Sarcoidosis neuropathy …

Jinny O Tavee MD

Peripheral Neuropathies

Updated 02.27.2024
Released 04.23.1996
Expires For CME 02.27.2027

Sarcoidosis neuropathy

Author: Jinny O Tavee MD

See Contributor Disclosures

Editor: Louis H Weimer MD

Sarcoidosis neuropathy

In This Article

Quick Link

Introduction

Overview

The author reviews current concepts of sarcoidosis-associated neuropathies. Clinical features, diagnostic considerations, and management strategies are discussed. In particular, the recent literature on sarcoidosis-associated small fiber neuropathy and possible new target-directed treatment options are highlighted. Concepts regarding the use of immunomodulatory agents are also highlighted.

Key points

	• Sarcoidosis can involve the peripheral nervous system in a variety of ways.
	• Patients can have a motor, sensory, sensorimotor, or autonomic neuropathy; the neuropathy may be primarily axonal or demyelinating.
	• Patients can have involvement of isolated peripheral nerves, such as an ulnar neuropathy, or generalized involvement.
	• Sarcoidosis is associated with virtually all peripheral neuropathy subtypes, eg, large fiber sensorimotor, pure motor, etc.
	• Small fiber sensory neuropathy is the most common peripheral nerve manifestation and is seen in up to a third of patients with systemic disease.
	• Small fiber sensory neuropathy is commonly associated with autonomic dysfunction.
	• Intraepidermal nerve fiber density analysis, autonomic testing, and more recently, corneal confocal microscopy, provide objective confirmation for the diagnosis of small fiber neuropathy.
	• Sarcoidosis-associated neuropathy may respond to immunosuppressive medications.

Historical note and terminology

Sarcoidosis was first described by Sir Jonathan Hutchinson more than a century ago (33; 12). The term "sarcoidosis" is derived from "sarkoid," used by Caesar Boeck at the turn of the twentieth century (10). Neurologic manifestations of sarcoidosis were reviewed as early as 1935 by Levin (41). Peripheral nerve involvement with sarcoidosis was first recorded by Winkler and Mazza (84; 45).

Clinical manifestations

Presentation and course

Sarcoidosis is best thought of as a multisystemic granulomatous disorder that typically involves the lungs, lymph nodes, skin, and eyes (35; 34). Neurologic manifestations of sarcoidosis occur in 5% to 10% of patients with sarcoidosis, although subclinical involvement may be found in up to 27% of sarcoidosis patients at autopsy (44; 73). Patterns of neurologic involvement include cranial neuropathies, meningeal disease, hydrocephalus, CNS parenchymal disease, neuropathy, and myopathy (71).

Neurologic disease can be the presenting feature of sarcoidosis or can develop during the course of known sarcoidosis. Neurosarcoidosis tends to occur within the first 2 years of illness onset. Patients can have several neurologic manifestations, but after presentation, it is relatively unlikely that new categories of neurologic disease will develop. Not uncommonly, patients with a sarcoidosis-associated peripheral neuropathy can present with their neurologic disease as the initial feature of sarcoidosis (60).

Neuropathies can take the form of entrapment syndromes, pure sensory (87) or motor (25) axonal disorders, sensorimotor axonopathy, mononeuropathy, and mononeuritis multiplex (63). Reports of an acute or subacute demyelinating motor neuropathy with a presentation similar to the Guillain-Barré syndrome have raised the question of the relationship between sarcoidosis and the Guillain-Barré syndrome (46; 87; 60; 19). Chronic demyelinating forms of sarcoidosis neuropathy mimicking chronic inflammatory demyelinating polyneuropathy have also been described (65). A polyradiculopathy associated with anti-neurofascin (NF)-155 and NF-140 antibodies has been reported in a patient with sarcoidosis who also demonstrated multiple cranial neuropathies, although the significance of the antibodies is unknown (11).

Sarcoidosis-associated neuropathies can be of acute or chronic onset. The clinical course may be monophasic, chronically progressive, or remitting relapsing. Large fiber neuropathy is not always painful, but it can be (87). A patient with painful sensory mononeuropathies evolving to a symmetric sensory neuropathy has been described (17). Patients may also develop subclinical mononeuritis multiplex (14) or multifocal motor nerve conduction block (39).

The sensory or motor loss associated with a neuropathy is dependent on the specific nature of the disturbance. For instance, an intercostal neuropathy or radiculoneuropathy has been described with dermatomal sensory loss (57; 13; 78). Hypoventilation has been associated with phrenic neuropathy (58). A “neuromyopathy” characterized by fatigue, myalgia, and areflexia and associated with selective inflammation of intramuscular nerve fibers has been described (24). Clinically it may be difficult to distinguish a widespread mononeuritis multiplex from a generalized sensorimotor neuropathy.

A commonly recognized entity associated with sarcoidosis is small fiber neuropathy, which may present with somatic and autonomic symptoms (32). Somatic manifestations include painful paresthesias and dysesthesias that often occur in a non-length dependent manner in which the face, trunk, or arms are more affected than the distal lower extremities (70; 37). Autonomic dysfunction is common as well. In a series of 115 patients with sarcoidosis small fiber neuropathy, autonomic symptoms were reported by over half of the patients (72). Symptoms included gastrointestinal disturbances, bowel or bladder dysfunction, sweating abnormalities, palpitations, and orthostasis. Blurred vision, which can also be a manifestation of autonomic dysfunction, was reported by 20% of patients with sarcoidosis small fiber neuropathy in a case series (23).

Prognosis and complications

Patients with a sarcoidosis-associated neuropathy can have a monophasic course with symptom resolution (20). More commonly, however, patients have a protracted illness with progressive deterioration, a static deficit, or a remitting-relapsing course (13). Although immunosuppressive therapy can lead to improvement, it is unclear whether treatment alters the natural history of the disease.

Patients are at risk for any of the complications associated with a neuropathy. These include, for instance, contractures, anesthetic injuries, decubiti, and falls.

Clinical vignette

A 53-year-old woman with a known history of sarcoidosis presented with loss of sensation in her feet and paresthesias in all distal limbs. Pertinent medications consisted of prednisone 7.5 mg daily. Examination revealed a stocking glove decrease in pain and temperature sensation in the distal extremities with a band of hyperpathia about the ankles. Strength was normal. Muscle stretch reflexes were diminished at the ankles. Tests for thyroid function, vitamin B12 level, and diabetes were unremarkable. The patient’s prednisone dose was increased to 20 mg daily, and her symptoms improved. A mild pain and temperature gradient was detectable in her distal limbs. She had a sustained response to prednisone in the 10 to 15 mg per day range.

Biological basis

Etiology and pathogenesis

The cause of sarcoidosis is unknown. A hypothesis addresses the possibility of a genetically based immune activation directed against as yet unknown antigens. A genome-wide association study defined an association with the gene coding for annexin A11, which has a role in apoptosis and cellular proliferation (28).

The inciting event in the pathogenesis of sarcoidosis is unknown. Inflammatory cells, particularly Th1 helper cells, are activated (02; 34). CD4 cells congregate at sites of disease activity. The cells secrete various cytokines, including interleukin-2, interleukin-12, interferon-gamma, and tumor necrosis factor. Monocytes and macrophages form granulomas, and ultimately irreversible fibrosis can develop. Small foci of ischemic necrosis can be found, presumably a result of vascular compromise from perivascular inflammation. Polyclonal immunoglobulin synthesis occurs.

An entrapment neuropathy can develop at sites of nerve compression from neurogenic or nonneurogenic granulomatous infiltration. The classic example is at the carpal tunnel with compression of the median nerve. However, the cause of most neuropathic manifestations of sarcoidosis is not well defined. Granulomas can be seen in peripheral nerves, typically in an epineural and perineural distribution (63; 60; 82). There is increasing evidence that in some cases the presence of diffuse perineural granulomas may potentially be a cause of small fiber neuropathy in sarcoidosis due to local compression (48; 36). Inflammation can develop about and within blood vessels, with luminal compromise (22; 60). The major histologic feature is that of an axonopathy (63) with relative sparing of unmyelinated fibers (49). Vital and colleagues note that necrotizing vasculitis was observed in 8 of 38 cases of sarcoidosis-associated neuropathy and microvasculitis without associated necrosis in two additional cases (80). Demyelination can be seen but is not the predominant pathologic feature. Perhaps a combination of nerve ischemia (50; 81) and the actions of cytokines leads to damage to the peripheral nerves (22). Why an axonal or demyelinating process develops in a specific individual is unknown.

With respect to small fiber neuropathy, a cytokine-mediated pathology rather than granulomatous inflammation is suspected; pro-inflammatory cytokine profiles are found to be increased in the affected skin of sarcoidosis patients with small fiber neuropathy (77). Early pathologic changes are manifested as axonal swelling followed by degeneration with loss of nerve fibers and then sprouting and regeneration (56). Additionally, in a report of patients with cutaneous sarcoidosis who had pain in the region of the skin manifestations, perineural granulomas were identified on skin biopsy and, thus, may also play a role in neuropathic pain symptoms (48).

Diagnostic workup

The diagnosis of sarcoidosis is most secure if noncaseating granulomas can be demonstrated in multiple organ systems (34). If organ dysfunction is obvious, attention should be directed at this site in the hope of obtaining pathologic confirmation of the diagnosis. If there is no overt systemic disease, the inflammatory process is most likely to involve the lymph nodes, lungs, skin, and eyes. Therefore, particular attention should be directed at these sites in the hope of detecting an abnormality.

In patients in whom the diagnosis of sarcoidosis is being considered and in whom there is no overt organ dysfunction, several diagnostic approaches can be followed:

	• A careful skin and lymph node examination may detect an abnormality that can be biopsied.
	• Blood tests (including an angiotensin converting enzyme assay, calcium level, liver and renal function, and quantitative immunoglobulins) can yield abnormalities suggestive of a systemic illness. Although an elevated serum angiotensin-converting enzyme assay is suggestive of the diagnosis of sarcoidosis, it can be abnormal in other conditions such as Gaucher disease. The other laboratory tests are relatively nonspecific as to a diagnosis of sarcoidosis.
	• An ophthalmological evaluation can find iritis, conjunctival nodules, uveitis, and retinal inflammation. The conjunctiva can be biopsied; this is best done if a nodule is detected.
	• A chest x-ray can reveal pulmonary lesions or mediastinal or hilar adenopathy. If the chest x-ray is unremarkable, pulmonary function tests, including a diffusion capacity, can reveal occult disease, as can a CT scan of the chest. If the pulmonary function tests or CT scan are abnormal, bronchoscopic or mediastinal biopsy can yield a diagnosis.
	• If there are any sinus or nasal symptoms, an endoscopic examination can reveal mucosal abnormalities that can be biopsied.
	• A whole-body gallium scan can demonstrate lacrimal, parotid, and salivary gland inflammation, which, if bilateral, is suggestive of a diagnosis of sarcoidosis (68). The gallium scan can also detect intrathoracic or intra-abdominal inflammation.
	• A whole-body PET scan with fluorine-18-fluorodeoxyglucose can detect increased metabolic activity suggestive of sarcoidosis (74). This is a nonspecific finding in that malignancy and infection can cause foci of increased metabolic activity. The demonstration of an abnormal focus of activity can guide a diagnostic biopsy.
	• An increase in 24-hour urinary calcium excretion is suggestive of a diagnosis of sarcoidosis.
	• A muscle magnetic resonance scan can detect foci of inflammation. A biopsy can be directed at these sites.
	• A skin test or QuantiFERON analysis for tuberculosis should be considered to evaluate the possibility of infection.

If there are neurologic symptoms or signs, in addition to a neuropathy, attention should be directed to further evaluating these findings with appropriate CT or MRI scans or a CSF evaluation.

Large fiber neuropathy can be assessed with electromyography (63). However, there is nothing specific about the findings to suggest the diagnosis of sarcoidosis. In axon loss lesions, the sensory and motor nerve amplitudes may be reduced or absent depending on the severity of the neuropathy, whereas demyelinating lesions may result in prolonged latencies, slowed motor conduction velocities, or conduction block. Needle examination can demonstrate denervation in appropriate muscles and help characterize the problem as a mononeuritis multiplex, radiculopathy, or symmetric polyneuropathy (63).

The CSF may demonstrate a number of abnormalities in patients with sarcoidosis-associated neuropathy, including an elevated CSF protein level, a modest, predominately lymphocytic pleocytosis, a low CSF glucose, an elevated IgG, and the presence of oligoclonal bands (50; 63). The value of a CSF angiotensin converting enzyme assay in patients with a sarcoidosis-associated neuropathy is unknown but is likely of low yield.

If a patient with a neuropathy of unknown cause undergoes a nerve biopsy and noncaseating granulomas are found, an evaluation should be pursued to define the possible multisystemic nature of the disorder. In addition to histologic examination and microbial cultures of the biopsy specimen, consideration should be given to employing DNA technology to search for subtle evidence of tuberculous infection. Consideration should also be given to obtaining a muscle biopsy, especially if there is evidence of muscle inflammation.

In patients with small fiber neuropathy symptoms, a skin biopsy with quantification of intraepidermal nerve fiber density is a widely used test that can help confirm the diagnosis, with a sensitivity that ranges from 28% when only the distal leg is sampled to 84% when the biopsy is obtained from the distal leg and thigh (32; 04; 52; 72). In a series of 72 patients with sarcoidosis on no immunosuppressive therapy, 58 patients had symptoms suggestive of small fiber neuropathy (04). One third of these 58 individuals had an abnormal intraepidermal nerve fiber density; two patients without neuropathic symptoms had an abnormal biopsy. Other diagnostic tests that may be helpful include quantitative sensory testing (or just the thermal threshold testing portion), laser evoked potentials, quantitative sudomotor axon reflex testing, and cardiac scintigraphy with iodine-123 MIBG (30; 31; 52; 72; 69; 56). A small fiber neuropathy screening questionnaire has also been developed to help with clinical diagnosis as well, as a research outcome measure (29). In clinical trials, corneal confocal microscopy evaluating corneal nerve fiber parameters (eg, number and density) has been used to confirm the presence of small fiber neuropathy in patients with sarcoidosis (79; 15).

Autonomic testing can be used to assess the extent and severity of an autonomic neuropathy. In some cases, it may be used as a complementary test to confirm the diagnosis of a small fiber neuropathy, even if there are no autonomic manifestations (72).

The patient with known sarcoidosis in whom a neuropathy develops can be initially assumed to have a sarcoidosis-associated neuropathy, after other common causes of neuropathy, such as B12 deficiency, diabetes mellitus, thyroid disease, and other autoimmune disorders, are reasonably excluded. In one study of patients with sarcoidosis and small fiber neuropathy, 20% were found to have another potential cause for the neuropathy with the most common being diabetes mellitus (72). Having excluded more common etiologies, if the patient does not respond to treatment, consideration should be given to obtaining a nerve or skin biopsy to further evaluate the problem.

Studies have demonstrated the presence of paraneoplastic autoantibodies in patients with small fiber neuropathy, the most common of which was antiganglionic acetylcholine receptor antibodies (43; 51). Although in some cases this may represent false positive test results, one study found positive autoantibodies in 22% of patients with sarcoidosis small fiber neuropathy compared to only 6.5% of those with similar symptoms but no diagnosis of sarcoidosis (43). Larger studies are needed to elucidate the significance of these findings, but they may be suggestive of a possible antibody-mediated mechanism for some patients with sarcoidosis small fiber neuropathy.

Management

Supportive measures are discussed in Peripheral neuropathies: supportive measures and rehabilitation.

The mainstay of treatment of sarcoidosis is corticosteroid therapy (75). Unfortunately, there has never been a rigorous prospective trial to define the efficacy of corticosteroids for the neurologic complications of sarcoidosis. Nevertheless, most authors advocate the use of corticosteroid therapy for patients with a functional deficit from a sarcoidosis-associated neuropathy (63).

Prednisone is usually begun at a dose of 40 to 60 mg daily; some physicians will prescribe 0.5 to 1.0 mg/kg per day. The higher dose range is reserved for patients with severe deficits. This dose is continued for 2 to 4 weeks as the clinical status is observed. As the patient's functional state is monitored, the dose can be adjusted by 5 mg decrements every 2 weeks or so. Once stabilized, patients can often tolerate a dose reduction to approximately 10 mg (or 0.1 mg/kg) daily. Near this level, patients are most likely to relapse. The patient can be observed for 4 weeks, and, if all is well, the dose can be further lowered in 1 mg decrements every 2 to 4 weeks as the clinical status is watched. If the patient deteriorates, often doubling the prednisone dose (unless the patient was at a small dose) can lead to improvement. Patients may require a prolonged treatment program, with constant attempts to slowly taper the prednisone to the lowest therapeutic level and upward adjustments as warranted by the clinical course.

If the patient is severely ill or if the question arises whether an increase in immunosuppression can help the patient, a 3- to 5-day course of intravenous methylprednisolone, 20 mg/kg per day or 1 gm per day, can be administered initially followed by an oral prednisolone taper. This may be helpful for acute presentations of large or small fiber neuropathy (61). The clinical status can be observed over the next 2 to 4 weeks while prednisolone 0.5 to 1.0 mg/kg daily is maintained. Another therapeutic option for severely ill patients is a trial of infliximab, a monoclonal antibody directed at tumor necrosis factor alpha (06; 85; 54; 16; 38).

If corticosteroid treatment is contraindicated, severe corticosteroid adverse effects have developed, or the patient has deteriorated in spite of "optimal" corticosteroid therapy, alternate immunosuppressive medications can be tried (08; 62). These include agents such as azathioprine, mycophenolate mofetil (40), methotrexate (01; 09), cyclosporine (67), cyclophosphamide (66), chlorambucil, and cladribine (76). Hydroxychloroquine (64), pentoxifylline (86), and thalidomide (05) have also been used as immunomodulatory drugs for the treatment of sarcoidosis. Periodic administration of infliximab or similar tumor necrosis factor antagonists (adalimumab, etanercept) may be another therapeutic strategy, although etanercept may not be as beneficial as infliximab (07). These drugs usually allow the dose of prednisone to be lowered gradually, but rarely is it possible to stop the prednisone. The decision as to which drug to employ depends, in part, on the potential adverse drug effects that need to be avoided. For instance, thalidomide and leflunomide can cause sensory neuropathy. Infliximab has also been reported to cause a demyelinating polyneuropathy (03).

Occasionally, a clinical response is obtained with polypharmacy that is better than that obtained with corticosteroid monotherapy. Moravan and Segal found a beneficial response to combination therapy with infliximab and mycophenolate mofetil in seven patients with refractory CNS sarcoidosis (47). Although one reported case of sarcoidosis-associated peripheral neuropathy did not respond to intravenous immunoglobulin (IVIG) treatment (42), a subsequent report of three patients with small fiber neuropathy (53) and one case of large fiber neuropathy (26) noted anecdotal improvement with IVIG therapy. In addition, a case of multifocal motor nerve conduction block associated with sarcoidosis also responded to IVIG (39).

In a study evaluating the use of immune-modulating treatment for sarcoidosis-associated small fiber neuropathy, symptomatic improvement was seen in 47 of 62 patients who received IVIG, 8 of 12 patients who received anti-TNF, and 10 of 14 patients who received combination therapy (72). However, a retrospective study involving 35 patients with sarcoidosis small fiber neuropathy showed no significant improvement of small fiber neuropathy symptoms (as measured by the small fiber neuropathy screening list) with infliximab (55). In addition, there was no correlation between the effects of infliximab on systemic inflammation, which was reduced on PET scan, and neuropathy symptoms, which did not change. Cibenitide (previously known as ARA-290), an experimental erythropoietin agonist that targets specific receptors involved in pro-inflammatory cytokine production was shown to reduce autonomic and neuropathic pain symptoms in a small pilot trial of patients with sarcoidosis-associated small fiber neuropathy (27). Follow-up studies have shown improved quality of life measures and increased corneal fiber parameters in this population (79; 15).

Supportive therapy is key. Appropriate bracing and pain management with medications such as antiepileptics and antidepressants can help optimize patient function. Physical and occupational therapy may be beneficial as well. The patient should be cautioned about the risk for burns or otherwise unsuspected injuries. A skin inspection should be routine.

References

01: Agbogu BN, Stern BJ, Sewell C, Yang G. Therapeutic considerations in patients with refractory neurosarcoidosis. Arch Neurol 1995;52:875-9. PMID 7661724
02: Agostini C, Adami F, Semenzato G. New pathogenetic insights into the sarcoid granuloma. Curr Opin Rheumatol 2000;12:71-6. PMID 10647958
03: Alshekhlee A, Basiri K, Miles JD, Ahmad SA, Katirji B. Chronic inflammatory demyelinating polyneuropathy associated with tumor necrosis factor-alpha antagonists. Muscle Nerve 2010;41(5):723-7. PMID 20405504
04: Bakkers M, Merkies LS, Lauria G, et al. Intraepidermal nerve fiber density and its application in sarcoidosis. Neurology 2009;73:1142-8. PMID 19805731
05: Baughman RP, Judson MA, Teirstein AS, Moller DR, Lower EE. Thalidomide for chronic sarcoidosis. Chest 2002;122:227-32. PMID 12114363
06: Baughman RP, Lower EE. Infliximab for refractory sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2001;18:70-4. PMID 11354550
07: Baughman RP, Lower EE, Bradley DA, Raymond LA, Kaufman A. Etanercept for refractory ocular sarcoidosis: results of a double-blind randomized trial. Chest 2005;128(2):1062-7. PMID 16100213
08: Baughman RP, Ohmichi M, Lower EE. Combination therapy for sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2001;18:133-7 PMID 11436533
09: Baughman RP, Winget DB, Lower EE. Methotrexate is steroid sparing in acute sarcoidosis: results of a double blind, randomized trial. Sarcoidosis Vas Diffuse Lung Dis 2000;17:60-6. PMID 10746262
10: Boeck C. Multiple benign sarcoid of the skin. J Cutan Genito-Urin Dis 1899;17:543-50.
11: Brier MR, Everett EA, Bucelli RC. An atypical and multifactorial acute immune polyradiculopathy: a case report. Neurohospitalist 2020;10(2):118-20. PMID 32373275
12: Burns TM. Neurosarcoidosis. Arch Neurol 2003;60(8):1166-8. PMID 12925378
13: Burns TM, Dyck PJ, Aksamit AJ, Dyck PJ. The natural history and long-term outcome of 57 limb sarcoidosis neuropathy cases. J Neurol Sci 2006;244(1-2):77-87.** PMID 16524595
14: Challenor YB, Felton CP, Brust JC. Peripheral nerve involvement in sarcoidosis: an electrodiagnostic study. J Neurol Neurosurg Psychiatry 1984;47:1219-22. PMID 6094734
15: Culver DA, Dahan A, Bajorunas D, et al. Cibinetide improves corneal nerve fiber abundance in patients with sarcoidosis-associated small nerve fiber loss and neuropathic pain. Invest Ophthalmol Vis Sci 2017;58(6):BIO52-60. PMID 28475703
16: Doty JD, Mazur JE, Judson MA. Treatment of sarcoidosis with infliximab. Chest 2005;127(3):1064-71. PMID 15764796
17: Dreyer M, Vucic S, Cros DP, Chong PS. Multiple painful sensory mononeuropathies (MPSM), a novel pattern of sarcoid neuropathy. J Neurol Neurosurg Psychiatry 2004;75(11):1645-6. PMID 15489408
18: Edmonds LC, Stubbs SE, Ryu JH. Syphilis: a disease to exclude in diagnosing sarcoidosis. Mayo Clin Proc 1992;67:37-41. PMID 1732690
19: Fahoum F, Drory VE, Issakov J, Neufeld MY. Neurosarcoidosis presenting as Guillain-Barré-like syndrome. A case report and review of the literature. J Clin Neuromusc Dis 2009;11:35-43. PMID 19730020
20: Ferriby D, de Seze J, Stojkovic T, et al. Long-term follow-up of neurosarcoidosis. Neurology 2001;57(5):927-9. PMID 11552036
21: Fidler HM, Rook GA, Johnson NM, McFadden J. Mycobacterium tuberculosis DNA in tissue affected by sarcoidosis. BMJ 1993;306:546-9. PMID 8461766
22: Galassi G, Gibertoni M, Mancini A, et al. Sarcoidosis of the peripheral nerve: clinical, electrophysiological and histological study of two cases. Eur Neurol 1984;23(6):459-65. PMID 6096153
23: Gavrilova N, Starshinova A, Zinchenko Y, et al. Small fiber neuropathy in sarcoidosis. Pathophysiology 2021;28(4):544-50. PMID 35366250
24: Gemignani F, Bellanova MF, Salih S, Margarito FP, Marbini A. Sarcoid neuromyopathy with selective involvement of the intramuscular nerves. Acta Neuropathol (Berl) 1998;95:437-41. PMID 9560024
25: Godwin JE, Sahn SA. Sarcoidosis presenting as progressive ascending lower extremity weakness and asymptomatic meningitis with hypoglycorrhachia. Chest 1990;97:1263-5. PMID 2331931
26: Heaney D, Jennian F, Geddes MD, Nagendren K, Swash M. Sarcoid polyneuropathy responsive to intravenous immunoglobulin. Muscle Nerve 2004;29:447-50. PMID 14981747
27: Heij L, Niesters M, Swartjes M, et al. Safety and efficacy of ARA 290 in sarcoidosis patients with symptoms of small fiber neuropathy: a randomized, double-blind pilot study. Mol Med 2013;18:1430-6. PMID 23168581
28: Hofmann S, Franke A, Fischer A, et al. Genome-wide association study identifies ANXA11 as a new susceptibility locus for sarcoidosis. Nat Genet 2008;40:1103-6. PMID 19165924
29: Hoitsma E, De Vries J, Drent M. The small fiber neuropathy screening list: construction and cross-validation in sarcoidosis. Respir Med 2011;105:95-100. PMID 20889323
30: Hoitsma E, Drent M, Verstraete E, et al. Abnormal warm and cold sensation thresholds suggestive of small-fibre neuropathy in sarcoidosis. Clin Neurophysiol 2003;114(12):2326-33. PMID 14652091
31: Hoitsma E, Faber CG, van Kroonenburgh MJ, et al. Association of small fiber neuropathy with cardiac sympathetic dysfunction in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2005;22(1):43-50. PMID 15881279
32: Hoitsma E, Marziniak M, Faber CG, et al. Small fibre neuropathy in sarcoidosis. Lancet 2002;359(9323):2085-6. PMID 12086764
33: Hutchinson J. Cases of Mortimer's malady (lupus vulgaris multiplex non-ulcerans and non-serpiginous). Arch Surg (London) 1898;9:307-14.
34: Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med 2007;357:2153-65. PMID 18032765
35: Johns CJ, Michele TM. The clinical management of sarcoidosis. A 50-year experience at the Johns Hopkins Hospital. Medicine 1999;78:65-111. PMID 10195091
36: Kazi R, Kazlouskaya V, Ho J, Karunamurthy A. Sarcoidosis with cutaneous perineural granulomas and neurological manifestations: a potential mimicker of leprosy. J Cutan Pathol 2020;47(7):625-7. PMID 32022940
37: Khan S, Zhou L. Characterization of non-length-dependent small-fiber sensory neuropathy. Muscle Nerve 2012;45:86-91. PMID 22190313
38: Kobylecki C, Shaunak S. Refractory neurosarcoidosis responsive to infliximab. Pract Neurol 2007;7:112-5. PMID 17430876
39: Kono Y, Omoto S, Sengoku R, et al. Multifocal conduction block in a patient with sarcoid neuropathy: successful treatment with intravenous immunoglobulin. Intern Med 2013;52(9):999-1002. PMID 23648721
40: Kouba DJ, Mimouni D, Rencic A, Nousari HC. Mycophenolate mofetil may serve as a steroid-sparing agent for sarcoidosis. Br J Dermatol 2003;148(1):147-8. PMID 12534610
41: Levin PM. The neurological aspects of uveo-parotid fever. J Nerv Ment Dis 1935;81:176-91.
42: Levy Y, Uziel Y, Zandman G, et al. Response of vasculitic peripheral neuropathy to intravenous immunoglobulin. Ann N Y Acad Sci 2005;1051:779-86. PMID 16127015
43: Lower EE, Sturdivant M, Baughman RP. Presence of onconeural antibodies in sarcoidosis patients with parasarcoidosis syndrome. Sarcoidosis Vasc Diffuse Lung Dis 2019;36(4):254-60. PMID 32476961
44: Manz HJ. Pathobiology of neurosarcoidosis and clinicopathologic correlation. Can J Neurol Sci 1983;10(1):50-5. PMID 6839229
45: Mazza G. On multiple benign sarcoid of the skin, Boeck. Arch Derm Syph (Berl) 1908;91:57-78.
46: Miller R, Sheron N, Semple S. Sarcoidosis presenting with an acute Guillain-Barré syndrome. Postgrad Med J 1989;65:765-7. PMID 2694139
47: Moravan M, Segal BM. Treatment of CNS sarcoidosis with infliximab and mycophenolate mofetil. Neurology 2009;72:337-40. PMID 19171830
48: Munday WR, McNiff J, Watsky K, DiCapua D, Galan A. Perineural granulomas in cutaneous sarcoidosis may be associated with sarcoidosis small-fiber neuropathy. J Cutan Pathol 2015;42:465-70. PMID 25757612
49: Nemni R, Galassi G, Cohen M, et al. Symmetric sarcoid polyneuropathy: analysis of a sural nerve biopsy. Neurology 1981;31(10):1217-23. PMID 6287346
50: Oh SJ. Sarcoid polyneuropathy: a histologically proved case. Ann Neurol 1980;7:178-81. PMID 6245618
51: Oishi M, Mukaino A, Kunii M, et al. Association between neurosarcoidosis with autonomic dysfunction and anti-ganglionic acetylcholine receptor antibodies. J Neurol 2021;268(11):4265-79. PMID 33881596
52: Oudejans LC, Niesters M, Brines M, Dahan A, van Velzen M. Quantification of small fiber pathology in patients with sarcoidosis and chronic pain using cornea confocal microscopy and skin biopsies. J Pain Res 2017;10:2057-65. PMID 28894389
53: Parambil JG, Tavee JO, Zhou L, et al. Efficacy of intravenous immunoglobulin for small fiber neuropathy associated with sarcoidosis. Respir Med 2011;105:101-5. PMID 20926271
54: Pritchard C, Nadarajah K. Tumour necrosis factor alpha inhibitor treatment for sarcoidosis refractory to conventional treatments: a report of five patients. Ann Rheum Dis 2004;63(3):318-20. PMID 14962969
55: Raasing L, Vogels OJ, Veltkamp M, Grutters JC. Infliximab decreases inflammatory activity but has no effect on small fiber neuropathy related symptoms in Dutch patients with sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2022;39(4):e2022033. PMID 36533604
56: Raasing LRM, Vogels OJM, Datema M, Tannemaat MR, Veltkamp M, Grutters JC. Fully automatic, semiautomatic, and manual corneal nerve fiber analysis in patients with sarcoidosis. Transl Vis Sci Technol 2023;12(12):3. PMID 38047722
57: Reshad K, Sekine T, Tanaka F, Miura H. A case of intercostal neuropathy (Th 2-9) due to sarcoidosis. Nippon Kyobu Shikkan Gakkai Zasshi 1993;31:1462-7. PMID 8277619
58: Robinson LR, Brownsberger R, Raghu G. Respiratory failure and hypoventilation secondary to neurosarcoidosis. Am J Respir Crit Care Med 1998;157:1316-8. PMID 9563755
59: Rybicki BA, Iannuzzi MC, Frederick MM, et al. Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS). Am J Respir Crit Care Med 2001;164(11):2085-91. PMID 11739139
60: Said G, Lacroix C, Plante-Bordeneuve V, et al. Nerve granulomas and vasculitis in sarcoid peripheral neuropathy: a clinicopathological study of 11 patients. Brain 2002;125(Pt 2):264-75. PMID 11844727
61: Saito H, Yamaguchi T, Adachi Y, et al. Neurological symptoms of sarcoidosis-induced small fiber neuropathy effectively relieved with high-dose steroid pulse therapy. Intern Med 2015;54(10):1281-6. PMID 25986271
62: Scott TF, Yandora K, Valeri A, Chieffe C, Schramke C. Aggressive therapy for neurosarcoidosis: long-term follow-up of 48 treated patients. Arch Neurol 2007;64:691-6. PMID 17502468
63: Scott TS, Brillman J, Gross JA. Sarcoidosis of the peripheral nervous system. Neurol Res 1993;15:389-90. PMID 7907406
64: Sharma OP. Effectiveness of chloroquine and hydroxychloroquine in treating selected patients with sarcoidosis with neurological involvement. Arch Neurol 1998;55:1248-54. PMID 9740120
65: Singhal NS, Irodenko VS, Margeta M, Layzer RB. Sarcoid polyneuropathy masquerading as chronic inflammatory demyelinating polyneuropathy. Muscle Nerve 2015;52(4):664-8. PMID 25786655
66: Souayah N, Chodos A, Krivitskaya N, et al. Isolated severe vasculitic neuropathy revealing sarcoidosis. Lancet Neurol 2008;7:756-60. PMID 18635023
67: Stern BJ, Schonfeld SA, Sewell C, Krumholz A, Scott P, Belendiuk G. The treatment of neurosarcoidosis with cyclosporine. Arch Neurol 1992;49:1065-72. PMID 1329698
68: Sulavik SB, Spencer RP, Palestro CJ, Swyer AJ, Teirstein AS, Goldsmith SJ. Specificity and sensitivity of distinctive chest radiographic and/or 67Ga images in the noninvasive diagnosis of sarcoidosis. Chest 1993;103(2):403-9. PMID 8432127
69: Tavee J. Peripheral neuropathy in sarcoidosis. J Neuroimmunol 2022;368:577864. PMID 35585009
70: Tavee J, Culver D. Sarcoidosis and small fiber neuropathy. Curr Pain Headache Rep 2011;3:201-6. PMID 21298560
71: Tavee JO, Stern BJ. Neurosarcoidosis. Clin Chest Med 2015;36(4):643-56. PMID 26593139
72: Tavee JO, Karwa K, Ahmed Z, Thompson N, Parambil J, Culver DA. Sarcoidosis-associated small fiber neuropathy in a large cohort: clinical aspects and response to IVIG and anti-TNF alpha treatment. Respir Med 2017;126:135-8.** PMID 28318820
73: Tavee JO, Stern BJ. Neurosarcoidosis. Continuum (Minneap Minn) 2014;20:545-59. PMID 24893233
74: Teirstein AS, Machac J, Almeida O, Lu P, Padilla ML, Iannuzzi MC. Results of 188 whole-body fluorodeoxyglucose positron emission tomography scans in 137 patients with sarcoidosis. Chest 2007;132:1949-53. PMID 17925421
75: Thomas KW, Hunninghake GW. Sarcoidosis. JAMA 2003;289(24):3300-3. PMID 12824213
76: Tikoo RK, Kupersmith MJ, Finlay JL. Treatment of refractory neurosarcoidosis with cladribine. N Engl J Med 2004;350(17):1798-9. PMID 15103013
77: Uceyler N, Kafke W, Riediger N, et al. Elevated proinflammatory cytokine expression in affected skin in small fiber neuropathy. Neurology 2010;74:1806-13. PMID 20513817
78: Uzawa A, Kojima S, Yonezu T, Kanesaka T. Truncal polyradiculopathy due to sarcoidosis. J Neurol Sci 2009;281:108-9. PMID 19339022
79: van Velzen M, Heij L, Niesters M, et al. ARA 290 for treatment of small fiber neuropathy in sarcoidosis. Expert Opin Investig Drugs 2014;23(4):541-50. PMID 24555851
80: Vital A, Lagueny A, Ferrer X, et al. Sarcoid neuropathy: clinico-pathological study of 4 new cases and review of the literature. Clin Neuropathol 2008;27:96-105. PMID 18402389
81: Vital C, Aubertin J, Ragnault JM, Amigues H, Mouton L, Bellance R. Sarcoidosis of the peripheral nerve: a histological and ultrastructural study of two cases. Acta Neuropathol (Berl) 1982;58:111-4. PMID 6295049
82: Vital C, Vital A, Canron MH, et al. Combined nerve and muscle biopsy in the diagnosis of vasculitic neuropathy. A 16-year retrospective study of 202 cases. J Peripher Nerv Syst 2006;11(1):20-9. PMID 16519779
83: Voortman M, Hendriks CMR, Elfferich MDP, et al. The burden of sarcoidosis symptoms from a patient perspective. Lung 2019;197(2):155-61. PMID 30778661
84: Winkler M. Contribution to the question of sarcoid of Boeck and the subcutaneous nodular tuberculid of Darier. Arch Derm Syph (Berl) 1905;77:1-23.
85: Yee AM, Pochapin MB. Treatment of complicated sarcoidosis with Infliximab anti-tumor necrosis factor-alpha therapy. Ann Intern Med 2001;135:27-31. PMID 11434729
86: Zabel P, Entzian P, Dalhoff K, Schlaak M. Pentoxifylline in treatment of sarcoidosis. Am J Respir Crit Care Med 1997;155:1665-9. PMID 9154873
87: Zuniga G, Ropper AH, Frank J. Sarcoid peripheral neuropathy. Neurology 1991;41:1558-61. PMID 1656324

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Jinny O Tavee MD

Dr. Tavee of National Jewish Health received consulting fees from Argenx, a research grant from Kabafusion Infusion Services as an investigator, lecture fees from Alexion, and travel fees from CSL Behring as an external advisor.
See Profile

Editor

Louis H Weimer MD

Dr. Weimer of Columbia University has no relevant financial relationships to disclose.
See Profile

Former Authors

Barney J Stern MD

Patient Profile

Age range of presentation: 2 to 65+ years
Sex preponderance: male=female
Heredity: Heredity may be a factor
Population groups selectively affected: African-Americans

Dutch
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Sarcoidosis: 135.0
ICD-10: Sarcoidosis: D86
OMIM: Sarcoidosis: #181000

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Sarcoidosis neuropathy

Associated Disorders

Neurosarcoidosis

Differential Diagnosis

other inflammatory or infiltrating neuropathies
leprosy
syphilis
Wegener granulomatosis
lymphomatoid granulomatosis
- tuberculosis
- AIDS-related diffuse infiltrative lymphocytosis syndrome

Sarcoidosis neuropathy …

Sarcoidosis neuropathy

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Autoantibodies: mechanism and testing

NF2-related schwannomatosis

Familial dysautonomia

Peripheral nerve complications of HIV-1 infection

Neuropathies associated with cytomegalovirus infection

Multiple sclerosis: treatment of its symptoms

Disulfiram neuropathy

Mercury neuropathy

Sarcoidosis neuropathy

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Autoantibodies: mechanism and testing

NF2-related schwannomatosis

Familial dysautonomia

Peripheral nerve complications of HIV-1 infection

Neuropathies associated with cytomegalovirus infection

Multiple sclerosis: treatment of its symptoms

Disulfiram neuropathy

Mercury neuropathy

This is an article preview.
Start a Free Account
to access the full version.