- Email: [email protected]
Neurological complications of miliary tuberculosis
Clinical Neurology and Neurosurgery 112 (2010) 188–192
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Neurological complications of miliary tuberculosis Ravindra Kumar Garg a,∗ , Rohitash Sharma a , Alok Mohan Kar a , Ram Avadh Singh Kushwaha b , Maneesh Kumar Singh a , Rakesh Shukla a , Atul Agarwal a , Rajesh Verma a a b
Department of Neurology, Chhatrapati Shahuji Maharaj Medical University, Lucknow 226003, Uttar Pradesh, India Department of Pulmonary Medicine, Chhatrapati Shahuji Maharaj Medical University, Lucknow, Uttar Pradesh, India
a r t i c l e
i n f o
Article history: Received 17 January 2009 Received in revised form 5 November 2009 Accepted 11 November 2009 Available online 23 December 2009 Keywords: Pulmonary tuberculosis Tuberculous meningitis Cerebral tuberculoma Transverse myelitis
a b s t r a c t Introduction: The symptomatic central nervous system involvement is often seen in patients with miliary tuberculosis. Materials and methods: In this study, we evaluated 60 consecutive miliary tuberculosis patients, who presented with some neurological manifestations. Evaluation included neurological examination, a battery of blood tests, HIV serology, sputum examination, cerebrospinal fluid (CSF) examination along with imaging of the brain and spinal cord. The patients were followed up after completion of 6 months of antituberculous treatment. Results: Patients ranged between 14 and 53 years in age. Three patients tested HIV positive. Forty-eight (80%) patients had tuberculous meningitis. In 12 (20%) patients, the CSF examination was normal. In 27 patients with tuberculous meningitis, neuroimaging revealed intracerebral tuberculoma. Fourteen patients showed multiple tuberculomas, while 7 had a solitary tuberculoma. In six patients, the tuberculomas were small and numerous. In two patients, neuroimaging revealed a spinal tuberculoma. For three patients with tuberculous brain masses, the CSF was normal. Nine (15%) patients presented with myelopathy. Three patients exhibited Pott’s paraplegia. Three patients had transverse myelitis (with normal neuroimaging). In three patients, the spinal MRI revealed an intramedullary tuberculoma. On follow-up, 15 (25%) patients expired. Thirty-one (52%) patients showed significant improvement. Eight patients (13%) showed nil or partial recovery. Six of the patients with no improvement developed vision loss. Six (10%) patients were lost to follow up. Conclusion: A variety of neurological complications were noted in military tuberculosis patients, tuberculous meningitis and cerebral tuberculomas being the most frequent complications. However, a majority of patients improved following antituberculous treatment. © 2009 Elsevier B.V. All rights reserved.
1. Introduction The term miliary tuberculosis refers to a progressive and disseminated form of tuberculosis. Miliary tuberculosis, comprising 1% of all tuberculosis cases [1], is a potentially life-threatening condition, caused by the hematogenous spread of Mycobacterium tuberculosis. It develops either during primary dissemination or after years of untreated tuberculosis, affecting any body organ, including the central nervous system. Prompt diagnosis of this disorder is important because early treatment results in better clinical improvement [2,3]. Central nervous system involvement is often observed in miliary tuberculosis patients, though its frequency of occurrence is roughly estimated at around 22% [4]. Most of the existing knowledge on
∗ Corresponding author. Tel.: +91 522 4003496; fax: +91 522 2258852. E-mail address: [email protected] (R.K. Garg). 0303-8467/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2009.11.013
neurological complications of miliary tuberculosis is restricted to isolated case reports and small case series. In this paper, we present our study of 60 miliary tuberculosis patients who also exhibited some neurological manifestations. 2. Materials and methods This study was conducted between July 2005 and March 2007 in the Department of Neurology of Chhatrapati Shahuji Maharaj Medical University, Uttar Pradesh, Lucknow, India. Our institution provides tertiary care medical facilities to approximately 100 million of the population of North India, as tuberculosis is highly endemic to this region. The institute’s ethics committee approved of the study. Informed consent was obtained either from the patients or from legal guardians (in the case of minors). During the study period, 89 miliary tuberculosis patients were registered in our institution. Miliary pattern on X-ray chest consists of diffuse small interstitial pulmonary nodules of soft tissue density, approximately the size of millet seeds (1–3 mm).
R.K. Garg et al. / Clinical Neurology and Neurosurgery 112 (2010) 188–192
In this study, we included 62 consecutive miliary tuberculosis patients who were evaluated for some neurological symptoms. Thirty-four patients had presented to the Neurology inpatient and outpatient clinics. Twenty-eight patients were referred to us from the Department of Pulmonary Medicine and Department of Internal Medicine. Patients were enrolled between July 2005 and August 2006. Two patients, who immediately after inclusion expressed their inability to continue in the study, were excluded. All patients were clinically evaluated. Several laboratory tests, including complete blood count, plasma glucose, serum creatinine, electrolyte and erythrocyte sedimentation rate, were performed. Sputum was examined for acid-fast bacillus. Three sputum specimens were obtained on 3 consecutive days. Enzyme-linked immunosorbent assays (ELISA) for human immunodeficiency virus (HIV) and tuberculosis in serum were also performed. Cerebrospinal fluid (CSF) was examined for biochemical and cytological parameters along with ELISA test for tuberculosis. The ELISA test in serum and CSF was performed to detect IgG antibodies to A60 antigen, using commercially available kits (Anda Biologicals, Strausberg, France) [5]. Normal CSF biochemical values were 15–45 mg/dl protein and 50–80 mg/dl glucose (two-thirds of blood glucose). Normal CSF contains 0–5 mononuclear cells [6]. CSF sediments were examined with Gram stain, AFB staining, staining for malignant cells and India ink preparation. Contrast-enhanced computed tomography (CT) of brain was performed in all patients. Gadolinium-enhanced cranial or spinal MRI was performed in 15 patients with brainstem and spinal cord involvement. Tuberculous meningitis was diagnosed based on clinical, CSF and radiological criteria. The essential criteria were the presence of meningitic syndrome comprising headache, vomiting and fever for 2 weeks or more, along with characteristic CSF abnormalities (dominant lymphocytic pleocytosis, with raised protein). A contrast-enhanced CT scan demonstrated the presence of exudates, hydrocephalus, tuberculoma and infarction, singly or in combination [7,8]. Tuberculoma on CT scans featured as single or multiple lesions that revealed intense contrast enhancement and perilesional edema. Tuberculous brain abscess on the CT scan was characterized as having a solitary lesion, large sized (>3 cm in diameter), thin walled, and multiloculated. Patients were recognized to have myelopathy if the neurological evaluation revealed paraparesis or quadriparesis, a truncal sensory level and/or bladder dysfunction. Bacteriological diagnosis was confirmed by the presence of acidfast bacillus in sputum and CSF, positive serum serology, and a clinical response to antituberculous treatment [9]. CSF culture for M. tuberculosis was not performed. We did not test M. tuberculosis isolates for susceptibility to standard antituberculous drugs. Antituberculous treatment was immediately started. Antituberculous regimen included 2 months’ therapy comprising isoniazid (5 mg/kg of body weight; maximum, 300 mg), rifampicin (10 mg/kg; maximum, 600 mg), pyrazinamide (25 mg/kg; maximum, 2 g/day), and ethambutol (20 mg/kg; maximum, 1200 mg), followed by oral isoniazid, rifampicin, and pyrazinamide at the same doses for 6 months. Patients were also provided appropriate symptomatic treatment (intravenous fluids, dexamethasone, mannitol, antiepileptic drugs and/ analgesics if required). Dexamethasone was used orally, starting at a total of 12 mg/day and decreasing by 1 mg each week [10]. Patients with stage II and stage III meningitis and those with papilloedema were treated with dexamethasone. Patients with tuberculous transverse myelitis were given intravenous methyl prednisolone (1 g daily for 5 days). To patients with difficulty with swallowing, oral drugs were given via nasogastric tube. However, none of the patients received antiretroviral drugs or any second-line antituberculous drugs. All patients included in the study were hospitalized for at least 1 month. After discharge they were followed up every month for
189
Fig. 1. Contrast-enhanced computed tomography showing basal exudates in sylvian fissures (fine arrows) and basal cisterns, meningeal enhancement (arrow heads), third ventricular enlargement (thick arrow) and left basal ganglionic infarct (notched arrow). This patient presented with tuberculous meningitis.
6 months. All the patients had a contrast-enhanced CT of brain repeated after 6 months following the initiation of antituberculous treatment. The outcome was assessed by Barthel index (BI) after 6 months. The Barthel index consists of 10 items that measure a person’s daily functioning, specifically the activities of daily living and mobility, including feeding, moving from wheelchair to bed and return, grooming, transferring to and from a toilet, bathing, walking on level surface, going up and down stairs, dressing, continence of bowels and bladder. Barthel index score was taken as complete (BI 20), partial (BI 12–19) or poor (BI < 12) [7]. Paradoxical deterioration during antituberculous therapy is defined as the clinical or radiological worsening of pre-existing tuberculous lesions or the development of new central nervous system lesions in a patient who shows initial improvement [11]. 3. Results In 22 patients, the bacteriological diagnosis of miliary tuberculosis was established by the detection of AFB either in sputum or in the CSF. In 27 patients, diagnosis was based upon positive serum and/or CSF ELISA test. In the remaining 11 patients, diagnosis was made on clinical response to antituberculous treatment (Table 1). Forty-eight (80%) patients showed clinical, neuroimaging features and CSF changes of tuberculous meningitis (Fig. 1). Meningeal signs were evident in approximately 50% of the tuberculous meningitis patients. Six patients scored less than 12 on the Glasgow coma scale. In 27 (56%) patients with tuberculous meningitis neuroimaging, at the time of inclusion, either single or multiple tuberculomas were noted (Fig. 2). Fourteen patients had multiple small 10–20mm diameter tuberculomas. In six patients, cerebral lesions were small and ‘too numerous to count’. In two such patients, neuroimaging revealed numerous tuberculomas involving the central nervous
190
R.K. Garg et al. / Clinical Neurology and Neurosurgery 112 (2010) 188–192
Table 1 Epidemiological, clinical and neuroimaging characteristics of patients with miliary tuberculosis (n = 60). Age (year) (mean ± SD) (range)
26 ± 8 (14–53)
Sex Male Female
32 (53%) 28 (47%)
HIV-positive BCG non-vaccinated Sputum positive for AFB Positive serum ELISA Duration of illness (weeks) (mean ± SD)
3 (5%) 9 (15%) 16 (27%) 29 (48%) 4 ± 5 (2–13)
TBM staginga (n = 48) Stage I Stage II Stage III
21 (44%) 19 (40%) 08 (16%)
Clinical features Fever, weight loss, headache, and/or vomiting Glasgow coma score (mean ± SD) (range) Hemiparesis Monoparesis Paraplegia cranial nerve palsy Seizures Papilloedema Meningeal signs
60 (100%) 13 ± 5 (7–15) 13 07 09 12 17 04 25
CSF Normal Abnormal Smears positive for AFB Positive CSF ELISA
10 (17%) 50 (83%) 06 (10%) 37 (62%)
CT abnormalities Hydrocephalus Meningeal enhancement Infarction Tuberculoma Basilar exudates Normal
28 (47%) 41 (68%) 11 (18%) 30 (50%) 26 (27%) 13 (27%)
Follow-up (6 months after start of treatment) Death Improved (BI 20) Partially improved (BI 12–19) Not improved (BI < 12)
15 (25%) 21 (35%) 10 (17%) 08 (13%)
a
Stage I: meningitis only; Stage II: meningitis with focal neurological deficit; stage III: meningitis with altered sensorium; AFB: acid-fast bacillus; CSF: cerebrospinal fluid; HIV: human immunodeficiency virus; BI: Barthel index; TBM: tuberculous meningitis; ELISA: enzyme-linked immunosorbent assay.
system (cerebral cortex, cerebellar hemispheres, brainstem and spinal cord) (Fig. 2). In seven patients with tuberculous meningitis, solitary tuberculomas were observed, involving either cerebral parenchyma or the brainstem. Three HIV-infected patients presented with tuberculous meningitis having multiple small cerebral parenchymal tuberculoma (Table 2). Three patients with cerebral lesions revealed normal CSF. Two patients had multiple small cerebral tuberculomas, while one patient had a large tuberculous abscess diagnosed histopathologically, which was surgically removed (Fig. 3). Patients with tuberculoma and normal CSF presented with new-onset partial motor seizures. Nine patients (15%), who presented with paraplegia, had myelopathy. Three patients had Pott’s spine and paraplegia. In three patients with myelopathy, spinal MRI revealed the presence of an intramedullary tuberculoma (Fig. 4). In the remaining three patients, who had a syndrome of acute transverse myelitis, normal spinal neuroimaging was seen (Table 2). Seven patients with myelopathies had normal CSF. Fifteen (including three HIV-infected) patients died during the 6-month follow-up period. In 10 patients, death occurred early
Fig. 2. Gadolinium-enhanced cranial magnetic resonance imaging showing multiple small tuberculomas in a patient with tuberculous meningitis.
in the course of the disease (within 1 month). Thirty-one (52%) patients showed improvement. Eight (13%) patients showed little or no recovery, or regained only partial recovery; six of the patients with no improvement developed significant vision loss. In 12 patients (out of 30 patients) with intracranial tuberculoma, the follow-up CT scans returned normal. In seven patients, the number of lesions as well as perilesional edema reduced. In the remaining 11 patients no changes in the neuroimaging abnormalities were observed. Four patients who developed drug-induced hepatitis had the antituberculous treatment temporarily withdrawn. Antituberculous treatment was reinstituted after liver function tests were normalized. Three patients who presented with acute transverse myelitis significantly improved following methyl prednisolone treatment. Six (10%) patients were lost to follow up. Incidentally,
Table 2 Spectrum of neurological complications in patients with miliary tuberculosis (n = 60). Tuberculous meningitis
21 (35%)
Tuberculous meningitis with tuberculoma Multiple tuberculomaa Single tuberculoma brain Single tuberculoma brainstem Miliary tuberculomab
27 (45%) 14 5 2 6
Tuberculoma with normal CSF Multiple small tuberculomas Tuberculous abscess
3 (5%) 2 1
Thoracic transverse myelopathy Pott’s spine and paraplegia Intramedullary tuberculoma Acute transverse myelitis
9 (15%) 3 3 3
a
Three human immunodeficiency virus infected patients belonged to this group. Two patients in addition to miliary cerebral tuberculomas had spinal intramedullary tuberculoma. CSF: cerebrospinal fluid. b
R.K. Garg et al. / Clinical Neurology and Neurosurgery 112 (2010) 188–192
191
Fig. 3. Contrast-enhanced computed tomography showing a large parasaggital tuberculous abscess.
paradoxical deterioration during antituberculous therapy was not seen in any of the patients (Table 2). 4. Discussion Our study demonstrated that miliary tuberculosis was associated with a variety of central nervous system complications, of which tuberculous meningitis occurred most frequently. Kalita et al. [7] in a similar observation, noted that 12% (20 out of 165) tuberculous meningitis patients had miliary tuberculosis. Thwaites et al. [12] observed that approximately 28% of tuberculous meningitis patients, irrespective of whether HIV-infected or not, had miliary tuberculosis. Our observations further suggest that the hematogenous dissemination of causative bacteria influences the pathogenesis of tuberculous meningitis. Bacillemia that accompanies miliary tuberculosis leads to the formation of meningeal or sub-cortical Rich focus, which may caseate and give rise to tuberculous meningitis [13]. We also observed that tuberculous meningitis in miliary tuberculosis patients is often complicated by cerebral tuberculoma formation. A study from Pakistan also revealed similar observations. In a retrospective review of 102 intracranial tuberculoma patients, chest radiographs showed miliary tuberculosis in 20% of them. Approximately half of the cerebral tuberculoma patients had clinical or laboratory evidence of concomitant tuberculous meningitis [14]. Thwaites et al. [15] observed that tuberculomas in patients with tuberculous meningitis were associated with prolonged fever; however, the occurrence of tuberculomas was not associated with poor clinical outcome. When intracranial tuberculomas become symptomatic, antituberculous therapy generally does not need to be changed. Tuberculomas in tuberculous meningitis patients have the propensity to paradoxically enlarge or appear on standard antituberculous therapy though the majority remain asymptomatic and eventually resolve uneventfully. We did not observe paradoxical deterioration during antituberculous therapy in any of our patients.
Fig. 4. Gadolinium-enhanced spinal magnetic resonance imaging showing an intramedullary tuberculoma in thoracic region.
In six patients, in our series, neuroimaging revealed miliary pattern of brain involvement. In a published case report very small parenchymal granulomas (less than 2 mm in diameter) were observed mostly associated with miliary tuberculosis, which resolved rapidly following antituberculous therapy [16]. Gupta et al. performed contrast MR study of brain in seven miliary tuberculosis patients with no symptoms or signs suggestive of central nervous system involvement. Imaging revealed that all patients had asymptomatic brain involvement. Four patients showed multiple lesions less than 3 mm in diameter. The remaining three patients had multiple lesions 3 mm or more in diameter. In all the patients, a gradual resolution of lesions was noted on follow-up [17]. Death occurred in our patients with tuberculous meningitis and intracranial tuberculoma due to a rise in intracranial pressure. Six patients in our study developed vision loss. In tuberculous meningitis, optic nerve involvement results in vision loss. There are several possible reasons for optic nerve involvement, like optochiasmatic arachnoiditis, third ventricular compression of the optic chiasma in patients with large hydrocephalus, optic nerve granulomas or ethambutol toxicity. Optochiasmatic tuberculoma is a rare cause of progressive visual failure in tuberculous meningitis [18]. Three patients in our study were HIV positive. Our HIVinfected patients expressed similar clinico-radiological features to those seen in non-HIV-infected patients. They presented with tuberculous meningitis with multiple small cerebral parenchymal
192
R.K. Garg et al. / Clinical Neurology and Neurosurgery 112 (2010) 188–192
tuberculomas. Concomitant HIV infection significantly reduces the survival rate in patients with tuberculous meningitis [12]. All three of our HIV-infected patients died during follow-up. In nine patients, miliary tuberculosis was complicated by spinal cord involvement. Three patients had intramedullary spinal tuberculoma. Patients often present with acute thoracic transverse myelopathy syndrome. Intramedullary tuberculoma in miliary tuberculosis patients usually responds satisfactorily to antituberculous treatment. Some patients respond better to surgery [19]. Intramedullary tuberculoma concomitant with disseminated intracerebral tuberculoma has rarely been reported in the literature [20]. Three of our patients presented a syndrome of possibly immunemediated acute transverse myelitis. Wasay et al. [21] reviewed the clinical and neuroimaging features of 10 similar patients. Due to its association with miliary tuberculosis immune-mediated acute transverse myelitis is termed “tuberculous myelitis”. Tuberculous myelitis predominantly affects the thoracic spinal cord. MR may show signal changes in the involved segments. Most spinal cord lesions appear as hyperintense on T2 and iso- or hypointense on T1-weighted images [21,22]. However, our patients had normal MR studies. In our series, another equally frequent mechanism of spinal cord involvement was Pott’s paraplegia. Vertebral involvement is rarely reported in miliary tuberculosis patients. Shah et al. [23] reported a similar case in an immunocompetent patient with multi-drug resistant miliary tuberculosis. In conclusion, miliary tuberculosis, though quite an uncommon form of tuberculosis, frequently shows central nervous system involvement. The common complications include tuberculous meningitis and intracranial tuberculomas. Patients are often admitted to the hospital more often because of a central nervous system involvement rather than pulmonary involvement. Fortunately, a majority of patients improve following antituberculous treatment. References [1] Baker SK, Glassroth J. Miliary tuberculosis. In: Rom WN, Garry SM, editors. Tuberculosis. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2004. p. 427–44. [2] Geppert EF, Leff A. The pathogenesis of pulmonary and miliary tuberculosis. Arch Intern Med 1979;139:1381–3.
[3] Sharma SK, Mohan A, Sharma A, Mitra DK. Miliary tuberculosis: new insights into an old disease. Lancet Infect Dis 2005;5:415–30. [4] Benzarti M, Jerray M, Souissi J, Hayouni A, Garrouche A, Klabi N. Brain abscess in the course of miliary tuberculosis: a case report and review of the literature. Int J Tuberc Lung Dis 1997;1:477–81. [5] Anuradha S, Kaur R, Singh NP, Baveja UK. Serodiagnosis of extra pulmonary tuberculosis using A-60 antigen. J Common Dis 2001;33:12–6. [6] Seehusen DA, Reeves MM, Fomin DA. Cerebrospinal fluid analysis. Am Fam Phys 2003;68:1103–8. [7] Kalita J, Misra UK, Ranjan P. Tuberculous meningitis with pulmonary miliary tuberculosis: a clinicoradiological study. Neurol India 2004;52:194–6. [8] Thwaites GE, Chau TT, Stepniewska K, Phu NH, Chuong LV, Sinh DX, et al. Diagnosis of adult tuberculous meningitis by use of clinical and laboratory features. Lancet 2002;360:1287–92. [9] Del Brutto OH, Mosquera A. Brainstem tuberculoma mimicking glioma: the role of antituberculous drugs as a diagnostic tool. Neurology 1999;52:210–1. [10] Girgis NI, Farid Z, Kilpatrick ME, Sultan Y, Mikhail IA. Dexamethasone adjunctive treatment for tuberculous meningitis. Pediatr Infect Dis J 1991;10:179–83. [11] Nicolls DJ, King M, Holland D, Bala J, del Rio C. Intracranial tuberculomas developing while on therapy for pulmonary tuberculosis. Lancet Infect Dis 2005;5:795–801. [12] Thwaites GE, Duc Bang N, Huy Dung N, Thi Quy H, Thi Tuong Oanh D, Thi Cam Thoa N, et al. The influence of HIV infection on clinical presentation, response to treatment, and outcome in adults with tuberculous meningitis. J Infect Dis 2005;192:2134–41. [13] Donald PR, Schaaf HS, Schoeman JF. Tuberculous meningitis and miliary tuberculosis: the Rich focus revisited. J Infect 2005;50:193–5. [14] Wasay M, Moolani MK, Zaheer J, Kheleani BA, Smego RA, Sarwari RA. Prognostic indicators in patients with intracranial tuberculoma: a review of 102 cases. J Pak Med Assoc 2004;54:83–7. [15] Thwaites GE, Macmullen-Price J, Tran TH, Pham PM, Nguyen TD, Simmons CP, et al. Serial MRI to determine the effect of dexamethasone on the cerebral pathology of tuberculous meningitis: an observational study. Lancet Neurol 2007;6:230–6. [16] Alkhani A, Al-Otaibi F, Cupler EJ, Lach B. Miliary tuberculomas of the brain: case report. Clin Neurol Neurosurg 2006;108:411–4. [17] Gupta RK, Kohli A, Gaur V, Lal JH, Kishore J. MRI of the brain in patients with miliary pulmonary tuberculosis without symptoms or signs of central nervous system involvement. Neuroradiology 1997;39:699–704. [18] Garg RK. Tuberculosis of the central nervous system. Postgrad Med J 1999;75:133–40. [19] Yen HL, Lee RJ, Lin JW, Chen HJ. Multiple tuberculomas in the brain and spinal cord: a case report. Spine 2003;28:E499–502. [20] Ramdurg SR, Gupta DK, Suri A, Sharma BS, Mahapatra AK. Spinal intramedullary tuberculosis: a series of 15 cases. Clin Neurol Neurosurg 2009;111:115–8. [21] Wasay M, Arif H, Kheleani B, Ahsan H. Neuroimaging of tuberculous myelitis: analysis of ten cases and review of literature. J Neuroimaging 2006;16:197–205. [22] Putruele AM, Lagarreta CG, Limongi L, Rossi SE. Tuberculous transverse myelitis: case report and review of literature. Clin Pulm Med 2005;12:46–52. [23] Shah A, Panjabi C, Maurya V, Khanna P. Multidrug resistant miliary tuberculosis and Pott’s disease in an immunocompetent patient. Saudi Med J 2004;25:1468–70.
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Neurological complications of miliary tuberculosis Ravindra Kumar Garg a,∗ , Rohitash Sharma a , Alok Mohan Kar a , Ram Avadh Singh Kushwaha b , Maneesh Kumar Singh a , Rakesh Shukla a , Atul Agarwal a , Rajesh Verma a a b
Department of Neurology, Chhatrapati Shahuji Maharaj Medical University, Lucknow 226003, Uttar Pradesh, India Department of Pulmonary Medicine, Chhatrapati Shahuji Maharaj Medical University, Lucknow, Uttar Pradesh, India
a r t i c l e
i n f o
Article history: Received 17 January 2009 Received in revised form 5 November 2009 Accepted 11 November 2009 Available online 23 December 2009 Keywords: Pulmonary tuberculosis Tuberculous meningitis Cerebral tuberculoma Transverse myelitis
a b s t r a c t Introduction: The symptomatic central nervous system involvement is often seen in patients with miliary tuberculosis. Materials and methods: In this study, we evaluated 60 consecutive miliary tuberculosis patients, who presented with some neurological manifestations. Evaluation included neurological examination, a battery of blood tests, HIV serology, sputum examination, cerebrospinal fluid (CSF) examination along with imaging of the brain and spinal cord. The patients were followed up after completion of 6 months of antituberculous treatment. Results: Patients ranged between 14 and 53 years in age. Three patients tested HIV positive. Forty-eight (80%) patients had tuberculous meningitis. In 12 (20%) patients, the CSF examination was normal. In 27 patients with tuberculous meningitis, neuroimaging revealed intracerebral tuberculoma. Fourteen patients showed multiple tuberculomas, while 7 had a solitary tuberculoma. In six patients, the tuberculomas were small and numerous. In two patients, neuroimaging revealed a spinal tuberculoma. For three patients with tuberculous brain masses, the CSF was normal. Nine (15%) patients presented with myelopathy. Three patients exhibited Pott’s paraplegia. Three patients had transverse myelitis (with normal neuroimaging). In three patients, the spinal MRI revealed an intramedullary tuberculoma. On follow-up, 15 (25%) patients expired. Thirty-one (52%) patients showed significant improvement. Eight patients (13%) showed nil or partial recovery. Six of the patients with no improvement developed vision loss. Six (10%) patients were lost to follow up. Conclusion: A variety of neurological complications were noted in military tuberculosis patients, tuberculous meningitis and cerebral tuberculomas being the most frequent complications. However, a majority of patients improved following antituberculous treatment. © 2009 Elsevier B.V. All rights reserved.
1. Introduction The term miliary tuberculosis refers to a progressive and disseminated form of tuberculosis. Miliary tuberculosis, comprising 1% of all tuberculosis cases [1], is a potentially life-threatening condition, caused by the hematogenous spread of Mycobacterium tuberculosis. It develops either during primary dissemination or after years of untreated tuberculosis, affecting any body organ, including the central nervous system. Prompt diagnosis of this disorder is important because early treatment results in better clinical improvement [2,3]. Central nervous system involvement is often observed in miliary tuberculosis patients, though its frequency of occurrence is roughly estimated at around 22% [4]. Most of the existing knowledge on
∗ Corresponding author. Tel.: +91 522 4003496; fax: +91 522 2258852. E-mail address: [email protected] (R.K. Garg). 0303-8467/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2009.11.013
neurological complications of miliary tuberculosis is restricted to isolated case reports and small case series. In this paper, we present our study of 60 miliary tuberculosis patients who also exhibited some neurological manifestations. 2. Materials and methods This study was conducted between July 2005 and March 2007 in the Department of Neurology of Chhatrapati Shahuji Maharaj Medical University, Uttar Pradesh, Lucknow, India. Our institution provides tertiary care medical facilities to approximately 100 million of the population of North India, as tuberculosis is highly endemic to this region. The institute’s ethics committee approved of the study. Informed consent was obtained either from the patients or from legal guardians (in the case of minors). During the study period, 89 miliary tuberculosis patients were registered in our institution. Miliary pattern on X-ray chest consists of diffuse small interstitial pulmonary nodules of soft tissue density, approximately the size of millet seeds (1–3 mm).
R.K. Garg et al. / Clinical Neurology and Neurosurgery 112 (2010) 188–192
In this study, we included 62 consecutive miliary tuberculosis patients who were evaluated for some neurological symptoms. Thirty-four patients had presented to the Neurology inpatient and outpatient clinics. Twenty-eight patients were referred to us from the Department of Pulmonary Medicine and Department of Internal Medicine. Patients were enrolled between July 2005 and August 2006. Two patients, who immediately after inclusion expressed their inability to continue in the study, were excluded. All patients were clinically evaluated. Several laboratory tests, including complete blood count, plasma glucose, serum creatinine, electrolyte and erythrocyte sedimentation rate, were performed. Sputum was examined for acid-fast bacillus. Three sputum specimens were obtained on 3 consecutive days. Enzyme-linked immunosorbent assays (ELISA) for human immunodeficiency virus (HIV) and tuberculosis in serum were also performed. Cerebrospinal fluid (CSF) was examined for biochemical and cytological parameters along with ELISA test for tuberculosis. The ELISA test in serum and CSF was performed to detect IgG antibodies to A60 antigen, using commercially available kits (Anda Biologicals, Strausberg, France) [5]. Normal CSF biochemical values were 15–45 mg/dl protein and 50–80 mg/dl glucose (two-thirds of blood glucose). Normal CSF contains 0–5 mononuclear cells [6]. CSF sediments were examined with Gram stain, AFB staining, staining for malignant cells and India ink preparation. Contrast-enhanced computed tomography (CT) of brain was performed in all patients. Gadolinium-enhanced cranial or spinal MRI was performed in 15 patients with brainstem and spinal cord involvement. Tuberculous meningitis was diagnosed based on clinical, CSF and radiological criteria. The essential criteria were the presence of meningitic syndrome comprising headache, vomiting and fever for 2 weeks or more, along with characteristic CSF abnormalities (dominant lymphocytic pleocytosis, with raised protein). A contrast-enhanced CT scan demonstrated the presence of exudates, hydrocephalus, tuberculoma and infarction, singly or in combination [7,8]. Tuberculoma on CT scans featured as single or multiple lesions that revealed intense contrast enhancement and perilesional edema. Tuberculous brain abscess on the CT scan was characterized as having a solitary lesion, large sized (>3 cm in diameter), thin walled, and multiloculated. Patients were recognized to have myelopathy if the neurological evaluation revealed paraparesis or quadriparesis, a truncal sensory level and/or bladder dysfunction. Bacteriological diagnosis was confirmed by the presence of acidfast bacillus in sputum and CSF, positive serum serology, and a clinical response to antituberculous treatment [9]. CSF culture for M. tuberculosis was not performed. We did not test M. tuberculosis isolates for susceptibility to standard antituberculous drugs. Antituberculous treatment was immediately started. Antituberculous regimen included 2 months’ therapy comprising isoniazid (5 mg/kg of body weight; maximum, 300 mg), rifampicin (10 mg/kg; maximum, 600 mg), pyrazinamide (25 mg/kg; maximum, 2 g/day), and ethambutol (20 mg/kg; maximum, 1200 mg), followed by oral isoniazid, rifampicin, and pyrazinamide at the same doses for 6 months. Patients were also provided appropriate symptomatic treatment (intravenous fluids, dexamethasone, mannitol, antiepileptic drugs and/ analgesics if required). Dexamethasone was used orally, starting at a total of 12 mg/day and decreasing by 1 mg each week [10]. Patients with stage II and stage III meningitis and those with papilloedema were treated with dexamethasone. Patients with tuberculous transverse myelitis were given intravenous methyl prednisolone (1 g daily for 5 days). To patients with difficulty with swallowing, oral drugs were given via nasogastric tube. However, none of the patients received antiretroviral drugs or any second-line antituberculous drugs. All patients included in the study were hospitalized for at least 1 month. After discharge they were followed up every month for
189
Fig. 1. Contrast-enhanced computed tomography showing basal exudates in sylvian fissures (fine arrows) and basal cisterns, meningeal enhancement (arrow heads), third ventricular enlargement (thick arrow) and left basal ganglionic infarct (notched arrow). This patient presented with tuberculous meningitis.
6 months. All the patients had a contrast-enhanced CT of brain repeated after 6 months following the initiation of antituberculous treatment. The outcome was assessed by Barthel index (BI) after 6 months. The Barthel index consists of 10 items that measure a person’s daily functioning, specifically the activities of daily living and mobility, including feeding, moving from wheelchair to bed and return, grooming, transferring to and from a toilet, bathing, walking on level surface, going up and down stairs, dressing, continence of bowels and bladder. Barthel index score was taken as complete (BI 20), partial (BI 12–19) or poor (BI < 12) [7]. Paradoxical deterioration during antituberculous therapy is defined as the clinical or radiological worsening of pre-existing tuberculous lesions or the development of new central nervous system lesions in a patient who shows initial improvement [11]. 3. Results In 22 patients, the bacteriological diagnosis of miliary tuberculosis was established by the detection of AFB either in sputum or in the CSF. In 27 patients, diagnosis was based upon positive serum and/or CSF ELISA test. In the remaining 11 patients, diagnosis was made on clinical response to antituberculous treatment (Table 1). Forty-eight (80%) patients showed clinical, neuroimaging features and CSF changes of tuberculous meningitis (Fig. 1). Meningeal signs were evident in approximately 50% of the tuberculous meningitis patients. Six patients scored less than 12 on the Glasgow coma scale. In 27 (56%) patients with tuberculous meningitis neuroimaging, at the time of inclusion, either single or multiple tuberculomas were noted (Fig. 2). Fourteen patients had multiple small 10–20mm diameter tuberculomas. In six patients, cerebral lesions were small and ‘too numerous to count’. In two such patients, neuroimaging revealed numerous tuberculomas involving the central nervous
190
R.K. Garg et al. / Clinical Neurology and Neurosurgery 112 (2010) 188–192
Table 1 Epidemiological, clinical and neuroimaging characteristics of patients with miliary tuberculosis (n = 60). Age (year) (mean ± SD) (range)
26 ± 8 (14–53)
Sex Male Female
32 (53%) 28 (47%)
HIV-positive BCG non-vaccinated Sputum positive for AFB Positive serum ELISA Duration of illness (weeks) (mean ± SD)
3 (5%) 9 (15%) 16 (27%) 29 (48%) 4 ± 5 (2–13)
TBM staginga (n = 48) Stage I Stage II Stage III
21 (44%) 19 (40%) 08 (16%)
Clinical features Fever, weight loss, headache, and/or vomiting Glasgow coma score (mean ± SD) (range) Hemiparesis Monoparesis Paraplegia cranial nerve palsy Seizures Papilloedema Meningeal signs
60 (100%) 13 ± 5 (7–15) 13 07 09 12 17 04 25
CSF Normal Abnormal Smears positive for AFB Positive CSF ELISA
10 (17%) 50 (83%) 06 (10%) 37 (62%)
CT abnormalities Hydrocephalus Meningeal enhancement Infarction Tuberculoma Basilar exudates Normal
28 (47%) 41 (68%) 11 (18%) 30 (50%) 26 (27%) 13 (27%)
Follow-up (6 months after start of treatment) Death Improved (BI 20) Partially improved (BI 12–19) Not improved (BI < 12)
15 (25%) 21 (35%) 10 (17%) 08 (13%)
a
Stage I: meningitis only; Stage II: meningitis with focal neurological deficit; stage III: meningitis with altered sensorium; AFB: acid-fast bacillus; CSF: cerebrospinal fluid; HIV: human immunodeficiency virus; BI: Barthel index; TBM: tuberculous meningitis; ELISA: enzyme-linked immunosorbent assay.
system (cerebral cortex, cerebellar hemispheres, brainstem and spinal cord) (Fig. 2). In seven patients with tuberculous meningitis, solitary tuberculomas were observed, involving either cerebral parenchyma or the brainstem. Three HIV-infected patients presented with tuberculous meningitis having multiple small cerebral parenchymal tuberculoma (Table 2). Three patients with cerebral lesions revealed normal CSF. Two patients had multiple small cerebral tuberculomas, while one patient had a large tuberculous abscess diagnosed histopathologically, which was surgically removed (Fig. 3). Patients with tuberculoma and normal CSF presented with new-onset partial motor seizures. Nine patients (15%), who presented with paraplegia, had myelopathy. Three patients had Pott’s spine and paraplegia. In three patients with myelopathy, spinal MRI revealed the presence of an intramedullary tuberculoma (Fig. 4). In the remaining three patients, who had a syndrome of acute transverse myelitis, normal spinal neuroimaging was seen (Table 2). Seven patients with myelopathies had normal CSF. Fifteen (including three HIV-infected) patients died during the 6-month follow-up period. In 10 patients, death occurred early
Fig. 2. Gadolinium-enhanced cranial magnetic resonance imaging showing multiple small tuberculomas in a patient with tuberculous meningitis.
in the course of the disease (within 1 month). Thirty-one (52%) patients showed improvement. Eight (13%) patients showed little or no recovery, or regained only partial recovery; six of the patients with no improvement developed significant vision loss. In 12 patients (out of 30 patients) with intracranial tuberculoma, the follow-up CT scans returned normal. In seven patients, the number of lesions as well as perilesional edema reduced. In the remaining 11 patients no changes in the neuroimaging abnormalities were observed. Four patients who developed drug-induced hepatitis had the antituberculous treatment temporarily withdrawn. Antituberculous treatment was reinstituted after liver function tests were normalized. Three patients who presented with acute transverse myelitis significantly improved following methyl prednisolone treatment. Six (10%) patients were lost to follow up. Incidentally,
Table 2 Spectrum of neurological complications in patients with miliary tuberculosis (n = 60). Tuberculous meningitis
21 (35%)
Tuberculous meningitis with tuberculoma Multiple tuberculomaa Single tuberculoma brain Single tuberculoma brainstem Miliary tuberculomab
27 (45%) 14 5 2 6
Tuberculoma with normal CSF Multiple small tuberculomas Tuberculous abscess
3 (5%) 2 1
Thoracic transverse myelopathy Pott’s spine and paraplegia Intramedullary tuberculoma Acute transverse myelitis
9 (15%) 3 3 3
a
Three human immunodeficiency virus infected patients belonged to this group. Two patients in addition to miliary cerebral tuberculomas had spinal intramedullary tuberculoma. CSF: cerebrospinal fluid. b
R.K. Garg et al. / Clinical Neurology and Neurosurgery 112 (2010) 188–192
191
Fig. 3. Contrast-enhanced computed tomography showing a large parasaggital tuberculous abscess.
paradoxical deterioration during antituberculous therapy was not seen in any of the patients (Table 2). 4. Discussion Our study demonstrated that miliary tuberculosis was associated with a variety of central nervous system complications, of which tuberculous meningitis occurred most frequently. Kalita et al. [7] in a similar observation, noted that 12% (20 out of 165) tuberculous meningitis patients had miliary tuberculosis. Thwaites et al. [12] observed that approximately 28% of tuberculous meningitis patients, irrespective of whether HIV-infected or not, had miliary tuberculosis. Our observations further suggest that the hematogenous dissemination of causative bacteria influences the pathogenesis of tuberculous meningitis. Bacillemia that accompanies miliary tuberculosis leads to the formation of meningeal or sub-cortical Rich focus, which may caseate and give rise to tuberculous meningitis [13]. We also observed that tuberculous meningitis in miliary tuberculosis patients is often complicated by cerebral tuberculoma formation. A study from Pakistan also revealed similar observations. In a retrospective review of 102 intracranial tuberculoma patients, chest radiographs showed miliary tuberculosis in 20% of them. Approximately half of the cerebral tuberculoma patients had clinical or laboratory evidence of concomitant tuberculous meningitis [14]. Thwaites et al. [15] observed that tuberculomas in patients with tuberculous meningitis were associated with prolonged fever; however, the occurrence of tuberculomas was not associated with poor clinical outcome. When intracranial tuberculomas become symptomatic, antituberculous therapy generally does not need to be changed. Tuberculomas in tuberculous meningitis patients have the propensity to paradoxically enlarge or appear on standard antituberculous therapy though the majority remain asymptomatic and eventually resolve uneventfully. We did not observe paradoxical deterioration during antituberculous therapy in any of our patients.
Fig. 4. Gadolinium-enhanced spinal magnetic resonance imaging showing an intramedullary tuberculoma in thoracic region.
In six patients, in our series, neuroimaging revealed miliary pattern of brain involvement. In a published case report very small parenchymal granulomas (less than 2 mm in diameter) were observed mostly associated with miliary tuberculosis, which resolved rapidly following antituberculous therapy [16]. Gupta et al. performed contrast MR study of brain in seven miliary tuberculosis patients with no symptoms or signs suggestive of central nervous system involvement. Imaging revealed that all patients had asymptomatic brain involvement. Four patients showed multiple lesions less than 3 mm in diameter. The remaining three patients had multiple lesions 3 mm or more in diameter. In all the patients, a gradual resolution of lesions was noted on follow-up [17]. Death occurred in our patients with tuberculous meningitis and intracranial tuberculoma due to a rise in intracranial pressure. Six patients in our study developed vision loss. In tuberculous meningitis, optic nerve involvement results in vision loss. There are several possible reasons for optic nerve involvement, like optochiasmatic arachnoiditis, third ventricular compression of the optic chiasma in patients with large hydrocephalus, optic nerve granulomas or ethambutol toxicity. Optochiasmatic tuberculoma is a rare cause of progressive visual failure in tuberculous meningitis [18]. Three patients in our study were HIV positive. Our HIVinfected patients expressed similar clinico-radiological features to those seen in non-HIV-infected patients. They presented with tuberculous meningitis with multiple small cerebral parenchymal
192
R.K. Garg et al. / Clinical Neurology and Neurosurgery 112 (2010) 188–192
tuberculomas. Concomitant HIV infection significantly reduces the survival rate in patients with tuberculous meningitis [12]. All three of our HIV-infected patients died during follow-up. In nine patients, miliary tuberculosis was complicated by spinal cord involvement. Three patients had intramedullary spinal tuberculoma. Patients often present with acute thoracic transverse myelopathy syndrome. Intramedullary tuberculoma in miliary tuberculosis patients usually responds satisfactorily to antituberculous treatment. Some patients respond better to surgery [19]. Intramedullary tuberculoma concomitant with disseminated intracerebral tuberculoma has rarely been reported in the literature [20]. Three of our patients presented a syndrome of possibly immunemediated acute transverse myelitis. Wasay et al. [21] reviewed the clinical and neuroimaging features of 10 similar patients. Due to its association with miliary tuberculosis immune-mediated acute transverse myelitis is termed “tuberculous myelitis”. Tuberculous myelitis predominantly affects the thoracic spinal cord. MR may show signal changes in the involved segments. Most spinal cord lesions appear as hyperintense on T2 and iso- or hypointense on T1-weighted images [21,22]. However, our patients had normal MR studies. In our series, another equally frequent mechanism of spinal cord involvement was Pott’s paraplegia. Vertebral involvement is rarely reported in miliary tuberculosis patients. Shah et al. [23] reported a similar case in an immunocompetent patient with multi-drug resistant miliary tuberculosis. In conclusion, miliary tuberculosis, though quite an uncommon form of tuberculosis, frequently shows central nervous system involvement. The common complications include tuberculous meningitis and intracranial tuberculomas. Patients are often admitted to the hospital more often because of a central nervous system involvement rather than pulmonary involvement. Fortunately, a majority of patients improve following antituberculous treatment. References [1] Baker SK, Glassroth J. Miliary tuberculosis. In: Rom WN, Garry SM, editors. Tuberculosis. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2004. p. 427–44. [2] Geppert EF, Leff A. The pathogenesis of pulmonary and miliary tuberculosis. Arch Intern Med 1979;139:1381–3.
[3] Sharma SK, Mohan A, Sharma A, Mitra DK. Miliary tuberculosis: new insights into an old disease. Lancet Infect Dis 2005;5:415–30. [4] Benzarti M, Jerray M, Souissi J, Hayouni A, Garrouche A, Klabi N. Brain abscess in the course of miliary tuberculosis: a case report and review of the literature. Int J Tuberc Lung Dis 1997;1:477–81. [5] Anuradha S, Kaur R, Singh NP, Baveja UK. Serodiagnosis of extra pulmonary tuberculosis using A-60 antigen. J Common Dis 2001;33:12–6. [6] Seehusen DA, Reeves MM, Fomin DA. Cerebrospinal fluid analysis. Am Fam Phys 2003;68:1103–8. [7] Kalita J, Misra UK, Ranjan P. Tuberculous meningitis with pulmonary miliary tuberculosis: a clinicoradiological study. Neurol India 2004;52:194–6. [8] Thwaites GE, Chau TT, Stepniewska K, Phu NH, Chuong LV, Sinh DX, et al. Diagnosis of adult tuberculous meningitis by use of clinical and laboratory features. Lancet 2002;360:1287–92. [9] Del Brutto OH, Mosquera A. Brainstem tuberculoma mimicking glioma: the role of antituberculous drugs as a diagnostic tool. Neurology 1999;52:210–1. [10] Girgis NI, Farid Z, Kilpatrick ME, Sultan Y, Mikhail IA. Dexamethasone adjunctive treatment for tuberculous meningitis. Pediatr Infect Dis J 1991;10:179–83. [11] Nicolls DJ, King M, Holland D, Bala J, del Rio C. Intracranial tuberculomas developing while on therapy for pulmonary tuberculosis. Lancet Infect Dis 2005;5:795–801. [12] Thwaites GE, Duc Bang N, Huy Dung N, Thi Quy H, Thi Tuong Oanh D, Thi Cam Thoa N, et al. The influence of HIV infection on clinical presentation, response to treatment, and outcome in adults with tuberculous meningitis. J Infect Dis 2005;192:2134–41. [13] Donald PR, Schaaf HS, Schoeman JF. Tuberculous meningitis and miliary tuberculosis: the Rich focus revisited. J Infect 2005;50:193–5. [14] Wasay M, Moolani MK, Zaheer J, Kheleani BA, Smego RA, Sarwari RA. Prognostic indicators in patients with intracranial tuberculoma: a review of 102 cases. J Pak Med Assoc 2004;54:83–7. [15] Thwaites GE, Macmullen-Price J, Tran TH, Pham PM, Nguyen TD, Simmons CP, et al. Serial MRI to determine the effect of dexamethasone on the cerebral pathology of tuberculous meningitis: an observational study. Lancet Neurol 2007;6:230–6. [16] Alkhani A, Al-Otaibi F, Cupler EJ, Lach B. Miliary tuberculomas of the brain: case report. Clin Neurol Neurosurg 2006;108:411–4. [17] Gupta RK, Kohli A, Gaur V, Lal JH, Kishore J. MRI of the brain in patients with miliary pulmonary tuberculosis without symptoms or signs of central nervous system involvement. Neuroradiology 1997;39:699–704. [18] Garg RK. Tuberculosis of the central nervous system. Postgrad Med J 1999;75:133–40. [19] Yen HL, Lee RJ, Lin JW, Chen HJ. Multiple tuberculomas in the brain and spinal cord: a case report. Spine 2003;28:E499–502. [20] Ramdurg SR, Gupta DK, Suri A, Sharma BS, Mahapatra AK. Spinal intramedullary tuberculosis: a series of 15 cases. Clin Neurol Neurosurg 2009;111:115–8. [21] Wasay M, Arif H, Kheleani B, Ahsan H. Neuroimaging of tuberculous myelitis: analysis of ten cases and review of literature. J Neuroimaging 2006;16:197–205. [22] Putruele AM, Lagarreta CG, Limongi L, Rossi SE. Tuberculous transverse myelitis: case report and review of literature. Clin Pulm Med 2005;12:46–52. [23] Shah A, Panjabi C, Maurya V, Khanna P. Multidrug resistant miliary tuberculosis and Pott’s disease in an immunocompetent patient. Saudi Med J 2004;25:1468–70.