Case Discussion <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> Ng, Y.Y. et al. Spurious hyperchloremia and decreased anion gap in a patient with dextromethorphan bromide. Am J Nephrol 12, 268-70 (1992). James, L.P., Farrar, H.C., Griebel, M.L. & Bates, S.R. Bromism: intoxication from a rare anticonvulsant therapy. Pediatr Emerg Care 13, 268-70 (1997). Horowitz, B.Z. Bromism from excessive cola consumption. J Toxicol Clin Toxicol 35, 315-20 (1997). Vasuyattakul, S., Lertpattanasuwan, 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). Danel, V.C., Saviuc, P.F., Hardy, G.A., Lafond, J.L. & Mallaret, M.P. Bromide intoxication and pseudohyperchloremia. Ann Pharmacother 35, 386-7 (2001). van Leeuwen, F.X. & Sangster, B. The toxicology of bromide ion. Crit Rev Toxicol 18, 189-213 (1987). Wang, Y.T., Yang, S.Y., Wu, V.C., Wu, K.D. & Fang, C.C. Pseudohyperchloraemia due to bromvalerylurea abuse. Nephrol Dial Transplant 20, 1767-8 (2005). 繼續教育考題 1. (B) The normal equals of anion gap？ A 4-6 mEq/L B 10-14 mEq/L C 13-15mEq/L D 16-18 mEq/L 2. (D) Which of the prescription about anion gap is wrong？ A Indicates the quality of added acids. B The fall in [HCO3-] equals the rise in anion gap. C Is useful in following the patients' response to therapy. D Helps in detecting laboratory errors, anion proteins, and mixed acid-base disorders. 3. (D) Which is not the presentation of bromide intoxication? A negative anion gap and hyperchloremia B disturbed mental status with confusion C auditory and visual hallucinations D loss of long term memory 4. (B) The treatment choice for bromide intoxication is Not A saline hydration and diuretic treatment B Plasmapheresis C diuretic treatment D emergent hemodialysis 5. (C) Which is not the symptoms and signs related to bromide intoxication A Long -term use of over-the-counter (OTC) agents B Negative anion gap C Epilepsy D Unusual high chloride level 6. (A) How to calculate anion gap? A ([Na+] - [Cl-] - [HCO3- ]) B ([Na+] - [Cl-] + [HCO3- ]) C ([Na+] + [Cl-] - [HCO3- ]) D ([Na+] + [Cl-] + [HCO3- ]) 7. (E) A decrease of anion gap may due to, A An increase in unmeasured cations B The addition to the blood of abnormal cations, such as lithium or plasma cell dyscrasias. C A reduction in the major plasma anion albumin concentration (nephritic syndrome). D A decrease in the effective anionic charge on albumin by acidosis. E All of above 8. (D) Which one is not high anion gap？ A Hemoconcentration B Lactic acidosis C  Hyperphosphatemia D Hypoaldosteronism 9. (B) Which one is not negative anion gap？ A Hypernatremia ( > 170 mea/L) B Short bowel syndrome C Hyperlipidemia D Bromide intoxication 10. (B) Which one is not normal anion gap？ A D-lactic acidosis B Methanol intoxication. C Toluene exposure ( glue-sniffing) D Short bowel syndrome 答案解說 (B ) The anion gap ([Na+] - [Cl-] - [HCO3-]), calculation for diagnostic convenience: , normal equals 12 ± 2 mEq/ L (D ) anion gap helps in detecting cationic proteins, (D ) Bromide intoxication presented a seriously disturbed mental status with confusion, disorientation, auditory and visual hallucinations, and loss of short-time memory. A markedly increased serum pseudohyperchrolemia and negative anion gap was noted. (B ) Although emergent hemodialysis is very effective due to its rapid clearance, it is unusual to use as the first choice because most patients had good response to saline diuresis. (Nephrol Dial Transplant. 2005 Aug;20(8):1767-8.) (J Toxicol Clin Toxicol. 1997;35(3):315-20) (C ) The presence of epilepsy is not a condition for the development of bromide intoxication. (J Hist Neurosci. 1997 Apr;6(1):61-71.) (A ) The anion gap ([Na+] - [Cl-] - [HCO3-]) (E ) Braunwald et al. Harrison's principles of internal medicine 15 th, page 284, (Eugene Braunwald) (D ) If body fluid losses are severe, hemoconcentration (leading to hyperalbuminemia), lactic acidosis( due to hypoperfusion), and hyperphosphatemia (resulting from academia-induced release of phosphate from the cells) all may combine to raise the anion gap. However, Hypoaldosteronnism always contribute to type 4 RTA, which is always normal anion gap metabolic acidosis. (B ) In rare case, the anion gap has a negative value. Most often due to a laboratory artifact in severe hypernatremia. ( the true concentration of sodium is underestimated), marked hyperlipidemia(where light scattering in the colorimetric assay can result in marked overestimation of the plasma chloride concentration, occasionally to above 200 meq/L), or bromide intoxication just like this case. (B ) Patients with overproduce organic acids can present with a normal anion gap: D-lactic acidosis and toluene exposure (glue-sniffing). Filtered L-lactate, the normal isomer produced in humans, is reabsorbed in the proximal tubule via a Na+-L-lactate cotransporter in the luminal membrane. This transporter is stereospecific and does not bind D-lactae, which may be overproduced in patients with a short bowel syndrome. As a result , D-lactate is rapidly excreted in the urine, lowering the anion gap toward normal.