<Brief
History>
A 73-year-old man with no chronic
disease history developed incoherent speech and loss of
short-time memory since one year ago, dysarthria, deteriorated
cognitive function, and frequent falling down were also
noticed for 6 months. Ten days ago, he was found lying down on
the floor at home with preserved consciousness and worsened
dysarthria and incoherent speech. Delirium was also noted for
the following several days. At arrival to our Emergency
Department, neurological examination revealed incoherent
speech, disorientation to place and time, mild dysarthria,
poor gag reflex with easy choking and gait disturbance
(wide-based). His muscle power was full. Bilateral deep tendon
reflex, the sensory system and autonomic function were intact.
The Romberg's test was negative but he failed to perform
tandem gait. Rapid alternamg movements and Finger-Nose-Finger
test were performed clumsily. Other physical examination was
unremarkable. Initial laboratory studies revealed the
hemogram, electrolyte (including sodium, potassium, and
calcium), the liver function and renal function tests were all
within normal range, except marked hyperchloremia (179
mmole/L) and a negative anion gap (the calculated anion gap
[Na+-(Cl-+HCO3-
)] was -67.1 mEq/L.). The
workups for negative anion gap, including serum lithium level
(suspicion of lithium toxicity), and electrophoresis with
immunofixation electrophoresis (suspicion of multiple myeloma)
were all negative.
<Laboratory and Image
Study>
1. CBC/DC & coagulation
profiles:
Date |
WBC K/μL |
RBC M/μL |
Hgb g/dL |
Hct % |
MCV fL |
MCHC g/dL |
Plt K/μL |
93/1/17 |
11.44 |
4.02 |
12.2 |
37.4 |
93 |
32.6 |
284 |
93/2/1 |
9.19 |
4.2 |
12.8 |
38.6 |
91.9 |
33.2 |
325 |
Date |
Blast |
Meta |
Band |
Seg |
Eos |
Baso |
Mono |
Lym |
93/1/17 |
0 |
0 |
0 |
76.2 |
1.4 |
0.1 |
7.1 |
14.9 |
93/2/1 |
0 |
0 |
0 |
76.3 |
3.4 |
0.4 |
5.1 |
14.8 |
2. Biochemistry
Date |
BUN mg/dl |
Cre mg/dl |
Na mmol/l |
K mmol/l |
Cl mmol/l |
Ca mmol/l |
P mmol/l |
Mg mmol/l |
93/1/17 |
10.2 |
0.6 |
142 |
4.4 |
179 |
2.3 |
3.9 |
1.07 |
93/2/1 |
5.2 |
0.43 |
142 |
3.85 |
111 |
2.16 |
3.83 |
0.81 |
93/2/6 |
|
|
138 |
2.99 |
104 |
1.85 |
|
|
3. Urine analysis:
Date |
Appearance |
Sp. gr |
pH |
Protein mg/dL |
Glu g/dL |
Ketones |
O.B |
Urobil EU/dL |
Bil |
93/1/17 |
R;T |
1.015 |
8.0 |
- |
- |
- |
- |
0.1 |
- |
Date |
Nitrite |
RBC /HPF |
WBC /HPF |
EpithCell / HPF |
Cast /LPF |
Crystal |
Bact |
93/1/17 |
- |
4-5 |
5-6 |
0 |
- |
- |
- |
4. Arterial blood gas
|
PH |
PaO2 |
PaCO2 |
HCO3 |
BE |
Anion Gap |
|
* |
mmHg |
mmHg |
mEq/L |
mEq/L |
mEq/L |
93/1/17 |
7.43 |
76.8 |
46.5 |
30.1 |
5.4 |
-67.1 |
93/2/6 |
7.48 |
121.9 |
31.8 |
23.2 |
0.4 |
11.7 |
5. Electroencephalogram 1/15 Abnormal
EEG, intermittent diffuse slow waves at 6-7 Hz, 10-20uV with
rare generalized slow waves at 3-5Hz, up to 75uV. Mild diffuse
cortical dysfunction with generalized delta wave.
2/3
Abnormal , intermittent diffuse theta waves at 5-6Hz, 20-50uV
. Moderate diffuse cortical dysfunction
<Course and
Treatment>
The workups for negative anion gap, including serum lithium
level (suspicion of lithium toxicity), and electrophoresis
with immunofixation electrophoresis (suspicion of multiple
myeloma) were all negative. By the way, the serum chloride
level is rarely as high as our patient in lithium toxicity or
multiple myeloma. During the hospitalization, he also
presented persecutory delusion and bizarre behavior as well as
both visual and auditory hallucination. Brain MRI showed
periventricular leukoaraiosis and possible microangiopathy. An
electroencephalogram (EEG) recording revealed patterns of
moderate diffuse cortical dysfunction.
A careful medication history inquiry with his family
revealed the patient took ”Ming-Tong Chih Tong Dan (MTCTD)”, a
nonsteroidal anti-inflammatory drugs (NSAID) containing BVU.
It was a kind of over-the-counter drug and he took four to
five packages of the prescription daily about five to six
years for his habitual headache, which contains
ethoxybenzamide 350mg, caffeine anhydrous 50mg, acetaminophen
200mg, bromvalerylurea 200mg per package. Six months prior
this admission, the total daily dosage was gradually increased
to ten to fifteen packages per day for worsened headache.
We examined the serum draw at about 11 days after the last
dose of MTCTD and the result showed a bromide level of
101.5±1.9 mg/dL, measured by inductively coupled plasma mass
spectrometer (ICP-MS). Forced diuresis with intravenous normal
saline, as well as intravenous furosemide were administered.
Neurological symptoms and signs (dysarthria, delirium and
cerebellar ataxia) recovered rapidly about 3-5 days later.
Repeated analysis at about 24 days after last dose of MTCTD
showed both serum chloride and bromide level declined
(Chloride: 104 mmole/L measured by ISE and Bromide: 6.15±2.6
mg/dL measured by ICP-MS). Two weeks later, the Mini-Mental
State Examination (MMSE) showed significant improvement.
<Analysis>
Occasional cases about bromide
intoxication were reported 1-6, mainly because of
the use of bromide containing products in nonprescription
preparations, such as analgesic, antitussive or antiepileptic
drugs. As our patient, most of the diagnosis was often aided
by a negative anion gap and hyperchloremia because bromide is
always regarded as chloride in automated analysis measured by
the methods of ion-selective electrode (ISE). The ISE method
causes the greatest positive interference of the chloride
concentration in sera containing bromide or other halide
6
.
The neurological manifestations seem to
be dose related, but the correlation between blood level of
bromide and its toxicity is uncertain. Serum level >20
mg/dL are considered to be toxic 4. The bromides
has a long half-life (10-14days) and is eliminated mainly
through the kidney. The half-life could be reduced from 12
days to less than 3 days with saline diuresis alone
7 and 1-2 hours with hemodialysis therapy
3. Although emergent hemodialysis is very effective
due to its rapid clearance 5
, it is unusual to use as the first choice
because most patients had good response to saline
diuresis.
In conclusion, although bromism is rare
today, to review the medical history for bromide containing
compounds is necessary if there is not a reasonable cause for
a negative anion gap and hyperchloremia. Finally it should be
confirmed by measuring the serum bromide
level8
.
<Reference>
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hyperchloremia and decreased anion gap in a patient with
dextromethorphan bromide. Am J Nephrol 12, 268-70 (1992).
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M.L. & Bates, S.R. Bromism: intoxication from a rare
anticonvulsant therapy. Pediatr Emerg Care 13, 268-70
(1997).
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315-20 (1997).
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N., Vareesangthip, K., Nimmannit, S. & Nilwarangkur, S.
A negative anion gap as a clue to diagnose bromide
intoxication. Nephron 69, 311-3 (1995).
- Kawakami, T. et al. Chronic
bromvalerylurea intoxication: dystonic posture and
cerebellar ataxia due to nonsteroidal anti-inflammatory drug
abuse. Intern Med 37, 788-91 (1998).
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and pseudohyperchloremia. Ann Pharmacother 35, 386-7 (2001).
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The toxicology of bromide ion. Crit Rev Toxicol 18, 189-213
(1987).
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