neurosarcoidosis duc tran, m.d. september 2003. general multisystem granulomatous disease etiology...
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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.