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Dorchester Center, MA 02124
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.
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. and later modified by Marangoni et al. 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 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 angiotensin-converting 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.
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 ).
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. 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 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.
Intraparenchymal involvement may manifest as multiple (35%) or solitary (10%), supra- or infratentorial lesions ( Fig. 14.4 ). 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.
CN involvement in NS is reported to occur in up to 50% of cases, either when the nerves traverse the subarachnoid space or 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 ).