Central Nervous System Tuberculosis

www.npjournal.org The Journal for Nurse Practitioners - JNP 319

Central Nervous System

TuberculosisBarry Harris and Tara Morris

319-325_YJNP392_Harris_CP 4/26/07 8:50 AM Page 319

May 2007320 The Journal for Nurse Practitioners - JNP

Why should we care about tuberculosis (TB)? Recentreports have estimated that the incidence of TB hasdeclined in the United States.

Worldwide, it is estimated by the World HealthOrganization that each year, there are more than eight mil-lion new cases of TB, and three million people each yeardie of TB.1 Overall, it is estimated that 19% to 43% of theworld’s population has TB, including 15 to 30 millionAmericans.According to the Centers for Disease Control(CDC), 14,517 new cases of TB were reported in theUnited States during 2004, with foreign-born persons con-stituting 54%.The top five countries of origin of foreign-born persons with TB were Mexico, the Philippines,Vietnam, India, and China.Additionally, US-born blacksrepresented 45% of TB cases in the United States and morethan 20% of all cases. Of note,Texas, California, and NewYork accounted for 42% of the overall cases reported in2004.2

Although the overall incidence of TB has declined inthe United States in recent years,2 it is a formidable diseasebecause of its highly infectious nature, insidious presenta-tion, and propensity for latency. Health care workers in theUnited States need to be able to identify persons who are at

risk of or who have contracted TB.As is well known,TBcan affect multiple organ systems, the most common beingpulmonary. However, research shows that as many as 10% ofpersons with pulmonary TB develop central nervous system(CNS) TB, which can manifest as meningitis or lesions ofthe brain or spine.3-5 In addition, extrapulmonary TB,including miliary (disseminated) disease, is on the rise sec-ondary to its increased prevalence in HIV-infected persons,medically underdeveloped populations, and alcohol andintravenous drug abusers.1,6 For these reasons, it is imperativeto maintain a high degree of suspicion when patients withTB risk factors present with neurologic complaints.

CASE STUDIESTB meningitis can present in several ways. Let us reviewa few case studies.

Case Study 1Patient: 44-year-old manPast medical history (PMH): HIV, CD4 count of 53,

miliary TB of the chest Presentation: headache, vertigo, nausea, vomitingMagnetic resonance imaging (MRI): multiple ring-enhancing

lesions (Figures 1 and 3) and cerebral edema (Figure 2)Differential diagnoses: lymphoma, CNS/neuro tuberculomaSurgery: right temporal open brain biopsySpecimen: positive for acid-fast bacillus (AFB)Rx: ethambutol (EMB), isoniazid (INH), pyrazinamide

(PZA), rifabutin

Case Study 2Patient: 66-year-old manPMH: rheumatoid arthritisPresentation: 4 weeks of headache and fatigueMRI: enhancing right temporal lesion with vasogenic

edema (Figures 4-6)Differential diagnoses: suspected glioma, lymphoma,

CNS/neuro tuberculomaSurgery: frontal-temporal craniotomy, excisional biopsy,

and temporal lobectomySpecimen: frozen: hypercellular, suspected malignancy;

final:AFBRx: patient referred to and transferred to the infectious

disease team

ABSTRACTAlthough the incidence of tuberculosis (TB) hasdecreased in the United States, this infection is aformidable force worldwide.TB can have aninsidious presentation, affecting multiple organsystems, including the central nervous system(CNS).Although this may be a rare complicationof TB, it can be a devastating omission for thepatient.Therefore, it is imperative for health careproviders to keep CNS TB in the differentialwhen evaluating neurologic issues.The goal ofthis article is to enlighten the midlevel providerabout the possible presentations of CNS TB,review diagnostic and laboratory studies, andexplain treatment options.Keywords: brain, central nervous system, CNS,meningitis,TB, tuberculoma, tuberculosis, spine



Case Study 3Patient: 22-year-old Mexican man (recently moved from

Mexico to the United States)PMH: NonePresentation: 3 months of headacheComputed tomography (CT) scan: posterior fossa mass, mild

obstructive hydrocephalusMRI: 3-cm ring-enhancing mass in the superior vermis

(Figures 7-9)Differential diagnoses: lymphoma, CNS/neuro TBSurgery: suboccipital craniotomy, mass resection, dural

patch, right occipital intraventricular catheterSpecimen: frozen: granulomatous mass; final:AFBRx: EMB, INH, PZA, rifabutin

INCIDENCEThe incidence of TB is increasing worldwide.6 Somereports keep TB as the “leading cause of death due to asingle infectious agent” and the seventh leading cause ofdeath and disability worldwide.3,7 Many factors predis-pose a person to TB. Bayindir et al8 state that 95% oftheir patients had low social, economic, and nutritionalconditions.There are approximately 300 to 400 cases ofTB meningitis in the United States each year.9 CNStuberculomas are seen in 0.55% to 15% of systemic TBcases, depending on the study reviewed.3,8,10 Intracranialtuberculomas are seen in about 1% of all patients withTB,6 whereas intradural spinal tuberculomas are reportedto be 2% to 5% of CNS tuberculomas.11

Figure 1. Axial MRI showing typical ring

enhancing lesions of CNS TB.

Figure 2. Axial MRI (Flare sequence)

showing cerebral edema.

Figure 3. Coronal MRI showing typical

ring enhancing lesions of CNS TB.

Figure 4. Coronal MRI with multiple ring

enhancing lesions.

Figure 5. MRI showing typical

vasongenic edema.

Figure 6. Coronal MRI with ring enhancing

mass and associated edema.

Figure 7. Axial MRI with an abnormally shaped

ring enhancing lesions typical of CNS TB.

Figure 8. Sagital MRI showing ring enhancing

lesion (seen in coronal view on Figure 9).

Figure 9. Coronal MRI showing ring enhancing

lesion (seen in sagital view on Figure 8).

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PATHOGENESISTB is an infectious disease caused by the obligate aerobicbacillus, Mycobacterium tuberculosis.12 It is transmittedthrough inhalation of as few as 1 to 10 aerosolizeddroplets containing the bacteria.As the bacteria multiplyin the alveoli and macrophages of the lung, the complexcell-mediated immune response generates a granuloma-tous reaction, resulting in a tubercle and caseating necrosis(a small rounded lesion with a necrosing center).9 Itsouter waxy capsule makes it more resistant to destruction.As a result, this bacterium can persist in old necrotic andcalcified lesions and is capable of reinitiating growth. Ifthe bacteria are not contained, the infection can behematogenously spread to other sites.9

The location of TB spread to the CNS is directlyrelated to the pattern of blood flow and usually spreadsto the cerebral hemispheres and basal ganglia in adultsand to the cerebellum in children.The ratio ofintramedullary to intracranial lesions are found to relateto spinal cord versus brain weight, about 1:42.10 Spinallesions are most often found in the thoracic spine andoften present as subacute cord compression.12

A tubercle that ruptures in the subarachnoid spaceresults in TB meningitis, whereas deep lesions causetuberculomas or abscesses.The tuberculoma capsule iscomposed of fibroblasts, lymphocytes, epithelioid cells,and Langhans giant cells, and its core is a necroticcaseous center.13,14 When this core liquefies, the lesionbecomes a tuberculous abscess, packed with AFB.Vascularinflammation, vasculitis, and edema, which can occuraround the lesions, are products of the immune responseand can cause additional clinical complications.TBmeningitis is a result of an intense hypersensitivity reaction that gives rise to inflammatory changes involv-ing cranial nerves.The inflammation can also affectblood vessels, resulting in vasculitis and subsequentthrombosis or infarction, causing strokelike syndromes.Communicating hydrocephalus can also occur secondaryto impedance of cerebrospinal fluid (CSF) circulationand reabsorption.1 (The arachnoid layer is the primarylayer where CSF is reabsorbed.)

RISK FACTORSRisk factors associated with acquiring TB are listed in Table 1. Only patients with pulmonary TB are infec-tious1; however, the risk factors for developing pul-monary and extrapulmonary TB are comparable.

PRESENTING SIGNS AND SYMPTOMSCNS TB presents in many different ways.A patient maybe asymptomatic, have pulmonary symptoms, or haveneurologic deficits alone.As one can see from the casestudies, all of the patients had headaches, but one hadvertigo and another fatigue. CNS TB usually has signsand symptoms of increased intracranial pressure or space-occupying lesions in the brain or spine.15 Common com-plaints may include headache, stiff neck, fever, weightloss, blurry vision, confusion, lethargy, nausea, vomiting,and, for spinal cord lesions, lower extremity weakness orbowel or bladder symptoms. Signs of meningitis mayinclude altered mental status, fever, seizure, cranial nervedeficits, papilledema, or meningismus. Patients withtuberculomas will have a physical examination that isconsistent with the location in the brain of the space-occupying lesion, which may include cranial nervedeficits, altered mental status, visual changes, hemiparesis,or seizures. Patients with spinal cord lesions will have aphysical examination consistent with the location of thelesion in the spinal cord.8,15

DIAGNOSTIC TESTINGImagingA CT scan of the brain should be done if there is suspi-cion for intracranial or intramedullary TB.The CT scanshould be done with and without contrast. Immaturelesions are hypodense and nonenhancing. Mature lesionsare isodense to hyperdense with solid, ring, or mixedenhancement.There is a typical target sign suggestive of

Table 1. Risk Factors

• Immunosuppression, HIV, AIDS

• Alcoholism

• Immigration

• Diabetes

• Underlying malignancies

• Chronic renal failure

• Immunosuppressive drugs

• Intravenous drug abuse

• Contact with people known to have TB

• Poor ventilation

• Homelessness

• Crowding (ie, incarceration, group home, etc)



TB. CT findings are similar to that of many other CNSlesions, including fungal infections, neurosarcoidosis, bac-terial infections, and some metastatic disease.16

An MRI scan is more specific and sensitive than aCT scan and should be done with and without contrast.T1-weighted images show central isointensity.T2-weighted images show an isotense to hypertense coreand a hyperintense rim, ring, or conglomerate of ringswith enhancement.3 MRI findings may also mimic sev-eral of the aforementioned lesions.

Laboratory TestsLaboratory results are not discussed much in the liter-ature. Diagnosis is often made on history and physical,suspicion, and diagnostic imaging.Some laboratory findings are listedhere.

Cerebrospinal fluid. Lumbar punc-tures that remove 10 to 15 mL providethe best information. CSF studies mayshow normal findings17 or have elevatedprotein, decreased glucose, or pleocytosis.Results of CSF polymerase chain reaction tests may bediagnostic.15,16 Most patients will have an elevated openingpressure as well.18

Always get an AFB smear when testing CSF.Although there are a fair amount of false negatives, withserial AFB smears (up to 4) the diagnostic yield is 87%.9

Mantoux tests. Mantoux tests may be positive ornegative.

Other blood work. Sedimentation rate, C-reactiveprotein, and white blood cell count may also be elevated.

Biopsy of the lesion should be done if the diagnosisis unclear and the lesion is in an accessible area or if neu-rologic compromise is present. Histopathology may showa central necrosis, lymphocytes, Langerhans giant cells, orepithelioid cells.8,11 Bacilli may or may not be present.

DIAGNOSTIC PATHWAYNo definitive diagnostic pathway is available for CNSTB. Many times the diagnosis is discovered on biopsy.Often, the clinical diagnosis is neoplasm; therefore, it isappropriate to work up the lesion as a neoplasm.

When a patient has a history that is consistent withrisk factors for TB, a Mantoux test is an appropriateplace to start. If there are any signs of headache or neu-rologic deficit, CT scan, MRI scan, or both are impor-

tant tests to order. Scans that reveal lesions should imme-diately be referred to a neurosurgery team for furtherworkup and diagnosis. Once the diagnosis is finalized, itis important to use a multidisciplinary approach topatient care.

DIFFERENTIAL DIAGNOSISPossible differential diagnoses include necrotic tumors,pyogenic abscess, toxoplasmosis, meningitis,lymphoma, and neoplasm.

TREATMENTSurgical intervention for intracranial tuberculomas isgenerally not recommended because prolonged pharma-

cologic therapy combined with corti-costeroids is usually effective in treat-ing these lesions. However, surgerymay be warranted if immediatedecompression is necessary or if biopsyis required for definitive diagnosis.3

CDC guidelines recommend a 9-to 12-month pharmacologic treatment

regimen for CNS TB and offer four regimens for adminis-tering treatment.The initial phase of treatment in the first2 months should include INH, rifampin (RIF), PZA, andEMB.The medications can be given daily throughout thefirst phase, daily for 2 weeks, and then twice weekly for 6weeks, or three times weekly throughout.With differingadministration schedules come differing doses of thedrugs. If the organism’s drug susceptibilities are known,and it is fully susceptible, EMB need not be included inthe initial phase. PZA should be avoided in severe liverdisease, gout, and, perhaps, pregnancy.The continuationphase should consist of INH and RIF for 7 to 10 months,and this timeline should be prolonged if the patient wasinitially slow to respond to treatment.15,19,20 When patientswith intracranial tuberculomas experience increasedintracranial pressure or neurologic symptoms, corticos-teroids can be added to the regimen, although their valueis still under investigation.6,15,17

Several cases of paradoxical enlargement of intracra-nial tuberculomas or development of new ones duringtreatment have been observed.3,6,15,17 Initiation of steroidsin these patients was helpful in many cases, often helpingto prevent surgical intervention.3 The development ofintracranial TB lesions while on anti-TB therapy shouldnot be considered a failure of treatment. Rather, treat-

Always get an AFB smear when

testing CSF.



ment should be continued for a prolonged course, andhigh-dose corticosteroids added to the regimen. RepeatMRI scans should be done every few months to trackthe lesion or lesions.3,21

In addition, many special circumstances are consid-ered when initiating treatment. Drug resistance or his-tory of previous therapy may change the pharmacologicconstituents and duration of treatment. In anotherexample, the regimen for children is much the same asthe regimen for adults; however, EMB is not frequentlyused because of its serious side effects of blurred vision,sudden changes in vision, and inability to see the colorsred and green. In patients who are HIV positive, theonce weekly dosing regimen for the continuation phaseis not an option because of the development of resist-ance to RIF, and those with a CD4 count of less than100 should receive daily or three times weekly dosing.Furthermore, anti-TB medications interact with anti-retroviral agents; therefore, it is recommended thattreatment of these patients be deferred to an HIV-relat-ed TB specialist. For patients with renal insufficiency orend-stage renal disease, special dosing considerationsmust be addressed. In the face of liver disease, prudentuse of anti-TB drugs is recommended. INH, RIF, andPZA can cause hepatitis or worsen liver disease.However, because of the effectiveness of these drugs,their use is still recommended, depending on results ofliver enzyme tests.

If serum aspartate transaminase is more than threetimes the normal level before initiation of treatment, theCDC offers several alternative regimens. In women whoare pregnant or breastfeeding, streptomycin is the onlydrug that is documented to be harmful to the fetus,causing deafness. (Streptomycin is not commonly used intreatment because of high rates of resistance.) Womenwho are taking first-line anti-TB drugs can continuebreastfeeding because the small concentrations of thedrugs in the breast milk do not cause toxicity in thenewborn.19 Dosing and regimen specifics can be found atthe CDC website, www.cdc.gov.

The CDC also recommends directly observed thera-py for the following situations: pulmonary TB with posi-tive sputum smears, treatment failure, drug resistance,relapse, HIV infection, previous treatment, current orprior substance abuse, psychiatric illness, memory impair-ment, previous nonadherence to therapy, and childrenand adolescents.19

Social issues that must be considered in successful TBtreatment are language barriers, socioeconomic differ-ences, access to resources (transportation, clinic, etc),insurance issues, child care, and housing.19 As is common-ly known, having an effective social support system isessential for successful treatment of most ailments.

PROGNOSISPrognosis varies depending on the studies that are exam-ined. Bayindir et al8 and Wang et al4 believe that the out-come depends on the age and clinical stage of thepatient. Both studies also suggest that prognosis is worsewhen there is a rapid deterioration in the patient’s neu-rologic status. However, Muthukumar et al11 suggest thatmedical and surgical outcomes have had good results.Some researchers speculate that a treatment regimeninvolving surgery (depending on the superficiality of thelesion) and a regimen that is purely pharmacologic willboth result in resolution of symptoms. However, it ispossible that patients treated with drugs alone are morelikely to return to baseline.15

SUMMARYAlthough CNS TB is a rare complication of TB, it is a seri-ous disease, and early recognition and treatment are imper-ative. Early diagnosis can prevent further deterioration andresult in better prognosis.When a patient with known TBhas neurologic complaints, immediate action must be takento evaluate for CNS TB. In addition, this diagnosis shouldbe on the differential for any patient seeking treatmentwith neurologic symptoms, whether or not the patient hasbeen diagnosed with pulmonary TB. CSF studies, CT andMRI scans, the Mantoux test, and brain biopsy, if necessary,can aid in establishing a diagnosis of CNS TB.Althoughthere are varying opinions as to duration of treatment, theaddition of corticosteroids, and the role of surgery in treat-ment, it is generally agreed that the pharmacologic regi-men is the mainstay of treatment.

References

1. Leonard, MK. (2002, 10/01/2002). Tuberculosis: forms of tuberculosis. 2002Oct 1. Available at: www.medscape.com/viewarticle/534783?rss m. AccessedMay 25, 2006.

2. Centers for Disease Control and Prevention. Reported Tuberculosis in theUnited States, 2004. Atlanta, GA: US Department of Health and HumanServices, CDC, September 2005.

3. Wasay M, Kheleani BA, Moolani MK, et al. Brain CT and MRI findings in 100consecutive patients with intracranial tuberculoma. Neuroimaging.2003;13(3):240-247.

4. Wang KC, Lin SM, Chen Y, Tseng SH. Multiple tuberculous brain abscesses.Scand J Infect Dis. 2002;34(12):931-934.


http://www.cdc.gov

http://www.medscape.com/viewarticle/534783?rssm


5. Skendros P, Kamaria F, Kontopoulos V, Tsitouridis I, Sidiropoulos L.Intradural, extramedullary tuberculoma of the spinal cord as a complicationof tuberculous meningitis. Infection. 2003;31(2):115-117.

6. Bas NS, Guzey FK, Emel E, Alatas I, Sel B. Paradoxical intracranialtuberculoma requiring surgical treatment. Pediatr Neurosurg.2005;41(4):201-205.

7. Akritidis N, Galiastsou E, Kakadellis J, Dimas K, Paparounas K. Braintuberculomas due to miliary tuberculosis. South Med J. 2005;98(1):111-113.

8. Bayindir C, Mete O, Bilgic B. Retrospective study of 23 pathologicallyproven cases of central nervous system tuberculomas. Clin NeurolNeurosurg. 2006;108(4):353-357.

9. Porth CM, Kunert MP. Pathophysiology: Concepts of Altered Health States.Philadelphia, PA: Lippincott, 2002.

10. Jaiswal AK, Jaisqal S, Gupta SK, Singh Gautam VK, Kumar S. Intramedullarytuberculoma of the conus. J Clin Neurosci. 2006;13(8):870-872.

11. Muthukumar N, Venkatesh G, Senthilbabu S, Rajbaskar R. Surgery forintramedullary tuberculoma of the spinal cord: report of 2 cases. SurgNeurol. 2006;66(1):69-74.

12. Citow JS, Ammirati M. Intramedullary tuberculoma of the spinal cord: casereport. Neurosurgery. 1994;35(2):327-330.

13. Torii H, Takahashi T, Shimizu H, Watanabe M, Tominaga T. Intramedullaryspinal tuberculoma. Neurol Med Chir (Tokyo). 2004;44(5):266-268.

14. Kim TK, Chang KH, Kim CJ, Goo JM, Kook MC, Han MH. Intracranialtuberculoma: comparison of MR with pathologic findings. Am JNeuroradiol. 1995;16(9):1903-1908.

15. Nicolls DJ, King M, Holland D, Bala J, del Rio C. Intracranial tuberculomasdeveloping while on therapy for pulmonary tuberculosis. Lancet Infect Dis.2005;5(12):795-801.

16. Corr PD. Tuberculosis, CNS. 2004 Nov 5. Available at:www.emedicine.com/radio/topic720.htm. Accessed November 18, 2005.

17. Chanet V, Baud O, Deffond D, Romaszko JP, Beytout J. Pseudotumorpresentation of intracerebral tuberculomas. South Med J. 2005;98(4):489-491.

18. Unal S, Sutlas PN. Clinical and radiological features of symptomatic centralnervous system tuberculomas. Eur J Neurol. 2005;12(10):797-804.

19. American Thoracic Society; CDC; Infectious Diseases Society of America.Treatment of tuberculosis. MMWR Recomm Rep. 2003;52(RR-11):1-77.Available at: www.cdc.gov/mmwr/preview/mmwrhtml/rr5211a1.htm.Accessed January 5, 2007.

20. Bajaj BK. Duration of therapy for tubercular meningitis. 2002 Dec 16.Available at: www.medscape.com/viewarticle/444649. Accessed January 10,2007.

21. Dennison P, Rajakaruna G. Cerebral tuberculoma [case report]. Thorax.2006;61(10):922.

Barry Harris, RN, BSN, MSN, CRNP-BC, and TaraMorris, MHR, MHS, PA-C, work in the Department ofNeurosurgery at the Sinai Hospital of Baltimore, part of theLife Bridge Health System, and neither author has a rela-tionship with business or industry to disclose. Harris can bereached at [email protected].

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Central Nervous System Tuberculosis

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