Keywords
sarcoidosis - neurosarcoidosis - psychiatric manifestations - pathology
Palavras-chave
sarcoidose - neurosarcoidose - manifestações psiquiátricas - patologia
Introduction
Sarcoidosis is a multisystem inflammatory disease of unknown etiology in which non-caseating
granulomas are found in the affected organs (mainly the lungs, the skin, and the lymph
nodes).[1] The incidence of sarcoidosis in Brazil is of 10/100,000 inhabitants, and the worldwide
incidence of neurosarcoidosis is estimated to be ∼ 0.2/100,000 inhabitants. The incidence
of the disease is higher among women and black men aged between 20 and 40 years, and
it is rarely seen in children.[1]
[2]
[3]
[4]
[5]
A genome study has shown that human leukocyte antigens (HLAs) DRB1 and DQB1 are risk
factors for the association with sarcoidosis.[6]
[7] Neurosarcoidosis is rare, and 5–15% of the patients with sarcoidosis will have the
central nervous system, brain, and spine cord affected; among these, 50% will present
symptoms.[8]
[9]
[10]
Case Report
A 26-year-old black female patient presented frontal headache for 1 year, as well
as sadness, tearfulness, and decreased appetite for the previous 15 days. She sought
medical attention and was treated with risperidone and clonazepam, but there was no
clinical improvement. During the neurological examination, she presented time and
space disorientation, so a skull tomography ([Fig. 1]) was requested, evidencing hypodensity and loss of cortical-subcortical differentiation
in the right frontal region. Following the investigation, nuclear magnetic resonance
imaging (MRI) was used, which revealed a meningeal lesion with infiltration of the
cerebral parenchyma associated with lytic lesions in the cranial calotte ([Fig. 2]).
Fig. 1 A Skull CT (axial cut) shows a lytic lesion in the right frontal region and loss
of cortical-subcortical differentiation.
Fig. 2 An MRI shows the frontal and interhemispheric pachymeningeal thickening, which is
predominantly right, associated with contrast enhancement. The presence of impairment
of the cranial calotte and infiltration of the superior frontal gyrus and frontobasal
can be observed.
Thoracic and total abdominal screening tests were performed, and showed a focal lesion
(1.6 cm) in the spleen with late uptake compatible with hemangioma and focal bronchiectasis
in the lower lobe of the left lung ([Fig. 3]), as well as bilateral subsegmental atelectasis. The echocardiogram and cerebrospinal
fluid (CSF) examination were normal.
Fig. 3 Thoracic tomography (axial cut).
Meningeal and brain tissue biopsies were performed using a surgery approach, with
supraorbital access and right supraciliary incision. During this period, the patient
was treated with corticoids due to cerebral edema and mass effect; she showed an improvement
in the signs and symptoms.
The anatomopathological analysis showed a small amount of granulomas in the bone region
and meninges ([Fig. 4] and [5]). Immunohistochemistry: CD99 negative, BCL6 negative, BCL2 negative, AE1/AE3 negative,
CD68 positive, kappa and lambda immunoglobulin chains positive, PAX positivity (25%),
KI67 focal positivity (10%), CD1a negative, HHF35 negative, calretinin negative, and
S100 with focal positivity < 2%. Thus, the morphological aspects and the immunomarkers
showed a limphohistiocytic lesion with a polytypic aspect compatible with a reactional
lesion.
Fig. 4 Multiple non-caseating well-defined granulomas with fibrosis in the skull.
Fig. 5 Decalcified section of involved area of the skull (osseous tissue).
Clinical Manifestations
The symptoms of sarcoidosis depend on the affected organ, and the most nonspecific
are fever, weight loss, night sweats, and fatigue. Neurological and cardiac symptoms
are rare; however, when they are present, they indicate severe illness.[4] The clinical presentation of neurosarcoidosis is usually optic neuropathy, facial
paralysis, meningitis, chronic meningitis, diabetes insipidus, hydrocephalus, elevated
intracranial pressure, spinal cord syndromes, vasculitis, cerebral infarction, dysfunctional
hypothalamus, myelopathy, myopathy, peripheral neuropathy, and encephalitis ([Table 1]); the presentation of psychiatric symptoms and osseous involvement is rare.[3]
[10]
[11]
[12]
[13]
[14]
Table 1
Percentages of neurological signs and symptoms
|
Peripheral mononeuropathy
|
69%
|
|
Depression
|
60–66%
|
|
Stress
|
55%
|
|
Cranial nerve
|
50%
|
|
Headache
|
17–48%
|
|
Myelopathy
|
16–43%
|
|
Polyradiculoneuropathy
|
39%
|
|
Hydrocephalus
|
5–38%
|
|
Meningeal disease
|
10–20%
|
|
Seizures
|
15%
|
|
Osseous involvement
|
13%
|
Cranial nerve alteration is present in 50–75% of the patients with neurosarcoidosis,
and the most common affected nerves are, in descending order, cranial nerves VII,
II and VIII. Cranial nerve VII is unilaterally affected in 65% of the cases, and bilaterally
affected in 35%;[7]
[15] cranial nerve II is affected in 5–25% of the patients.[1] Bone involvement of the skull and bone involvement of the spine are rare; however,
when the latter exists, it is located in the lower thoracic spine, or in the lumbar
spine in most cases.[16]
Diagnosis
The diagnosis is based on the clinical condition and radiological presentations; MRI
with contrast is the chosen exam, and laboratory tests such as CSF analysis must be
evaluated. However, for the diagnostic confirmation, the exclusion of other inflammatory
granulomatous diseases is necessary.[17] The investigation with thorax imaging usually shows strong indications for the diagnosis
and helps distinguish it from differential diagnoses ([Table 2]).[5]
Table 2
Differential diagnoses
|
Involvement of brain parenchyma
|
Meningeal involvement
|
|
Multiple sclerosis
|
Bacterial meningitis
|
|
Cerebral metastasis
|
Tuberculous meningitis
|
|
Cerebral lymphoma
|
Carcinomatous meningitis
|
|
Neurotuberculosis
|
Meningioma
|
|
Fungal infections of the brain
|
Leukemic infiltration
|
|
Low- and high-grade glioma
|
Meningeal plasmacytoma
|
The Japanese Sarcoidosis Society and the Japanese Society of Respiratory Disease presented
new diagnostic criteria for neurosarcoidosis that must consider two of six exams:
bilateral pillar lymphadenopathy; abnormal uptake of 67Ga scintigraphy; alveolar lavage
fluid examination; elevated serum angiotensin-converting enzyme (ACE); negative tuberculin
reaction; and elevated serum or urinary calcium level. Besides these exams, there
must be a compatible clinical history.[18]
The definitive diagnosis is made by biopsy of brain tissue, evidencing inflammatory
tissue associated with non-caseating granuloma and systemic disease compatible with
the diagnostic hypothesis; other possible causes must be excluded.[19]
Discussion
Pulmonary manifestations are present in 90% of the patients, but most of them are
asymptomatic. Pulmonary involvement tends to be bilateral and asymmetrical, predominating
in the upper lobes, and present atypical radiological aspects in 25% of the cases.[20] Bronchiectasis is a typical, uncommon finding, mainly located in the lower lobes
and unilateral, as presented in this case report. Pulmonary fibrosis is another finding
that is present in bronchiectasis caused by sarcoidosis.
The psychiatric symptoms of apathy, agitation, delirium, hallucinations, irritability,
lethargy, and depression improve with the use of corticosteroids.[15] Involvement of the skull is uncommon; when it involves the bone in general, the
incidence is between 1–13%,[16] and is usually asymptomatic, as in the case presented here.
Brain parenchyma involvement may present multiple lesions (35%) or single lesions
(10%) analyzed in the MRI contrast phase.[19] The MRI is the most sensitive test for the diagnosis of neurosarcoidosis, but a
normal examination does not rule out the diagnosis, especially if the patient is under
corticosteroid treatment. In MRI with contrast, leptomeningeal involvement is observed
in 40% of the cases, and it is more common in the frontobasal and suprasellar regions.[5]
[19] The CSF may present hyperproteinemia in 73% of the patients and lymphocytosis in
55%; normal CSF is uncommon.[2]
[5]
[11]
The non-caseating granuloma of sarcoidosis has immunological origin, and is formed
by giant cells and epithelioid cells (consisting of histiocytes modified by T lymphocytes).
The presence of giant and epithelioid cells is a sign of high cellular turnover. Granulomas
are uniform, and have as their components histiocytes of broad and eosinophilic cytoplasm,
oval or twisted vesicular nucleus, and prominent nucleoli.[4]
[13]
[21] Fibrinoid necrosis is present in 35% of the cases.[21]
As radiological differential diagnoses we could mention glioblastoma, lymphoma, abscess,
metastasis and even variations of multiple sclerosis. Nevertheless, among the lesions
that can affect the skull and brain, we can list metastasis, lymphoma; primary skull
tumors, such as chondrosarcoma, chordoma, esthesioneuroblastoma and malignant histiocytic
tumor; and tumor-like lesions, such as fibrous dysplasia eosinophilic granuloma.[22]
[23]
The treatment is clinical, with prednisolone 40–80 mg (oral administration) at first;
as an alternative for more severe cases, intravenous methylprednisolone can be used.[9] In case of refractoriness, there are options such as: mycophenolate, methotrexate,
cyclophosphamide, azathioprine, chloroquine and tumor necrosis factor alpha (TNF-α);[7] another alternative is radiotherapy.[15] In cases of systemic suspicion of neurosarcoidosis, stereotactic biopsy can be used
for confirmation.[7]
Conclusion
Neurosarcoidosis is a serious and rare condition. The discussed case presented a single
extracranial alteration: asymptomatic pulmonary bronchiectasis located in an atypical
region. The intracranial manifestations presented were: lytic bone lesion and psychiatric
symptoms (rare occurrence in the literature). Thus, this case may contribute to the
diagnosis of other cases with rare presentation.
