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Case 7: Fever and Altered Mental Status
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Patient Presentation
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History
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Physical Exam
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Laboratory Data
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Differential Diagnosis
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Conclusive Laboratory Findings
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Diagnosis
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Treatment
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Discussion
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Learning Points
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References
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Patient Presentation
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A 32-year-old HIV-infected man with a recent CD4 count of 146 cells/µL presented to Mulago Hospital in Kampala, Uganda, with fever, altered mental status, and vomiting.

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History
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At the time of our assessment, the patient was too altered to provide a history. According to family members, he was in his usual state of health until 3 days before admission, when he developed fevers and confusion, and began vomiting. He complained of a headache and neck stiffness. He was taken to a local clinic, where he was diagnosed with malaria based on 3 of 3 positive blood smears (malarial species not documented). The patient was treated for malaria, but his family members could not recall which antimalarial drugs he was given. At the time of his presentation to Mulago Hospital, he had not passed urine for one day.

The patient had been seen at the Infectious Diseases Institute clinic at Mulago Hospital, but had never been on antiretroviral therapy. He was not taking any medications before the onset of his illness and had no known drug allergies. His last CD4 count of 146 cells/µL was measured a month and a half before admission. The patient smokes tobacco and reportedly has a history of significant alcohol intake.

At the time of admission, the patient was treated empirically for cerebral malaria and bacterial meningitis with intravenous (IV) quinine and IV cefuroxime, respectively. He was hydrated with dextrose-containing IV fluids. Following 3 days of treatment, his mental status had not improved, but he was making some urine. A lumbar puncture was performed on hospital day 4.

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Physical Exam
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(Hospital Day 3)

General: ill-appearing, thin man; somnolent but arouses to touch, moaning incomprehensibly, intermittently opens eyes in response to stimuli

Vital signs: Temperature--39.0°C; blood pressure--100/60; heart rate--90 beats per minute; respiratory rate--16 breaths per minute; oxygen saturation--not available

HEENT (head, eyes, ears, nose, throat): mild scleral icterus; pupils equal, round, reactive to light (PERRL); extraocular movement (EOM) intact except for limitation on lateral gaze with right eye only (consistent with right 6th cranial nerve palsy)

Neck: no jugular venous distention; positive neck stiffness; positive jolt sign; no cervical lymphadenopathy

Chest: rhonchi breath sounds bilaterally, no wheezes or rales

Cardiovascular: regular rate and rhythm; normal s1 and s2; no murmurs, rubs, or gallops; point of maximal impulse (PMI) was focal, nondisplaced, and of normal intensity

Abdomen: soft, nondistended, nontender; no hepatosplenomegaly; normoactive bowel sounds

Extremities: no clubbing, cyanosis, or edema; 2+ distal pulses

Neurological: Glasgow Coma Score (GCS)--11 (motor responsiveness = 5, eye opening = 4, verbal performance = 2); moving all extremities spontaneously

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Laboratory Data
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White blood count (WBC): 4,500 cells/µL

Hemoglobin: 13.4 g/dL

Hematocrit: 40.3%

Platelets: 245,000 cells/µL

Chloride: 103 mmol/L

Potassium: 3.9 mmol/L

Creatinine: 124.5 µmol/L (reference range: 53-133 µmol/L)

Total bilirubin: 29 µmol/L (reference range: 0-17 µmol/L)

Direct bilirubin: 25.9 µmol/L (reference range: 0-5.1 µmol/L)

Alkaline phosphatase: 163 U/L (reference range: 100-290 U/L)

Alanine aminotransferase (ALT): 10 U/L (reference range: 0-40 U/L)

Gamma-glutamyltransferase (GGT): 66 U/L (reference range: 0-55 U/L)

Albumin: 34 g/L (reference range: 35-50 g/L)

Chest X ray: bilateral fluffy infiltrates, left side greater than right side

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Differential Diagnosis
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  • Cerebral malaria

  • Tuberculous (TB) meningitis

  • Bacterial or viral meningitis

  • Cryptococcal meningitis

  • African trypanosomiasis

  • Viral encephalitis

  • Mass lesions:
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    • Toxoplasmosis

    • Central nervous system lymphoma

    • Tuberculoma

  • Brain abscess

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Conclusive Laboratory Findings
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Cerebrospinal Fluid (CSF) Collection (hospital day 4)

Appearance: slightly xanthochromic, otherwise clear

Wet prep: moderate red blood cells, few WBCs, no yeast cells or parasites

WBC: 30 cells/µL; lymphocytes--83%; neutrophils--17%

Protein: 80 mg/dL

Glucose: 2.95 mmol/L (53.1 mg/dL) (serum glucose level at time of lumbar puncture unknown)

India ink: no capsulated yeast

Ziehl-Neelsen stain: pus cells, no organisms

Gram stain: negative for organisms

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Diagnosis
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Given the patient's immunocompromised status and failure to improve with appropriate therapy for cerebral malaria and typical bacterial meningitis, the medical team began to favor TB meningitis as an alternative diagnosis.

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Treatment
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On hospital day 5, the patient was noted to be tachypneic and his mental status had not improved. Because of his worsening clinical condition, the patient was started on empiric treatment for TB meningitis with rifampin, isoniazid, pyrazinamide, ethambutol, and prednisolone.

As mentioned, the patient was initially treated for cerebral malaria and covered empirically with antibiotics for bacterial meningitis. Because CSF was obtained several days after the start of treatment, interpreting the results of laboratory findings on those samples was somewhat difficult. The low-level leukocytosis with lymphocyte predominance and absence of organisms on Gram stain supported a diagnosis of TB meningitis, cerebral malaria, or viral meningoencephalitis. Cryptococcal meningitis was unlikely given the patient's recent CD4 count of >100 cells/µL and negative India ink stain. African trypanosomiasis was also a definite possibility, but CSF was not examined for immunoglobulin M or for the Trypanosoma parasite itself. Mass lesions could not be excluded because the cost of a computed tomography (CT) scan was prohibitive. It would have been ideal to exclude mass lesions with a CT scan before the lumbar puncture in this immunocompromised patient with an altered level of consciousness and a focal cranial nerve palsy.(1)

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Discussion
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Cerebral malaria was initially the primary consideration in the differential diagnosis for this patient, given his history of 3 positive results from blood smears for Plasmodium. The species of malarial parasite was not documented in this patient, but it is very likely that it was Plasmodium falciparum, as the organism causes 95% of malaria cases in Uganda. Cerebral malaria, one the most severe forms of falciparum malaria, should be suspected in any patient with an impaired level of consciousness in a malaria-endemic region. Sub-Saharan Africa has the greatest intensity of malaria transmission in the world. In Uganda, 39% of outpatient visits and 35% of hospitalizations are related to malaria, and there is an estimated incidence of 0.64-1.8 episodes per individual per year for patients above 5 years of age.(2) The proposed World Health Organization (WHO) definition of cerebral malaria includes coma (inability to respond to noxious stimuli), exclusion of other causes of encephalopathy, and detection of asexual forms of P falciparum on peripheral blood smears. Adults with cerebral malaria, as opposed to children, are less likely to have seizures (20% vs 80%). More typical signs include gradually worsening mental status, jaundice, lactic acidosis, symmetrical upper motor neuron signs, and multiorgan system dysfunction (eg, shock; coagulopathy; and hepatic, renal, and pulmonary compromise). Brainstem signs, which are present in more than 30% of children, are less common in adults. Cerebral malaria has a very high mortality rate, approximately 20% in adults despite treatment.(3)

Risk factors for cerebral malaria include age (with increased incidence in both children and adults as opposed to infants), host genetic susceptibility, HIV infection, history of splenectomy, transmission intensity, and altitude of residence. High transmission rates provide a protective effect against cerebral malaria, a phenomenon thought to be caused by an adaptive immune response from prior exposure to the malarial parasite. At higher altitudes, decreased transmission intensity results in a higher incidence of cerebral malaria.(4)

There is mounting evidence of an association between HIV and malaria. Several studies have shown that patients infected with HIV have a higher incidence of malaria infection,(5,6,7) although earlier reports did not show an interaction.(8) In one observational study in Malawi (n = 349), the overall incidence of parasitemia in HIV-infected individuals was 4.8 (95% confidence interval [CI]: 4.0-5.7), as compared with 2.3 (95% CI: 1.8-3.1) in HIV-seronegative individuals over a 6-month period (adjusted hazards ratio: 1.9; 95% CI: 1.4-2.6). HIV infection and a lower CD4 count were both associated with increased risk of symptomatic malarial infection as defined by fever and parasite density, but rates of severe malaria or cerebral malaria were not recorded.(6) Conversely, there is also evidence that malaria may increase the rate of HIV transmission in endemic areas, owing to a transient increase in HIV viral load.(9,10) Recently, a mathematical model was designed to evaluate the potential for increased HIV transmission rates and increased susceptibility to malaria in a region of Kenya with a population of 200,000 and an HIV prevalence of 25%. Using this model, Abu-Raddad and colleagues estimated an additional 8,500 HIV infections related to malaria and 980,000 additional malaria episodes associated with HIV in that region since 1980.(11)

Studies have shown that daily cotrimoxazole (trimethoprim/sulfamethoxazole) prophylaxis decreases the incidence of malaria in HIV-infected individuals. One prospective cohort study in Uganda showed a decreased malaria incidence from 50.8 episodes per 100 person-years to 9.0 episodes per 100 person-years (adjusted incidence rate ratio: 0.24; 95% CI: 0.15-0.38) after the initiation of cotrimoxazole prophylaxis.(12)

Routinely, cerebral malaria has been treated with IV quinine. Data also support the use of artemisinin derivatives, which clear circulating parasites faster than other antimalarial drugs and are available in suppository and parenteral formulations. A metaanalysis comparing artemisinin drugs with quinine treatment for cerebral malaria showed a decreased mortality rate (odds ratio: 0.63; 95% CI: 0.44-0.88) favoring the artemisinin drugs; however, the benefit was no longer significant when analysis was restricted to blinded studies.(13) Subsequent studies have more convincingly supported artemisinin-based treatment over quinine for severe malaria. In one nonblinded, randomized trial in Southeast Asia (n = 1,461), mortality was significantly decreased in the artesunate recipients (15%) compared with those receiving quinine (22%), with an absolute risk reduction of 34.7% in the artesunate vs the quinine group (95% CI: 18.5-47.6; p = .0002).(14) Generally, clinical improvement is seen within 48 hours after the initiation of treatment.(3) However, parenteral formulations of artemisinin drugs are not readily available in Uganda.

In this case, the constellation of fever, altered mental status, and vomiting, combined with meningeal signs and cranial nerve palsy on examination, was certainly consistent with TB meningitis as well. Mycobacterium tuberculosis can affect the central nervous system in 3 ways: meningitis, intracranial tuberculoma, and spinal tuberculous arachnoiditis. In sub-Saharan Africa, owing to high rates of HIV infection, TB meningitis is now the most common form of bacterial meningitis. In children, TB meningitis typically follows primary infection. In adults, it is more frequently the result of reactivation of a dormant subcortical or meningeal focus. Specifically, there is rupture of a subependymal tubercle into the subarachnoid space, resulting in local inflammation that may affect cranial nerves and penetrating vessels. Manifestations may include cranial nerve palsies, communicating hydrocephalus, focal neurologic deficits, meningismus, decreased level of consciousness, seizures, and symptoms of elevated intracranial pressure (eg, headache and vomiting).(15,16)

The chest X ray is abnormal in about 50% of TB meningitis cases, as it was in this one. The severity of TB meningitis at presentation, as determined by initial GCS and presence or absence of focal neurologic signs, has been shown to be strongly predictive of mortality.(17) In this case, the patient was classified as Grade II based on his GCS of 11 at our initial exam.

Table 1. Grading of Tuberculous Meningitis
GradeDescription
IAlert and oriented without focal neurological deficit
IIGlasgow coma score (GCS) of 10-14 with or without focal neurological deficit, or GCS of 15 with focal neurological deficit
IIIGCS of less than 10 with or without focal neurological deficit
Source: British Medical Research Council. Streptomycin treatment of tuberculous meningitis. BMJ 1948;1:582-597.
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However, diagnostic tests are notoriously insensitive in yielding a definitive diagnosis of TB meningitis. Lumbar puncture is perhaps the most useful test, with the "classic" picture showing a modestly elevated WBC count with lymphocytic predominance, high protein, and low glucose (CSF glucose to blood glucose ratio <0.5 in 95% of cases). In this case, all of these criteria were met except for the low CSF glucose, which may still have been less than half the serum glucose level, considering that the patient was receiving dextrose-containing IV fluids. However, we could not calculate this ratio as his serum glucose was not measured. A diagnostic rule with 86% sensitivity and 79% specificity was developed by Thwaites and colleagues; included were age, serum WBC, length of illness, CSF WBC, and percentage of CSF neutrophils. By this rule, our patient scored a zero on a scale in which a score of <=4 suggests TB meningitis in the appropriate clinical context. Ziehl-Neelsen staining for acid-fast organisms has a sensitivity of only 10-20%, but this can be improved to 80% by repeated sampling of a large volume (>5 mL) of CSF. Culture of CSF, the gold standard for diagnosis of most other meningitides, had a sensitivity of 71% in a recent study (as compared with <50% in other studies), but results are usually not available for several weeks.(17) A recent systematic review and metaanalysis of nucleic acid amplification tests demonstrated a sensitivity of 56% and specificity of 98% for diagnosis of TB meningitis. These results suggest that molecular methods are no better than bacteriologic methods in the typical case, but may have a role in diagnosis after treatment with antituberculin drugs has been started, when bacteriologic methods become less sensitive.(18) Advanced imaging with CT or magnetic resonance, looking for basal meningeal enhancement or tuberculomas, can be a valuable tool for diagnosis but is unlikely to be feasible in resource-limited areas.(19)

Because of the high morbidity and mortality of patients with TB meningitis, the consensus opinion is that 4-drug therapy should be started immediately after the diagnosis is suspected. Intensive-phase chemotherapy for the first 2 months should include isoniazid, rifampin, pyrazinamide, and ethambutol. Guidelines of the joint committee of the American Thoracic Society, U.S. Centers for Disease Control and Prevention, and the Infectious Diseases Society of America issued in 2003 recommend an additional 7-9 months of therapy with isoniazid and rifampin.(17) The use of adjunctive corticosteroids is controversial. A recent randomized controlled trial involving adolescents and adults found that treatment with dexamethasone was associated with a reduced risk of death (relative risk: 0.69; 95% CI: 0.52-0.92; p = .01), but did not prevent severe disability among the survivors. Even with maximal medical therapy, this study and previous ones have found that TB meningitis kills or severely disables more than half of the patients who have it.(20)

HIV is a major risk factor for the development of TB meningitis. Moreover, coinfection with HIV has a substantial effect on the clinical course of patients with TB meningitis. A prospective study of 96 HIV-infected patients with TB meningitis showed that they had a 65% mortality rate at 9 months and that their survival rate was significantly less than that of patients without HIV (relative risk of death from any cause: 2.91; 95% CI: 2.14-3.96; p < .001). However, the same study showed that HIV infection did not alter the presenting neurological features of TB meningitis and did not adversely affect the outcome of disability in survivors. The authors postulate that the increased mortality in the HIV-infected population reflects undiagnosed opportunistic infections in patients who had a median CD4 count of 67 cells/µL and were not taking antiretroviral drugs.(21) The authors also found that dexamethasone was associated with a reduction in mortality that was not statistically significant in the subgroup analysis of HIV patients.(20)

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Learning Points
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  • Cerebral malaria has a mortality rate of approximately 20% despite treatment, whereas TB meningitis kills or severely disables more than half of the patients who have it (and the mortality rate is even higher among HIV-infected patients).

  • HIV is associated with an increased incidence of both malaria and TB meningitis.

  • Patients with suspected cerebral malaria should be treated with IV quinine or IV artemisinin derivatives and should begin responding within 48 hours.

  • Patients with suspected TB meningitis should have multiple, large-volume lumbar punctures in order to increase diagnostic yield, and should be started immediately on 4-drug therapy with adjunctive corticosteroids.

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References

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1.   Hasbun R, Abrahams J, Jekel J, et al. Computed tomography of the head before lumbar puncture in adults with suspected meningitis. N Engl J Med. 2001 Dec 13;345(24):1727-33.
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2.   U.S. Centers for Disease Control and Prevention. Malaria Control Programs: Uganda. Atlanta: CDC; April 2004. Available at: http://www.cdc.gov/malaria/control_prevention/uganda.htm
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3.   Idro R, Jenkins NE, Newton CR. Pathogenesis, clinical features, and neurological outcome of cerebral malaria. Lancet Neurol. 2005 Dec;4(12):827-40.
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4.   Reyburn H, Mbatia R, Drakeley C, et al. Association of transmission intensity and age with clinical manifestations and case fatality of severe Plasmodium falciparum malaria. JAMA. 2005 Mar 23;293(12):1461-70.
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5.   French N, Nakiyingi J, Lugada E, et al. Increasing rates of malarial fever with deteriorating immune status in HIV-1-infected Ugandan adults. AIDS. 2001 May 4;15(7):899-906.
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6.   Patnaik P, Jere CS, Miller WC, et al. Effects of HIV-1 serostatus, HIV-1 RNA concentration, and CD4 cell count on the incidence of malaria infection in a cohort of adults in rural Malawi. J Infect Dis. 2005 Sep 15;192(6):984-91.
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7.   Kamya MR, Gasasira AF, Yeka A, et al. Effect of HIV-1 infection on antimalarial treatment outcomes in Uganda: a population-based study. J Infect Dis. 2006 Jan 1;193(1):9-15.
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8.   Chandramohan D, Greenwood BM. Is there an interaction between human immunodeficiency virus and Plasmodium falciparum? Int J Epidemiol. 1998 Apr;27(2):296-301.
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9.   Kublin JG, Patnaik P, Jere CS, et al. Effect of Plasmodium falciparum malaria on concentration of HIV-1-RNA in the blood of adults in rural Malawi: a prospective cohort study. Lancet. 2005 Jan 15-21;365(9455):233-40.
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10.   Hoffman IF, Jere CS, Taylor TE, et al. The effect of Plasmodium falciparum malaria on HIV-1 RNA blood plasma concentration. AIDS. 1999 Mar 11;13(4):487-94.
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11.   Abu-Raddad LJ, Patnaik P, Kublin JG. Dual infection with HIV and malaria fuels the spread of both diseases in sub-Saharan Africa. Science. 2006 Dec 8;314(5805):1603-6.
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12.   Mermin J, Ekwaru JP, Liechty CA, et al. Effect of co-trimoxazole prophylaxis, antiretroviral therapy, and insecticide-treated bednets on the frequency of malaria in HIV-1-infected adults in Uganda: a prospective cohort study. Lancet. 2006 Apr 15;367(9518):1256-61.
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13.   McIntosh HM, Olliaro P. Artemisinin derivatives for treating uncomplicated malaria. Cochrane Database Syst Rev. 2000;(2):CD000256.
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14.   Dondorp A, Nosten F, Stepniewska K, et al; South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) group. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet. 2005 Aug 27-Sep 2;366(9487):717-25.
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15.   Golden MP, Vikram HR. Extrapulmonary tuberculosis: an overview. Am Fam Physician. 2005 Nov 1;72(9):1761-8.
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16.   Donald PR, Schoeman JF. Tuberculous meningitis. N Engl J Med. 2004 Oct 21;351(17):1719-20.
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17.   Thwaites GE, Tran TH. Tuberculous meningitis: many questions, too few answers. Lancet Neurol. 2005 Mar;4(3):160-70.
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18.   Pai M, Flores LL, Pai N, et al. Diagnostic accuracy of nucleic acid amplification tests for tuberculous meningitis: a systematic review and meta-analysis. Lancet Infect Dis. 2003 Oct;3(10):633-43.
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19.   Abdelmalek R, Kanoun F, Kilani B, et al. Tuberculous meningitis in adults: MRI contribution to the diagnosis in 29 patients. Int J Infect Dis. 2006 Sep;10(5):372-7.
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20.   Thwaites GE, Nguyen DB, Nguyen HD, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med. 2004 Oct 21;351(17):1741-51.
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21.   Thwaites GE, Duc Bang N, Huy Dung 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 Dec 15;192(12):2134-41.
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