A diagnosis you can’t afford to miss

4 out of 5 stars

Antibody-Mediated Encephalitis. Dalmau J, Graus F. N Engl J Med 2018 Mar 1;378:840-851.


TPR has posted before about anti-NMDA receptor encephalitis, a must-know, can’t-miss, humbling diagnosis that is distressingly easy to overlook. Although it is not a toxicologic condition, all toxicologists and emergency physicians should be thoroughly familiar with its presentation and clinical course. Let me explain why.

NMDAR encephalitis often begins with behavioral changes, mood swings, and memory deficits in relatively young patients. According to this somewhat technical but excellent review, the median age is 21 years, with a 4:1 ratio of females to males. Because of the initial symptoms, patients are often diagnosed as having new-onset psychiatric disease. It is not unusual for these patients to then be treated with antipsychotic medication in an attempt to control abnormal and agitated behavior.

This is where a toxicologist may be consulted. As the authors point out in this review, patients with NMDAR encephalitis seem to have increased susceptibility to developing neuroleptic malignant syndrome (NMS) after receiving antipsychotics. When these patients then develop movement disorders, autonomic instability, and altered mental status, the toxicology service is brought in to advise about the treatment of NMS.

If the diagnosis of NMDAR encephalitis is not considered, the outcome can be catastrophic. As the authors of this review note “spontaneous clinical improvement is infrequent.” Early treatment with immunotherapy can result in a good outcome. In the case of anti-NMDAR encephalitis, diagnosis is confirmed by finding specific antibodies cerebrospinal fluid. Lumbar puncture is essential, since testing serum for these enzymes yields a false negative in as many as 14% of cases. Optimal treatment has not yet been defined, but current regimens begin with glucocorticoids, IV immune globulin, and plasma exchange transfusion . In resistant cases, medications such as rituximab and cyclophosphamide can be used. It is also critically important to find and remove associated tumors — most commonly teratomas in young women.

This review article is well worth reading, but too detailed and technical to serve as a good introduction to this very important condition. It also covers many other forms of autoimmune encephalitis. Those looking for an introduction to anti-NMDAR encephalitis can consult the following:

One more essential read is Brain on Fire, an account of anti-NMDAR encephalitis from the patient’s point of view. Written by a journalist who was stricken with the condition before much was known about it, the book is so vivid and unforgettable that after reading it you’re unlikely ever to miss the diagnosis again.

Flubromazolam: a potent designer benzodiazepine


3 out of 5 stars

Flubromazolam — A new life-threatening designer benzodiazepine. Lukasik-Glebocka M et al. Clin Toxicol 2016;54:66-68.


Last month, the Peoria (IL) Journal-Star reported that local police had seized samples of two rarely seen designer sedatives: flubromazolam (alleged street name “liquid Xanax“) and etizolam.

This paper from Poland presents a case report of flubromazolam exposure. A 27-year-old male known to use psychotropic drugs was brought to hospital after being found unconscious at home. On arrival he was comatose with a Glasgow Coma Scale of 3. On exam, he was breathing at rate of 6-8/min and was intubated. He had multiple pressure sores over the right side of his body, as well as hypotonia, hypotension (80/40) and hyporeflexia. He was treated with 1500 ml normal saline. Gelofusine, and pressors. He showed no response to naloxone.

Head CT was unremarkable. Creatine kinase was 15,960 U/L and creatinine 1.53 mg/dL (reference 0.7 – 1.4.) Because the urine drug screen was positive for benzodiazepines, flumazenil was administered in doses 0.5 mg with partial improvement in level of consciousness.

A second head CT on day 3 showed “hypoxic-ischemic changes within the internal capsules bilaterally.” After the patient’s mental status improved and he could provide history, he reported ingesting flubromazolam “3 mg” purchased over the internet. Specific toxicologic testing confirmed the presence of flubromazolam in serum and urine.

The authors suggest that this case indicates that flubromazolam can cause “severe, long-lasting depression of the central nervous system with cardiorespiratory failure, complicated with brain hypoxic-ischemia changes.” Unfortunately, it’s not clear from the paper how thorough the screening was for other drugs such as fentanyl. The key take-home points are that flubromazolam may have extremely potent sedative effects, apparently shows up a benzodiazepine on the urine drug screen and is at least partially reversed by flumazenil.

Etizolam is a short-acting benzodiazepine analog with typical sedative-hypnotic properties. It is used medically in some parts of the world but not approved for use in the United States. Although not scheduled on the federal level, it is restricted in a number of states (AL, AK, GA, VA, FL, IN, MS, TX, LA.) A relatively recent case report indicates that flumazenil may readily reverse the effects of etizolam.

Can we improve prognostic indications in acetaminophen-induced hepatic failure?

2.5 out of 5 stars

Hypoglycemia and lactic acidosis outperform King’s College criteria for predicting death or transplant in acetaminophen toxic patients. Levine M et al. Clin Toxicol 2018 Jan 5 [Epub ahead of print]


The standard tool used in evaluating acetaminophen-poisoned patients for possible orthotopic liver transplantation (OLT) is the King’s College Criteria (KCC).

The KCC identify 2 groups of patients who are expected to have a poor prognosis after overdosing on acetaminophen:

arterial pH < 7.30 after resuscitation


INR > 6.5 (PT > 100 sec)
serum creatinine > 3.4 mg/dl
Hepatic encephalopathy (Grade III or IV)

Some versions of KCC also include lactic acidosis as a poor prognostic indicator.

It’s important to take note of the limitations inherent in the KCC. It was derived in the 1980s, which means modern advances in use of N-acetylcysteine and standard ICU care were not available. All patients were evaluated and treated at King’s College Hospital in London, bringing into question whether the results are generalizable to other centers. In addition, inclusion of advanced hepatic encephalopathy as a criterion for OLT means that some patients may be too sick for surgery by the time they qualify.

This multi-center retrospective cohort study looked at adult patients (> 14 years old) admitted to hospital and discharged with a diagnosis of acetaminophen-induced liver failure. The objective was to compare the markers of hypoglycemia (glucose < 50 mg/dL,) coagulopathy, and lactic acidosis (lactate above hospital’s “normal” range) in predicting a composite endpoint of death or liver transplantation.

The authors identified 334 unique cases. 19 of these were listed for transplant, and 13 actually received liver transplant. (2 transplanted patients subsequently died.) Although 96 patients (29%) met the King’s College Criteria, it is not clear how many of these who were not transplanted died. There were 40 deaths in all.

After some statistical manipulation  which was not at all nearly described, the authors conclude that:

The combination of hypoglycemia, coagulopathy, and lactic acidosis performed better than the King’s College criteria for predicting death or transplant.

I’d submit that “better” is really a helpful word in describing the permanence of these dueling criteria. Despite reading the paper several times, I could not tell exactly what the authors meant by “better.” In any case, I don’t think this study design could have met their objectives even for the purpose of a pilot study. The composite endpoint muddles everything. True, death is a firm, obvious outcome, but the decision to transplant is subjective, and certainly based in part on some of the criteria being tested.