Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2014 Dec; 158(4):662-667.

Neurosarcoidosis: Two case reports with multiple cranial nerve involvement
and review of the literature
Milija Mijajlovica, Mihailo Mirkovicb, Violeta Mihailovic-Vucinicc, Vuk Aleksica, Nadezda Covickovic-Sternica
Background. Involvement of the central nervous system is registered in a relatively small number of patients with
sarcoidosis. In this article we present two cases with various neurological symptoms that fulfill criteria for neurosarcoidosis (NS). In addition, we review the literature on NS with special attention to isolated cranial nerve involvement.
Methods and Results. First patient: Neurological examination identified multiple cranial neuropathy, moderate rightsided hemiparesis, polyradiculoneuritis of the lower limbs and positive meningeal signs. Laboratory tests showed
serum and cerebrospinal fluid (CSF) inflammatory abnormalities, with increased values of the angiotensin-converting
enzyme (ACE). CSF analysis also showed presence of 9 oligoclonal IgG bands. Brain and spine magnetic resonance
imaging (MRI) revealed diffuse meningopathy, and focal granulomatous lesion in the body of the L5 vertebra. Lung
sarcoidosis was confirmed by additional diagnostic procedures. The patient was treated with Methylprednisolone
and a tapering course of oral Prednisone, which reduced the pain in the back and legs and improved the strength of
the right leg. However, the other neurological deficiencies remained. After confirming lung sarcoidosis, the patient
received Methotrexate in addition to Prednisone but during the following 2 years the patient’s condition progressively
worsened and ended in death.
Second patient: Neurological findings showed weakness of the right n. oculomotorius and the right n. trochlearis, as
well as the right-side face weakness. We found raised level of the ACE in serum and CSF. Thorax high-definition computed tomography (HDCTT) showed ribbon-like domains of discrete changes in the pulmonary parenchyma. MRI of
the brain showed multiple white matter lesions. This patient also received Methylprednisolone followed by Prednisone,
and after two months, ocular motility normalized.
Conclusion. The diagnosis of NS is always a challenge. For this rerason definitive diagnosis requires the exclusion of
other causes of neuropathy. Multiple cranial neuropathies should always arouse suspicion of NS.
Key words: sarcoidosis, neurosarcoidosis, multiple cranial neuropathies
Received: November 24, 2012; Accepted with revision: June 6, 2013; Available online: June 27, 2013
http://dx.doi.org/10.5507/bp.2013.047
Neurology Clinic, Clinical Center of Serbia and School of Medicine, University of Belgrade, Serbia
Department of Neurology, Health Center Valjevo, Valjevo, Serbia
c
Clinic for Pulmonary Diseases and Tuberculosis, Clinical Center of Serbia and School of Medicine, University of Belgrade, Serbia
Corresponding author: Milija Mijajlovic, e-mail: milijamijajlovic@yahoo.com
a

b

INTRODUCTION
Sarcoidosis is a chronic systemic granulomatous disease of unknown etiology, which can only be diagnosed
with certainty by histological examination. The prevalence
of clinical involvement of the central and peripheral nervous system in sarcoidosis is estimated to 5-15%, and
very rarely it may selectively involve the nervous system1.
Neurosarcoidosis (NS) is a diagnostic challenge, especially if systemic symptoms are absent, which happens
in about 3% of patients with NS. Neurological symptoms
are the primary manifestation of the disease in 62-74% of
cases of NS (ref.2,3). Majority of patients with NS develop
systemic symptoms after presenting neurological signs
of disease.
CASE REPORT 1
A 45-year-old woman with a history of suspected
cervical carcinoma underwent total hysterectomy when
662

she was 34 years old, but likely, suspicion was never confirmed. When she was 43, a regular oncological examination by chest radiography revealed a lesion in the apical
part of the right lung. Because of that, thorax high-definition computed tomography (HDCTT) was performed,
followed by fiber bronchoscopy. A malignant process was
not identified. The patient was a smoker for many years
and for several years she spoke in a hoarse voice. She also
suffered from pneumonia a few times.
The patient’s father died of lung cancer at the age
of 70 and the patient's grandfather suffered from lung
tuberculosis.
First neurological difficulties manifested at the
age of 37 when she was hospitalized at the Neurology
Department of the Health Centre Valjevo. At that time,
the moderate right-sided hemiparesis was identified, so
we first performed computed tomography (CT) scan of
the brain, which showed normal findings.
At the age of 45 she felt numbness of the feet and pain
in the back, which gradually spread to the legs. In the
course of one year the patient noticed weakness of dorsi-

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2014 Dec; 158(4):662-667.

Fig. 1. MRI scan of the brain (fluid attenuated inversion
recovery-FLAIR sequence): diffuse meningopathy.

flexion of the left foot, unstable walking, as well as certain
difficulty while climbing the stairs. During that period
she gradually developed slightly reduced visual acuity on
the left eye, sensory loss and weakness in the left side of
face followed by loss of taste over the anterior two-thirds
of the left side of the tongue and reduced lacrimation on
the left eye, left-sided hearing loss, swallowing difficulties
and numbness in the left side of the tongue. As associated
symptoms and signs, intermittent sub febrile temperature,
fatigue, weight loss and palm rash, were recorded
Laboratory tests showed serum and CSF inflammatory abnormalities, with increased values of the angiotensin-converting enzyme (ACE), but both were negative on
infectious diseases. CSF analysis also showed presence of
9 oligoclonal IgG bands. Brain and spine MRI revealed
diffuse meningopathy (Fig. 1, 2), and focal granulomatous
lesion in the body of the L5 vertebra (Fig. 3). Chest radiographs, HDCTT and bronchoscopy with transbronchial
biopsy confirmed lung sarcoidosis. Bone scintigraphy
showed normal findings.
General examination showed only inguinal and axillary lymphadenopathy. Neurological findings identified
multiple cranial neuropathy (II, V, VII, VIII, IX, XI and
XII nerves), moderate right-sided weakness, polyradiculoneuritis of the lower limbs and positive meningeal signs.
Following these neurological findings, further examination focused on neurosarcodiosis, so the patient was
hospitalized at the Neurology Department of the Health
Care Centre Valjevo for the second time. Laboratory tests
yielded: white blood cells count - 11.300/mm3, ACE in
serum and CSF were 71.5 U/L and 2.0 U/L (0-0), respectively. CSF analysis indicated lymphocytic pleocytosis
(10 cells), raised protein level (0.77g/L), hypoglycorrhachia (2.3 mmol/L) and the presence of 9 oligoclonal IgG
bands detected by CSF electrophoresis. Cultures for my663

Fig. 2. MRI scan of the brain (T1 weighted sequence): diffuse
meningopathy.

Fig. 3. MRI scan of the spinal column (T1 weighted sequence): focal granulomatous lesion in the body of the L5 vertebra.

cobacterium and Mantoux test were negative and malignant cells in CSF were not identified.
Other causes of granulomatous diseases, such as infections (cryptococcus, histoplasma, toxoplasma, treponema, and Whipple’s disease), inflammatory disorders
(Wegener’s granulomatosis, giant cell arteritis, systemic
lupus erythematosus, and Churg–Strauss syndrome) were
excluded by additional analyses. Influence of chemicals,
radiotherapy and chemotherapy was also excluded.

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Chest radiography showed a change in the upper part
of the right lung. HDCTT showed parenchymal tissue
changes in the right lung, along with hilar and mediastinal
lymph node enlargement. There was a progression of the
changes compared to the initial findings.
The patient was treated with Methylprednisolone
(1000 mg/day for three days) and a tapering course of
oral Prednisone, which reduced the pain in the back and
legs and improved the strength of the right leg. However,
the rest of the neurological deficiency remained.
The patient was then referred to the Neurology Clinic
in Belgrade for additional tests as NS was suspected. The
laboratory tests conducted there showed ACE in the serum 47.2 U/L and CSF 4.3 U/L (0-0), respectively. Tumor
markers Cyfra 21-1, NSE, AFP, CA 15-3 and CA 19-9
were within referential value range, while CA 125 and
CEA were high.
CSF analysis revealed 3 lymphocytes and 164 erythrocytes, raised protein level (0.95 g/L), hypoglycorrhachia
(1.8 mmol/L), and the presence of 9 oligoclonal IgG
bands, detected by electrophoresis.
Lower limbs electromyoneurography (EMNG) test
revealed a strong and chronic lesion of the S1 and L5 root
on the right side, while on the left side there was a strong
subacute lesion of the L5 and a mild lesion of the L4 root.
Transbronchial biopsy isolated epithelioid granulomatous foci and confirmed lung sarcoidosis.
Therefore, the patient was transferred to the Institute for
Pulmonary Diseases in Belgrade, where therapy included
Methotrexate in addition to Prednisone, but during next
2 years the patient’s condition progressively worsened and
ended in patient's death.
CASE REPORT 2
A 70-year-old man was admitted at the Neurology
Clinic of the Clinical Center of Serbia because of the
right-sided ptosis and predominant vertical double vision,
worse on downward gaze, the most pronounced during
attempted medial gaze. Seven years before, at the age of
63, he was treated for peripheral weakness of the right
side of the face designated as Bell’s palsy.

Past medical history showed slightly higher glucose
blood level and elevated blood pressure as well as irregular
heartbeats i.e. premature ventricular contractions (PVC).
Neurological findings showed involvement of the right
n. oculmotorius, severe right n. trochlearis palsy and the
peripheral weakness of the right side of the face with
synkinetic movements of the right corner of the mouth
during eye squeezing (as the late sequelae of Bell's palsy).
Other neurological findings were normal.
The ACE level in serum was 102.3 U/L (8-52), and
in CSF 3.9 U/L (0-0), respectively. CSF analysis showed
normal protein level, normal glycorrhachy, 1 lymphocyte,
and no presence of oligoclonal IgG bands. Cultures for
mycobacterium and Mantoux test were negative, while the
cytological examination of CSF did not reveal any malignant cells. Additional examination excluded other causes
of granulomatous diseases. Prostigmine test was negative.
MRI of the brain showed multiple white matter, T2weighted and fluid attenuated inversion recovery hyperintense lesions, in the periventricular areas. HDCTT
showed ribbon-like domains of discrete changes in pulmonary parenchyma, but with regular mediastinum configuration and with no signs of lymphadenomegaly. Cerebral
Magnetic Resonance Angiography (MRA) revealed no
stenosis, aneurysm or arteriovenous malformations, but
only slightly reduced terminal branches of both middle
cerebral arteries. Twenty-four hour holter electrocardiographic monitoring was performed, but no PVCs were
found. Structural heart diseases were ruled out by conventional cardiac examinations.
The patient was treated with Methylprednisolone
(1000 mg/day for three days), followed by 60 mg of
Prednisone a day. The patient was monitored for two
months, after which double vision disappeared and bulbous motility was normal.
DISCUSSION
Sarcoidosis is an inflammatory granulomatous disease
affecting multiple organ systems. NS is characterized by
central nervous system involvement and even though is a
less common manifestation of sarcoidosis, its symptoms

Table 1. Diagnostic criteria for neurosarcoidosis2.
Proposed criteria for the diagnosis of neurosarcoidosis
Definite
Probable

Possible

• clinical presentation suggestive of neurosarcoidosis
• positive nervous system histology
• clinical syndrome suggestive of neurosarcoidosis
• laboratory support for CNS inflammation (elevated levels of CSF protein and/or cells, the presence of
oligoclonal bands and/or MRI evidence compatible with neurosarcoidosis)
• evidence for systemic sarcoidosis (either through positive histology, including Kveim test, and/or at least two
• indirect indicators from Gallium scan, chest imaging and serum ACE)
• exclusion of alternative diagnoses
• clinical presentation suggestive of neurosarcoidosis
• exclusion of alternative diagnoses where the above criteria are not met

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can be devastating and may present to the physician in a
number of guises.
Reviewing 68 cases of NS, Zajicek et al. formulated a
series of diagnostic criteria for NS, which are presented in
Table 1 (ref.2). On the basis of these criteria, the diagnosis of NS can be: definite, probable or possible. Here we
report two patients, the first one with probable diagnosis
(clinical syndrome suggestive of neurosarcoidosis with
laboratory support for CNS inflammation and exclusion
of alternative diagnoses) and the second one with possible
diagnosis (clinical presentation suggestive of neurosarcoidosis with exclusion of alternative diagnoses) of NS.
The clinical course may be acute, subacute or chronic
with insidious onset. Systemic inflammatory indicators
are altered only occasionally in NS.
Clinical symptoms of intracranial neurosarcoidosis
depend on the location of lesions. Meninges of the skull
base, hypothalamus and pituitary gland are the most common sites4-12.
The most common neurological symptoms are cranial nerve deficits, headache and seizures 2,7,10-17. The
facial nerve is most frequently affected, either due to a
meningeal reaction or secondary to inflammation in the
parotid gland. Facial palsies may occur unilaterally and
simultaneously or sequentially bilaterally2,18. With exception of paresis of the VII cranial nerve, due to proximate
inflammation of the parotid gland, nervous system involvement is not prone to spontaneous remission19. Both
patients described here suffered from peripheral facial
weakness, which did not improve in our first patient, while
the second patient manifested incomplete resolution of
peripheral facial weakness, after the treatment with corticosteroids.
In addition, syndromes deriving from the involvement
of virtually every other cranial nerve have been reported2.
In addition to the left facial nerve palsy, our first patient
manifested damage of the left optic, trigeminal, auditory,
hypoglossal, and the right accessory nerve, while in the
second patient involvement of the right oculomotor and
trochlear nerve was determined.
Meningeal symptoms may be acute or chronic.
Symptoms and signs include fever, headache, neck rigidity, and sterile CSF with pleocytosis (particularly lymphocytes) (ref.20). Sometimes mental status changes and
polyradiculopathy could be present21,22. Our first patient
suffered from poliradiculopathy and there were positive
meningeal signs.
NS is difficult to diagnose, partly because the neurological presentation is polymorphic and nonspecific and
it should be suspected after ruling out other inflammatory diseases, including cases of cryptogenic subacute
meningo-myelopathies, especially when they respond to
corticosteroids but tend to recur after suspending the
drug. Hence, differential diagnosis includes chronic and
subacute meningitis, multiple sclerosis, myelopathies and
tumour-like lesions23-25. In both cases we performed extensive examination in order to exclude other differential
diagnostic possibilities.
ACE levels are raised in 50% of patients with neurosarcoidosis (range 35-75%). Some authors regard ACE levels
665

in CSF as being useful in both the diagnosis and follow-up
of NS (ref.26,27). However, many authorities now regard
this test as non-specific and insensitive. CSF ACE may be
raised in infections and malignancy, and appears unhelpful in any therapeutic decision making28. This is illustrated
by one study of 32 patients with sarcoidosis, including
20 with NS: CSF ACE levels were raised in only 55% of
patients with NS, in 5% of patients with sarcoidosis not
apparently involving the nervous system, and in 13% of
patients with other neurological diseases29. In both of our
patients levels of ACE in serum and CFS were raised.
Hypercalcaemia is often seen in pulmonary sarcoidosis (a result of additional ahydroxylation occurring in
the sarcoid lesions in the lung), while many cases of NS
are reported with completely normal calcium levels, and
similarly the erythrocyte sedimentation rate is raised only
in a minority of cases. Both blood tests were normal in
our presented patients.
The diagnostic value of chest radiography in suspected
systemic sarcoidosis is undisputable: abnormalities are
seen in 90%, but of course, a normal chest X-ray does
not exclude generalized sarcoidosis30. HDCTT is useful in
diagnosing pulmonary sarcoidosis and also assists in targeting transbronchial biopsy. It is approximately 89% and
98% sensitive for hilar and mediastinal lymphadenopathy
respectively, and 23% sensitive for pulmonary infiltrates31.
Both diagnostic methods were positive in our first patient.
CSF abnormalities in NS are usually nonspecific,
varying and they change over time and include mild
pleocytosis, high protein content, and sometimes slightly
lowered glucose concentrations (in about a fifth of patients) (ref.32). These changes may be marked and dictate
differential diagnosis with tuberculous meningitis, or exhibit oligoclonal bands and orient diagnosis towards a
demyelinating disease. Furthermore, increases in the concentration of ACE (ref.26,27,33-37), IgG-index38-40, oligoclonal
bands38,39,41, CD4/CD8 lymphocyte ratios42, lysosymes
and beta 2-microglobulin concentrations43 in CSF have
been reported. Most studies report evidence of intrathecal synthesis of immunoglobulins with oligoclonal bands
in about 30-40% of patients with NS (ref.2) while others
suggest that this is uncommon38. CSF showed signs of inflammation accompanied with intrathecal synthesis of immunoglobulins with oligoclonal bands in our first patient.
About a third of patients with NS have normal CSF
(ref.31,44,45), which was the case with our second patient,
while Marangoni at al. claim that CSF analysis may be
normal, but only after cycles of treatment with corticosteroids and/or immunosuppressants46. A number of elements may help to differentiate NS from tuberculous
meningitis: failure to identify bacteria, negative cultures
and polymerase chain reactions in 3 consecutive samples,
persistently negative tuberculin tests, less aggressive clinical course, failure to respond to anti-tuberculous therapy.
Moreover, in disorders such as multiple sclerosis and systemic lupus erythematosus, similar CSF abnormalities
could be found.
MRI is also far superior in defining parenchymal involvement, with a reasonable level of sensitivity for intracranial abnormalities (up to 82%) but poor specificity,

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with a wide spectrum of imaging findings47,48. About 40%
of patients with NS have either leptomeningeal enhancement with gadolinium (present in the first patient), or
multiple white matter lesions in the periventricular areas
(present in our second patient) that may be difficult to
distinguish from those seen in multiple sclerosis49. The
unenhanced MRI is unsatisfactory because of the artifacts near bone, CSF and meninges on both T1 and T2weighted images. Tuberculosis, other bacterial, fungal, and
neoplastic processes such as meningeal carcinoma, lymphoma and leukemia, may also enhance with gadolinium
and mimic sarcoid radiographically. The MRI lesions
in NS are more diffuse and smaller than those usually
seen in tuberculous meningitis46. 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.
The diagnostic procedure should always aim to locate
a site of disease that is accessible to biopsy. HDCTT, broncheoalveolar lavage (BAL) and contrast enhanced MRI
scans are valuable means of suspecting the diagnosis and
authorizing immunosuppressant therapy, when diagnostic
biopsy is not possible.
In the absence of positive histology, the diagnosis may
be supported by other types of investigation, such as BAL
with analysis of the lymphocyte subpopulations. A prevalence of CD4 lymphocytes on BAL, with a CD4:CD8
ratio higher than 3.5, has a positive predictive value of
76%, with 53% sensitivity and 94% specificity50.
The prognosis may be negatively influenced by various
factors, including genetic factors and onset after 40 years
of age51. Sarcoidosis has a variable natural course: about
30% of cases show spontaneous remission, while disorders
become chronic in 10-30% of cases52. One to five percent
of patients die, mainly from respiratory insufficiency,
myocardiopathy or CNS lesions. In fact, disability and
mortality rates are high in patients with CNS involvement3,53.
Conventional treatment of pulmonary sarcoidosis is
based on oral corticosteroids, but no studies have been
published that define optimum dose or duration54. Hence,
therapy is generally adjusted to patient response. Most
patients affected by NS responded to corticosteroids only
partially, prompting the need to associate an immunosuppressant drug3,55,56. Our first patient manifested a partial
improvement caused by corticosteroid therapy, so that
Methotrexate was added to the treatment, while the second patient responded well to corticosteroids.
Establishing a diagnosis of NS is therapeutically essential, since corticosteroid and immunosuppressant treatment must be started and continued for years in order to
prevent, or at least limit, otherwise permanent disability.
Early drug reduction led to a return of symptoms in all
described cases. Neurological impairment results not only
from florid inflammation, but also from progression of
the fibrosis, which entraps the roots, compresses and deforms the spinal cord profile and brain base structures.
This late stage of the disease may also benefit from immunosuppressant therapy.
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ABBREVIATIONS
ACE, angiotensin-converting enzyme; BAL, broncheoalveolar lavage; CSF, cerebrospinal fluid; CT, computed tomography; EMNG, electromyoneurography test;
ESR, erythrocyte sedimentation rate; HDCTT, thorax
high-definition computed tomography; MRA, magnetic
resonance angiography; MRI, magnetic resonance imaging; NS, neurosarcoidosis; PVC, premature ventricular
contractions.
AKNOWLEDGEMENT
This work was granted by the Ministry of Education
and Science of the Republic of Serbia. (Project No.
175022).
Authorship contributions: All authors equally contributed to preparing the manuscript.
Conflict of interest statement: None declared.
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