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Uncommon case of Mycobacterium bovis brain abscess complicated by suppurative fistula, and review of the literature

I. Panero, R. San-Juan, C. Eiriz, D. García-Pérez, I. Paredes, C. González, R. Recio, O. Carretero, A. Lagares, P.A. Gómez   Journal 69(10)Publication date 16/11/2019 ● Nota ClínicaViews 3728 ● Downloads 115 Castellano English

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[REV NEUROL 2019;69:417-422] PMID: 31713228 DOI: https://doi.org/10.33588/rn.6910.2019194

INTRODUCTION. Mycobacterium bovis is an infrequent cause of central nervous system tuberculosis in Spain, with few cases described in the literature. Since compulsory pasteurization of milk and implementation of eradication programs on infected cattle, human sporadic illness with this organism has dramatically declined in developed countries. CASE

REPORT. A 71-year-old immunocompromised male, who presented a calvarial lytic lesion. A craniotomy for the total resection of the lesion was performed and the microbiology results were positive for M. bovis, therefore antituberculous therapy was initiated. Despite of the correct treatment, the patient developed a tuberculous abscess that required an aggressive surgical management followed by a suppurative fistula. Based on the treatment of tuberculous lymphadenitis, we decided to perform a conservative management with antituberculous therapy (isoniazid + rifampicin + ethambutol + moxifloxacin + steroids during 12 months) and avoided new surgical cleanings of the surgical bed obtaining a good response and a good clinical evolution.

CONCLUSIONS. As far as we know, this is the first case reported of a suppurative fistula after the resection of a cerebral abscess caused by M. bovis, therefore, there is no report in the literature about the treatment of this complication.

Antituberculous therapy Calvarial lytic bone lesion Mycobacterium bovis Suppurative fistula Tuberculoma Tuberculous abscess Infecciones

Introduction


Central nervous system (CNS) infections caused by Mycobacterium bovis are rare, with few cases described in the literature. Most of the reported cases have been related to the bacillus Calmette-Guérin (BCG), a live attenuated strain of wild type M. bovis, that is used in the treatment of superficial bladder carcinoma and widely used for vaccination against tuberculosis [1]. Report of cases of CNS infection due to M. bovis wild type is exceptional.

M. bovis is one of the seven species included in the named M. tuberculosis complex [2]. Since compulsory pasteurization of milk and implementation of eradication programs on infected cattle, human sporadic illness with this organism has dramatically declined in developed countries. However, in other nations with less rigorous eradication programs or consumption of unpasteurized milk, morbidity and mortality due to M. bovis is still a significant problem [3].

We report an uncommon case in an immunocompromised patient, who presented sporadic calvarial lesion, followed by brain abscess and suppurative fistula caused by M. bovis.
 

Case report


A 71-year-old male was attended at the emergency room due to a traumatic brain injury (TBI) after an accidental fall. A liver transplant had been performed one year before due to intrahepatic portal hypertension related to nodular regenerative hyperplasia. The immunosuppressive treatment included prednisone, tacrolimus, and mycophenolate mofetil. He also received trimethoprim-sulfamethoxazole prophylaxis.

Cranial axial computerized tomography (CT) was performed, which revealed a calvarial lytic bone lesion, with no other relevant findings (Fig. 1).

 

Figure 1. a) Axial computerized tomography of the head: bone window reveals a small focal lytic area; b) Cranial MR: sagittal T1-weighted images showed epidural collection that infiltrates and encroach the sagittal superior sinus; c) Postsurgical cranial MR: sagittal T1-weighted images showed an hipointense lesion, exist a hydroaerial level inside the formation and presents perilesional edema; d) Axial T2-weighted images showed an isointense lesion with a hyperintense contour; e) Sagittal T1-weighted images showed a ring enhancement lesion.






 

Physical and neurological examination was unremarkable, but given the medical history and the radiological findings, the study was completed with a cranial magnetic resonance image (MRI). MRI showed a lytic lesion in the right frontal bone with a small epidural collection (Fig. 1). A biopsy of the cranial vault was programmed. The patient presented again to the emergency room with fever and seizures, and, finally, a craniotomy was performed. The lesion was more yellowish and softer than the remaining bone tissue, and a minimal epidural collection of seropurulent appearance was found below the bone, which was removed without injuring the duramatter.

An urgent PCR (Xpert MTB/RIF assay) for M. bovis was positive in surgical samples and therefore antituberculous therapy was initiated composed by four antibiotics: pyranzinamide + isoniazid + rifampicin and ethambutol. The biopsy of the bone tissue revealed chronic granulomatous lesion. TC-body was performed without findings and blood cultures were sterile. The patient’s purified protein derivative test was negative. Finally, two weeks later, cultures yielded growth of M. bovis, susceptible to all first-line tuberculostatics, with the exception of pyranzinamide.

Ten days after surgery, the patient presented fever, drowsiness, disorientation and headache. A new MRI showed a right frontal lobe intra-axial lesion, with thick wall, and ring-enhancing mass with peri­lesional edema. These findings were compatible with a tuberculoma or tuberculous abscess or a post-surgical pyogenic abscess (Fig. 1). Initially, conservative management was decided. Ethambutol was removed from the treatment and moxifloxacin was added, due to its greater sensitivity to M. bovis. After twenty days of admission the patient was asymptomatic with a control MRI showing no significant changes. Few days later, he was discharged under treatment.

Two months after a cranial MRI was performed showing a similar size and the patient remained asymptomatic. The patient was readmitted to the emergency department two months later because of headache, mild drowsiness and gait imbalance. A new MRI was performed that revealed an increase of the size of the lesion and more edema with mass effect (Fig. 2). Since the clinical and radiological findings worsened, a new craniotomy with resection of the lesion was performed. The tumor outcropped in the cortex and infiltrated the superior sagittal sinus, the appearance was violaceous and had a hard-gummy consistency. An en bloc-resection was performed. The biopsy showed a lesion composed of fibrous tissue with activated fibroblasts and inflammatory infiltrate with lymphoplasmacytic predominance. A new Xpert MTB/RIF assay was positive in surgical samples although the mycobacterial culture was sterile. The patient was discharged without complications and continued with isoniazid and rifampicin.

 

Figure 2. Typical MR appearances of a tuberculous abscess: a) Axial T1-weighted image showed a hypointense mass (37 × 24 mm) occupying the right frontal lobe with isointense periphery with perilesional edema; b). Gadolinium-enhanced axial T1-weighted image showed a lesion with a thick capsule with an intense peripheral enhancement and central non-enhancing caseus core; c) Gadolinium-enhanced sagittal T1-weighted showed that the lesion reaches the previous lytic lesion of the calvarian.






 

One month later he was reassessed in the emergency department because of dehiscence of the craniotomy wound with output of seropurulent material. So, an urgent surgical repair was performed. So, moxifloxacin was newly added to the tuberculostatic treatment. Nevertheless, in the postoperative course, the wound presented a new dehiscence due to the reappearance of a suppurative fistula. A control MRI showed good radiological evolution, with no abscess and less edema (Fig. 3). A new intervention was carried out to place a drainage in the porencephaly cavity and was kept for three weeks. Even so, the wound presented a new dehiscence requiring another surgery with a rotational flap of the dermis in order to repair the skin defect of the wound. Finally, 3 months later the patient could be discharged with isoniazid and rifampicin, being moxifloxacin discontinued.

 

Figure 3. Upper images showed a cranial RM performed 1 month after the last surgery T1-gadolinium-enhanced sagittal (a) and axial (b, c) images showed a poroencephaly cavity with anfractuous edges that enhance contrast, disappearance of the abscess, but it continues presenting hyperintensity of signal that has expanded to the left hemisphere. Lower images showed a cranial performed after one year with antituberculous therapy. T1-gadolinium-enhanced axial (d) and sagittal (e, f) images showed a decrease of the poroencephaly cavity with small subdural collections with peripheral contrast enhancement and minimal remains of edema.






 

The subsequent clinical and radiological evolution was favorable (Fig. 3). There were no further complications in the wound and the tuberculostatic treatment was kept for 12 months.
 

 

Discussion


We presented an unusual case of M. bovis CNS infection with an unfavorable outcome despite adequate treatment. Complications following BCG vaccination or carcinoma bladder treatment have been infrequently described; and only a few cases of CNS infection have been reported [4]. This situation is favored in patients with immunodeficiency. In our case, the patient was a solid-organ transplant recipient. Our patient had never lived with animals and even less with cows; he had always taken pasteurized milk, had not received treatment with attenuated BCG for bladder cancer; but was vaccinated for tuberculosis with attenuated BCG in childhood.

Initially, the patient presented a lytic lesion in the frontal calvarian bone. Calvarial tuberculosis (CTB) is a rare entity. It happens in only 0.01% of all patients with mycobacterial infections. The incidence of CTB, however, seems to be on the rise, especially in developing countries due to immunodeficiency, malnutrition or poor socio-economic conditions. In 1842 Ried et al reported the first case in the literature [5]. Since then, a few cases-series have been reported. Among all active tuberculosis cases, approximately 1-2% have involvement of the skeletal system of which only 0,2-1,3% constitute CTB [6]. Raut et al reported 42 cases of CTB over a 10-year period and concluded that it was an entity more frequent in young people [7]. The frontal and the parietal bones are more commonly involved [5,8]. It is believed that skull affectation occurs as a consequence of the haematogenous seeding of bacilli to the diploe from a primary tuberculous infection elsewhere in the body.

Surgical intervention may be required, especially in cases with large extradural collections causing neurodeficits or large scalps swellings, but is not indicated for small lesions [6,9,10]. It is usually not possible to reach a conclusive diagnosis on the basis of imaging or symptomatology alone; being there­fore the surgery necessary for a microbiological or histological confirmation [5]. Other authors propose a radical debridement and subsequent medical therapy, obtaining in their series better rates of response and healing [10,11].

The post-surgical development of a frontal abscess was unexpected in our patient. Lymphatic and/or venous dissemination after the prior calvarian surgery is a possible explanation. Tuberculomas are relatively rare in the CNS, they account for 10% to 30% of intracranial masses in tuberculous-endemic areas. The most common manifestation of tuberculosis in the CNS is tuberculous meningitis, followed by tuberculomas and less frequent by a tuberculous abscess [12,13]. It is necessary to make the differential diagnosis of these last two entities. Normally, the clinical course of the tuberculoma is subacute, and presents headache, intracranial hypertension, seizures, and papilledema. The MRI showed an iso­intense to gray matter lesion on T1-weighted images and may have a slightly hyperintense rim. Tuberculous abscess presents with fever, headache and neurologic focal signs and the MRI showed a central area of hyperintensity on T2-weighted images and greater mass effect and edema [13].

The appearance of tuberculomas as a consequence of the start of tuberculosis treatment has been reported; this worsening course is known as ‘paradoxical response’ [2,12,14-19].

Nonetheless, the clinical-radiological evolution after four months of antituberculous therapy in our patient was not as expected, presenting clinical and radiological worsening. So, finally a surgery was performed. In the literature it is reported that initially a conservative management must be carried out and that surgery should be reserved for certain cases: when the diagnosis is in doubt, atypical imaging features, typical suspected tuberculoma that does not respond to empiric therapy or increase in size. Surgical treatment is also proposed in cases in which the patient presents clinical data of intracranial hypertension, focal neurological deficit or consciousness alterations [12]. In our case, we performed a microsurgical radical excision. After surgery the histopatological examination a lesion composed of fibrous tissue with activated fibroblasts and inflammatory infiltrate with lymphoplasmacytic predominance was observed; it must to be note that these characteristics are most typical in the tuberculoma than in the tuberculous abscess [12,13,20,21]. The staining was negative and nor growth was obtained in LJ cultures; however the Xpert MTB/RIF assay still showed positivity to M. bovis. It is reported in the literature that Xpert MTB/RIF presents a sensitivity of 50-55% and specificity of 95-100% in diagnosing tuberculosis [13,22].

Despite the correct antituberculous therapy the patient developed a suppurating fistula in the wound, which required multiple surgical repairs. It should be noted that in none of the surgical repairs the abscess cavity was cleaned, only the repair of the skin was performed, requiring in the third and he last surgery a cutaneous rotational flap. As far as we know, this is the first study describing a M. bovis brain suppurating fistula; and its management. It is known that M. bovis was historically a common cause of tuberculous lymphadenitis. Infectious Disease Society of America recommends surgical excision for cervical lymphadenitis only in unusual circumstances, and these circumstances are not explicitly defined [23-25]. Surgical excision should also be considered as an adjunct to antibiotic therapy for disease caused by drug-resistant organism or in those cases involving uncontrolled paradoxical upgrading reactions or fluctuant lymph nodes [23-29]. Management of this patient was partially decided based on the experience of the treatment of cervical lymphadenitis.

To our knowledge, only 10 patients with CNS infections due to M. bovis have been reported to date, most of them were M. bovis meningitis. Only seven patients developed a tuberculoma, as in our case; but in none of them they developed a suppurating fistula (Table) [1,3,21,30-34].

 

Table. Literature review.
 

Age (years)
/Sex

Clinical
presentation

Risk
factor

History of tuberculosis/
Vaccination

Brain CT/MRI

Treatment

Outcome/
Follow-up


Pedersen et al [30]

6/Female

Symptoms of increased intracranial pressure

Lymphoblastic leukemia

No/Vaccination five months before

Enhancing mass
(left temporal lobe)
+ ring enhancing

Craniotomy + isoniazid + rifampicin + ethambutol

Death,
10 weeks later


Heath et al [31]

29/Female

Fever, euphoric papilloedema, disartria, mild left hemiparesis

Hodgkin’s disease

Raw milk with
calcified abdominal lymphnodes

Multiple small
enhancing brain
lesions

Biopsy, quadruple antituberculous therapy a

Death,
6 weeks later


Guest et al [3]

31/Female

Headache,
neck pain, lethargy

No

No

Multiple
enhancing lesions

Biopsy, isoniazid + rifampicin + ethambutol

Death,
5 weeks later


Tardieu et al [32]

5/Male

Fever,
meningeal sings

No

Vaccination
at age 8 days

Hydrocephalus,
enhancing mass
(left temporal lobe)

CSF samples/
isoniazid + rifampicin + ethambutol, 18 months

Recovery/
4 years

4/Female

Fever,
meningeal sings

No

Vaccination
at age 3 years

Normal CT

CSF samples/
isoniazid + rifampicin + ethambutol ,18 months

Recovery/
3 years


Coppes et al [21]

6/Female

Headache, fever,
nucal rigidity

Lymphoblastic leukemia

No

Enhancing left
temporal lobe mass
+ ring enhancing

Craniotomy + isoniazid + rifampicin + pyranzinamide, 12 months

Recovery/–


Stone et al [33]

3/Female

Headache, fever

Lymphoblastic leukemia

No

Hydrocephalus

CSF samples/
isoniazid + rifampicin + pyranzinamide + streptomycin, 12 months

Recovery/–

5/Male

Headaches,
rhinorrhea,
weight loss

Lymphoblastic leukemia

No

Normal CT

CSF samples/
isoniazid + rifampicin + pyranzinamide + streptomycin, 12 months

Recovery/–


Golub et al [1]

73/Male

Headache,
dizziness, tremor

Transitional bladder carcinoma

No/Intravesical treatment with BCG three years before

Three enhancing mass
(left frontal, temporal
and basal ganglia)

Biopsy + isoniazid + rifampicin + ethambutol
+ moxifloxacin

Recovery/–


Sheron et al [34]

74/Male

Dizziness, vertigo,
gait ataxia, vomiting

Transitional bladder carcinoma

No/Intravesical treatment with BCG
one year before

Enhancing mass (cerebellum)

Biopsy+ isoniazid + rifampicin + ethambutol
+ moxifloxacin

Recovery/–


BCG: bacillus Calmette-Guérin; CSF: cerebrospinal fluid; CT: computerized tomography. a Treatment not specified in the report.

 

In conclusion, M. bovis is an infrequent cause of CNS tuberculosis in our country. Brain biopsy or surgical excision are reserved in case of doubt in the diagnoses or worsening evolution with antituberculous therapy. As far as we know, this is the first case reported of a suppurative fistula after the resection of a cerebral abscess caused by M. bovis, therefore, there is no report in the literature about the treatment of this complication. Based on the treatment of tuberculous lymphadenitis, we decided to perform a conservative management with anti­tuberculous therapy (isoniazid + rifampicin + ethambutol  + moxifloxacin) and avoided new surgical cleanings of the surgical bed, obtaining a good response and a good clinical evolution.

 

References
 


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 2.  DeLance AR, Safaee M, Oh MC, Clark AJ, Kaur G, Sun MZ, et al. Tuberculoma of the central nervous system. J Clin Neurosci 2013; 20: 1333-41.

 3.  Guest SS, Sivit CJ, Meisler WJ, Stevens AC, Simon GL. Intracranial tuberculosis due to Mycobacterium bovis. Comput Radiol 1987; 11: 151-4.

 4.  Argaret M, Annier NM V, Usan S, Torch KS, Arol C, Eterson P, et al. Brief report: meningitis due to iatrogenic BCG infection in two immunocompromised children. N Engl J Med 1995; 333: 561-3.

 5.  Datta SGS, Bhatnagar V, Pan S, Mehta R, Sharma C. Primary calvarial tuberculosis: a report of three cases. Br J Neurosurg 2019; 33: 196-201.

 6.  Diyora B, Kumar R, Modgi R, Sharma A. Calvarial tuberculosis: a report of eleven patients. Neurol India 2009, 57: 607-12.

 7.  Raut AA, Nagar AM, Muzumdar D, Chawla AJ, Narlawar RS, Fattepurkar S, et al. Imaging features of calvarial tuberculosis: a study of 42 cases. AJNR Am J Neuroradiol 2004; 25: 409-14.

 8.  Santra A, Sen A, Chatterjee A. Calvarial tuberculosis in a preschool-aged child: an uncommon entity. Sultan Qaboos Univ Med J 2017; 17: e484-6.

 9.  Ip M, Tsui E, Wong KL, Jones B, Pung CF, Ngan H. Disseminated skeletal tuberculosis with skull involvement. Tuber Lung Dis 1993; 74: 211-4.

 10.  Ramdurg SR, Gupta DK, Suri A, Sharma BS, Mahapatra AK. Calvarial tuberculosis: uncommon manifestation of common disease –a series of 21 cases. Br J Neurosurg 2010; 24: 572-7.

 11.  Mohanty S, Rao CJ, Mukherjee KC. Tuberculosis of the skull. Int Surg 1981; 66: 81-3.

 12.  Rajshekhar V. Surgery for brain tuberculosis: a review. Acta Neurochir (Wien) 2015; 157: 1665-78.

 13.  García-Moncó JC. Tuberculosis. Handb Clin Neurol 2014; 121: 1485-99.

 14.  Ramachandran R, Muniyandi M, Iyer V, Sripriya T, Priya B, Govindarajan TG. Dilemmas in the diagnosis and treatment of intracranial tuberculomas. J Neurol Sci 2017; 381: 256-64.

 15.  Wasay M. Central nervous system tuberculosis and paradoxical response. South Med J 2006; 99: 331-2.

 16.  Alemayehu T, Ergete W, Abebe W. Frontal lobe tuberculoma: a clinical and imaging challenge. Ethiop J Health Sci 2017; 27: 677-80.

 17.  Shah I, Borse S. Paradoxical tuberculomas after completion of antituberculous treatment. Trop Med Health 2012; 40: 15-7.

 18.  Afghani B, Lieberman JM. Paradoxical enlargement or development of intracranial tuberculomas during therapy: case report and review. Clin Infect Dis 1994; 19: 1092-9.

 19.  García-Moncó JC, Ferreira E, Gómez-Beldarrain M. The therapeutic paradox in the diagnosis of tuberculous meningitis. Neurology 2005; 65: 1991-2.

 20.  Kaplan SR, Topal J, Sosa L, Malinis M, Huttner A, Malhotra A, et al. A patient with central nervous system tuberculomas and a history of disseminated multi-drug-resistant tuberculosis. J Clin Tuberc Other Mycobact Dis 2018; 10: 9-16.

 21.  Coppes MJ, Olivieri NF, Howes M, Pusic M, Gold R, Richardson SE. Mycobacterial brain abscess possibly due to Bacille Calmette-Guérin in an immunocompromised child. Clin Infect Dis 1992; 14: 662-5.

 22.  Sharma K, Sharma M, Chaudhary L, Modi M, Goyal M, Sharma N, et al. Comparative evaluation of Xpert MTB/RIF assay with multiplex polymerase chain reaction for the diagnosis of tuberculous meningitis. Tuberculosis 2018; 113: 38-42.

 23.  American Thoracic Society, CDC, Infectious Diseases Society of America. Treatment of tuberculosis. MMWR Recomm Rep 2003; 52: 1-77 [erratum: MMWR Recomm Rep 2005; 53: 1203].

 24.  Asimacopoulos EP, Berry M, Garfield B, Roesner M, Jepson A, McCarthy J, et al. The diagnostic efficacy of fine-needle aspiration using cytology and culture in tuberculous lymphadenitis. Int J Tuberc Lung Dis 2010; 14: 93-8.

 25.  Omura S, Nakaya M, Mori A, Oka M, Ito A, Kida W, et al. A clinical review of 38 cases of cervical tuberculous lymphadenitis in Japan –the role of neck dissection. Auris Nasus Larynx 2016; 43: 672-6.

 26.  Polesky A, Grove W, Bhatia G. Peripheral tuberculous lymphadenitis: epidemiology, diagnosis, treatment, and outcome. Medicine (Baltimore) 2005; 84: 350-62.

 27.  Fain O, Lortholary O, Djouab M, Amoura I, Babinet P, Beaudreuil J, et al. Lymph node tuberculosis in the suburbs of Paris: 59 cases in adults not infected by the human immuno-deficiency virus. Int J Tuberc Lung Dis 1999; 3: 162-5.

 28.  Ammari FF, Bani Hani AH, Ghariebeh KI. Tuberculosis of the lymph glands of the neck: a limited role for surgery. Otolaryngol Head Neck Surg 2003; 128: 576-80.

 29.  Kim IY, Jung S, Jung TY, Kang SS, Moon KS, Joo SP. Intracranial tuberculoma with adjacent inflammatory aneurysms. J Clin Neurosci 2008; 15: 1174-6.

 30.  Pedersen FK, Engbaek HC, Hertz H, Vergmann B. Fatal BCG infection in an immunocompetent girl. Acta Paediatr 2018; 67: 519-23.

 31.  Heath PD, Grant JW. Intracranial infection due to Mycobacterium bovis in Hodgkin’s disease. Br Med J 1984; 288: 465-6.

 32.  Tardieu M, Carriere JP, Truffot-Pernot C, Dupic Y, Landrieu P. Tuberculous meningitis due to BCG in two previously healthy children. Lancet 1988; 331: 440-1.

 33.  Stone MM, Vannier AM, Storch SK, Peterson C, Nitta AT, Zhang Y. Meningitis due to iatrogenic BCG infection in two immunocompromised children. N Engl J Med 1995; 333: 561-3.

 34.  Sheron MW, Holt SL, Ingram CW. Mycobacterium bovis cerebellar abscess following treatment with Bacillus Calmette-Guérin. J Pharm Pract 2016; 30: 378-80.

 

Caso insólito de absceso cerebral por Mycobacterium bovis complicado con fístula supurativa y revisión de la bibliografía

Introducción. Mycobacterium bovis es una causa infrecuente de tuberculosis del sistema nervioso central en España, del cual existen pocos casos descritos en la bibliografía. Desde la pasteurización obligatoria de la leche y la implementación de programas de erradicación del ganado infectado, la enfermedad esporádica humana con este organismo ha disminuido drásticamente en los países desarrollados.

Caso clínico. Varón inmunoafectado de 71 años, que presentaba una lesión lítica esporádica en la calota. Se realizó una craneotomía de la lesión y los resultados de microbiología fueron positivos para M. bovis, por lo que se inició tratamiento con terapia antituberculosa. A pesar del tratamiento correcto, el paciente desarrolló un absceso tuberculoso, que requirió un tratamiento quirúrgico agresivo, seguido de una complicación con una fístula supurativa. Sobre la base del tratamiento descrito para la linfadenitis tuberculosa, se decidió realizar un tratamiento conservador de la fístula supurativa, sin realizar nuevas limpiezas del lecho quirúrgico, y mantener de manera prolongada la terapia antituberculosa (isoniacida + rifampicina + etambutol + moxifloxacino + esteroides durante 12 meses), con lo que presentó una buena evolución clínica.

Conclusiones. Hasta la fecha, éste es el primer caso descrito de una fístula supurativa después de la resección de un absceso cerebral causado por M. bovis, por lo que no existe en la bibliografía artículo alguno que describa el tratamiento adecuado de esta complicación.

Palabras clave. Absceso tuberculoso. Fístula supurativa. Lesión ósea lítica en calota. Mycobacterium bovis. Terapia antituberculosa. Tuberculoma.

 

© 2019 Revista de Neurología

 

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