eMedicine Specialties > Neurology > Inflammatory and Demyelinating Diseases

Neurosarcoidosis

Author: Gabriel Bucurescu, MD, MS, Staff Neurologist, Neurology Service, Philadelphia Veterans Affairs Medical Center
Coauthor(s): Amer Suleman, MD, Consultant in Electrophysiology and Cardiovascular Medicine, Department of Internal Medicine, Division of Cardiology, Medical City Dallas Hospital
Contributor Information and Disclosures

Updated: Nov 7, 2006

Introduction

Background

Sarcoidosis is a multisystem disease process whose pathogenesis involves formation of an inflammatory lesion known as a granuloma. 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. The lungs are affected most frequently, but the eyes, nervous system, heart, kidneys, bones, and joints also may be affected.

Sarcoidosis is a disease of unknown etiology. Involvement of the central nervous system is referred to as neurosarcoidosis. Neurosarcoidosis is an uncommon but severe, sometimes life-threatening, manifestation of sarcoidosis. It generally occurs only if the disease has had 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.

Pathophysiology

Histologically, neurosarcoidosis is characterized by formation of granulomas in the central nervous system. The lesion consists of lymphocytes and mononuclear phagocytes surrounding a noncaseating epithelioid cell granuloma. These granulomas represent an autoimmune response to central nervous system tissues.

Frequency

United States

The prevalence of sarcoid varies widely, but generally it is more common in African Americans. The prevalence is much higher in both blacks and whites in the southeastern United States than in the rest of the country. In New York, the prevalence is 30 cases per 100,000 population; it is also seen in the Puerto Rican population, reaching a prevalence as high as 175 cases per 100,000 population in one retrospective study. In Los Angeles, Mexican immigrants constituted 7% of the observed cases, compared to 82% for blacks. The frequency of neurologic involvement is generally 5% of all cases of sarcoid, but in some series it was noted to vary from 5-16%. These figures are considered to be underestimated because of the usually silent manifestation of the disease and unavailability of tissue diagnosis in all cases.

International

The incidence of sarcoid varies from 0.04 case 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%). One study done in Paris showed that 13% of individuals from Martinique were affected with sarcoid. In Asia it is extremely rare, being almost unknown in Chinese and Southeast Asians. Data from Japan showed native Japanese to be affected.

Mortality/Morbidity

About two thirds of patients with neurosarcoidosis have a self-limited monophasic illness, and the rest have a chronic remitting relapsing course. With treatment, death from neurologic disease is unusual.

Neurological involvement is a major cause of disability in sarcoidosis.

Race

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

Sex

Slightly more common in women than men, one study found 55% of the subjects were women.

Age

• Neurosarcoidosis commonly occurs in adults aged 25-50 years.
• Neurosarcoidosis is uncommon in children, but when it occurs, it affects children aged 9-15 years. Sarcoidosis of early childhood ( <8 y), when it does occur, has a different clinical manifestation than in adults, 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.

Clinical

History

Onset of neurosarcoidosis is most often in the fourth or fifth decade of life, but the disease affects children and the elderly as well. In patients known to have sarcoid, the appearance of neurologic symptoms usually poses no diagnostic problems, but the possibility of unrelated disease must be kept in mind, especially infections. When nervous disease complicates systemic sarcoidosis, it usually does so within 2 years of onset. Symptoms can include the following:

• Mononeuropathy - Cranial nerve involvement
  • Facial palsy (the most commonly affected cranial nerve), either unilaterally or bilaterally - Heerfordt syndrome is characterized by fever, uveitis, swelling of the parotid gland, and facial nerve palsy and represents a type of neurosarcoidosis. The lesion site has been controversial, but direct nerve compression by parotid gland swelling or by a lesion within the facial canal has been assumed, in light of observations of accompanying taste disturbance.
  • Impaired taste and smell
  • Blindness, blurry vision, double vision, visual field defects, pupillary abnormalities, dry and sore eyes
  • Slurred speech, impaired swallowing, hoarseness
  • Vertigo, sensorineural deafness, tinnitus
  • Weakness of trapezius and sternocleidomastoid muscles
  • Tongue deviation and atrophy
• Peripheral nerve involvement - Mononeuropathy, mononeuropathy multiplex, polyneuropathy
  • Sensory neuropathy - Characterized by loss of sensation and abnormal sensation (eg, tingling, numbness, painful patches over the thorax, stocking/glove deficits)
  • Motor neuropathy - Characterized by weakness, leading to immobility and joint stiffness
• Central nervous system involvement may affect the hypothalamus/pituitary gland, cerebral cortex, cerebellum, and spinal cord (rarely), resulting in the following:
  • Polydipsia
  • Polyuria
  • Diabetes insipidus
  • Changes in appetite
  • Changes in sleep cycle (somnolence)
  • Impaired temperature regulation (hyperthermia, hypothermia)
  • Obesity
  • Alveolar hypoventilation
  • Impotence
  • Change in menstrual period
  • Galactorrhea
  • Amenorrhea
  • Generalized confusion
  • Dementia
  • Amnesia, both short term and long term
  • Loss of judgment
  • Acalculia
  • Generalized fatigue
  • Headache
  • Meningitis
  • Corticospinal signs
  • Cerebellar signs
  • Brainstem signs
  • Focal seizures
• Generalized or localized muscle weakness, muscle soreness

Physical

Patient may have signs of the following:

• Mononeuropathy, mononeuropathy multiplex, plexopathy
• Polyneuropathy
  • Sensory neuropathy
  • Motor neuropathy
  • Sensorimotor neuropathy
• Space-occupying lesion of brain: Although necrotizing sarcoidosis has been reported most commonly in the lungs and rarely in other organ systems, sarcoidosis and its necrotizing variant should be considered in the differential diagnosis of an agranulomatous mass lesion involving the CNS, particularly in the context of a history of systemic disease.
• Hypopituitarism
• Optic neuritis leading to optic atrophy (see Images 1-2)
• Eye involvement leading to blindness, including uveitis, iritis, choroiditis, and cyclitis
• Meningitis, rarely recurrent meningitis, especially basal brain involvement, leading to cranial nerve deficits, hydrocephalus, cauda equina signs, ependymitis, and encephalopathy
• Peripheral signs of sarcoidosis, such as erythema nodosum
• Cerebral infarct or transient ischemic attack due to vasculitis
• Spinal cord lesions are rare, affecting 0.3-0.4% of patients with systemic sarcoidosis. Intramedullary lesions resembling demyelinating disease may possibly respond to steroids, as does demyelinating disease. Extramedullary sarcoid lesions are even rarer than intramedullary ones, but have been reported.
• Myopathy is characterized by atrophy, tenderness, muscles feeling "hard" on palpation, and weakness.
• Brain stem (sarcoid brainstem encephalitis) and cerebellar involvement: This is rare and can manifest as demyelination, hemorrhagic infarction, or parenchymal infiltration by granulomatous masses. A recently reported case of sarcoid brainstem encephalitis showed nemaline rods in every muscle examined (see Workup).
• Seizures may be the first manifestation of neurosarcoidosis. Generally, seizures indicate a chronic course with poor prognosis. Cases associated with isolated mass lesions and simple partial or complex partial seizures (with or without secondary generalization) may be associated with better outcomes than patients with generalized tonic-clonic seizures only.

Causes

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 cells proliferate, resulting in an exaggerated response. The T-helper lymphocytes undergo differentiation to a Th1-type cell under the influence of interleukin-4 (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 granuloma. IFN-gamma increases the expression of major histocompatability class (MHC) class II on macrophages, and activated macrophages receptors carry an Fc receptor of immunoglobulin G (IgG) which potentiates their phagocytosis function. Tissue destruction results and granuloma formation is thought to be a secondary process.

Several hypotheses have been proposed to explain the mechanism: (1) a persistent antigen (either foreign or self) triggers the T-helper cell response; (2) response of the suppressor arm of the immune response is inadequate, preventing T-helper cells from shutting down; or (3) a possible inherited or acquired (genetic) difference in response genes leads to the exaggerated response.

In addition to the exaggerated cellular immune response, active sarcoid shows 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.

• Search for CME/CE on This Topic »

• Sarcoidosis and Neuropathy (Neurology)
• Sarcoidosis (Ophthalmology)

• Infliximab Combo Curbs CNS Sarcoidosis

• Prognosis of Refractory Neurosarcoidosis Altered By Thalidomide: A Case Report
• Multiple Cranial Neuropathies
• Review: Therapies for Interstitial Lung Disease: Past, Present and Future