Brandon P. Moss and Jinny Tavee
KEY POINTS FOR THE CLINICIAN
• Neurologic complications are seen in 5% to 10% of patients with systemic sarcoidosis, but are the presenting symptom in half of these cases.
• Sarcoidosis can affect any part of the nervous system.
• Diagnosis relies on confirming nervous system involvement, excluding alternate diagnoses, and biopsy confirmation when possible.
• Hydrocephalus, intraparenchymal mass lesions, seizures at onset, multiple cranial neuropathies, spinal cord lesions, and chronic meningitis are associated with a worse prognosis.
• Tumor necrosis factor-alpha (TNF-alpha) antagonists have emerged as a promising treatment for refractory neurosarcoidosis.
Sarcoidosis is a systemic inflammatory disorder characterized by nonnecrotizing granulomas on pathology. It causes neurologic complications in 5% to 10% of cases (1–4). Any part of the nervous system may be affected, leading to overlap in presentation with many other diseases. However, a systematic approach to establishing objective evidence of neurologic disease along with a careful evaluation for systemic involvement can expedite diagnosis and lead to appropriate treatment.
Sarcoidosis has an estimated prevalence of 1 to 40 per 100,000 worldwide (1,5,6). Although the disease can affect all ethnic groups, it is more common in African Americans and people of Scandinavian descent (1,5,6). Peak incidence is in the third to fifth decades of life, although African Americans tend to present late in the fourth decade (1). Women also appear to have a later age of onset and more commonly have neurologic complications and systemic disease compared to men (1,5).
Sarcoidosis most commonly affects the lungs, skin, and lymph nodes. Neurologic complications are seen in 5% to 10% of patients with systemic sarcoidosis and are the presenting symptom in half of these cases (1–4). Extraneural manifestations eventually develop in over 80% of neurosarcoidosis cases (2).
Neurologic complications are seen in approximately 5% to 10% of patients with systemic sarcoidosis and are the presenting symptom in half of these cases.
Sarcoidosis can affect any part of the nervous system. The most commonly affected sites are the cranial nerves and meninges. Involvement of the brain parenchyma, spinal cord, and hypothalamic-pituitary axis may also be seen with the clinical presentation reflecting the location of the lesion. Large-fiber peripheral neuropathy and myopathy are rare, although muscle involvement may be underestimated due to subclinical disease.
Sarcoidosis can affect any part of the nervous system, but most commonly involves the cranial nerves and meninges.
Sarcoidosis can affect cranial nerves at the level of the nucleus or along the nerve tract. In addition, inflammation of the leptomeninges can cause both isolated and multiple cranial nerve involvement.
FACIAL NERVE PALSY
Facial nerve palsy is the most common neurologic manifestation, reported in 20% to 50% of neurosarcoidosis cases (2,4) with bilateral involvement seen in 30% to 40% of cases (4,7). Symptoms are typically self-limited and resolve within a few weeks with little to no residual deficits.
Optic neuropathy is reported nearly as frequently as facial nerve palsy, with some estimates over 20% (2). Outcomes are mixed, with some series reporting improvement with treatment (4,8), while others reporting marked long-term visual impairment (6,9).
VESTIBULOCOCHLEAR AND TRIGEMINAL NERVE INVOLVEMENT
Other cranial nerves are less frequently affected. Vestibulocochlear nerve involvement can cause severe and often acute hearing loss. Patients typically recover at least partially with corticosteroid treatment, although chronic hearing loss is common with bilateral involvement. Trigeminal nerve involvement most commonly presents with severe lancinating pain characteristic of trigeminal neuralgia.
OTHER CRANIAL NERVE INVOLVEMENT
Other cranial nerves can be involved as well, causing a variety of manifestations including vocal cord paralysis, dysphagia, diplopia, and olfactory disturbances.
Leptomeningeal inflammation is common in neurosarcoidosis (10). Most patients present with a subacute to chronic course predominantly involving the basal regions of the brain (11). Headache is a frequent manifestation. Hydrocephalus may also develop due to obstruction of the ventricles or impaired absorption of cerebrospinal fluid (CSF) by the arachnoid villi. This can lead to cognitive changes and, in severe cases, stupor or encephalopathy.
Intraparenchymal Brain Lesions
Intraparenchymal brain lesions have been reported in 20% to 45% of cases (7,9,12,13). Lesions are typically hyperintense on T2-weighted sequences with enhancement after administration of gadolinium contrast (12,14). Their frequent occurrence near areas of meningeal involvement suggests the possibility of local spread (12,14). Clinical presentation is variable depending on the location of the lesion, but can include headaches, focal neurological deficits, hydrocephalus, and seizures. Multiple nonenhancing white matter lesions are also common and may be indistinguishable from multiple sclerosis (MS) in some cases (15,16).
Isolated spinal cord involvement is rare (17,18). The cervical and upper thoracic cords are the most commonly involved, although the entire cord may be affected (17,19–21). Compared to other neurologic manifestations, the prognosis for functional recovery with spinal cord involvement is often poor. Despite aggressive treatment, most patients are left with residual deficits (17,19).
Hypothalamic–pituitary dysfunction can occur as a result of direct structural invasion or basal meningeal inflammation (Figure 42.1). In the largest case series, the most common features were gonadotropin deficiency, thyroid stimulating hormone deficiency, and hyperprolactinemia (22). Most patients had long-standing endocrine dysfunction.
Ischemic stroke related to neurosarcoidosis is rare and may be caused by granulomatous infiltration of the endothelial wall resulting in stenosis or occlusion (23). Central nervous system (CNS) vasculitis, embolic infarcts related to cardiac sarcoidosis, and intracerebral hemorrhage have also been reported (23).
Estimates of the prevalence of peripheral nerve involvement in people with sarcoidosis vary widely. Because there are many other causes of peripheral neuropathy, it can be hard to determine which cases are sarcoidosis related. In addition, case series do not always distinguish between small fiber and large fiber neuropathy, which require different approaches to diagnosis and management.
LARGE FIBER NEUROPATHY
Large fiber nerve involvement typically presents as an axonal, non–length-dependent polyneuropathy caused by granulomatous compression or infiltration of the nerve fibers and vasculitis (24). The asymmetric distribution of findings as opposed to a distal stocking-glove pattern can help distinguish sarcoidosis-related neuropathy from more common causes, such as diabetes or vitamin deficiencies. Rarely, sarcoidosis can cause a demyelinating polyneuropathy similar to an acute or chronic inflammatory demyelinating polyradiculoneuropathy (25). With immunomodulatory treatment, the prognosis is favorable for a substantial number of patients with sarcoidosis-related peripheral neuropathy, especially when the presentation is less severe and the onset of symptoms is more recent (24).
SMALL FIBER NEUROPATHY
Estimates vary, but small fiber neuropathy symptoms have been reported in up to 40% of patients with sarcoidosis (26). Sarcoidosis-associated small fiber neuropathy typically presents with pain and paresthesias either in a distal stocking-glove pattern or patchy non–length-dependent pattern involving the face, trunk, and proximal limbs. Autonomic manifestations include orthostatic intolerance, gastrointestinal dysmotility, and sweating abnormalities. The pathogenesis is thought to be cytokine mediated rather than granulomatous in nature (27). Assessment of intraepidermal nerve fiber density (by skin biopsy or corneal confocal microscopy) and assessment of autonomic function (by quantitative sudomotor axonal reflex testing or quantitative sensory testing) can aid in the diagnosis (28,29). Other causes of small fiber neuropathy must be excluded such as diabetes and vitamin deficiencies. In a large case series, 76% of patients treated with intravenous immunoglobulin and 67% treated with TNF-alpha antagonists had symptomatic improvement (30). In addition, in a phase II, double-blind, randomized, placebo-controlled trial, cibinetide showed a significant improvement in pain control over the control arm as well as a significant increase in corneal nerve fiber area and regenerating nerve fibers at a dose of 4 mg/d (31).
Sarcoidosis myopathy typically presents with generalized weakness, myalgias, and fatigue. In some cases, intramuscular nodules can be palpated under the skin. There is likely a significant amount of subclinical disease as granulomatous muscle involvement has been found in up to 50% of sarcoidosis cases at autopsy (32).
Because there are many different manifestations of neurosarcoidosis, the differential diagnosis is broad (Table 42.1).
The modified Zajicek criteria are the most commonly used diagnostic criteria for neurosarcoidosis, defining three levels of diagnostic probability: definite, requiring biopsy confirmation from nervous system tissue; probable, requiring evidence of CNS inflammation and systemic sarcoidosis (histologic confirmation or at least two of the following indirect indicators: fluorodeoxyglucose-PET [FDG-PET], chest imaging, gallium scan, serum angiotensin converting enzyme [ACE]); and possible, for a clinical presentation suggestive of neurosarcoidosis that does not meet the first two criteria (33).
The gold standard for diagnosis of neurosarcoidosis is the presence of nonnecrotizing granulomas in nervous system tissue. However, given the potential morbidity associated with biopsy of eloquent nervous system structures in cases when tissue is not readily or safely available, the goal should be to confirm the presence of neurologic involvement and evaluate for an extraneural source of biopsy or other supporting evidence of systemic sarcoidosis. See Table 42.2 for a general approach to diagnosis.
MRI with and without gadolinium contrast is the initial test of choice to establish CNS inflammation. The most common intracranial findings are parenchymal lesions, dural nodules or thickening, leptomeningeal enhancement, and cranial nerve enhancement (2).
The most common radiographic abnormality is leptomeningeal enhancement, which tends to affect the basal surfaces of the brain (34). Lesions often vary in appearance and may be smooth or nodular, diffuse or focal, or a combination of features (34). See Figure 42.2 for an example of sarcoidosis-related leptomeningeal enhancement as seen on MRI.
Step 1: Confirm neurologic involvement
– MRI brain with and without gadolinium
• Cervical, thoracic, and lumbosacral spinal cord depending on index of suspicion for spinal cord involvement
– CSF analysis
• Cell count and differential
• IgG indices
• Oligoclonal bands
– MRI muscle if indicated
– Skin biopsy or corneal confocal microscopy for evaluation of intraepidermal nerve fiber density and small fiber neuropathy
– Autonomic testing
Step 2: Evaluate for systemic disease and exclude alternative diagnoses
• CT chest, abdomen, and pelvis
• FDG-PET body
• Pulmonary function tests
• Comprehensive metabolic panel
• Soluble interleukin-2 receptor level
• Serum ACE level
• Screen for mimics
– Serological studies
– CSF studies
• Fungal PCR
• Fungal cultures
• Flow cytometry
Step 3: Tissue biopsy
• Bronchoscopy or endobronchial ultrasound with fine needle aspiration and lung biopsy
• Lymph node biopsy
• Nerve or muscle biopsy
• Brain meningeal or parenchymal biopsy for amenable target