1. By : Prof. Dr.: Fawzy Megahed
Commentary case
By :
Prof. Dr.: Fawzy Megahed

2. A 26-year old man presented to our hospital for evaluation of fever, agitation, and altered mental status.

3. He had been seen previously at another facility for vague abdominal pain, nausea, and fever. He had become subacutely agitated and was transferred to our institution because of altered mental status and vomiting.

4. On admission, he was febrile (temperature, 39
On admission, he was febrile (temperature, 39.3⁰ C) and tachycardic (heart rate, 118 beats/ min); his blood pressure was 134/96 mm Hg, and his oxygen saturation was 100% while breathing room air.

5. Physical examination findings were notable for intermittent altered mental status with restlessness, agitation, inattention, and pain with neck flexion and posterior neck palpation.

6. Findings on work-up at the outside facility included a sodium level of 118 mmol/L and no abnormalities detected on head computed tomography (CT) and chest radiography.

7. His pupils were mildly constricted but responded to light
His pupils were mildly constricted but responded to light. Admission laboratory studies yielded a normal white blood cell count of 10.1 * 10⁹/L and an improved sodium concentration of 133 mmol/L.

8. 1. Which one of the following is the most appropriate next step?
a. Psychiatric consultation b. Lumbar puncture c. Measurement of inflammatory markers d. Empirical replacement of thiamine e. Administration of naloxone

9. Lumbar puncture

10. Psychiatric consultation
Our patient had delirium, with waxing and waning mental status. Common causes of delirium in a young person include drug overdose or withdrawal, infection including meningitis, and electrolyte imbalance. A psychiatric diagnosis should be entertained only after organic diagnoses have been ruled out.

11. Lumbar puncture
In the setting of altered mental status and fever in a young person, meningitis must be ruled out. A lumbar puncture would be the most appropriate next step.

12. Measurement of inflammatory markers
Inflammatory markers are a nonspecific tool and would not provide information to guide treatment.

13. Empirical replacement of thiamine
Thiamine deficiency can be found in populations with poor nutrition, commonly in the setting of alcohol abuse. Symptoms include altered mental status, ataxia, diplopia, and incoordination. Thiamine deficiency is not the likely cause of this patient’s symptoms.

14. Administration of naloxone
Naloxone is used to reverse the effects of opioid overdose, which typically presents with sedation, pinpoint pupils, and, in severe cases, respiratory suppression. This patient does not have clinical evidence of opioid overdose .

15. Proceeding with the case ……..
Results of blood cultures and a urine Gram stain were negative. The patient underwent lumbar puncture to acquire 18 mL of cerebrospinal fluid (CSF) .

16. CSF findings: color and appearance, yellow; nucleated cells, 549/mL (76% neutrophils); glucose, less than 20 mg/dL; and total protein, 344 mg/dL.

17. 2. These findings are most consistent with …. ?
a. Normal CSF b. Viral meningitis c. Subarachnoid hemorrhage d. Bacterial meningitis e. Fungal meningitis

18. Bacterial meningitis

19. Normal CSF
Normal CSF is typically clear and colorless with fewer than 5 nucleated cells/mL, glucose level greater than 60% of a concurrent serum value, and protein level of 0-35 mg/dL. This patient’s CSF has atypical findings and is not normal.

20. Viral meningitis
In viral meningitis, the CSF is clear with minimally elevated nucleated cells, glucose concentration of 50 to 100 mg/dL, and a mildly elevated total protein level of 50 to 100 mg/dL, thought to reflect breakdown of the blood-brain barrier.

21. Subarachnoid hemorrhage
In subarachnoid hemorrhage, CSF findings include xanthochromia, a mild increase in white blood cell count, normal glucose level, and slightly elevated protein level, reflecting blood leaked in through hemorrhage.

22. Bacterial meningitis
In bacterial meningitis, the CSF is often cloudy with increased number of nucleated cells (often >500/mL) with a neutrophilic predominance, CSF glucose is less than 40% of the concurrent serum glucose value, and protein is elevated ( mg/dL).

23. Fungal meningitis
Fungal meningitis manifests with CSF findings similar to those in a bacterial infection, but abnormalities in protein ( mg/dL), glucose (slightly reduced), and nucleated cells (often <300/mL) with predominantly lymphocytes are not as markedly abnormal.

24. Proceeding with the case ……..
CSF Gram stain and acid fast smear yielded negative results, and the patient was given empirical antibiotic therapy for bacterial meningitis that included vancomycin, cefepime, metronidazole, and doxycycline.

25. The patient’s delirium continued, and he remained intermittently febrile.

26. In the setting of suspected bacterial meningitis with negative results on CSF Gram stain and bacterial cultures and with negative blood culture results, brain MRI was performed to evaluate for abscess.

27. The MRI revealed leptomeningeal enhancement within the basilar cisterns, sylvian fissures, and surface of the brain stem consistent with meningitis.

28. Serologic screening was negative for HIV infection
Serologic screening was negative for HIV infection . Antimicrobial therapy was broadened to include antifungal and antiviral coverage.

29. Concern was raised for tuberculous meningitis (TBM), and QuantiFERON test, was ordered, and the results were negative, and review of his chest radiograph revealed no evidence of pulmonary TB.

30. On hospital day 5, the patient became obtunded
On hospital day 5, the patient became obtunded. His vital signs remained stable with adequate oxygenation while breathing room air.

31. 3. According to this patient’s change in mental status, what is next to do?
a. Electroencephalography b. Repeated lumbar puncture c. Intubation d. Electrocardiography e. Non-contrast CT of the head

32. Non-contrast CT of the head

33. Electroencephalography
Nonconvulsive status epilepticus is a rare cause of new-onset change in mental status. In a patient with recent CSF findings consistent with bacterial meningitis, nonconvulsive status epilepticus is not the most likely cause of new-onset somnolence .

34. Repeated lumbar puncture
New diagnoses that could be supported by repeating CSF analysis, such as hemorrhage or hydrocephalus, would be better identified with head CT.

35. Intubation
If a patient is unable to maintain airway patency, it would be reasonable to intubate before imaging. However, at this time, with no changes in our patient’s vital signs, it is more appropriate to proceed to imaging.

36. Electrocardiography
Electrocardiography would not be the most appropriate response to change in mental status in a hemodynamically stable patient with no previous cardiac involvement.

37. Non-contrast CT of the head
Rapid deterioration of consciousness in a patient with CSF findings consistent with bacterial meningitis is suspicious for the development of hydrocephalus. Urgent diagnosis is critical in these patients because shunting procedures can improve the clinical outcome.

38. Proceeding with the case ……..
CT of the head revealed acute hydrocephalus, and the patient was treated with an external ventricular drain.

39. Failure to respond to broad-spectrum antimicrobials prompted reevaluation for other possible infectious etiologies in the setting of subacute bacterial meningitis progressing to hydrocephalus .

40. Tuberculous meningitis was revisited as a potential diagnosis
Tuberculous meningitis was revisited as a potential diagnosis. Lumbar puncture was repeated to acquire 18 mL of CSF.

41. CSF findings: color and appearance, yellow; nucleated cells, 1815/mL (83% neutrophils); glucose, less than 20 mg/dL; and total protein, 2908 mg/dL.

42. 4. which one of the following is the best next step to evaluate for TBM?
a. Repeated QuantiFERON test on CSF b. Tuberculin skin test (TST) c. Repeated CSF acid-fast stain d.PCR analysis, probing for Mycobacterium TB e. Wait for results of mycobacterial CSF cultures

43. PCR analysis, probing for Mycobacterium TB

44. QuantiFERON test on CSF
QuantiFERON test assays are of unknown utility in diagnosing TBM, although there is some evidence that they may be more sensitive than bacterial culture if performed on CSF.

45. Tuberculin skin test (TST)
In the diagnosis of TBM, the TST has anecdotal sensitivity of approximately 60% but is thought to be of limited value, except in infants. Importantly, a negative TST result never excludes active TB.

46. Repeated CSF acid-fast stain
CSF acid-fast stain detects organisms in only 5% to 40% of positive cases and often less because of inadequate examination technique.

47. PCR analysis, probing for Mycobacterium tuberculosis
A PCR analysis of the CSF for TB is 75% sensitive and 94% specific, is able to be completed within hours, and is currently the best method for rapid diagnosis of TBM. A negative test result would not, however, rule out the diagnosis of TBM.

48. Mycobacterial CSF cultures
Cerebrospinal fluid culture has a sensitivity of 50% to 80% in identifying TBM, but positive mycobacterial culture results can take 4 to 6 weeks. In a patient with suspected TBM, it would not be appropriate to wait for positive culture results.

49. Proceeding with the case ……..
Therefore, in the setting of strongly suspected TBM, empirical antituberculous therapy is recommended. We empirically initiated antituberculous medications including isoniazid, ethambutol, rifampin, and pyrazinamide and also administered dexamethasone.

50. A PCR test for TB performed on the CSF yielded positive results, strongly supporting a diagnosis of TB. Results of repeated smear for acid-fast bacilli remained negative.

51. Of note, subsequent acid-fast smear, TB PCR, and TB cultures of tracheal secretions yielded positive results.

52. 5. The most important prognostic factor in this patient is …….
a. Stage of TBM b. Time to onset of treatment c. Patient age d. BCG vaccine status e. HIV status

53. Stage of TBM

54. Stage of TBM
Stage of TBM at the beginning of therapy is the strongest indicator of prognosis. Other predictors of a negative outcome include time to onset of treatment of more than 3 days, coma, advanced age, focal weakness, cranial nerve findings, and hydrocephalus.

55. This patient’s TBM would be classified as stage III and he has confirmed hydrocephalus, but he is not elderly and does not have focal weakness or cranial nerve involvement.

56. BCG vaccine status
The BCG vaccine is used worldwide to prevent TB in highly endemic populations, although it has variable efficacy (estimated at 50%) and does not have a defined effect on prognosis.

57. HIV status
Human immunodeficiency virus infection predisposes patients to TB infection and the development of TBM. However, there is no evidence that coinfection with HIV affects the outcome of TBM.

58. Proceeding with the case ……..
The patient was dismissed from the hospital after 50 days of inpatient therapy and had ongoing neurologic sequelae at that time.

59. DISCUSSION

60. The outcome of TBM is closely related to the duration of symptoms and the stage of disease based on the clinical picture on presentation. TBM has a protean clinical presentation that can delay suspicion for the disease and consequently delay diagnosis and treatment.

61. Because of the lack of rapid sensitive tests, TBM can be difficult to diagnose definitively or rule out. However, there are findings on clinical evaluation that, if recognized, are sufficiently suggestive of TBM to indicate the initiation of antituberculous therapy.

62. TBM presents as a subacute bacterial meningitis, often with the characteristic CSF findings of bacterial meningitis and a several-week history of headache, vomiting, and meningeal signs progressing to focal deficits and cranial nerve palsies.

63. Standardized staging assists in characterizing the severity of illness
Standardized staging assists in characterizing the severity of illness. In stage I (early), nonspecific symptoms are present, and in stage II (intermediate), patients are confused or have minor focal neurologic signs.

64. In stage III (advanced), patients are comatose or have severe neurologic deficits. Left untreated, the mortality in each stage is 45%, 70%, and 90%, respectively.

65. Where imaging is available, CT and MRI can contribute to a diagnosis by identifying hydrocephalus, thickened basilar meninges, or mass lesions consistent with tuberculomas.

66. Follow-up CT at 1 week and 1 month after the initial scan could identify early complications as well as track the response to treatment, although most CT abnormalities persist beyond 6 months despite clinical improvement.

67. The differential diagnosis for TBM is broad, and several tests are available to confirm a diagnosis. However, the sensitivity of any single test is not independently sufficient to rule out TBM.

68. Early treatment of TBM is essential for survival, and when there is high suspicion for TBM, it is important to initiate treatment with antituberculous medications as soon as possible, because delay of treatment is associated with worse outcome.

69. Even with appropriate treatment, clinical improvement may not be apparent for weeks to months.

70. The medication regimen suggested for TBM is both aggressive and prolonged, including 2 months of isoniazid, rifampin, pyrazinamide, and ethambutol followed by continued treatment with isoniazid and rifampin for a total of 9 to 12 months.

71. In addition to this regimen, corticosteroid therapy is recommended for HIV-negative patients with TBM at a dose of 0.3 to 0.4 mg/kg per day on a taper, for a total duration of 8 weeks.

72. There are higher rates of drug resistance in some regions of the world, and for every new diagnosis with an isolated organism, susceptibilities should be obtained.

73. Antituberuclous medications are not without adverse effects, and when it is possible to confirm the diagnosis, confirmation should be pursued .

74. When TBM is suspected, it is important to initiate isolation protocols and sputum screening because 30% to 50% of patients with TBM also have findings consistent with pulmonary TB.

75. Because the primary mechanism of TB transmission is through droplet spread, a patient who does not have an active pulmonary infection does not need to remain in isolation.

76. Early recognition of the classic constellation of findings associated with TBM and prompt initiation of appropriate treatment are key in avoiding complications and longer hospital stays and in decreasing morbidity and mortality.

77. Thank You