234 Practical Neurology

REVIEW Pract Neurol 2007; 7: 234–244

Sarcoidosis of the
nervous system
F G Joseph, N J Scolding
Although sarcoidosis is rarely confined to the nervous system, any
neurological features that do occur frequently happen early in the course of
the disease. The most common neurological presentation is with cranial
neuropathies, but seizures, chronic meningitis and the effects of mass lesions
are also frequent. The diagnostic process should first confirm nervous system
involvement and then provide supportive evidence for the underlying disease;
in the absence of any positive tissue biopsy, the most useful diagnostic tests
are gadolinium enhanced MRI of the brain and CSF analysis, although both
are non-specific. The mainstay of treatment is corticosteroids, but these often
have to be combined with other immunosuppressants such as methotrexate,
hydroxychloroquine or cyclophosphamide. There is increasing evidence that
infliximab is a safe treatment with good steroid sparing capacity.

arcoidosis is a multisystem granulo- heightened accumulation and activation of

F G Joseph
Specialist Registrar in Neurology
N J Scolding
Professor of Clinical Neurosciences
Department of Neurology, Institute
of Clinical Neurosciences,
University of Bristol, Bristol, UK
Professor N J Scolding, Department
of Neurology, Institute of Clinical
Neurosciences, University of
Bristol, Frenchay Hospital, Bristol
BS16 1LE, UK; N.J.Scolding@
bristol.ac.uk
10.1136/jnnp.2007.124263
S matous disease usually diagnosed
between the ages of 20 and 40 years.
It has a propensity for the lungs,
anterior uvea, lymph nodes and skin, but any
organ can be affected resulting in an illness
that may range from mild to life threatening.
It has a prevalence of 40 per 100,000,
although in certain racial groups such as
West Africans it can be substantially higher.1, 2
The cause remains speculative, but the
documented ethnicity, histocompatibility
associations and familial case reports suggest
an underlying genetic predisposition.3, 4 Also
implicated in the pathogenesis are perhaps
certain pathogens such as mycobacteria and
propionobacterium acnes which may trigger
the immunological effects—a dichotomy of
CD4+ helper T cells and macrophages in the
affected organs (with release of various
cytokines and proinflammatory factors) and
depressed systemic cellular immunity.5, 6 The
pathological hallmark of the disease is the
presence of multiple non-caseating epitheloid
granulomas (structured masses of activated
macrophages and their derivatives).
The Danish ophthalmologist, Heerfordt,
first reported neurological manifestations of
the illness in 1909 in his description of
‘‘uveoparotid fever’’ complicated by cranial
neuropathies9 (although it has been sug-
gested that long before this, sarcoidosis may
have been responsible for the bewildering and
complex medical condition that plagued
Ludwig van Beethoven10–13). In practice,
 Joseph, Scolding 235

neurological involvement is a relatively rare

though much feared complication. The cur-
Facial palsy is the most common cranial
rent literature suggests that less than 10% of neuropathy, being unilateral in 65% and bilateral
patients with sarcoidosis develop clinical in 35%
evidence of neurological disease, with a
course that may be acute, subacute or chronic The appearance of uveitis, parotid-gland
with insidious onset.14–16 However, autopsy enlargement, fever and cranial neuropathy
studies show a significant proportion with (usually involving the facial nerve) is often
subclinical disease, and suggest that only referred to as Heerfordt’s syndrome, and is
50% of cases are being diagnosed ante very suggestive of sarcoidosis. Interestingly,
mortem.17, 18 Although sarcoidosis is rarely there appears to be an increased frequency of
confined to the nervous system, its neurolo- both eye and cardiac involvement in patients
gical features frequently occur early in the with neurosarcoidosis compared with other
course of the disease leading to diagnostic patients with sarcoidosis,23 and indeed optic
confusion.15, 19 nerve involvement is the second most
common cranial neuropathy. Papilloedema is
THE MANIFESTATIONS OF frequently reported and results from obstruc-
NEUROSARCOIDOSIS tion to CSF flow caused by chronic meningitis,
or from the mass effect of large granulomata
Our knowledge of the clinical features of
in the orbit or the cranial cavity, which may
neurosarcoidosis is derived from a handful of
lead to optic atrophy. A subacute optic
relatively large case series published over the
neuritis with little response to steroids and
last 40 years.14–22 Most have relied for diagnosis
poor recovery on long-term follow-up is also
on the presence of recognisable neurological
seen.
symptoms and signs in the context of a
In addition, syndromes deriving from the
granulomatous multisystem disease, often
involvement of virtually every other cranial
supported by a tissue diagnosis from organs
nerve have been reported.19
such as the liver, lungs (hilar nodes and/or
parenchymal involvement) and skin (particu-
larly erythema nodosum; fig 1), but only
Epileptic seizures
These often suggest a more severe progres-
infrequently with nervous tissue confirmation.
sive or relapsing clinical course, and are most
likely a reflection of underlying intracranial
Cranial neuropathies mass lesions, vasculopathy, or hydrocepha-
This is the commonest manifestation seen in lus.24 They are often poorly responsive to
approximately 50–75% of patients with corticosteroids.22, 25 In one study of 79
neurosarcoidosis.15, 19, 20 It may be caused by patients with neurosarcoidosis, 15% had
increased intracranial pressure, nerve granu- seizures, and this was the first manifestation
lomas or—most commonly—by granuloma- of neurosarcoidosis in 10%. All types of
tous basal meningitis. Facial palsy is the most
common cranial neuropathy, being unilateral Figure 1
Typical erythema nodosum in sarcoid.
in 65% and bilateral in 35%.19, 20 A prominent
meningitic reaction around the brainstem
appears to be the underlying cause, rather
than the previously assumed disease of the
parotid gland—a fact supported by the lack of
any temporal relation between facial nerve
paralysis and parotitis, and the often abnor-
mal brainstem auditory evoked potentials and
cerebrospinal fluid (CSF) findings.21 Facial
nerve palsy alone appears to be associated
with a good prognosis, but other presenta-
tions of neurosarcoidosis are reported to have
a poor outcome.22
www.practical-neurology.com
236 Practical Neurology
seizure are seen, but most are generalised
Hypothalamic and tonic-clonic.25
pituitary gland
Meningitis
involvement is Acute or chronic meningitis is seen in 3–26%
common of neurosarcoidosis cases. A lymphocytic CSF
with raised protein levels is common, and
approximately one fifth have a low CSF
glucose level.26, 27 Acute meningitis is usually
steroid-responsive, but chronic meningitis
often requires long-term steroids because of
further relapses. Hydrocephalus and an
‘‘idiopathic intracranial hypertension’’-like
syndrome may complicate sarcoid meningi-
tis.6, 20
Mass lesions
Localised granulomatous mass lesions may
affect any part of the central nervous system
(CNS). These may be single or multiple and
vary from small abnormalities to large tumours
causing headache, lethargy and seizures.20, 28, 29
However, as neurosarcoidosis often has a
predilection for the base of the brain, hypotha-
lamic and pituitary gland involvement is
common and may cause neuroendocrine
effects with hyperprolactinaemia, the galactor-
rhoea-amenorrhea syndrome, hypothalamic
hypothyroidism or diabetes insipidus. These
features commonly present difficult diagnostic
problems, especially when they are the only
manifestation. Normal pituitary function tests
(in particular serum prolactin levels) do not
exclude hypothalamic or pituitary sarcoidosis.
Brainstem and cerebellar lesions are recog-
nised, but are less common. Sarcoid mass
lesions may also affect the optic nerve in the
orbit, mimicking a meningioma, with conse-
quent visual impairment, papilloedema and
optic atrophy. Periventricular white matter
lesions resembling multiple sclerosis are
frequently observed on brain MRI.30
Spinal cord disease
This includes extradural, intradural or intra-
medullary lesions, which may be radiographi-
cally indistinguishable from a neoplastic
process.31 Any segment of the cord may be
involved producing various manifestations
such as paraparesis, tetraparesis, radicular
pain, autonomic failure, cauda equina syn-
drome or sphincteric disturbances. Clinically
such presentations are rare and are usually
preceded by a history of systemic sarcoidosis,
10.1136/jnnp.2007.124263
but autopsy studies have revealed asympto-
matic involvement of the spinal cord in a
third of patients with sarcoidosis. There may
be a CSF pleocytosis, with increased protein
levels, and oligoclonal bands. Most patients
presenting with spinal cord disease deteriorate
significantly over 18 months or more.26, 32–34
Psychiatric manifestations
These occur in about 20% of those with
neurosarcoidosis, reflecting the potential for
granulomatous infiltration of any part of the
CNS. It is not unheard of for patients to have
been committed to psychiatric care for a wide
range of mental symptoms, including apathy,
lack of judgement, agitation, delirium, hallu-
cinations, irritability, lethargy and depres-
sion.35–37 Cognitive or psychiatric symptoms in
a patient with multisystem sarcoidosis should
therefore prompt detailed assessment because
these may improve with corticosteroids.
Movement disorders
Some, such as cerebellar ataxia are commonly
reported, but chorea, hemiballismus and
parkinsonism are rare.26, 38
Peripheral nerve and muscle
disease
Peripheral neuropathies occur in approximately
15% of neurosarcoidosis patients and usually
have a better prognosis than CNS involvement.26
There are various forms including axonal or
demyelinating sensory and/or motor neuropa-
thies, which may affect single or multiple
nerves,26 and rarely Guillain-Barré syn-
drome.22, 39 Asymptomatic skeletal muscle invol-
vement is more common than symptomatic
muscle disease, with the latter having nodular,
acute, or more commonly chronic myopathic
forms that tend to affect females in their sixth
decade.26, 40 Nodular myopathy is important
because it may be confused with a soft tissue
tumour. The response to corticosteroids is often
unpredictable.41
HOW SHOULD WE MAKE THE
DIAGNOSIS OF
NEUROSARCOIDOSIS?
The clinical diagnosis of neurosarcoidosis is
relatively straightforward in patients with
multisystem sarcoidosis who later develop
the typical neurological features described
above. However, as early involvement of any
 Joseph, Scolding 237

part of the nervous system is not infrequent,

this may pose a serious diagnostic challenge
to the neurologist. How then should one
make a diagnosis in such circumstances?
(table 1). Clearly, the first step is to confirm
the clinical impression of neurological invol-
vement with targeted investigations. If these
do suggest the possibility of neurosarcoidosis,
the next step is a thorough search for any
supportive systemic features of the disease to
help secure the diagnosis.
Confirming neurosarcoidosis
Many investigations can point towards or
support a diagnosis of possible neurosarcoido-
sis, unfortunately none short of biopsy proves it.
Brain imaging
Magnetic resonance imaging has displaced
contrast enhanced CT as the most useful test
TABLE 1 Proposed criteria for the diagnosis of neurosarcoidosis
(modified from Zajicek et al 199919 and Marangoni et al54)
Definite: clinical presentation suggestive of neurosarcoidosis + positive
nervous system histology + exclusion of other possible diagnoses (ie, sarcoid
mimics)
Probable: clinical presentation suggestive of neurosarcoidosis + laboratory
support for CNS inflammation (raised CSF protein +/2 cells, oligoclonal
bands and/or CSF CD4:CD8 ratio .5 and/or MRI evidence compatible with
neurosarcoidosis) + exclusion of alternative diagnoses +/2 evidence of
systemic sarcoidosis (either by positive histology, and/or at least 2 indirect
indicators from gallium scan, high definition CT of the chest,
bronchoalveolar lavage with CD4:CD8 ratio .3.5)
Possible: clinical presentation suggestive of neurosarcoidosis with exclusion
of alternative diagnoses where above criteria are not met
the diagnosis or identifying a site for
potential biopsy in a puzzling case, particu-
Figure 2
larly when MRI and other investigations do Meningeal enhancement on
not provide sufficient information.45 T1-weighted MRI.

for detecting basal sarcoid meningeal disease.

MRI is also far superior in defining parench-
ymal involvement, with a reasonable level of
sensitivity for intracranial abnormalities (up
to 82%) but poor specificity, with a wide
spectrum of imaging findings.42, 43 The unen-
hanced MRI is unsatisfactory because of the
artefacts near bone, CSF and meninges on
both T1 and T2-weighted images. About 40%
of patients with neurosarcoidosis have either
leptomeningeal enhancement with gadoli-
nium (fig 2), or multiple white matter lesions
in a periventricular distribution that may be
difficult to distinguish from those seen in
multiple sclerosis.30 Infections with tubercu-
losis, other bacteria and fungi, and neoplastic
processes such as meningeal carcinoma,
lymphoma and leukaemia may also enhance
with gadolinium and mimic sarcoid radio-
graphically. The low diagnostic yield for MRI
in some series may reflect the effect of
therapy because the MRI changes can
disappear with successful treatment of the
disease. In acute myositis, MRI can show
increased signal intensity in the muscles.40
Fluorodeoxyglucose positron emission
tomography (FDG-PET) may reveal areas of
brain hyper- or hypometabolism, and areas of
hypermetabolism outside the brain, suggest-
ing neuro- or systemic sarcoidosis respec-
tively.44 Although we would not routinely
recommend PET scanning in suspected neu-
rosarcoidosis, it can be helpful in supporting
www.practical-neurology.com
238 Practical Neurology
TABLE 2 Distinguishing between multiple sclerosis and
neurosarcoidosis: in favour of neurosarcoidosis
Systemic features May be already present, or appear later in the course
of the disease
Neurological Most common are cranial neuropathies (especially
features lower motor neuron facial weakness), seizures,
meningitis, and effects of mass lesions
MRI brain Leptomeningeal enhancement with gadolinium, mass
lesions (but periventricular lesions may also occur)
CSF Often significant protein elevation (.2 g/l), mild
lymphocytosis. CSF oligoclonal bands may be seen, but
generally associated with CSF protein elevation
Systemic Serum ACE, ESR, and calcium may be elevated; CXR, CT
investigations thorax, gallium scan, and systemic tissue biopsy may
be positive
Cerebrospinal fluid
Cerebrospinal fluid examination is helpful in the
sense that it often demonstrates both a
pleocytosis—predominantly a lymphocytosis
ranging from 10–200 lymphocytes per cubic
mm20 (but mean 24 lymphocytes from Zajicek
biopsy positives cases)19—and raised protein
(mean 2.7 g/l (unpublished data) and median
2.6 g/l from Zajicek biopsy positive cases). In our
own study the figures were a mean of 30
lymphocytes and protein of 2 g/l (unpublished
data). There may also be a high opening
pressure, and in some cases a low glucose level
consistent with a leptomeningitic process.
Clearly such changes should also prompt CSF
stains and cultures for fungi and mycobac-
teria.20 Patients with localised space-occupying
lesions may have unremarkable CSF findings.
Some regard CSF angiotensin converting
enzyme (ACE) levels as being useful in both
the diagnosis and follow-up of neurosarcoi-
dosis.46, 47 However, many authorities now
regard this test as non-specific and insensi-
tive. CSF ACE may be raised in infections and
malignancy, and appears unhelpful in any
therapeutic decision making.48 This is illu-
strated by one study of 32 patients with
sarcoidosis, including 20 with neurosarcoido-
sis: CSF ACE levels were raised in only 55% of
patients with neurosarcoidosis, in 5% of
patients with sarcoidosis not apparently
involving the nervous system, and in 13%
of patients with other neurological diseases.49
Most studies report evidence of intrathecal
synthesis of immunoglobulins with oligoclo-
nal bands in about 30%–40% of patients with
10.1136/jnnp.2007.124263
neurosarcoidosis,19 while others suggest that
this is uncommon.27 In one of the largest
retrospective neurosarcoidosis series, all
patients positive for CSF oligoclonal bands
also had a raised CSF protein.19 This finding
has been reproduced in our subsequent (as
yet unpublished) study of 30 new cases of
neurosarcoidosis. Therefore, in those band-
positive patients with additional clinical or
radiographic similarities to multiple sclerosis
sufficient to cause diagnostic uncertainty, a
raised CSF protein may contribute as a
discriminant, pointing to sarcoid not multiple
sclerosis (table 2).
Additional CSF markers have shown some
promise but are not widely employed:
N CSF lysosome and beta 2-microglobulin
are raised in some cases and are due to
local CNS secretion rather than leakage
through the blood-brain barrier.50, 51
N An increased helper-suppressor T-lym-
phocyte ratio may help differentiate
neurosarcoidosis from multiple sclero-
sis52, 53 and in combination with raised
CSF ACE, provides support for the
diagnosis.
N A CD4:CD8 ratio .5 in the CSF has been
proposed as another useful diagnostic
criterion for neurosarcoidosis.54
Neurophysiology
Visual, auditory or somatosensory evoked
potentials can detect cranial nerve or spinal
cord lesions, but their value is principally in
disclosing subclinical abnormalities, rather
than directly aiding differential diagnosis,
for example versus multiple sclerosis.55, 56
The EEG adds little diagnostic information
and is often non-specifically abnormal, but it
may detect the early stage of acute ence-
phalomeningitis and epileptic discharges
caused by the disease.24, 57 Peripherally, elec-
tromyography and nerve conduction studies
can demonstrate myopathy and large-fibre
neuropathy associated with the disease.
Temperature threshold testing or skin biopsy
are needed to assess small-fibre neuropathy.58
Direct neural tissue biopsy
Ideally, a secure diagnosis of neurosarcoidosis
requires histological evidence, with direct
biopsy showing typical granulomas consisting
of epithelioid cells and macrophages in the
centre of non-caseating lesions surrounded

by lymphocytes, plasma cells and mast cells
(fig 3). In favour of doing a brain biopsy is an
accessible brain lesion, little or no supportive
evidence of systemic disease, and a likelihood
of using immunosuppressants. Accessing
cerebral tissue of course carries substantially
greater risks than biopsy of other tissues, and it
is not surprising that case series of neurosar-
coidosis have limited numbers of patients with
histological proof of the diagnosis.
Of course, a history of systemic sarcoidosis
does not necessarily prove any new neurolo-
gical problem in the patient is attributable to
the disease. And even when a ‘‘positive’’
biopsy is obtained, further careful evaluation
is needed to rule out other causes of
granulomatous diseases or reactions such as
infections (cryptococcus, histoplasma, toxo-
plasma, treponema, tuberculosis and
Whipple’s disease), chemicals (silica, beryllium
and contrast agents), tumours (carcinoma,
lymphoma, pinealoma), inflammatory disor-
ders (Wegener’s granulomatosis, giant cell
arteritis, systemic lupus erythematosus,
Churg–Strauss syndrome), and radiotherapy
and chemotherapy induced changes.
DEMONSTRATING SARCOIDOSIS
Blood tests
Serum ACE levels are raised in 50% of
patients with neurosarcoidosis (range 35–
75%). Soluble interleukin-2R level probably
has the same specificity but higher sensitivity
(83%) than the serum ACE in pulmonary
sarcoidosis and may be an indicator of
disease progression,59 but its use in helping
to diagnose neurosarcoidosis requires further
evaluation. Other biochemical indices are
unhelpful in establishing neurological invol-
vement; hypercalcaemia is often seen in
established pulmonary disease (a result of
additional a-hydroxylation occurring in the
sarcoid lesions in the lung), but many cases of
neurosarcoidosis are reported with comple-
tely normal calcium levels, and similarly the
erythrocyte sedimentation rate (ESR) is only
raised in a minority.
Chest radiography
The diagnostic value of chest radiography in
suspected systemic sarcoidosis is undisputed:
abnormalities are seen in 90%, but of course,
a normal chest x ray at presentation does not
Joseph, Scolding 239
exclude generalised sarcoidosis.14 Most com- Figure 3
monly observed is bilateral hilar lymphadeno- Histopathology of neurosarcoid
(parietal lobe; H&E, x10).
pathy, which is usually asymptomatic and
subsides without treatment in 80–90% of
patients. Less common are pulmonary infil-
trations with symptoms of dyspnoea, cough
and fever that may also resolve, or pulmonary
fibrosis leading to permanent bullae forma-
tion, associated with restrictive lung defects.
Chest x ray abnormalities in neurosarcoidosis
are variable, with a reported frequency
ranging from 31%–80%.19, 22 This clearly
means that one cannot be reassured by a
normal chest x ray when considering a
diagnosis of neurosarcoidosis.
High definition CT thorax
This is useful in diagnosing pulmonary disease
and also assists in targeting transbronchial
biopsy. It is approximately 89% and 98%
sensitive for hilar and mediastinal adenopathy
respectively, and 23% sensitive for pulmonary
infiltrates.60 High definition CT and bronch-
oalveolar lavage with immunocytochemistry
showing a CD4:CD8 ratio .3.5 has been
proposed as an additional diagnostic criterion
of neurosarcoidosis,54 though there have been
no exhaustive studies of sensitivity and
specificity.
Gallium scanning
Whole body gallium scanning, although of
relatively low specificity, has a sensitivity
of 60–90%43 and is a useful indicator of
www.practical-neurology.com
240 Practical Neurology
systemic disease. Ga-67 citrate is taken up at
sites of active sarcoidosis, but also by other
inflammatory and malignant diseases, includ-
ing tuberculosis and lymphomas. Although a
typical pattern of uptake in the salivary
glands, chest and muscle is well recognised
among patients with active sarcoidosis,
increased uptake in the cranium is reported
relatively infrequently.40, 61, 62
Kveim–Siltzbach test
This test is now largely only of historical value
because it is rarely available, but its notable
success in contributing to the diagnosis of
neurosarcoidosis deserves special mention.
Material for the test is obtained from human
sarcoid spleen and is injected intradermally. In
patients with active sarcoidosis, epithelioid
cell granulomata gradually develop and can
be demonstrated following biopsy of the
purplish-red nodule that is formed. The test
is highly sensitive for neurosarcoidosis, posi-
tive in up to 85% of cases—only slightly less
sensitive than direct positive histology from
tissue outside the affected nervous system.19
However, other than the potential for the
transfer of infection there are two distinct
disadvantages of this test: 4–6 weeks must
elapse before a biopsy can be performed,
which may be a crucial delay, and steroids
may make the test negative.
Systemic (‘‘blind’’) organ tissue
biopsy
Biopsy of a lymph node, lung, liver, skin or
conjunctiva may be considered if involvement
is suspected following clinical and/or radi-
ological assessment.20, 63–65 And even without
apparent involvement, such biopsies may still
be performed ‘‘blind’’ when there is suspicion
of neurosarcoidosis but no systemic clinical
abnormality. An example is asymptomatic
muscle involvement, which occurs in 50–80%
of patients or more.66 A generous muscle
biopsy with multiple sectioning could there-
fore help to confirm the presence of typical
granulomas surrounded by normal muscle:
gastrocnemius, vastus lateralis or brachial
biceps are possible target muscles.67
How certain can we be of the
diagnosis of neurosarcoidosis?
Although the criteria on which a clinical
diagnosis of neurosarcoidosis is made in the
10.1136/jnnp.2007.124263
absence of positive nervous tissue histology
have not been firmly established, one gen-
erally requires a clinically compatible picture,
exclusion of other neurological disease, and
histological confirmation of sarcoid else-
where. Zajicek and colleagues19 formulated a
series of diagnostic criteria in 1999 to include
biochemical abnormalities and important
diagnostic techniques such as MRI, gallium
scanning, chest x ray, CSF and the Kveim–
Siltzbach test, which help to define probable
and possible disease. Others have since
refined these criteria to exclude the Kveim–
Stilbach test (which as already mentioned is
no longer used), chest x ray and serum ACE
(which as described above are relatively poor
markers of CNS disease). Instead they have
included high definition CT of the chest and
bronchoalveolar lavage with a CD4:CD8 ratio
.3.5, and a CD4:CD8 ratio .5 in the CSF.54
Table 1 incorporates these modifications to
provide reasonable diagnostic criteria.
TREATMENT
Considering the rarity of neurosarcoidosis and
the difficulties in diagnosis, it is unsurprising
to find there are no randomised controlled
trials of treatment. Recommendations are
therefore based on retrospective case series,
anecdotal experience, and randomised con-
trolled trials in pulmonary sarcoidosis. It is
generally accepted that treatment is difficult,
and this is reflected by the significant
associated morbidity and mortality from the
disease.
Corticosteroids remain the cornerstone of
therapy, but adverse effects are prominent,
because the required dosage can be high, with
the frequent need for prolonged ther-
apy.19, 22, 68–70 The daily dose of prednisolone
varies from 40–80 mg, but the symptoms tend
to recur at less than 20 mg/day, making
withdrawal difficult.6 Any concomitant anti-
epileptic drug that induces hepatic microsomal
enzymes may reduce prednisolone concentra-
tion and efficacy, necessitating even higher oral
doses. Bolus-pulsed intravenous methylpredni-
solone gives a high initial loading dose of
corticosteroid and may help to avoid the
adverse effects associated with long-term oral
treatment. Treatment is therefore often
initiated with 1 g of intravenous methyl
prednisolone daily for three days followed by

0.5–1 mg/kg oral prednisolone per day. An
enhanced MRI brain scan at this stage may be
useful—persistent or new enhancement sug-
gests that further reduction in corticosteroid
therapy may lead to an exacerbation of the
disease.71 Conversely, persistent CSF abnormal-
ities do not necessarily correlate with disability
and are therefore not an indication for
continuing therapy.6 If the disease does become
quiescent on a low dose of prednisolone, the
daily dose can be further tapered by 1 mg every
2–4 weeks.6 Methotrexate or hydroxychloro-
quine may then be added, especially if the
response to steroids is inadequate.23, 69
Methotrexate used weekly at an oral dose
of 10 mg, is well tolerated with minimal
adverse effects and may be of value in
maintaining optimal disease suppression
together with intravenous or oral steroids.19
It is recommended that patients undergo a
liver biopsy after every gram of methotrexate
administered, but irreversible liver damage is
fortunately rare.
Chloroquine has now largely been replaced
by the less toxic hydroxychloroquine at a dose
of 200 mg/day, and may be used for up to
one year as a first line agent with metho-
trexate. Hydroxychloroquine is also particu-
larly effective in patients with skin lesions,
and its hypoglycaemic effect may be useful in
those with steroid-induced hyperglycaemia.
Few data are available to support the use
of other forms of immunotherapy in neuro-
sarcoidosis. Chlorambucil, cyclophosphamide,
cyclosporin, azathioprine and mycophenolate
mofetil have all been used, with variable
results,6, 19, 68, 72, 73 usually in combination with
corticosteroids which can rarely be withdrawn
altogether—the best combination being a
moderate dose of prednisolone with an
adjunct therapy.6 One study of cyclosporin
treatment in neurosarcoidosis showed only
a modest response and allowed a mere 30–
55% reduction in the steroid dosage.72
Cyclophosphamide is often considered, sev-
eral studies reporting significant neurological
improvement.23, 68, 74, 75 Compared with oral
treatment, pulsed intravenous cyclophospha-
mide is associated with better patient com-
pliance and lower risk of malignancy,
especially bladder cancer.
Although the chemokine and cytokine
pathways that regulate granuloma formation
Joseph, Scolding 241
PRACTICE POINTS
l Although sarcoidosis is rarely confined to the nervous system, its
neurological features frequently occur early in the course of the disease
leading to diagnostic confusion.
l Presentation with cranial neuropathies (particularly nerves VII, II) is the
most common, but seizures, chronic meningitis and the effects of mass
lesions are also frequent manifestations of neurosarcoidosis.
l The diagnostic process should first confirm nervous system involvement
and then provide supportive evidence for systemic disease.
l In the absence of direct tissue biopsy, the most useful diagnostic tests for
neurosarcoidosis are gadolinium enhanced MRI of the brain and CSF
analysis.
l The diagnostic criteria for neurosarcoidosis have been modified to include
high definition CT of the chest and bronchoalveolar lavage with a CD4:CD8
ratio .3.5, and a CD4:CD8 ratio .5 in the CSF.
l The mainstay of treatment is corticosteroids, which often need to be
combined with other immunosuppressants.
are not well understood, tumour necrosis
factor-alpha (TNF-a) is implicated.76 The TNF-
a antagonists pentoxifylline and thalidomide
are reported to be useful in refractory
systemic and neurosarcoidosis.77, 78 Infliximab
(a monoclonal antibody against TNF-a) in
particular has a growing body of literature
supporting its effectiveness, and appears to
be a safe treatment with good steroid sparing
effects.79–83
The long-term complications of these
cytotoxic agents should not be underesti-
mated, with awareness for the effects of
immunocompromise. Infections such as tox-
oplasmosis, tuberculous and cryptococcal
meningitis may occur, and also lymphoproli-
ferative disorders, which may be overlooked
as some features of these diseases may
themselves mimic sarcoidosis.
Antiepileptic drugs are indicated for sei-
zures associated with the disease. Depression
is common and appropriate antidepressant
therapy should not be withheld. Phenytoin
(and also methotrexate) may cause hilar and
mediastinal lymphadenopathy, which may be
indistinguishable from sarcoidosis.
Radiotherapy is a treatment option usually
limited to those patients whose symptoms
cannot be controlled on steroids and/or
cytotoxic drugs, or for those who cannot
tolerate their adverse effects.6 The mechanism
can only be extrapolated from our knowledge
of the radiobiological effects on normal and
neoplastic tissue: metabolically active cells of
www.practical-neurology.com
242 Practical Neurology
granulomata are probably more susceptible to
radiation damage than normal CNS tissue.
Case reports have shown variable clinical and
radiological outcomes.84–86
Neurosurgical intervention is indicated in
life-threatening situations or when medical
treatment fails. Asymptomatic ventricular
enlargement does not usually require surgery,
and mild symptomatic hydrocephalus may
simply respond to corticosteroids.15 More
significant hydrocephalus will require a CSF
diversion procedure, usually ventriculoperito-
neal shunting,87 although endoscopic treat-
ment may be successful.88 Shunt obstruction
may occur in these patients by inflamed CSF,
ependyma or rarely non-caseating granulo-
mas.89 Resection of intracranial or spinal
granulomata may be required, especially
when they result in raised intracranial
pressure.
ACKNOWLEDGEMENTS
The authors are grateful to Professor Seth
Love and Dr Marcus Likeman for the kind
provision of illustrative material. This article
was reviewed by Myles Connor, Edinburgh,
UK.
REFERENCES
1. Hosoda Y, Sasagawa S, Yasuda N. Epidemiology of
sarcoidosis: new frontiers to explore. Curr Opin
Pulm Med 2002;8:424–8.
2. Baughman RP, Teirstein AS, Judson MA, et al.
Clinical characteristics of patients in a case control
study of sarcoidosis. Am J Respir Crit Care Med
2001;164:1885–9.
3. Rybicki BA, Iannuzzi MC, Frederick MM, et al.
Familial aggregation of sarcoidosis. A case-control
etiologic study of sarcoidosis (ACCESS). Am J Respir
Crit Care Med 2001;164:2085–91.
4. Martinetti M, Tinelli C, Kolek V, et al. ‘‘The
sarcoidosis map’’: a joint survey of clinical and
immunogenetic findings in two European
countries. Am J Respir Crit Care Med
1995;152:557–64.
5. Moller DR, Chen ES. What causes sarcoidosis? Curr
Opin Pulm Med 2002;8:429–34.
6. Stern BJ. Neurological complications of sarcoidosis.
Curr Opin Neurol 2004;17:311–16.
7. Trevenzoli M, Cattelan AM, Marino F, et al.
Sarcoidosis and HIV infection: a case report and a
review of the literature. Postgrad Med J
2003;79:535–8.
8. Morris DG, Jasmer RM, Huang L, et al. Sarcoidosis
following HIV infection: evidence for CD4+
lymphocyte dependence. Chest 2003;124:929–35.
9. Heerfordt CF. Über eine ‘‘Febris uveo-parotidea
subchronica’’ an der Glandula parotis und der Uvea
des Auges lokalisiert und häufug mit Paresen
cerebrospinaler Nerven kompliziert. Albrecht von
Grafes Archiv für Ophthalmologie 1909;70:254–73.
10.1136/jnnp.2007.124263
10. Keynes M. The personality, deafness, and bad
health of Ludwig van Beethoven. J Med Biogr
2002;10:46–57.
11. Sharma OP. Beethoven’s illness: Whipple’s disease
rather than sarcoidosis? J R Soc Med
1994;87:283–5.
12. Drake ME Jr. Deafness, dysesthesia, depression,
diarrhea, dropsy, and death: the case for
sarcoidosis in Ludwig van Beethoven. Neurology
1994;44:562–5.
13. Palferman TG. Classical notes: Beethoven’s medical
history. Variations on a rheumatological theme.
J R Soc Med 1990;83:640–5.
14. Oksanen V. Neurosarcoidosis: clinical presentations
and course in 50 patients. Acta Neurol Scand
1986;73:283–90.
15. Stern BJ, Krumholz A, Johns C, et al. Sarcoidosis
and its neurological manifestations. Arch Neurol
1985;42:909–17.
16. Chen RC, McLeod JG. Neurological complications of
sarcoidosis. Clin Exp Neurol 1989;26:99–112.
17. James DG, Sharma OP. Neurosarcoidosis. Proc R Soc
Med 1967;60:1169–70.
18. Iwai K, Tachibana T, Takemura T, et al. Pathological
studies on sarcoidosis autopsy. I. Epidemiological
features of 320 cases in Japan. Acta Pathol Jpn
1993;43:372–6.
19. Zajicek JP, Scolding NJ, Foster O, et al. Central
nervous system sarcoidosis—diagnosis and
management. QJM 1999;92:103–17.
20. Nowak DA, Widenka DC. Neurosarcoidosis: a review
of its intracranial manifestation. J Neurol
2001;248:363–72.
21. Kohler A, Chofflon M, Sztajzel R, et al.
Cerebrospinal fluid in acute peripheral facial palsy.
J Neurol 1999;246:165–9.
22. Sharma OP. Neurosarcoidosis: a personal
perspective based on the study of 37 patients.
Chest 1997;112:220–8.
23. Lower EE, Broderick JP, Brott TG, Baughman RP.
Diagnosis and management of neurological
sarcoidosis. Arch Intern Med 1997;157:1864–8.
24. Sponsler JL, Werz MA, Maciunas R, et al.
Neurosarcoidosis presenting with simple partial
seizures and solitary enhancing mass: case reports
and review of the literature. Epilepsy Behav
2005;6:623–30.
25. Krumholz A, Stern BJ, Stern EG. Clinical implications
of seizures in neurosarcoidosis. Arch Neurol
1991;48:842–4.
26. Delaney P. Neurologic manifestations in
sarcoidosis: review of the literature, with a
report of 23 cases. Ann Intern Med
1977;87:336–45.
27. Borucki SJ, Nguyen BV, Ladoulis CT, et al.
Cerebrospinal fluid immunoglobulin abnormalities
in neurosarcoidosis. Arch Neurol 1989;46:270–3.
28. Veres L, Utz JP, Houser OW. Sarcoidosis presenting
as a central nervous system mass lesion. Chest
1997;111:518–21.
29. Gizzi MS, Lidov M, Rosenbaum D. Neurosarcoidosis
presenting as a tumour of the basal ganglia and
brainstem: sequential MRI. Neurol Res
1993;15:93–6.
30. Miller DH, Kendall BE, Barter S, et al. Magnetic
resonance imaging in central nervous system
sarcoidosis. Neurology 1988;38:378–83.
31. Rieger J, Hosten N. Spinal cord sarcoidosis.
Neuroradiology 1994;36:627–8.

32. Sharma OP, Sharma AM. Sarcoidosis of the nervous
system. A clinical approach. Arch Intern Med
1991;151:1317–21.
33. Bogousslavsky J, Hungerbuhler JP, Regli F, et al.
Subacute myelopathy as the presenting
manifestation of sarcoidosis. Acta Neurochir (Wien)
1982;65:193–7.
34. Caroscio JT, Yahr MD. Progressive myelopathy due
to sarcoid. Clin Neurol Neurosurg 1980;82:217–22.
35. Bona JR, Fackler SM, Fendley MJ, et al.
Neurosarcoidosis as a cause of refractory
psychosis: a complicated case report.
Am J Psychiatry 1998;155:1106–8.
36. O’Brien GM, Baughman RP, Broderick JP, et al.
Paranoid psychosis due to neurosarcoidosis.
Sarcoidosis 1994;11:34–6.
37. Sabaawi M, Gutierrez-Nunez J, Fragala MR.
Neurosarcoidosis presenting as schizophreniform
disorder. Int J Psychiatry Med 1992;22:269–74.
38. Stoudemire A, Linfors E, Houpt JL. Central nervous
system sarcoidosis. Gen Hosp Psychiatry
1983;5:129–32.
39. Miller R, Sheron N, Semple S. Sarcoidosis
presenting with an acute Guillain-Barre syndrome.
Postgrad Med J 1989;65:765–7.
40. Otake S, Ishigaki T. Muscular sarcoidosis. Semin
Musculoskelet Radiol 2001;5:167–70.
41. Fayad F, Liote F, Berenbaum F, et al. Muscle
involvement in sarcoidosis: a retrospective and
followup studies. J Rheumatol 2006;33:98–103.
42. Pickuth D, Heywang-Kobrunner SH.
Neurosarcoidosis: evaluation with MRI.
J Neuroradiol 2000;27:185–8.
43. Mana J. Magnetic resonance imaging and nuclear
imaging in sarcoidosis. Curr Opin Pulm Med
2002;8:457–63.
44. Dubey N, Miletich RS, Wasay M, et al. Role of
fluorodeoxyglucose positron emission tomography
in the diagnosis of neurosarcoidosis. J Neurol Sci
2002;205:77–81.
45. Ng D, Jacobs M, Mantil J. Combined C-11
methionine and F-18 FDG PET imaging in a case of
neurosarcoidosis. Clin Nucl Med 2006;31:373–5.
46. Oksanen V, Fyhrquist F, Somer H, et al. Angiotensin
converting enzyme in cerebrospinal fluid: a new
assay. Neurology 1985;35:1220–3.
47. Tahmoush AJ, Amir MS, Connor WW, et al. CSF-ACE
activity in probable CNS neurosarcoidosis.
Sarcoidosis Vasc Diffuse Lung Dis 2002;19:191–7.
48. Dale J. determination of angiotensin-converting
enzyme levels in cerebrospinal fluid is not a useful
test for the diagnosis of neurosarcoidosis. Mayo
Clin Proc 1999;74:535.
49. Oksanen V. New cerebrospinal fluid,
neurophysiological and neuroradiological
examinations in the diagnosis and follow-up of
neurosarcoidosis. Sarcoidosis 1987;4:105–10.
50. Adachi N. Beta-2-microglobulin levels in the
cerebrospinal fluid: their value as a disease marker.
A review of the recent literature. Eur Neurol
1991;31:181–5.
51. Oksanen V, Gronhagen-Riska C, Tikanoja S, et al.
Cerebrospinal fluid lysozyme and beta 2-
microglobulin in neurosarcoidosis. J Neurol Sci
1986;73:79–87.
52. Li CY, Yam LT. Cytologic and immunocytochemical
studies of cerebrospinal fluid in meningeal
sarcoidosis. A case report. Acta Cytol
1992;36:963–7.
Joseph, Scolding 243
53. Stern BJ, Griffin DE, Luke RA, et al.
Neurosarcoidosis: cerebrospinal fluid lymphocyte
subpopulations. Neurology 1987;37:878–81.
54. Marangoni S, Argentiero V, Tavolato B.
Neurosarcoidosis: Clinical description of 7 cases
with a proposal for a new diagnostic strategy.
J Neurol 2006;253:488–95.
55. Oksanen V, Salmi T. Visual and auditory evoked
potentials in the early diagnosis and follow-up of
neurosarcoidosis. Acta Neurol Scand 1986;74:38–42.
56. Verma NP, Desai SG, Simon MR, et al.
Multimodality evoked potentials in sarcoidosis. J Lab
Clin Med 1988;111:692–700.
57. Matsumoto R, Shintaku M, Suzuki S, et al. Cerebral
perivenous calcification in neuropsychiatric lupus
erythematosus: a case report. Neuroradiology
1998;40:583–6.
58. Hoitsma E, Marziniak M, Faber CG, et al. Small fibre
neuropathy in sarcoidosis. Lancet
2002;359:2085–6.
59. Rothkrantz-Kos S, van Dieijen-Visser MP,
Mulder PG, et al. Potential usefulness of
inflammatory markers to monitor respiratory
functional impairment in sarcoidosis. Clin Chem
2003;49:1510–17.
60. Nuria A, Reis A, Bernardo J, et al. [Mediastinoscopy
in the diagnose of sarcoidosis]. Rev Port Pneumol
2003;9(Suppl 5):36–7.
61. Segal EI, Tang RA, Lee AG, et al. Orbital apex lesion
as the presenting manifestation of sarcoidosis.
J Neuroophthalmol 2000;20:156–8.
62. Makhija MC, Anayiotos CP. Gallium scan in
intracerebral sarcoidosis. Clin Nucl Med
1981;6:324–7.
63. Hegab SM, al-Mutawa SA, Sheriff SM.
Sarcoidosis presenting as multilobular limbal
corneal nodules. J Pediatr Ophthalmol Strabismus
1998;35:323–6.
64. Braun M, Jonas JB. [Band-like corneal degeneration
as the initial sign of sarcoidosis]. Klin Monatsbl
Augenheilkd 1996;209:328–9.
65. Volcker HE, Naumann GO. [Sarcoidosis of the eye.
Biomicroscopic and histopathologic findings]. Klin
Monatsbl Augenheilkd 1985;187:83–91.
66. Silverstein A, Siltzbach LE. Muscle involvement in
sarcoidosis. Asymptomatic, myositis, and
myopathy. Arch Neurol 1969;21:235–41.
67. Scola RH, Werneck LC, Prevedello DM, et al.
Symptomatic muscle involvement in
neurosarcoidosis: a clinicopathological study of 5
cases. Arq Neuropsiquiatr 2001;59:347–52.
68. Agbogu BN, Stern BJ, Sewell C, et al. Therapeutic
considerations in patients with refractory
neurosarcoidosis. Arch Neurol 1995;52:875–9.
69. Sharma OP. Effectiveness of chloroquine and
hydroxychloroquine in treating selected patients
with sarcoidosis with neurological involvement.
Arch Neurol 1998;55:1248–54.
70. Johns CJ, Michele TM. The clinical management of
sarcoidosis. A 50-year experience at the Johns
Hopkins Hospital. Medicine (Baltimore)
1999;78:65–111.
71. Dumas JL, Valeyre D, Chapelon-Abric C, et al.
Central nervous system sarcoidosis: follow-up at
MR imaging during steroid therapy. Radiology
2000;214:411–20.
72. Stern BJ, Schonfeld SA, Sewell C, et al. The
treatment of neurosarcoidosis with cyclosporine.
Arch Neurol 1992;49:1065–72.
www.practical-neurology.com
244 Practical Neurology
73. Kouba DJ, Mimouni D, Rencic A, et al.
Mycophenolate mofetil may serve as a steroid-
sparing agent for sarcoidosis. Br J Dermatol
2003;148:147–8.
74. Bullmann C, Faust M, Hoffmann A, et al. Five cases
with central diabetes insipidus and hypogonadism
as first presentation of neurosarcoidosis.
Eur J Endocrinol 2000;142:365–72.
75. Ferriby D, de Seze J, Stojkovic T, et al. [Clinical
manifestations and therapeutic approach in
neurosarcoidosis]. Rev Neurol (Paris)
2000;156:965–75.
76. Roach DR, Bean AG, Demangel C, et al. TNF
regulates chemokine induction essential for cell
recruitment, granuloma formation, and clearance
of mycobacterial infection. J Immunol
2002;168:4620–7.
77. Zheng L, Teschler H, Guzman J, et al. Alveolar
macrophage TNF-alpha release and BAL cell
phenotypes in sarcoidosis. Am J Respir Crit Care
Med 1995;152:1061–6.
78. Baughman RP, Strohofer SA, Buchsbaum J, et al.
Release of tumor necrosis factor by alveolar
macrophages of patients with sarcoidosis. J Lab
Clin Med 1990;115:36–42.
79. Doty JD, Mazur JE, Judson MA. Treatment of
sarcoidosis with infliximab. Chest
2005;127:1064–71.
80. Sollberger M, Fluri F, Baumann T, et al. Successful
treatment of steroid-refractory neurosarcoidosis
with infliximab. J Neurol 2004;251:760–1.
10.1136/jnnp.2007.124263
81. Carter JD, Valeriano J, Vasey FB, et al. Refractory
neurosarcoidosis: a dramatic response to
infliximab. Am J Med 2004;117:277–9.
82. Morcos Z. Refractory neurosarcoidosis responding
to infliximab. Neurology 2003;60:1220–1; author
reply 1220–1.
83. Pettersen JA, Zochodne DW, Bell RB, et al.
Refractory neurosarcoidosis responding to
infliximab. Neurology 2002;59:1660–1.
84. Kang S, Suh JH. Radiation therapy for
neurosarcoidosis: report of three cases from a
single institution. Radiat Oncol Investig
1999;7:309–12.
85. Manterola-Burgaleta A, Teijeira-Garcia M, Duenas-
Polo MT. [Neurosarcoidosis. Apropos of a case and
review of the literature]. Rev Neurol 2001;32:57–9.
86. Gelwan MJ, Kellen RI, Burde RM, et al. Sarcoidosis of
the anterior visual pathway: successes and failures.
J Neurol Neurosurg Psychiatry 1988;51:1473–80.
87. Foley KT, Howell JD, Junck L. Progression of
hydrocephalus during corticosteroid therapy for
neurosarcoidosis. Postgrad Med J 1989;65:481–4.
88. Hamada H, Hayashi N, Kurimoto M, et al. Isolated
third and fourth ventricles associated with
neurosarcoidosis successfully treated by
neuroendoscopy—case report. Neurol Med Chir
(Tokyo) 2004;44:435–7.
89. Maniker AH, Cho ES, Schulder M. Neurosarcoid
infiltration of the ventricular catheter causing
shunt failure: a case report. Surg Neurol
1997;48:527–9.