Pregabalin Neurotoxicity Associated with Triphasic Waves on Electroencephalogram. Conservative Management or Hemodialysis?

Hemodialysis? Harpreet Singh MD, Amanda R Kalupa MD, Chinmay Jani MD, Arashdeep Rupal MD, Alexander Walker MD, Harsh Patel & Kurt Hu MD 1 Department of Pulmonary and Critical Care, Medical College of Wisconsin, Milwaukee, WI, USA 2 Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA 3 Department of Medicine, Mount Auburn Hospital/Beth Israel Lahey Health, Cambridge, MA, USA 4 Harvard Medical School, Boston, MA, USA 5 Department of Internal Medicine, Weiss Memorial Hospital, Chicago, Illinois, USA * Corresponding Author: Harpreet Singh, MD., Medical College of Wisconsin, 8701 W Watertown Plank Road, Milwaukee, WI 53226. E-mail: hasingh@mcw.edu; Phone: 716-378-9697.


Case narration:
A 69-year-old woman was admitted to the intensive care unit with acute encephalopathy. Her medical history included HFrEF, CKD IIIb-IV, depression, and post traumatic distress disorder. Her psychotropic medications included pregabalin, quetiapine, and venlafaxine. Her family reported that she had become progressively short of breath for ten days leading up to her admission; therefore, her diuretic dose was increased. On presentation, she was arousable only to noxious stimulation. She had altered sensorium, unable to follow commands, and frequently falling asleep during the exam. Corneal reflexes and horizontal oculocephalic reflexes were present bilaterally. The pupils were equal, round, and reactive to light, and the pharyngeal reflex was present. There was spontaneous continuous myoclonus of the face. Muscle tone was normal. Plantar reflexes were equivocal bilaterally, and no clonus was observed on examination. The neck was supple.
Laboratory studies revealed an elevated serum creatinine of 3.86 mg/dL from a baseline creatinine of 2.3 mg/dL (normal: 0.60-1.30 mg/dL). Complete blood count and comprehensive metabolic panel at baseline. Her arterial blood gas showed a pH 7.49, pCO2 49 mmHg, bicarbonate 30 mmol/L.
Additional laboratory studies showed blood ethanol level < 3 mg/dl, and blood ammonia level 19 umol/L. The urine toxicology screen was negative. Acetaminophen and salicylate were undetectable.
CT head revealed no acute abnormalities. Her EEG is shown here (Figure 1) and revealed continuous moderate generalized slowing of the background and abundant intermittent bi-anterior predominant, bi-synchronous triphasic waves that often occurred over several second runs at 1.5-2.2 Hz. Given the patient's worsening renal function associated with oliguria, there was a concern about pregabalin and venlafaxine toxicity. She was treated with intravenous fluids for the next 24 hours without any clinical improvement. The patient was then hemodialyzed for 3 hours leading to complete resolution of encephalopathy, facial myoclonic, and triphasic waves on EEG.

Discussion:
Pregabalin is an anti-epileptic, anxiolytic, and analgesic medication often used for neuropathic pain.
Pregabalin binds selectively to the alpha2delta (A2D) subunits of presynaptic calcium channels in the central nervous system (Calandre EP, Rico-Villademoros F, Slim, 2016). This binding prevents calcium influx and blocks the calcium-dependent release of neurotransmitters, including serotonin, dopamine, norepinephrine, glutamate, and substance P (National Center for Biotechnology Information, 2021).
Pregabalin is well absorbed orally and has a bioavailability of >90%. It is excreted almost entirely unchanged in the urine (90%) and does not have any hepatic metabolism. To achieve comparable plasma drug concentrations in patients with creatinine clearance (CL cr ) values of < 60 ml/min, it is usually recommended that pregabalin doses be decreased by ∼50% for each 50% decline in CL cr www.scholink.org/ojs/index.php/rhs Triphasic morphology EEG discharge waveforms have three principal phases: a positive, sharp transient preceded and followed by negative waves of relatively lower amplitude (Figure 1). These discharges are bilaterally synchronous, occurring at a frequency of 1.5 to 2.2 Hz and only rare reports have shown an association between these discharges and pregabalin toxicity (Anand & Kaplan, 2018).
When triphasic waves are present in an individual with acute encephalopathy, it often indicates a more significant impairment, prolonged hospital course, and increased odds of mortality (Emmady & Murr 2021). Triphasic waves resemble certain EEG patterns associated with nonconvulsive status epilepticus.
However, unlike nonconvulsive status epilepticus, the encephalopathy associated with triphasic waves does not improve or resolve with the administration of benzodiazepines (Fountain & Waldman, 2001).
In our patient, the marked improvement in her EEG after dialysis suggests that her triphasic waves were related to pregabalin toxicity. Although serotonin syndrome has been described in association with triphasic waves, our patient had no hyperthermia, ankle clonus, dilated pupils, diaphoresis, or diarrhea to suggest this diagnosis.