Neurosarcoidosis

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Girish Bathla, Pankaj Watal, Bruno Policeni

INTRODUCTION Sarcoidosis is a chronic idiopathic, noninfectious, granulomatous disease characterized by the formation of noncaseating granulomas. It most commonly involves the lungs, skin, and lymph nodes, although any organ or organ system may be affected. The disease most commonly affects African Americans and persons of Scandinavian descent and has a slight female predilection. There is a bimodal age distribution with the initial peak in the third decade and a later peak seen in women above 50 years of age. Despite the multiple proposed causative etiologies—including infection, genetic predisposition, and environmental toxins—the underlying etiology remains elusive. Clusters of sarcoidosis in nurses and firefighters, including the high incidence of the disease in firefighters exposed to the World Trade Center “dust” during the September 11, 2001 collapse, suggest a role for environmental antigenic exposure. Generally sarcoidosis is believed to reflect an exaggerated response to a specific hitherto unidentified antigen. Involvement of the central nervous system (CNS) by sarcoidosis is referred to as neurosarcoidosis (NS) and is seen on neuroimaging in about 10% of patients with systemic disease. Clinical manifestations of CNS involvement are reportedly less common, occurring in approximately 5% of patients. Isolated NS (without other systemic organ involvement) is rare, estimated to affect approximately 1% of sarcoidosis patients. Interestingly, the prevalence of pathologic CNS involvement has been reported to be up to 15% to 25% in autopsy studies. These findings imply that most patients with NS remain clinically asymptomatic and that (similar to multiple sclerosis) magnetic resonance imaging (MRI) is more sensitive than clinical examination in detecting involvement of the neuroaxis. Clinically, the diagnosis of NS is challenging, as the presentation is variable and nonspecific. The variability of presentation relates to the multitude of potential sites of involvement, which includes the brain parenchyma and spinal cord, the leptomeninges, the pituitary-hypothalamic axis, the cranial nerves (CNs), the dura, and the bones and orbits (Fig. 14.1). Therefore patients may present with headache, cranial neuropathy, hemiparesis, or myelopathy as

well as endocrine dysfunction, seizure, or signs of increased intracranial pressure. Furthermore, CNS symptoms are not uncommonly the first manifestation of sarcoidosis, with neuroimaging performed before the diagnosis of systemic disease.

Neurosarcoidosis: In Greater Depth CNS involvement by sarcoidosis is presumably through hematogenous dissemination, since most granulomas on autopsy studies are noted in the vessel walls and perivascular connective tissues. Although wall involvement is known to occur in both arteries and veins, small perforating arterial vessels are most frequently affected. There is also a predilection for the basal meninges, often with involvement of the nearby contiguous structures like the HPA axis and optic chiasm. The deep brain substance is also frequently involved, secondary to preferential perivascular spread along the Virchow-Robin spaces at the base of the brain. Histopathologically, noncaseating granulomas are the hallmark of the disease (Fig. 14.2). These are formed by epithelioid cells, helper T cells and Langerhans giant cells, often in a perivascular distribution. These lesions may wax and wane in extent and severity, especially in patients treated with immunosuppressive medications. The clinical diagnostic criteria for NS were initially proposed by Zajicek et al.1 and later modified by Marangoni et al.2 in 2006; this divided the certainty of diagnosis into confirmed, probable, and possible. The diagnosis is only considered “confirmed/definite” in cases with positive neural tissue biopsy, “probable” when neural inflammation is present and there is biopsy-confirmed systemic disease, and “possible” when the presentation is typical but no biopsy confirmation is available and other potential granulomatous processes are yet to be excluded (such as tuberculosis). Establishing the diagnosis of systemic sarcoidosis without biopsy can also be challenging. The most reliable clinical test to confirm the diagnosis of underlying sarcoidosis is the Kveim test, which is positive in up to 70% of patients. However, this test requires the subcutaneous injection of nonautologous splenic tissue from a known sarcoidosis patient and subsequent monitoring for up

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Figure 14.1. Sites of potential neurosarcoid involvement in neuroimaging. 1, Leptomeningeal; 2, cranial nerve; 3, pachymeningeal; 4, HPA axis; 5, periventricular white matter changes; 6, parenchymal; 7, perivascular enhancement; 8, ventricular involvement/ependymitits; 9, osseous lesions.

With regard to extra-CNS imaging, chest radiographs are considered insensitive for the initial diagnosis of systemic sarcoidosis; however, high-resolution computed tomography (CT) has been advocated in the proposed initial workup for sarcoidosis to evaluate of parenchymal lung disease and adenopathy. A positive gallium-67 scan, showing both lambda (bilateral hilar and right paratracheal nodal uptake) and panda (symmetric bilateral lacrimal and parotid uptake) signs is considered specific for sarcoidosis but is seen in only about 60% of cases. Although 18-fluorodeoxyglucose positron emission tomography (FDG-PET) is not a specific method for diagnosing sarcoidosis or useful in the diagnosis of NS due to increased background brain activity, it can be useful to identify sites of extra-CNS disease for targeted biopsy, potentially avoiding a brain biopsy (Fig. 14.3).

NEUROIMAGING EVOLUTION: OVERVIEW Figure 14.2. Low-power hematoxylin and eosin image of a brain biopsy shows a typical multinucleated giant cell granuloma (arrow) in a patient with neurosarcoidosis.

to 4 to 6 weeks for the formation of a noncaseating granuloma at the site of the skin injection. Limitations of this test include false-negative results in patients receiving glucocorticoid therapy and the concern for transmission of infection, including bovine spongiform encephalopathy. This test is currently not approved by the US Food and Drug Administration. Serum angiotensinconverting enzyme (ACE) levels are elevated in up to 50% of sarcoidosis patients and ACE in the cerebrospinal fluid (CSF) may also be elevated, although this finding is nonspecific and can also occur in other pathologies.

A large number of patients with NS remain asymptomatic. However, there are reported cases of rapidly progressive cranial neuropathies as well as aseptic meningitis with hydrocephalus leading to fatal outcomes; these point to a potentially malignant disease course, especially in the untreated population. Therefore the evolution of disease is likely reflective of a complex interplay between disease severity, site of involvement, and host immune response. In a case series by Scott et al.3 consisting of 43 NS patients (categorized as definite or probable NS) with an additional 5 patients with isolated NS (diagnosed by brain or meningeal biopsy), six neuroimaging manifestations are described, which include intraparenchymal, extra-axial, pituitary-hypothalamic, hydrocephalic, CN, and spinal diseases. The most common CNS imaging manifestation was intraparenchymal disease, which was present in over 60% of patients in this series. Extra-axial disease was the next most common CNS imaging manifestation, which was present in over 30% of patients in this series. Given the small

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rarely from perineural extension of sinonasal sarcoidosis. The involved CN may be thickened and demonstrate smooth or nodular enhancement on MRI. Clinically, facial nerve symptoms are most common (reportedly affecting up to 70% of NS patients) and may be bilateral in up to 30% to 40% of cases. Notably, the optic nerves are most commonly involved on imaging (Fig. 14.8).

LEPTOMENINGEAL INVOLVEMENT Leptomeningeal involvement is seen in about 40% of cases and preferentially involves the basal meninges (Fig. 14.9).5 This is often best evaluated on postcontrast images, manifesting as abnormal smooth or nodular meningeal enhancement. Perivascular enhancement may coexist, reflecting spread of the inflammatory process along the Virchow-Robin spaces (Fig. 14.10).

PACHYMENINGEAL INVOLVEMENT

Figure 14.3. Whole-body F-18 fluorodeoxyglucose positron emission tomography maximum intensity projection image in a patient with multisystem involvement by sarcoidosis demonstrates multiple foci of radiotracer uptake involving the neck, thorax, and abdomen, thereby providing an excellent overview of the extent of disease as well as sites for potential biopsy.

number of patients in most case series, the percent distribution of location involvement varies greatly, and the percentages attributed to the sites described later are estimates based on the available literature.

BRAIN INVOLVEMENT Intraparenchymal involvement may manifest as multiple (35%) or solitary (10%), supra- or infratentorial lesions (Fig. 14.4).4 Small parenchymal granulomas are more common and may be visualized only after contrast administration. Larger masses are often isointense on T1 and hypointense on T2, although intralesional hemorrhage may occur and alter the imaging appearance (Fig. 14.5). Calcification and necrosis are rare. After contrast administration, lesions often show diffuse or rim enhancement, although nonenhancing lesions may infrequently occur. Concurrent leptomeningeal or CN involvement may also be present. Besides the parenchymal granulomas, another fairly common parenchymal manifestation is the presence of periventricular T2 hyperintense lesions in white matter (Fig. 14.6). These lesions often do not enhance or have mass effect and are frequently asymptomatic clinically. Since NS is predominantly a perivascular process, it is not surprising that the process will manifest with lesions that are perivascular in distribution. They have been variably described in 12.5% to 54% of patients with NS and are even thought to be the most common manifestation of NS by some authors. Therefore NS has been known to mimic multiple sclerosis, although concurrent parenchymal or meningeal granulomas often help to distinguish the two entities. Over time, patients with NS may show worsening white matter changes and parenchymal volume loss, suggesting that the disease can be progressive in nature (Fig. 14.7). In patients treated with immunosuppressive therapy, these lesions remain unchanged, unlike CN or spinal cord lesions, which often demonstrate improvement.

CRANIAL NERVE INVOLVEMENT CN involvement in NS is reported to occur in up to 50% of cases,4 either when the nerves traverse the subarachnoid space or

Involvement of the pachymeninges is seen in about 34% of cases, occurring most frequently in the posterior fossa.6 Lesions often demonstrate T2 hypointensity, a nonspecific but occasionally helpful finding. After contrast administration, lesions typically demonstrate uniform enhancement and may have a dural tail (Fig. 14.11A to C). Interestingly, dural and leptomeningeal involvement rarely affects the same region, a finding attributed to the arachnoid barrier cells, which limit spread of disease through the arachnoid membrane. Involvement of the cavernous sinus is rare and may be unilateral, as predominantly described in isolated case reports. On imaging, cavernous sinus lesions may show T2 hypointensity and enhancement with or without a dural tail.

HYPOTHALAMIC-PITUITARY-ADRENAL INVOLVEMENT Involvement of the HPA axis may be seen in about 18% of cases and can present clinically with hypopituitarism.6 The unique predilection for this site is felt to be secondary to its close relationship to the basal meninges. MRI shows nonspecific thickening and enhancement of the pituitary, infundibulum, and/or hypothalamus, which may extend into the surrounding meninges (Figs. 14.12 and 14.13).

SPINE Intramedullary spinal involvement in NS was previously thought to be rare but has been observed more commonly with the widespread use of MRI for spinal imaging, now reported in up to 25% of patients with NS.6 Junger et al.7 proposed four phases of progression in spinal cord sarcoidosis, beginning with early inflammation and linear enhancement along the surface of the cord in phase 1 (Fig. 14.14). This is followed by centripetal spread of the inflammatory process along the Virchow-Robin spaces to manifest as parenchymal swelling and cord enhancement in phase 2 (Fig. 14.15). In phase 3, the swelling becomes less prominent while foci of enhancement persist (Fig. 14.16). Finally, in phase 4, there is resolution of the inflammatory process and enhancement, leaving behind a normal-sized or atrophic cord (Fig. 14.17). In patients with spinal cord involvement, the cervical and upper thoracic segments are most commonly involved. The involvement may be focal, although extension over multiple segments is more common. Leptomeningeal involvement occurs in up to 60% of patients with spinal sarcoidosis and is thought to be a precursor of intramedullary lesions. Fusiform enlargement of the affected cord segment may occur, especially in the early, active phases of the disease. Lesions show T1/T2 hyperintensity, unlike parenchymal Text continued on p 127

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Figure 14.4. Multiple parenchymal lesions in two patients with neurosarcoidosis. Axial T2 (A) and postcontrast T1 (B) images obtained in one patient at presentation demonstrate parenchymal granulomas in the basal ganglia with T2 hypointensity (A, arrows) and homogenous enhancement (B). Follow-up imaging after therapy demonstrates partial resolution of the lesions (C). Axial postcontrast (D) image in another patient reveals multiple parenchymal and leptomeningeal granulomas with mild ventricular dilation.

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C Figure 14.5. Solitary parenchymal lesion in a patient with neurosarcoidosis. Axial T2WI (A), coronal FLAIR (B), and axial GRE (C) images reveal a mixed-intensity lesion in the left frontal lobe with intralesional hemorrhage. There is patchy peripheral enhancement on the postcontrast T1 image (D). Biopsy revealed noncaseating granulomas consistent with neurosarcoidosis.

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Figure 14.6. (A and B) Periventricular white matter lesions in a patient with neurosarcoidosis. Sagittal FLAIR images in a patient with neurosarcoidosis reveal prominent bilateral periventricular white matter foci of T2 hyperintensity.

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Figure 14.7. Progressive parenchymal changes in a patient with neurosarcoidosis (same patient as in Fig. 14.6). Axial FLAIR images at the level of the corona radiata obtained at presentation (A), 1 month (B), and 6 months (C) demonstrate progressively worsening white matter changes, predominantly in a periventricular distribution.

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Figure 14.8. Cranial nerve involvement in a patient with neurosarcoidosis. (A) Axial postcontrast images reveal abnormal enhancement of both optic nerves (arrows), (B) both oculomotor nerves (worse on the right) (arrowhead), and (C) the left trigeminal nerve (long arrow).

Figure 14.9. Leptomeningeal involvement in a patient with neurosarcoidosis. Axial postcontrast images at the level of the skull base (A and B) reveal extensive leptomeningeal enhancement predominantly along the basal meninges, cerebellar foliae, and optic nerves. More cranially, there is no appreciable meningeal enhancement (C).

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C Figure 14.10. Perivascular space involvement in two patients with neurosarcoidosis. Axial (A) and coronal (B) post contrast images reveal scattered perivascular enhancement involving both cerebral hemispheres. Axial post contrast image (C) in another patient reveals similar perivascular involvement of the brainstem and cerebellum.

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Figure 14.11. Pachymeningeal involvement in two patients with neurosarcoidosis. Axial T2 (A) and axial and coronal postcontrast (B and C) images reveal right temporo-occipital dural-based soft tissue with T2 hypointensity and postcontrast enhancement extending along the tentorium. Axial T2 (D) and axial and sagittal postcontrast T1 with fat saturation (E and F) through the spine in another patient reveal a dural-based lesion with homogenous enhancement, again reflecting pachymeningeal involvement. Scattered leptomeningeal enhancement is also seen (F).

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C Figure 14.12. Hypothalamic involvement in a patient with neurosarcoidosis. Coronal T2 (A) reveals a T2 hypointense mass involving the hypothalamus with surrounding T2 hyperintense vasogenic edema. Coronal postcontrast T1 (B) demonstrates homogenous enhancement corresponding to the site of T2 hypointensity. Coronal postcontrast image more posteriorly (C) reveals a similar mass-like process in the left sylvian fissure.

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Figure 14.13. Hypothalamic and meningeal involvement in a patient with neurosarcoidosis before and after treatment. Sagittal postcontrast image (A) reveals typical disease distribution in neurosarcoidosis with involvement of the pituitary-hypothalamic axis as well as the basal meninges and posterior fossa. Follow-up imaging 6 months after initiation of immunosuppressive therapy (B) reveals significant interval improvement.

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Figure 14.14. Phase 1 cord involvement in neurosarcoidosis. Sagittal T2 (A) and postcontrast T1 (B) images through the cervical spine reveal plaque-like enhancement along the dorsal cord surface and central cord substance with minimal cord edema.

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Figure 14.15. Phase 2 cord involvement in two patients with neurosarcoidosis. Axial (A) and sagittal (B) T2 images reveal cord expansion and intramedullary signal abnormalities. Sagittal (C) postcontrast image shows irregular intramedullary enhancement and abnormal enhancement along the cord surface. Coronal postcontrast image (D) in another patient reveals isolated intramedullary conus medullaris involvement.

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Figure 14.16. Phase 3 cord involvement. Sagittal T2 (A) and postcontrast T1 (B) images through the cervical spine in the same patient as in Fig. 14.15. Interval partial improvement in the cord edema, swelling, and enhancement is evident with residual abnormal intramedullary and cord surface enhancement.

brain lesions, which occasionally show T2 hypointensity. On postcontrast imaging, enhancement often involves the surface of the cord with variable extension into the cord substance. Isolated involvement of the spinal nerve roots is uncommon in NS, although it can present as polyneuropathy. Nodularity or diffuse thickening of the spinal nerve roots with enhancement are common imaging features, which can mimic leptomeningeal metastasis or infection. Extramedullary intradural lesions are rare and may show T2 hypointensity and homogenous enhancement, similar to intracranial lesions (see Fig. 14.11D–F). Finally, although patients with spinal involvement often have concurrent intracranial involvement, isolated spinal cord involvement in the absence of or preceding brain involvement may rarely occur.

BONES Although osseous skull and vertebral involvement is reported to occur in approximately 13% of patients with systemic sarcoidosis, it is likely underestimated, since most lesions are clinically asymptomatic.7 Most commonly, the disease affects long tubular bones and the appendicular skeleton, Bony lesions of the cranium and spine may coexist with CNS involvement, although the lower thoracic and upper lumbar spine are more commonly affected. On CT imaging, lesions are often lytic but may instead demonstrate a mixed or sclerotic appearance (Fig. 14.18). MRI typically parallels the CT findings, with iso- to hypointense signal on T1 that may have hyperintense or hypointense T2 signal in predominantly lytic or sclerotic lesions, respectively. MRI is also useful for evaluating an associated soft tissue/extraosseous component. These lesions enhance, may be multiple, and can involve the posterior spinal elements and intervertebral disc spaces (Fig. 14.19).

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Figure 14.17. Phase 4 cord involvement. Sagittal T2 images at presentation (A) and at 2-year follow-up (B) demonstrate interval resolution of the cord edema with associated parenchymal volume loss. Postsurgical changes of prior cord biopsy are also noted (B).

COMPLICATIONS Vascular Cerebrovascular events in NS are rare, despite the common vascular involvement noted on autopsy studies. Nevertheless sporadic reports describing cerebral vasculitis and ischemic or hemorrhagic strokes secondary to underlying NS do exist. Punctate ischemic strokes are attributed to small vessel involvement and can occur in the basal ganglia and pons (Fig. 14.20).8 Rarely, patients may have multiple lacunar strokes over time, which may be clinically silent. Similarly, single or multiple parenchymal hemorrhagic lesions may occur in patients with NS, best seen on gradient echo (GRE)/ susceptibility-weighted imaging (SWI) sequences. Parenchymal hemorrhages in patients with NS are more likely to be supratentorial, punctate, and multiple (Fig. 14.21). Vascular involvement manifesting as a moya-moya pattern, subarachnoid hemorrhage, or dural venous sinus thrombosis is extremely rare but has been described.

Hydrocephalus About 5% to 12% of patients with NS develop communicating hydrocephalus; this is felt to be secondary to impaired CSF resorption from diffuse leptomeningeal involvement.7 Less commonly, however, localized ependymitis or focal adhesions may occur, resulting in isolated ventricular dilation and CSF trapping (Fig. 14.22). In such cases, additional findings can include a focally

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Figure 14.18. Computed tomography (CT) of bony involvement in two patients with sarcoidosis. Axial CT image (A) through the skull base reveals the presence of a lytic lesion involving the clivus on the left. Sagittal CT image through the lumbar spine (B) in the same patient reveals a mixed lytic-sclerotic lesion at L2 (arrow) and a faint lytic lesion at L3 (arrowhead). Biopsy revealed noncaseating granulomas consistent with sarcoid. Axial CT image in another patient (C) shows a well-defined lytic lesion involving the frontal bone on the right.

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Figure 14.19. Magnetic resonance imaging of bony involvement in two patients with sarcoidosis. Sagittal postcontrast images through the thoracic (A) and lumbar (B) spine (same patient as Fig. 14.18) demonstrate multifocal marrow enhancement with involvement of the vertebral bodies and posterior elements. Sagittal postcontrast image in another patient (C) shows multiple punctate foci of enhancement, giving a “peppered” appearance to the spine. Mild loss of height involving one of the midthoracic vertebral bodies is also noted.

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Figure 14.20. Infarction in a patient with neurosarcoidosis. Axial DW (A) and ADC (B) images in a young patient with neurosarcoidosis reveal lacunar infarct in the left corona radiata. Extensive workup for embolic stroke was unrevealing.

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Figure 14.21. Parenchymal hemorrhage in a patient with neurosarcoidosis. Axial SWI image (A) at the level of the centrum semiovale reveals multiple small scattered hemorrhagic foci of variable size in both cerebral hemispheres. Axial postcontrast image through the posterior fossa (B) reveals subtle leptomeningeal enhancement along the cerebellar hemispheres.

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Figure 14.22. Obstructive hydrocephalus in a patient with neurosarcoidosis. Axial T2W (A), FLAIR (B), and postcontrast (C) images reveal a moderately dilated entrapped right temporal horn with internal septations and moderate transependymal flow, presumably secondary to ependymitis.

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Figure 14.23. Ventricular entrapment and midline shift in a patient with neurosarcoidosis. Axial (A) and coronal (B) postcontrast images reveal dilated, entrapped bilateral temporal horns, worse on the right side, which also shows transependymal flow of cerebrospinal fluid, midline shift, and uncal herniation. There is associated abnormal enhancement along the right tentorium (arrow in A) and left temporal convexity (arrow in B), consistent with pachymeningeal disease involvement.

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Figure 14.24. Superimposed infection as complication of sarcoidosis immunosuppressive therapy. Axial postcontrast (A) image in a patient with sarcoidosis reveals prominent leptomeningeal enhancement along both cerebellar foliae. The patient was started on steroid therapy and improved initially, followed by a rapid clinical decline. Follow-up postcontrast image (B), obtained during clinical deterioration, reveals extensive bilateral leptomeningeal enhancement. Cryptococcal antigen in cerebrospinal fluid was positive, confirming cryptococcal meningitis, presumably secondary to immunosuppression.

dilated ventricle, transependymal flow of CSF with periventricular T2 and FLAIR hyperintense signal, abnormal ependymal enhancement, and increased FLAIR signal of the trapped CSF secondary to elevated protein and exudates. Ventricular entrapment may result in acute hydrocephalus with consequent mass effect and midline shift, presenting as a neurosurgical emergency (Fig. 14.23).

superimposed on the background NS changes (Fig. 14.24). These may present as a paradoxical worsening of symptoms and imaging findings not otherwise explained by the primary disease after the initiation of therapy.

Infection

NS can have a myriad of appearances on imaging based on the predominant site of involvement. The differential considerations (both clinically and on imaging) are summarized in Table 14.1. In many cases, review of the patient’s medical history as well as

Patients receiving immunosuppressive therapy are vulnerable to atypical infections, some of which may involve the brain and are

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TABLE 14.1  Differential Diagnosis Based on Pattern of Involvement Parenchymal

White Matter

Neoplastic

Glioma Metastasis Lymphoma

Paraneoplastic

Infectious

Tuberculosis Fungal infections

Cerebrovascular

Hemorrhage

HIV PML Lyme disease Microvascular disease

Inflammatory

Infarct Demyelination

Demyelination/MS

Leptomeningeal

Pachymeningeal

Cranial Nerve

Metastasis Lymphoma Metastasis Chloroma Meningitis

Meningioma Lymphoma

Metastasis PNTS

Tuberculosis Fungal infections

Ramsay hunt

Rosai-Dorfman disease Idiopathic pachymeningitis GPA

Neuromyelitis optica Bell palsy

HPI Axis Lymphoma Metastasis Histiocytosis

Spinal Glioma Lymphoma

Myelitis Arachnoiditis

Vasculitis

GPA

Behçet disease GPA

Hypophysitis

MS

Erdheim-Chester disease

Transverse myelitis ADEM SLE

ADEM, Acute disseminated encephalomyelitis; EBV, Epstein-Barr virus; GPA, granulomatosis with polyangiitis; HIV, human immunodeficiency virus; HPI, hypothalamic-pituitary-infundibular; MS, multiple sclerosis; PML, progressive multifocal leukoencephalopathy; PNTS, perineural tumor spread; SLE, systemic lupus erythematosus; SMT, smooth muscle tumors.

clinical and biochemical findings can help to narrow the imagingbased diagnostic possibilities. The differential considerations are as follows: 1. Meningeal pathologies: Both leptomeningeal and pachymeningeal processes can mimic NS on imaging. The leptomeningeal processes include lymphoma, carcinomatous meningitis, and intracranial infections (bacterial, tubercular, or fungal). Postcontrast imaging will show abnormal meningeal or CN enhancement that may be nodular, especially with lymphoma and carcinomatosis. Meningeal involvement with intracranial lymphoma may be primary or secondary (Fig. 14.25), although it is more commonly seen with secondary lymphoma (i.e., those cases with systemic lymphoma). Rarely, patients may have primary leptomeningeal lymphoma, which may result in considerable diagnostic confusion and can require extensive workup before a final diagnosis is made. In patients with leptomeningeal carcinomatosis, the underlying primary malignancy is often known (Fig. 14.26). Intracranial infections such as pyogenic, tubercular, and fungal meningitis can also closely mimic NS on imaging. With pyogenic meningitis, clinical decompensation is relatively rapid and CSF cytology findings and cultures are often confirmatory. Tubercular meningitis is less common, especially in developed countries. CSF findings are again helpful, especially in endemic regions. Imaging may show a combination of meningitis, hydrocephalus, and brain infarcts, a typical triad of tuberculous meningitis. Fungal infections may occur, especially in immunocompromised patients. These also have a predilection for the basal meninges, similar to sarcoidosis. Underlying immunosuppression and clinical evolution of symptoms are useful clues pointing to an infectious etiology, since the imaging findings are nonspecific. 2. Hypophysitis: Involvement of the pituitary gland in NS may be indistinguishable from lymphocytic hypophysitis as well as other cause of hypophysitis. Peri- or postpartum occurrence should raise suspicion for lymphocytic hypophysitis. Clinically, these patients may have symptoms of panhypopituitarism. Imaging reveals diffuse thickening of the pituitary gland and stalk with prominent parasellar T2 hypointensity and homogeneous contrast enhancement. Patients with ipilimumab-induced

hypophysitis, on the other hand, typically have symptoms of anterior hypopituitarism without diabetes insipidus, a history of melanoma, and known drug intake with rapid resolution of imaging findings upon cessation of drug therapy (Fig. 14.27). 3. Vasculitis: Vasculitis is a great mimicker and may be difficult to differentiate from cerebrovascular manifestations of NS, especially since both entities can present with parenchymal hemorrhages and infarcts (Fig. 14.28). Patients with primary angiitis of the CNS (PACNS) can have similar granulomatous vascular inflammation histopathologically, although this is more likely to follow an aggressive clinical course, remaining confined to the CNS and having abnormal angiographic findings in up to 85% of patients. Additionally, patients with NS often have more florid involvement of the meninges, CNs, or hypothalamus and usually follow a more indolent course. Additionally, coexisting extra-CNS sarcoidosis, if present, may confirm the diagnosis. 4. Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS): CLIPPERS is a recently described entity referring to involvement of the brain stem and especially the pons by an inflammatory disorder of uncertain etiology. The disease often presents with subacute, nonspecific neurologic symptoms, although ataxia as well as visual and facial sensory symptoms are more common. Imaging shows a “peppered” appearance of the brain stem, especially the pons (see Fig. 14.28). Less commonly, the deep gray nuclei and spinal cord may also be involved. Unlike NS, CLIPPERS (Fig. 14.29) is a nongranulomatous disorder with no extra-CNS manifestations and predominant localization to the brain stem.

SUMMARY Sarcoidosis is a great mimicker, not only clinically but also on imaging. Although imaging findings are often helpful in pointing to the diagnosis, assessing response to therapy, and evaluating for complications, the spectrum of imaging manifestations remains broad and nonspecific. A heightened awareness of this entity is therefore essential and may help to expedite diagnosis, especially in clinically challenging situations.

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C Figure 14.25. Lymphoma mimicking neurosarcoidosis. Coronal FLAIR (A) image reveals extensive signal abnormalities involving both deep cerebral hemispheres and extending into the brain stem. Axial (B) and coronal (C) postcontrast images reveal patchy areas of leptomeningeal and parenchymal enhancement. Biopsy revealed lymphoma.

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Figure 14.26. Leptomeningeal carcinomatosis mimicking neurosarcoidosis. Axial postcontrast FLAIR images (A and B) reveal extensive leptomeningeal hyperintense signal overlying the cerebral convexities. Cerebrospinal fluid cytology was consistent with metastatic breast cancer.

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Figure 14.27. Ipilimumab-induced hypophysitis mimicking neurosarcoidosis. Sagittal midline precontrast (A) and coronal postcontrast (B) T1 images reveal an enlarged pituitary gland and stalk with homogeneous enhancement. The patient had melanoma and was on ipilimumab. Findings resolved following drug cessation (not shown).

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Figure 14.28. Vasculitis mimicking neurosarcoidosis. Axial DWI (A) and SWI (B) images through the posterior fossa reveal an acute left cerebellar infarct and scattered parenchymal microhemorrhages (arrowheads in B). Axial postcontrast image (C) at the level of the centrum semiovale reveals leptomeningeal and perivascular enhancement. Biopsy revealed nongranulomatous vasculitis.

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C Figure 14.29. Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) mimicking neurosarcoidosis. Axial (A) and coronal (B) postcontrast T1 images reveal diffuse symmetric perivascular enhancement involving the pons. Follow-up axial postcontrast T1 imaging following steroid therapy (C) reveals interval resolution of the perivascular enhancement, consistent with CLIPPERS. (Images courtesy Dr. Suyash Mohan, University of Pennsylvania, Philadelphia, PA.)

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