There are always exciting case vignettes under the heading "Clinical Challenge" in the journal JAMA Neurology (Journal of the American Medical Association). A published case comes from Montreal, Canada, and underlines the importance of physical examination and context, especially for people returning from a trip.
The “Clinical Challenge” section reports on a 69-year-old female patient who was on her way home to Canada after a holiday in Cuba.1 At the Havana airport she developed generalized weakness, increased sweating, severe nausea, and vomiting. During the approximately four-hour flight, drowsiness, vomiting, and urinary incontinence occurred. Directly from the destination airport, she was taken to the emergency room. Upon arrival, she was stuporous and required intubation. She was well until two hours before the flight home and had no relevant pre-existing conditions or allergies.
In the initial laboratory analysis, mild anemia (Hb 10.9 g/dl), elevated creatinine (1.31 mg/dl), and acidosis (pH 7.22, anion gap normal) were observed. Electrolytes, leukocyte count, blood sugar, creatine kinase, lactate, TSH, coagulation, and liver enzymes were within normal ranges. The ECG showed sinus bradycardia (53 bpm) and borderline QT prolongation (QTc 465 ms). CSF analysis was performed without pathological findings. Malaria diagnosis was negative (blood smear, antigen test, PCR, cultures of cerebrospinal fluid, blood, and urine). A CT of the head showed hyperintensities of the globi pallidi on both sides. The toxicological examination of the urine was negative for paracetamol, salicylates, opiates, barbiturates, cocaine, and ethanol.
Within a few hours, vigilance improved spontaneously and the patient was extubated. She was awake but disoriented. Her blood pressure was 99/61 mmHg, heart rate 80 bpm, temperature 37.6 °C and oxygen saturation under room air was 99%. Her pupils were narrow and sensitive to light. The patient showed slight proximal muscle weakness with normal muscle tone and occasional bilateral fasciculations of the upper and lower extremities and choppy movements. In addition, involuntary twitches of the facial muscles were observed. The reflexes were triggered normally on the same side (no Babinski sign). The sensation of pain and vibration was normal.
The changes visible in cranial imaging are consistent with senile calcifications of the globus pallidus. "The key to diagnosis was the constellation of signs and symptoms during a physical examination," the authors write. Vigilance reduction, bradycardia, vomiting, diaphoresis, urination, miosis, muscle weakness, fasciculations, and myoclonic twitches made the attending physicians think of intoxication with a cholinergic substance.
Further investigations revealed a reduced pseudocholinesterase and acetylcholinesterase activity, consistent with cholinesterase inhibition. Mass spectrometry revealed a trace of the thiophosphoric acid ester temephos in serum. Poisoning with organophosphates leads to irreversible acetylcholinesterase inhibition and thus indirect parasympathomimetic activity through covalent binding to the active site of cholinesterase, resulting in extremely long enzyme inhibition.2
Organophosphates are used, for example, as insecticides, endo- and ectoparasites, chemical warfare agents, and as therapeutic agents for glaucoma (paraoxon).2 Intoxication usually occurs through occupational exposure or with suicidal intent. Intoxication can be ingested through drinking, inhalation of vapors, or contact with the skin.3
The specific source of poisoning in the patient was unclear, but temephos is a larvicide widely used in Cuba. Cuba relies on aggressive fumigation with insecticides to control mosquitoes and minimize Zika outbreaks. The patient's serum also showed the presence of 3-phenoxy-benzoic acid (3-PBA), a breakdown product of pyrethroid insecticides. As the population is constantly exposed to such insecticides, for example through residues on fruit and vegetables, 3-PBA has been detected in the urine of many citizens.4
The patient was the only person in her travel group who had bought and consumed a sandwich (ham, cheese, salad, mayonnaise) and table water at the airport about half an hour before the onset of symptoms.
On the second day after admission, the symptoms subsided and after four days the patient was discharged in good condition to her home environment. At the follow-up examination after five months, however, she reported a loss of appetite and weight (18kg), daily headaches, disturbances in concentration and memory, tinnitus and swaying, and painful “glove” paresthesia with numbness and cold hands.
An MRI of the head was inconspicuous except for the previously known calcifications. Pseudocholinesterase activity had recovered moderately and acetylcholinesterase activity had normalized. The attending physicians considered organophosphate-induced time-delayed neuropathy highly likely.
Using various validated test batteries, relevant neurocognitive impairment was confirmed in the patient. Disturbances of attention, executive function, and memory were found. This is described in the literature in connection with organophosphate neurotoxicity, including 2016-2018 in American and Canadian diplomats and their families in Cuba. Vestibulopathies are also known; the patient was found to have both an auditory neuropathy and a brainstem lesion. Exposure to low doses of organophosphates and other insecticides in the environment is suspected to be the cause of the so-called “Havana syndrome”.
Prevention efforts include banning very toxic types of organophosphates. Organophosphate pesticides are among the most common causes of poisoning worldwide. Almost 3 million intoxications are reported annually, including 300 thousand deaths.3,5
References:
1. Serlin, Y., Minuk, J. & Schondorf, R. Neurological Impairments in a Patient Returning From Cuba. JAMA Neurol (2020) DOI:10.1001/jamaneurol.2020.3193.
2. Pschyrembel Online | Organophosphate Poisoning. https://www.pschyrembel.de/Organophosphat-Vergiftung/B0P5F.
3. organophosphate poisoning - Organophosphate poisoning - qwe.wiki. https://de.qwe.wiki/wiki/Organophosphate_poisoning#Epidemiology.
4. medical journal, D. Ä. G., Editorial Office German. Increased cardiovascular mortality risk for pyrethroid insecticides... German medical journal https://www.aerzteblatt.de/nachrichten/108485/Erhoehtes-kardiovaskulaeres-Sterberisiko-fuer-Pyrethroid-Insektizide-entdeckt (2020).
5. Robb, E. L. & Baker, M. B. Organophosphate Toxicity. in StatPearls (StatPearls Publishing, 2020).