TB rounds

Case Presentation

Kumud DahalInfectious Disease Fellow

History

• 47 y/o Haitian born lady

• PMH: DM,HTN, recently diagnosed HIV/AIDS on Feb 2011(through heterosexual transmission)

• Nadir CD4 on 2/11/11: 135, VL 40,300

• Pt was started on HAART (abacavir/lamivudine plus boosted darunavir) 6 weeks after HIV diagnosis, with daily bactrim prophylaxis

Follow up labs on 3/11/11: CD4:257, VL 484

• Initially admitted (3/31/11) with c/o severe unrelenting headache and neck pain for 3 days

• No fever/nausea/vomiting/photophobia

Physical Examination

Vitals: T: 98, P: 72, R: 12, BP: 140/70

•General: Nontoxic, well-nourished

•Neuro: AAO x3; intact speech; no meningismus, Cranial Nerves intact

•PERLA, EOMI

•No gait imbalance

•No nystagmus

•Power: normal and symmetric

•Plantars down; gait: normal; Romberg’s sign –ve

•No significant LAN

•No clubbing

•Rest of physical findings: unremarkable

Diagnostics

• Initial CT head: no acute abnormalities except hydrocephalous

• Patient underwent spinal tap

LP findings:

• WBC 84 (L 100%), RBC 340, Glucose 56, protein 115

• Gram stain and AFB stain: -ve

• Bacterial/Fungal Cultures –ve

• Cryptococcal antigen –ve

• Serum and CSF VDRL –ve

MRI brain (April 4, 2011):

• Obstructive hydrocephalous, secondary to T2 hypointense peripherally enhancing lesion in right tectum causing mass effect. Extensive T2 and FLAIR hyperintense signal in surrounding white matter tracts.

• No midline shift

Other multiple enhancing mass lesionsOther multiple enhancing mass lesions:

• Lt paramedian pons: 7 mm

• RT tectum: 8 mm

• Rt putamen: 4mm

• RT thalamus 7 mm

• Lt thalamus: 2 mm

Further Diagnostics

• CXR: normal

• Induced sputum for AFB: -ve x 3

• CSF AFB cultures –ve

• Repeat high volume tap also –ve for AFB

• Serum and CSF Toxo serology negative

• PPD –ve (on multiple occasions)

Summary

• 47 yr old F with HIV/AIDS, responding to HAART came with c/o severe headache and found to have aseptic meningitis on spinal tap and multiple ring enhancing lesions on brain MRI.

Top Differential Diagnosis

•CNS TB-IRIS

•CNS toxoplasmosis

Follow up

• Anti-tubercular therapy (RIPE) started along with tapering dose of steroids

• CNS Toxo therapy also started

• Repeat spinal tap (six days after initial tap): WBC 63(91%L), RBC 2, glucose 50, protein 106

• MRI repeat (2 weeks after initial MRI): decreased ventriculomegaly; decreased size and edema of peripherally enhancing lesion in brain stem and basal ganglia

Follow up continued

• Headache improved

• Pt clinically improved and discharged

Follow-up MRI (11/11/11)

• 7 months later Repeat MRI done to document response to therapy Pt is still on RIPE

• CD4 is now 350, VL <48

Follow up MRI Reading

• Interval increase in size of Rt midbrain lesion which now demonstrates increased size increased size of enhancing nodular portion which measures 1.1x1.1x1.1 cm(previously 0.7x0.7x0.7cm)

• Also increase of surrounding T2/FLAIR hyperintense signal

• All other prior ring enhancing lesions have near complete resolution with decreased edema

Clinical Follow Up

• Clinically: Patient continues to have dizziness and now has disequilibrium/gait instability

• Decreased headache

• No nystagmus

• CSF cultures remain negative for AFB

WHAT TO DO NEXT?

Diagnostic and Management Dilemma

1. Is the patient taking her TB therapy?

2. Is her TB therapy effective?

3. Is there adequate CNS levels of drugs?

4. Should the dose of TB meds be increased?

5. Should we be adding more TB drugs now?

• Dominique J. Pepper et al. Neurologic Manifestations of ParadoxicalTuberculosis-Associated Immune Reconstitution Inflammatory Syndrome: A

Case Series Clinical Infectious Diseases 2009; 48:e96–107• Meintjes G, Lawn SD, Scano F, et al. Tuberculosis-associated immune

reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis 2008; 8:516–23.

• Yukari C. Manabe et al. Unmasked Tuberculosis and Tuberculosis ImmuneReconstitution Inflammatory Disease: A Disease Spectrum after Initiation of

Antiretroviral Therapy. The Journal of Infectious Diseases 2009; 199:437– 44

TB Associated IRIS: Paradoxical TB-IRIS vs Unmasked TB-IRIS

• Development of TB after ART initiation, or “ART associated TB”: increasingly important

• TB-IRIS may present in one of two ways: first as paradoxical worsening of symptoms after commencement of ART, and second, as an ‘unmasking’ syndrome

• Among ART-associated TB cases, “unmasked TB” defined as that which occurs in the subset who develop clinically recognizable TB after the initiation of ART because of the restoration of TB antigen– specific functional immune responses

• Only a proportion of individuals with these unmasked TB (reactivation) cases will develop rapid, often destructive necrotic inflammation that is consistent with immune reconstitution inflammatory syndrome (IRIS)

•The temporal sequence of events distinguishes paradoxical TB-IRIS from unmasking TB-IRIS.

•Antitubercular treatment precedes ART in paradoxical TB-IRIS, whereas ART precedes tuberculosis diagnosis in unmasking TB-IRIS.

Unmasked tuberculosis (TB).

Manabe Y C et al. J Infect Dis. 2009;199:437-444

© 2009 by the Infectious Diseases Society of America

•Thus, unmasked TB excludes patients whose TB is primary and is only temporally associated with ART (i.e., these patients do not have rapid recall of TB antigen–specific memory immune responses).

•In this group of patients with primary TB, it would be unlikely that TB-IRIS would develop soon after the initiation of ART.

• Lymph node enlargement and pulmonary involvement are common manifestations of TB-IRIS; clinical and radiological features are well described.

• Neurological TB-IRIS, although accounting for over 10% of paradoxical TB-IRIS cases in a hospital setting, is less well documented; only one clinical case series and one radiological case series reported so far(Marias et al.).

• No case series of unmasked TB and TB-IRIS exist.

• Ours is a case of Unmasked CNS TB-IRIS; lymphocytic meningitis and multiple tuberculomas that became clinically evident in a patient with AIDS only after the initiation of ART and virological suppression.

• The clinical presentation of meningitis is consistent with CNS TB-IRIS and it was Unmasked because it was not diagnosed before ART despite evaluation.

How to explain the New/worsened mid-brain SOL 7 months after starting

antitubercular therapy?

Is it a Paradoxical CNS TB IRIS?Is it a Paradoxical CNS TB IRIS? If yes, should we intensify the steroid therapy?

Is it a co-infection with CNS Is it a co-infection with CNS toxoplasmosis?toxoplasmosis?

Is it something else?Is it something else?

Meintjes G, Lawn SD, Scano F, et al. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis 2008; 8:516–23.

Neuroradiological features associated with CNS TB-IRIS

•MRI features of TBM-IRIS been described in only one radiological case series(16 cases) : meningeal enhancement on imaging subsequent to commencement of ART, intra- and extraaxial lesions with peripheral contrast enhancement involving basal cisterns.

•Although parenchymal tuberculomas are commonly reported in HIV-1 infected patients, some studies suggest that multiple tuberculomas occur less frequently than in non-HIV-1-infected patients.(69% vs 33%).

•The imaging appearance of intracranial tuberculomas is non-specific, toxoplasmosis being the most frequent differential diagnosis in HIV-1-infected persons not on ART.

S. Marais et al. Neuroradiological features of the tuberculosis-associated immune reconstitution inflammatory syndrome. INT J TUBERC LUNG DIS 2010 14(2):188–196

• Dual infection of the CNS with M. tuberculosis and Toxoplasma gondii has also been reported1,2

• In the context of ART and Bactrim prophylaxis, diagnosis of ‘unmasking’ toxoplasmosis becomes less likely, but should still be considered

• In the absence of invasive brain biopsy, the diagnosis of solitary or multiple parenchymal lesions remains presumptive based on a combination of imaging findings together with CSF findings, ancillary tests (toxoplasmosis serology, CD4+ T-lymphocyte count, evidence for TB or TB-IRIS elsewhere) and response to treatment


1. Katrak S M, Shembalkar P K, Bijwe S R, Bhandarkar L D. The clinical, radiological and pathological profile of tuberculous meningitis in patients with and without human immunodeficiency virus infection. J Neurol Sci 2000; 181: 118–126.

2. Berenguer J, Moreno S, Laguna F, et al. Tuberculous meningitis in patients infected with the human immunodefi ciency virus. N Engl J Med 1992; 326: 668–672

• Common neuroradiological findings in TBM include basal meningeal enhancement, hydrocephalus and infarction.

• In HIV-1-infected patients with TBM, these findings occur with the following frequencies: meningeal enhancement 23–33%,hydrocephalus 20– 42%,obstructive hydrocephalus 5.5% and infarcts 39%.

• In TBM, presence of meningeal enhancement (33% vs. 82%) and obstructive hydrocephalus (5.5% vs. 64%) have previously been reported to be less frequent in profoundly immune-suppressed HIV-1 infected patients than in non-HIV-1-infected patients. It was ascribed to the attenuated immune response confirmed on histology (though inconsistent findings).


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