Neurosarcoidosis: a clinical approach to diagnosis and management
Neurosarcoidosis: a clinical approach to diagnosis and management
Richard T. Ibitoye 0 1 2
A. Wilkins 0 1 2
N. J. Scolding 0 1 2
0 Institute of Clinical Neurosciences, University of Bristol , Bristol BS10 5NB , UK
1 Department of Neurology, Southmead Hospital , Southmead Road, Bristol BS10 5NB , UK
2 & Richard T. Ibitoye
Sarcoidosis is a rare but important cause of neurological morbidity, and neurological symptoms often herald the diagnosis. Our understanding of neurosarcoidosis has evolved from early descriptions of a uveoparotid fever to include presentations involving every part of the neural axis. The diagnosis should be suspected in patients with sarcoidosis who develop new neurological symptoms, those presenting with syndromes highly suggestive of neurosarcoidosis, or neuro-inflammatory disease where more common causes have been excluded. Investigation should look for evidence of neuro-inflammation, best achieved by contrast-enhanced brain magnetic resonance imaging and cerebrospinal fluid analysis. Evidence of sarcoidosis outside the nervous system should be sought in search of tissue for biopsy. Skin lesions should be identified and biopsies taken. Chest radiography including highresolution computed tomography is often informative. In difficult cases, fluorodeoxyglucose positron emission tomography and gallium-67 imaging may identify subclinical disease and a target for biopsy. Symptomatic patients should be treated with corticosteroids, and if clinically indicated other immunosuppressants such as hydroxychloroquine, azathioprine, cyclophosphamide or methotrexate should be added. Anti-tumour necrosis factor alpha therapies may be considered in refractory disease but caution should be exercised as there is evidence to suggest they may unmask disease.
Neurosarcoidosis; Diagnosis; Sarcoidosis; Treatment; Management
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Purpose of review
Neurosarcoidosis (NS) is a rare neuro-inflammatory
disorder with protean manifestations which presents a
diagnostic challenge to general physicians and neurologists
alike. In 2007, we highlighted how case series continued to
refine our understanding, and that anti-tumour necrosis
factor alpha (TNF-a) therapies may hold promise as
steroid-sparing agents in difficult disease [1, 2]. Nine years on,
we provide a clinically focused update on the management
of NS, guided by knowledge from new case series,
refinements in diagnostic criteria and further reports on
anti-TNF-a and other immunosuppressive therapies.
Definition and epidemiology
Sarcoidosis is a multi-organ granulomatous disease of
unknown aetiology, and is characterised pathologically by
multiple non-caseating granulomata in the absence of a
defined infective or toxic trigger [3]. In a US based study,
incidence (in person-years) was estimated at 10.9/100,000
in Americans of European ancestry and 35.5/100,000 in
those of African ancestry [4].
Neurosarcoidosis, the involvement of the nervous
system by sarcoid granulomata, is uncommon, occurring
symptomatically in 5–16% of patients with sarcoidosis
[5–8]. Our regional hospital-based study of patients in
South West England and South Wales estimated a
prevalence of 1/100,000 [9]. Across two case series, we found a
mean age at diagnosis of 39 years and similar prevalence in
females and males (47 vs. 53% across 98 patients) [2, 9]. A
significant proportion of NS is subclinical as confirmed by
autopsy studies; one showed nervous system involvement
in 14% of those with sarcoidosis [10]; another found only
in 50% was NS diagnosed in life [11].
The first case description of sarcoidosis is attributed to
Hutchinson in 1869 when he described a coal-wharf worker
with skin changes in his hands and legs [12]. The first account
of a neurological syndrome attributable to sarcoidosis was by
Heerfordt, who in 1909 reported three males with uveitis,
parotid enlargement and fever; two had a facial nerve palsy
[13]. Kveim’s observation that sarcoid lymph node tissue
generated an immunological response when injected
intradermally in patients with sarcoidosis, provided evidence for
a non-tubercular basis to the uveoparotid syndrome [14].
Siltzbach and colleagues subjected this to clinical trial and
confirmed the Kveim–Siltzbach test highly specific (95%)
and sensitive (79%) for sarcoidosis [15].
Case series with heterogeneous definitions of NS
expanded our understanding of NS beyond Heerfordt’s
uveoparotid fever [16]. Zajicek et al.’s diagnostic criteria
provided a much needed framework for case definition,
separating definite disease (with a positive biopsy from the
nervous system) from probable and possible disease [2].
Refinements of these criteria have since been proposed,
guided by emerging technologies such as thoracic
highresolution computed tomography (HRCT), and
immunohistochemistry for CD4:CD8 lymphocyte ratios in
broncho-alveolar lavage (BAL) specimen [17].
The natural history of NS is poorly characterised due to its
rarity, variability in diagnostic criteria and the freque (...truncated)