Sarcoidosis and Neuropathy

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Author

N K Nikhar, MD, MRCP, Assistant Professor, Department of Neurology, George Washington University School of Medicine

Nothing to disclose.

Coauthor(s)

Haresh Mani, MD,, Associate Medical Director, Pulmonary and Mediastinal Pathology, American International Pathology Laboratories

Nothing to disclose.

Specialty Editor(s)

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine

eMedicine Salary Employment

Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Chief of Neurology, St Louis ConnectCare, Consulting Staff, Barnes Jewish Hospital

Nothing to disclose.

Paul E Barkhaus, MD, Professor, Department of Neurology, Medical College of Wisconsin; Director of Neuromuscular Diseases, Milwaukee Veterans Administration Medical Center

Nothing to disclose.

Chief Editor

Nicholas Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants

Nothing to disclose.

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 definitely linked.

Primarily, the lymphoreticular system is affected with prominent cervical and mediastinal lymphadenopathy (eg, perihilar and peritracheal nodes) and also involvement of the smaller scattered lymphatic collections in solid organs (eg, spleen, liver) and lymphoid 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 or severe vasculitic neuropathy. A significant increase of the HLA allele DQB 1 0602 has been reported in sarcoidosis patients with small fiber neuropathy and this allele has been associated with severe course of disease.[1]

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.

Epidemiology

Frequency

United States

Neurosarcoidosis occurs in approximately 5% of patients with sarcoidosis and approximately half the patients with neurosarcoidosis present with neurologic difficulties when sarcoidosis is first diagnosed. 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. Pediatric neurosarcoidosis is rarely reported.

International

In a French series, 40% of 35 patients with neurosarcoidosis had peripheral neuropathy; 91% of these patients were Caucasian and 9% were black. The large discrepancy between the 2 groups may exist because the white population with neurosarcoidosis may be 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.

Allen et al report a more frequent neurologic involvement of 26% in a prospective study from Australia. Neurologic involvement was identified in 32 of 123 patients (15 male, 17 female, all white), mean age 48 years, age range 21-80 years, over a 3-year period. Of the 32 patients, the following frequencies of abnormalities were observed: papilloedema (6%), cranial neuropathy (59%), peripheral neuropathy (47%), mononeuropathy (25%), myopathy (25%), psychiatric disorders (19%), cerebellar ataxia (13%), and hydrocephalus (6%). A neurologic improvement was seen in 16 of 19 (84%) following steroid therapy, and spontaneous improvement occurred in 5 of 13 (38%) who were untreated.[2]

Mortality/Morbidity

Race

Sex

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

Age

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

History

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

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, sometimes in a sequential manner mimicking Lyme disease. When associated with fever, uveitis, and parotid gland enlargement, some patients may be thought to have Heerfordt syndrome.[4] Carpal tunnel syndrome may be more common among patients with sarcoidosis than the general population.[5, 6, 7] Audiovestibular manifestations of sarcoidosis (especially sensory hearing loss) are likely to be primarily a result of vestibulocochlear nerve neuropathy.[8]

In a large series, 57 patients with biopsy-proven sarcoidosis causing limb neuropathy were reviewed to delineate the characteristic symptoms, impairments, disability, course, outcome, and response to corticosteroid treatment of limb sarcoid neuropathy. Typically, the neuropathy had a definite date of symptomatic onset. Prominent were positive neuropathic sensory symptoms (P-NSS), especially pain, overshadowing weakness, and sensory loss. The pattern was almost always asymmetric and not length-dependent (unlike distal polyneuropathy). The pathologic process was focal or multifocal, involving most classes of nerve fibers and variable levels of proximal to distal levels of roots and peripheral nerves.[9]

Additional features aiding in diagnosis were (1) systemic symptoms such as fatigue, malaise, arthralgia, fever, and weight loss; (2) involvement of multiple tissues (ie, skin, lymph nodes, eye); (3) the patterns of neuropathy; (4) MRI features; and (5) ultimately tissue diagnosis. Axonal degeneration predominated, although an acquired demyelinating process, was observed in 3 patients. For most cases, the disease had a chronic monophasic course.

Some patients with sarcoidosis may have small fiber neuropathy with autonomic involvement. This may manifest as unexplained pain and dysesthesia, reduced warm and cold sensitivity, or even cardiac autonomic disturbances. Recognition of cardiac autonomic disturbances may be of clinical relevance due to their associated morbidity.[10]

Physical

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

Causes

The causes of sarcoidosis are unknown.

Laboratory Studies

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 pathological diagnosis of noncaseating granulomas, in neural or extraneural sites.

Imaging Studies

Other Tests

Procedures

Histologic Findings

The diagnostic hallmark of sarcoidosis is the presence of granulomas in the involved tissue. Granulomas are predominately 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.[12]

Vital et al reviewed neuropathological findings in 38 cases of sarcoid neuropathy (4 of theirs and 34 previously reported in literature), including 17 cases with chronic sensory motor neuropathy, 13 cases with mononeuropathy multiplex, 3 cases with painful neuropathy, and 5 with atypical chronic inflammatory demyelinating polyneuropathy (CIDP). Of these 38 cases, the characteristic noncaseating granulomas (NCG) were observed 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. Moreover, necrotizing vasculitis was present in nerve biopsies from 8 cases and microvasculitis without obvious necrosis in 2 cases.[13]

Vital et al concluded that nerve fiber lesions, which are mainly axonal, are probably related to mechanical compression by NCG 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.[13]

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 in 7. Inflammatory lesions were associated with variable, asymmetrical involvement of nerve fascicles and axon loss.[14]

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. In addition to nerve involvement, all patients had at least 1 other tissue or organ affected, including muscle in 9 patients, lungs and/or intrathoracic lymph nodes in 8, skin in 3, arthritis in 2, and peripheral lymph nodes, stomach, and eye in 1 patient each.[14]

A case report by Bos et al revealed that nemaline rods can be found on muscle biopsy in neurosarcoidosis.[15]

Medical Care

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

Medication Summary

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.

Class Summary

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

Prednisone (Orasone, Sterapred, Deltasone)

Clinical Context:  Most commonly used oral corticosteroid, works by altering immune system and decreasing inflammatory reaction that is responsible for granuloma formation. Tuberculin skin test required prior to commencing high daily dose of steroids. Improvement has been reported in patients with sarcoid polyneuropathy who received methylprednisolone (1 g/wk for 8 wk) when oral prednisone failed. Disagreement exists about optimal treatment dose, but doses listed here are typical.

Often, high dose required for period of 2-4 wk before tapering; taper may need to be continued for several months before discontinuing treatment altogether.

Occasionally, patients respond to methylprednisolone pulses when high-dose oral prednisone fails.

Class Summary

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

Cyclosporine (Sandimmune, Neoral)

Clinical Context:  Used extensively in patients who have undergone transplant. Beneficial effects in neurosarcoidosis have been reported, although most clinical scenarios have been central and not peripheral nervous system sarcoidosis. Has been found to have benefit when used as adjunct to steroids in 6 patients with CNS involvement of neurosarcoidosis.

Azathioprine (Imuran)

Clinical Context:  Cytostatic drug that has been used in numerous immune-mediated diseases. Active component, 6-mercaptopurine, thought to have immune-suppressing properties.

Methotrexate (Folex, Rheumatrex)

Clinical Context:  Antimetabolite used as immunosuppressant, often in rheumatoid arthritis, severe psoriasis, and certain neoplastic diseases. Its use for neurosarcoidosis has not been tested sufficiently.

Further Outpatient Care

Prognosis

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

The long-term course of neurosarcoidosis has not been clearly defined. Nevertheless, some generalizations are possible based upon observations of treated individuals:

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