A REVIEW ON NEUROSARCOIDOSIS

NARESH MULLAGURI MD, PGY4NEUROLOGY AND NEUROSURGERY GRANDROUNDS - 12/2016

UNIVERSITY OF MISSOURI HEALTHCARECOLUMBIA-MISSOURI

DISCLOSURES

REASON FOR DOING THIS REVIEW

• Lot of unknowns starting from etiology to management. No randomized controlled trials till date.

• A challenge for both subspecialties in diagnosing and managing patients.

• It is a great mimicker in our world. To raise awareness of the condition.

OBJECTIVES

• Historical account• Definition• Epidemiology• Clinical manifestations• Diagnosis and Monitoring• Management• Prognosis

Historical account

Definition of Sarcoidosis

Neurosarcoidosis

• Pathologically characterized by the presence of non-caseating granulomas composed of compact clusters of activated Macrophages and other epithelioid cells surrounded by T lymphocytes.

Other conditions that cause granulomas inflammation

Types of AntigensInfections: Propionibacterium acnesMycobacteria

Environmental: Pesticides, mold, metallic particles

Genetic:Annexin A11 gene polymorphism involved in apoptosis

Neurosarcoidosis• Develops clinically in 5% of patients with Sarcoidosis. Asymptomatic

involvement is higher in autopsy studies upto 15%.

• Nervous system dysfunction can be a presenting feature of Sarcoidosis in 50-70% of patients with Neurosarcoidosis.

• Isolated Neurological involvement without systemic disease can occur in 10-17% of the Neurosarcoidosis patients.

• Any part of the nervous system can be involved.

• 1/3 of the patients have refractory illness that is associated with considerable morbidity and possible mortality.

EPIDEMIOLOGY

• More prevalent in African Americans and Scandinavian descent but ranges between 1-40/100,000 worldwide. Somewhat less in Asian population.

• Affects the age group 30-50 years.

• African Americans tend to have a delayed onset in 40s especially in women and more frequently has Neurosarcoidosis and systemic disease compared to men.

Clinical Features of Neurosarcoidosis

• Cranial Neuropathy 50-75%• Parenchymal Disease 25-45%• Aseptic Meningitis 10-20%• Hydrocephalus 10%• Peripheral Neuropathy 5-10%• Small fiber Neuropathy – recent

addition.• Myopathy 10%

Differential Diagnosis of Neurosarcoidosis

Cranial Neuropathies

Facial Nerve - 30-40% of cases have bilateral involvement (simultaneous or sequential). most of the patients will have complete resolution in few weeks.

Optic Nerve - Recovery may not be complete. May involve long segments of the Optic Nerve including chiasm and tracts. Can be intermittant or progressive.

Vestibulocochlear Nerve – Severe and often acute hearing loss and severe vestibular dysfunction.

Trigeminal Nerve – Less commonly facial numbness and Trigeminal Neuralgia like symptoms.

** The lesions can be nuclear and infra-nuclear. The cranial nerves can also be involved secondary to skull base inflammation.

25-50% 0f NS patients

Meningitis(Aseptic)

• Sub-acute or chronic meningitis.

• Mostly involves basal regions and Leptomeninges.

• Usually presents with Headache and hydrocephalus(both communicating and non-communicating)

• Cranial nerve and hypothalamic pituitary axis dysfunction.

Neurosarcoidosis – Myelopathic formDistribution of Lesions• Mostly involves Cervicothoracic regions.• Both Parenchymal and Leptomeningeal

lesions• Cauda equina syndrome.

Symptoms:• Subjective weakness with intact strength

on the exam.• Patchy, non-contiguous sensory loss due

to the patchy involvement of the leptomeninges, parenchyma and radicles of the nerves.

• Bladder and bowel symptoms are common.

• Mostly result in severe disability ending up in severe spinal cord atrophy.

Intracranial Lesions• Presenting symptoms

are Headache, seizures and cognitive dysfunction. • Can vary from

periventricular white matter lesions to mass like lesions.• Great Mimicker.

Neuroendocrine Symptoms

• Affects the hypothalamic-pituitary axis.

• Causes Central Hypothyroidism, Hypogonadism, Hyperprolactinemia, DI both central and nephrogenic and SIADH.

• Symptoms : Changes in menstrual periods, excessive tiredness, excessive thirst and high urine output. Hypothalamic vegetative dysfunction.

Headache and Seizures• Secondary to Acute or Chronic

Meningitis or mass lesions.

• Due to Opportunistic infections resulting from chronic immunosuppression.

• Optic Neuritis, Trigeminal Neuralgia.

• Exacerbation of chronic Migraines

Neurovascular manifestations• Can cause ischemic stroke secondary to

Leptomeningeal inflammation.• Endothelial walls of large/small artery

occlusion secondary to granulomas in vessel walls.• Can occur secondary to mass lesions and

extrinsic vessel compression.• CNS vasculitis.• Cardiogenic emboli due to arrhythmias,

Cardiomyopathy due to cardiac granulomatous inflammation.• Cerebral venous thrombosis secondary to

inflammatory process.

Neuropsychiatric Manifestations• “Sarcoidosis FOG”

• Memory loss, fatigue, mood disturbances and behavioral changes with or without CNS lesions.

• Sleep disturbances including sleep apnea and primary hypersomnia also contribute to Sarcoidosis fog from hypothalamic inflammation.

Neuromuscular manifestations

• Peripheral Neuropathy which is painful.

• Polyradiculopathy• Mononeuritis multiplex• Sub-acute demyelinating

polyradiculoneuropathy(GBS)• Vasculitis• Small fiber Neuropathy

40% length dependent classic glove and stocking and the rest will have migratory non-length dependent pattern.

Neuropathy types and symptoms

Neurosarcoidosis – Neuropathy• Small Fiber Neuropathy: Non length

dependent and migratory.

1. Pain in Face, trunk and proximal limbs.2. Autonomic Neuropathy – Orthostatic

intolerance, gastrointestinal dysmotility, sweating which is CYTOKINE mediated.

3. Called Paraneurosarcoidosis* as there are no pathological granulomas identified. It is a diagnosis of exclusion.

* Term coined by updated version of ACCESS study.

Neuromuscular – Muscle involvement

• Acute Myositis

• Gradually progressive weakness

• 50% of the patients have subclinical involvement found in autopsy

• Nodular Myopathy

• Men will have palpable intramuscular nodules

Differential Diagnosis

CN dysfunction:

Multiple Sclerosis, Lyme’s disease Chronic infections like Tuberculosis.

If there are multiple CN palsies – Consider Carcinomatous or lymphomatous meningitis

Parenchymal Lesions

• Granulomatous masses can masquerade as an Astrocytoma, primary or secondary brain tumor

• Multiple white matter T2 hyperintensities on MRI are non-specific and are associated with MS or other inflammatory disorders.

• 10 cases of PML complicating sarcoidosis were described in one report, among them only 8 had received immunotherapy, usually corticosteroids alone. Symptoms and MRI findings are mistakenly attributed to Neurosarcoidosis in eight patients, perhaps contributing to the high fatality rate of 57%.

MS PML

Vasculopathy

Can mimic Syphilis or CNS vasculitis

Meningeal Disease

• Indistinguishable from viral meningitis including HIV, TB or syphilis.

• A granulomatous meningeal mass may look like Meningioma on imaging studies.

Peripheral Nerve Lesions• Toxic metabolic neuropathy• Inflammatory Neuropathy• Polymyositis should be considered if a myopathic

process is considered.

Time will tell – Observation of clinical course will help.

Clinical Evaluation

• Search for extra neural Sarcoidosis lesions as obtaining neural tissue for diagnostic evaluation is often difficult.

• Preferably the diagnostic evaluation should happen in a rapid fashion prior to corticosteroid or immunosuppressant use as they can eliminate evidence of systemic inflammation.

Where to look• Skin, lymph nodes and Lungs• Ophthalmologic evaluation• Endoscopic nasal and sinus examination• Chest x-ray or CT of the Chest to look

for hilar adenopathy or parenchymal changes

• Serum ACE may be helpful if elevated however it is non-specific. May not be elevated if the patients have isolated Neurosarcoidosis.

• Gallium scan and FDG-PET highlight occult areas of inflammation amenable to biopsy

GALLIUM SCAN – PANDA SIGN

Gallium scan "panda" sign: A gallium scan demonstrates the "panda" sign of increased radiotracer uptake in the lacrimal, parotid, and salivary glands bilaterally.

FDG-PET

Neurodiagnostic testing• No Neurodiagnostic tests are pathognomonic.• Help determine the extent of the disease and eliminate the mimics

particularly infection and malignancy• Presumptive diagnosis can often be made on the basis of MRI and Lumbar

puncture results in the appropriate clinical setting.

Neuroimaging:MRI with contrast – In 29 patients with Neurosarcoidosis, approximately 40% demonstrated Meningeal enhancement and /or T2 white matter lesions. Will also help find parenchymal masses, Hydrocephalus, cranial nerve involvement and cauda equina of spinal cord.

Will also be able to see inflammation extending along the Virchow-Robin spaces deep into the Brain and Spinal cord.

Lumbar Puncture• Opening pressure – elevated in 10%.

• Total protein – Elevated in 2/3 patients typically upto 250mg/dL.

• Pleocytosis in 50% patients mostly mononuclear cells.

• Glucose can be normal or low.

• IgG index can be elevated and Oligoclonal bands may be present.

• CSF ACE concentration occasionally elevated but no reliable normative data. Can also be increased in infection or Carcinomatous meningitis. If serum ACE is elevated with a breach in blood brain barrier, CSF ACE can be elevated as well.

CSF soluble Interleukin-2 receptor levels

• Elevated.• Not widely available.• Levels>150pg/mL suggested NS in one report(Sensitivity:

61% and Specificity: 93%) in comparison to healthy controls and other inflammatory diseases such as MS and CNS vasculitis.• Can also be false positive in the setting of infection.

Other test relevant for the clinical presentation• EEG• Evoked potentials• Angiography• NCS/EMG can help localize the lesions• Calcium levels

Kveim-Slitzbach test

• Suspension of granuloma containing spleen or lymph node of patient injected intra dermally. Positive if a papule erupts in 4-6 weeks showing non Caseating granulomas.

• Rare false positives. Good sensitivity and specificity and may be diagnostic of Sarcoidosis.

Drawbacks:Not standardized.Not FDA approved.Not universally available.Concerns regarding transmission of HIV, Hepatitis as it is human tissue.

Diagnostic Criteria for Neurosarcoidosis

Zajicek et al.

Judson et al.

Biopsy• Extraneural tissue is preferable if

amenable to biopsy. If diagnosis is questionable, Meningeal, Brain or spinal cord biopsy is occasionally indicated.

• Skin, LN, Conjunctival, Transbronchial lung biopsy can be economical and very high yield.

• Muscle and Peripheral nerve biopsy including Epidermal biopsy for small fiber Neuropathy can all be easily performed.

ASTEROID BODIES

Schaumann body/Conchoidal bodies

Concentric Calcium oxylate and protein inclusions in Langhans giant cells

Treatment – No randomized controlled trials

• Corticosteroids are the first line, the dose and duration of therapy should be dictated by severity and response to therapy.• Cranial Nerve dysfunction and aseptic meningitis are treated by

Prednisone 0.5mg/kg per day dose for 2 weeks typically.• Myopathy and Neuropathy for 4 weeks• Meningeal, parenchymal mass lesion, encephalopathy/vasculopathy

or symptomatic hydrocephalus often requires 1mg/kg -1.5mg/kg daily for 4 weeks.• IV Methylprednisolone 20mg/kg per day X 3 days followed by

Prednisone 1mg/kg to 1.5mg/kg for 2-4 weeks for severely incapacitated and rapidly progressing pts.

Corticosteroids taper• Slow taper of 5mg/week upto a dose of

10mg/day and then 1mg/day decrements as relapses are common at this maintenance dose.

• If a relapse occurred at lower doses, double the Prednisone dose.

• MRI can help to monitor response.

• Don’t chase CSF normalization – leads to profound immunosuppression.

Adverse Effects of Steroids

Immunomodulatory therapies• Mycophenolate mofetil• Methotrexate• Azathioprine, Cyclophosphamide- Target therapy to hematologic

endpoints of white count <3500/Lymphocyte count <1000 per mm3

• Leflunomide• Rituximab – Infusion therapy beneficial in refractory patients.• -----------------------------------------------------------------------------------------• Infliximab – Infusion therapy - Human murine antihuman antibody for

TNF-alpha.• Adalimumab – injectable TNF-alpha antagonist tried for small fiber

Neuropathy.

• Patients do better if they are on moderate dose of steroids while on these immunomodulatory therapies.

Surgical Interventions

• Resection of CNS mass is rarely indicated. Indicated only if the lesion is persistent or enlarging despite adequate immunosuppressive therapy.

• VP drain can be life saving in patients with acute hydrocephalus.

• Inflammation due to Neurosarcoidosis often leads to shunt obstruction necessitating multiple revisions.

Radiation Therapy

• For refractory cases to corticosteroids and at least 2 other immunomodulatory therapies.• Can also be used in patients with acute,

life threatening disease.• Immunosuppression should continue

during the Radiation therapy albeit, at less intense levels.

Treatment

General Measures

• Endocrine deficiencies – Thyroid, Testosterone replacement based upon testing. Thyroid hormone replacement requires T4 concentration as in hypothalamic hypothyroidism, TSH can be normal or low.• Seizures are relatively well controlled if the

inflammatory process is managed well.

• Dietary counseling to prevent weight gain from steroids, bone loss etc.

Prognosis1. 2/3 patients will have monophasic illness.2. Historically, 10% of patients died due to inflammatory process or its

treatment but with current management, the survival have substantially improved.

3. Long-term course not clearly defined.4. Facial Nerve palsy improve completely in 2-4 weeks while other cranial

neuropathies follow a similar course.5. Optic Neuropathy – some patients will progress to blindness6. Aseptic meningitis – several weeks but pleocytosis persists in CSF7. Endocrinopathy, Encephalopathy, vasculopathy, Hydrocephalus,

Peripheral neuropathies and Myopathy are often progressive and deteriorate over time.

8. Hypothalamic vegetative functions improve with immunosuppression.

Take home points• 5-10% of patients with Sarcoidosis will develop Neurosarcoidosis.• Diagnosis of exclusion. No test is confirmatory at this point.• If suspected, look for signs of systemic Sarcoidosis and possibly

obtain a biopsy to confirm the diagnosis as treatment can be long term and potentially dangerous if misdiagnosed.• Most patients have monophasic illness but relapsing remitting or

progressive course of the disease is not uncommon with episodic deteriorations.• Steroids are first line. If they fail two more immunosuppressive

medications, it is called refractory Neurosarcoidosis and TNF antagonists, Rituximab and Radiation therapy can be tried. There are no double blind randomized controlled trials at this point.

Suggested reading

• Sarcoidosis Michael C. Iannuzzi, M.D., Benjamin A. Rybicki, Ph.D., and Alvin S. Teirstein, M.D – NEJM 2007

• https://www.uptodate.com/contents/neurologic-sarcoidosis/abstract/39• Katz JM et al. Pathogenesis and treatment of Optic Neuritis in Neurosarcoidosis, a

unique therepeutic response to Infliximab – Arc. Neurology 2003• Treatment of Neurosarcoidosis with infliximab and Mycophenolate – Moravan M, Segal

BM. Neurology 2009, 72:337• Role of radiotherapy in the treatment of Neurosarcoidosis. AM J Clin Oncology 2003;

26:e115. Menninger et al.• Hoitsma E, Faber CG et al. Improvement of small fiber Neuropathy in a patient with

Sarcoidosis after treatment with Infliximab. Sarcoidosis Vasc Diffuse Lung Disease 2006; 23:73

• Continuum Neurology of systemic disease 2013, Minneap, MN