Neurosarcoidosis

Sarcoidosis is a multisystem disease process of unknown etiology whose pathogenesis involves formation of an inflammatory lesion known as a granuloma. ^[1] Histologically, noncaseating granulomas are prominent in biopsies from lymph nodes or affected organs. The lungs are affected most frequently, but the eyes, nervous system, heart, kidneys, bones, and joints also may be affected.

Most patients with sarcoidosis do not have any symptoms; the disease often is detected on routine chest radiograph. Symptoms, if present, include cough, shortness of breath, and arthritis.

Involvement of the central nervous system, or neurosarcoidosis, occurs in 5–15% of cases of sarcoidosis. Neurosarcoidosis is a severe and sometimes life-threatening disorder.

Neurosarcoidosis generally occurs only in cases of sarcoidosis with substantial systemic involvement, and signs of neurologic involvement usually are seen in patients known to have active disease. Strictly neurologic forms are seen in fewer than 10% of patients; a subset has predominantly neuromuscular involvement.

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 (see Workup).

Neurosarcoidosis has no known cure. Spontaneous remission ha s been observed, but long-term therapy often is required. Immunosuppression is the principal method of controlling the disease, and corticosteroids are the cornerstone of therapy (See Treatment).

Sarcoidosis primarily affects the lymphoreticular system, with prominent cervical and mediastinal lymphadenopathy (eg, perihilar and peritracheal nodes). There is 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 lesion consists of lymphocytes and mononuclear phagocytes surrounding a noncaseating epithelioid cell granuloma.

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, while 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 caused by compression from the granulomas, by regional toxic effects, or by 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 significantly higher prevalence of the HLA allele DQB1*0602 has been reported in sarcoidosis patients with small fiber neuropathy, and this allele has been associated with a severe course of disease. ^[8]

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, a tissue for which sarcoid granulomas have a particular predilection.

The causes of sarcoidosis are not clear. The present evidence suggests that active sarcoidosis results from an exaggerated cellular immune response to either foreign or self-antigens. T-helper lymphocytes proliferate, resulting in an exaggerated response.

The T-helper cells undergo differentiation to a Th1-type cell under the influence of interleukin (IL)–4 and co-stimulator CD28. The Th1 cell induces IL-2 and interferon-gamma (IFN-gamma) on the macrophages, followed by a cascade of chemotactic factors that promote formation of granulomas.

IFN-gamma increases the expression of major histocompatibility class (MHC) class II receptors on macrophages, and activated macrophages carry an Fc receptor of immunoglobulin G (IgG) that potentiates their phagocytosis function. Tissue destruction results and granuloma formation is thought to be a secondary process.

Three hypotheses have been proposed to explain the mechanism, as follows:

• A persistent antigen (either foreign or self) triggers the T-helper cell response

• Response of the suppressor arm of the immune response is inadequate and cannot prevent T-helper cells from shutting down

• A possible inherited or acquired (genetic) difference in response genes leads to the exaggerated response

In addition to the exaggerated cellular immune response, patients with active sarcoid demonstrate hyperglobulinemia, with antibodies against several infectious agents (eg, Mycobacterium tuberculosis) as well as IgM anti–T-cell antibodies. However, no evidence exists to suggest that these antibodies play a role in disease pathogenesis; rather, their presence seems to be due to a nonspecific polyclonal stimulation of B cells by activated T cells at the site.

A rare case of anti-Ma2 (Ma2-Ab) antibodies circulating in CSF was described in a female patient with diencephalitis thought to be paraneoplastic in origin. ^[9] Ma2-Abs have been described in men with testicular cancer and paraneoplastic damage to the limbic system and the diencephalon. In women, Ma2-Abs have been found in cases of lung or breast cancer.

One pediatric case of neurosarcoidosis diagnosed by brain biopsy following a La Crosse virus encephalitis has been reported. ^[10] The exact association was not clear, but the patient did show La Crosse virus immunoglobulins M and G in serum and cerebrospinal fluid.

United States statistics

The prevalence of sarcoid varies widely, but generally it is more common in African Americans. In the southeastern United States, the prevalence is much higher in both blacks and whites than in the rest of the country. In New York, the prevalence is 30 cases per 100,000 population.

In Los Angeles, Mexican immigrants constituted 7% of the observed cases, compared with 82% for blacks.

The frequency of neurologic involvement is generally 5% of all cases of sarcoid, ^[11] but in some series it was noted to vary from 5-16%. In one prospective study, neurologic complications occurred in 32 of 123 (26%) patients with sarcoidosis. These figures are considered to be underestimates because of the usually silent manifestation of the disease and unavailability of tissue diagnosis in all cases.

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; of this population, 85% was African American and 15% was white. Pediatric neurosarcoidosis is rarely reported.

Neurosarcoidosis is also seen in the Puerto Rican population, reaching a prevalence as high as 175 cases per 100,000 population in one retrospective study.

International statistics

The incidence of sarcoid varies from 0.04 cases per 100,000 population in Spain to 64 cases per 100,000 population in Sweden. The prevalence in London was found to be 27 cases per 100,000 population for patients born in the United Kingdom, 97 cases per 100,000 population among Irishmen, and 200 cases per 100,000 population in men from the West Indies (5%). In southwest England and south Wales, one study showed a prevalence of 1 in 100 000 in a population of about 3 million. ^[12] One study done in Paris showed that 13% of individuals from Martinique were affected with sarcoid.

In Asia, sarcoid is extremely rare, being almost unknown in Chinese and Southeast Asians. Data from Japan showed native Japanese to be affected.

In a prospective study from Australia, Allen et al reported neurologic involvement in 26% of white patients with sarcoidosis (32 of 123). The following frequencies of neurologic abnormalities were observed: ^[13]

• Papilledema (6%)

• Cranial neuropathy (59%)

• Peripheral neuropathy (47%)

• Mononeuropathy (25%)

• Myopathy (25%)

• Psychiatric disorders (19%)

• Cerebellar ataxia (13%)

• Hydrocephalus (6%)

Racial differences in incidence

Neurosarcoidosis is more common in Africans and people of African descent, including those living in the West Indies, than people of any other race. In the United States, the ratio of affected blacks to affected whites ranges from 10:1 to 17:1. In Europe, however, the disease affects mostly whites. Neurosarcoidosis is very uncommon in Chinese people, Southeast Asians, Inuits, Canadian aboriginals, and New Zealand Maoris.

While sarcoidosis in general is more common in the black population than in other races, it is also seen in whites, 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.

Sex- and age-related differences in incidence

Neurosarcoidosis is slightly more common in women than men. The female-to-male ratio ranges from 55:45 to 63:37. All ages are affected, but young adults are especially susceptible. Neurosarcoidosis commonly occurs in adults aged 25-50 years. One exception to the sex difference mentioned above was in a study of 30 new cases in England and Wales, which showed 53% males and 47% females. ^[12]

Neurosarcoidosis is uncommon in children, but when it occurs it tends to affect children aged 9-15 years. Sarcoidosis of early childhood (before age 8 y), when it does occur, has a different clinical manifestation than in adults, being characterized by the triad of cutaneous nodules, arthritis, and uveitis. The rate of ocular involvement was reported to reach 100% in these patients; iritis and/or anterior vitreitis was observed in almost all cases. Children older than 8 years have a clinical picture similar to that of adults.

Spontaneous resolution of neurosarcoidosis after 4–6 months may occur but is uncommon. Many patients have a slowly progressive chronic course with intermittent exacerbations. About 5% of patients with sarcoidosis die of this disorder. Brainstem involvement can be life-threatening. Two cases of sudden death have been attributed to cardiac sarcoidosis and hypothalamic infiltration. ^[14]

Although the neuropathy generally responds to steroid therapy, the long-term outcome of neurosarcoidosis has not been clearly defined. Nevertheless, the following generalizations are possible on the basis of observations of treated individuals:

• Peripheral facial nerve palsy tends to improve over 2–4 weeks

• Optic neuropathy can improve over several weeks, but some patients have a progressive course ending in blindness

• Peripheral neuropathic and myopathic illness tends to be chronic and progressive, although remissions are possible

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.