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Sarcoidosis is granulomatous auto inflammatory autoimmune remitting relapsing disease affecting every organ in the body, it is the most difficult disease to diagnose in the absence of serum or imaging biomarker
Differential diagnosis is broad which included inflammatory, infective, neurodegenerative and neoplastic, histological biopsy is the only confirmative marker, and even histological confirmation is not robust as infection, malignancy and some drugs can induce granuloma, the most common organs affected are lung, lymph nodes, skin, eyes, liver, and less commonly pituitary gland, bones, brain, peripheral nerves, and heart, causing bilateral hilar lymphadenopathy, granulomatous lymphadenitis.
Lupus pernio and erythema nodosum, optic neuritis, granulomatous hepatitis, Diabetes insipidus, Periosteal bone erosion, pachymeningitis and leptomeningitis, cardiomyopathy and conduction arrhythmia are not uncommon manifistation of sarciodosis affecting skin,eyes,liver, pitutatry glad, hypothalamus,brain,spinal cord ,and heart respectivly.
Two well described syndromes, the first one Hereford syndrome which encompass granulomatous Uveitis, parotid and submandibular lymphadenitis, and 7th nerve neuropathy, other cranial nerve might be involved, and second syndrome is Lofgren syndrome which comprise fever, arthritis, erythema nodosum, and hilar lymphadenopathy.
Prevalence of the disease is highest in western countries than Asian and middle east population, it affects females more than males, the age of onset above 45 years up to 60, women can be affected at an elder age, sarcoidosis can be presented as subacute monofocal affecting one system or multifocal affecting few systems at the same time, mortality rate is greater than in general population if it affected the heart or brain, sarcoidosis can be remitting relapsing where patient will be fully asymptomatic after the relapse, or could be primary progressive where patient will never inter into complete remission after the first relapse or it could be secondary progressive where patients continue to have residual illness after each relapse.
Neurosarciodosis is a serious uncommon disease which could affect cranial nerves, meninges, brain parenchyma including pia matter and subarachnoid, it could also affect spinal cord and cauda equina, spinal vertebra, peripheral nerves and muscles.
Neurosarciodosis had a very broad clinical manifestations which can masquerade as many other diseases like malignancy, infective, inflammatory or neurodegenerative in nature.
Spontaneous remissions occur in about 50% of patients with neurosarcoid, all current practice stemmed from retrospective and autopsy series and from patients with systemic disease, that is why there is no guidelines about best approach for investigating, diagnosing and treating neurosarciodosis [1, 2, 3, 4].
Cranial neuropathy is the most common neurological manifestation of sarcoidosis, facial nerve is the most common to be affected, and it is commonly unilateral and less commonly bilateral.
In the most recent series optic neuritis started to be more common, bilateral optic neuritis can also occur, symptoms and signs included retro orbital pain specially with movement of the eye, blurring of vision, afferent pupillary defect, papilledema, decreased acuity of vision and impaired colour vision, field defects which included central, ventrocaudal and altitudinal, other cranial involvements are V111 nerve causing auditory and vestibular dysfunction, 111,V1 and V1 nerves can be affected in patients with involvement of leptomeninges causing compression of the cavernous sinus, olfactory nerve is rarely affected causing impaired taste and anosmia , every patient should have MRI with gadolinium to look at enhancement of cranial nerve, compressive optic neuropathy my arise when disease affects the orbital apex and might cause hydrocephalus due to increased intracranial pressure.
CSF usually is bland or show increased protein, matched oligoclonal ban is uncommon, sometimes CSF will show unmatched monoclonal band in isolated cranial neuropathy, isolated trigeminal involvement had been reported and posed a diagnostic problem in the presence of normal imaging and mildly active CSF with detection of unmatched oligoclonal band, Isolated neuropathy of the lower cranial nerves is very uncommon but had been reported causing weakness and atrophy of one side of the tounge in addition to bulbar symptoms in the form of dysphonia and dysphagia, involvement of the lower cranial nerves occurs more commonly with Basel meningitis rather than isolated cranial neuropathy, active CSF is common in Basel meningitis, with elevated protein, matched oligoclonal band and low CSF sugar with simultaneous serum sugar [5,6,7].
Hypothalamic involvement is very common causing polydipsia and diabetes insipidus due to subependymal granulomatous inflammation of the third ventricle, the two common manifestations are hyperprolactinemia and polydipsia due to diabetes insipidus, leptomeningeal inflammation and infiltration can cause mass lesion resulting in increased intracranial pressure, hydrocephalus, and cerebellopontine angle lesion simulating neurofibromatosis type 11.
Neurosarciodosis should be in the differential diagnosis of seizures as it caused seizure in up to 20% of patients with neurosarciodosis, which could be focal, generalized, focal with secondary generalization and even can turn into status epilepticus and occasionally non convulsive status epilepticus, due to leptomeningeal disease, parenchymal involvement, or metabolic disturbances due to hypothalamic involvement, usually CSF will be active with increased protein, lymphocytosis, low sugar and matched oligoclonal band, prognosis is poor in sever disease and patient might need to stay on indefinite anticonvulsant, steroid, immunosuppressive and biologic are indicated in difficult seizure to control [8,9,10,11].
Peripheral neuropathy occurs in 10%-20% of patients, it can occur in isolation which caused a diagnostic.
Dilemma or concomitant with central neurosarciodosis, isolated peripheral neuropathy presents as uncommon manifestation of neurosarcoid, diagnosis usually confirmed with histological diagnosis for non-caveating granuloma, symptoms are mainly sensory or sensomotor, sarcoid peripheral neuropathy could be small fiber neuropathy where nerve conduction study is normal, thermal threshold and cutaneous autonomic responses are subnormal in addition to intraepidermal nerve fiber density is reduced, in a series of 115 patients with small fiber neuropathy, 50% had cardiovascular instability, disorders of sweating, gastrointestinal delay as an autonomic complications, acute inflammatory demyelinating polyradiculopathy is uncommon, nerve conduction study usually showed multiple conduction blocks, normal motor action potential, biopsy usually showed granulomatous infiltration and usually patients are steroid responsive, and CSF is usually active, other types of peripheral neurosarciodosis are axonal neuropathy, chronic inflammatory demyelinating neuropathy and mononeuritis multiplex.
Mononeuropathy which is quite common manifistations for ulnar and radial nerves involvment, Cranial neuropathy are more commonly encountered with Acute inflammatory demyelinating neuropathy and multifocal mononeuropathy, despite that diagnosis is usually confirmed by granulomatous infiltration, not uncommon that necrotizing vasculitis or microvasculitis are encountered in the biopsy [12,13,14].
Dural involvement is common in nerosarciodosis with predilection to Basel region and convexity, around 50% of patients with pachymeningitis will develop mass lesions causing seizures, common symptoms are headaches, orbital pain, diplopia, nausea, vomiting, reduced acuity of vision, impaired colored vision, visual field defect, cavernous sinus syndrome (pulsatile ophthalmopathy, third, fourth and sixth nerve palsy, encephalopathy) specially when the orbital apex is involved, patient may develop severe headache due to hydrocephalus, outcome is good if patient was timely diagnosed and received timely appropriate treatment (Steroid, Immunosuppressive and biologic) imaging is usually abnormal in all patients and CSF is active [15, 16].
Most patients have severe form of the disease in the form of meningoencephalitis, 50% of patients developed diencephalic dysfunction in the form of hydrocephalus and brain stem disease, patients with convexity Basel meningitis might develop cavernous sinus syndrome and encephalopathy, imaging is always abnormal, CSF protein correlates with the severity of hydrocephalus, patient should be treated with steroid, immunosuppressive and biologic, steroid alone is not optimum treatment.
Patients with leptomeningitis might develop large or small vessel stroke due to inflammatory involvement of small and medium vessel arteries causing stenosis of the vessels, of note patients with stroke due to leptomeningitis will not benefit from antiplatelet but will improve with steroids.
Focal stenosis of internal carotid, middle cerebral and anterior cerebral arteries might develop abnormalities resembling Moya disease, few patients might develop subclinical disease with no symptom’s.
Patients with leptomeningitis might develop spontaneous intracranial bleed in a lobar distribution, infratentorial and even subarachnoid bleed needing urgent endovascular treatment, Few patients reported to have cortical vein thrombosis due to inflammation of the veins [17, 18].
Involvement of the brain and spinal cord are common in leptomeningeal disease and mimics neurosarcoid patchy meningeal disease, Isolated disease of the spinal cord and cauda equine are also encountered, disease is usually subacute, extensive longitudinal disease of the spinal cord usually occur in leptomeningitis, smaller involvement of the cord occurs in pachymeningitis, most of the patients with lower dorsal spinal disease can have involvement of the cauda equina, early sphincteric dysfunction and painless sensory loss is common in dorsal and cauda equina involvement, in spinal disease with root involvement, patient will be manifested with amyotrophic signs which could be difficult to distinguish from motor neuron disease if sensation is intact but usually active CSF will be discriminating factor.
Patients with isolated neurosarcoid are still difficult to diagnose, contrast MRI, CSF and PET scan when imaging are negative, are essential investigation, histology and biopsy when possible is important for confirming the diagnosis, hypercalcemia and hypercalciuria are complementary findings if patient has subclinical systemic disease, reduced CSF / Plasma ratio is supportive of the diagnosis.
Patients with isolated cranial disease has less active CSF than patients with systemic disease, 50% of patients with systemic sarcoid have elevated Angiotensin – Converting enzyme, it is nonspecific and found to be raised in other diseases like TB and cancer, flow cytometry from CSF/ is Charactersieb by elevated CD4/CD8 ratio because of the absence of solid biomarkers to diagnose neurosarciodosis, neurosarciodosis diagnosis is classified to:
1- Definite neurosarcoid if biopsy is positive (despite that malignancy and some infection can induce granuloma)
2- Probable neurosarcoid if investigation is supportive of the diagnosis, like elevated protein, presence of unmatched oligoclonal band, decreased SCF sugar with simultaneous serum sugar.
Lymphocytosis, MRI with contrast showing enhancement of inflamed areas are evidence of systemic sarcoid, other criteria like ACE, chest X ray with bilateral hilar lymphadenopathy, Hypercalcemia, hypercalciuria possible, other investigation are negative for differential diagnosis [19, 20, 21, 22].
Differential diagnosis for neurosarcoidosis is wide and broad which included infection, inflammation, neoplastic and neurodegenerative diseases.
Neoplastic diseases which mimics neurosarcoid included lymphoma (Steroid responsive) meningioma, metastatic carcinoma, neurofibromatosis type 11, glioblastoma, astrocytoma, glioma. Infections like mycobacterium TB, Mycobacterium Lepra, Brucellosis, Bartonella, Toxoplasmosis.
Primary angiitis of the central nervous system, idiopathic hypertrophic pachymeningitis, Neuromyelitis Optical spectrum disorder, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS), Sjogren syndrome, IGG-4 disease, Langerhans histiocytosis, Glial fibrillar acidic protein Astro cytopathy, Erdheim -Chester disease.
Collagen diseases, immune reconstitution syndrome, could mimics neurosarcoid treatment treatment with check point inhibitor should be ruled our check point inhibitor for cancer should be ruled out [23].
Steroid is the cornerstone of treatment, patient with leptomeningitis needs a high dose of steroid, and most patients will need immunosuppressive.
From series of Royal Free Hospital Dr Desmond P Kidd found that methotrexate 15-25 mg weekly is effective in his series, he also found that intravenous Cyclophosphamide is promising in sever disease despite the side effect which included serious infections and reduced relapse frequency, leptomeningeal disease is very serious and needs steroid, immunosuppressive and biologic treatment.
Infliximab was found to be very effective in invasive leptomeningeal disease, patient should be screened for latent TB and hepatitis B before commencement of medication, most literatures mentioned treatment should be continued for a minimum of two years, IL-6 blocker tocilizumab was used with success, Anti CD 20 rituximab showed promising results in few patients from the literatures [24-31].
One can never be 100% confidant of the diagnosis of neurosarcoid even with a brain biopsy as infection, malignancy and some drugs can induce granulomatous infection, There is no one test or image to confirm the diagnosis but what might support, diagnosis of neurosarcoidosis is the presence of other organ manifistation like erythema nodosum, bilateral hilar lymphoadeopathy,subperiosteal bone disease, V11 nerve palsy neurosarcoid is a treatable disease if diagnosed early and treated in a timely manner, patients should be treated with high dose steroid and immunosuppressive, patients with invasive disease will need to be treated with steroid, immunosuppressive and biologic.
1. Valeyra D, Prasse A, Nunes H, et al. Sarcoidosis. Lancet 2014; 383:1155-1167.
2. Baughman PR, Teristen AS, Judson MA, et al Clinical Characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med 2001; 1885-1889
3. Pietinalho A, Ohmichi M, Hiraga Y, et al The mode of presentation of sarcoidosis in Finland and Hokkaido, Japan. A comparative analysis of 571 Finish and 686 Japanese patients, Sarcoidosis Vasc Diffuse Lung Dis 1996; 13:159-166.
4. Fritz D, Voortman M, Van de Beek D, et al. many faces of neurosarciodosis from chronic meningitis to myelopathy. Curr Opin Med 2017; 23:439-446.
5. Judson MA, Costabel U, drent M, et al. the WASOG sarcoidosis organ assessment instrument: an update on a previous clinical tool. Sarciodosis Vasc Diffuse Lung Dis: 2014; 31:19-27.
6. Mao L., Jin H., Wang M., Hu Y., Chen D., He Q. neurological manifestation of hosppitlized patients with coronavirus disease 2019 in Wuhan, China. JAMANeural. 2020;77(6)683-690
7. Tomita M, koike H, Kawagshira Y, et al. Clincopathological features of neuropathy associated with lymphoma, Brain. 2013; 136(Pt 8):2563-2578.
8. Baehring JM, Damek D, Martin EC, Betensky RA, Hochberg FH. Neurolyphomatosis. Neuro Oncol. 2003; 5(2): 104-115.
9. Langrand C, Bihan H, Raverot G, et al. hypothalamo- pituitary sarcoidosis: Multicenter study of 24 patients. QJM. 2012; 105(10):981-95
10. Statement on Sarciodosis, AM J Crit Care. 1999; 160:736-55
11. M. Bakkers, I. S. Merkies, G. Lauria et al, intraepidermal nerve fibre density and its application in neurosarciodosis, Neurology, vol. 73, no.14, PP. 1142-1148, 2009
12. Hebel R, Dubaniewicz-Wybieralska M, dubaniewicz A. Overview of neurosarciodosis: recent advances. J Neurol. 2016; 262(2): 258-67.
13. Hovaguimian and C. H. Gibbons, Diagnosis and treatment of Pain in small – fibre neuropathy, Current Pain and Headache Reports, Vol15, no.3, PP. 193-200, 2011.
14. Gerad Said, Catherine Lacroxi, Violaine plante- Bordeneuve Le Page, Fernando Pico, et al. Nerve granulomas and vasculitis in sarcoid peripheral neuropathy. Clinicopathological study of 11 patients. Brain. 2002; 125:264-275.
15. Fitzgerald PA. Chapter26. Endocrine Disorders. McPHee SJ, Papadakis MA, Rehow MW, eds. CURRENT Medical Diagnosis Treatment 2021. New York: McGraw-Hill; 2021
16. Burns TM. Neurosarciodosis. Arch Neurol Stern BJ, Krumholz A, et al. Sarciodosis and its neurological manifestations. 2003:60:1166.
17. Bopp FP et al. Heerfordt Syndrome: a cause of facial paralysis. J La State Med Soc.1990; 142(2):13-5.
18. Fried ED, Landau AJ, Sher JH, Rao C. Spinal cord Sarciodosis: a case report and review of the literature. J Assoc Acad Min Phys 1993; 4:132-137.
19. Glaser GH. Neurological complications of internal disease. In Baker AB, Baker LH (eds) Clinical Neurology. Hagerstown: Maryland harper, Row, 1979:3(44):1-53.
20. Bihan H, Christozova V, Dumas JL, et al. Sarciodosis: Clinical, hormonal, and MRI manifestations of hypothalamic-pitutary disease in 9 Patients and review of the literature. Medicine (Baltimore) 2007; 86-2590.
21. Pawate S, Moses H, Siram S. presentations and outcomes of neurosarciodosis: a study 54 cases. QJM 2009; 102:449.
22. Lower EE et al. Diagnosis and management of Neurological Sarciodosis. Arch Intern Med. 1997; 157(16) 1864-1868.
23. Luke RA, stern BJ, Krumholz A, Johns CJ. Neurosarciodosis: The long -term clinical course. Neurology 1987; 37:461.
24. Gullapalli D, Phillips LH. Neurological manifistations of Sarciodosis. Neurol Clin 2002; 20: 59-83.
25. Joseph FG, Scolding NJ, Sarciodosis of the nervous, Review. Pract Neurol 2007; 7:234-244.
26. Zajicek JP, Scolding NJ, foster O, et al. Central nervous system Sarciodosis – diagnosis and management. QJM. 1999; 92: 103-17.
27. Baughman RP, Lo, wer EE. Chapter 329. Sarciodosis. in: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison Principles of Internal Medicine. 18th ed. New York: Mc Graw-Hill; 2021.
28. Siddharama P, Continuum: Sarcoidosis and the Nervous System. 2020 June; 26(3):695-715.
29. Briner VA, Muller A, Gebbers JO Schweenka DC. a iz Med wochenschr. Neurosarciodosis. 1998 May 23; 128(21)799-810.
30. Nowak DA, Widenka DC. Neurosarciodosis: a review of its intracranial manifistations. J Neurol2001; 248:363-72.
31. Hoistma E, Faber CG, Drent M, et al. Neurosarciodosis: a clinical dilemma. Lancent Neurol 2004; 3:397.