Neurosarcoidosis is a multisystem granulomatous disease of unknown etiology where noncaseating granulomas can affect multiple organs including the lungs, heart, skin and nervous system. It most commonly involves the lungs in 90% of cases. The central nervous system is involved in 5-16% of cases, with cranial neuropathies, encephalitis, meningitis and mass lesions being common neurological manifestations. Treatment involves corticosteroids as the mainstay, with immunosuppressants also used in refractory cases. Prognosis depends on location and type of involvement, with 72% of neurological cases deteriorating within 18 months if not treated.

1. Neurosarcoidosis Duc Tran, M.D. September 2003

2. 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

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

4. 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)

5. Etiology HHV-8 HIV Mycobacterium Borrelia Propionibacterium acnes Aluminum, beryllium, zirconium

6. 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

7. 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

8. 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

9. Neurologic Involvement Series 68 pts CNS involvement 62% (optic, CN palsies increased rate to 72%. Spinal 28% Posterior Fossa 21% Cognitive decline 10%

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%)

11. 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

12. 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

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

14. 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

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

16. Parenchymal Disease Clinical features depend on location Hypothalmic – impairment of neuroendocrine system (thyroid, adrenal, sexual dysfucntion, sleep, temperature, electrolyte balance, appetite) Mass lesions

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

18. 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

19. 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

20. 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

21. Treatment Cyclosporine. Azathioprine. Methotrexate. Cyclophosphamide Radiation.. Surgery

22. Treatment Tacrolimus (Prograf) – macrolide immunosuppresant. Inhibit T-cell activation Sirolimus (Rapamune) – macrolide immunosuppressant. Anticytokine therapy Anticellular adhesion molecules Gene therapy targeting proinflammatory cytokines

23. 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

24. Treatment Shunt in selected cases Surgical resection rarely curative Seizure control Peripheral involvement treat if symptomatic

25. 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

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