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

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Editor: Louis H Weimer MD

Sarcoidosis neuropathy

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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.

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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.
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Editor

Louis H Weimer MD

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

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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

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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

Neuropathies associated with cytomegalovirus infection

Anti-IgLON5 disease

Anti-LGI1 encephalitis

Giant cell arteritis

Chronic inflammatory demyelinating polyradiculoneuropathy

Amyotrophic lateral sclerosis

Amiodarone neuropathy

Autoimmune autonomic neuropathy

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