Commentary case
By :
Prof. Dr.: Fawzy Megahed
A 26-year old man 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,
39.3⁰ 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.
Physical examination findings were notable
for intermittent altered mental status with
restlessness, agitation, inattention, and pain
with neck
palpation.
flexion and posterior
neck
Findings on work-up at the outside facility
included a sodium level of 118 mmol/L and
no
abnormalities
computed
radiography.
detected
tomography
(CT)
on
head
and
chest
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?
a. Psychiatric consultation
b. Lumbar puncture
c. Measurement of inflammatory markers
d. Empirical replacement of thiamine
e. Administration of naloxone
Lumbar puncture
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.
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.
Measurement of inflammatory
markers
Inflammatory markers are a nonspecific tool
and would not provide information to guide
treatment.
Empirical replacement of thiamine
Thiamine
deficiency
can
be
found
in
populations with poor nutrition, commonly
in the setting of alcohol abuse. Symptoms
include
diplopia,
altered
and
mental
status,
incoordination.
ataxia,
Thiamine
deficiency is not the likely cause of this
patient’s symptoms.
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 .
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) .
CSF findings: color and appearance, yellow;
nucleated cells, 549/mL (76% neutrophils);
glucose, less than 20 mg/dL; and total
protein, 344 mg/dL.
2. These findings are most
consistent with …. ?
a. Normal CSF
b. Viral meningitis
c. Subarachnoid hemorrhage
d. Bacterial meningitis
e. Fungal meningitis
Bacterial meningitis
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.
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.
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.
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 (100-1000 mg/dL).
Fungal meningitis
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/mL)
with
predominantly
lymphocytes are not as markedly abnormal.
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.
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
performed to evaluate for abscess.
MRI
was
The
MRI
revealed
leptomeningeal
enhancement within the basilar cisterns,
sylvian fissures, and surface of the brain stem
consistent with meningitis.
Serologic screening was negative for HIV
infection
.
Antimicrobial
therapy
was
broadened to include antifungal and antiviral
coverage.
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.
On hospital day 5, the patient became
obtunded. His vital signs remained stable
with adequate oxygenation while breathing
room air.
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
Non-contrast CT of the head
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 .
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.
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.
Electrocardiography
Electrocardiography would not be the most
appropriate response to change in mental
status in a hemodynamically stable patient
with no previous cardiac involvement.
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.
Proceeding with the case ……..
CT 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 .
Tuberculous meningitis was revisited as a
potential diagnosis. Lumbar puncture was
repeated to acquire 18 mL of CSF.
CSF findings: color and appearance, yellow;
nucleated cells, 1815/mL (83% neutrophils);
glucose, less than 20 mg/dL; and total
protein, 2908 mg/dL.
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
PCR analysis, probing for
Mycobacterium TB
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.
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.
Repeated CSF acid-fast stain
CSF acid-fast stain detects organisms in only
5% to 40% of positive cases and often less
because
technique.
of
inadequate
examination
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.
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.
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.
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.
Of note, subsequent acid-fast smear, TB PCR,
and TB cultures of tracheal secretions yielded
positive results.
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
Stage of TBM
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.
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.
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.
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.
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.
DISCUSSION
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.
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.
TBM presents as a subacute bacterial
meningitis, often with the characteristic CSF
findings of bacterial meningitis and a severalweek history of headache, vomiting, and
meningeal signs progressing to focal deficits
and cranial nerve palsies.
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. Left
untreated, the mortality in each stage is 45%,
70%, and 90%, respectively.
Where imaging is available, CT and MRI can
contribute to a diagnosis by identifying
hydrocephalus, thickened basilar meninges,
or
mass
tuberculomas.
lesions
consistent
with
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.
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.
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.
Even with appropriate treatment, clinical
improvement may not be apparent for weeks
to months.
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.
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.
There are higher rates of drug resistance in
some regions of the world, and for every new
diagnosis
with
an
isolated
susceptibilities should be obtained.
organism,
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.
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.
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.