organism has been linked.

The lymphoreticular system is affected with prominent cervical and mediastinal lymphadenopathy (eg, perihilar and peritracheal nodes) and involvement of the smaller scattered lymphatic collections in solid organs (eg, spleen, liver) and in lymphatic tissue surrounding glandular organs such as the parotid and lacrimal glands.

Debate continues as to whether sarcoidosis results from a dysfunctional immune system or a secondary response to environmental antigens. Sarcoid granulomas may be seen in solid organs such as liver, kidney, and spleen. Neurosarcoidosis results from nervous system involvement by sarcoid granulomas.

The clinical features of neurosarcoidosis depend on the site of neuraxis involved. While neurosarcoidosis most commonly affects the central nervous system, a subset of patients demonstrate predominantly peripheral nervous system involvement. This may manifest as a myopathy and/or a peripheral neuropathy depending on the distribution of the granulomas.

The true incidence of peripheral neuropathy in sarcoidosis is unknown, as a significant number of asymptomatic patients with sarcoidosis have subclinical peripheral nerve involvement.

Neuropathy occurs via 2 mechanisms. The tissue can be involved directly: in muscle, a slow and indolent myositis results, and in the nerve, a neuropathy results. Granulomas in the nerve are seen most often in the perineurium and the epineurium, with local effects leading to axonal damage.

Some studies reveal sparing of the endoneurium, but others show prominent infiltration of the endoneurium, suggesting that all 3 nerve layers may be involved. Occasionally, myelin loss is prominent, with appearance of myelin ovoids. Whether the latter are due to compression from the granulomas, a result of regional toxic effects, or a result of specific targeting of the myelin sheath is unclear.

Tajima suggested a predominance of helper T cells in the sarcoid granulomas. Inflammation of the vasa nervorum or the arterioles to the muscles can result in ischemic injury. Peripheral nerve injury from these mechanisms may result in a diffuse polyneuropathy, mononeuritis multiplex, focal mononeuropathies, or polyradiculopathy from involvement of spinal root sheaths. The spinal root sheaths are an extension of the pachymeninges and a tissue for which sarcoid granulomas have a particular predilection.

Frequency

United States

Neurosarcoidosis occurs in approximately 5% of patients with sarcoidosis. Peripheral neuropathy is seen in 5-15% of those with neurosarcoidosis. In a series from Johns Hopkins University, 2 of 33 patients with neurosarcoidosis had peripheral neuropathy. Eighty-five percent of this patient population was African American and 15% was white.

International

Forty percent of 35 patients with neurosarcoidosis in a French series had peripheral neuropathy. Ninety-one percent of these patients were Caucasian, and 9% were black. The large discrepancy between the 2 groups may exist because the white population with neurosarcoidosis is more predisposed to peripheral neuropathy than the black population. The term "black" is used rather than African American because it refers to members of the African race and is less restrictive in its description of different nationalities.

Mortality/Morbidity

• The mortality rate is difficult to assess.
• Most patients with peripheral neuropathy from sarcoidosis also exhibit other systemic or CNS manifestations of the disease. These manifestations pose greater morbidity and mortality risks than polyneuropathy alone.
• The proportion of patients who have exclusively sarcoid polyneuropathy is unknown.

Race

• Neurosarcoidosis is far more prevalent in the black population than in Caucasians: as many as 85% of patients with neurosarcoidosis are black. While sarcoidosis in general is more common in blacks than in other races, it is also seen in Caucasians, as shown in numerous studies from Europe. Whether the percentage of patients with peripheral neuropathy from sarcoidosis is higher in blacks than in whites is not clear.
• No racial predilection for the development of sarcoid neuropathy is known.

Sex

The female-to-male ratio ranges from 55:45 to 63:37.

Age

All ages are affected, but young adults are especially susceptible.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Neuropathy can be the presenting feature of sarcoidosis, but this is rare; more commonly, neuropathy reflects a neurological extension of existing sarcoidosis.

• Some patients present with a diffuse sensorimotor neuropathy, whereas others present with distal to proximal slowly progressive weakness or distal numbness and dysesthesia. Occasionally they may present with multifocal neuropathies that mimic mononeuritis multiplex. Studies investigating the involvement of small diameter unmyelinated fibers have revealed a higher prevalence of small-fiber neuropathy than previously recognized.
• More focal findings present with symptoms referable to the nerve involved. Thus, in polyradiculopathy involving the cauda equina, patients may have progressive lower extremity weakness with or without sphincteric involvement.
• Mononeuropathies present with symptoms reflecting impairment of function in the particular nerve distribution.
• Numerous studies suggest that most of the neuropathies associated with sarcoidosis are initially multifocal and eventually become confluent, thus the initial presentation may be that of mononeuritis multiplex. This is seen most frequently in the cranial nerves, where lower motor neuron neuropathy of the facial nerve (which is the nerve most frequently involved) may present along with other cranial neuropathies or as bilateral facial neuropathies.

Physical

Clinical findings depend on the type and the nature of the peripheral nerve involvement.

• In diffuse polyneuropathy, patients experience weakness with a distal predominance.
• Deep tendon reflexes are attenuated or absent.
• Sensory modalities are impaired in a stocking and glove distribution, with large-fiber modalities (eg, proprioception, vibration) more severely affected than small-fiber functions (eg, pain, temperature). Recent findings suggest a higher prevalence of small-fiber neuropathy with pain as a symptom than hitherto recognized.
• Pure sensory neuropathy has been reported.
• Distal atrophy may be noted, depending on the duration of the neuropathy.
• Focal neuropathies result in dysfunction in the distribution of that nerve. The most common of these neuropathies is that of unilateral lower motor neuron facial nerve, and patients often are thought to have Bell palsy at presentation. Facial nerve neuropathy also can be bilateral.
• Polyradiculopathy commonly affects the cauda equina and presents as an asymmetrical weakness of the lower extremities, with loss of the deep tendon reflexes and patchy sensory loss, including the perianal region.

Causes

The causes of sarcoidosis are unknown.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Porphyria
Toxins such as alcohol and drugs (both therapeutic and recreational)
Neuropathies associated with monoclonal bands and paraproteinemias
Myopathy of all types
Carcinomatous and lymphomatous meningitis with resultant polyradiculopathy
Berylliosis
Vitamin B-12 deficiency
Paraneoplastic neuropathy
Paraproteinemic neuropathy

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• A complete blood (CBC) count with differential may show the following, and while these conditions have no known association with sarcoidosis, they may present with clinical features similar to those of sarcoidosis.
• • Normochromic normocytic anemia of chronic disease
  • Megaloblastic changes of vitamin B-12 deficiency
  • Basophilic stippling of lead toxicity
  • Other dyshematopoietic states
  • Lymphopenia (from lymphoma) or eosinophilia (from polyarteritis nodosa or Churg-Strauss syndrome)
• Erythrocyte sedimentation rate (ESR) may be elevated in systemic sarcoidosis.
• Angiotensin-converting enzyme (ACE) level is rarely elevated in isolated neuropathy but may be elevated in systemic sarcoidosis.
• 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.
• Serum vitamin B-12 deficiency and thyroid disorders have no known association with sarcoidosis, but the clinical presentations may be similar.

Imaging Studies

• Chest radiography
• • Chest radiography often demonstrates perihilar lymphadenopathy or the interstitial lung disease of sarcoidosis. These abnormalities also may suggest lymphoma or other systemic diseases.
  • Even in patients with primary neurosarcoidosis (without history of sarcoidosis) that presents with peripheral nerve involvement, pulmonary abnormalities can be identified sometimes.
• Whole-body gallium scan is useful in revealing subclinical areas of involvement, demonstrating the extent of disease, and suggesting possible biopsy sites.
• Magnetic resonance imaging (MRI) of the spinal roots, with gadolinium, is indicated when nerve root involvement is suspected.
• Imaging studies of specific regions or organ systems may be appropriate if clinically indicated or if laboratory testing suggests involvement of that organ system.

Other Tests

• Skin tests: Cutaneous anergy can be seen in systemic or active pulmonary sarcoidosis. However, it almost never occurs in pure neurosarcoidosis.
• Lumbar puncture
• • Cerebrospinal fluid (CSF) examination shows pleocytosis and elevated protein if the root sheaths or meninges are involved.
  • In these situations, glucose levels also may be reduced.
  • When the involvement is purely peripheral (eg, diffuse peripheral neuropathy or myopathy), the CSF findings are normal.
• Electrophysiologic studies
• • Nerve conduction studies (NCS) and electromyography (EMG) demonstrate the presence of a diffuse, focal, or multifocal neuropathy or polyradiculopathy.
  • EMG often shows features of an axonal polyneuropathy.

Procedures

• To diagnose sarcoid neuropathy definitively, exclude all other causes of neuropathy and confirm the sarcoid granulomas by histologic analysis.
• 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.

Histologic Findings

The diagnostic hallmark of sarcoidosis is the presence of granulomas in the involved tissue. Granulomas are predominately noncaseating. Nerve biopsy reveals axonal degeneration with atrophy of nerve fibers. Myelin ovoids, which suggest demyelination, are seen occasionally.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Several treatment regimens have been proposed. However, no definitive treatment exists.

• Corticosteroids remain the standard treatment.
• Immunosuppressants such as cyclosporine, methotrexate, and cyclophosphamide have been used with varying results. Almost all of the studies completed to date have involved treatment of CNS sarcoidosis as opposed to peripheral neuropathy. A case report of a biopsy-proven axonal sensorimotor polyneuropathy responding to intravenous immunoglobulin while unresponsive to steroid therapy is described.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medications used in peripheral neuropathy in sarcoidosis are the same as those used for systemic sarcoidosis and neurosarcoidosis. Immunosuppressants are used to dampen or alter the inflammatory activity. Corticosteroids are preferred. Nonresponders may be tried on cyclosporine, azathioprine, and/or methotrexate.

Drug Category: Immunosuppressants

Corticosteroids alter the immune response and may lead to resolution of the granulomas in sarcoidosis.

Drug Category: Cytotoxic drug/immunosuppressants

These agents suppress the autoimmune response, which is responsible for granuloma formation.

Drug Name	Azathioprine (Imuran)
Description	Cytostatic drug that has been used in numerous immune-mediated diseases. Active component, 6-mercaptopurine, thought to have immune-suppressing properties.
Adult Dose	50 mg/d PO initial dose; increase by 50 mg/d weekly to desired dose 3-5 mg/kg PO usual dose for all age groups
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; relative contraindications include known liver disease, bone marrow suppression with cytopenias
Interactions	Allopurinol increases toxicity; ACE inhibitors may induce severe leukopenia; methotrexate may increase plasma levels of methotrexate metabolite; may decrease effects of anticoagulants; may decrease plasma levels of cyclosporine; may decrease or reverse pharmacologic actions of neuromuscular blockers
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Use in pregnancy must be decided after recognizing teratogenic potential of azathioprine; GI or systemic reaction may develop within 2 wk of initiating azathioprine, necessitating discontinuation of medication

Drug Name	Methotrexate (Folex, Rheumatrex)
Description	Antimetabolite used as immunosuppressant, often in rheumatoid arthritis, severe psoriasis, and certain neoplastic diseases. Its use for neurosarcoidosis has not been tested sufficiently.
Adult Dose	Dosage varies depending on indication; one patient with CNS neurosarcoidosis has been described as benefiting from 25 mg/wk PO Starting dose varies from 25-30 mg/d PO; maintenance dose usually 7.5 mg/d
Pediatric Dose	Not established except for cancer therapy
Contraindications	Documented hypersensitivity; liver disease; blood dyscrasias
Interactions	NSAIDs administered concurrently with methotrexate can cause fatal interaction Oral aminoglycosides may decrease absorption and blood levels; charcoal lowers plasma levels of both oral and IV methotrexate, particularly with high-dose therapies; etretinate may increase hepatotoxicity; folic acid or its derivatives contained in some vitamins may decrease response; indomethacin and phenylbutazone can increase plasma levels, possibly by inhibiting renal prostaglandin synthesis or through competitive renal secretion; may decrease phenytoin serum concentrations; probenecid, salicylates, and sulfonamides, including TMP-SMZ, may increase therapeutic and toxic effects; procarbazine may increase nephrotoxicity; may increase plasma levels of thiopurines
Pregnancy	X - Contraindicated in pregnancy
Precautions	May have toxic effects on hematologic, renal, gastrointestinal, pulmonary, or neurologic systems; monitor CBC counts monthly, and liver and renal function every 1 to 3 months, during therapy—monitor frequently during initial dosing or when changing doses, also when risk of elevated levels, such as dehydration; stop drug immediately if significant drop in blood counts Aspirin, NSAIDs, or low-dose steroids may be administered concomitantly with this medication, but possibility of increased toxicity with concomitant NSAIDs, including salicylates, has not been tested

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Treatment is guided by the clinical response to corticosteroids.
• If the response is favorable (ie, steady amelioration of symptoms), then the dose may be tapered over several months.

Prognosis

• Although the neuropathy generally responds to steroid therapy, long-term outcome of peripheral neuropathy associated with sarcoidosis is unknown.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Sarcoidosis in general can at times be notoriously difficult to diagnose. A delay in diagnosis can result in increased morbidity (and in rare occasions death).

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Mar 8, 2007