AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Sarcoidosis is a multisystem disease process whose pathogenesis involves formation of an inflammatory lesion known as a granuloma. Most patients with sarcoidosis do not have any symptoms; the disease often is detected on routine chest radiograph. Symptoms, if present, include cough, shortness of breath, and arthritis. The lungs are affected most frequently, but the eyes, nervous system, heart, kidneys, bones, and joints also may be affected.

Sarcoidosis is a disease of unknown etiology. Involvement of the central nervous system is referred to as neurosarcoidosis. Neurosarcoidosis is an uncommon but severe, sometimes life-threatening, manifestation of sarcoidosis. It generally occurs only if the disease has had substantial systemic involvement, and signs of neurologic involvement usually are seen in patients known to have active disease. Strictly neurologic forms are seen in fewer than 10% of patients.

Pathophysiology

Histologically, neurosarcoidosis is characterized by formation of granulomas in the central nervous system. The lesion consists of lymphocytes and mononuclear phagocytes surrounding a noncaseating epithelioid cell granuloma. These granulomas represent an autoimmune response to central nervous system tissues.

Frequency

United States

The prevalence of sarcoid varies widely, but generally it is more common in African Americans. The prevalence is much higher in both blacks and whites in the southeastern United States than in the rest of the country. In New York, the prevalence is 30 cases per 100,000 population; it is also seen in the Puerto Rican population, reaching a prevalence as high as 175 cases per 100,000 population in one retrospective study. In Los Angeles, Mexican immigrants constituted 7% of the observed cases, compared to 82% for blacks. The frequency of neurologic involvement is generally 5% of all cases of sarcoid, but in some series it was noted to vary from 5-16%. These figures are considered to be underestimated because of the usually silent manifestation of the disease and unavailability of tissue diagnosis in all cases.

International

The incidence of sarcoid varies from 0.04 case per 100,000 population in Spain to 64 cases per 100,000 population in Sweden. The prevalence in London was found to be 27 cases per 100,000 population for patients born in the United Kingdom, 97 cases per 100,000 population among Irishmen, and 200 cases per 100,000 population in men from the West Indies (5%). One study done in Paris showed that 13% of individuals from Martinique were affected with sarcoid. In Asia it is extremely rare, being almost unknown in Chinese and Southeast Asians. Data from Japan showed native Japanese to be affected.

Mortality/Morbidity

About two thirds of patients with neurosarcoidosis have a self-limited monophasic illness, and the rest have a chronic remitting relapsing course. With treatment, death from neurologic disease is unusual.

Neurological involvement is a major cause of disability in sarcoidosis.

Race

Neurosarcoidosis is more common in Africans, including those living in the West Indies, than any other people. The ratio in the United States of affected blacks to affected whites ranges from 10:1 to 17:1. In Europe, however, the disease affects mostly whites. It is very uncommon in Chinese, Southeast Asians, Inuits, Canadian Indians, and New Zealand Maoris.

Sex

Slightly more common in women than men, one study found 55% of the subjects were women.

Age

• Neurosarcoidosis commonly occurs in adults aged 25-50 years.
• Neurosarcoidosis is uncommon in children, but when it occurs, it affects children aged 9-15 years. Sarcoidosis of early childhood ( <8 y), when it does occur, has a different clinical manifestation than in adults, characterized by the triad of cutaneous nodules, arthritis, and uveitis. The rate of ocular involvement was reported to reach 100% in these patients; iritis and/or anterior vitreitis was observed in almost all cases. Children older than 8 years have a clinical picture similar to that of adults.

CLINICAL

Section 3 of 11  

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History

Onset of neurosarcoidosis is most often in the fourth or fifth decade of life, but the disease affects children and the elderly as well. In patients known to have sarcoid, the appearance of neurologic symptoms usually poses no diagnostic problems, but the possibility of unrelated disease must be kept in mind, especially infections. When nervous disease complicates systemic sarcoidosis, it usually does so within 2 years of onset. Symptoms can include the following:

• Mononeuropathy - Cranial nerve involvement
• • Facial palsy (the most commonly affected cranial nerve), either unilaterally or bilaterally - Heerfordt syndrome is characterized by fever, uveitis, swelling of the parotid gland, and facial nerve palsy and represents a type of neurosarcoidosis. The lesion site has been controversial, but direct nerve compression by parotid gland swelling or by a lesion within the facial canal has been assumed, in light of observations of accompanying taste disturbance.
  • Impaired taste and smell
  • Blindness, blurry vision, double vision, visual field defects, pupillary abnormalities, dry and sore eyes
  • Slurred speech, impaired swallowing, hoarseness
  • Vertigo, sensorineural deafness, tinnitus
  • Weakness of trapezius and sternocleidomastoid muscles
  • Tongue deviation and atrophy
• Peripheral nerve involvement - Mononeuropathy, mononeuropathy multiplex, polyneuropathy
• • Sensory neuropathy - Characterized by loss of sensation and abnormal sensation (eg, tingling, numbness, painful patches over the thorax, stocking/glove deficits)
  • Motor neuropathy - Characterized by weakness, leading to immobility and joint stiffness
• Central nervous system involvement may affect the hypothalamus/pituitary gland, cerebral cortex, cerebellum, and spinal cord (rarely), resulting in the following:
• • Polydipsia
  • Polyuria
  • Diabetes insipidus
  • Changes in appetite
  • Changes in sleep cycle (somnolence)
  • Impaired temperature regulation (hyperthermia, hypothermia)
  • Obesity
  • Alveolar hypoventilation
  • Impotence
  • Change in menstrual period
  • Galactorrhea
  • Amenorrhea
  • Generalized confusion
  • Dementia
  • Amnesia, both short term and long term
  • Loss of judgment
  • Acalculia
  • Generalized fatigue
  • Headache
  • Meningitis
  • Corticospinal signs
  • Cerebellar signs
  • Brainstem signs
  • Focal seizures
• Generalized or localized muscle weakness, muscle soreness

Physical

Patient may have signs of the following:

• Mononeuropathy, mononeuropathy multiplex, plexopathy
• Polyneuropathy
• • Sensory neuropathy
  • Motor neuropathy
  • Sensorimotor neuropathy
• Space-occupying lesion of brain: Although necrotizing sarcoidosis has been reported most commonly in the lungs and rarely in other organ systems, sarcoidosis and its necrotizing variant should be considered in the differential diagnosis of an agranulomatous mass lesion involving the CNS, particularly in the context of a history of systemic disease.
• Hypopituitarism
• Optic neuritis leading to optic atrophy (see Images 1-2)
• Eye involvement leading to blindness, including uveitis, iritis, choroiditis, and cyclitis
• Meningitis, rarely recurrent meningitis, especially basal brain involvement, leading to cranial nerve deficits, hydrocephalus, cauda equina signs, ependymitis, and encephalopathy
• Peripheral signs of sarcoidosis, such as erythema nodosum
• Cerebral infarct or transient ischemic attack due to vasculitis
• Spinal cord lesions are rare, affecting 0.3-0.4% of patients with systemic sarcoidosis. Intramedullary lesions resembling demyelinating disease may possibly respond to steroids, as does demyelinating disease. Extramedullary sarcoid lesions are even rarer than intramedullary ones, but have been reported.
• Myopathy is characterized by atrophy, tenderness, muscles feeling "hard" on palpation, and weakness.
• Brain stem (sarcoid brainstem encephalitis) and cerebellar involvement: This is rare and can manifest as demyelination, hemorrhagic infarction, or parenchymal infiltration by granulomatous masses. A recently reported case of sarcoid brainstem encephalitis showed nemaline rods in every muscle examined (see Workup).
• Seizures may be the first manifestation of neurosarcoidosis. Generally, seizures indicate a chronic course with poor prognosis. Cases associated with isolated mass lesions and simple partial or complex partial seizures (with or without secondary generalization) may be associated with better outcomes than patients with generalized tonic-clonic seizures only.

Causes

The causes of sarcoidosis are not clear. The present evidence suggests that active sarcoidosis results from an exaggerated cellular immune response to either foreign or self-antigens. T-helper cells proliferate, resulting in an exaggerated response. The T-helper lymphocytes undergo differentiation to a Th1-type cell under the influence of interleukin-4 (IL-4) and co-stimulator CD28. The Th1 cell induces IL-2 and interferon gamma (IFN-gamma) on the macrophages, followed by a cascade of chemotactic factors that promote formation of granuloma. IFN-gamma increases the expression of major histocompatability class (MHC) class II on macrophages, and activated macrophages receptors carry an Fc receptor of immunoglobulin G (IgG) which potentiates their phagocytosis function. Tissue destruction results and granuloma formation is thought to be a secondary process.

Several hypotheses have been proposed to explain the mechanism: (1) a persistent antigen (either foreign or self) triggers the T-helper cell response; (2) response of the suppressor arm of the immune response is inadequate, preventing T-helper cells from shutting down; or (3) a possible inherited or acquired (genetic) difference in response genes leads to the exaggerated response.

In addition to the exaggerated cellular immune response, active sarcoid shows hyperglobulinemia, with antibodies against several infectious agents (eg, Mycobacterium tuberculosis) as well as IgM anti–T-cell antibodies. However, no evidence exists to suggest that these antibodies play a role in disease pathogenesis; rather, their presence seems to be due to a nonspecific polyclonal stimulation of B cells by activated T cells at the site.

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

Brain tumors

WORKUP

Section 5 of 11  

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Lab Studies

• Findings of cerebrospinal fluid (CSF) analysis are normal in 30% of cases, specifically in patients with cranial nerve and peripheral nerve involvement. When CSF analysis findings are abnormal, they reflect a nonspecific pattern with high protein level (>0.5 g/L), high leukocyte count (>5 cells/µL), usually lymphocytosis, and normal or low glucose level; this combination coupled with negative cytology and culture results support the diagnosis of neurosarcoidosis. Sometimes serial CSF analyses may be necessary. In one study of 68 patients, the CSF leukocyte count was in the range of 5-220 cells/µL.
• Levels of angiotensin-converting enzyme (ACE), lysozyme, and beta2-microglobulin can be elevated in the CSF in more than half the patients; changes in these markers can parallel the clinical course.
• High IgG, Ig index, and oligoclonal bands have been reported in the CSF. Studies of subpopulations of T lymphocytes have shown a high T4/T8 ratio, which can help in differentiating sarcoidosis from multiple sclerosis.
• Hypochromic microcytic anemia of chronic disease can be seen.
• Endocrine studies should be performed whenever involvement of the pituitary-hypothalamic axis is suspected. This includes thyroid function tests, prolactin, testosterone, growth hormone, luteinizing hormone, follicle-stimulating hormone, corticotropin-releasing hormone, estradiol, urine osmolality determination, and insulinlike growth factor.
• Creatine kinase, erythrocyte sedimentation rate, and aldolase may be useful in cases of myopathy.
• Calcium levels, liver enzymes may be helpful.
• Antineutrophil cytoplasmic antibody (C-ANCA) titers may be needed to differentiate from Wegener granulomatosis.

Imaging Studies

• Both a CT scan and an MRI of the brain and spine are indispensable in assessing nervous system involvement.
• • The MRI has become the modality of choice because of the superior images obtained.
  • The use of gadolinium and fluid-attenuated inversion recovery (FLAIR) has increased the sensitivity of an MRI.
  • Some series have shown that gadolinium enhancement demonstrated leptomeningeal involvement in cases that unenhanced images might have missed. The enhancement can follow the contour of the brain, extending into the cortical sulci. Gadolinium also can leak into the contiguous CSF because of disruption of capillary endothelial tight junctions of the arachnoid matter. A thick and ragged pial enhancement is indicative of invasion along perivascular spaces, leading to a meningoencephalovasculopathy. Enhancement of linear and nodular areas from the pial surface into the white matter indicates infiltration along Virchow-Robin spaces.
  • In the FLAIR technique, the signal from the CSF is suppressed, and mild or heavy T2 weighting (long TE) is used to detect lesions. This technique is of value in detecting low-contrast lesions. It also can be used to improve the accuracy of detecting T2 prolongation in the temporal lobe in cases of mesial temporal sclerosis. The nulling of the CSF signal maximizes the sensitivity of the sequence to changes in the T1 of the CSF. The FLAIR technique is valuable in diffusion weighting and is especially sensitive to contrast enhancement. It also can be combined with fat suppression.
• An MRI may demonstrate the following:
• • Periventricular high-signal lesions on T2-weighted images
  • Multiple supratentorial and infratentorial brain lesions
  • Solitary intra-axial mass
  • Solitary extra-axial mass
  • Leptomeningeal enhancement
  • Optic nerve enhancement (see Images 3-7)
  • Spinal cord intramedullary mass resembling demyelinating disease
• Chest radiograph reveals sarcoidosis (see Images 8-9).
• Fluorodeoxyglucose positron emission tomography imaging may show areas of hypermetabolism or hypometabolism in the CNS, and this information may be compared to a systemic PET scan in patients with systemic sarcoidosis, thus establishing a firmer diagnosis.

Other Tests

• EMG/nerve conduction studies can be used to confirm neuropathy.
• • Findings include slowing of motor nerve conduction velocities; abnormal sensory nerve conduction consisting of absent potentials, reduced amplitude, and mild slowing; mixed compound nerve action potentials may be seen as well.
  • The most characteristic electrodiagnostic finding is mononeuropathy multiplex, showing axonal degeneration and segmental demyelination.
  • With treatment and clinical improvement, motor, sensory, and mixed nerve conduction tend to improve.
  • In cases of myopathy, the EMG shows myopathic potentials.
• Evoked potential (EP) studies may be of value in supporting the diagnosis and monitoring the course of the disease. Visual evoked potentials (VEPs) and brainstem auditory evoked potentials (BAEPs) tend to be abnormal in about one third of the patients with neurosarcoidosis. Somatosensory evoked potentials tend to show abnormalities less frequently. All 3 modalities of EPs can show abnormalities in patients before the appearance of clinical signs.
• Visual field testing

Procedures

• Nerve and muscle biopsy can help confirm the diagnosis.
• • In asymptomatic patients, biopsies show granulomas surrounded by normal muscle. This is the most common type of involvement and is seen in 50-80% of asymptomatic patients. A recent case report of neurosarcoidosis (sarcoid brainstem encephalitis) demonstrated nemaline rods in every muscle examined.
  • Because the granulomas can be scarce, a large sample should be taken.
  • Granulomas are not specific for neurosarcoidosis and can be seen in patients with tuberculosis, fungal infections, collagen vascular disorders, or carcinoma.
  • In symptomatic patients, nodules are less frequent. In some cases, noncaseous granulomatous myositis or chronic myopathic changes can be seen.
  • Peripheral nerve biopsies may show segmental demyelination, degenerating nerve roots with inflammatory cells, and mechanical destruction of nerves by granulomas.
• Brain biopsy may be required in selected cases with isolated brain involvement; in other cases the patient's history, MRI scans, and chest radiograph may be sufficient for arriving at the correct diagnosis.
• Blood vessel biopsies of both arteries and veins can show involvement of the vessel wall, most frequently in the perforating arteries.
• Ventriculoperitoneal shunting may be needed in cases of hydrocephalus.

Histologic Findings

Noncaseating granulomas are seen in affected tissues (see Images 10-11).

TREATMENT

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Medical Care

Neurosarcoidosis has no known cure. Treatment alleviates symptoms that are severe or progressive. The disease can follow a monophasic, relapsing, or chronic course.

• Immunosuppression is the principal method of controlling the disease, and corticosteroids are the cornerstone of therapy. Spontaneous remission has been observed, but long-term therapy often is required. In cases of exacerbation, intravenous pulsed methylprednisolone followed by oral taper may be necessary. Relapses may respond poorly, however, requiring chronic steroid therapy.
• • A retrospective report of 26 patients with refractory neurosarcoidosis monitored for a mean of 81.2 months demonstrated steroid sparing in 10 of 26 patients and clinical improvement in 15 of 26 patients treated with alternative medications, including azathioprine (AZA; 14 courses), cyclophosphamide (CYA; 14 courses), cyclosporine (CTX; 3 courses), chloroquine (CHL; 1 course), methotrexate (MTX; 3 courses), and irradiation (3 courses). Positive response to a course of therapy was recorded in 8 of 14 patients who received AZA, 11 of 14 who received CYA, 2 of 3 who received CTX, 3 of 3 treated with irradiation, 1 of 3 who received MTX, and in the only patient given CHL.

    On the basis of this experience, the authors believed that AZA and CYA should be used as the alternative agents of choice in corticosteroid-resistant neurosarcoidosis and that MTX should be reserved for patients who either do not respond to or are intolerant of those alternative agents. AZA has been used as an alternative to corticosteroids when the adverse effects are intolerable, but reports in the literature are sparse.

  • CTX has been reported to lead to improvement in some patients. It has been successful in controlling the disease in patients undergoing transplantation. In one series, the response rate was 75%, but the patients had relapses once the therapy was stopped.
  • MTX can be used as a steroid-sparing agent. It is generally well tolerated, with minimal adverse effects except for potential liver toxicity. Thus, patients on long-term dosing need to have careful monitoring of liver function, including liver biopsies. In one study, the remission rate for patients on MTX was 61%.
  • CYA use has been more limited. Short-term therapy has not been associated with good response. Therapy lasting at least several months is needed to determine efficacy. In one study, intermittent intravenous CYA was associated with better compliance and lower risk of malignancy, especially bladder malignancy; however, bladder toxic effects did occur. Patients showed improvement in the course of the disease.
  • CHL and hydroxychloroquine also have been used. In a study by Sharma et al, CHL and hydroxychloroquine were effective in controlling neurological sarcoidosis in those patients who did not respond to corticosteroids or developed severe adverse effects. Ten of 12 patients had their symptoms stabilized or controlled.
  • Recently, a single case was reported of treatment with antimetabolite cladribine (2-chlorodeoxyadenosine). Used in only one patient with aggressive suprasellar disease, it resulted in loss of vision. Results were encouraging, however, and this antimetabolite could be considered in cases refractory to other agents.
• Radiation: Some patients clearly demonstrate symptomatic benefits from low-dose radiation. Since the adverse effects of low-dose cranial irradiation are minimal, using radiation therapy may be prudent for patients whose disease is refractory to steroids or who have adverse effects to high-dose steroids.
• Neuropathy and myopathy: Patients may require extended steroid therapy. The prognosis with peripheral neuropathy is more favorable than with central nervous system involvement.
• Dementia: Treatment should comprise safety intervention and assistance.
• Hypopituitarism: Patients require incorporation of hormone replacement therapy.
• Psychosis: Risperidone and other antipsychotic drugs have been used for the treatment of psychosis associated with neurosarcoidosis.

Surgical Care

Removal of the space-occupying lesions in the brain has little or no benefit and should be attempted only in extreme cases. Hydrocephalus may require shunting.

Consultations

• Rheumatologist
• Endocrinologist
• Neurosurgeon
• Pulmonologist

Diet

No special dietary preferences/recommendations are given.

Activity

• Physical therapy is of some benefit for patients with involvement of the feet.
• Specific activity recommendations should be given on a case-by-case basis to decrease predilection to falls.

MEDICATION

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Immunosuppression with corticosteroids is the mainstay of treatment.

Drug Category: Corticosteroids

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Drug Category: Immunosuppressant agents

These agents inhibit immune cell growth and proliferation, decreasing immune system activity.

Drug Category: Antimalarials

Chloroquine phosphate and hydroxychloroquine sulfate have been used in the treatment of patients with neurosarcoidosis who either do not respond to corticosteroid therapy or develop unacceptable side effects. In a sarcoidosis clinic at a university teaching hospital, 12 patients with biopsy-proven sarcoidosis, 6 women and 6 men with neurologic involvement aged 20-49 years were administered antimalarials.

Patients had regular clinical evaluation, determination of serum and CSF ACE levels, CT scan or MRI, chest radiography, lung function testing, and slit-lamp examination of the eyes.

Chloroquine or hydroxychloroquine either stabilized or controlled neurologic symptoms in 10 of 12 patients; 2 patients did not respond. CSF abnormalities, including lymphocytosis, were seen in 3 patients.

Drug Category: Immunomodulators

These agents can change the immune system or block cytokine effects.

FOLLOW-UP

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Further Outpatient Care

• Follow-up by a neurologist every 3-6 months to monitor the progress of the disease

Complications

• Permanent neurologic loss
• Progressive neurologic loss
• Brainstem involvement (can be life threatening)

Prognosis

• Spontaneous resolution may be seen in 4-6 months but is uncommon.
• Many patients have a slowly progressive chronic course with intermittent exacerbations.
• About 5% of patients with sarcoidosis die of this disorder.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Care should be taken while diagnosing neurosarcoidosis in children. It is not common in children, and care must be taken to exclude other pathologies before this diagnosis is made.

Special Concerns

• Before initiating immunosuppressive therapy, an infectious etiology for the symptoms must be excluded.

MULTIMEDIA

Section 10 of 11  

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Media file 1:  Atrophic right optic disc of a 37-year-old man with neurosarcoidosis and involvement of both optic nerves. Vision was lost. The disc is pale with sharp borders.
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Media file 2:  Atrophic left optic disc of a 37-year-old patient with neurosarcoidosis and involvement of both optic nerves. The disc is pale with sharp borders. Vision was largely preserved.
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Media file 3:  MRI of the brain in a 37-year-old man with neurosarcoidosis who had complete loss of vision in the right eye for 2 months and occasional blurry vision in the left. T1-weighted sagittal image shows intact optic nerves.
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Media type:  MRI

Media file 4:  MRI of the brain in a 37-year-old man with neurosarcoidosis who had complete loss of vision in the right eye and mild left eye blurriness. This fluid-attenuated inversion recovery (FLAIR) axial image shows a wedge-shaped area of infarction in the right temporo-occipital area. The optic nerves exhibit abnormal signal.
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Media type:  MRI

Media file 5:  MRI of the brain in a 37-year-old patient with sarcoidosis who had right eye blindness and mild blurry vision in the left eye. This postgadolinium, T1-weighted axial image shows right optic nerve enhancement along almost the entire intraorbital portion and a small amount in the prechiasmatic portion. The left optic nerve enhances from the level of the optic chiasm to the distal intraorbital portion. The right temporo-occipital infarct is seen as a faint hypodensity; it does not enhance after gadolinium administration.
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Media type:  MRI

Media file 6:  MRI of the brain in a 37-year-old man with sarcoidosis who had loss of vision in the right eye and blurry vision in the left eye. This scan was taken 6 months after the scan shown in Pictures 3, 4, and 5. Both the right and left optic nerves are enlarged and show abnormal signal on this T1-weighted axial image. The patient remained on oral prednisone from the time of the first scan and did not exhibit any further loss of vision in the left eye. Vision in the right eye never returned.
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Media type:  MRI

Media file 7:  MRI of the brain in a 37-year-old man with sarcoidosis who had loss of vision in the right eye and blurry vision in the left. This postgadolinium, T1-weighted axial image shows abnormal enhancement of both optic nerves, with the left optic nerve appearing worse on this study than in the study shown as Picture 5, which was done 6 months earlier. The right temporo-occipital hypodensity represents the old infarction.
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Media type:  MRI

Media file 8:  Early chest radiograph findings in sarcoidosis.
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Media file 9:  Advanced chest radiograph findings in sarcoidosis.
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Media file 10:  Noncaseating granuloma surrounded by epithelioid cells, from the medulla oblongata. Also shown are nodular inflammatory infiltrates consisting of multinucleated giant cells, macrophages, and lymphocytes (hematoxylin and eosin, 40x).
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Media file 11:  Noncaseating granuloma in medulla oblongata showing the granuloma surrounded by epithelioid cells and nodular inflammatory infiltrates (hematoxylin and eosin, 20x).
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REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
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• Miscellaneous
• Multimedia
• References

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• Garcia Berrocal JR, Trinidad A, Vargas JA, et al. [Sudden hearing loss and uveitis as a form of presentation of neurosarcoidosis]. Acta Otorrinolaringol Esp. Aug-Sep 1998;49(6):488-90. [Medline].
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• Gott PS, Kumar V, Kadakia J, Sharma OP. Significance of multimodality evoked potential abnormalities in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. Sep 1997;14(2):159-64. [Medline].
• Hoitsma E, Faber CG, Drent M, Sharma OP. Neurosarcoidosis: a clinical dilemma. Lancet Neurol. Jul 2004;3(7):397-407. [Medline].
• James DG. Life-threatening situations in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. Sep 1998;15(2):134-9. [Medline].
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Article Last Updated: Nov 7, 2006