Spinal Cord Syphilitic Gumma Presenting with Brown-Séquard

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Annals of Clinical & Laboratory Science, vol. 49, no. 2, 2019 265 Spinal Cord Syphilitic Gumma Presenting with Brown- Séquard Syndrome: A Case Report and Literature Review

Yin-Hui Huang1,* , Qing-Xiao Shi1,*, Mian-Mian Xu1,*, Chuan-Zhen Chen1,*, Mei-Li Yang2,*, Jun-jing Li3,*, Ya-Fang Chen2,*, Zhi-Qiang Lin1,*, and You-Yu Lin4

1Department of Neurology, Jinjiang Municipal Hospital, Jinjiang, 2Department of Neurology, Second Affiliated Hospital of Fujian Medical University, Quanzhou, 3Department of Neurology, Quanzhou First Hospital, Quanzhou, and 4Department of Neurosurgery, Jinjiang Municipal Hospital, Jinjiang, Fujian, China

Abstract. Background. Spinal neurosyphilis manifesting as a solitary syphilitic gumma is exceedingly rare. There are non-specific imaging findings and challenges in the diagnosis of spinal syphilitic gumma, which could be easily misdiagnosed as tumor lesions and require surgical resection or biopsy. Clinical Presenta- tion. We report the case of a 45-year-old female patient who was diagnosed with Spinal syphilitic gumma. Our case is the first reported case of spinal cord syphilitic gumma with intradural-extramedullary and intramedullary involvement. Conclusion. Spinal syphilitic gumma exhibits diverse clinical manifestations, lacks specific imaging features, accompanied by the patient's history deliberately concealed. Since clinicians do not have sufficient knowledge about such rare cases, misdiagnosis and missed diagnosis will be likely. When there is clinical suspicion for spinal syphilitic gumma, clinicians should pay close attention to relevant medical history, carry out a comprehensive physical examination and specific serological tests and cerebrospinal fluid (CSF) analysis. In summary, in cases with stable neurologic conditions, a trial administration of intravenous penicillin with follow-up imaging may be the optimal treatment option, and in cases with rapid progression or acute exacerbation, a surgical resection together with systemic antibiotic treatment for syphilis after surgery may be the best treatment strategy.

Key words: neurosyphilis, Spinal cord gumma, spinal cord.

Introduction Case Report

Neurosyphilis is a clinical syndrome caused by A 45-year-old woman was admitted to the Neurology Treponema pallidum (syphilis) infection of the department with complaints of right lower limb weak- nervous system (which involve either the brain) the ness, left lower limb numbness for 10 days in October th spinal cord or meningeal blood vessels. Spinal neu- 26 , 2015. She had no history of hypertension, diabetes mellitus or coronary artery disease, also of tuberculosis rosyphilis manifesting as a solitary syphilitic gum- or AIDS or sick contacts, and denied feculent sexual life ma is exceedingly rare; Only about 8 cases have history. Neurologic examination revealed muscle been described worldwidely [1-8]. There are non- strength of grade 3/5 in right lower extremities and loss specific imaging findings and challenges in the di- of superficial sensation of grade 3/10 below the umbili- agnosis of spinal syphilitic gumma, which could be cus on the left side, Grade 3 ankle and knee hyperreflexia easily misdiagnosed as tumor lesions and require on the right side, positive Babinski sign and Chaddock surgical resection or biopsy [9]. Therefore, we re- sign. Syphilis serology showed a rapid plasma reagin port a case of spinal syphilitic gumma and review (RPR) test positive with a titer of 1:2 and the T. pallidum the previous relevant published literature to in- particle agglutination test positive with a titer of 1:43.89. crease awareness of the disease. Tests for HIV and hepatitis B and other routine blood tests were negative. A CSF examination was not performed due to the patient's lumbar puncture refusal. *These authors contributed equally to this work. Address correspondence to Mrs. Ya-Fang Chen and Mr. Mei-Li Yang; Spinal MRI showed an irregular nodule at the T8 level Department of Neurology, Second Affiliated Hospital of Fujian combined intradural-extramedullary and intramedullary Medical University, Quanzhou, Fujian, China, No.34, Zhongshan North Road, Quanzhou City, Fujian Province, China; phone: +86 involvement. The nodule had a slightly hyperintense sig- 0595 85659153; fax:+86 0595 85659153; e mail:251045413@ nal on T1-weighted imaging and a heterogeneously hy- qq.com. perintense signal on T2-weighted imaging, which was

0091-7370/19/0200-265. © 2019 by the Association of Clinical Scientists, Inc. 266 Annals of Clinical & Laboratory Science, vol. 49, no. 2, 2019 A preoperative diagnosis of space occupying lesion in thoracic spinal canal was made, and a surgical lesionectomy was performed via a posterior midline approach. The lesion was found to be a solid mass at the level of T8-T9 combined intradural-extramedullary (about 3×1.5×0.5cm in size) and intramedullary (about 1.8×1.3×0.6cm in size) involvement. The lesion didn’t have a clear borderline and coating, with medium hardness, had medium hardness and not so rich blood supply. It lay at the lateral side of spinal canal. The lesion was located in the spinal canal laterally, bound at the nerve root with severe adhesions. Lesion debulking was performed. A diagnosis of the lesion could not be made on the intraoperative frozen section, which showed spindle cells. 5 days later, pathologic examination of paraffin section revealed granulomatous inflammation with small areas of caseous necrosis, and multinucleated giant cells infiltration, surrounded by large numbers of lymphocytes and small numbers of neutrophils. It Figure 1. The nodule had a slightly hyperintense signal on also showed swelling and hyperplasia of some vascular T1-weighted imaging and a heterogeneously hyperintense endothelial cells with massive infiltration of lympho- signal on T2-weighted imaging, was significantly and ho- cytes and plasma cells around the blood vessels. A sus- mogeneously enhanced on Gadolinium-enhanced MRI pected diagnosis of syphilis infection was made based (Gd-MRI). on patient history. Immunohistochemical analysis revealed immunopositivity with glial fibrillary acidic protein, myelin basic protein, neurofilament protein, CD3, CD45RO, and CD68 but was negative for peri- odicacid Schiff and CD56. Acid-fast staining was negative; further Warthin Starry staining confirmed spiro- chete infection. A definitive diagnosis of spinal intramedullary gumma was made (Figure 2). And the treatment for syphilis was administered with intravenous penicillin G (19.6 million U/day, and 4.9 million U QID) for 14 days, then intramuscular benzathine penicillin G (2.4 million U QW) for 21 days.

After the treatment, the patient’s right lower limb weakness and left lower limb numbness were improved. Figure 2. Pathological examination of paraffin section re- After discharge, the muscle strength of her legs im- vealed granulomatous inflammation with small areas of ca- proved to grade 4/5. Three months later, she has com- seous necrosis, and multinucleated giant cells infiltration, pletely recovered from her illness. surrounding by large numbers of lymphocytes and small numbers of neutrophil. It also showed swelling and hyperplasia of some vascular endothelial cells with a massive infil- Literature Review tration of lymphocytes and plasma cells around the blood vessels. PubMed and Embase searches were performed between the years of 1960 and 2017 based on the significantly and homogeneously enhanced on following keywords: 1. (spine OR spinal) AND Gadolinium-enhanced MRI (Gd-MRI). The nodule size (approx) was 1.8×0.7×0.9cm. Adjacent meninges had (gumma OR syphilitic granuloma); 2. (spine OR cord-like enhanced, and contiguous spinal cord became spinal) AND (syphilis OR syphilitic). Seven case thicken with a striped slightly hyperintense signal on T2- reports of spinal syphilitic gumma were identified, weighted imaging. A radiological diagnosis of spinal cord including 3 English case reports [1-3] and 5 non- vascular malformations or space-occupying lesions with English case reports in Spanish, French, rich blood supply at the T8 level was made (Figure 1). Portuguese, and Chinese [4-8] (Tables 1-3). Role of platelet microparticles as biomarkers 267 R, al , le. se er, RP st on ng ent s; nt en si st lab ty ra WI ema ri , ng , le si , ce ru nt em ai ra al nt ri ed ent al T1 ri ri s vi , , en , , in nt se nc co ni al WI st al pe t av em pe l se nt ou d sp cy en ra ha Co ra th WI WI WI ni on st ion ra T1 th ty oi nc no hy en A, ne an nt en ac si A; en rt si nt A ra is ra wi st T1 wi N/A nt T2 T2 ha tr oi ge ly le , A, N/ ht phe st ac , nt en N/ fi ci po ri ra is N/ y ty ri Co st in us en ty ri ty ig , tr al , ra cs it N/ si , nt mo co le de WI nt pe si ra si pe a. al th ti eo st l pe in br ty ty in nt oi ns en d; ho , , , nt is si si hy no dd WI ni T1 ra ra wi Co WI is ten sp er, ten te em co nt ui d , ra en en ly nt ter s in mi fl t t; Co in in ty nt ri T2 ty ty WI WI WI mu ed T2 al an phe l ac si e nt nt ht si si er ac co ce A ou ent ent ent en en A pe po po ri in terogen al tr T1 T1 T1 l ty im oi oi ig na ar ns en nt en en yp ne se si sp hy N/ pe is sl hy N/ hy in is ra he n em em em em em st st st on te pi ca ch nt nt , , ,h , , , , , , , , od , ge si en en a; ra ra ra fi in nc nc nc nc nc ri ri os is ures ma al le phe nt nt , nt nt nt WI WI WI WI WI WI WI WI WI WI WI br WI mo pe po pe ha ha ha ha ha at em ri ri gni oi oi hu gn re , T1 T1 T2 en T1 Si en T1 N/A N/A T1 en pe T1 hy pe T2 Co T1 CT is en ed Co Fe T1 T2 is hy ho si en Co hy T2 ce IV , A) ry ;H SF la N/ s; ry ry ry hy ul ;C ls la la la ru st ai ap ed ul ul ul gy te on on et gr ed ed ed si si at at am (d ry ate le le tr mo am am am - to on on l ul rd in ry ry l tr tr tr to al si si ra ve co l d la la ng le le ve ex ex ex ur le ed bo g ci l ve ul ul le al an al al al al al ad t ut le in La 9 ve in L1 ed ed tr ur ur ry ur ur ur gh le ag -T -3 sp 2- mp la in ch ri ad ad ad ad ad am am l l l ul l ar Im tr tr co in tr tr tr tr tr T1 T3 T2 ed in , ve ve s ve se ve ed in in in ex in ex in at at T8 at at on in le le le le on on ti Re al al al al al al al CT am si si on on on on mb -8 e -5 ca in in in in in in in C3 C5 tr g; le le si si si si as le Sp le Co ex Sp le Sp Sp Sp at T6 1 Sp at Lo Sp 3 le T4 in se ag Di im al d re te ne hs hs hs hs s gh on s Ve ys ys ei ti ar nt nt nt nt , ys ar ra ye da da -w mo mo mo da mo RL 10 10 10 2 ye 3 Du T2 , VD ; WI , g 2 st a, e , 2 e ia le T2 bi y 2 in nc t eg nc n te es g; or pl pa ba a gh , 2 ba io pho in a. nc ra ns ri gi ia at ur ur me me to ck , e ag se ba pa st st in eg ro ro ple in ba mm , nc di ur pl di im ut pho ra e d in pa y gia, st y ra gl Gu ba pa s nc synd synd an pa di ea, or ted or ck ag pa ur , al ple , ba us ic ns st rd rd ns er, gh ck om ra ba he in pin ur se di ei se icle na d ua ua ter ba ac pa st , rt pa ic mpt -w d ould nc s tras e, ck di he Séq Séq gia, gia, pa er Sy sh ter es hi an In y T1 ar an ch ba le , t ld t ple nc or I, ka th ap er se um es adac ck mb akn ou ra d sp own- own- hi ns tr wi id 1W Pa Br se we Bac an Lu Ch Br He sp Sh te low On Ne s ll se ;T pa le a Ca lab x in em ai F F F M M F M F Se F es on av ur t ep at rs) no Tr e Fe ea A, A, 49 45 48 51 51 25 40 47 Ag (y 65 ng N/ PP e e h h h h agi sh ;T e; es es is e is is is ch e u li st al Im in in gl gl gl ag an rt es en te d ve. En En Po gu Ch Ch Fr En Sp gu Eng Lan ti fem in an si 3 , F, ag 1 al ; po al ic re le 014 is 016 er in 8 ,2 li 5 r lt , 4 ,2 d ma ma Cl al , na et al sa al su as an se 013 al 1. a-O 000 012 es et M, pl et g ma 7 6 e ca 2 ,2 : t re i et in ,2 ,2 d r as an ou se te bl Qu 09 es ng et al al 13 79 an pi *T Ou No Ti ra 20 Coll 19 Wu Zh El et Dh et Mol 20 Ca Ya Ta Zh 268 Annals of Clinical & Laboratory Science, vol. 49, no. 2, 2019

Discussion 3 3 3 3 few mm mm mm

ls Treponema pallidum invades the central nervous sys- 4/ ry /mm 0/ 5/ CSF Cel Ve 76 N/A 50 N/A 16 N/A 48 N/A tem, causes occlusive arteritis or periarteritis, leads to a

L) granulomatous lesion which oppresses nervous tissue ose F g/d A A A A A A

uc and causes neurological symptoms [1,10]. There are CS Gl (m 57 25 N/ 46 N/ N/ N/ N/ N/ only 6 cases of syphilitic gumma found in 15,000 au-

* topsies. Isolated spinal syphilitic gumma is extremely ed L) in at rare, only seen in some case reports. Thus, clinicians A te A A A 0* 2* 0 F g/d ev

N/ lack of knowledge about it, are likely to have a missed N/ 29 >2 79 N/ 50 El N/ CS Pro (m diagnosis or a misdiagnosis. We review the available

A) literature to describe clinical features, imaging studies,

N/ and laboratory findings of spinal syphilitic gumma to

ter increase the awareness. ti RL *( ve VD * * ti

A We summarized the clinical manifestations of the pub- A A A A si F 32 4* 16 N/ N/ 1: 1: Po 1: N/ N/ N/ lished cases, found that spinal syphilitic gumma may CS have following characteristics: (1) The age of onset: At A)

N/ the age of onset, 1 patient was aged 20–40 years, 7

ter aged 40–60, and one aged 60 years or over. Thus, mid- ti 0* PA

*( dle age seems to be the preferable age of onset for spi- s 48 ve TP st 0* 0, ti nal syphilitic gumma, since neurosyphilis can occur 1 F A A A A A si Te 64 8* >2 to 25 years after infection [11]. (2) The time of symp- CS 1: 1: 1: N/ N/ N/ N/ Po N/ ry

to tom onset: symptoms begun 1-30 days after infection ra * RL in 3 cases, 1-12 months in 4 cases, and 1-10 years in 2 A A A A A A A bo rum 32 Se VD 1: N/ N/ N/ N/ N/ N/ N/ La cases. Therefore, symptoms of spinal syphilitic gumma can occur at any time after the infection. (3) The site of the lesion: There were intradural-extramedullary le-

0* sions in 3 cases, extradural lesions in 2 cases, intramed- * 9 48 40 a. ullary lesions in 2 cases, intradural-extramedullary and 0, 80 ,2 PA A A A A A rum mm 43.8 >2 12 10 intramedullary lesion in our case. Thus, spinal syphi- Se TP 1: 1: N/ N/ N/ 1: N/ N/ 1: Gu litic gumma can occur in any region of the intraspinal * nal * space. As we know, our case is the first reported case of R A A A A A pi rum 64 2 32 8 Se RP 1: 1: N/ N/ N/ 1: N/ N/ 1: the lesion with intradural-extramedullary and intra- tras

In medullary involvement. Besides, we found that 2 cases

th were located in the cervical spinal canal, 6 thoracic, 1 wi

s lumbar. So we assumed that spinal syphilitic gumma st se ve ve ve ve ve ve

Te preferably affected thoracic spinal cord. (4) clinical Ca V gati gati gati gati gati gati A A A

in manifestation: The clinical manifestations of spinal HI Ne Ne N/ Ne N/ Ne Ne N/ Ne

ngs syphilitic gumma are highly variable. They include di 4 neck, shoulder, and back pain, tetraplegia, sensory dis- 8 5 2 012 turbance, Headache, nausea, photophobia, lower y Fin 013 ,2 000 013 or al ,2 3 ,2

,2 backache, paraplegia, sensory disturbance, Brown- 6 1 7 an et al al r

014 Séquard syndrome, and so on. So syphilis has been borat 016 Ti 979 et ie 009 ,2 r ,1 ,2 d

La known as "the great imitator". In our case, spinal syph- al ,2 na et al sa al an se al 2. a-Ol es et et

g ilitic gumma presented with Brown-Séquard syn- ma e ca i et in r as an ou se bl Qu ng et drome, developed distally first, traveled more proxi- Ca Ya Dh Zh Ta Mol El Coll Wu Zh Ou mally. Nowadays there are only 2 cases reported. It can Role of platelet microparticles as biomarkers 269

Table 3. Treatment and Outcome in Cases with Intraspinal Gumma.

Case Treatment Follow-Up Outcome

Yang et al,20161 Complete lesionectomy +prednisone (20 mg/day) 29 months Partial improvement +aqueous penicillin G (24 million U/day for 14 days) Dhasmana Biopsy + prednisolone (40 mg/day for 3 days) 6 months Significant improvement et al,20132 +benzylpenicillin (24 million U/day for 17 days) Zhou et al,20143 Methylprednisolone+ aqueous penicillin G 4 years Complete recovery (0.2 million U/kg/day for 15 days), followed by benzathine penicillin (2.4 million U/week for 3 weeks) +complete lesionectomy Molina-Olier Lesionectomy+ceftriaxone sodium (2 g/day for 14 days) 6 months No improvement et al,20124 El Quessar Lesionectomy+penicillin G(dosage N/A) 10 months Partial improvement et al,20005 Colli et al,19796 Lesionectomy 18 months Partial improvement Wu et al,20097 N/A N/A N/A Zhang and Tian, Lesionectomy N/A N/A 20138 Our case lesionectomy+intravenous penicillin G 3 months Complete recovery (19.6 million U/day, and 4.9 million U QID) for 14 days, then intramuscular benzathine penicillin G (2.4 million U QW) for 21 days be easily misdiagnosed as extramedullary tumor. In the VDRL test is very specific (its sensitivity is 100%) for setting of a positive Treponema pallidum particle aggluti- neurosyphilis though its sensitivity is low. So it's re- nation test, the diagnosis of spinal syphilitic gumma placed by a more sensitive test such as RPR test (its sen- should take into account. sitivity is also 100%) [1,12-14]. A positive CSF-RPR- test makes the diagnosis of neurosyphilis. Although Magnetic resonance imaging of spinal syphilitic gumma TPHA test is highly sensitive, it can also yield false-neg- demonstrated isointense to hypointense signal on T1- ative results. A serum CSF-TPPA-titre >1:80 is a pre- weighted imaging, hyperintense signal on T2-weighted dictor for neurosyphilis, while a negative result can al- imaging, and nodular or ring-like enhancement on most rule out neurosyphilis. Overall, a combination of Gadolinium-enhanced MRI. It can also be seen in other serum and CSF laboratory tests can help diagnose or space-occupying lesions, such as glioma, metastases, tu- confirm a diagnosis of neurosyphilis. berculoma, sarcoma and fungal infection. The radio- graphic manifestation of spinal syphilitic gumma is non- We also analyzed the treatment and prognosis of the specific, so an imaging diagnosis of spinal syphilitic published cases, found that three patients with excellent gumma may be challenging. recovery were treated with high dose penicillin, and all patients benefited from intravenous penicillin treat- We analyzed laboratory tests of the published cases: found ment. High intravenous doses of penicillin should be some features as follows: (1) All the tests for HIV were used as first-line treatment for neurosyphilis including negative in the published cases while a data showed a dif- central nervous system gummas [15]. Some experts rec- ferent result that the incidence of neurosyphilis was rising ommended ceftriaxone as alternative therapy [16]. due to an increase in HIV-coinfected patients in recent Early diagnosis of neurosyphilis and appropriate antibi- years [12]. Thus, more research is needed on the relation- otic treatment can result in clinical improvement and ship between neurosyphilis and HIV-coinfection. (2) All assist in avoiding unnecessary surgery [17]. In summa- patients had a positive RPR, TPPA, VDRL test and CSF- ry, in cases with stable neurologic conditions, a trial ad- TPPA and -VDRL-test, while the titers ranged widely. ministration of intravenous penicillin with follow-up 270 Annals of Clinical & Laboratory Science, vol. 49, no. 2, 2019

imaging may be the optimal treatment option, and 4. Molina-Olier O, Tunon-Pitalua M, Alcala-Cerra G, Nino- Hernandez L, Moscote-Salazar L: Spinal cord compression in cases with rapid progression or acute exacerba- due to intraspinal syphilitic gumma in one patient. Clinical tion, a surgical resection together with systemic an- case. Acta OrtopMex,26:197-201 [in Spanish],2012. tibiotic treatment for syphilis after surgery may be 5. El Quessar A, El Hassani R, Chakir N, Jiddane M, Boukhrissi N: Syphilitic spinal cord gumma.J the best treatment strategy. Neuroradiol,27:207-210 [in French],2000. 6. Colli BO, Araujo LP, Martelli N, Barbieri Neto J: Intraspinal In short, spinal syphilitic gumma exhibits diverse syphilitic gumma causing spinal cord compression. Report of a case,Arq Neuropsiquiatr,37:197-201 [in clinical manifestations, lacks specific imaging fea- Portuguese],1979. tures, accompanied by the patient's history deliber- 7. Wu YW, Xiao Q: Analysis of 4 cases with misdiagnosed neurosyphilis and review of literatures. Chinese J Contemp ately concealed. So clinicians do not have sufficient Neurol Neurosurg, 9:494-498,2009. knowledge about such rare cases, misdiagnosis and 8. Zhang HW, Tian W: MRI findings of intraspinal gumma: missed diagnosis will be highly likely. When there is case report. Chinese J Med Imaging Technol,29:1347,2013. 9. Li JC, Mahta A, Kim RY: Cerebral syphilitic gumma: a case clinical suspicion for spinal syphilitic gumma, clini- report and review of the literature.Neurol cians should pay close attention to relevant medical Sci,33(5):1179,2012. history, carry out a comprehensive physical exami- 10. Agrons GA, Han SS, Husson MA:MR imaging of cerebral gumma. AJNR, 12: 80-81,1991. nation and specific serological tests and cerebrospi- 11. Lee CW, Lim MJ, Son D, Lee JS, Cheong MH, Park IS: A nal fluid (CSF) analysis. In summary, in cases with case of cerebral gumma presenting as brain tumor in a human immunodeficiency virus (HIV)-negative patient. stable neurologic conditions, a trial administration Yonsei Med J,50:284-288,2009. of intravenous penicillin with follow-up imaging 12. Merins V, Hahn K: Syphilis and neurosyphilis: HIV- may be the optimal treatment option, and in cases coinfection and value of diagnostic parameters in cerebrospinal fluid. Eur J Med Res,20:81,2015. with rapid progression or acute exacerbation, a sur- 13. Marra CM, Tantalo LC, Maxwell CL, Ho EL, Sahi SK, gical resection together with systemic antibiotic Jones T: The rapid plasma reagin test cannot replace the treatment for syphilis after surgery may be the best Venereal Disease Research Laboratory Test for neurosyphilis diagnosis. Sex Transm Dis,39:453-457,2012. treatment strategy. 14. Salamano R, Balleste R, Perna A, Rodriguez N, Lombardo D, García N: Cerebrospinal fluid examination may be useful References in diagnosing neurosyphilis in asymptomatic HIVþ patients with syphilis. Arq Neuropsiquiatr,74:128-132,2016. 1. Chenlong Yang, Guang Li, Jingyi Fang:Spinal Intramedullary 15. Li JC, Mahta A, Kim RY, Saria M, Kesari S: Cerebral syphi- Syphilitic Gumma: An Unusual Presentation of Neurosyphilis. litic gumma: a case report and review of the literature. Spinal Intramedullary Syphilitic Gumma, 95: 622. Neurol Sci, 33:1179-1181,2012. e17-e23,2016. 16. Yoon YK, Kim MJ, Chae YS, Kang SH: Cerebral syphilitic 2. Dhasmana D, Joshi J, Manavi K: Intracerebral and spinal cord gumma mimicking a brain tumor in the relapse of secondary syphilitic gummata in an HIV-negative man: a case report.Sex syphilis in a human immunodeficiency virus negative pa- Transm Dis,40:629-631,2013. tient. J Korean Neurosurg Soc,53:197-200,2013. 3. Zhou HJ, Zhan RY, Chen MT, Cao F, Zheng XJ: Solitary spi- 17. Darwish BS, Fowler A, Ong M, Swaminothan A, Abraszko nal dural syphilis granuloma mimicking a spinal meningioma. R: Intracranial syphilitic gumma resembling malignant Turk Neurosurg,24:288-291,2014. brain tumour.J Clin Neurosci,15:308-310,2008.