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26-Year-Old Man With Nausea, Delirium, and Fever

      A 26-year-old-man who had been living in Indonesia until 4 months previously presented to our hospital for evaluation of fever, agitation, and altered mental status. 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. On admission, he was febrile (temperature, 39.3°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. Physical examination findings were notable for intermittent altered mental status with restlessness, agitation, inattention, and pain with neck flexion and posterior neck palpation. 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. 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.
      • 1.
        Which one of the following is the most appropriate next step in the evaluation of this patient's altered mental status?
        • a.
          Psychiatric consultation
        • b.
          Lumbar puncture
        • c.
          Measurement of inflammatory markers
        • d.
          Empirical replacement of thiamine
        • e.
          Administration of naloxone
      Some primary psychiatric diagnoses can be confused with hyperactive delirium, including mania or agitated depression. However, these disorders typically exhibit less fluctuation than seen with delirium. Our patient had delirium, with waxing and waning mental status characterized by a disturbance in attention and awareness. 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.
      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. Inflammatory markers are a nonspecific tool and would not provide information to guide treatment. 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, and supplementation is not the most appropriate next step. 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, and naloxone administration is not the appropriate next step.
      Results of blood cultures and a urine Gram stain were negative. The patient underwent lumbar puncture to acquire 18 mL of cerebrospinal fluid (CSF), which yielded the following findings: color and appearance, yellow; nucleated cells, 549/μL (76% neutrophils); glucose, less than 20 mg/dL; and total protein, 344 mg/dL.
      • 2.
        These findings are most consistent with which one of the following?
        • a.
          Normal CSF
        • b.
          Viral meningitis
        • c.
          Subarachnoid hemorrhage
        • d.
          Bacterial meningitis
        • e.
          Fungal meningitis
      Normal CSF is typically clear and colorless with fewer than 5 nucleated cells/μL, 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. 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. This patient's glucose level and nucleated cell count were not consistent with viral meningitis. Subarachnoid hemorrhage may escape detection by head CT, but CSF findings may support the diagnosis if xanthochromia is present (yellowish discoloration of the CSF) along with a mild increase in white blood cell count, normal glucose level, and slightly elevated protein level, reflecting blood leaked in through hemorrhage. Although this patient's CSF was yellow, this discoloration was likely related to the high protein level because the CSF findings were not otherwise consistent with subarachnoid hemorrhage. In bacterial meningitis, the CSF is often cloudy secondary to a substantially increased number of nucleated cells (often >500/μL) with a neutrophilic predominance, CSF glucose is decreased to less than 40% of the concurrent serum glucose value, and protein is substantially elevated (100-1000 mg/dL), reflecting the breakdown of the blood-brain barrier. These characteristics most closely resemble our patient's CSF findings. Fungal meningitis manifests with CSF findings similar to those in a bacterial infection, but abnormalities in protein (50-200 mg/dL), glucose (slightly reduced), and nucleated cells (often <300/μL) with predominantly lymphocytes are not as markedly abnormal. The patient's CSF findings are most consistent with bacterial meningitis.
      Cerebrospinal fluid 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. The patient's delirium continued, and he remained intermittently febrile. In the setting of suspected bacterial meningitis with negative results on CSF Gram stain and bacterial cultures and with negative blood culture results, brain magnetic resonance imaging (MRI) was performed to evaluate for abscess. The MRI revealed leptomeningeal enhancement within the basilar cisterns, sylvian fissures, and surface of the brain stem consistent with meningitis. Antimicrobial therapy was broadened to include antifungal and antiviral coverage. Serologic screening was negative for human immunodeficiency virus (HIV) infection. Concern was raised for tuberculous meningitis (TBM), and an interferon gamma release assay, QuantiFERON-TB Gold In-Tube (Celestis Ltd), was ordered, and the patient was briefly placed in airborne infection isolation. The QuantiFERON test results were negative, and review of his chest radiograph revealed no evidence of pulmonary tuberculosis (TB). On hospital day 5, the patient became obtunded. His vital signs remained stable with adequate oxygenation while breathing room air.
      • 3.
        Which one of the following should be performed in response to this patient's change in mental status?
        • a.
          Electroencephalography
        • b.
          Repeated lumbar puncture
        • c.
          Intubation
        • d.
          Electrocardiography
        • e.
          Noncontrast CT of the head
      The patient did not have visible evidence of seizure activity. 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, and electroencephalography is not indicated.
      New diagnoses that could be supported by repeating CSF analysis, such as hemorrhage or hydrocephalus, would be better identified with head CT. 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.
      Electrocardiography would not be the most appropriate response to change in mental status in a hemodynamically stable patient with no previous cardiac involvement. 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.
      • Lu C.H.
      • Chang W.N.
      • Chang H.W.
      The prognostic factors of adult tuberculous meningitis.
      Head CT is the most appropriate response to this patient's change in mental status.
      Computed tomography of the head revealed acute hydrocephalus, and the patient was treated with an external ventricular drain. Failure to respond to broad-spectrum antimicrobials prompted reevaluation for other possible infectious etiologies in the setting of subacute bacterial meningitis progressing to hydrocephalus in a man from Indonesia. Tuberculous meningitis was revisited as a potential diagnosis. Lumbar puncture was repeated to acquire 18 mL of CSF, which yielded the following findings: color and appearance, yellow; nucleated cells, 1815/μL (83% neutrophils); glucose, less than 20 mg/dL; and total protein, 2908 mg/dL.
      • 4.
        In this patient with negative test results for TB, which one of the following is the best next step to evaluate for TBM?
        • a.
          Repeated interferon gamma release assay on CSF
        • b.
          Tuberculin skin test (TST)
        • c.
          Repeated CSF acid-fast stain
        • d.
          Polymerase chain reaction (PCR) analysis, probing for Mycobacterium tuberculosis
        • e.
          Wait for results of mycobacterial CSF cultures
      Each of the tests performed to diagnose TB is insufficiently sensitive to rule out the diagnosis. Interferon gamma release 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.
      • Prasad K.
      • Singh M.B.
      Corticosteroids for managing tuberculous meningitis.
      In the diagnosis of TBM, the TST has anecdotal sensitivity of approximately 60%
      • Bidstrup C.
      • Andersen P.H.
      • Skinhøj P.
      • Andersen A.B.
      Tuberculous meningitis in a country with a low incidence of tuberculosis: still a serious disease and a diagnostic challenge.
      but is thought to be of limited value, except in infants.
      • Thwaites G.E.
      • Tran T.H.
      Tuberculous meningitis: many questions, too few answers.
      Importantly, a negative TST result never excludes active TB. Cerebrospinal fluid acid-fast stain detects organisms in only 5% to 40% of positive cases
      • Lu C.H.
      • Chang W.N.
      • Chang H.W.
      The prognostic factors of adult tuberculous meningitis.
      • Desai D.
      • Nataraj G.
      • Kulkarni S.
      • et al.
      Utility of the polymerase chain reaction in the diagnosis of tuberculous meningitis.
      • Golden M.P.
      • Vikram H.R.
      Extrapulmonary tuberculosis: an overview.
      • Rock R.B.
      • Olin M.
      • Baker C.A.
      • Molitor T.W.
      • Peterson P.K.
      Central nervous system tuberculosis: pathogenesis and clinical aspects.
      and often less because of inadequate examination technique. Recommended technique includes centrifuging the CSF specimen and examining the sediment on a slide,
      • Rock R.B.
      • Olin M.
      • Baker C.A.
      • Molitor T.W.
      • Peterson P.K.
      Central nervous system tuberculosis: pathogenesis and clinical aspects.
      using at least 6 mL of fluid for examination, and looking at high-powered fields for at least 30 minutes.
      • Rock R.B.
      • Olin M.
      • Baker C.A.
      • Molitor T.W.
      • Peterson P.K.
      Central nervous system tuberculosis: pathogenesis and clinical aspects.
      • Schoeman J.F.
      • Donald P.R.
      Tuberculous meningitis.
      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,
      • Desai D.
      • Nataraj G.
      • Kulkarni S.
      • et al.
      Utility of the polymerase chain reaction in the diagnosis of tuberculous meningitis.
      making it the best next step for our patient. A negative test result would not, however, rule out the diagnosis of TBM.
      • Desai D.
      • Nataraj G.
      • Kulkarni S.
      • et al.
      Utility of the polymerase chain reaction in the diagnosis of tuberculous meningitis.
      Cerebrospinal fluid culture has a sensitivity of 50% to 80% in identifying TBM, but positive mycobacterial culture results can take 4 to 6 weeks.
      • Rock R.B.
      • Olin M.
      • Baker C.A.
      • Molitor T.W.
      • Peterson P.K.
      Central nervous system tuberculosis: pathogenesis and clinical aspects.
      In a patient with suspected TBM, it would not be appropriate to wait for positive culture results.
      • Lu C.H.
      • Chang W.N.
      • Chang H.W.
      The prognostic factors of adult tuberculous meningitis.
      • Schoeman J.F.
      • Donald P.R.
      Tuberculous meningitis.
      • Galimi R.
      Extrapulmonary tuberculosis: tuberculous meningitis new developments.
      Observation of acid-fast bacilli, either on a smear or in culture, continues to be the criterion standard for diagnosis,
      • Rock R.B.
      • Olin M.
      • Baker C.A.
      • Molitor T.W.
      • Peterson P.K.
      Central nervous system tuberculosis: pathogenesis and clinical aspects.
      even though these tests have relatively weak sensitivity and a negative smear result for acid-fast bacillus and negative culture growth do not exclude the diagnosis.
      • Golden M.P.
      • Vikram H.R.
      Extrapulmonary tuberculosis: an overview.
      • Rock R.B.
      • Olin M.
      • Baker C.A.
      • Molitor T.W.
      • Peterson P.K.
      Central nervous system tuberculosis: pathogenesis and clinical aspects.
      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. 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 using appropriate technique remained negative. Of note, subsequent acid-fast smear, TB PCR, and TB cultures of tracheal secretions yielded positive results.
      • 5.
        Which one of the following factors is most important when determining this patient's prognosis?
        • a.
          Stage of TBM
        • b.
          Time to onset of treatment
        • c.
          Patient age
        • d.
          BCG vaccine status
        • e.
          HIV status
      Stage of TBM (I-III, described subsequently) at the beginning of therapy is the strongest indicator of prognosis.
      • Mehta J.B.
      New face of the old foe: central nervous system tuberculosis.
      Other predictors of a negative outcome (death or major neurologic sequelae) include time to onset of treatment of more than 3 days, coma, advanced age,
      • Mehta J.B.
      New face of the old foe: central nervous system tuberculosis.
      focal weakness, cranial nerve findings, and hydrocephalus.
      • Misra U.K.
      • Kalita J.
      • Srivastava M.
      • Mandal S.K.
      Prognosis of tuberculous meningitis: a multivariate analysis.
      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.
      • Misra U.K.
      • Kalita J.
      • Srivastava M.
      • Mandal S.K.
      Prognosis of tuberculous meningitis: a multivariate analysis.
      Overall, his risk of dying was approximately 50% to 72%; he had a 13% chance of recovery with some neurologic sequelae, and a 14% chance of recovery without neurologic sequelae. 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.
      • Aronson N.E.
      • Santosham M.
      • Comstock G.W.
      • et al.
      Long-term efficacy of BCG vaccine in American Indians and Alaska Natives: a 60-year follow-up study.
      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.
      The patient was dismissed from the hospital after 50 days of inpatient therapy and had ongoing neurologic sequelae at that time.

      Discussion

      It has been observed that TBM is disproportionately prevalent in immigrants to the United States.
      • Lu C.H.
      • Chang W.N.
      • Chang H.W.
      The prognostic factors of adult tuberculous meningitis.
      • Bidstrup C.
      • Andersen P.H.
      • Skinhøj P.
      • Andersen A.B.
      Tuberculous meningitis in a country with a low incidence of tuberculosis: still a serious disease and a diagnostic challenge.
      • Rock R.B.
      • Olin M.
      • Baker C.A.
      • Molitor T.W.
      • Peterson P.K.
      Central nervous system tuberculosis: pathogenesis and clinical aspects.
      These cases may present with exclusively extrapulmonary involvement, making it important to maintain a high index of suspicion in patients from areas of high endemicity. In the United States, other risk factors associated with TBM include alcoholism, injection drug abuse, head trauma, and corticosteroid use,
      • Lu C.H.
      • Chang W.N.
      • Chang H.W.
      The prognostic factors of adult tuberculous meningitis.
      as well as malignant diseases and use of immunosuppressive agents.
      • Rock R.B.
      • Olin M.
      • Baker C.A.
      • Molitor T.W.
      • Peterson P.K.
      Central nervous system tuberculosis: pathogenesis and clinical aspects.
      The outcome of TBM is closely related to the duration of symptoms and the stage of disease based on the clinical picture on presentation.
      • Lu C.H.
      • Chang W.N.
      • Chang H.W.
      The prognostic factors of adult tuberculous meningitis.
      • Thwaites G.E.
      • Tran T.H.
      Tuberculous meningitis: many questions, too few answers.
      Tuberculous meningitis has a protean clinical presentation that can delay suspicion for the disease and consequently delay diagnosis and treatment. Because of the lack of rapid sensitive tests, TBM can be difficult to diagnose definitively or rule out.
      • Desai D.
      • Nataraj G.
      • Kulkarni S.
      • et al.
      Utility of the polymerase chain reaction in the diagnosis of tuberculous meningitis.
      • Golden M.P.
      • Vikram H.R.
      Extrapulmonary tuberculosis: an overview.
      However, there are findings on clinical evaluation that, if recognized, are sufficiently suggestive of TBM to indicate the initiation of antituberculous therapy.
      Tuberculous meningitis presents as a subacute bacterial meningitis,
      • Ranjan P.
      • Kalita J.
      • Misra U.K.
      Serial study of clinical and CT changes in tuberculous 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.
      • Lu C.H.
      • Chang W.N.
      • Chang H.W.
      The prognostic factors of adult tuberculous meningitis.
      • Schoeman J.F.
      • Donald P.R.
      Tuberculous meningitis.
      Worldwide, the diagnosis of TBM is often clinical. 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. In stage III (advanced), patients are comatose or have severe neurologic deficits.
      • Rock R.B.
      • Olin M.
      • Baker C.A.
      • Molitor T.W.
      • Peterson P.K.
      Central nervous system tuberculosis: pathogenesis and clinical aspects.
      Left untreated, the mortality in each stage is 45%, 70%, and 90%, respectively.
      • Lu C.H.
      • Chang W.N.
      • Chang H.W.
      The prognostic factors of adult tuberculous meningitis.
      Where imaging is available, CT and MRI can contribute to a diagnosis by identifying hydrocephalus, thickened basilar meninges, or mass lesions consistent with tuberculomas,
      • Golden M.P.
      • Vikram H.R.
      Extrapulmonary tuberculosis: an overview.
      • Rock R.B.
      • Olin M.
      • Baker C.A.
      • Molitor T.W.
      • Peterson P.K.
      Central nervous system tuberculosis: pathogenesis and clinical aspects.
      • Galimi R.
      Extrapulmonary tuberculosis: tuberculous meningitis new developments.
      • Bernaerts A.
      • Vanhoenacker F.M.
      • Parizel P.M.
      • et al.
      Tuberculosis of the central nervous system: overview of neuroradiological findings.
      and it has been proposed that the presence of basal meningeal enhancement or tuberculoma on imaging can specifically help distinguish central nervous system tuberculosis from other bacterial meningitides,
      • Rock R.B.
      • Olin M.
      • Baker C.A.
      • Molitor T.W.
      • Peterson P.K.
      Central nervous system tuberculosis: pathogenesis and clinical aspects.
      with MRI being superior to CT in identifying diagnostic findings.
      • Bernaerts A.
      • Vanhoenacker F.M.
      • Parizel P.M.
      • et al.
      Tuberculosis of the central nervous system: overview of neuroradiological findings.
      Follow-up CT at 1 week and 1 month after the initial scan have further been found to be of use in following the evolution of infection with early identification of complications as well as tracking the response to treatment,
      • Rock R.B.
      • Olin M.
      • Baker C.A.
      • Molitor T.W.
      • Peterson P.K.
      Central nervous system tuberculosis: pathogenesis and clinical aspects.
      • Ranjan P.
      • Kalita J.
      • Misra U.K.
      Serial study of clinical and CT changes in tuberculous meningitis.
      • Bernaerts A.
      • Vanhoenacker F.M.
      • Parizel P.M.
      • et al.
      Tuberculosis of the central nervous system: overview of neuroradiological findings.
      although most CT abnormalities persist beyond 6 months despite clinical improvement.
      • Ranjan P.
      • Kalita J.
      • Misra U.K.
      Serial study of clinical and CT changes in tuberculous meningitis.
      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. Performing multiple tests or repeating tests is recommended when TBM is strongly suspected.
      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,
      • Mehta J.B.
      New face of the old foe: central nervous system tuberculosis.
      even before the diagnosis is confirmed, because delay of treatment is associated with worse outcome.
      • Youssef F.G.
      • Afifi S.A.
      • Azab A.M.
      • et al.
      Differentiation of tuberculous meningitis from acute bacterial meningitis using simple clinical and laboratory parameters.
      Even with appropriate treatment, clinical improvement may not be apparent for weeks to months.
      • Ranjan P.
      • Kalita J.
      • Misra U.K.
      Serial study of clinical and CT changes in tuberculous meningitis.
      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.
      • Thwaites G.E.
      • Tran T.H.
      Tuberculous meningitis: many questions, too few answers.
      • Golden M.P.
      • Vikram H.R.
      Extrapulmonary tuberculosis: an overview.
      • Schoeman J.F.
      • Donald P.R.
      Tuberculous meningitis.
      • Galimi R.
      Extrapulmonary tuberculosis: tuberculous meningitis new developments.
      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. Isoniazid, augmented by ethambutol, is effective in killing the rapidly replicating bacteria within the first 2 weeks of treatment. Rifampin and pyrazinamide are responsible for “sterilizing” lesions and are critical for successful long-term therapy because rifampin kills nonreplicating organisms and pyrazinamide is able to penetrate sites inaccessible by other drugs.
      • Thwaites G.E.
      • Tran T.H.
      Tuberculous meningitis: many questions, too few answers.
      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. In addition to antituberculous medications, adjunctive corticosteroid therapy with dexamethasone for the first 6 to 8 weeks of therapy has been associated with reduced neurologic sequelae and mortality.
      • Prasad K.
      • Singh M.B.
      Corticosteroids for managing tuberculous meningitis.
      • Thwaites G.E.
      • Tran T.H.
      Tuberculous meningitis: many questions, too few answers.
      • Mehta J.B.
      New face of the old foe: central nervous system tuberculosis.
      Antituberuclous medications are not without adverse effects, and when it is possible to confirm the diagnosis, confirmation should be pursued. 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.
      • Thwaites G.E.
      • Tran T.H.
      Tuberculous meningitis: many questions, too few answers.
      • Golden M.P.
      • Vikram H.R.
      Extrapulmonary tuberculosis: an overview.
      • Rock R.B.
      • Olin M.
      • Baker C.A.
      • Molitor T.W.
      • Peterson P.K.
      Central nervous system tuberculosis: pathogenesis and clinical aspects.
      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.
      Appropriate medical and surgical interventions produced a positive outcome for our patient. 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.

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      CORRECT ANSWERS: 1. b, 2. d, 3. e, 4. d, 5. a