Neurosarcoidosis

Background

Sarcoidosis is a multisystem disease process of unknown etiology whose pathogenesis involves formation of an inflammatory lesion known as a granuloma.^[1] Histologically, noncaseating granulomas are prominent in biopsies from lymph nodes or affected organs. The lungs are affected most frequently, but the eyes, nervous system, heart, kidneys, bones, and joints also may be affected.

Most patients with sarcoidosis do not have any symptoms; the disease often is detected on routine chest radiograph. Symptoms, if present, include cough, shortness of breath, and arthritis.

Involvement of the central nervous system, or neurosarcoidosis, occurs in 5-15% of cases of sarcoidosis. Neurosarcoidosis is a severe and sometimes life-threatening disorder.

Neurosarcoidosis generally occurs only in cases of sarcoidosis with substantial systemic involvement, and signs of neurologic involvement usually are seen in patients known to have active disease. Strictly neurologic forms are seen in fewer than 10% of patients; a subset has predominantly neuromuscular involvement.

Definitive diagnosis of neurosarcoidosis requires the exclusion of other causes of neuropathy and the identification of noncaseating sarcoid granulomas by histologic analysis of nerve and muscle biopsy specimens (see Workup).

Neurosarcoidosis has no known cure. Spontaneous remission ha s been observed, but long-term therapy often is required. Immunosuppression is the principal method of controlling the disease, and corticosteroids are the cornerstone of therapy (See Treatment).

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Pathophysiology

Sarcoidosis primarily affects the lymphoreticular system, with prominent cervical and mediastinal lymphadenopathy (eg, perihilar and peritracheal nodes). There is 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 lesion consists of lymphocytes and mononuclear phagocytes surrounding a noncaseating epithelioid cell granuloma.

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, while 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 caused by compression from the granulomas, by regional toxic effects, or by 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 significantly higher prevalence of the HLA allele DQB1*0602 has been reported in sarcoidosis patients with small fiber neuropathy, and this allele has been associated with a severe course of disease.^[2]

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, a tissue for which sarcoid granulomas have a particular predilection.

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Etiology

The causes of sarcoidosis are not clear. The present evidence suggests that active sarcoidosis results from an exaggerated cellular immune response to either foreign or self-antigens. T-helper lymphocytes proliferate, resulting in an exaggerated response.

The T-helper cells undergo differentiation to a Th1-type cell under the influence of interleukin (IL)–4 and co-stimulator CD28. The Th1 cell induces IL-2 and interferon-gamma (IFN-gamma) on the macrophages, followed by a cascade of chemotactic factors that promote formation of granulomas.

IFN-gamma increases the expression of major histocompatibility class (MHC) class II receptors on macrophages, and activated macrophages carry an Fc receptor of immunoglobulin G (IgG) that potentiates their phagocytosis function. Tissue destruction results and granuloma formation is thought to be a secondary process.

Three hypotheses have been proposed to explain the mechanism, as follows:

• A persistent antigen (either foreign or self) triggers the T-helper cell response
• Response of the suppressor arm of the immune response is inadequate and cannot prevent T-helper cells from shutting down
• A possible inherited or acquired (genetic) difference in response genes leads to the exaggerated response

In addition to the exaggerated cellular immune response, patients with active sarcoid demonstrate hyperglobulinemia, with antibodies against several infectious agents (eg, Mycobacterium tuberculosis) as well as IgM anti–T-cell antibodies. However, no evidence exists to suggest that these antibodies play a role in disease pathogenesis; rather, their presence seems to be due to a nonspecific polyclonal stimulation of B cells by activated T cells at the site.

A rare case of anti-Ma2 (Ma2-Ab) antibodies circulating in CSF was described in a female patient with diencephalitis thought to be paraneoplastic in origin.^[3] Ma2-Abs have been described in men with testicular cancer and paraneoplastic damage to the limbic system and the diencephalon. In women, Ma2-Abs have been found in cases of lung or breast cancer.

One pediatric case of neurosarcoidosis diagnosed by brain biopsy following a La Crosse virus encephalitis has been reported.^[4] The exact association was not clear, but the patient did show La Crosse virus immunoglobulins M and G in serum and cerebrospinal fluid.

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Epidemiology

United States statistics

The prevalence of sarcoid varies widely, but generally it is more common in African Americans. In the southeastern United States, the prevalence is much higher in both blacks and whites than in the rest of the country. In New York, the prevalence is 30 cases per 100,000 population.

In Los Angeles, Mexican immigrants constituted 7% of the observed cases, compared with 82% for blacks.

The frequency of neurologic involvement is generally 5% of all cases of sarcoid,^[5] but in some series it was noted to vary from 5-16%. In one prospective study, neurologic complications occurred in 32 of 123 (26%) patients with sarcoidosis. These figures are considered to be underestimates because of the usually silent manifestation of the disease and unavailability of tissue diagnosis in all cases.

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 Johns Hopkins University, 2 of 33 patients with neurosarcoidosis had peripheral neuropathy; of this population, 85% was African American and 15% was white. Pediatric neurosarcoidosis is rarely reported.

Neurosarcoidosis is also seen in the Puerto Rican population, reaching a prevalence as high as 175 cases per 100,000 population in one retrospective study.

International statistics

The incidence of sarcoid varies from 0.04 cases per 100,000 population in Spain to 64 cases per 100,000 population in Sweden. The prevalence in London was found to be 27 cases per 100,000 population for patients born in the United Kingdom, 97 cases per 100,000 population among Irishmen, and 200 cases per 100,000 population in men from the West Indies (5%). In southwest England and south Wales, one study showed a prevalence of 1 in 100 000 in a population of about 3 million.^[6] One study done in Paris showed that 13% of individuals from Martinique were affected with sarcoid.

In Asia, sarcoid is extremely rare, being almost unknown in Chinese and Southeast Asians. Data from Japan showed native Japanese to be affected.

In a prospective study from Australia, Allen et al reported neurologic involvement in 26% of white patients with sarcoidosis (32 of 123). The following frequencies of neurologic abnormalities were observed^[7] :

• Papilledema (6%)
• Cranial neuropathy (59%)
• Peripheral neuropathy (47%)
• Mononeuropathy (25%)
• Myopathy (25%)
• Psychiatric disorders (19%)
• Cerebellar ataxia (13%)
• Hydrocephalus (6%)

Racial differences in incidence

Neurosarcoidosis is more common in Africans and people of African descent, including those living in the West Indies, than people of any other race. In the United States, the ratio of affected blacks to affected whites ranges from 10:1 to 17:1. In Europe, however, the disease affects mostly whites. Neurosarcoidosis is very uncommon in Chinese people, Southeast Asians, Inuits, Canadian aboriginals, and New Zealand Maoris.

While sarcoidosis in general is more common in the black population than in other races, it is also seen in whites, 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.

Sex- and age-related differences in incidence

Neurosarcoidosis is slightly more common in women than men. The female-to-male ratio ranges from 55:45 to 63:37. All ages are affected, but young adults are especially susceptible. Neurosarcoidosis commonly occurs in adults aged 25-50 years. One exception to the sex difference mentioned above was in a study of 30 new cases in England and Wales, which showed 53% males and 47% females.^[6]

Neurosarcoidosis is uncommon in children, but when it occurs it tends to affect children aged 9-15 years. Sarcoidosis of early childhood (before age 8 y), when it does occur, has a different clinical manifestation than in adults, being characterized by the triad of cutaneous nodules, arthritis, and uveitis. The rate of ocular involvement was reported to reach 100% in these patients; iritis and/or anterior vitreitis was observed in almost all cases. Children older than 8 years have a clinical picture similar to that of adults.

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Prognosis

Spontaneous resolution of neurosarcoidosis after 4-6 months may occur but is uncommon. Many patients have a slowly progressive chronic course with intermittent exacerbations. About 5% of patients with sarcoidosis die of this disorder. Brainstem involvement can be life-threatening. Two cases of sudden death have been attributed to cardiac sarcoidosis and hypothalamic infiltration.^[8]

Although the neuropathy generally responds to steroid therapy, the long-term outcome of neurosarcoidosis has not been clearly defined. Nevertheless, the following generalizations are possible on the basis of observations of treated individuals:

• Peripheral facial nerve palsy tends to improve over 2-4 weeks
• Optic neuropathy can improve over several weeks, but some patients have a progressive course ending in blindness
• Peripheral neuropathic and myopathic illness tends to be chronic and progressive, although remissions are possible

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.

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History

Onset of neurosarcoidosis is most often in the fourth or fifth decade of life, but the disease affects children and the elderly as well. Neuropathy is rarely the presenting feature of sarcoidosis; commonly it reflects a neurologic extension of existing sarcoidosis, usually occurring within 2 years of onset of systemic illness (eg, fatigue, malaise, arthralgia, fever, and weight loss).

In patients known to have sarcoid, the appearance of neurologic symptoms usually poses no diagnostic problems. However, the possibility of unrelated disease, especially infections, must be kept in mind. The symptoms can be acute, subacute, or chronic.

• Clinical presentations are diverse and include the following:
• Diffuse sensorimotor neuropathy
• Distal-to-proximal slowly progressive weakness
• Distal numbness and dysesthesia
• Multifocal neuropathies that mimic mononeuritis multiplex
• Mononeuropathy
• An acute generalized demyelinating motor neuropathy similar to Guillain-Barré syndrome
• Generalized or localized muscle weakness or soreness

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: lower motor neuron neuropathy of the facial nerve (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 neuropathy is associated with fever, uveitis, and parotid gland enlargement, some patients may be thought to have Heerfordt syndrome.^[9] Carpal tunnel syndrome may be more common in patients with sarcoidosis than in the general population.^{[10, 11, 12]} Audiovestibular manifestations of sarcoidosis (especially sensory hearing loss) are likely to be primarily a result of vestibulocochlear nerve neuropathy.^[13]

In a series of 57 patients with biopsy-proven sarcoidosis causing limb neuropathy, most patients noted a definite date of clinical onset. Positive neuropathic sensory symptoms—especially pain—were prominent, 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.^[14]

A case of neurosarcoidosis presenting as complicated sinusitis has been reported, but the incidence of sinonasal cases is rare, ranging from 1-4% of patients. Head and neck manifestations occur in approximately 10-15% of patients with sarcoid.^[15]

Cranial nerve mononeuropathy

The facial nerve is the most commonly affected cranial nerve in neurosarcoidosis. Either unilateral or bilateral involvement may occur.

Heerfordt syndrome is a rare manifestation characterized by fever, uveitis, swelling of the parotid gland, and facial nerve palsy. It represents a type of neurosarcoidosis. The lesion site has been controversial, but direct nerve compression by parotid gland swelling or by a lesion within the facial canal has been assumed, in light of observations of accompanying taste disturbance.

A rare case of gingival sarcoidosis has been described in a patient with cranial nerve involvement.^[16]

Cranial nerve mononeuropathies may produce the following manifestations:

• Impaired taste and smell
• Blindness, blurry vision, double vision, visual field defects, pupillary abnormalities, dry and sore eyes
• Slurred speech, impaired swallowing, hoarseness
• Vertigo, sensorineural deafness, tinnitus
• Weakness of trapezius and sternocleidomastoid muscles
• Tongue deviation and atrophy

Peripheral neuropathies

Peripheral nerve involvement may result in sensory or motor mononeuropathy, mononeuropathy multiplex, or polyneuropathy. Sensory neuropathy is characterized by loss of sensation and abnormal sensation (eg, tingling, numbness, extremity pain, low back pain, painful patches over the thorax, stocking/glove deficits) Motor neuropathy is characterized by weakness, leading to immobility and joint stiffness. Bell-shaped truncal tightening and pain with sensory disturbance of superficial and deep sensations has also been described.^[17]

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

Central nervous system involvement

Central nervous system involvement may affect the hypothalamus/pituitary gland, cerebral cortex, cerebellum, and spinal cord (rarely), resulting in the following:

• Polydipsia
• Polyuria
• Diabetes insipidus
• Changes in appetite
• Changes in sleep cycle (somnolence, hypersomnia^[18] )
• Impaired temperature regulation (hyperthermia, hypothermia)
• Obesity
• Alveolar hypoventilation
• Impotence
• Change in menstrual period
• Galactorrhea
• Amenorrhea
• Generalized confusion
• Dementia
• Amnesia, both short term and long term
• Loss of judgment
• Acalculia
• Generalized fatigue
• Headache
• Meningitis
• Corticospinal signs
• Cerebellar signs
• Brainstem signs
• Cerebral infarct or transient ischemic attack
• Seizures
• Kleine-Levine-Critchley syndrome (rare)^[19]
• Parkinsonism (with basal ganglia infiltration)^[20]
• Hydrocephalus^[21]
• Sudden death^[22]

Seizures may be the first manifestation of neurosarcoidosis. Generally, seizures indicate a chronic course with poor prognosis. Patients with isolated mass lesions and simple partial or complex partial seizures (with or without secondary generalization) may have better outcomes than patients with generalized tonic-clonic seizures only.

Autonomic involvement

Some patients with neurosarcoidosis 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 because of their associated morbidity.^[23]

Sudden death from systemic sarcoidosis is highly unusual. Rare cases of sudden death have been reported. The mechanism of action in one case was suspected to be involvement of the nucleus of the solitary tract in the brainstem, and the cause of death was attributed to central hypoventilation.^[22] Another report describes a case of a woman aged 24 years who was found unconscious and subsequnetly died. No neurological symptoms were observed prior to this. Autopsy showed obstructive hydrocephalus.^[24]

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Physical Examination

Patient may have signs of the following:

• Mononeuropathy
• Mononeuropathy multiplex
• Plexopathy
• Polyneuropathy
• Sensory neuropathy
• Motor neuropathy
• Sensorimotor neuropathy
• Polyradiculopathy^[25]

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). However, the prevalence of small-fiber neuropathy with pain as a symptom may be more frequent than previously recognized. Pure sensory neuropathy has been reported.

Myopathy is characterized by tenderness, muscles feeling "hard" on palpation, and weakness. 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.^[26]

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

Eye involvement may be evident on examination; vision may be affected. Neurosarcoidosis may produce optic neuritis leading to optic atrophy. See the images below.

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Atrophic right optic disc of a 37-year-old man with neurosarcoidosis and involvement of both optic nerves. Vision was lost. The disc is pale with shar....

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Atrophic left optic disc of a 37-year-old patient with neurosarcoidosis and involvement of both optic nerves. The disc is pale with sharp borders. Vis....

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Approach Considerations

Definitive diagnosis of neurosarcoidosis requires the exclusion of other causes of neuropathy and the identification of noncaseating sarcoid granulomas by histologic analysis of nerve and muscle biopsy specimens. Other studies and diagnostic procedures may include the following:

• Blood studies
• Serum protein immune electrophoresis
• Lumbar puncture with cerebrospinal fluid (CSF) analysis
• Chest radiography
• Magnetic resonance imaging (MRI)
• Fluorodeoxyglucose positron emission tomography (FDG-PET)
• Electromyography/nerve conduction studies (EMG/NCS)
• Evoked potential (EP) studies
• Optical coherence tomography (OCT)

The diagnosis of peripheral neuropathy as a result of sarcoidosis is determined by establishing, in the first instance, the presence of a peripheral neuropathy; excluding the common causes of peripheral neuropathy, such as hyperglycemic states, deficiencies of vitamins, and presence of toxins such as heavy metals; and establishing a pathologic diagnosis of noncaseating granulomas in neural or extraneural sites.

Findings of cerebrospinal fluid analysis are normal in 30% of cases, specifically in patients with cranial nerve and peripheral nerve involvement. When CSF analysis findings are abnormal, they reflect a nonspecific pattern. Serial CSF analyses may be necessary in some cases.

On skin testing, cutaneous anergy can be seen in systemic or active pulmonary sarcoidosis. However, it almost never occurs in pure neurosarcoidosis.

Small-fiber neuropathy may be evaluated by thermal threshold testing (TTT). On the other hand, sympathetic skin responses and cardiac autonomic testing (by Ewing test and iodine-123 meta-iodobenzylguanidine [¹²³ I-MIBG] myocardial scanning) have been reported to have limited diagnostic value for evaluation of small- fiber neuropathy.

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Blood Studies

A complete blood count (CBC) with differential may show a variety of changes, as follows.

• Normochromic normocytic anemia
• Megaloblastic changes
• Basophilic stippling
• Other dyshematopoietic states
• Lymphopenia

The erythrocyte sedimentation rate (ESR) may be elevated in systemic sarcoidosis. Creatine kinase, ESR, and aldolase may be useful in cases of myopathy.

Tests for hyperglycemic states should be performed, including fasting glucose and glycosylated hemoglobin levels to exclude diabetes mellitus. If those results are normal, a 2-hour oral glucose tolerance test is needed.

A serum vitamin B-12 level should be measured to exclude deficiency. If the level is on the low side, the diagnosis should be pursued by measuring serum homocysteine and methylmalonic acid levels, which are expected to be high in B-12 deficiency.

Blood urea nitrogen (BUN), creatinine, and serum calcium should be checked to rule out long-standing metabolic derangements, which can result in neuropathy. Hypercalcemia is a known feature of systemic sarcoidosis, and abnormalities of renal functions may reflect a wider involvement of the primary disease process.

Liver function tests (eg, alanine aminotransferase, aspartate aminotransferase, bilirubin, alkaline phosphatase, gamma glutamyl transpeptidase), if abnormal, may reflect systemic involvement by either sarcoidosis or other diseases. Antineutrophil cytoplasmic antibody (C-ANCA) titers may be needed to differentiate neurosarcoidosis from Wegener granulomatosis.

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Endocrine Studies

Endocrine studies should be performed whenever involvement of the pituitary-hypothalamic axis is suspected. This includes tests of the following:

• Thyroid function
• Prolactin
• Testosterone
• Growth hormone
• Luteinizing hormone
• Follicle-stimulating hormone
• Corticotropin-releasing hormone
• Estradiol
• Urine osmolality
• Insulinlike growth factor

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Chest Radiography

Chest radiography often demonstrates perihilar lymphadenopathy or the interstitial lung disease of sarcoidosis. These abnormalities also may suggest lymphoma or other systemic diseases. See the images below.

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Early chest radiograph findings in sarcoidosis.

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Advanced chest radiograph findings in sarcoidosis.

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Magnetic Resonance Imaging

MRI scans of the brain and spine are indispensable in assessing nervous system involvement. Imaging studies of specific regions or organ systems may be appropriate if clinically indicated or if laboratory testing suggests involvement of that organ system. Although computed tomography may also be used, MRI has become the modality of choice because of the superior images obtained.

The use of gadolinium and fluid-attenuated inversion recovery (FLAIR) has increased the sensitivity of an MRI, helping identify T2 enhancement of nerve roots, plexuses, and limb nerves. MRI of peripheral nerves may occasionally show a diffusely enlarged nerve as a soft tissue mass.

Some series have shown that gadolinium enhancement demonstrated leptomeningeal involvement in cases that unenhanced images might have missed. The enhancement can follow the contour of the brain, extending into the cortical sulci. Gadolinium also can leak into the contiguous CSF because of disruption of capillary endothelial tight junctions of the arachnoid matter.

A thick and ragged pial enhancement is indicative of invasion along perivascular spaces, leading to a meningoencephalovasculopathy. Enhancement of linear and nodular areas from the pial surface into the white matter indicates infiltration along Virchow-Robin spaces.

In the FLAIR technique, the signal from the CSF is suppressed, and mild or heavy T2 weighting (long TE) is used to detect lesions. This technique is of value in detecting low-contrast lesions. It also can be used to improve the accuracy of detecting T2 prolongation in the temporal lobe in cases of mesial temporal sclerosis.

The nulling of the CSF signal maximizes the sensitivity of the sequence to changes in the T1 of the CSF. The FLAIR technique is valuable in diffusion weighting and is especially sensitive to contrast enhancement. It also can be combined with fat suppression.

An MRI may demonstrate the following:

• Periventricular high-signal lesions on T2-weighted images
• Multiple supratentorial and infratentorial brain lesions
• Solitary intra-axial mass
• Solitary extra-axial mass
• Leptomeningeal enhancement
• Optic nerve enhancement (see the images below)
• Spinal cord intramedullary mass resembling demyelinating disease

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  MRI of the brain in a 37-year-old man with neurosarcoidosis who had complete loss of vision in the right eye for 2 months and occasional blurry vision....

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  MRI of the brain in a 37-year-old man with neurosarcoidosis who had complete loss of vision in the right eye and mild left eye blurriness. This fluid-....

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  MRI of the brain in a 37-year-old patient with sarcoidosis who had right eye blindness and mild blurry vision in the left eye. This postgadolinium, T1....

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  MRI of the brain in a 37-year-old man with sarcoidosis who had loss of vision in the right eye and blurry vision in the left. This postgadolinium, T1-....

   

  

   

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Positron Emission Tomography

Fluorodeoxyglucose positron emission tomography (FDG-PET) imaging may show areas of hypermetabolism or hypometabolism in the central nervous system, and this information may be compared to a systemic PET scan in patients with systemic sarcoidosis, thus establishing a firmer diagnosis. However, because the brain has high metabolic activity, it may be difficult to interpret PET imaging in the evaluation of neurosarcoidosis. Whole-body FDG-PET was fojnd to be more sensitive than gallium scanning for assessing activity of sarcoidosis.^[27] It has proven of great value in detecting occult diagnostic biopsy sites and in assessing residual activity in fibrotic pulmonary sarcoidosis and may help in making therapeutic decisions.

Whole-body FDG-PET scanning may reveal otherwise occult/subclinical areas of involvement, demonstrate the extent of disease, and suggest possible biopsy sites.

The combination of FDG- and F-18 fluorothymidine (FLT) PET/CT scanning can help in differentiating neurosarcoidosis from malignancy and in localizing biopsy sites.^[28]

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Electromyography/Nerve Conduction Studies

Electromyography/nerve conduction studies (EMG/NCS) can be used to confirm neuropathy. Findings include slowing of motor nerve conduction velocities, as well as abnormal sensory nerve conduction consisting of absent potentials, reduced amplitude, and mild slowing. Mixed compound nerve action potentials may be seen as well.

The most characteristic electrodiagnostic finding is mononeuropathy multiplex, showing axonal degeneration and segmental demyelination. In cases of myopathy, the EMG shows myopathic potentials. With treatment and clinical improvement, motor, sensory, and mixed nerve conduction tend to improve.

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Evoked Potential Studies

Evoked potential studies may be of value in supporting the diagnosis and in monitoring the course of the disease. Visual evoked potentials (VEPs) and brainstem auditory evoked potentials (BAEPs) tend to be abnormal in about one third of the patients with neurosarcoidosis.

Somatosensory evoked potentials tend to show abnormalities less frequently. All 3 modalities of EPs can show abnormalities in patients before the appearance of clinical signs.

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CSF Analysis

When the involvement is purely peripheral (eg, diffuse peripheral neuropathy or myopathy), the CSF findings are normal. CSF examination shows a nonspecific pattern of pleocytosis and elevated protein (>0.5 g/L) if the root sheaths or meninges are involved. Glucose levels may be normal or low. In one study of 68 patients, the CSF leukocyte count was in the range of 5-220 cells/µL. These CSF findings, coupled with negative cytology and culture results, support the diagnosis of neurosarcoidosis.

levels of angiotensin-converting enzyme (ACE), lysozyme, and beta2-microglobulin can be elevated in the CSF in more than half the patients; changes in these markers can parallel the clinical course. The ACE level is rarely elevated in isolated neuropathy but may be elevated in systemic sarcoidosis.

High IgG, Ig index, and oligoclonal bands have been reported in the CSF. Studies of subpopulations of T lymphocytes have shown a high T4/T8 ratio, which can help in differentiating sarcoidosis from multiple sclerosis.

A recent study reported elevated levels of soluble CSF interleukin 2 receptor (sIL2-R) in patients with neurosarcoidosis, suggesting this as a possible marker for the diagnosis of the disease and for treatment and follow up of disease activity.^[29]

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Optical Coherence Tomography

Optical coherence tomography (OCT) appears to be a better tool in discovering retinal abnormalities before they appear on ophthalmologic examination. In a study of patients with neurosarcoidosis, 75% demonstrated quantitative OCT abnormalities, compared with 25% who had detectable abnormalities on detailed ophthalmological assessment. In the same study, 33% of patients with no ophthalmologic symptoms showed detectable abnormalities on OCT, compared with 8% of such patients who had abnormalities upon ophthalmologic examination.^[30] [#WorkupProcedures]

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Biopsy

Biopsy of an enlarged lymph node or an active area on gallium scan may reveal noncaseating granulomas, which suggest sarcoidosis as the pathologic etiology. Biopsy of the sural nerve may reveal fiber loss with a combination of axonal injury and demyelination.

Biopsies show granulomas surrounded by normal muscle in 50-80% of asymptomatic patients. A case report of neurosarcoidosis (sarcoid brainstem encephalitis) demonstrated nemaline rods in every muscle examined.^[31]

Because the granulomas can be scarce, a large sample should be taken. Granulomas are not specific for neurosarcoidosis and can be seen in patients with tuberculosis, fungal infections, collagen vascular disorders, or carcinoma.

In symptomatic patients, nodules are less frequent. In some cases, noncaseous granulomatous myositis or chronic myopathic changes can be seen. Peripheral nerve biopsies may show segmental demyelination, degenerating nerve roots with inflammatory cells, axonal degeneration, and mechanical destruction of nerves by granulomas.

Brain biopsy may be required in selected patients with isolated brain involvement. In other cases, the patient's history, MRI scans, and chest radiograph may be sufficient for arriving at the correct diagnosis. Blood vessel biopsies of both arteries and veins can show involvement of the vessel wall, most frequently in the perforating arteries.

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Histologic Findings

The diagnostic hallmark of sarcoidosis is the presence of granulomas in the involved tissue (see the images below). Granulomas are predominantly noncaseating (or solid), discrete, and naked, with a relative paucity of lymphocytes and plasma cells in the periphery. Nerve biopsy reveals secondary axonal degeneration with atrophy of nerve fibers. Myelin ovoids, which suggest demyelination, are occasionally seen.^[32]

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Noncaseating granuloma surrounded by epithelioid cells, from the medulla oblongata. Also shown are nodular inflammatory infiltrates consisting of mult....

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Noncaseating granuloma in medulla oblongata showing the granuloma surrounded by epithelioid cells and nodular inflammatory infiltrates (hematoxylin an....

In a review by Vital et al of neuropathologic findings in 38 cases of sarcoid neuropathy, the characteristic noncaseating granulomas were found on the nerve in 11 cases, on the muscle alone in 5 cases, on both muscle and nerve in 10 cases, and in the nerve and another parenchyma (mainly lung or lymph node) in 12 cases. These cases included chronic sensory motor neuropathy, mononeuropathy multiplex, painful neuropathy, and atypical chronic inflammatory demyelinating polyneuropathy (CIDP).^[33]

Moreover, necrotizing vasculitis was present in nerve biopsies from 8 cases and microvasculitis without obvious necrosis in 2 cases. Vital et al concluded that nerve fiber lesions, which are mainly axonal, are probably related to mechanical compression by noncaseating granulomas and/or to an ischemic process due to vasculitis. Cytokines and immune factors may also play a role, especially in certain cases with a clinical presentation of CIDP.^[33]

In a separate series, Said et al found epineurial granulomas and perineuritis in all nerve specimens in 11 patients. The inflammatory infiltrates invaded the endoneurium, following connective tissue septae and blood vessels, in 5 patients. Multinucleated giant cells were found in 8 patients, and necrotizing vasculitis was found in 7. Inflammatory lesions were associated with variable, asymmetrical involvement of nerve fascicles and axon loss.^[34]

A muscle specimen sampled during the same sitting in 10 patients showed inflammatory infiltrates and granulomas in 9 patients and necrotizing vasculitis in 2. Immunolabeling showed a mixed inflammatory infiltrate of T cells (predominantly CD4⁺ cells) and macrophages, in keeping with a delayed hypersensitivity reaction.^[34] A case report by Bos et al revealed that nemaline rods can be found on muscle biopsy in neurosarcoidosis.^[31]

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Approach Considerations

Neurosarcoidosis has no known cure. Spontaneous remission has been observed, but long-term therapy often is required. Treatment alleviates symptoms that are severe or progressive.

Immunosuppression is the principal method of controlling the disease, and corticosteroids are the cornerstone of therapy. In cases of exacerbation, intravenous pulsed methylprednisolone followed by oral taper may be necessary. Treatment is guided by the clinical response to corticosteroids. If the response is favorable (ie, steady amelioration of symptoms), then the dose may be tapered over several months. Follow-up by a neurologist every 3-6 months to monitor the progress of the disease is important.

Relapses may respond poorly, however, requiring long-term steroid therapy. The prognosis with peripheral neuropathy is more favorable than with central nervous system involvement.

A variety of immunosuppressant agents (eg, cyclosporine, methotrexate, cyclophosphamide) have been used in patients with refractory neurosarcoidosis, with varying results. Almost all of the studies completed to date have involved treatment of central nervous system sarcoidosis as opposed to peripheral neuropathy.

There have been anecdotal reports of improvement with intravenous immunoglobulin therapy in patients in whom conventional therapy has failed.^[35] The response may be related to amelioration of vasculitic neuropathy.

In patients with brain involvement, low-dose radiation has produced clear symptomatic benefits in some patients. Since the adverse effects of low-dose cranial irradiation are minimal, using radiation therapy may be prudent for patients whose disease is refractory to steroids or who have had adverse responses to high-dose steroids. Removal of the space-occupying lesions in the brain has little or no benefit and should be attempted only in extreme cases. Hydrocephalus may require ventriculoperitoneal shunting.

Adjunctive measures for specific neurologic manifestations include the following:

• Dementia: safety intervention and assistance
• Hypopituitarism: hormone replacement therapy
• Psychosis: risperidone and other antipsychotic drugs
• Foot involvement or balance problems: physical therapy with activity recommendations for decreasing falls

Consultation with the following specialists is advisable in the management of neurosarcoidosis:

• Rheumatologist
• Endocrinologist
• Neurosurgeon
• Pulmonologist

• References

Immunosuppressant Therapy

Immunosuppressants such as cyclosporine, methotrexate, and cyclophosphamide have been used with varying results. Almost all of the studies completed to date have involved treatment of CNS sarcoidosis as opposed to peripheral neuropathy.

A retrospective report of 26 patients with refractory neurosarcoidosis monitored for a mean of 81.2 months demonstrated steroid sparing in 10 of 26 patients and clinical improvement in 15 of 26 patients treated with alternative medications or irradiation. Medications and results were as follows:

• Azathioprine : positive response in 8 of 14 patients
• Cyclophosphamide: positive response in 11 of 14 patients
• Cyclosporine: positive response in 2 of 3 patients
• Chloroquine: positive response in 1 of 1 patient
• Methotrexate: positive response in 1 of 3 patients

On the basis of this experience, the authors recommend azathioprine and cyclophosphamide as the alternative agents of choice in corticosteroid-resistant neurosarcoidosis, with methotrexate reserved for patients who either do not respond to those alternative agents or are intolerant of them. Azathioprine has been used as an alternative to corticosteroids when the adverse effects are intolerable, but reports in the literature are sparse.

Cyclosporine has been reported to lead to improvement in some patients. It has been successful in controlling the disease in patients undergoing transplantation. In one series, the response rate was 75%, but the patients had relapses once the therapy was stopped.

Methotrexate can be used as a steroid-sparing agent. It is generally well tolerated, with minimal adverse effects except for potential liver toxicity. Thus, patients on long-term dosing need to have careful monitoring of liver function, including liver biopsies. In one study, the remission rate for patients on methotrexate was 61%.

Cyclophosphamide use has been more limited. Short-term therapy has not been associated with good response. Therapy lasting at least several months is needed to determine efficacy. In one study, intermittent intravenous cyclophosphamide was associated with better compliance and lower risk of malignancy, especially bladder malignancy; however, bladder toxic effects did occur. Patients showed improvement in the course of the disease.

Chloroquine and hydroxychloroquine also have been used. In a study by Sharma, chloroquine and hydroxychloroquine were effective in controlling neurologic sarcoidosis in patients who did not respond to corticosteroids or developed severe adverse effects. These agents stabilized or controlled symptoms in 10 of 12 patients.

Several recent reports have shown successful treatment with infliximab,^{[36, 37, 38]} rituximab,^[39] mycophenolate mofetil.^{[38, 40]} Mycophenolate was not effective in treating sarcoid myopathy, however.^[40] Combination treatment with infliximab and mycophenolate mofetil also appears promising.^[38]

Tumor necrosis factor–α (TNF-α) is believed to be a key cytokine in the pathogenesis of sarcoidosis, and TNF-α inhibitors are being increasingly used to treat refractory sarcoidosis. Several cases of refractory neurosarcoidosis treated with thalidomide have been reported. Treatment ranged from 4 weeks to 6 months.^[41] Similarly, preliminary evidence suggests a possible benefit from infliximab in the treatment of neurosarcoidosis.^{[42, 43, 44]}

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Radiation

A case of neurosarcoidosis involving the pituitary gland and hypothalamus treated with stereotactic radiotherapy described in the literature showed excellent results.^[45] For localized lesions, stereotactic radiotherapy may be indicated, although the responses so far have been variable.

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Medication Summary

Medications used in peripheral neuropathy in sarcoidosis are the same as those used for systemic sarcoidosis and neurosarcoidosis. Immunosuppressants are used to dampen or alter the inflammatory activity. Corticosteroids are preferred. Nonresponders may be tried on cyclosporine, azathioprine, and/or methotrexate. Preliminary evidence also suggests possible benefit from the use of tumor necrosis factor–α (TNF-α) antagonists in refractory cases.

• References

Prednisone

• Dosing, Interactions, etc.

Clinical Context:  Prednisone, the most commonly used oral corticosteroid, works by altering the immune system and decreasing the inflammatory reaction that is responsible for granuloma formation in sarcoidosis. A negative tuberculin skin test is required prior to commencing high daily doses of steroids.

Prednisone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear neutrophil (PMN) activity. It stabilizes lysosomal membranes and suppresses lymphocytes and antibody production. Use the lowest possible maintenance dose.

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Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli and are the mainstay of treatment in neurosarcoidosis.

Oral prednisone is the corticosteroid most commonly used. When high-dose oral prednisone fails, patients may respond to methylprednisolone pulses (eg, 1 g/wk for 8 wk). Disagreement exists about the optimal dose, but doses listed here are typical. Often, high doses are required for 2-4 wk before tapering; taper may need to be continued for several months before discontinuing treatment altogether.

• References

Thalidomide (Thalomid)

• Dosing, Interactions, etc.

Clinical Context:  Thalidomide is an immunomodulatory agent that acts to inhibit production of TNF-α, which is an important mediator of central nervous system inflammation. Thalidomide enhances TNF- α messenger RNA degradation. It inhibits the upregulation of interleukin-6 and downregulates nuclear factor-κβ activity. Both of these molecules are elevated during the CNS inflammatory process in neurosarcoidosis.

• References

Cyclophosphamide

• Dosing, Interactions, etc.

Clinical Context:  Cyclophosphamide is an antimitotic agent mainly used as steroid-sparing therapy.

• References

Cyclosporine (Sandimmune, Neoral, Gengraf)

• Dosing, Interactions, etc.

Clinical Context:  Cyclosporine is used extensively in patients who have undergone transplantation. In neurosarcoidosis, beneficial effects of cyclosporine as an adjunct to steroids have been reported, although mostly in CNS rather than peripheral nervous system involvement.

• References

Azathioprine (Imuran, Azasan)

• Dosing, Interactions, etc.

Clinical Context:  Cytostatic drug that has been used in numerous immune-mediated diseases. Active component, 6-mercaptopurine, thought to have immune-suppressing properties.

• References

Methotrexate (Trexall, Rheumatrex)

• Dosing, Interactions, etc.

Clinical Context:  Methotrexate is an antimetabolite used as an immunosuppressant, often in rheumatoid arthritis, severe psoriasis, and certain neoplastic diseases. Its use for neurosarcoidosis has not been tested sufficiently.

• References

Class Summary

These agents inhibit immune cell growth and proliferation, decreasing immune system activity.

• References

Chloroquine phosphate (Aralen)

• Dosing, Interactions, etc.

Clinical Context:  Chloroquine produces an anti-inflammatory effect by suppressing lymphocyte transformation and may have a photoprotective effect.

• References

Hydroxychloroquine (Plaquenil)

• Dosing, Interactions, etc.

Clinical Context:  Hydroxychloroquine inhibits chemotaxis of eosinophils and locomotion of neutrophils and impairs complement-dependent antigen-antibody reactions. Hydroxychloroquine sulfate 200 mg is equivalent to 155 mg hydroxychloroquine base and 250 mg chloroquine phosphate.

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Class Summary

The antimalarial agents chloroquine phosphate and hydroxychloroquine sulfate have been used in the treatment of patients with neurosarcoidosis who either do not respond to corticosteroid therapy or develop unacceptable side effects.

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Infliximab (Remicade)

• Dosing, Interactions, etc.

Clinical Context:  Infliximab inhibits the release of tumor necrosis factor-α (TNF- α), which is released in high concentrations by alveolar macrophages in active sarcoidosis. Agents that reduce TNF- α or block its effect have been shown to produce improvement in refractory cases.

• References

Class Summary

These agents can change the immune system or block the effects of cytokines.

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