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Neurologic Manifestations of Systemic Disease

Neurologic manifestations of sarcoidosis

Dakshinamurty Gullapalli MD

Lawrence H. II MD

From the Department of Neurology, University of Virginia, Charlottesville,

Virginia

Address reprint requests to, Lawrence H. II, MD, Box 800394,

Department of Neurology, University of Virginia, Charlottesville, VA 22908,

e-mail: lhp3n@...

Copyright © 2002 by Mosby, Inc.

0733-8619/02 $15.00 + .00

Sarcoidosis is a multisystem granulomatous disease of unknown etiology.

Though first described as a cutaneous disorder, it commonly affects the

lungs and other organs. Neurologic manifestations occur usually as a part of

the spectrum of the systemic disease. Though relatively uncommon,

neurosarcoidosis is a serious disease associated with poor outcome. Much

progress has been made in the understanding of the immunopathogenesis, but

there is limited knowledge about appropriate therapy, and very little is

known of its etiology. The epidemiologic features, immunopathogenesis, and

immunomodulatory therapy of neurosarcoidosis do not differ from the systemic

disease. Most of the appreciation of neurosarcoidosis is gained from studies

involving patients with systemic sarcoidosis, individual case reports, and

case series of patients with nervous system disease. Patients with

sarcoidosis do not generally undergo neurologic evaluation unless neurologic

manifestations are prominent. Most patients with neurosarcoidosis also have

other organ systems involved by the inflammatory process. In light of these

reasons, it is important to understand the general features of sarcoidosis

to evaluate and manage patients with neurosarcoidosis.

General Aspects of Systemic Sarcoidosis

Hutchinson initially described the cutaneous aspects of the

disease, but mistook them for gout. Caesar Boeck subsequently described

several patients with similar skin manifestations and called them “sarkoid,”

because of the resemblance of the histologic features to sarcoma.[46] [69]

He emphasized the systemic nature of the disease. Ansgar Kveim and Louis

Siltzbach developed a cutaneous test for diagnosis of the disease. Heerfordt

in 1909, in his description of “uveoparotid fever,” first reported

neurologic manifestations in the form of cranial nerve palsies. The first

large case series of neurosarcoidosis was reported by Colover in 1948.[22]

In the last 2 decades the understanding of the disease has been improved by

several reports that describe the immunopathologic and epidemiologic

aspects. It most commonly affects middle-aged adults.[84] The annual

incidence rate is 0.85% for whites and 2.4% for blacks,[102] and the

prevalence is 40 per 100,000. The highest rates are observed in Swedes,

Danes, and African-Americans. The mortality rate in sarcoidosis is 1% to 5%,

mostly because of respiratory failure.[36] [84] Familial studies in

African-Americans[40] and in human leukocyte antigens (HLA) studies[34] show

a higher prevalence of the disease among first-generation relatives of

patients with sarcoidosis. The increased risk in particular racial or ethnic

populations, familial clustering of cases, and disease association with

certain HLA phenotypes in some countries, argue for the role of genetic

factors in the disease process. [3] [131] Spatial, seasonal, and familial

clusterings of cases have been observed, suggesting possible transmission of

an infective pathogen, common exposure to environmental agents, and genetic

factors. Several organisms have been proposed as the causative agents,

including viruses, mycobacteria, Borrelia, and, more recently,

propionibacterium acnes, but none have shown strong evidence.[3] [131]

Noninfectious enviromental agents like aluminum, beryllium, and zirconium

are also believed to trigger the disease because of their ability to induce

a granulomatous response.[3]

The inflammatory process is associated initially with an accumulation of

activated T cells and macrophages that release interferon-ã, interleukin-2,

and other cytokines and proinflammatory factors.[3] [37] [101] The T cell

antigen receptor (TCR) repertoire in sarcoidosis suggests an interaction of

sarcoid antigen with a combination of specific T cell antigen receptor and

HLA antigen presentation molecules, which would trigger the immune-mediated

inflammatory response.[131] Contrary to earlier views of suppressed

immunity, there is now evidence that suggests sarcoidosis is associated with

heightened immunity, mediated primarily by CD4+ helper cells and

macrophages.[47] The immunology of sarcoidosis is associated with a

dichotomy of depressed systemic cellular immunity and heightened T

lymphocyte activity locally in the affected organs. [59] [84]

The diagnostic histopathologic lesion of sarcoidosis is a noncaseating

epitheloid cell granuloma.[72] There is an accumulation of CD4 cells at

sites of active inflammation.[128] The inflammatory process is similar in

all organs affected by sarcoidosis, including the nervous system.[107] These

granulomas resolve spontaneously or with treatment. Persistence of the

inflammatory process induces fibrotic changes, resulting in irreversible

tissue damage. Similar granulomatous changes are observed in conditions

other than sarcoidosis such as some carcinomas, regional lymph nodes of

carcinomas, and lymphomatous disorders.[8] About 20% of granulomatous

lesions have an undetermined etiology. These clinical syndromes are grouped

under the rubric “GLUS” (Granulomatous Lesions of Unknown Significance).[8]

The elevated serum angiotensin converting–enzyme (SACE) levels noted in

sarcoidosis are results of increased release from epitheloid cells derived

from macrophages. [118]

The clinical presentation of sarcoidosis varies with the specific organ

involved. The lungs are involved in 90% of patients with sarcoidosis, and

the severity ranges from asymptomatic to severe interstitial lung disease.

Other organs commonly involved include the lymph nodes (33%), liver

(histopathologic abnormalities seen in 50% to 80% of biopsy specimens), skin

(25%), eyes (11%–83%), musculoskeletal system (25%–39%), and endocrine

glands.[3] Sarcoidosis in children occurs more commonly in caucasions.[31]

The distribution of organ involvement is similar to adults, but is usually

associated with a better prognosis.[54] [63] Sarcoidosis does not usually

affect the outcome of pregnancy, but the disease may worsen after delivery.

Sarcoidosis is a disease of exclusion. An effective diagnostic approach to

sarcoidosis involves accurate clinical assessment of the extent, severity,

and nature of the pathology affecting different organs. This is supported by

various diagnostic tools and histologic confirmation of the presence of

noncaseating granulomata. Developments in diagnostic tools like fiberoptic

bronchoscope, bronchoalveolar lavage (BAL), SACE, and imaging techniques

have made the diagnostic process more effective and less dangerous.

The natural history and prognosis of the disease vary depending on specific

organ involvement and extent, as well as ethnicity and genetic factors.

Spontaneous remissions occur in about two thirds of patients,[31] the

majority within the first 2 years.[100] Approximately 10% to 20% of

sarcoidosis patients develop a chronic form of the disease. Most of the

functional disability is from cardiac, ocular, neurologic, or severe

pulmonary disease.[3] Serious extrapulmonary involvement is present in 4% to

7% of patients at presentation. Most patients with systemic sarcoidosis

improve or stabilize with or without treatment, but relapse occurs in 16% to

74%. The mortality rate varies from 1% to 5%, mainly related to severe

pulmonary, cardiac, and neurologic disease.[3] [67]

An acute presentation is generally considered to be associated with a good

outcome. Poor prognostic signs or factors include age at onset >40 years,

black race, lupus pernio, chronic uveitis, chronic hypercalcemia,

progressive pulmonary pathology, nasal mucosal disease, bone cysts, cardiac

involvement, and neurosarcoidosis.

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