Neurosarcoidosis

Duc Tran, M.D.

September 2003

General

• Multisystem granulomatous disease• Etiology unknown• Lungs, heart, bone, nervous system• 1909 – Uveoparotid fever/cranial nerve palsies• Incidence 0.85% whites, 2.4% blacks• Children – more common in whites. Usually better

prognosis• Prevalence 40/100,000• Mortality 1-5%. Usually secondary to respiratory failure

Clinical

• Lungs involved most often (90%)• Lymph nodes (33%)• Liver (50-80%)• Skin (25%)• Eyes • Musculoskeletal (25-39%)• Endocrine

Genetics

• Higher prevalence first generation relatives• Familial clustering of cases• HLA-B8 UK, Italian, Czech• HLA-DR17 Scandinavian• Polymorphisms C-C chemokine receptor (monocyte

chemoattractant protein)

Etiology

• HHV-8• HIV• Mycobacterium• Borrelia• Propionibacterium acnes• Aluminum, beryllium, zirconium

Immunology

• Accumulation activated T cells and macrophages• Release of interferon gamma, interleukin-2, cytokines• Interaction sarcoid antigen with specific T cell receptor

and antigen presenting cell to trigger inflammatory response

Pathology

• Noncaseating epitheliod cell granuloma• Accumulation of CD4• Multinucleated giant cells may be present• Inflammation similar in all organs affected• Fibrosis leads to tissue damage

Neurologic Involvement

• Frequency 5-16%• Occurs at later age than systemic • Majority have systemic disease• Neurologic symptoms presenting features 50% cases• Acute – isolated CN or aseptic meningitis • Chronic – parenchymal, multi CN, hydrocephalus, PNS

Neurologic Involvement

• Series 68 pts CNS involvement 62% (optic, CN palsies increased rate to 72%.

• Spinal 28%• Posterior Fossa 21%• Cognitive decline 10%

Manifestations

• Encephalopathy (14-30%) anxiety, dementia, vascular dementia

• Mass lesions (3-26%).• Hypothalamic (10-26%)• Meningitis (8-40%).• Hydrocephalus (6-17%).• Seizures (18-34%)• Posterior Fossa (9-26%).• Spinal Cord (3-10%).• Peripheral Nerve (6-40%)• Muscle (9-23%)

Diagnosis

• Verification of systemic sarcoid• CT – hyperdense, enhance with contrast. Periventricular

white matter lesions common• MRI sensitivity (82%).• PET• Gallium scans • VEP/BAEP• Kviem-Siltzbach (KT) 67-92%• Serum ACE may correlate with clinical disease• Biopsy if feasible

Diagnosis• CSF nonspecific• CSF 80% abnormal

– elevated cell count (<50 WBC/mm)– protein (<100 mg%)– elevated pressure– decreased glucose

• CSF ACE level elevated 50% cases. ?Use (usually elevated with elevated protein)

• IgG Index/Oliogoclonal Bands reported• Elevated CD4/CD8 ratio• Lysozyme/B2m elevated in half of patients

Diagnosis

• Multiple Sclerosis• Idiopathic Bell’s Palsy• Granulomatous Infections• Lyme• Vasculitis• Neoplasms• Meningeal Carcinomatosis• HIV/AIDS• Herpes Encephalitis

Cranial Nerve

• 37-61%• Facial nerve most often involved• CN VIII, Optic, Trigeminal• Other CNs less often involved leading to anosmia,

disturbance of ocular movements, pharygeal/vocal cord involvement

Meningeal Involvement

• 60% of cases• Aseptic meningitis• Meningeal mass lesion• Obstructive or communicating hydrocephalus• Cranial neuropathies from basilar meningitis

Parenchymal Disease

• Clinical features depend on location• Hypothalmic – impairment of neuroendocrine system

(thyroid, adrenal, sexual dysfucntion, sleep, temperature, electrolyte balance, appetite)

• Mass lesions

Encephalitis/Seizures

• Delirium, psychiatric, memory disturbance• TIAs/vasculopathy• Seizures 20% of patients – generalized or focal• Seizures associated with poorer prognosis

Peripheral System

• PN – 15-18% of cases• Axonal sensorimotor most common• Mononeuritis multiplex, polyradiculopathy, GBS• Most are assymptomatic• Epineurium/perineurium involvement axonal

degeneration• Endoneurium involvement demyelinating neuropathy

Peripheral System

• Muscle involvement is common.• Symptomatic – less 1% of systemic cases• Acute or chronic myopathy, myositis, intramuscular

nodules, pseudohypertrophy• More common in women (4:1), especially

postmenopausal

Corticosteroids

• Mainstay of treatment• Proposed mechanism

– Inhibition of lymphocyte/mononuclear phagocytic activity– Inhibition of transcription of proinflammatory cytokines– Downregulation of cellular receptors– Interference with collagen synthesis

• May not change natural history

Treatment

• Cyclosporine.• Azathioprine.• Methotrexate.• Cyclophosphamide• Radiation..• Surgery

Treatment

• Tacrolimus (Prograf) – macrolide immunosuppresant. Inhibit T-cell activation

• Sirolimus (Rapamune) – macrolide immunosuppressant.• Anticytokine therapy• Anticellular adhesion molecules• Gene therapy targeting proinflammatory cytokines

Treatment

• Consider combination therapy, refractory cases• Isolated facial palsies – favorable outcome• Certain cases, e.g. parenchymal involvement, may

require longer course of treatment• Consider biopsy of intracranial lesions

– Before initiating therapy– Refractory to treatment– Diagnosis unclear

Treatment

• Shunt in selected cases• Surgical resection rarely curative• Seizure control• Peripheral involvement treat if symptomatic

Prognosis

• Monophasic, relapsing, progressive• 2/3 neurologic symptoms may improve with treatment• Depends on location of involvement• 72% deterioration with spinal cord 18 months or more• Acute or subacute presentations have better prognosis

than chronic• 1/3 may relapse• Mortality 8-12% if neurological involvement

References

• Zajicek JP. Neurosarcoidosis. Current Opinion in Neurology. 2000; 13:323-325.• Oksanen V. Neurosarcoidosis. Sarcoidosis. 1994; 11:76-79.• Gullapalli D, Phillips LH. Neurologic Manifestations of Systemic Disease.

Neurologic Clinics. 2002; 20(1).• Mana J. Magnetic Resonance Imaging and Nuclear Imaging in Sacoidosis. Current

Opinions in Pulmonary Medicine. 2002; 8(5): 457-463.• Scott TF. Neurosacoidosis: Progress and Clinical Aspects. Neurology. 1993; 43:8-

12.• Kang S, Suh JH. Radiation Therapy for Neurosarcoidosis: Report of Three Cases

from a Single Institution. Radiation Oncology Investigations. 1999; 7:309-312.• Nowak DA, Widenka DC. Neurosarcoidosis: a review if its intracranial

manifestations. Journal Neurology. 2001; 248:363-372.• Zajicek JP, Scolding NJ, et al. Central Nervous System Sarcoidosis-diagnosis and

management. Quarterly Journal of Medicine. 1999; 92:103-111.