Tuberculosis as a risk factor for brain and spinal injuries

Introduction: Intracranial tuberculomas are granulomatous lesions that can occur in approximately 1% of the patients with active tuberculosis (TB). Although it is an uncommon disease, it usually causes severe neurological deficits, including altered mental status, hydrocephalus, cranial nerve palsy, hemiparesis, and seizures. Concomitant presentation of brain and spinal involvement is a rare entity and few cases have been described in the medical literature. Case Report: We report a case of a 38-year-old female who presented with brain and spinal cord injuries due to TB without pulmonary changes. The patient first complained about intense holocranial headache and underwent cranial computed tomography with normal result. In a 6-year period, she had several different symptoms, underwent various types of laboratory and imaging exams, followed some drug therapies, and underwent some surgical procedures. After a diagnosis of intracranial granulomas compatible with TB, she followed a rifampicin + isoniazid + pyrazinamide + ethambutol (RIPE) scheme. However, after some months, she had seizures despite the use of anticonvulsant drugs, felt dizzy, experienced loss of Julia Brasileiro de Faria Cavalcante1, Renata Brasileiro de Faria Cavalcante2, Volmer Fernandes Valente Junior2, José Edison da Silva Cavalcante3, Italo Nogarotto Cembraneli1, Pedro Nogarotto Cembraneli1 Affiliations: 1Medical Sciences Course, Health Sciences School, Faculdade Ceres (FACERES), São José do Rio Preto, SP, Brazil; 2Neurosurgeon, Member of the Brazilian Society of Neurosurgery, Santa Mônica Hospital, Goiânia, GO, Brazil; 3Neurosurgeon, PhD in Neurosurgery, Member of the Brazilian Society of Neurosurgery, Professor at Santa Mônica Hospital, Goiânia, GO, Brazil. Corresponding Author: Julia Brasileiro de Faria Cavalcante, Av. Anísio Haddad, 6751, Jardim Francisco Fernandes, São José do Rio Preto, SP, Brazil; Email: jubf.cavalcante@ outlook.com Received: 06 June 2020 Accepted: 03 August 2020 Published: 15 September 2020 balance, and had severe headaches again. After a diagnosis of ventricular dilation, she started taking acetazolamide in addition to the previous prescription, but soon after she needed ventriculoperitoneal shunt implantation. Conclusion: The history of this patient raises the hypotheses of reactivation of TB due to inefficacy of medication or because of drug resistance. The diagnosis of TB should always be taken into consideration in nodular or pseudotumoral forms in the brain, even in immunocompetent patients without a history of this disease.


INTRODUCTION
Tuberculosis (TB), an infectious illness caused by Mycobacterium tuberculosis, is one of the oldest known human diseases, but it still has a major impact on health services in underdeveloped, developing, and even developed countries. The disease can affect several organs and systems, especially the lungs, kidneys, and brain and spinal cord in rare instances [1]. In 2018, eight countries accounted for two-thirds of the total number of TB cases: India (leading the count), China, Indonesia, the Philippines, Pakistan, Nigeria, Bangladesh, and South Africa [2]. Int J Case Rep Images 2020;11:101164Z01JC2020. www.ijcasereportsandimages.com Cavalcante et al. 2 Central nervous system (CNS) involvement represents 5-10% of extra pulmonary TB cases worldwide, with great potential lethality [3]. It can be classified in three categories: tuberculous meningitis, intracranial tuberculoma, and tuberculous spinal arachnoiditis [4]. All three categories are described in the regions of the world where TB is high [2,5].
Tuberculous meningitis is the primary manifestation of CNS TB [5], and it is also the most severe form of TB, which disproportionately affects people in developing countries and results in significant morbidity and mortality [6]. Intracranial tuberculomas are avascular granulomatous intracranial lesions, which can be single or multiple and can develop without cerebral palsy [7], occurring in approximately 1% of the patients with active TB [8]. Tuberculous spinal arachnoiditis is a rare complication of CNS TB that can cause severe peripheral neurological deficit [9]. It may occur primarily or secondarily to intracranial or vertebral infection and often involves the spinal cord, meninges, and nerve roots, different from other types of arachnoiditis [10].
Although it is an uncommon disease, CNS TB usually causes severe neurological deficits, including altered mental status, hydrocephalus, cranial nerve palsy, hemiparesis, and seizures [11]. Brain and spinal cord involvement is rare and few cases have been reported in the medical literature. We report the case of a patient with brain and spinal cord injury due to TB without pulmonary changes.

CASE REPORT
In May 2014, a previously healthy 38-year-old female woke up in the morning with an intense holocranial headache. She did not have any previous medication history to treat headaches or any known pathologies. She sought hospital care and reported to our team, "I have a terrible headache as I have never had before." She was immediately treated with analgesics and underwent cranial computed tomography (CT). Since the CT result was normal, she was discharged from the hospital.
After a few weeks, although the intensity of the pain subsided, it still bothered her, and she returned to the hospital. At a new neurological examination, in addition to the headache, she complained of paresthesia in the right hemibody. Magnetic resonance imaging (MRI) showed an 8-mm hyperintense juxtacortical fluid-attenuated inversion recovery (FLAIR) lesion associated with T1 hypointensity, without gadolinium enhancement, oval, and extra-axial, at the base of the left parietal-occipital groove and isointense in T2 with tail signal, compatible with plaque meningioma ( Figure  1). A lumbar puncture revealed increased protein level in the cerebrospinal fluid (664 mg/dL). As the lesion did not cause any mass effect or perilesional edema, as soon as the patient's complaints disappeared, she was discharged from the hospital.
In October 2014, she started experiencing malaise, neck pain, progressive and very severe back pain, and decided to return to the hospital, where she stated, "I can barely hold a glass." Magnetic resonance imaging of the entire spine revealed a rounded intradural and intramedullary lesion, measuring approximately 1 cm in diameter, at level C1 ( Figure 2). A symptomatic treatment was prescribed, and our team recommended periodical follow-up imaging exams.
In July 2015, control MRI was done and, as the brain lesion increased slightly, our team decided to perform a craniotomy for excision of the lesion. During surgery, a hardened, little vascularized lesion adhered to the dura mater and to the cortex, and dural thickening anterior and posterior to the main lesion were observed. The microscopical aspect suggested a meningioma. However, the histopathological examination of the lesion showed intracranial granulomas compatible with TB ( Figure 3). Chest CT was normal, with no evidence of pulmonary TB. After surgery, the patient underwent a drug treatment following a rifampicin + isoniazid + pyrazinamide + ethambutol (RIPE) scheme, associated with corticosteroid therapy, for two months, and rifampicin + isoniazid for seven months. The patient remained clinically stable, with improvement of pain and malaise. On periodical follow-up MRI, the  intramedullary lesion was no longer visible and the intracranial dural thickening decreased.
In January 2017, the patient had seizures despite the use of anticonvulsant drugs, and the doses of these medications were increased. She remained stable until May 2017, when she felt dizzy, experienced loss of balance, and had headaches. She underwent skull MRI that showed an area of cerebral ischemia of non-specific cause and slight dilation of the ventricular system ( Figure  4).
In July 2017, since the headache intensified and she reported malaise again, she underwent MRI and it evidenced increased ventricular dilation. The patient started taking acetazolamide in addition to the previous prescriptions. Nonetheless, soon after, the ventricular dilation increased, and our team decided to perform a ventriculoperitoneal shunt implantation. She progressively improved and was regularly followed up by our team and an infectious disease specialist.
In July 2019, she had temporary vision loss, with no posterior decreased acuity and/or visual field loss. No significant changes were found on MRI.
The patient remained stable for eight months, but in March 2020, headaches, visual disturbance, and paresthesia in the body relapsed. Results of MRI showed two new lesions on the brain, and the MRI spectroscopy suggested that they were granulomatous lesions with reactional edema (Figure 5). A new therapeutic RIPE regimen was prescribed, with larger doses. She continues being followed up by our team.

DISCUSSION
Despite being considered one of the oldest known human diseases, TB still affects many people worldwide. Inasmuch as the most severe form of TB involves the CNS, with high mortality and morbidity rates, early diagnosis is necessary for appropriate treatment [12].
Intracranial tuberculomas, usually present as intracranial lesions located in the frontal and parietal lobes of the brain, are a serious and rare form of TB due to the hematogenous spread of M. tuberculosis [13]. Intramedullary tuberculomas are very rare entities, typically located in the dorsal spine, corresponding to 0.2-5% of all cases of CNS tuberculomas [14]. The ratio of intramedullary TB to intracranial TB is approximately 1/42 and spinal tuberculomas are commonly located in the thoracic cord [15]. The correlation of intracranial and intramedullary tuberculoma is extremely uncommon, with only a few cases reported in the literature [16]. Neurocysticercosis, cerebral toxoplasmosis, abscesses, and metastases are differential diagnoses of intracranialspinal tuberculomas [17,18].
The clinical picture and radiological findings of intracranial tuberculoma are often non-specific, sometimes leading to diagnostic errors [13]. The test of choice for detecting minimal brain involvement is MRI. Stereotactic biopsy may be indicated in some cases, but this procedure can promote the spread of the disease [19]. Typical tuberculomas show a granulomatous reaction consisting of epithelioid cells and giant cells mixed with mononuclear inflammatory cells (predominantly lymphocytes) that form a granuloma [11]. Int J Case Rep Images 2020;11:101164Z01JC2020. www.ijcasereportsandimages.com Cavalcante et al. 4 As a general principle in the treatment of CNS TB, drugs that penetrate the CNS are used, particularly the RIPE scheme. To the best of our knowledge, no studies have detailed the specific combination and duration of the treatment for CNS TB [20,21]. Surgical treatment depends on the location of the brain injury and the clinical conditions of the patient [22].

CONCLUSION
The history of the patient of this case report raises the hypotheses of reactivation of TB due to inefficacy of the medication released by the public health system or because of drug resistance. Given that both the Pan American Health Organization and the World Health Organization are committed to eradicate TB by 2030 in all the countries of the Americas, it is necessary to employ new technologies, such as rapid molecular testing, and work with the most vulnerable populations, providing them with timely diagnosis and early treatment. Since CNS tuberculomas can mimic several other entities, the diagnosis of TB should always be taken into consideration in the presence of nodular or pseudotumoral forms in the brain, even in immunocompetent patients without a history of this disease. *********

Author Contributions
Julia Brasileiro de Faria Cavalcante -Conception of the work, Design of the work, Acquisition of data, Analysis of data, Interpretation of data, Drafting the work, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved Renata Brasileiro de Faria Cavalcante -Conception of the work, Design of the work, Acquisition of data, Analysis of data, Interpretation of data, Drafting the work, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that Int J Case Rep Images 2020;11:101164Z01JC2020. www.ijcasereportsandimages.com Cavalcante et al. 5 questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved Volmer Fernandes Valente Junior -Conception of the work, Design of the work, Acquisition of data, Analysis of data, Interpretation of data, Drafting the work, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved José Edison da Silva Cavalcante -Conception of the work, Design of the work, Acquisition of data, Analysis of data, Interpretation of data, Drafting the work, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved Italo Nogarotto Cembraneli -Conception of the work, Design of the work, Acquisition of data, Analysis of data, Interpretation of data, Drafting the work, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved Pedro Nogarotto Cembraneli -Conception of the work, Design of the work, Acquisition of data, Analysis of data, Interpretation of data, Drafting the work, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved

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Written informed consent was obtained from the patient for publication of this article.