Sarcoidosis and Small Nerve Fiber Neuropathy

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Sarcoidosis and Neuropathy

Author: N K Nikhar, MD, MRCP, Assistant Professor, Department of Neurology, Washington University School of MedicineCoauthor(s): Haresh Mani, MD,, Associate Medical Director, Pulmonary and Mediastinal Pathology, American International Pathology LaboratoriesContributor Information and Disclosures

Updated: Feb 11, 2010

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Overview Differential Diagnoses & Workup Treatment & Medication Follow-up

References Keywords

Introduction

Background

In its most common form, the idiopathic multisystem disorder sarcoidosis is characterized by pulmonary, lymphoreticular system, and skin involvement. Histologically, noncaseating granulomas are prominent in biopsies from lymph nodes or affected organs. Neurological involvement occurs in 5-15% of cases. Among those with neurosarcoidosis, a subset has predominantly neuromuscular involvement.

Pathophysiology

Sarcoidosis is idiopathic, and the trigger antigen inciting granuloma formation is unknown. The prominent involvement of the pulmonary system has raised the possibility of inciting airborne agents, but to date no infectious organism has been definitely linked. Primarily, the lymphoreticular system is affected with prominent cervical and mediastinal lymphadenopathy (eg, perihilar and peritracheal nodes) and also involvement of the smaller scattered lymphatic collections in solid organs (eg, spleen, liver) and lymphoid tissue surrounding glandular organs such as the parotid and lacrimal glands.

Debate continues as to whether sarcoidosis results from a dysfunctional immune system or a secondary response to environmental antigens. Sarcoid granulomas may be seen in solid organs such as liver, kidney, and spleen. Neurosarcoidosis results from nervous system involvement by sarcoid granulomas.

The clinical features of neurosarcoidosis depend on the site of neuraxis involved. While neurosarcoidosis most commonly affects the central nervous system, a subset of patients demonstrate predominantly peripheral nervous system involvement. This may manifest as a myopathy and/or a peripheral neuropathy depending on the distribution of the granulomas.

The true incidence of peripheral neuropathy in sarcoidosis is unknown, as a significant number of asymptomatic patients with sarcoidosis have subclinical peripheral nerve involvement.

Neuropathy occurs via 2 mechanisms. The tissue can be involved directly: in muscle, a slow and indolent myositis results, and in the nerve, a neuropathy results. Granulomas in the nerve are seen most often in the perineurium and the epineurium, with local effects leading to axonal damage.

Some studies reveal sparing of the endoneurium, but others show prominent infiltration of the endoneurium, suggesting that all 3 nerve layers may be involved. Occasionally, myelin loss is prominent, with appearance of myelin ovoids. Whether the latter are due to compression from the granulomas, a result of regional toxic effects, or a result of specific targeting of the myelin sheath is unclear.Tajima suggested a predominance of helper T cells in the sarcoid granulomas. Inflammation of the vasa nervorum or the arterioles to the muscles can result in ischemic injury or severe vasculitic neuropathy. A significant increase of the HLA allele DQB 1 0602 has been reported in sarcoidosis patients with small fiber neuropathy and this allele has been associated with severe course of disease.1

Peripheral nerve injury from these mechanisms may result in a diffuse polyneuropathy, mononeuritis multiplex, focal mononeuropathies, or polyradiculopathy from involvement of spinal root sheaths. The spinal root sheaths are an extension of the pachymeninges and a tissue for which sarcoid granulomas have a particular predilection.

Frequency

United States

Neurosarcoidosis occurs in approximately 5% of patients with sarcoidosis and approximately half the patients with neurosarcoidosis present with neurologic difficulties when sarcoidosis is first diagnosed. Peripheral neuropathy is seen in 5-15% of those with neurosarcoidosis. In a series from s Hopkins University, 2 of 33 patients with neurosarcoidosis had peripheral neuropathy. Eighty-five percent of this patient population was African American and 15% was white. Pediatric neurosarcoidosis is rarely reported.

International

In a French series, 40% of 35 patients with neurosarcoidosis had peripheral neuropathy; 91% of these patients were Caucasian and 9% were black. The large discrepancy between the 2 groups may exist because the white population with neurosarcoidosis may be more predisposed to peripheral neuropathy than the black population. The term black is used rather than African American because it refers to members of the African race and is less restrictive in its description of different nationalities. et al report a more frequent neurologic involvement of 26% in a prospective study from Australia. Neurologic involvement was identified in 32 of 123 patients (15 male, 17 female, all white), mean age 48 years, age range 21-80 years, over a 3-year period. Of the 32 patients, the following frequencies of abnormalities were observed: papilloedema (6%), cranial neuropathy (59%), peripheral neuropathy (47%), mononeuropathy (25%), myopathy (25%), psychiatric

disorders (19%), cerebellar ataxia (13%), and hydrocephalus (6%). A neurologic improvement was seen in 16 of 19 (84%) following steroid therapy, and spontaneous improvement occurred in 5 of 13 (38%) who were untreated.2

Mortality/Morbidity

The mortality rate is difficult to assess. Most patients with peripheral neuropathy from sarcoidosis also exhibit other systemic or CNS manifestations of the disease. These manifestations pose greater morbidity and mortality risks than polyneuropathy alone. The proportion of patients who have exclusively sarcoid polyneuropathy is unknown.

Race

While sarcoidosis in general is more common in the black population than in other races, it is also seen in Caucasians, as shown in numerous studies from Europe. Whether the percentage of patients with peripheral neuropathy from sarcoidosis is higher in blacks than in whites is not clear. No racial predilection for the development of sarcoid neuropathy is known.

Sex

The female-to-male ratio ranges from 55:45 to 63:37.

Age

All ages are affected, but young adults are especially susceptible.

Clinical

History

Neuropathy can be the presenting feature of sarcoidosis, but this is rare; more commonly, neuropathy reflects a neurological extension of existing sarcoidosis.

Clinical presentation is diverse and includes diffuse sensorimotor neuropathy, distal to proximal slowly progressive weakness, distal numbness and dysesthesia, multifocal neuropathies that mimic mononeuritis multiplex, mononeuropathy, or even an acute generalized demyelinating motor neuropathy similar to the Guillain-Barre syndrome. The symptoms can be acute, subacute, or chronic. Bell-shaped truncal tightening and pain with sensory disturbance of superficial and deep sensations has also been described.3

More focal findings present with symptoms referable to the nerve involved. Thus, in polyradiculopathy involving the cauda equina, patients may have progressive lower extremity weakness with or without sphincteric involvement. Mononeuropathies present with symptoms reflecting impairment of function in the particular nerve distribution.

Numerous studies suggest that most of the neuropathies associated with sarcoidosis are initially multifocal and eventually become confluent; thus, the initial presentation may be that of mononeuritis multiplex. This is seen most frequently in the cranial nerves where lower motor neuron neuropathy of the facial nerve (which is the nerve most frequently involved) may present along with other cranial neuropathies or as bilateral facial neuropathies, sometimes in a sequential manner mimicking Lyme disease. When associated with fever, uveitis, and parotid gland enlargement, some patients may be thought to have Heerfordt syndrome.4 Carpal tunnel syndrome may be more common among patients with sarcoidosis than the general population.5,6,7 Audiovestibular manifestations of sarcoidosis (especially sensory hearing loss) are likely to be primarily a result of vestibulocochlear nerve neuropathy.8

In a large series, 57 patients with biopsy-proven sarcoidosis causing limb neuropathy were reviewed to delineate the characteristic symptoms, impairments, disability, course, outcome, and response to corticosteroid treatment of limb sarcoid neuropathy. Typically, the neuropathy had a definite date of symptomatic onset. Prominent were positive neuropathic sensory symptoms (P-NSS), especially pain, overshadowing weakness, and sensory loss. The pattern was almost always asymmetric and not length-dependent (unlike distal polyneuropathy). The pathologic process was focal or multifocal, involving most classes of nerve fibers and variable levels of proximal to distal levels of roots and peripheral nerves.9 Additional features aiding in diagnosis were (1) systemic symptoms such as fatigue,

malaise, arthralgia, fever, and weight loss; (2) involvement of multiple tissues (ie, skin, lymph nodes, eye); (3) the patterns of neuropathy; (4) MRI features; and (5) ultimately tissue diagnosis. Axonal degeneration predominated, although an acquired demyelinating process, was observed in 3 patients. For most cases, the disease had a chronic monophasic course.

Some patients with sarcoidosis may have small fiber neuropathy with autonomic involvement. This may manifest as unexplained pain and dysesthesia, reduced warm and cold sensitivity, or even cardiac autonomic disturbances. Recognition of cardiac autonomic disturbances may be of clinical relevance due to their associated morbidity.10

Physical

Clinical findings depend on the type and the nature of the peripheral nerve involvement.

In diffuse polyneuropathy, patients experience weakness with a distal predominance. Deep tendon reflexes are attenuated or absent. Sensory modalities are impaired in a stocking and glove distribution, with large-fiber modalities (eg, proprioception, vibration) more commonly and more severely affected than small-fiber functions (eg, pain, temperature). Recent findings suggest a higher prevalence of small-fiber neuropathy with pain as a symptom than hitherto recognized. Pure sensory neuropathy has been reported. Distal atrophy may be noted, depending on the duration of the neuropathy. Focal neuropathies result in dysfunction in the distribution of that nerve. The most common of these neuropathies is that of unilateral lower motor neuron facial nerve, and patients often are thought to have Bell palsy at presentation. Facial nerve neuropathy also can be bilateral.11

Polyradiculopathy commonly affects the cauda equina and presents as an asymmetrical weakness of the lower extremities, with loss of the deep tendon reflexes and patchy sensory loss, including the perianal region.

Causes

The causes of sarcoidosis are unknown.

More on Sarcoidosis and Neuropathy

Overview: Sarcoidosis and Neuropathy

Differential Diagnoses & Workup: Sarcoidosis and Neuropathy

Treatment & Medication: Sarcoidosis and Neuropathy

Follow-up: Sarcoidosis and Neuropathy

References

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Further Reading

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Keywords

sarcoidosis, neuropathy, granulomas, neurosarcoidosis, sarcoid granulomas, peripheral neuropathy, neurosarcoidosis symptoms, neurosarcoidosis treatment

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Contributor Information and Disclosures

Author

N K Nikhar, MD, MRCP, Assistant Professor, Department of Neurology, Washington University School of MedicineN K Nikhar, MD, MRCP is a member of the following medical societies: American Academy of Neurology Disclosure: Nothing to disclose.

Coauthor(s)

Haresh Mani, MD,, Associate Medical Director, Pulmonary and Mediastinal Pathology, American International Pathology LaboratoriesDisclosure: Nothing to disclose.

Medical Editor

E Barkhaus, MD, Professor, Department of Neurology, Medical College of Wisconsin; Director of Neuromuscular Diseases, Milwaukee Veterans Administration Medical Center E Barkhaus, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Neurological Association Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicineDisclosure: eMedicine Salary Employment

Managing Editor

Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Chief of Neurology, St Louis ConnectCare, Consulting Staff, Jewish HospitalGlenn Lopate, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and Phi Beta Kappa Disclosure: Nothing to disclose.

Chief Editor

Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants Lorenzo, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Neurology Disclosure: Nothing to disclose.

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