Background: Sarcoidosis is a multi-organ disease of unknown etiology characterised by the presence of epithelioid granulomas, without caseous necrosis. Systemic sarcoidosis is rare among children, while neurosarcoidosis in children is even rarer whether it is systemic or not. Case presentation: We described the case of a 12-year-old boy who presented with monocular vision loss accompanied by unusual MRI features of an extensive meningeal infiltrating mass lesion. The patient underwent surgical resection (biopsy) via a frontotemporal craniotomy to establish a definitive diagnosis based on the histopathology, since neurosarcoidosis remains a very difficult diagnosis to establish from neuroradiogenic imagings. Based on the histopathology of the resected mass lesion, neurosarcoidosis was diagnosed. On follow-up after 3 months of steroid therapy, the patient displayed a good response on the imaging studies. MRI revealed that the preexisting mass lesion had regressed extremely. We also conducted a small literature review on imaging studies, manifestations, appropriate treatments, etc., in particular neurosarcoidosis including children. Conclusion: Although extremely rare, neurosarcoidosis, even in children, should be considered in the differential diagnosis of skull base mass lesions to avoid unnecessary aggressive surgery and delay in treatment, since surgery may have little role in the treatment of sarcoidosis. Keywords: Neurosarcoidosis, Pediatric, Sarcoidosis, Intracranial mass lesion, MRI Background have a space-occupying lesion. More recently, Rao et al. Sarcoidosis is an idiopathic granulomatous disease which  reviewed neurosarcoidosis in pediatric patients. commonly involves the lungs, skin, and eyes, with simultan- They found that only 53 examples of neurosarcoidosis eous or metachronous features [1, 2]. Sarcoidosis involving had been reported in the pediatric population, with the central nervous system (CNS; neurosarcoidosis) occurs nine of these cases being isolated neurosarcoidosis. The in approximately 5-15% of adults with systemic sarcoidosis most common manifestations included cranial neur- [3, 4]. Even fewer cases of sarcoidosis have been reported in opathy (21%), papilledema or optic neuritis (15%), children, especially cases affecting the CNS . Baumann seizures (24.5%), and hypothalamic dysfunction (17%), and Robertson  reviewed pediatric neurosarcoidosis and with the latter two conditions being more likely in concluded that childhood neurosarcoidosis differs in its younger children. presenting signs and symptoms from neurosarcoidosis in We described here the rare clinical and radiological adults; children are more likely to have seizures, less likely manifestations of 12-year-old boy with monocular vision to have cranial nerve palsies, and perhaps more likely to loss who was initially thought to have a skull base tumor, but was subsequently confirmed to have neurosarcoido- sis with systemic sarcoidosis. In addition, we present a * Correspondence: firstname.lastname@example.org small literature review of neurosarcoidosis, especially in Department of Neurological Surgery, Nihon University School of Medicine, pediatric patients. 30-1 Oyaguchi-Kamimachi, Itabashi-ku, Tokyo 173-8610, Japan Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Shijo et al. BMC Neurology (2018) 18:77 Page 2 of 6 Case presentation evident after contrast medium administration. Perile- History and examinations sional edema was not obviously found in the adjacent A 12-year-old boy was introduced to our institution because brain except the right temporal lobe. Furthermore, an he displayed visual disturbance and was described as having enhanced nodular shadow of 12 mm in size was detected an intracranial mass lesion by another hospital. His family in the lower part of the fourth ventricle. Spinal MRI history was unremarkable. His past history included a right revealed no abnormality throughout the spinal cord. Right neck mass lesion: this had expanded to 40 mm in 1 month internal carotid artery and external carotid artery angiog- and was histologically suspected to be associated with sar- raphies showed week staining where the mass was located coidosis by another hospital 2 years ago. Subsequently, he on the MRI, although it was difficult to locate the origin was followed up at that hospital, but there was no obvious of these feeding arteries. The above imaging findings abnormality until 3 months ago when visual disturbance indicated an extra-axial large tumor of the right skull base was identified at an annual school medical checkup. suggesting meningioma, solitary fibrous tumor, etc. His consciousness level was clear and neurological examinations demonstrated no abnormalities except for Surgery the ophthalomological problem. Neurological examina- The patient underwent surgical resection (biopsy) via a tions, including the I and III – XII cranial nerves, de- frontotemporal craniotomy to establish a definitive diag- tected no abnormality. Ophthalomological evaluations nosis based on the histopathology, since neurosarcoido- revealed concentric contraction of the visual field and sis remains a very difficult diagnosis to establish from diminished visual acuity of the right eye. His best cor- neuroradiogenic imagings. rected visual acuity was 0.2/20 (n.c) in the right eye and The intraoperative findings indicated that the tumor 4/20 (1.2pxS-1.5D) in the left eye. The pupils were semi- was hard, and visually and tactually resembled like a dilated and the pupillary light reflex was sluggish on the meningioma. The lesion was found immediately after right side, while a normal size and normal reaction were opening the sylvian fissure, and was easy to separate evident on the left side. In a fundus examination, his from the surrounding brain parenchyma in the frontal right optic disc was found to be pale. cortex, but had no distinct boundaries in the temporal Routine laboratory tests including renal function and cortex. When reaching deeply into the sylvian fissure, the hormonal tests demonstrated no obvious abnormalities. As internal cerebral artery was seen to be involved within the a marker for sarcoidosis, his serum angiotensin-converting lesion. The immediate pathology revealed that the speci- enzyme (ACE) was slightly increased at 22.5 U/L (8.3 to men consisted of a proliferation of short spindle cells 21.5 U/L). His chest X-ray performed on admission without necrosis, with multinucleated giant cells. Surgical showed no obvious abnormalities, but a subsequent chest exploration was therefore terminated at this stage. computed tomography (CT) scan revealed small scattered pulmonary nodules in the bilateral lungs. Histopathological examinations A CT scan and magnetic resonance imaging (MRI) of The definitive histopathology of the resected mass lesion the head demonstrated that a leaf-shaped extra-axial showed epithelioid cell granulomas and Langhans type mass of about 73 mm in length was present around the multinucleated giant cells that were rich in dense fibrous right cavernous sinus, straddling the sella turcica, tissue with lymphocytes and plasma cells. Necrosis was frontal, middle, and posterior cranial fossa, with dural not clear in the granulomas observed in the specimen thickness to the tentorium cerebrii (Figs. 1, 2, 3). The (Fig. 4). Grocott-positive fungi and Ziehl-Neelsen stain- greater part of this lesion showed iso signal intensity on ing positive anti-acid bacteria were not clearly found. T1 weighted images and low signal intensity on T2 Non-caseating granulomatous inflammation consistent weighted images, while homogeneous enhancement was with neurosarcoidosis was diagnosed. Fig. 1 Preoperative plain CT scan of the head showing a slightly high density huge skull base mass lesion on the right side Shijo et al. BMC Neurology (2018) 18:77 Page 3 of 6 Fig. 2 Preoperative axial MRI of the brain. T1-weighted (upper row) and fluid-attenuated inversion recovery (FLAIR; middle row) images demonstrated iso-intensity and a low-intensity mass lesion with edema in the right skull base, respectively. T1-weighted images after administration of gadolinium (lower row) revealed an homogeneous enhanced leaf-shaped huge mass lesion with pachymeningeal and leptomeningeal enhancement involving the tentorium Post-operative course 1.0 mg/kg body weight per day; reduction of the prednisol- Based on the histopathology of the resected mass lesion, one was made at 5 mg every 4 weeks). Fortunately, during neurosarcoidosis was diagnosed. Although steroid therapy this delayed time, his neurological examinations did not was planned, the start was delayed due to epidural abscess change and brain MRI also indicated no local growth of of the surgical wound, which required a surgical procedure the lesion where the mass lesion was left. and antibacterial therapy. Three months after the biopsy, On follow-up after 3 months of steroid therapy, the the patient was started on steroid therapy (prednisolone at patient displayed a good response on the imaging Fig. 3 Sagittal T1-weighted MRI with gadolinium (left) demonstrating a small enhanced mass of the fourth ventricle and an homogeneous enhanced mass in the pituitary and infundibulum. Further, coronal T1-weighted MRI with gadolinium (right) revealed extensive involvement of the right cavernous sinus and the Fig. 4 Biopsy specimen showing noncaseating epithelioid cell presence of dural enhancement resembling a dural tail sign in the granulomas with multinucleated giant cells (hematoxylin and eosin right middle cranial fossa stain: original magnification × 100) Shijo et al. BMC Neurology (2018) 18:77 Page 4 of 6 studies. MRI revealed that the preexisting mass lesion had that F-FDG PET/CT is a valuable tool for the diag- regressed extremely. The enhanced small nodular shadow nostic evaluation of patients suspected of sarcoidosis in the lower part of the fourth ventricle had disappeared. and is also important for other major diagnostic dis- Only around the right cavernous sinus, did the findings crimination, including lymphoma and metastasis . show a residual small mass of iso signal intensity on Although imaging studies are nonspecific, MRI is a very T1-weighted images and an extremely low signal intensity sensitive diagnostic tool for the finding and detection of on T2-weighted images with no enhancement effect after intracranial lesions due to neurosarcoidosis . Previous contrast medium administration (Fig. 5). reports have regarded mass lesions as rare in pediatric When the prednisolone reaches 25 mg/day, additional neurosarcoidosis , however Baumann and Robertson treatment using methotrexate in combination with pred- reported 24% had mass lesions on imaging and it is un- nisolone is planned for the patient. clear whether children have different patterns from adults . The lesions are frequently reported to be isointensive Discussion and conclusions on T1-weighted images and hypointensive masses on Intracranial pseudotumors are uncommon, but it is T2-weighted images, and to be uniformly enhanced after important to recognize such lesions. They may occur in contrast medium injection . Other common findings in inflammatory diseases (systemic diseases, vasculitis, and pediatric neurosarcoidosis include periventricular high demyelinating diseases), infectious diseases, vascular dis- signal lesions on T2-weighted images and leptomeningeal eases, and radionecrosis . Among such conditions, enhancement on T1-weighted images with contrast . sarcoidosis is a multi-organ disease of unknown etiology, Wiśniewski et al.  pointed out the relationship but is thought to be associated with an abnormal immune between the observation of extremely low signal on response, and develops from young people to elderly T2-weighted images and noncaseating granuloma in their people with a peak in the fourth decade [1, 8]. The clinical neurosarcoidosis case. In our patient, the low signals on symptoms at the time of onset are diverse, and the subse- T2-weighted images further advanced after steroid ther- quent clinical course is also diverse. Sarcoidosis most apy, which may indicate an inactive lesion, although we commonly affects the lungs and thoracic lymph nodes; need to continue observation of the future course. however, virtually any organ system can be involved in- One of the typical images of neurosarcoidosis is lepto- cluding the eyes, skin, kidney, heart, and CNS [2, 3, 8]. meningeal involvement which usually appears as a thick- Sarcoidosis may involve any of the intracranial regions ening and diffuse and/or focal enhancement [1, 4, 10]. including the supratentorial and infratentorial compart- Such an image may be readily misidentified for diseases ments as well as leptomeningeal and intraparenchymal such as glioma, meningioma, metastatic tumor, demye- areas, with solitary or multiple lesions, and such in- linating disease, vasculitis, and other granulomatous dis- volvement gives rise to a broad variety clinical manifes- eases including tuberculosis, Wegener’s granulomatosis, tations [1, 3, 9, 10]. Thus, a significant number of etc. [3, 13]. Thus, even in children, we need to include patients with neurosarcoidosis may have asymptomatic the possibility of neurosarcoidosis in the differential lesions or be misdiagnosed . It has been reported diagnosis of intracranial lesions [3, 13, 14]. Fig. 5 T2-weighted MRI (upper row) and T1-weighted MRI with gadolinium (lower row) at 3 months after medical therapy demonstrating that the mass, with iso signal intensity on T1-weighted images and extremely low signal intensity on T2-weighted images, had involuted considerably with a reduction in enhancement Shijo et al. BMC Neurology (2018) 18:77 Page 5 of 6 It has been reported that cranial neuropathies, which general, corticosteroids are the most commonly used may involve one or more nerves and occur unilateral or first line agents and are often effective [5, 6]. For adult bilaterally , are seen in about 60% of adult patients patients, other agents such as immunomodulating and/ with neurosarcoidosis [4, 8]. Among them, facial nerve or cytotoxic agents, including azathioprine, cyclophos- palsy is suggested to be the most commonly encoun- phamide, cyclosporine A, methotrexate, etc. have been tered neurologic complication [4, 6], although it could employed in combination with corticosteroids to provide include cases related to parotitis. Carlson et al. , who better outcomes, in either severe cases, steroid-resistant reviewed the cranial base manifestations of neurosarcoi- cases, recurrent cases, or cases in which steroids cause dosis, found that the optic, trigeminal, and facial side effects [1, 5, 6, 10]. 25% of the patients are refrac- nerve(s) represented the most frequently involved neu- tory to steroid treatment and 20 - 40% of such refractory ropathies, in that order. On the other hand, Rao et al. patients are not responsive to immunomodulating , who reviewed neurosarcoidosis in pediatric patients, agents . Although it has been indicated that adults indicated that the prepubertal aged group most com- with seizures and other intracranial lesions could be less monly presented with seizures, while postpubertal chil- responsive to treatment , our patient displayed a good dren presented similarly to adults and were more likely response to high-dose prednisolone with slow taper to have cranial neuropathy; facial nerve palsy was the treatment for 3 months including significant evidence of most common condition, followed by acoustic neur- radiological and clinical improvement. This may be opathy and optic nerve involvement. The mechanism of because pediatric patients can show improved lesions such neuropathy may not only result from nerve granu- with corticosteroids alone . The efficacy of immuno- loma, but may also be due to increased intracranial modulating and/or cytotoxic agents in children with pressure or granulomatous basal meningitis [4, 8]. neurosarcoidosis has not yet been fully elucidated . Several studies have indicated that increased serum We clearly need to undertake carefull follow-up of our ACE levels may be observed in sarcoidosis, but not in all patient’s future course. cases . Furthermore, elevated ACE levels are not Abbreviations specific for sarcoidosis because other diseases have also ACE: Angiotensin-converting enzyme; CNS: Central nervous system; revealed elevated serum ACE levels including tubercu- CT: Computed tomography; MRI: Magnetic resonance imaging losis, lung cancer, Hodgkin lymphoma, liver cirrhosis, Funding etc. . Thus, an elevated serum ACE does not provide None of the authors have received any financial assistance for this a definitive diagnosis . It is also controversial as to manuscript. whether the level of ACE in the cerebral spinal fluid is Availability of data and materials useful for the diagnosis of neurosarcoidosis . How- All data related to this case report are contained within the manuscript. ever, sequential serum ACE levels have been employed as a marker of disease progression in sarcoidosis . Authors’ contributions KS and AY contributed the concept of the manuscript and drafted the Although criteria for the pediatric diagnosis of neuro- manuscript. NM revised the manuscript and contributed the conception of sarcoidosis have not yet been established, the most the manuscript. MS, MW, HY and ST contributed to the obtaining and widely used criteria are those developed for adults by interpreting of the clinical information. TH analyzed the pathology of the mass lesion. All authors read and approved the final version of the Zajicek et al. [4, 15]. Definitive diagnosis is based on manuscript. histological evidence, which can prove non-caseating granulomas and multinucleated giant cells with sur- Ethics approval and consent to participate Not applicable. rounding lymphocytes , and must exclude differential diagnoses such as tuberculosis, berryliosis, and Sjögren’s Consent for publication syndrome which can elicit a similar histological picture. The patient’s guardians have consented to submission of this case report to the journal, and we have obtained a written informed consent. [4, 5]. It is important and necessary therefore to estab- lish a histopathological diagnosis as far as possible, and Competing interests to carry out an exclusion diagnosis adequately. Dural or The authors declare that they have no competing interests. leptomeningeal involvements with sarcoidosis are pre- ferred for biopsies, because such sites require less inva- Publisher’sNote sive procedures as compared to brain or spinal cord Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. biopsies . The most appropriate treatment for pediatric neuro- Author details sarcoidosis is remains uncertain. There is no evidence of Department of Neurological Surgery, Nihon University School of Medicine, 30-1 Oyaguchi-Kamimachi, Itabashi-ku, Tokyo 173-8610, Japan. Department clinical benefit from surgical removal for neurosarcoido- of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, sis , and the role of surgical removal may be limited 3 Japan. Division of Human Pathology, Department of Pathology and to diagnostic biopsy rather than therapeutic resection. 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Published: May 29, 2018