Neurosarcoidosis: Diagnostic Challenges and Mimics A Review

Abstract

Purpose of Review

Neurosarcoidosis is a rare manifestation of sarcoidosis that is challenging to diagnose. Biopsy confirmation of granulomas is not sufficient, as other granulomatous diseases can present similarly. This review is intended to guide the clinician in identifying key conditions to exclude prior to concluding a diagnosis of neurosarcoidosis.

Recent Findings

Although new biomarkers are being studied, there are no reliable tests for neurosarcoidosis. Advances in serum testing and imaging have improved the diagnosis for key mimics of neurosarcoidosis in certain clinical scenarios, but biopsy remains an important method of differentiation.

Summary

Key mimics of neurosarcoidosis in all cases include infections (tuberculosis, fungal), autoimmune disease (vasculitis, IgG4-related disease), and lymphoma. As neurosarcoidosis can affect any part of the nervous system, patients should have a unique differential diagnosis tailored to their clinical presentation. Although biopsy can assist with excluding mimics, diagnosis is ultimately clinical.

Introduction

Sarcoidosis is a multisystem inflammatory disease characterized by the formation of granulomas, which may develop in any organ. Involvement of the nervous system, termed neurosarcoidosis, affects 5–10% of patients but may lead to potentially devastating outcomes [1••, 2••, 3–5]. Common presentations of neurosarcoidosis include cranial neuropathies, leptomeningeal disease, intraparenchymal lesions, and myelitis. However, initial presentations of stroke, seizure, cerebral vasculopathy, intracranial mass, hypopituitarism, neuropsychiatric symptoms, and encephalopathy have been reported [1••, 2••]. Establishing the diagnosis can be difficult due to the wide variety of clinical manifestations, the variability of coexistent systemic disease, and the challenges associated with obtaining a central nervous system (CNS) biopsy for definitive diagnosis.

In order to diagnose neurosarcoidosis based on current guidelines, the patient must have a compatible neurological clinical presentation and exclusion of other causes. Patients meeting these criteria can be classified as “possible” neurosarcoidosis [6•]. A biopsy revealing granulomatous inflammation is necessary for diagnosing definite (nervous system biopsy) and probable (biopsy of systemic site) neurosarcoidosis. Yet, this is not sufficient for diagnosis since many granulomatous diseases including infections, autoimmune conditions, and neoplastic disorders mimic sarcoidosis and initially respond to corticosteroid treatment. In patients with a known diagnosis of biopsy-proven systemic sarcoidosis, there is potential to overlook other etiologies when they develop cranial neuropathies or leptomeningeal disease suggestive of neurosarcoidosis. It is important to recognize these patients do not automatically meet criteria for “probable” neurosarcoidosis prior to consideration of mimics. Other diagnoses such as atypical infection and malignancy, particularly in light of treatment related complications, should be considered.

In this review, we will highlight notable clinical presentations of neurosarcoidosis and key mimics to consider. We will then discuss the role of diagnostic testing including serum and cerebrospinal fluid analysis, imaging, and biopsy in confirming the diagnosis of neurosarcoidosis.

Differential Diagnosis and Mimics

Several diseases are known to mimic neurosarcoidosis both clinically and radiographically. Table 1 describes important conditions that mimic neurosarcoidosis in different clinical scenarios, comparing their shared and distinguishing features.

Table 1.

Distinguishing common mimics of neurosarcoidosis

	Shared CNS features	Shared systemic features	Distinguishing features	Diagnostic testing
Tuberculosis	Predilection for the skull base (basilar meningitis) Leptomeningeal enhancement Cranial neuropathies Dural masses Steroid responsive initially	Pulmonary disease Lymphadenopathy Ocular inflammation Constitutional symptoms Arthropathy	TB is more likely to cause clinical meningitis, basilar exudates on neuroimaging, caseating granulomas on biopsy	CSF AFB smear, culture and PCR
Cryptococcus	Leptomeningeal enhancement Cranial neuropathies Dural masses Steroid responsive initially	Pulmonary disease Lymphadenopathy Ocular inflammation Constitutional symptoms	Cryptococcus is more likely to cause clinical meningitis and hydrocephalus Pulmonary presentation may cause acute pneumonia or ARDS	Serum cryptococcal antigen testing by LAF CSF culture
PACNS	White matter lesions Leptomeningeal enhancement Vasculitis with noncaseating granulomas on biopsy Steroid responsive	PACNS does not have systemic features	PACNS does not have systemic features PACNS is more likely than neurosarcoidosis to cause CNS vasculitis	CNS biopsy
GPA	White matter lesions Steroid responsive Pachymeningeal enhancement Ocular inflammation	Pulmonary disease Lymphadenopathy Ocular inflammation Sinusitis Constitutional symptoms Arthropathy	GPA is more likely to cause diffuse alveolar hemorrhage, rapidly progressive glomerulonephritis, vasculitic skin rashes	Biopsy of CNS or other systemic organ (skin, renal, lung) ANCA, anti-MPO, anti-PR3
IgG4-RD	Pachymeningeal enhancement Intraparenchymal mass Cranial neuropathies Steroid responsive	Lymphadenopathy Ocular inflammation with or without pseudotumor Sinusitis Constitutional symptoms	IgG4-RD is more likely to cause pancreatitis, retroperitoneal fibrosis, and kidney infiltration Vasculitis more frequently seen with IGG4-RD	CNS biopsy, staining for IgG4 plasma cells, and looking for evidence of storiform fibrosis and obliterative phlebitis Serum IgG4 levels (nondiagnostic)
PCNSL	Intracranial masses White matter lesions Cranial neuropathies Vasculitis Steroid responsive	PCNSL does not have systemic features	PCNSL does not have systemic features Steroid response wanes for PCNSL	CNS biopsy, multiple may be required. CSF cytology and flow cytometry

It is important to note that the term “meningitis” in the literature has multiple meanings. In our article, we will refer to clinical meningitis as a patient who presents with symptoms of fever, headache, nuchal rigidity, and nausea/vomiting. Although clinical meningitis, particularly the fever, is rarely seen in neurosarcoidosis, patients can present with headache and neurological symptoms along with radiographic findings of meningitis such as leptomeningeal enhancement [1••]. Neurosarcoidosis also causes chronic meningitis, in which cerebrospinal fluid findings of inflammation persist for over four weeks [1••, 2••, 7•, 8]. When acute clinical meningitis occurs in neurosarcoidosis, it presents similarly to other causes of acute aseptic meningitis which includes atypical infections, malignancies, and autoimmune diseases.

Infection

Essentially, all granulomatous infections can mimic neurosarcoidosis when they infiltrate into the central nervous system. These infections include atypical bacteria (mycobacterial, syphilis, Whipple’s disease, brucellosis, nocardiosis, actinomycosis), fungi (aspergillosis, cryptococcosis, and endemic mycoses), and parasites (toxoplasmosis, schistosomiasis, neurocysticercosis, toxocariasis) [9•, 10]. Many of these infections are rare, requiring a high index of suspicion to diagnose, but are important to exclude prior to initiating immunosuppressive therapies. A thorough exposure history and examination will guide diagnostic testing. Mycobacterial and fungal infections commonly mimic sarcoidosis and should be evaluated in all patients with suspected neurosarcoidosis.

Mycobacterium tuberculosis is an opportunistic chronic bacterial infection that commonly mimics pulmonary and systemic sarcoidosis and is a leading cause of death from infection worldwide [11]. CNS tuberculosis can present with cranial neuropathies, aseptic meningitis, transverse myelitis, or as masses in the spine or brain [12•]. Both CNS tuberculosis and neurosarcoidosis have a predilection for the skull base and a preference to affect the leptomeninges. Neurosarcoidosis patients may have radiologic features of leptomeningeal enhancement without associated typical meningeal signs of fever with headache, nuchal rigidity, and nausea/vomiting. For example, patients may have isolated facial palsy with radiographic evidence of meningitis [13••]. In contrast, CNS tuberculosis typically presents with both radiographic and clinical meningitis. Cerebrospinal fluid (CSF) studies are similar, most frequently showing a lymphocytic pleocytosis with or without elevated protein and, in rare cases, a low glucose [14, 15]. The diagnosis of CNS tuberculosis is complex. As with other extrapulmonary tuberculosis presentations, tuberculin skin testing is often negative [16]. Acid fast bacillus (AFB) culture and smear on CSF and polymerase chain reaction (PCR)-based testing should be sent, but lack sufficient sensitivity, and repeat testing may be indicated [17, 18]. Newer studies show promise in the use of CSF lipoarabinomannan, a cell wall component for TB, or CSF interferon-release gamma assays [19, 20]. Biopsy is more likely to show caseating granulomas in TB as opposed to the noncaseating granulomas in sarcoidosis, but this is not a dependable way to distinguish the two, and culture remains the gold standard for diagnosis [21, 22].

Fungal infections cause granulomatous inflammation and mimic sarcoidosis, but rarely affect immunocompetent individuals. The infections that should be considered in individuals who do not clearly appear to be immunodeficient (particularly in the setting of uncontrolled diabetes) include cryptococcosis (C. gattii), aspergillosis (A. flavus), mucormycosis (Apophysomyces), and endemic mycoses such as coccidioidomycosis [23–26]. Cryptococcosis is the most common fungal meningitis [27, 28]. The most common neurologic presentation is clinical meningitis that may present with cranial neuropathy and hydrocephalus. Cranial nerve enhancement, leptomeningeal enhancement (often gyriform and nodular), nonenhancing mass lesions (cryptococcomas), and vascular abnormalities may be seen on imaging [29]. Lateral flow assay for serum cryptococcal antigen is a quick, affordable point of care test that is sensitive and specific for cryptococcal meningitis [30, 31]. Cerebrospinal fluid culture is the gold standard but may take up to two weeks for confirmatory testing.

Malignancy

CNS lymphoma encompasses both lymphoma originating in the CNS (primary CNS lymphoma (PCNSL)) and lymphoma that has metastasized to the brain (secondary CNS lymphoma). Typical symptoms include focal neurological impairments, nonspecific neuropsychiatric or cognitive changes, and signs of increased intracranial pressure, the latter two of which are uncommon in neurosarcoidosis [1••] [32•, 33•]. PCNSL is usually supratentorial and commonly involves the optic tracts and basal ganglia [34], whereas in neurosarcoidosis, mass-like lesions are typically located at the skull base [35•].

Patients with secondary CNS lymphoma may have associated lymphadenopathy or splenomegaly. A lymph node biopsy is required to differentiate sarcoidosis from secondary CNS lymphoma as there are no serum tests to definitively differentiate the two. Excisional biopsy should be performed over needle aspiration or core biopsy because preservation of lymph node architecture is crucial for evaluating lymphoma. Cerebrospinal fluid cytology and cytometry have poor sensitivity for lymphoma, and a brain biopsy may be required to establish this diagnosis [36••]. CNS biopsy may miss the diagnosis, especially in patients who have been treated with steroids, and repeat biopsy may be warranted [37].

Autoimmune

Many systemic autoimmune diseases share features with and can mimic neurosarcoidosis when the CNS is involved.

Neurosarcoidosis and CNS vasculitis have considerable overlap, with shared neuroimaging features, common laboratory and cerebrospinal fluid results, and even the presence of granulomas on biopsy [38••]. Systemic sarcoidosis is known to cause variable vessel vasculitis rarely, and case reports have shared that neurosarcoidosis may present with CNS vasculitis [39, 40•].

Primary angiitis of the CNS (PACNS) may present as white matter lesions and leptomeningeal enhancement [41]. Both diagnoses may also present as pachymeningitis, though less commonly [1••]. Biopsy in PACNS can reveal noncaseating granulomas [42]. A key difference is that PACNS does not have systemic manifestations. One study has demonstrated that involvement of the spinal cord, basilar meninges, or cranial nerves on imaging tends to favor a diagnosis of neurosarcoidosis over CNS vasculitis [38••].

ANCA vasculitis including limited granulomatosis with polyangiitis (GPA) may present as hypertrophic pachymeningitis, with neurosarcoidosis and other systemic vasculitides on the differential [43]. These include polyarteritis nodosa, rheumatoid vasculitis, relapsing polychondritis, neuro-Behcet’s disease, and Cogan syndrome [44••, 45].

IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory disease of unknown origin that can affect virtually any organ system and is often on the differential diagnosis for atypical presentations of systemic sarcoidosis. This condition presents insidiously and is associated with inflammatory pseudotumors mimicking cancer [46]. Patients with CNS involvement classically will have a finding of hypertrophic pachymeningitis or hypophysitis and diagnosis is elusive, often requiring a meningeal biopsy with special staining for IgG4 plasma cells [47••, 48, 49]. Lymphadenopathy, orbital inflammation, and sinus involvement are seen in both diseases, but IgG4-RD is more likely to affect the pancreas, salivary glands, and lacrimal glands which are some of its prominent features [50]. The presence of granulomas on biopsy excludes IgG4-RD except when found coincidentally with the typical features of dense lymphoplasmacytic infiltrate, storiform-type fibrosis, and obliterative phlebitis [51, 52•].

Clinical Features and Diagnostic Testing

Clinical Presentations of Neurosarcoidosis

About fifty percent of patients with neurosarcoidosis present with neurological symptoms prior to systemic involvement [1••]. In the other half, a review of systemic symptoms will help narrow the differential.

The most common systemic sites affected in patients with neurosarcoidosis are the pulmonary system, lymph nodes, eyes, and skin [1••]. All patients should receive chest imaging to look for bilateral hilar/mediastinal lymphadenopathy or upper lobe predominant interstitial lung disease (reticulonodular opacities) [53, 54]. However, many granulomatous diseases including tuberculosis, fungal infections, and berylliosis may present with identical pulmonary imaging findings since granulomatous deposition is more likely to occur in the apices due to impairment of lymphatics [55]. Ocular sarcoidosis is frequently an initial manifestation of sarcoidosis, and any part of the eye can be affected [56]. The most common features are uveitis, dry eyes, and conjunctival nodules [57]. Ocular inflammation can co-occur with optic neuritis, which we will discuss in the section on cranial nerve palsies. Finally, a wide variety of rashes can manifest, but the clinician should focus on looking for key patterns including erythema nodosum, lupus pernio, and a papulonodular rash affecting tattoos [58–60].

In the following sections, we will cover four prominent presentations of neurosarcoidosis including cranial nerve palsies, spinal involvement, meningeal involvement, and parenchymal involvement. In each section, we will cover the differential diagnosis and key distinguishing features.

Cranial Nerve Palsies

Peripheral facial palsy is most commonly caused by Bell’s palsy (idiopathic), Lyme disease, variants of Guillain–Barre syndrome, viral infections (HIV, EBV, CMV), and sarcoidosis. The facial nerve is the most commonly affected cranial nerve in sarcoidosis and may be the first manifestation [13••, 61]. Sarcoidosis can cause facial palsy through multiple mechanisms including meningeal inflammation, parotitis, spinal disease, stroke/vasculitis, or compression from intraparenchymal lesions. Though unilateral involvement is common, simultaneous or sequential bilateral involvement may occur [13••]. MRI is often normal, but when abnormal, the most common findings are facial nerve enhancement or leptomeningeal enhancement [13••]. When bilateral facial palsy is seen, Lyme disease should be excluded.

When facial palsy occurs with unilateral throat or neck pain and swelling, parotitis should be considered. Heerfordt-Waldenström syndrome which causes parotitis, facial palsy, fever, and ocular inflammation is pathognomonic for sarcoidosis [62–64]. Recent cases demonstrate that this can present with other findings of neurosarcoidosis such as with other cranial nerve palsies or with radiculopathy [64].

Neurosarcoidosis may also involve the optic nerve [1••]. Patients may present with a subtle, painless optic neuritis diagnosed incidentally on MRI or a slowly progressive optic neuropathy (ischemic rather than inflammatory) [65••]. Thirty percent of patients have bilateral disease, and 36% had concurrent eye inflammation, usually uveitis. Uveitis is also caused by infections (TB, candida, and varicella zoster virus most commonly) and other autoimmune diseases, most commonly inflammatory bowel disease and Behcet’s. Ocular lymphoma can masquerade as scleritis or uveitis [66]. Sarcoidosis can also cause orbital inflammation, presenting as a mass (pseudotumor) which mimics malignancy, lymphoproliferative diseases secondary to systemic connective tissue diseases, and IgG4-RD [67•].

Demyelinating disorders such as multiple sclerosis (MS) and infections such as tuberculosis can also cause both uveitis and optic neuritis simultaneously [68–71]. The presence of leptomeningeal enhancement, intraparenchymal masses, or linear enhancement affecting blood vessels adjacent to white matter lesions on MRI favors neurosarcoidosis over MS [72]. Optical coherence tomography can pick up subclinical retinal changes and may assist with differentiating sarcoidosis from infectious or other mimics [73, 74].

Neurosarcoidosis may cause cranial neuropathies via direct compression, meningeal irritation, or skull base inflammation [1••, 2••]. Tumors and infections causing cavernous sinus syndrome are the most common causes of multiple cranial neuropathies [75, 76•]. Other systemic autoimmune diseases including lupus, Sjogren’s syndrome, and vasculitis have been reported to cause multiple cranial neuropathies [77].

Recently, a CNS limited form of granulomatosis with polyangiitis has been described that can present with chronic sinusitis, otitis or mastoiditis, autoimmune hearing loss, and multiple cranial neuropathies with pachymeningitis on neuroimaging [78]. ANCA can be low titer or negative, leading to misdiagnosis [78]. MRI findings of a parapharyngeal epicenter and lack of necrosis favor GPA over infection, but there are no described distinguishing features from neurosarcoidosis [79•].

Spinal Involvement

Spinal sarcoidosis, sometimes referred to as sarcoid myelopathy, can cause significant disability. It usually presents with lower extremity weakness and paresthesias and more commonly co-occurs with brain involvement [80, 81]. Any segment of the spine can be affected, and imaging may show what appears to be an intramedullary mass, mimicking cancer [82]. The most common MRI finding is leptomeningeal enhancement [82, 83], and three radiographic patterns have been described: longitudinally extensive transverse myelitis, short tumefactive myelitis, and spinal meningitis with extramedullary enhancement [84•].

Longitudinal extensive transverse myelitis (LETM) is defined by a spinal lesion extending across more than three vertebrae and is most commonly due to neuromyelitis optica spectrum disorder (NMOSD). Distinguishing features between spinal  sarcoidosis and NMOSD are subtle and may not be reliable [85, 86] in a study investigating differences between the two, female sex, history of concurrent optic neuritis, and systemic autoimmunity were more often seen with NMOSD [86]. However, these features commonly overlap with sarcoidosis. Symptoms of intractable hiccups, nausea, and vomiting suggest area postrema syndrome, a pathognomonic and unique manifestation of NMOSD [87]. Other important causes of LETM to consider are spinal infections such as tuberculosis, leptomeningeal carcinomatosis including lymphoma, toxic myelopathies, and idiopathic transverse myelitis.

Meningeal Involvement

Neurosarcoidosis most commonly affects the leptomeninges (pia and arachnoid mater). It has a predilection for the base of the skull but can occur throughout the brain or spinal cord [35•]. Headaches are common in patients with radiographic leptomeningeal inflammation, but the additional presence of fever and nuchal rigidity to suggest clinical meningitis is rarely seen [14]. In the brainstem, compression of exiting nerve roots may cause cranial neuropathies. The presence of cognitive or vision changes associated with headaches should raise suspicion for the rare but dangerous complication of obstructive hydrocephalus, which may require surgical intervention [32•]. Notably, myelin-oligodendrocyte glycoprotein-associated disease (MOGAD), characterized by anti-myelin oligodendrocyte glycoprotein antibodies, should be considered for patients with leptomeningitis associated with optic neuritis or myelitis [88]. In contrast to neurosarcoidosis, MOGAD does not usually cause brainstem or cerebellar symptoms [89]. Similarly, autoimmune encephalitis (AE) must be on the differential for patients with leptomeningitis and CSF lymphocytic pleocytosis. Clinical features more often seen in AE such as seizures and subacute onset of neuropsychiatric symptoms localizing to the limbic system can help distinguish it from neurosarcoidosis. The brain MRI in AE may show bilateral medial temporal T2/FLAIR hyperintensities which would be unusual for neurosarcoidosis [90].

Sarcoidosis can also cause pachymeningitis (inflammation of the dura mater). Dural involvement may happen throughout the cranium where it can be diffuse or mass-like. Patients with pachymeningitis may experience seizures, progressive hearing loss, headaches, or cognitive dysfunction [91]. The differential diagnosis of pachymeningitis is broad and includes IgG4-related disease, granulomatosis with polyangiitis, dural-based metastases, and infections such as Lyme disease, tuberculosis, and syphilis [92, 93]. The most common cause of chronic, progressive pachymeningitis is idiopathic hypertrophic pachymeningitis [94].

Parenchymal Involvement

Parenchymal involvement of neurosarcoidosis causes symptoms specific to the location involved. Multifocal lesions are more frequently observed than solitary lesions [91, 95]. In rare instances, a mass-like appearance is seen on imaging [96]. These lesions can mimic malignancy (primary, metastatic, or lymphoma) or infections (tuberculoma, cryptococcoma). Masses that lack enhancement or show central necrosis should prompt further evaluation for malignancy as these features would not be expected in neurosarcoidosis [97]. A mass lesion with open ring enhancement adjacent to gray matter is more typical for tumefactive demyelination as can be seen in the Marburg variant of MS [72]. In rare instances, neuroimaging may demonstrate multifocal lesions with an appearance that can mimic MS [98].

Serum Biomarkers

There are no serum markers that can definitively separate sarcoidosis from its mimics. Serum angiotensin-converting enzyme is a marker of granulomatous inflammation, but lacks sufficient sensitivity and specificity [1••]. Recent studies show that serum soluble IL-2 receptor, which is a surrogate for T cell activation, could be a promising biomarker for sarcoidosis. One study showed a sensitivity of 88% and specificity of 85%, but this may be confounded by a testing bias resulting in a higher pretest probability. Other autoimmune diseases can also increase the serum soluble IL-2 receptor [99].

The most useful serologic tests for diagnosing neurosarcoidosis may be tests to exclude other diseases such as mycobacterial and fungal cultures, cytology, and other targeted tests for infections and autoimmune diseases. It is possible that each manifestation of neurosarcoidosis will have its own unique serum biomarker profile. More research is needed to investigate these possibilities.

Cerebrospinal Fluid Studies

There are no cerebrospinal fluid tests that are diagnostic for neurosarcoidosis. Cerebrospinal fluid testing may reveal lymphocytic pleocytosis with elevation of protein and low glucose. Recent studies suggest that CD8 T cells may be predominant [100] in the cerebrospinal fluid. Other tests including IgG index, oligoclonal bands, and CSF angiotensin-converting enzyme levels may also be elevated in about 40–60% of patients [1••]. However, these are not specific nor sensitive for neurosarcoidosis [1••, 15, 101, 102]. New potential CSF biomarkers are being investigated, including soluble IL-2 receptor or CD4/CD8 T cell ratio [103]. Hopefully, better CSF biomarkers will be identified soon that can aid in diagnosis.

Role of Biopsy

Diagnostic criteria for neurosarcoidosis rely on biopsy to obtain a diagnosis of “probable” or “definite” neurosarcoidosis. The expected results of biopsy are noncaseating granulomas, but no other specific patterns exist that will help distinguish granulomas from sarcoidosis with other granulomatous diseases. Granulomas are organized clusters of inflammatory cells characterized by central core of T cells, macrophages, multinucleated giant cells, and epithelioid cells surrounded by tissue. In sarcoidosis, they are thought to form in response to an unknown antigen, possibly by cross-reactivity, leading to infiltration into different areas of the body and consequent inflammatory damage [104]. Sarcoid granulomas are typically nonnecrotizing (noncaseating), in contrast to the caseating granulomas seen in tuberculosis and other infections [104]. When granulomas in sarcoidosis resolve either due to treatment or spontaneously, fibrosis may result [104, 105]. However, it is important to note that caseation cannot reliably be used to distinguish sarcoidosis from infections and that occasionally biopsy may not reveal granulomas. The CNS remains a difficult area for biopsy, and thus, investigation for another systemic site such as the skin, lymph node, or lung which are more accessible areas can be beneficial to establishing the presence of granulomas.

Neuroimaging Findings

Imaging remains an essential tool in evaluation of sarcoidosis. However, as with systemic sarcoidosis, many of the imaging findings in neurosarcoidosis can be caused by its mimics (Table 2). In general, contrasted MRI is the preferred imaging modality for neurosarcoidosis as it can reveal enhancement corresponding with active inflammation. Figure 1 highlights several MRI findings seen in neurosarcoidosis.

Table 2.

Differential diagnosis of neurosarcoidosis according to radiographic features

	Leptomeningeal enhancement	Extra-axial intracranial lesions	Transverse myelitis	Interstitial lung disease	Hilar/mediastinal lymphadenopathy
Tuberculosis	+  +  +  Involvement of basal cisterns	+  +  +  Tuberculoma	+  Can cause LETM*	+  +  +	+  +  +  More likely unilateral/asymmetric
Cryptococcus	+  +  +	–	+	+  Associated with pulmonary nodules or pneumonia	+  +  +  Rarely can present as isolated lymphadenopathy on chest imaging
PACNS	+  +  +	+	+  Unlikely without concurrent brain involvement	–	–
GPA	+  More commonly causes pachymeningitis	+	+	+  Associated with diffuse alveolar hemorrhage	+  +  +  Rarely can present as isolated lymphadenopathy on chest imaging
IgG4-RD w/ CNS involvement	+  More commonly causes pachymeningitis	+  +  +	+	+	+  +  +
PCNSL	+  +  +  Isolated enhancement is rare, but enhancement with mass lesions is common	+  +  +	+  Can cause LETM	– Consider other lymphoma subtypes	– Common in secondary CNS lymphoma

“ +  +  + ” means that the radiographic finding is common for the corresponding disease. “ + ” means that the radiographic finding is seen, but rare, for the corresponding disease. And “–” means that the radiographic finding is either extremely rare or not seen

^*LETM longitudinally extensive transverse myelitis

Fig. 1.

Selected MRI (T1 with contrast) imaging findings from patients with neurosarcoidosis. A Diffuse basilar leptomeningitis. B Longitudinally extensive myelitis in the cervical spine. C Pachymeningitis causing pachymeningeal enhancement. D Lumbar nerve roots showing enhancement. E Dorsal subpial leptomeningeal enhancement resulting in a “Trident Sign”

The contrasted T1 sequence is particularly useful for demonstrating leptomeningeal involvement, myelitis, or parenchymal lesions. The T2/FLAIR sequence is useful for identifying chronic lesions and for assessing the pattern and location of inflammatory damage. Since any region of the CNS can be affected, care should be taken when determining which sections to image. Dedicated imaging of the entire neuraxis (orbits, brain, and spine) may be necessary. Although nerve root involvement distinguishes neurosarcoidosis from other CNS diseases (e.g., MS and NMOSD), it can be seen in other inflammatory conditions such as Guillain–Barre syndrome [106].

Leptomeningeal involvement can occur in either the brain or spinal cord. The most common area of involvement in the cerebrum is the basilar leptomeninges affecting around 40% of patients [107, 108]. It may appear serpentine as it follows the sulci where it must be carefully distinguished from blood vessels which also appear hyperintense when filled with contrast. Care should also be taken to look at the noncontrasted T1 sequence to distinguish from other causes of T1 hyperintense signal in the leptomeninges such as methemoglobin (subarachnoid hemorrhage) or melanin from metastatic melanoma [109••]. A pathognomonic finding in the spinal cord is the “Trident Sign” with a characteristic dorsal subpial pattern of enhancement [110].

Involvement of dura mater, causing pachymeningitis, with thickening and contrast enhancement, can be seen on contrasted T1 imaging. Hydrocephalus can be seen in around 5–12% of cases and is visible on T2/FLAIR or T1 images [32•, 108].

For sarcoid vasculitis, computed tomography angiography (CTA) or magnetic resonance angiography (MRA) is typical for initial diagnostic evaluation. If suspicion remains high despite inconclusive findings, digital subtraction angiography may be needed [111]. Sarcoid vasculitis is a variable vessel vasculitis (similar to Behcet’s) and, like most vasculitides, causes vessel narrowing on imaging and may lead to ischemic strokes [95, 112].

If neurosarcoidosis is presenting with parenchymal involvement, multiple intraparenchymal lesions are seen more frequently than solitary mass-like lesions [8]. These typically appear T2/FLAIR hyperintense and may contrast enhance on contrasted T1-weighted imaging [95]. Periventricular lesions, best seen on FLAIR, can appear demyelinating, but if there are other lesions in locations typical of demyelinating disease (juxtacortical, infratentorial) then comorbid MS should be considered [113].

Conclusions

Neurosarcoidosis can be a diagnostic challenge. Exclusion of mimics remains an important aspect of management, especially when patients do not respond appropriately to therapy. The diversity of manifestations in neurosarcoidosis is such that each patient may present with a unique set of findings that will dictate the relevant differential diagnosis for that individual. Important mimics that share systemic and neurologic features, laboratory workup, imaging findings, and biopsy results are infections (mycobacterial, fungal), lymphoma, autoimmune vasculitis (PACNS, GPA), and IgG4-RD. However, with thorough and thoughtful review of history, physical exam, and targeted testing, these may be differentiated from neurosarcoidosis.

Data Availability

The data that support the findings of this study are available for subscribed members to this journal or members of the American Academy of Neurology.

Compliance with Ethical Standards

Conflict of Interest

The authors of this manuscript have no conflicts to disclose.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.