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Show Journal of Neuro- Ophthalmology 16( 4): 269- 273, 1996. © 1996 Lippincott- Raven Publishers, Philadelphia Neurosarcoidosis Presenting as an Intracranial Mass in Childhood Hana Leiba, M. D., R. Michael Siatkowski, M. D., William W. Culbertson, M. D., and Joel S. Glaser, M. D. A 13- year- old boy presented with bilateral panuveitis and a superior oblique palsy. Exhaustive laboratory workup was unremarkable, but magnetic resonance imaging ( MRI) revealed an enhancing pontine mass. The mass was resected, and histopathology revealed a necrotizing granuloma. Although rare, particularly in the pediatric population, the combination of panuveitis and an intracranial mass likely represents sarcoidosis. Necrosis, although also rare, may similarly be seen in neurosarcoidosis. Key Words: Neurosarcoidosis- Childhood- Uveitis- Intracranial mass- Necrotizing. Sarcoidosis is an inflammatory disorder of unknown etiology that may involve any organ system. It most commonly affects adults between 20 and 40 years of age. In the United States, the prevalence is > 10 times higher among blacks than whites, and women are slightly more susceptible than men ( 1). The typical presentation follows an insidious onset, with fever, cough, and weight loss being the most common symptoms. Up to 90% of patients show radiologic evidence of pulmonary hilar lymphadenopathy early in the disease course ( 1,2). Sarcoidosis in early childhood, however, is a different clinical entity than that in adults, and is characterized by the triad of cutaneous nodules, arthritis, and uveitis ( 3). Ocular involvement has been reported to approach 100% in these patients ( 3,4), with iritis and/ or anterior vitritis almost universally present. Children > 8 years of age have a clinical picture more similar to that of adults. Pediatric sarcoidosis is, itself, relatively rare, with < 350 patients < 15 of age reported in the literature ( 5- 7). Manuscript received September 22, 1995; accepted October 20, 1995. From the Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami School of Medicine, Miami, Florida, U. S. A. Address correspondence and reprint requests to Dr. R. M. Siatkowski, Bascom Palmer Eye Institute, 900 NW 17th Street, Miami, FL 33163, U. S. A. Presented in part as a paper at the 27th annual meeting of the Frank W. Walsh Society, Washington DC, April 8, 1995. CASE REPORT A 13- year- old white boy presented in December 1993 with photophobia and bilateral anterior uveitis, managed with topical steroids. Initial pediatric, neurologic, and rheumatologic evaluations were unrevealing. In March 1994, the patient was asymptomatic with visual acuity of 20/ 20 in each eye, and normal color vision, visual fields, pupils, and ocular motility. There were 2+ granulomatous keratic precipitates, 3 + cells and flare in the anterior chambers, and 2 + anterior vitreous cells bilaterally. Intraocular pressures were normal. Both optic discs were mildly elevated and hyper-emic. In the temporal periphery of each eye, there were a few flat choroidal infiltrates. There were no 269 270 H. LEIBA ET AE. signs of retinal vasculitis or snow- banking of the pars plana. Work up at that time included chest radiography, CBC, ESR, ACE, ANA, Lyme titers, HLA B- 27, serum calcium, urinalysis, and PPD, all of which were normal. One month later, he developed binocular vertical diplopia. Visual acuity was 20/ 20 in each eye and external, slit- lamp, and fundus examinations remained unchanged. Motility examination revealed a flick of right hypertropia in the primary position that increased to 3 prism diopters on left gaze and 4 prism diopters on right head tilt. Double Maddox rod testing revealed 4° of excyclotor-sion, consistent with paresis of the right superior oblique. Magnetic resonance imaging ( MRI) of the brain revealed an enhancing pontomesencephalic lesion that appeared centered at the floor of the fourth ventricle just to the left of the midline and extending bilaterally into the cerebellum ( Fig. 1). A sec- FIG. 1. A: T1 gadolinium- enhanced sagittal image revealing large ponto- mesencephalic mass ( arrows) abutting forth ventricle and midline cerebellum. B: Coronal image shows mass centered left of midline. FIG. 2. T1 gadolinium- enhanced coronal image reveals bilateral enhancing lesions in the internal capsule/ basal ganglia ( arrows). Note prominent of temporal horns ( arrow heads). ond enhancing lesion was seen in the inferior portion of the right internal capsule, and a third zone was identified in the inferior left basal ganglial region ( Fig. 2). Early hydrocephalus was present, with prominent temporal horns. There was no enhancement of the leptomeninges, optic nerve, or chiasm; the lacrimal and parotid glands were normal. A suboccipital craniotomy was performed. At surgery, the tumor was seen to arise from the left side of brainstem, pushing the median raphe toward the right. The mass was completely resected. Cerebrospinal fluid ( CSF) taken intraoperatively from the cisterna magna showed normal levels of protein and glucose, and no malignant or inflammatory cells. Although frozen sections were interpreted as " focally calcified neoplasm consistent with astrocytoma," permanent sections revealed granulomatous inflammation with widespread necrosis, dystrophic calcification, and giant- cell formation ( Fig. 3). Special stains for acid- fast bacilli, fungi, and bacteria were negative. Because of the possibility of tuberculosis ( TB) infection, the patient was started on a full course of anti- TB medication while waiting for the final cultures. Treatment consisted of isoniazid ( INH) 300 mg q. i. d., ethambutol 800 mg q. i. d., rifampin 600 mg q. i. d., pyrazinamide / Neuro- Ophthalmol, Vol. 16, No. 4, 1996 NEUROSARCOIDOSIS IN CHILDHOOD 271 FIG. 3. Granulomatous inflammation with area of necrosis ( curved arrow), and giant cells ( arrow). Hema-toxylin- eosin, x10. . . - " • ' ' & • • •• i* . J -/.- » • 500 mg t. i. d., and vitamin B6 50 mg q. i. d., as well as prednisone 50 mg b. i. d. All special histological stains were negative, as was gene amplification for DNA of mycobacteria TB ( via the polymerase chain reaction). Repeat assays of CSF and blood were performed for bacterial, viral, mycobacterial, and fungal infections, as well as for cysticercosis. ACE and lysozyme levels were normal. The diagnosis of TB was thus ruled out and anti- TB treatment discontinued, together with gradual tapering off of steroids. Postoperatively, the patient had a transient left inter- nuclear ophthalmoplegia, as well as a peripheral facial nerve paresis and cerebellar ataxia. The fourth cranial nerve paresis persisted, and a contralateral superior oblique paresis became apparent. Repeat, gadolinium- enhanced MRI 3 weeks after surgery was normal. At 2 months postoperatively, while on prednisone 20 mg every other day, low- grade anterior uveitis remained, but more choroidal nodules appeared in the posterior pole and mid- peripheray bilaterally ( Fig. 4). In addition, a nodule was present in the right papillomacular bundle, elevating the macula at its temporal border. Visual acuity in the right eye dropped to 20/ 30. Prednisone was increased to 30 mg/ day and the choroidal nodules gradually resolved, with vision returning to 20/ 20. FIG. 4. Left fundus demonstrating multiple choroidal nodules ( arrows). / Neuro- Ophtlmlmol, Vol. 16, No. 4, 19% 272 H. LE1BA ET Ah. DISCUSSION Intraocular inflammation can be detected in 20- 40% of all adults with sarcoidosis ( 8). In addition, < 10% of all sarcoid patients initially present to an ophthalmologist, while - 7% of patients with persistent uveitis are ultimately diagnosed with sarcoidosis ( 9,10). Of 59 patients with uveitis found to have systemic sarcoidosis, 23 had involvement of the anterior segment only, 11 had intermediate and/ or posterior uveitis, and 25 had panuveitis ( 10). In another series of patients with sarcoid uveitis, central nervous system ( CNS) involvement was absent in all patients who had isolated anterior uveitis, while 11 of 26 patients with posterior or panuveitis had neurological symptoms ( 11). Brinkman and Rothova ( 12) similarly described six patients with neurosarcoidosis; all had panuveitis ( 12). Sarcoidosis involving the CNS is relatively uncommon, occurring only in 5% of patients with systemic sarcoidosis ( 1,2). Up to 50% of patients with neurosarcoidosis may present initially with neurologic dysfunction. On the other hand, systemic manifestations of sarcoidosis were found in 97% of patients presenting with neurosarcoidosis, typically at intrathoracic ( 88%) or ocular ( 55%) sites ( 13- 15). Nonetheless, a small number of patients who present with neurologic manifestations may have no evidence of extraneural disease ( 13,15- 17). As in adults, CNS involvement in children with sarcoidosis is rare. In a review of 261 cases of pediatric sarcoid, Weinberg ( 5) found only 11 cases with neurologic involvement ( 5). The most common manifestation of neurosarcoidosis is basilar granulomatous meningitis. Accordingly, typical signs and symptoms are those of cranial neuropathies ( especially seventh nerve palsies), aseptic meningitis, hydrocephalus, and endocrine disturbances secondary to hypothalamo-hypophyseal dysfunction ( 13- 16). Although presentation of neurosarcoidosis as an intracranial mass is rare, diagnostic accuracy of this condition is increasing due to advancements in neuroimag-ing, and the condition has been recognized in as many as 20% of patients with neurosarcoidosis ( 16). Cahill and Salcman ( 13) did a retrospective review of 20 cases ( 1947- 1980), to which they added two of their own cases, of CNS sarcoidosis presenting as a mass lesion. Gizzi et al. ( 16) found 25 cases ( 1980- 1986) and presented another case. In our review of the literature, we found nine additional cases of neurosarcoidosis presenting as an intracranial, intraparenchymal mass ( 12,18- 21). The youngest patient was 17 years old ( 21). Masses were most commonly located in the cerebral hemispheres ( 16,17,21,22), with only a few cases of lesions in the posterior fossa ( 16,18). In a review of 23 cases of pediatric neurosarcoidosis, only two patients had posterior fossa involvement ( 5). It has been suggested that parenchymatous masses in neurosarcoidosis result from extension of the inflammatory process through the spaces of Virchow- Robin ( 16). Progressive breakdown of pial- glial membranes allows extension of the granuloma into brain parenchyma, and coalescence of these may produce enhancing intra- axial masses identifiable on computed tomography ( CT) or MRI. MRI and CT appearances of neurosarcoid mass lesions, however, are nonspecific. On unen-hanced scans, sarcoid granulomas have a higher density than brain and show homogeneous moderate- to- high signal enhancement with contrast administration. Unfortunately, meningiomas, metastases, lymphomas, and gliomas may all have a similar appearance ( 22,23). White matter sarcoid lesions seen on T2- weighted MRI images may resemble those of multiple sclerosis ( 24). Histologically, the diagnostic feature of sarcoidosis is the noncaseating granuloma, a compact nodule of epithelial cells with a few lymphocytes, monocytes, and macrophages. Giant cells of either the foreign body or Langhan's type are common. As a rule, necrosis is absent, but even in cases that are clinically typical and from which infection is excluded, eosinophilic necrosis in the center of the lesion has been demonstrated ( 1). Necrotizing sarcoid granulomatosis was first described by Liebow in 1973 ( 25). The clinical manifestations are different from typical sarcoidosis. Almost half of these patients have systemic symptoms, such as fever, sweating, malaise, and weight loss; chest pain is common. Extrapulmonary manifestations are rare, although a few patients are reported with hepatic granulomas and/ or uveitis ( 1). Pathologically, the lesion consists of a collection of epithelioid granulomas in a background of fibrous tissue and nonspecific inflammatory cells. These granulomas are less discrete and less well encapsulated than are those of typical sarcoidosis. Extensive patches of fibrinoid or coagulative necrosis are present, as opposed to the discrete central necrosis seen in TB. This necrosis is probably the result of vasculitis involving both veins and arteries rather than a primary characteristic of the granuloma. Necrosis has also been reported as a feature of sarcoidosis involving the brain and meninges. Here, it is related to a characteristic periangiitis causing vascular occlusion ( 26). Of 13 cases of neu- / Neuro- Ophthalmol, Vol. 16, No. 4, 1996 NEUROSARCOIDOSIS IN CHILDHOOD 273 rosarcoidosis presenting as a mass lesion, only two cases showed necrotizing granulomatous inflammation ( 16,21). Additionally, Kelly and Green ( 27) described a patient with known sarcoidosis who developed optic nerve involvement. Histology of the optic nerve head revealed necrotic foci that were surrounded by granulomatous reaction. We believe that in the absence of evidence of infection of specific inflammatory process, our patient's clinical course and presentation are consistent with the diagnosis of sarcoidosis. Although atypical by virtue of demography ( a 13- year- old white boy), neuroanatomy ( multiple intracranial masses), and histopathology ( widespread necrosis), all such features have been reported previously. Fortunately, our patient has maintained good visual function, not developing severe and/ or bilateral visual loss ( 28) or requiring cyclosporine ( 29) or other immunosuppressive therapy. This case underscores the broad spectrum of this entity and is, to our knowledge, the first report of neu-rosarcoidosis presenting as a necrotizing posterior fossa mass lesion in the pediatric population. Acknowledgment: Supported in part by grants from the American Israeli Ophthalmological Society ( H. L.) and Research to Prevent Blindness, Inc., New York ( R. M. S., W. W. C.). REFERENCES 1. 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