Continuing Education Activity

Sarcoidosis is a systemic disease that results in the formation of granulomas which classically are non-caseating granulomas, that may be found throughout lymph nodes and organs, including the brain and nervous system. About 5 to 10 percent of patients with sarcoidosis will have neurologic complications. Neurosarcoidosis may be asymptomatic but can be life-threatening and tends to occur in cases with systemic involvement. This activity examines when this condition should be considered on differential diagnosis and how to properly evaluate for it. This activity highlights the role of the interprofessional team in caring for patients with this condition.

Objectives:

• Describe the common presenting features of neurosarcoidosis.
• Review how to properly evaluate for neurosarcoidosis.
• Outline the management of neurosarcoidosis.
• Explain how an interprofessional approach is imperative to the effective management of patients with neurosarcoidosis.

Introduction

Although the etiology is unknown, sarcoidosis is a systemic disease that results in the formation of granulomas. Classically, the granulomas in sarcoidosis are non-caseating granulomas, which may be found throughout lymph nodes and organs, including the brain and nervous system. About 5% to 10% of patients with sarcoidosis will have neurologic complications.[1][2] Although the majority of patients with sarcoidosis do not have symptoms, neurosarcoidosis may be life-threatening and tends to occur in cases with systemic involvement.

Neurosarcoidosis tends to occur in patients who have systemic features and active disease. The diagnosis of neurosarcoidosis is difficult and usually one of exclusion. Sometimes a nerve or muscle biopsy may reveal a non-caseating granuloma. There is no cure for neurosarcoidosis. Most patients require long-term treatment with corticosteroids.

Etiology

Although the cause is unclear, sarcoidosis is believed to be a hyperactive immune response. Th1 cells stimulate the release of IL-2 and IFN-gamma which then activate macrophages. In turn, the inflammatory response induced by macrophages causes granuloma formation. The most common neurological abnormalities reported include the following:

• Papilledema
• Cranial neuropathies
• Peripheral neuropathy
• Myopathy and mononeuropathy
• Neuropsychiatric disturbances
• Ataxia
• Hydrocephalus

Epidemiology

The prevalence of sarcoidosis has been estimated to be about 152 to 215 per 100,000.[3] About 5 to 10% of patients with sarcoidosis will have neurologic complications.[1] Regarding race, neurosarcoidosis has been documented more commonly within Africans and African descent.[4] However, about half of patients with sarcoidosis have systemic disease, with 30% to 70% who have concomitant neurologic signs when first diagnosed. The condition is rare in children.

Pathophysiology

A variety of theories have been used to explain the etiology of neurosarcoidosis. Sarcoidosis affects the lymphoreticular system, characterized by cervical and mediastinal lymphadenopathy.  Due to the distribution of lymphatics, the spleen and liver can also be affected. Neurosarcoidosis results from sarcoid granulomas within the nervous system. Pathologically, lymphocytes and mononuclear phagocytes surround a noncaseating epithelioid cell granuloma. Symptoms result from the location of where the granulomas lie in the nervous system. For example, granulomas in the muscle may cause myositis, while granulomas in the nerve within the perineurium and epineurium may cause axonal damage and as a result peripheral neuropathy. Nerve injury may cause diffuse polyneuropathy, mononeuritis multiplex, and polyradiculopathy due to spinal root sheath involvement.

Histopathology

The classical finding of sarcoidosis is noncaseating granulomas. Nerve biopsies demonstrate axonal degeneration with nerve atrophy. Myelin ovoids may be seen as a sign of demyelination.[5]

History and Physical

Common features of central or peripheral nervous system involvement include cranial mononeuropathy involving the facial nerve, neuroendocrine dysfunction involving the hypothalamus (i.e. neurogenic diabetes insipidus), myelopathy or radiculopathy if the spinal cord is affected (in rare cases cauda equina polyradiculopathy may occur), hydrocephalus, meningitis, mononeuropathy, mononeuritis multiplex, carpal tunnel, and muscle involvement which may cause proximal myopathy and muscle atrophy. Symptoms of neurosarcoidosis may be multifocal, commonly seen first in the cranial nerves. The facial nerve is the most common cranial nerve affected, which may mimic Lyme disease. Heerfordt syndrome is a rare manifestation of neurosarcoidosis which presents with facial nerve palsy and the presence of parotid gland enlargement, anterior uveitis, and fever.[6] Carpal tunnel may also be more frequent in sarcoidosis patients than in the rest of the population.[7] Another cranial nerve that may be affected is the vestibulocochlear nerve causing balance and hearing problems.[8] Cerebellar signs, such as ataxia, may be present with cerebellar involvement.[9] During the exam, it is important to assess for papilledema and mental status as psychiatric abnormalities may also occur. Chronic meningitis with basal meningeal involvement is a common manifestation of neurosarcoidosis. Meningitis may present with either leptomeningeal or pachymeningeal involvement. It is one of the several important causes of pachymeningitis.

In gathering a history, the first sign of neurosarcoidosis may be seizures, which generally confers a poor prognosis. Patients with simple partial or complex partial seizures may have a better prognosis in comparison to generalized tonic-clonic seizures.

Depending on the location of the disease in the brain, the patient may also present with:

• Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)
• Changes in appetite
• Somnolence
• Autonomic impairment
• Weight gain
• Impotence
• Galactorrhea
• Dementia
• Impaired cognition

Evaluation

Neurosarcoidosis should be considered in patients with sarcoidosis who develop neurologic abnormalities. However, the index of suspicion is lower and thus much more difficult in cases where a patient is not known to have sarcoid but has neurologic abnormalities. Unfortunately, there is no diagnostic marker for neurosarcoidosis. 

If neurosarcoidosis is suspected, it is important to assess for signs of systemic diseases, such as the skin, lymph nodes, and lungs. Tests to conduct include ophthalmologic exam (including optical coherence tomography), nasal/sinus examination, chest x-ray (for perihilar lymphadenopathy), angiotensin-converting enzyme (ACE) assay (not specific), and in rare cases a magnetic resonance, gallium or fluorodeoxyglucose emission tomographic scan for areas of inflammation that may be biopsied.

In evaluating peripheral neuropathy, it is important to rule out other common causes of neuropathy such as hyperglycemic states, vitamin deficiencies, kidney failure, and toxins. Thermal threshold testing may be used for small-fiber neuropathy.

Neurodiagnostic tests may help rule out other differentials such as infection and malignancy. The imaging of choice is a contrast-enhanced MRI. Typical findings are basal meningeal enhancement especially with contrast-enhancing lesions involving the hypothalamus, pituitary stalk, and adjacent tissues. (See MRI below). Gadolinium and fluid-attenuated inversion recovery (FLAIR) are helpful to identify T2 enhancement of nerve roots, plexuses, and nerves. Active inflammation may be seen with meningeal or parenchymal enhancement. Parenchymal, meningeal masses, and hydrocephalus may also be seen with MRI. 

As with other inflammatory states, ESR may be elevated. Creatinine kinase and aldolase may also be used to evaluate for myopathy. Liver function testing may also be abnormal, thereby reflecting the systemic involvement of sarcoidosis. If the pituitary-hypothalamic axis is affected, endocrine studies should be done. In recent years, F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) imaging has been used to evaluate for neurosarcoidosis. F-18 FDG PET/CT is gaining popularity in patients with suspected systemic sarcoidosis, especially with pulmonary or cardiac involvement. It can provide valuable information to the site of involvement by the disease and the selection of more surgically accessible sites for biopsy.

If the diagnosis remains uncertain, biopsies of the meninges, brain, or spinal cord may be indicated.[10] However, biopsies of the skin, lymph node, and lung are less risky and thus, are more preferred. A biopsy may also be considered for patients who do not respond to therapy.

Treatment / Management

Given the inflammatory process, corticosteroids are the main treatment for neural sarcoidosis. For facial nerve palsy or aseptic meningitis, prednisone is given every day for 2 weeks usually. In cases of meningeal, parenchymal mass lesion, or myopathy or neuropathy, prednisone should be given for at least 4 weeks. For deteriorating patients, intravenous (IV) methylprednisolone is given for 3 days followed by prednisone for 2 to 4 weeks. The steroid dose should be tapered over several months with follow-up by a neurologist every 3 to 6 months.

Immunosuppressants may also be considered, such as cyclosporine, methotrexate, and cyclophosphamide.

Low dose radiation is often given to patients in who steroids fail to work. Other treatments include:

Hormone replacement if there is hypopituitarism

Antipsychotics for behavior control and psychosis

Support for dementia

Recently tumor necrosis factor antagonists have been tried with partial improvement.

Differential Diagnosis

Other differentials to consider for neurosarcoidosis include primary brain tumors, toxin ingestion, neuropathies secondary to monoclonal proliferation or paraproteinemic neuropathy, paraneoplastic neuropathy, vitamin deficiency, leptomeningeal carcinomatosis, multiple sclerosis, central nervous system (CNS) lymphoma, or autoimmune conditions like systemic lupus erythematosus.

Prognosis

Neurosarcoidosis may present as either a monophasic illness, a relapsing-remitting course, or as a progressive disease with episodes of deterioration. It is not well known what the long-term effects of neurosarcoidosis are. Usually, patients with facial nerve palsy or other cranial mononeuropathies will improve. In contrast, cases with aseptic meningitis or meningeal/parenchymal mass lesions have a longer course. Hypothalamic vegetative symptoms rarely resolve although may respond to treatment.

Encephalopathy/vasculopathy tends to have a relapsing-remitting course with deterioration. Cases with hydrocephalus may either be asymptomatic or cause rapid deterioration. Facial palsy tends to improve over 4-6 weeks. The optic neuropathy may improve over a few weeks but in others, it may lead to blindness. Remissions are possible in peripheral neuropathy and myopathy cases, however, the course usually is chronic and progressive.

Pearls and Other Issues

With a diagnosis of sarcoidosis, physicians should be careful to monitor the signs and symptoms of neurosarcoidosis, with the most common symptom being cranial neuropathy involving the facial nerve. However, although most cases resolve, it is important to provide follow-up care to monitor for evolving symptoms. Treatment involves steroids to stop the inflammatory response caused by systemic sarcoidosis.

Enhancing Healthcare Team Outcomes

An interprofessional approach to neurosarcoidosis is recommended.

Cases of neurosarcoidosis require an interprofessional effort because the disorder has diverse presentations and has no specific test to make a diagnosis. Given the systemic involvement associated with neurosarcoidosis, a variety of specialists should be consulted such as rheumatology, endocrinology, and pulmonology. Neurosurgery may be consulted as well for resection of CNS masses. However, biopsy/excision procedures that involve the CNS can be associated with severe consequences, and remain a treatment of last choice. Thus, resection should be deferred, unless the mass continues to enlarge after immunosuppression. For cases with hydrocephalus, a ventriculoperitoneal shunt may be placed, albeit the risk of infection. Patients on prolonged steroids may benefit from a dietician consult to manage weight gain and to develop an exercise program and reduce bone loss. All patients started on corticosteroids need to be monitored for adverse effects by the pharmacist. As soon as symptoms subside, rapid tapering of the drug is recommended.[11]