Topic of the month: Radiological pathology of neurosarcoidosis

INDEX

INTRODUCTION

RADIOLOGICALMANIFESTATIONS OFNEUROSARCOIDOSIS

INTRODUCTION

CNS sarcoidosis is a disease that can involve any part of the CNS, producing varied clinicaland MR expressions. It can mimic other neurologic diseases, such as multiple sclerosis,tuberculosis, isolated angiitis of the CNS, and meningioma, and is often indistinguishablefrom them. Patients with symptoms usually have corresponding CNS lesions on MRimages. However, patients with cranial nerve deficits and pituitary dysfunction often haveno abnormal findings at routine contrast-enhanced MR imaging. On the other hand, MRfindings may be clinically silent. Patients with dura-based lesions, cranial nerve lesions,and, to a lesser degree, nonenhancing brain lesions faired better than did patients withleptomeningeal, brain parenchymal, and spinal lesions. In general, resolution of lesions onMR imaging lags behind resolution of clinical symptoms. The role of MR imaging in

neurosarcoidosis is to confirm clinical suspicion, establish subclinical disease, anddocument the response of pathologic lesions to treatment.

The pathophysiological mechanism behind sarcoidosis remains elusive. In theory, it isthought to represent an immune-mediated response to an as yet unidentified antigen. Bothan acute self-limited coarse with spontaneous resolution and an insidious, relentless courseultimately resulting in fibrosis have been identified. The disease most commonly afflictsAfrican Americans (female > male) in the third to fourth decade of life but can occur inevery race and has a wide age range. (11, 12).

NEUROLOGIC MANIFESTATIONS & GENERAL ASPECTS OF SARCOIDOSIS

Sarcoidosis is a multisystem granulomatous disease of unknown etiology. Though firstdescribed as a cutaneous disorder, it commonly affects the lungs and other organs.Neurologic manifestations occur usually as a part of the spectrum of the systemic disease.Though relatively uncommon, neurosarcoidosis is a serious disease associated with pooroutcome. Much progress has been made in the understanding of the immunopathogenesis,but there is limited knowledge about appropriate therapy, and very little is known of itsetiology. The epidemiologic features, immunopathogenesis, and immunomodulatorytherapy of neurosarcoidosis do not differ from the systemic disease. Most of theappreciation of neurosarcoidosis is gained from studies involving patients with systemicsarcoidosis, individual case reports, and case series of patients with nervous system disease.Patients with sarcoidosis do not generally undergo neurologic evaluation unless neurologicmanifestations are prominent. Most patients with neurosarcoidosis also have other organsystems involved by the inflammatory process. In light of these reasons, it is important tounderstand the general features of sarcoidosis to evaluate and manage patients withneurosarcoidosis.

Jonathan Hutchinson initially described the cutaneous aspects of the disease, but mistookthem for gout. Caesar Boeck subsequently described several patients with similar skinmanifestations and called them "sarkoid," because of the resemblance of the histologicfeatures to sarcoma. He emphasized the systemic nature of the disease. Ansgar Kveim andLouis Siltzbach developed a cutaneous test for diagnosis of the disease. Heerfordt in 1909,in his description of "uveoparotid fever," first reported neurologic manifestations in theform of cranial nerve palsies.

In the last 2 decades the understanding of the disease has been improved by severalreports that describe the immunopathologic and epidemiologic aspects. It most commonlyaffects middle-aged adults. The annual incidence rate is 0.85% for whites and 2.4% forblacks, and the prevalence is 40 per 100,000. The highest rates are observed in Swedes,Danes, and African-Americans. The mortality rate in sarcoidosis is 1 % to 5%, mostlybecause of respiratory failure. Familial studies in African- Americans, and in humanleukocyte antigens (HLA) studies, show a higher prevalence of the disease among first-generation relatives of patients with sarcoidosis. The increased risk in particular racial orethnic populations, familial clustering of cases, and disease association with certain HLA

phenotypes in some countries, argue for the role of genetic factors in the disease process.Spatial, seasonal, and familial clusterings of cases have been observed, suggesting possibletransmission of an infective pathogen, common exposure to environmental agents, andgenetic factors. Several organisms have been proposed as the causative agents, includingviruses, mycobacteria, Borrelia, and, more recently, propionibacterium acnes, but nonehave shown strong evidence. Noninfectious enviromental agents like aluminum, beryllium,and zirconium are also believed to trigger the disease because of their ability to induce agranulomatous response.

The inflammatory process is associated initially with an accumulation of activated T cellsand macrophages that release interferon-y, interleukin-2 and other cytokines andproinflammatory factors. The T cell antigen receptor (TCR) repertoire in sarcoidosissuggests an interaction of sarcoid antigen with a combination of specific T cell antigenreceptor and HLA antigen presentation molecules, which would trigger the immune-mediated inflammatory response. Contrary to earlier views of suppressed immunity, thereis now evidence that suggests sarcoidosis is associated with heightened immunity, mediatedprimarily by CD4+helper cells and macrophages. The immunology of sarcoidosis isassociated with a dichotomy of depressed systemic cellular immunity and heightened Tlymphocyte activity locally in the affected organs.

The diagnostic histopathologic lesion of sarcoidosis is a noncaseating epitheloid cellgranuloma. There is an accumulation of CD4 cells at sites of active inflammation. Theinflammatory process is similar in all organs affected by sarcoidosis, including the nervoussystem. These granulomas resolve spontaneously or with treatment. Persistence of theinflammatory process induces fibrotic changes, resulting in irreversible tissue damage.Similar granulomatous changes are observed in conditions other than sarcoidosis such assome carcinomas, regional lymph nodes of carcinomas, and lymphomatous disorders.About 20% of granulomatous lesions have an undetermined etiology. These clinicalsyndromes are grouped under the rubric "GLUS" (Granulomatous Lesions of UnknownSignificance). The elevated serum angiotensin converting enzyme (SACE) levels noted insarcoidosis are results of increased release from epitheloid cells derived from macrophages.

Figure 1. A, Sarcoidosis. Many Langhans giant cells (arrows) are seen surrounded byepithelioid histiocytes and an inflammatory reaction. Note absence of caseation necrosis asseen in tuberculosis. B, Sarcoidosis, high power, illustrating multi-nucleated Langhansgiant cell (large arrow) and epithelioid cells (small arrows) and dark lymphocytes.

The clinical presentation of sarcoidosis varies with the specific organ involved. The lungsare involved in 90% of patients with sarcoidosis, and the severity ranges fromasymptomatic to severe interstitial lung disease. Other organs commonly involved includethe lymph nodes (33%), liver (histopathologic abnormalities seen in 50% to 80% of biopsyspecimens), skin (25%), eyes (11%-83%), musculoskeletal system (25%- 39%), andendocrine glands. Sarcoidosis in children occurs more commonly in caucasions. Thedistribution of organ involvement is similar to adults, but is usually associated with a betterprognosis. Sarcoidosis does not usually affect the outcome of pregnancy, but the diseasemay worsen after delivery.

Figure 2. Tuberculosis of a lymph node,for comparison with sarcoidosis. Notecaseation necrosis (large arrow). Smallarrows indicate Langhans giant cell.

Sarcoidosis is a disease of exclusion. An effective diagnostic approach to sarcoidosisinvolves accurate clinical assessment of the extent, severity, and nature of the pathologyaffecting different organs. This is supported by various diagnostic tools and histologicconfirmation of the presence of noncaseating granulomata. Developments in diagnostictools like fiberoptic bronchoscope, bronchoalveolar lavage (BAL), SACE, and imagingtechniques have made the diagnostic process more effective and less dangerous.

The natural history and prognosis of the disease vary depending on specific organinvolvement and extent, as well as ethnicity and genetic factors. Spontaneous remissionsoccur in about two thirds of patients, the majority within the first 2 years. Approximately10% to 20% of sarcoidosis patients develop a chronic form of the disease. Most of thefunctional disability is from cardiac, ocular, neurologic, or severe pulmonary disease.Serious extrapulmonary involvement is present in 4% to 7% of patients at presentation.Most patients with systemic sarcoidosis improve or stabilize with or without treatment, butrelapse occurs in 16% to 74%. The mortality rate varies from 1% to 5%, mainly related tosevere pulmonary, cardiac, and neurologic disease.

Sarcoidosis is a granulomatous (mononuclear) inflammatory disease, systemic in scope,of undetermined etiology. While lymphoid tissue is particularly involved, any organ inthe head and neck area can be affected, especially lungs, skin,eyes,and salivary glands.Blacks are affected, at least in North American, ten times more often than whites.

Histopathology demonstrates granulomas composed of nodules of epithelioid histiocytesthat are non-caseating (unlike tuberculosis). A mixed inflammatory reaction commonlysurrounds the granulomas. Langhans type giant cells are common. Specialintracytoplasmic inclusions—stellate shapes called asteroid bodies—and also Schaumannbodies (laminated basophilic calcifications) are found. A similar picture may appear inother diseases so that eventually the diagnosis may become a matter of excluding aninfectious agent.

An acute presentation is generally considered to be associated with a good outcome. Poorprognostic signs or factors include age at onset > 40 years, black race, lupus pernio, chronicuveitis, chronic hypercalcemia, progressive pulmonary pathology, nasal mucosal disease,bone cysts, cardiac involvement, and neurosarcoidosis. Specific treatment withimmunosuppressants is generally held in asymptomatic or mild disease. Corticosteroidswere first used as therapeutic agents to treat sarcoidosis in 1951, and they have become themainstay of current therapy. Systemic corticosteroid treatment is definitely indicated inprogressive lung disease, cardiac, eye, or neurologic involvement.

Despite these advances in the understanding of the disease, specific triggering factors areunknown, and a single factor cannot be identified as a cause of the disease. The currentevidence suggests that the interaction of environmental factors a genetically susceptibleindividual is most likely responsible for induction of the disease. It appears that thechronicity of the sarcoid lesions is caused by persistence of an antigenic stimulus and/or anintrinsic dysregulation of the immune systems. Multinucleated giant cells may provide acellular reservoir for the antigen. There is an ongoing multicenter case-control study by theNIH to address the etiologic mechanisms of sarcoidosis.

RADIOLOGICAL MANIFESTATIONS OF NEUROSARCOIDOSIS

Dural Thickening/Mass

Dural/epidural mass lesions has an imaging appearance similar to that ofmeningioma/epidural lymphoma and are not associated with intraparenchymal extension.Dural/ epidural sarcoidosis probably represents blood borne deposits of the disease in theepidural spaces. The annual incidence of these lesions exceeds the annual incidence ofmeningiomas (2.3 per 100,000) (13) by 130 times. These lesions tend to be isointense withgray matter on T1-weighted MR images and hypointense on T2-weighted images, and theyenhance uniformly. This hypointensity on T2-weighted images has been reported

previously (14, 15) and is thought to be related to fibrocollagenous buildup. Unfortunately,this is not a unique finding. Eighteen percent of meningiomas (typically fibroblastic ortransitional types) demonstrate low signal on T2-weighted images (16). In addition tomeningioma, differential considerations for sarcoidosis involvement of the dura shouldinclude other causes of chronic meningitis, such as lymphoma, adenocarcinoma,Wegener's, idiopathic hypertrophic cranial pachymeningitis (IHCP), granulomatousinfection, and leukemia. Cheng et al (17) reviewed the cases of 37 patients who underwentbiopsy for chronic meningitis. Of the 16 diagnostic biopsies in this study, 31% revealedsarcoidosis and 25% revealed adenocarcinoma. Although most patients withneurosarcoidosis have systemic involvement (2), isolated dural involvement may beconfused pathologically with IHCP because both are granulomatous diseases negative forAFB or fungal staining. Unlike IHCP, which tends to manifest more diffuse involvement,dural sarcoidosis is often focal and has nonnecrotizing epithelioid granulomas (18–20).

Figure 3. 33-year-old white woman with chronic headache. A–D, An extraaxial left parietalmass is hypointense on noncontrast T2-weighted MR image (2517/90/1[TR/TE/excitations]) (A), enhances on contrast-enhanced T1-weighted (533/11/2) image(arrows, B), and is isointense with gray matter on noncontrast T1-weighted image

(450/19/2) (arrows, C). Substantial fibrocollagenous material and noncaseating granulomaswere seen at biopsy. The patient's symptoms resolved with steroids; however, a T1-weighted image (400/16/2) 28 months later showed only partial regression of the lesion (D).

Leptomeningeal Involvement

Leptomeningeal involvement is best shown on spin-echo contrast-enhanced T1-weightedimages (23). Leptomeningeal infiltration typically involves the suprasellar and frontal basalmeninges but may occur anywhere and is more concentrated in the depths of the sulci (5).Granulomatous lesions are accompanied by varying degrees of fibrosis and hyalinization(6). Occasionally, granulomas coalesce to form masslike lesions, particularly in the regionof the chiasm, floor of the third ventricle, and pituitary stalk (2). Clinical symptomscorrelate with the location of the lesion on MR images. Furthermore, it was found thatthese lesions recur frequently. Disease entities that can involve the basal leptomeninges andmimic leptomeningeal sarcoidosis on imaging include granulomatous disease (such astuberculosis), Wegener's granulomatosis and fungal meningitis, pyogenic meningitis,leptomeningeal lymphoma, demyelination, meningoangiomatosis, acute lymphocyticleukemia, and leptomeningeal carcinomatosis (10).

Figure 4. 33-year-old woman with right-sided visual loss, panhypopituitarism, polydipsia,and polyuria (with normal ADH). A and B, T1-weighted contrast-enhanced MR image(400/15/2) (A) shows basal meningeal enhancement and an enhancing pituitary massinvolving both lobes, the infundibulum, and the right optic nerve (not shown). Pituitary andmeningeal biopsy revealed noncaseating granulomas with negative AFB and fungal stains.

The visual symptoms resolved with steroid treatment; however, 21 months later shereturned with a left abducens palsy. A T1-weighted image (400/12/2) shows resolution ofthe pituitary lesion but new involvement of the left cavernous sinus (arrows, B).

The relatively low rate of occurrence of combined dural and leptomeningeal disease in thesame location can be explained by the presence of the arachnoid barrier cells. This portionof the arachnoid mater lacks extracellular spaces, has numerous cell junctions, and has abasement membrane separating it from the subarachnoid space. It can thus act to slowdown or prevent the infiltration of lymphocytic cells (10, 21).

Enhancing Brain Parenchymal Lesions

The frequent association of intraparenchymal granulomas with small arteries and veins(veins are more affected that arteries) suggests that lesions infiltrate the brain throughperivascular Virchow-Robin spaces (6, 24, 25). This usually occurs along the adventitia, butthe infiltration may, on occasion, destroy the elastic lamina and encroach on and occludethe vessel lumen, potentially causing infarction (5). It is often difficult to distinguishsarcoidosis angiitis from primary isolated angiitis of the CNS on a histopathologic basis (6,26, 27). Although no part of the CNS is immune to sarcoidosis, frequently affected brainparenchymal locations include the hypothalamus, brain stem, cerebral hemispheres, andcerebellar hemispheres (5, 6, 24–26, 28). Granulomatous infiltration into the subependymallayers of the ventricular system is thought to be responsible for hydrocephalus associatedwith neurosarcoidosis (5, 6, 12, 25). Involvement of the pituitary is less common.

The development of neurosarcoidosis is primarily leptomeningeal and vascular in nature. Itmay result in the disruption of the leptomeningeal blood-brain barrier, which permits thegranulomatous infiltrate to enter the brain parenchyma along the so-called perivascular orVirchow-Robin spaces that accompany the penetrating arteries up to the capillaries.Vasculitic lesions and perivascular involvement may cause stenosis, which results invasculopathy, and multiple granulomas may coalesce to produce intraaxial masses, oftenwith adjacent edema.

Figure 5. Diagram of the arrangement of the leptomeninges in the periarterial spaces(curved arrows) around the perforating brain vessels (based on data derived fromreferences 17-20). The pia matter (thick black arrow) separates the subarachnoid space ()from the subpial space (open arrow); the glial basement membrane (thin black arrow)overlies the cerebral cortex (arrowheads delineate the corticomedullary junction). Thelarger arterioles (A) in the cortex, which supply the deep white matter, have a periarteriallayer of leptomeninges that surround a continuous perivascular channel. The small subpialarterioles (B) have no pial sheath. The basal perforating arteries (C1, C2) have two coats ofleptomeninges that delineate the perivascular space (as described in the generally acceptedconcept of the vascular penetration of vessels with a free communication between theperivascular space and the subarachnoid space [C1]), but the perivascular space is, in fact,continuous around the arteries in the subarachnoid space (C2).

Enhancing brain parenchymal lesions commonly start in the subependymal or the pial(leptomeningeal) microvascular systems then invade the brain in a centrifugal orcentripetal ways forming multiple enhancing masses in the periventricular orcorticomedullary regions. Long standing lesions are commonly associated with tissuedestruction, encephalomalacia, reactive astrogliosis and extensive connective tissueformation. These reactive lesions are responsible for the MRI picture of confluent ornonconfluent nonenhancing white matter pathology in the periventricular regions.

Figure 6. 52-year-old man with seizure disorder. Imaging revealed hydrocephalus and abrain parenchymal lesion. His seizures gradually became more difficult to control. A andB, Contrast-enhanced T1-weighted MR images obtained 9 (483/13/2) (A) and 11 (500/16/2)(B) years after seizure onset show interim progression of meningeal thickening (arrows, B)and enlargement and multiplication of enhancing foci (arrowheads, B).

The most common symptom occurring with enhancing brain parenchymal lesions isseizures, although headache, encephalopathy, diabetes insipidus, and hypopituitarism alsooccur. Seizures have previously been associated with poorer prognosis in neurosarcoidosis(29). Histopathologically, this disease infiltrates via the perivascular spaces to reach thebrain parenchyma. It would thus be reasonable to hypothesize that if the disease is revealedby imaging to predominantly involve leptomeninges with little parenchymal involvement, itis at an earlier stage. The clinical course in patients with either leptomeningeal orparenchymal disease is hampered by recurrences or deterioration. Although diabetesinsipidus is often identified in neurosarcoidosis, it is frequently associated with a normalvasopressin level, thus implying hypothalamic dysfunction (30).

Figure 7. Midsagittal T1-weighted contrast-enhanced spoiled gradient-echo images (50/12,45° flip angle) in a 29-year-old man with a 2-year history of sexual impotency and sinusitisthat led to the diagnosis of sinonasal sarcoidosis with thoracic involvement. (A) Imageobtained before starting the high doses of corticosteroids shows an enlarged enhancedhypothalamus (thick solid arrow), tuber cinereum (thin solid arrow), lamina terminalis ofcerebrum (curved arrow), and lateral walls of the third ventricle (arrowheads). There is athickening of the mucosa (open arrow) of the septum and sphenoidal sinus (*). (B) Imageobtained after 4 months of attack treatment shows that the hypothalamic lesions haveregressed, but the punctate infundibular thickening (arrow) persists. The lesions describedabove progressed when the dose of corticosteroids was decreased. These later regressedwhen high doses were reintroduced. (Follow-up MR images obtained later are not shown.)

Figure 8. Cerebral sarcoid vasculopathy. A, Polypoid intimal granuloma - small cerebralartery. B, Transmural granuloma - small cerebral vein. C, D, Granulomatous obliterationof a small cerebral vein - Elastic stain.

Granulomatous angiitis is a frequent finding in sarcoidosis. Venous involvement is seen far more frequently than arterial involvement. Granulomas

may also be seen in lymphatics. Elastic tissue stains are very helpful in identifying these lesions, particularly in small

vessels where the lumen is completely obliterated Granulomatous angiitis, although highly characteristic, is not specific for sarcoidosis and

may also be seen in infectious granulomatous diseases, Wegener's granulomatosis,foreign body embolization, schistosomiasis, necrotizing sarcoid granulomatosis, andberyllium disease.

Figure 9. 34-year-old man with seizures, dysphagia, and lower extremity weakness. A, T2-weighted MR image (2416/90/1) shows multiple hyperintense lesions in the brain stem andcerebellum as well as the cerebral hemispheres and basal ganglia (not shown), whichdemonstrated contrast enhancement. B, Biopsy specimen shows atypical lymphoid tissuewith noncaseating granulomatous plaques (arrow) and granulomatous perivasculitis(arrowheads) (hematoxylin-eosin). The symptoms and MR abnormalities disappeared 15months after treatment with steroids and hydroxychloroquine sulfate.

Nonenhancing Brain Parenchymal Lesions (Periventricular white matter disease)

These lesions tend to occur in the periventricular white matter but may also occur in thebrain stem and basal ganglia and the corticomedullary junction. Periventricular lesions arenonspecific and can occur in association with multiple sclerosis, hypertension, andvasculitis. Theoretically, they can result from periventricular granulomas or from smallareas of infarction caused by granulomatous angiopathy. The exact nature of these lesionshas not been identified in the literature. They are not as often associated withleptomeningeal or enhancing brain parenchymal lesions, and we suggest that they coulddiffer pathologically from enhancing lesions that infiltrate basal meninges and associatedblood vessels, thus disturbing the blood-brain barrier. Of interest is that elevatedoligoclonal bands in the CSF, typically associated with multiple sclerosis, are often seenwith neurosarcoidosis as well (31). Symptomatic improvement usually did not correspondto improvement on MR imaging studies. This behavior differed from that of enhancingbrain lesions for which symptoms often correlated with imaging findings and symptomaticimprovement correlated with regression on MR images. These facts also imply that thenonenhancing brain parenchymal lesions and the enhancing lesions have differentpathophysiologic mechanisms.

These findings suggest that they are ancient, irreversible lesions. This pattern of evolutionhas been reported in the literature. These lesions are the chronic glial sequelae of previousinflammatory or ischemic lesions or may be directly due to granulomatous masses. Thedevelopment of irreversible chronic reactions after inflammation has been previouslyreported on the basis of the clinical data (2). The large medullary arterioles that supply thewhole depth of the white matter are surrounded by a continuous pial channel (23) thatcorrelates well with the deep periarterial draining of the inflammatory cells, which is

presumed to have occurred in the nonenhancing brain parenchymal lesions. These lesionsmay also be caused by ischemia that ranges from ischemic gliosis to infarction due toinvasion of the perivascular space of the perforating vessels by a granuloma (16). Thesewhite matter lesions are closely associated with local perivascular enhancement (15).

White matter disease is probably the end stage of a pathological spectrum which starts withleptomeningitis, that is followed by brain parenchymal invasion of the sarcoid granulomathrough the virchow robin spaces resulting in inflammatory or ischemic brain lesions(enhancing brain parenchymal lesions). The end result is white matter disease in theperiventricular and the corticomedullary regions (nonenhancing brain parenchymallesions). These white matter lesions are the chronic glial sequelae of previous inflammatoryor ischemic lesions or may be directly due to granulomatous masses (White matter diseasein neurosarcoidosis most probably represent tissue destruction, encephalomalacia, reactiveastrogliosis and extensive connective tissue formation secondary to the long standingprevious inflammatory or ischemic lesions). White matter disease is best seen on the MRIT2 and FLAIR studies and is seen as confluent or nonconfluent hyperintense patches in theperiventricular and corticomedullary regions. These patches do not show contrastenhancement and have no mass effect.

Table 1. Pathological stages in sarcoidosis

Stage CommentStage1

Leptomeningitis

Stage2

Enhancing brain parenchymal lesions

Stage3

Nonenhancing brain parenchymal lesions

Figure 10. A 30-year-old woman with a 10-year history of thoracic sarcoidosis andweakness who was treated with corticosteroids. (A) Transverse conventional dual-echointermediate-weighted spin-echo image (2,400/40) obtained at the level of the lateralventricles shows confluent hyperintense signal abnormalities (arrows) within theperiventricular white matter, mainly in the paraatrial areas. (B) Midsagittal T2-weightedfast spin-echo image (2,500/100, four signals acquired) of the cervical spine obtained at thesame time as in A shows areas of nonspecific increased signal intensity (arrowheads) withinthe cord. All lesions showed no contrast enhancement on the corresponding T1-weightedcontrast-enhanced spin-echo images (not shown), and on follow-up MR images (not shown)there was no evidence of regression after 4 years of steroid therapy

Figure 11. A 54-year-old womanwith a 30-year history of systemicsarcoidosis with no neurologicsymptoms in whom steroid therapywas started because of thoracic andophthalmologic involvement.Transverse T2-weighted spin-echoimage (2,400/100) obtained at thelevel of the lateral ventricles showsbilateral foci with high signalintensity (arrows) in the whitematter near the cortex in thefrontal and parietal lobes. Alllesions showed no contrastenhancement on the correspondingT1-weighted contrast-enhancedspin-echo images (not shown), andon follow-up MR images (notshown) there was no evidence ofregression after 18 months ofsteroid therapy.

Note These MR imaging features and the ability of neurosarcoidosis to cause multivisceral

vasculitis suggest that these parenchymal Lesions are microarteriolar ischemiccomplications consistent with true neurosarcoid vasculitis. These foci are predominantlypresent in the corticomedullary junction and the periventricular gray matter (thalamusand basal ganglia). They could be linked to the infiltration of the entire wall of smallleptomeningeal vessels, which led to thrombotic occlusion and to the surrounding patchyareas of ischemic tissue. The small subpial blood vessels entering the cortex have nolayer of pial cells, and the perivascular spaces around the capillaries are obliterated by thefusion of the endothelial and glial basement membranes. This prevents the perivasculardraining of the inflammatory cells into the subcortical white matter that is supplied by theterminal twigs of the longest cortical arterioles.

These abnormal hyperintense foci at the corticomedullary junction or the periventriculargray matter on T2-weighted images are nonspecific. They can be seen in a variety ofnoninflammatory and inflammatory disorders, including granulomatous vasculitis of thenervous system, also known as primary vasculitis of the central nervous system.Histopathologically, primary vasculitis of the CNS is very similar to neurosarcoidvasculitis. Primary vasculitis of the CNS has a special predilection for the smallleptomeningeal vessels and may appear with prominent leptomeningeal enhancement andminimal parenchymal findings on MR images.

Similarly, these vasculitic lesions in sarcoidosis are initially those of leptomeningealvasculopathy in which there had been no perivascular propagation of the granulomatous

process into the brain. There could also be an association between the enhancedhyperintense white matter foci and another systemic nonspecific thrombus-inducingpathophysiologic mechanism, such as circulating antiphospholipid antibodies. Thepresence of antiphospholipid antibodies in disseminated sarcoidosis and similar whitematter abnormalities in patients with nonsystemic lupus erythematosus and withantiphospholipid antibodies support this hypothesis. An increased frequency of focalwhite matter lesions has also been described in patients with inflammatory bowel disease.

Figure 12. A, Sequential MR images in a 32-year-old woman with a 4-year history ofsystemic sarcoidosis with uveitis who was treated with corticosteroids. (A) Transverse T2-weighted spin-echo image (2,400/100) obtained at the level of the lateral ventricles showsconfluent areas of hyperintensity (arrowheads) within the periventricular white matter andmultifocal areas of hyperintensity (arrows) within the subcortical white matter. Noenhanced lesion was observed on the corresponding T1-weighted contrast-enhanced spin-echo images (not shown). (B) Coronal T1-weighted contrast-enhanced spin-echo image(550/18) obtained after 2 years of treatment with minimal doses of corticosteroids showsnonenhanced demyelinated lesions (arrowheads) just above the bodies of the lateralventricles and micronodular enhanced lesions (arrows) in the subcortical and deep whitematter. This patient later showed complete regression of the enhanced lesions on T1-weighted contrast-enhanced spin-echo images obtained when high doses of corticosteroidswere reintroduced (not shown).

Figure 13. MR images in a 36-year-old woman with a 7-year history of systemic sarcoidosiswho had undergone steroid therapy and who had facial nerve palsy and asepticlymphocytic meningitis. (A) Transverse T2-weighted spin-echo image (2,400/100) at thelevel of the lateral ventricles shows multifocal hyperintense areas (arrows) within theperipheral white matter. A new frontal lesion appeared when this image was comparedwith initial MR images (not shown). All lesions showed no contrast enhancement oncorresponding T1-weighted contrast-enhanced spin-echo images (not shown). (B)Transverse T1-weighted contrast-enhanced spine-echo image (550/18) of the brainstemobtained at the same time as the image in A demonstrates the development of pialinvolvement, which is recognized by a thin linear area of enhancement (arrowheads) thatsurrounds the pons.

Cranial Nerve Involvement

Involvement of every cranial nerve has been described in association with sarcoidosis (2).Most frequently, the facial nerve is involved clinically. The annual incidence of Bell's palsyin the general population is 25 per 100,000 (32). In patients with sarcoidosis, it is 14 timesthat. Imaging, however, revealed that the optic nerve and/or chiasm are the mostfrequently affected cranial nerves.

Clinical and imaging cranial nerve involvement frequently do not concur, and,furthermore, clinical resolution often does not imply imaging resolution. Although mostpatients showed response to steroids, patients with optic nerve involvement often hadresidual symptoms or no response to treatment. We conjecture that this may be related tothe fact that other cranial nerves are surrounded by Schwann cells, which can regeneratemore readily than can oligodendroglial myelin, thus allowing for more effectiveregeneration of function (9).

Cranial nerve involvement is not well understood. Pathologic examination has revealedperivascular and intraneural lymphocytic infiltration (33). Nerve root and cranial nerveinvolvement are caused by compressive effects from adjacent granulomas (4).

Figure 14. Sequential MR images in a 48-year-old man with a 5-year history ofparenchymal neurosarcoidosis who had been and was treated with corticosteroids. (A)Transverse T1-weighted contrast-enhanced spin-echo image (550/18) obtained beforestarting the follow-up MR imaging to adapt the corticosteroid regimen showsmicronodular enhanced lesions (straight arrows) in the right basal ganglia and along themargin of the lateral ventricle (arrowheads) in the regions supplied by the lateral striatearteries. There is an ischemic lacuna (curved arrow). (B) Transverse T1-weighted contrast-enhanced spin-echo image (550/18) obtained at the same level as in a 6 years after the start

of long-term maintenance corticosteroid therapy shows a decrease in the marked contrastenhancement (arrows) depicted in A.

Spinal Cord and Nerve Root Involvement

Spinal cord and nerve root involvement has been reported as an unusual manifestation ofsarcoidosis. Furthermore, the majority of the patients are male. This is especiallyinteresting because sarcoidosis more frequently affects females. Most patients improve withsteroid or cyclophosphamide (Cytoxan) administration; however, long-term steroiddependence with episodes of recurrence associated with tapering the administration canoccur in patients with cord lesions. Improvement on MR images might lag behind steroidtreatment. A review of the literature by Nagai et al (34) found that early treatment withsteroids can result in remarkable recovery; however, with a delayed diagnosis andtreatment, the disease typically only partially resolves and may recur. Nagai et aladditionally commented that decompressive laminectomy as well as lysis of adhesions mayalso benefit the patient.

Figure 15. 36-year-old man with gradual onset of weakness, numbness, spasticity, andbowel and bladder dysfunction. A–C, T1-weighted MR image (450/15/2) (A) showsintramedullary enhancement and enhancement along the surface of the cord, associatedwith cord signal abnormality and disk herniation on T2-weighted fast spin-echo image (B).The patient underwent surgical diskectomy and initially did worse. His symptoms and thefindings on a T2-weighted fast spin-echo image (3000/102/2) (C) improved with steroids,but recurred 5 months later.

Figure 16. Midsagittal T1-weightedcontrast-enhanced spin-echo images(450/25) of the cervical spine in a39-year-old woman with a 9-yearhistory of thoracic sarcoidosis whohad weakness and sensory deficit.(A) Image obtained before startingthe steroid therapy shows anintramedullary nodular area ofenhancement (arrow). (B) After 7months of attack treatment, theimage shows that this area ofenhancement has completelydisappeared (arrow). Increasedsignal intensity abnormalitiespreviously observed within the cordon T2-weighted images (not shown)also disappeared.

Histopathologic specimens have shown granuloma formation with lymphocytic infiltrates.Lesions usually have an extramedullary component; however, pure intramedullary tumorshave been described (35). The lesions have been found to represent granulomatousmeningitis with nodular studding infiltrating the perivascular space and formingintramedullary granulomas (34). Lesions have been reported to occur throughout thespinal cord but more frequently in the cervical spine (34, 36). At imaging, they manifestcord swelling, with increased signal intensity on long TR images and a pattern ofenhancement that predominates in the periphery of the cord but includes patchy multifocalenhancement of the cord. Imaging findings are thus nonspecific and can mimic multiplesclerosis, cord tumor, vacuolar myelopathy, tuberculosis, or fungal infection (36–39).Junger et al (38) hypothesized that patients with spinal cord sarcoidosis progress in fourphases, which begin with a linear leptomeningeal pattern of enhancement and progress to aphase in which there is cord enlargement with faint enhancement or no enhancement.Enhancement then progresses but the cord begins to reduce in size until it reaches a finalstage of atrophy without any enhancement. Although it is fairly evident that patients whopresent with cord atrophy will most likely not respond to steroid treatment, it is unclearwhether the degree of enhancement plays a role in treatment response.

Table 2. CNS lesions in neurosarcoidosis

Type of lesions CommentDuralThickening/Mass

Dural/epidural mass lesions has an imaging appearance similar to thatof meningioma/epidural lymphoma and are not associated withintraparenchymal extension. These lesions tend to be isointense withgray matter on T1-weighted MR images and hypointense on T2-weighted images, and they enhance uniformly. This hypointensity on T2-weighted images has been reported previously (14, 15) and is thought tobe related to fibrocollagenous buildup.

LeptomeningealInvolvement

Stage 1

Leptomeningeal involvement is best shown on spin-echo contrast-enhanced T1-weighted images (23). Leptomeningeal infiltration typicallyinvolves the suprasellar and frontal basal meninges but may occuranywhere and is more concentrated in the depths of the sulci (5).Granulomatous lesions are accompanied by varying degrees of fibrosisand hyalinization (6). Occasionally, granulomas coalesce to formmasslike lesions, particularly in the region of the chiasm, floor of thethird ventricle, and pituitary stalk (2). Clinical symptoms correlate withthe location of the lesion on MR images. Furthermore, it was found thatthese lesions recur frequently. Disease entities that can involve the basalleptomeninges and mimic leptomeningeal sarcoidosis on imaging includegranulomatous disease (such as tuberculosis), Wegener's granulomatosisand fungal meningitis, pyogenic meningitis, leptomeningeal lymphoma,demyelination, meningoangiomatosis, acute lymphocytic leukemia, andleptomeningeal carcinomatosis (10).

Enhancing BrainParenchymalLesions

Stage 2

The frequent association of intraparenchymal granulomas with smallarteries and veins (veins are more affected that arteries) suggests thatlesions infiltrate the brain through perivascular Virchow-Robin spaces(6, 24, 25). This usually occurs along the adventitia, but the infiltrationmay, on occasion, destroy the elastic lamina and encroach on andocclude the vessel lumen, potentially causing infarction (5). It is oftendifficult to distinguish sarcoidosis angiitis from primary isolated angiitisof the CNS on a histopathologic basis (6, 26, 27). Although no part of theCNS is immune to sarcoidosis, frequently affected brain parenchymallocations include the hypothalamus, brain stem, cerebral hemispheres,and cerebellar hemispheres (5, 6, 24–26, 28). Granulomatous infiltrationinto the subependymal layers of the ventricular system is thought to beresponsible for hydrocephalus associated with neurosarcoidosis (5, 6, 12,25). Involvement of the pituitary is less common.

NonenhancingBrainParenchymalLesions(Periventricular

These lesions tend to occur in the periventricular white matter but mayalso occur in the brain stem and basal ganglia and the corticomedullaryjunction. Periventricular lesions are nonspecific and can occur inassociation with multiple sclerosis, hypertension, and vasculitis.Theoretically, they can result from periventricular granulomas or from

white matterdisease)

Stage 3

small areas of infarction caused by granulomatous angiopathy. Theexact nature of these lesions has not been identified in the literature.They are not as often associated with leptomeningeal or enhancing brainparenchymal lesions, and we suggest that they could differpathologically from enhancing lesions that infiltrate basal meninges andassociated blood vessels, thus disturbing the blood-brain barrier. Ofinterest is that elevated oligoclonal bands in the CSF, typicallyassociated with multiple sclerosis, are often seen with neurosarcoidosisas well (31). Symptomatic improvement usually did not correspond toimprovement on MR imaging studies. This behavior differed from thatof enhancing brain lesions for which symptoms often correlated withimaging findings and symptomatic improvement correlated withregression on MR images. These facts also imply that the nonenhancingbrain parenchymal lesions and the enhancing lesions have differentpathophysiologic mechanisms.

Cranial NerveInvolvement

Involvement of every cranial nerve has been described in associationwith sarcoidosis (2). Most frequently, the facial nerve is involvedclinically. The annual incidence of Bell's palsy in the general populationis 25 per 100,000 (32). In patients with sarcoidosis, it is 14 times that.Imaging, however, revealed that the optic nerve and/or chiasm are themost frequently affected cranial nerves.

Spinal Cord andNerve RootInvolvement

Spinal cord and nerve root involvement has been reported as an unusualmanifestation of sarcoidosis. Furthermore, the majority of the patientsare male. This is especially interesting because sarcoidosis morefrequently affects females. Most patients improve with steroid orcyclophosphamide (Cytoxan) administration; however, long-termsteroid dependence with episodes of recurrence associated with taperingthe administration can occur in patients with cord lesions.

References

1. Dantzker DR, Tobin MJ, Whatley RE. Respiratory diseases. In: Andreoli TE,Carpenter CCJ, Plum F, Smith LH, eds. Cecil Essentials of Medicine. Philadelphia:Saunders; 1986:149

2. Oksanen VE. Neurosarcoidosis. In: James DG, ed. Sarcoidosis and OtherGranulomatous Disorders. New York: Dekker; 1994:285–309

3. Siltzbach LE, James DG, Neville E, et al. Course and prognosis of sarcoidosisaround the world. Am J Med 1974;57:847-852

4. Stern BJ, Krumholz A, Johns C, Scott P, Nissan J. Sarcoidosis and its neurologicmanifestations. Arch Neurol 1985;42:909-917

5. Urich H. Neurological manifestations of sarcoidosis. Practitioner 1969;202:632-6366. Waxman JS, Sher JH. The spectrum of central nervous system sarcoidosis: a

clinical and pathologic study. Mt Sinai J Med 1979;46:309-317

7. Burger PC, Scheithauer BW. Reactive and inflammatory masses simulatingneoplasia. In: Tumors of the Central Nervous System: Atlas of Tumor Pathology.Third Series. Washington: Armed Forces Institute of Pathology; 1994:391–413

8. Nathan MPR, Chase PH, Elguezabel A, Weinstein M. Spinal cord sarcoidosis. N YState J Med 1976;76:748-752

9. Schmidt RE. Demyelinating diseases. In: Nelson JS, Parisi JE, Schochet SS, eds.Principles and Practice of Neuropathology. St Louis: Mosby-Year Book; 1993:361–397

10. Meltzer CC, Fukui MB, Kanal E, et al. MR imaging of the meninges, I: normalanatomic features and nonneoplastic disease. Radiology 1996;201:297-308

11. Seltzer S, Mark AS, Atlas SW. CNS sarcoidosis: evaluation with contrast-enhancedMR imaging. AJNR Am J Neuroradiol 1991;12:1227-1233

12. Lexa FJ, Grossman RI. MR of sarcoidosis in the head and spine: spectrum ofmanifestations and radiographic response to steroid therapy. AJNR Am JNeuroradiol 1994;15:973-982

13. Rohringer M, Sutherlans GR, Louw DF. Incidence and clinicopathologic features ofmeningioma. J Neurosurg 1989;71:665-672

14. Wilson JD, Castillo M, Van Tassel P. MR features of intracranial sarcoidosismimicking meningiomas. Clin Imaging 1994;18:184-188

15. Ranoux D, Devaux B, Lamy C, Mear JY, Roux FX, Mas JL. Meningeal sarcoidosis,pseudomeningioma, and pachymeningitis of the convexity. J Neurol NeurosurgPsychiatry 1992;300-303

16. Elster AD, Challa VR, Gilbert TH, Richardson DN, Contento JC. Meningiomas:MR and histopathologic features. Radiology 1989;170:857-862

17. Cheng TM, O'Neil BP, Scheithauer BW, Piepgras DG. Chronic meningitis: the roleof meningeal or cortical biopsy. Neurosurgery 1994;34:590-596

18. Finelli DA, Christopherson LA, Rhodes RH, Kiefer SP, Takaoka Y. Leptomeningealand calvarial sarcoidosis: CT and MR appearance. J Comput Assist Tomogr1995;19:639-642

19. Mamelak AN, Kelly WM, Davis RL, Rosenblum ML. Idiopathic hypertrophiccranial pachymeningitis: report of three cases. J Neurosurg 1993;79:270-276

20. Masson C, Henin D, Hauw JJ, et al. Hypertrophic cranial pachymeningitis ofunknown origin: a study of seven cases. Neurology 1993;43:1329-1334

21. Haines DE, Harkey HL, Al-Mefty O. The "subdural" space: a new look at anoutdated concept. Neurosurgery 1993;32:111-120

22. Mirfakhraee M, Crofford MJ, Guinto FC, Nauta HJW, Weedn VW. Virchow-Robinspace: a path of spread in neurosarcoidosis. Radiology 1986;158:715-720

23. Sherman JL, Stern BJ. Sarcoidosis of the CNS: comparison of unenhanced andenhanced MR images. AJNR Am J Neuroradiol 1990;11:915-923

24. Oksanen V. Neurosarcoidosis: clinical presentations and course in 50 patients. ActaNeurol Scand 1986;73:283-290

25. Aronson SM, Perl DP. Clinical neuropathological conference. Dis Nerv Syst1973;392-395

26. Scott TF. Diseases that mimic multiple sclerosis. Postgrad Med 1991;89:187-19027. Lee SC, Spencer J, Rumberg J, Dickson DW. Isolated central nervous system

granulomatosis resembling sarcoidosis. Neurology 1989;236:356-358

28. Chapelon C, Ziza JM, Piette et al. Neurosarcoidosis: signs, course and treatment in35 confirmed cases. Medicine (Baltimore) 1990;69:261-276

29. Krumholz A, Stern BJ, Stern EG. Clinical implications of seizures inneurosarcoidosis. Arch Neurol 1991;48:842-844

30. Bell NH. Endocrine complications of sarcoidosis. Endocrinol Metab Clin North Am1991;20:645-654

31. Miller DH, Kendakk BE, Barter S, et al. Magnetic resonance imaging in centralnervous system sarcoidosis. Neurology 1988;38:378-38

32. Katusic SK, Beard CM, Wiederholt WC, et al. Incidence, clinical features andprognosis in Bell's palsy, Rochester, Minnesota 1968–1982. Ann Neurol1986;20:622-627

33. Babin RW, Liu C, Aschenbrener C. Histopathology of neurosensory deafness insarcoidosis. Ann Otol Rhinol Laryngol 1984;93:389-393

34. Nagai H, Ohtsubo K, Shimada H. Sarcoidosis of the spinal cord: Report of anautopsy case and review of the literature. Acta Pathol Jpn 1985;35:1007-1022

35. Levivier M, Brotchi J, Baleriaux D, et al. Sarcoidosis presenting as an isolatedintramedullary tumor. Neurosurgery 1991;29:271-27

36. Sauter MK, Panitch HS, Kristt DA. Myelopathic neurosarcoidosis: diagnostic valueof enhanced MR. Neurology 1991;41:150-15

37. Kelly RB, Mahoney PD, Cawley KM. MR demonstration of spinal cord sarcoidosis:report of a case. AJNR Am J Neuroradiol 1988;9:197-199

38. Junger SS, Stern BJ, Levine SR, Sipos E, Marti-Masso JF. Intramedullary spinalsarcoidosis: clinical and magnetic resonance imaging characteristics. Neurology1993;43:333-337

39. Nesbit GM, Miller GM, Baker HL, Ebersol MJ, Scheithauer BW. Spinal cordsarcoidosis: a new finding at MR imaging with Gd-DTPA enhancement. Radiology1989;173:839-843

The Author

Professor Yasser Metwally

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