Glufosinate ammonium poisoning: A rare clinical presentation

INTRODUCTION

Glufosinate ammonium is a widely used herbicide for controlling weeds in orchards, rubber plantations, and non-arable lands all over the world. It is a phosphorus-containing amino acid that irreversibly inhibits the activity of glutamate synthetase in plants and hence inhibits the synthesis of glutamine from glutamate and ammonia. This prevents ammonia detoxification, leading to intracellular accumulation of ammonia, causing tissue necrosis and eventually death of the plant shoot.¹ Glufosinate is also an analogue of glutamate, an excitatory neurotransmitter in the central nervous system (CNS). After considering the differences in biochemical pathways and metabolism between plants and mammals, glufosinate ammonium formulations have been regarded as minimally toxic to humans and as safe products in agronomy, as long as they are handled according to the manufacturer’s instructions.² However, the ingestion of undiluted glufosinate ammonium herbicide can cause grave clinical outcomes, even death.

We report the clinical manifestations in a patient following the ingestion of glufosinate ammonium herbicide, which is an extremely rare presentation.

THE CASE

A 32-year-old male with no known comorbid conditions presented with a history of decreased urine output following an alleged history of deliberate self-harm by consuming an unknown quantity (approximately 100 ml) of an unknown compound, probably a herbicide Synkill^®—Glufosinate ammonium 13.5%, two days before presentation. The patient had undergone gastric lavage at a local hospital on the day of ingestion of the compound. At the time of admission, general physical examination revealed pulse 86 beats per minute, blood pressure 140/90 mmHg, and respiratory rate of 20 cycles per minute. Laboratory investigations revealed leucocytosis (11 900 cells/cmm³) with a high neutrophil (90%) to lymphocyte (5%) ratio of 18. Other investigations include a deranged renal function, where serum urea and serum creatinine were 66 mg/dl and 5.96 mg/dl, respectively; creatinine phosphokinase (340 i.u./L) and liver enzymes (serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase were 641 i.u./L and 229 i.u./L, respectively) were also found to be elevated. Serial renal function tests showed a worsening trend with oliguria for which the patient underwent a total of 8 sessions of haemodialysis. On day 6 of hospital stay, he developed right-sided lower motor neuron facial palsy. A provisional diagnosis of idiopathic Bell’s palsy was considered; the patient was initiated on treatment with oral glucocorticoids. The next day, the weakness progressed, and the patient had developed bilateral lower motor neuron facial palsy. Difficulty in swallowing both solids and liquids, secondary to bulbar palsy, was evident, with no history of nasal regurgitation. Over the next three hours, the patient developed respiratory distress, which required endotracheal intubation and mechanical ventilator support, in view of impending respiratory muscle paralysis.

During the subsequent days, a descending type of flaccid paralysis ensued, while on mechanical ventilator support, resulting in quadriplegia. MRI of the brain was normal. The electroneuromyography (ENMG) showed prolonged latency with reduced sensory nerve action potential (SNAP) amplitude and conduction velocity of bilateral median, ulnar, and sural nerve sensory conductions. The motor conduction studies performed on the bilateral median nerve and posterior tibial nerves showed prolonged distal latency with reduced compound muscle action potential (CMAP) amplitude, reduced conduction velocity, and prolonged F-wave. The bilateral ulnar nerve and common peroneal nerve motor conduction showed normal distal latency with reduced CMAP amplitude and conduction velocity. The ENMG report suggested both axonal and demyelinating types of neuropathy with a predominant demyelinating pattern. A repetitive nerve stimulation test performed on the bilateral abductor pollicis brevis and abductor digiti minimi showed a normal decrement response, which ruled out abnormal neuromuscular junction transmission. The sensorium of the patient worsened to a Glasgow Coma Scale (GCS) of E1VTM1 by day 11 of hospital stay. A video electroencephalogram (EEG) done for 30 minutes showed diffuse beta, theta, and delta activity. This was suggestive of a global cerebral dysfunction which could occur due to multiple aetiologies, including toxic or metabolic encephalopathy, sedative medications, meningoencephalitis, or structural lesions in the deep brainstem. CT imaging of the brain done after deterioration in the GCS showed no abnormality in the brain parenchyma. Plasma ammonia levels assessed by the enzymatic ultra-violet (UV) method were elevated (313 μg/dl), more than three times the upper normal range (17 to 90 μg/dl). On toxicological analysis, the urine sample tested positive for the presence of glufosinate by thin-layer chromatography. The patient was discharged against medical advice from the hospital and further follow-up details are not known.

DISCUSSION

The toxic manifestations of glufosinate ammonium are varied and have not been well documented due to the rarity of presentation. Among the various manifestations, gastrointestinal effects like nausea and vomiting were the most common, probably secondary to the irritative effect of the anionic surfactant present in the formulation.^2,3 Neurotoxicological effects are the second most commonly reported, the window period being 4–60 hours after ingestion.⁴ Acute glufosinate poisoning may cause seizures, amnesia, stupor, and coma.⁵ Glufosinate, which has structural similarity to glutamate, can cause both CNS excitation and depression in animals as well as in humans.⁶ Neurologic effects seen following ingestion of glufosinate are proposed to be caused by glufosinate, its metabolites or glufosinate induced imbalance between glutamate, ammonia and glutamine; and the toxic mechanism mediated through overstimulation of N-methyl-d-aspartate (NMDA) receptor.^7,8 The surfactants used in herbicide formulations (alcohol, ethoxylated monoether with sulphuric acid, sodium salts) are also presumed to have a role in this. Overstimulation of NMDA receptors, which are highly expressed in the hippocampus, can cause memory impairments like amnesia.⁹ The irreversible inhibition of glutamine synthetase causes hyperammonaemia, leading to neuronal cell death and tissue necrosis, responsible for other CNS manifestations. Ammonia levels serve as a prognostic indicator. The higher the peak levels of ammonia, the worse the neurological manifestations and eventually, the outcome.^10,11 A high neutrophil to lymphocyte ratio is also shown to be significant in predicting the development of neurotoxicity in these patients.¹² Glufosinate poisoning can also cause haemodynamic effects such as vasodilatation and cardiac suppression, which are thought to be caused by the anionic surfactant, sodium polyoxyethylene alkyl ether sulphate.¹³ This can result in hypotension and bradycardia in the patient. Glufosinate ammonium can also cause respiratory failure in patients, leading to intubation and mechanical ventilator support. This is commonly seen 10 to 36 hours following ingestion of the herbicide.³

Management of a patient with glufosinate toxicity is largely supportive. It consists of early gastrointestinal decontamination and administration of activated charcoal. Appropriate fluid therapy and close monitoring of the patient are usually performed. Haemodialysis and/or haemoperfusion have no definite efficacy in removing the glufosinate ammonium compound.¹⁴ In our patient, despite 8 cycles of haemodialysis, there was no significant improvement in renal function or clinical condition.

When a patient presents with unexplained symmetric cranial nerve palsies with paralysis of other muscles, the differential diagnosis mainly consists of Guillain–Barré syndrome, myasthenia gravis, or botulism.¹⁵ In our patient, there was acute renal failure and multiple cranial nerve palsy, requirement of mechanical ventilator on day 7 of admission, delayed-onset of progressive, descending type of flaccid paralysis which has never been reported in any case of glufosinate ammonium poisoning previously. The patient was treated with multiple sessions of haemodialysis and steroids. Hence, our case highlights the rare neurological manifestations in a patient with glufosinate ammonium intoxication.