Accepted Manuscript Isolated Oculomotor and Abducens Nerves Palsies as Initial Presentation of Cavernous Sinus Tuberculoma: Case Report and Literature Review Hesam Abdolhoseinpour, Soheila Abolghasemi, Ehsan Jangholi, Khadijeh Haji Naghi Tehrani PII: S1878-8750(18)31419-0 DOI: 10.1016/j.wneu.2018.06.203 Reference: WNEU 8516 To appear in: World Neurosurgery Received Date: 5 May 2018 Revised Date: 22 June 2018 Accepted Date: 23 June 2018 Please cite this article as: Abdolhoseinpour H, Abolghasemi S, Jangholi E, Naghi Tehrani KH, Isolated Oculomotor and Abducens Nerves Palsies as Initial Presentation of Cavernous Sinus Tuberculoma: Case Report and Literature Review, World Neurosurgery (2018), doi: 10.1016/j.wneu.2018.06.203. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT Isolated Oculomotor and Abducens Nerves Palsies as Initial Presentation of Cavernous Sinus Tuberculoma: Case Report and Literature Review Hesam Abdolhoseinpour1, Soheila Abolghasemi2, Ehsan Jangholi3,4, Khadijeh Haji Naghi Tehrani5* RI PT 1. Department of Neurosurgery, Bou Ali Hospital, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran 2. Department of Infectious Diseases, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran SC 3. Young Researchers and Elite Club, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran 4. Clinical Research Development Center, Amir-almomenin Hospital, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran M AN U 5. Department of Neurology, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran Corresponding Author: Khadijeh Haji Naghi Tehrani Tel: +9821-22006660 Fax: +9821-22846593 TE D Mailing address: Medical Research Center, Azad University, Tehran Medical Branch, Attarimoqaddam Ave, Haqani Ave, Dr. Shariati St, Tehran, Iran, P. O. BOX: 19395-1495, Tehran, Iran AC C EP Email: dr_tehrani10@yahoo.com ACCEPTED MANUSCRIPT Isolated Oculomotor and Abducens Nerves Palsies as Initial Presentation of Cavernous Sinus Tuberculoma: Case Report and Literature Review Abstract RI PT Introduction: Central nervous system (CNS) tuberculoma is the most severe manifestation of extrapulmonary tuberculosis, which caused high mortality. Cavernous sinus tuberculomas (CSTs) is a very rare presentation of CNS that few cases were reported in the literature. M AN U SC Case Report: We reported a 57- years-old woman who was admitted to our clinic with acute diplopia and headache limited to the right side. There was no any specific medical history expect migraine, depression, and anxiety, which controlled by oral medications. Physical examination revealed ptosis, mydriasis on the right eye that indicated right third and sixth cranial nerves palsies. Pituitary magnetic resonance imaging (MRI) showed right parasellar lesion at cavernous sinus wall and ophthalmic nerve. However, laboratory examinations and brain computed tomography (CT) scan showed negative findings. Initial differential diagnosis includes meningioma, sarcoidosis, tuberculoma, and lymphoma. However, results of more studies include blood and cerebrospinal fluid culture even Mycobacterium tuberculosis DNA assay were negative. She underwent biopsy of the cerebral lesion through the subfrontal approach, and the histopathological study confirmed CST. Finally, she treated by standard antituberculous regimen, and after 12 months’ follow-up, no any cerebral and clinical findings were seen. TE D Conclusions: CST was a rare presentation of M. tuberculosis, and its diagnosis is a difficult challenge. However, accurate diagnosis and timely treatment of CST in the suspected patients could prove complete cure. AC C EP Keywords: Tuberculoma; Mycobacterium tuberculosis; Central nervous system; Abducens; Cavernous Sinus ACCEPTED MANUSCRIPT Abbreviations and Acronyms: RI PT TB: Tuberculosis CST: Cavernous sinus tuberculomas CT: Computed tomography MRI: Magnetic resonance imaging SC CS: Cavernous sinus CSF: Cerebrospinal fluid AC C EP TE D M AN U CNS: Central nervous system ACCEPTED MANUSCRIPT Introduction SC RI PT Tuberculosis (TB) is a multi-systemic infectious disease that caused by various species of mycobacteria, typically Mycobacterium tuberculosis in humans.1 An unusual incidence of TB in different parts of the body is called tuberculomas. Although TB of the nervous system may be involved both central and peripheral nerves, tuberculomas are most often located in the cerebral hemispheres.2,3 Indeed, cavernous sinus tuberculomas (CSTs) are an extremely rare presentation. To the best of our knowledge, only 17 cases of CST have previously been reported in the literature.1-17 Hence, in this report, we present the first Iranian case of CST that presented with isolated third and sixth cranial nerves palsies. M AN U Case Presentation TE D A 57- years-old woman was admitted to our neurology clinic (Bou-Ali Hospital, Tehran) with the complaints of acute diplopia and headache limited to the right side of the head. Her medical history was included migraine, depression, anxiety for two years ago, and bilateral cataract surgery (for about four years). Hence, her medications that started 24 months prior were sodium valproate (500 mg daily), aspirin (80 mg daily), perphenazine (2 mg daily), alprazolam (0.5 mg daily) and nortriptyline (25 mg BID). There was no any specific pathological history including TB, and there was no history of exposure to TB. Neurological examinations showed ptosis, mydriasis and 10/10 visual acuity on the right eye that indicated right third and sixth nerves palsies. Also, bilateral eyes fundoscopy revealed normal optic disc without any vessels deficit. There were no additional findings on physical and laboratory examinations of the patient. AC C EP The brain computed tomography (CT) scan showed no abnormality (Figure-1). Pituitary magnetic resonance imaging (MRI) revealed a right parasellar lesion which occupied right cavernous sinus (CS) wall and the mild enlargement of the pituitary gland; the lesion was isointense on both T1- and T2-weighted sequences (Figure-2A and B). It enhanced homogeneously after intravenous (IV) gadolinium administration (Figure-2C). She underwent carotid Doppler ultrasonography that no any abnormal findings were reported. Brain MRA demonstrated normal sagittal sinus, strio-thalamic vein, internal cerebral veins, and vein of Galen that rolled out the CS thrombosis. Regarding the differential diagnosis, i.e., meningioma, sarcoidosis, tuberculoma, and lymphoma, further studies (include blood and cerebrospinal fluid [CSF] culture, PPD skin test, chest x-ray, polymerase chain reaction [PCR], and M. tuberculosis DNA assay) were performed, and their results were negative. Consequently, she underwent craniotomy and a biopsy of the CS wall and dura lesion through subfrontal approach. In the macroscopy view, a small, round shape, and yellowish mass was removed. Subsequently, pathological examination following the surgery confirmed CST (Figure-3) ACCEPTED MANUSCRIPT Anti-TB treatment was begun immediately with a four-drug regimen (rifampin, isoniazid, ethambutol, and pyrazinamide) for two months followed by a two-drug regimen (rifampin and isoniazid) for ten months, and dexamethasone for the first eight weeks. RI PT The postoperative course was uneventful with no surgical morbidity and clinical improvement in the weeks after that. The 1-year postoperative follow-up MRI showed complete regression of the lesion (Figure-4) and complete resolution of the symptoms. Discussion M AN U SC TB is still a leading cause of death among the infectious diseases. Central nervous system (CNS) tuberculoma is the fifth most frequent and severe manifestation of extrapulmonary TB diseases.3 CST, as the rare presentation of TB, accounts for between 10-30% of cases of CNS disease, though the reported frequency was varied.9,13 Despite the propensity to affect the hemispheres, unusual locations of CNS tuberculoma continue to be reported; including the cerebellopontine angle, the sellar and suprasellar regions, concurrent multiple intracranial and intramedullary conus tuberculoma, and as in our case, the CS.14,15 Intracranial tuberculomas can be solitary or multiple. Solitary lesions pose a diagnostic challenge as they can be indistinguishable from abscess or tumor.4 Symptoms include headaches, seizures, ocular nerve palsy, hydrocephalus, cerebral arterial involvement, and focal ischemia.9 However, headache and ocular involvement are the most initial presentations of CST that are consistent with our case.2-15 EP TE D MRI have a highly sensitive but low specificity for the diagnosis of CST. T1-weighted images show an area of hypo- or iso-intensity that revealing dural thickening and pachymeningeal contrast enhancement involving the CS, and T2-weighted images show a hypo- or iso-intense tumor with perilesional edema.7,9,10 Also, CT scans of a tuberculoma provide an iso – to – hyperdense lesion with varying contrast enhancement pattern.9 AC C The diagnosis of CST could be difficult due to various clinical manifestations, no history of TB, nonspecific laboratory, and chest radiographic findings. Even tuberculous bacilli are not always present in the CSF. Molecular techniques, e.g., PCR may also have an important role in diagnosis;9,10 however; this test was not diagnostic in our case. For a definitive diagnosis, take a tissue specimen is mandatory for bacteriologic and histopathologic evaluations. However, according to the literature, bacteriological examinations are positive in only 25% of CSF samples and 35% of tuberculoma tissue specimens, and results may take from 10 days to eight weeks. Consequently, negative bacteriological findings do not ruled out a diagnosis of tuberculomas.1,13,14 To the best of our knowledge, our patient was the first case of CST that tuberculous bacilli were absent, and cultures from the excised lesion were negative. Indeed, in contrast with the previous reports, there was no any evidence of extrapulmonary involvement. Also, results of culture for M. tuberculosis even in the CSF and the brain lesion were negative. The summary of previously published reports of CST are presented in Table1. ACCEPTED MANUSCRIPT RI PT Hence, in a majority of cases of CNS tuberculomas, the diagnosis was reached only after surgical biopsy of the lesion, often due to suspicion of meningioma.1,10-13 Indeed, when the diagnosis is not conclusive, a tissue biopsy is recommended to rule out other differential diagnoses (most often include meningiomas, lymphomas, metastases, and inflammatory diseases, for CS location). According to reported cases, timely treatment can prevent not only the progression of the disease but also a complete remission of the symptoms of the patient was expected. Conclusion Conflict of interest statement M AN U SC Our report indicated that CSTs is a very rare presentation of brain TB; however, regarding the ability of tuberculoma to mimic a brain neoplasm, makes tuberculomas an always suspected in the differential diagnosis. While diagnosis is difficult and often delayed, a careful search for extracranial sites of disease can lead to earlier and safer histopathological confirmation. Anti-TB therapy is effective in these cases, and adjunctive steroids are frequently included, but long-term clinical and radiological follow-up examinations are essential to securing a good outcome. References TE D The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EP 1. Morris JT, Joyce MP. Central nervous system tuberculoma presenting as a cavernous sinus tumor. Clin Infect Dis. 1992;15:181–182. AC C https://doi.org/10.1093/clinids/15.1.181 2. Phookan G, Towns GM. Tuberculoma of the cavernous sinus – a case report. Br J Neurosurg. 1995;9:205–207. https://doi.org/10.1080/02688699550041566 3. Bafna S, Lee AG. Presumed tuberculosis presenting as a cavernous sinus syndrome. J Neuroophtalmol. 1997;17:207–208. https://doi.org/10.1097/00041327-199709000-00014 ACCEPTED MANUSCRIPT PMid:9304538 https://doi.org/10.1097/00006123-199801000-00040 PMid:9442521 RI PT 4. Grayeli AB, Redondo A, Salama J, Rey A. Tuberculoma of the cavernous sinus: case report. Neurosurgery. 1998;42:179–181. SC 5. Goel A, Nadkarni T, Desai A.P. Tuberculoma in the Meckel's cave: a case report. Neurol India. 1999;47(3):238–240. M AN U PMid:10514587 6. Al Soub H, Al Alousi FS, Al-Khal AL. Tuberculoma of the cavernous sinus. Scan J Infec Dis. 2001;33:868–870. https://doi.org/10.1080/00365540110027268 TE D 7. Rebai R, Boudawara MZ, Bahloul K, Chabchoub I, Chaari S, Boudawara T. Cavernous sinus tuberculoma: diagnostic difficulties in a personal case. Surg Neurol. 2001;55:372–375. https://doi.org/10.1016/S0090-3019(01)00474-8 EP 8. Hui AC, Wong WS, Wong KS. Cavernous sinus syndrome secondary to tuberculous meningitis. Eur Neurol. 2002;47:125–126. https://doi.org/10.1159/000047966 AC C PMid:11844904 9. Yanardag H, Uygun S, Yumuk V, Caner M, Canbaz B. Cerebral tuberculosis mimicking intracranial tumour. Singapore Med J. 2005;46:731–733. PMid:16308650 10. Kesavadas C, Somasundaram S, Rao RM, Radhakrishnan VV. Meckel's cave tuberculoma with unusual infratemporal extension. J Neuroimaging. 2007;17:264–268. https://doi.org/10.1111/j.1552-6569.2007.00095.x ACCEPTED MANUSCRIPT PMid:17608916 RI PT 11. Boutarbouch M, Arkha Y, Gana R, El Maquili MR, Bellakhdar F. Tuberculoma of the cavernous sinus mimicking a meningioma: case report and review of the literature. J Neurol Sci. 2009;278:123–126. https://doi.org/10.1016/j.jns.2008.11.022 PMid:19126443 PMid:24381801 PMCid:PMC3872644 M AN U https://doi.org/10.4103/2152-7806.123203 SC 12. Jaimovich SG, Thea VC, Guevara M, Gardella JL. Cavernous sinus tuberculoma mimicking a neoplasm: case report, literature review, and diagnostic and treatment suggestions for tuberculomas in rare locations. Surg Neurol Int. 2013;4:158. 13. Kumar VR, Madhugiri VS, Verma SK, Barathi SD, Yadav AK, Bidkar P. Tuberculoma of the Cavernous Sinus and Meckel's Cave in a Child. Pediatr Neurosurg. 2013;49(6):369-73. TE D PMid:25428440 14. Haque MR, Chowdhury FH, Islam MS, Kawsar KA, Haque AM. Tuberculomas in the cavernous sinus, temporal lobe and basal subarachnoid spaces. Journal of Medicine. 2012;13(1):75-6. EP https://doi.org/10.3329/jom.v13i1.10056 AC C 15. Kapadia S, Patrawalla A. Extrapulmonary tuberculosis presenting as a cavernous sinus syndrome: Case report with review of existing literature. IDCases. 2014;1(4):97-100. https://doi.org/10.1016/j.idcr.2014.10.010 PMid:26839786 PMCid:PMC4735080 16. Intusoma U, Anuntaseree W, Pruekprasert P, Janjindamai S, Vasiknanonte P. First case report of cavernous sinus tuberculoma in a child. Journal of Pediatric Neurology. 2007;5(2):15760. ACCEPTED MANUSCRIPT 17. Konar MC, Ghosh T. Tuberculoma of Cavernous Sinus-An Atypical Presentation of Neurotuberculosis with Review of Existing Literature. Med Sci. 2016;5(11):85-8. https://doi.org/10.1590/S0004-282X2003000500028 SC PMid:14595496 RI PT 18. Gasparetto EL, Tazoniero P, Carvalho Neto Ad. Disseminated tuberculosis in a pregnant woman presenting with numerous brain tuberculomas: case report. Arquivos de neuropsiquiatria. 2003;61(3B):855-8. 19. Ogunrin A, Adeyekun A. Multiple intracranial tuberculomas in an HIV-negative 28 year old male-a case report. Nigerian journal of clinical practice. 2007;10(3):262-5. M AN U PMid:18072459 AC C EP TE D 20. Sakuma R, Jin K, Nagai M, Kinpara T, Shiga Y, Fujihara K, et al. A case of multiple intracranial tuberculoma diagnosed by open brain biopsy. Rinsho shinkeigaku= Clinical neurology. 1997;37(10):895-9. ACCEPTED MANUSCRIPT Table 1: Summary of previous CST reports in existing literature 33 M Headache, orbital pain, diplopia, facial pain, ptosis, ophthalmoplegia Bafna et al. [3] 65 F Periorbital pain, ptosis, ophthalmoplegia on right M Headache, orbital pain, left eye ptosis, left upward and medial gaze deficit. hemifacial hypesthesia F Headache, left facial paresthesia, left gaze diplopia, wasting of temporalis & masseter on the left, left CN V & VI deficit Grayeli et al. [4] Goel et al. [5] 48 35 Neg Operative removal revealing granulomas Pos Neg HRZ+ Pyridoxine Neg Neg Operative removal revealing granulomas Pos not mentioned HRZE Pyridoxine Neg Pos (cervical LN) Cervical LN biopsy Pos Pos HRZE + Methylprednisolon e Pos Neg AC C Phookan et al. [2] Diagnostic approaches Neg Al Soub et al. [6] 44 M Headache, periorbital pain, ptosis, ophthalmoplegia Rebai et al. [7] 44 F Headache, right ptosis, horizontal diplopia, AFB Smear Blood culture Extrapulmonary involvement RI PT F Orbital pain, ptosis, facial numbness, vision blurred Pulmonary involvement SC Initial presentations M AN U 42 Gender Pos (apical macronodolar hypodensities) TE D Morris et al. [1] Age, y EP Author (s) Operative removal revealing granuloma, CXR with sequelae of old TB Operative removal revealing tuberculoma Neg Pos Pos (lung infiltrate on CXR) Sputum culture Pos Pos capsulated Biopsy lesion (en- of Treatment protocol Outcome + Complete resolution of eye deficits, continued CN VII palsy Improved eye deficit at 2yrs but not resolved Partial improvement of ptosis and motility at 6 wks, imaging improvement HRE Complete resolution improved imaging not mentioned ATD for 18 mos Complete resolution improved imaging Pos Pos HRZ+ Pyridoxine for 2 mos, then HR for 10 mos, Prednisolone for 1mo Complete resolution improved imaging not mention not mentioned HRE Complete resolution Pos Pos Pos with with with with ACCEPTED MANUSCRIPT et Boutarbouch et al. [11] Jaimovich al. [12] 29 45 et Kumar et al. [13] M M 45 F 11 F Headache, periorbital pain, left hemifacial neuralgia, diplopia, ptosis, lateral gaze palsy Neg Neg Neg Neg Neg Headache, right ptosis, right hemifacial hypoesthesia, right ophthalmoplegia Right hemicranial headache, diplopia, numbness of the right side of her face, SC M Operative Operative removal revealing granuloma Operative removal revealing tuberculoma M AN U Kesavadas al. [10] 36 performed revealing tuberculoma Neg TE D Yanardag et al. [9] M EP 48 Neg AC C Hui [8] Headache, double vision, right eye abduction deficit, absent right corneal reflex, right eye ptosis, right CN III & IV & V, &VI deficits Headache, ptosis, diplopia, medial upward and lateral left gaze deficits, hemifacial hypoaesthesia in CN VI area Left-side facial numbness, decreased taste, right upper & lower extremity hypotonia weakness, left CN V sensory deficit, left temporalis & masseter wasting pleurisy) ed RI PT right CN III & V &VI deficits Neg Neg Neg Neg Pos (mastoid air cells) CSF lymphocytos is, operative removal revealing granuloma CSF lymphocytos is, operative removal revealing granuloma Operative removal revealing granuloma Operative removal revealing granuloma improved imaging ATD for 12 mos Residual right abducens nerve palsy HRE MR improved at 2 months; symptoms improved at 4 months Pos ATD for 4 mos Complete resolution with improved imaging Pos HRE for 3 mos then HR for 9 mos Complete resolution with improved imaging not mention ed Pos HRZE for 2 mos then HR for 4 mos + Dexamethasone for 8 wks not mention ed not mentioned Pos Pos Pos Pos Pos Pos HRZE for 18 mos Complete resolution improved imaging Complete resolution improved imaging with with ACCEPTED MANUSCRIPT Konar et al. [17] 3 4 M Sudden onset of highgrade fever, severe headache along with periorbital edema, bilateral proptosis, ptosis of both eyes, retroorbital pain, two episodes of generalized tonic-clonic convulsions Neg not mention ed not mentioned SC F Ptosis, medial gaze palsy of right eye, mild proptosis, 4 mm nonreactive pupil Operative removal revealing granuloma Neg Pos (subcarinal LN involvement) Pos Pos (lung infiltrate on CXR) Neg Quantiferon 1-GOLD test positive, biopsy of the subcarinal LN revealed granulomas & Pos for culture Presumed diagnosis, abnormal CXR, Pos culture M AN U F Diplopia, headache, photophobia, ptosis, lateral gaze palsy, diminished medial & downward gaze, facial hypoesthesia Neg TE D Intusoma et al. [16] 48 M EP Kapadia et al. [15] 35 Headache, right-sided ptosis, CN III palsy of right side AC C Haque et al. [14] RI PT right ear purulent discharge and hearing loss Pos (cervical LN) Biopsy of cervical LN revealed granulomas & Pos for culture not mention ed Pos Pos Pos Pos Pos ATD+anti convulsions for 18 mos HRZE + L for 3 mos, HR + L for 1 mo+ HR for 8 mos + Prednisolone Ocular symptoms improved within 4 wks with improved imaging at 18 mos Ocular symptoms improved rapidly with near complete resolution on MRI at 1 mo ATD for 12 mos Complete resolution with improved imaging ATD for 12 mos+ Dexamethasone for 7 days+ prednisolone for 7 wks Gradual reduction of periorbital edema with regression of proptosis within five days, the signs of CN affection resolved within two wks, the leftsided weakness persisted but was gradually improving ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT F: Female; M: Male; Pos: Positive; Neg: Negative; CN: Cranial nerve; LN: Lymph node; HRZE: [H =Isoniazid, R =Rifampicin, Z=Pyrazinamide, E =Ethambutol]; L: Levofloxacin ; ATD: Antitubercular drugs ; AFB: Acid Fast Bacilli; mo(s): Month(s) ; yrs: Years ; wks: Weeks AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT Figure-1. Brain CT with (A) and without contrast (B) demonstrated negative findings. TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP Figure-2. MRI of the patient. Axial view of sella showed a lesion in the right parasellar which occupied right cavernous sinus on T1weighted (A) and T2-weighted (B) images. Intravenous gadolinium administration demonstrated a lesion with homogeneous enhancement on the T1-weighted image (C). TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP Figure-3. Photomicrographs of the removed tissue specimen showed granulomatous inflammation with (A) and without (B) caseous necrosis (arrowhead), hematoxylin and eosin staining (original magnification 40x) AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT ACCEPTED MANUSCRIPT Figure-4. Brain MRI of the patient revealed no any lesions after 1-year follow-up. A: T1-weighted AC C EP TE D M AN U SC RI PT without contrast; B: T1-weighted with intravenous contrast; C: T2-weighted; D: T2-weighted FLAIR sequence ACCEPTED MANUSCRIPT RI PT SC M AN U TE D • EP • Tuberculosis as the global concern could affect any part of the nervous system; however, cavernous sinus tuberculomas (CSTs) is a rare condition. Both imaging and bacteriological studies provide diagnosis of CST. While in some cases, bacteriologic samples may be negative for Mycobacterium tuberculosis. We describe the first case of CST that tuberculous bacilli were absent, and cultures from cerebrospinal fluid and the excised mass, even M. tuberculosis DNA assay were negative. AC C •