Annals of B Pod - Acyclovir Toxicity
/HISTORY OF PRESENT ILLNESS
The patient is a female in her 70s with a history of end stage renal disease (ESRD) who is brought to the emergency department (ED) with a chief complaint of altered mental status and a rash on her neck. The patient is unable to provide history due to her altered mental state, therefore history is obtained from her daughter who brought her in for evaluation. The patient’s symptoms started approximately one week prior to presentation with a painful, non-pruritic rash on the left side of her neck. Five days prior to today’s presentation, the patient was seen at an urgent care for the rash and was prescribed valacyclovir for suspected herpes zoster infection. The following day, her mental status precipitously declined and she was noted to be somnolent, developed incomprehensible slurred speech, and was no longer able to ambulate with her walker. She also began to have auditory and visual hallucinations of deceased relatives. Despite her daughter ensuring compliance with all of her medications, and notable rapid progression of the rash to crusted lesions, the patient’s condition continued to deteriorate.
Past medical history: ESRD on hemodialysis, polycystic kidney disease, hypertension, coronary artery disease, cerebrovascular accident
Past surgical history: appendectomy, cholecystectomy
Medications: aspirin, sertraline, valacyclovir 1g every 8 hours
Allergies: No known allergies
Social history: 30 pack-year smoker, uses marijuana, past alcohol abuse
PHYSICAL EXAM
Vitals: T 36.5 HR 114 BP 124/78 RR 18 SpO2 100% on RA
The patient is ill-appearing and lethargic. She is oriented to self only. She is able to answer yes and no in response to questions, but cannot provide any information beyond verbalizing her name. Speech is noted to be dysarthric, however no receptive or expressive aphasia. Pupils are equal and reactive to light with intact extraocular movements. Visual fields are full to confrontation. There is no evidence of facial droop and cranial nerves are grossly intact. She has 4/5 strength in the right upper and lower extremities, and 5/5 strength in the left upper and lower extremities. There is no pronator drift in the bilateral upper extremities. Sensation is grossly intact in all four extremities to light touch. Skin exam is notable for a crusting rash to the left neck with healing vesicles, with no additional lesions noted elsewhere. She has a fistula in the right upper extremity with an audible bruit. Cardiopulmonary exam is otherwise unremarkable.
Diagnostics
WBC: 7.0 Hgb: 10.6 Hct: 34 Plt: 204
Na: 131 K: 5.0 Cl: 90 HCO3: 26 BUN: 32 Cr: 6.65 Glucose: 83
VBG: pH 7.36 pCO2 53 pO2 39 HCO3 30
Lactate: 0.9
Troponin: <0.04 BNP: 197
AST: 30 ALT: 14 Tbili: 0.6 Ammonia: 90
Acetaminophen: <10 Salicylate: <3 Ethanol: <10
TSH: 1.7 T4: 0.66
Syphilis screen: negative
Peripheral blood cultures x2: no growth to date
CXR: Demonstrates pulmonary edema. Focal left sided opacities.
Non-contrast head CT: No acute intracranial hemorrhage or mass effect.
Hospital course
Given the patient’s history of dialysis-dependent ESRD, and the acute development of neuropsychiatric symptoms with recent initiation of valacyclovir therapy, the emergency providers astutely had a high clinical suspicion for valacyclovir toxicity. They also assessed her for a superimposed bacterial infection, and chest X-ray noted focal opacities concerning for pneumonia. She was provided with empiric broad spectrum antibiotics, including vancomycin, ceftriaxone, and azithromycin. The patient was admitted to the nephrology service for urgent hemodialysis later that morning, and the infectious disease consultation team discontinued valacyclovir given the patient already had crusting of her lesions without new eruptions. Several hours after hemodialysis, the patient had significant improvement in her mental status with increased alertness and resolution of her dysarthria. She was dialyzed again on hospital day three and subsequently returned to her neurologic baseline. Repeat chest X-ray at that time showed resolution of her prior infiltrates. Antibiotics were de-escalated to azithromycin with plans to finish the course as an outpatient. She was then discharged home with family.
Acyclovir Toxicity
Pathophysiology and Clinical Presentation
Valacyclovir is an antiviral drug frequently used in the clinical treatment of leukemia, acute encephalitis, herpes simplex virus (HSV), and varicella zoster virus (VZV). It is a prodrug, rapidly converted by hepatic first-pass metabolism to acyclovir, which is then able to penetrate the central nervous system (CNS). [1] In its active form, acyclovir competitively inhibits viral DNA polymerase by acting as an analog to deoxyguanosine triphosphate (dGTP), with activity against HSV-1, HSV-2, VZV and Epstein-Barr virus (EBV). [2] Valacyclovir confers oral bioavailability three to five times that of acyclovir, allowing for less frequent dosing than that of acyclovir, which requires dosing five times daily . Oftentimes, however, acyclovir is several folds cheaper than valacyclovir, rendering it a more accessible therapy for most patients. It is important to note that the elimination of acyclovir is predominantly renal. The half-life of acyclovir ranges from two to three hours in healthy patients, but may extend up to fourteen hours in patients with ESRD. [3] As such, doses should be reduced according to creatinine clearance in those with renal disease, and may be as low as 500 mg every 24 hours in hemodialysis patients, compared to dosages of up to 1 gram three times daily in patients without renal impairment.
Adverse effects of acyclovir vary greatly in severity, and can include nausea, vomiting, headache, renal failure, and neurotoxicity. In addition to the dosing adjustments that are required in patients with underlying renal impairments, acyclovir itself may also cause acute renal damage. Acyclovir-induced renal failure is caused by precipitation of acyclovir crystals within the renal tubules, leading to obstructive nephropathy, acute interstitial nephritis, and acute tubular necrosis. [4] Undiagnosed, this can create a self-perpetuating cycle as the damaged kidneys fail to filter and excrete circulating acyclovir, and toxic metabolites accumulate. Renal impairment typically begins within 24-48 hours in toxic patients, and may present with nausea and flank pain secondary to obstruction from crystal deposition. Bolus intravenous dosing, dehydration, and underlying chronic renal failure place patients at higher risk of developing acyclovir-induced renal failure.
The first reported case of acyclovir-associated neurotoxicity was in 1998 by Linssen-Schuurmans et al, with multiple subsequent cases since. [5,6] Notable risk factors include chronic renal dysfunction, concomitant neurotoxic drugs, and advanced age. [7] Acyclovir neurotoxicity frequently presents as altered consciousness but may also include myoclonus, dysarthria, photophobia, ataxia, and seizures. Furthermore, acyclovir neurotoxicity has also been shown to manifest with psychiatric components including auditory and visual hallucinations, depression, and suicidality. Multiple case reports have described the association of acyclovir toxicity with Cotard’s syndrome or ‘death delusion.’ This syndrome is characterized by strong delusions of being dead, or convinced that others around the patient are dead. [8] When present, the neurotoxic effects of acyclovir typically manifest within 24 to 72 hours, and can resolve completely within four days, after cessation of the culprit drug. [6]
Diagnosis
The diagnosis of acyclovir toxicity is clinical, and should be suspected in patients with acute renal failure or new neuropsychiatric symptoms in the setting of the aforementioned risk factors. While acyclovir levels can be obtained from the blood, serum, cerebrospinal fluid (CSF), and urine, levels have not been found to correlate with clinical symptoms of toxicity. Further, the development of neurotoxic symptoms has been found to be delayed up to 48 hours after serum concentrations peak. [9] Notably, a downstream metabolite of acyclovir, 9-carboxymethoxymethylguanine (CMMG), has been identified in both serum and CSF of patients with acyclovir toxicity, with detection in the CSF only occurring in patients exhibiting neuropsychiatric symptoms. [10] While this is an interesting finding, testing for CMMG is not widely available and only facilitates, rather than confirms, the diagnosis. Urinalysis may demonstrate positively birefringent, needle-shaped crystals and pyuria, however this is again supportive rather than confirmatory, and absence of such findings does not reliably negate the diagnosis of acyclovir toxicity. [11] In all suspected cases, a basic metabolic panel is crucial, as chronic or acute renal failure precedes the onset of neurotoxicity.
When evaluating a patient with suspected acyclovir toxicity, it is also important to consider other organic mimics including meningitis, HSV encephalitis, herpes zoster associated encephalitis (HZAE), and stroke. Lumbar puncture is imperative, specifically to evaluate for HZAE, as well as other infectious etiologies. It was considered in our case above, however given rapid improvement in our patient’s mental status with dialysis, and the sheer availability of urgent dialysis in our case, her symptoms were thought to be more likely secondary to acyclovir toxicity, and thus further diagnostic work up was deferred. Clinically, the differentiation between such etiologies can prove difficult, as HZAE and acyclovir toxicity can both present with somnolence and confusion after the onset of a vesicular skin eruption. Expedient CSF analysis can prompt either continuation of acyclovir for HZAE, or cessation to prevent further toxicity. In the setting of the acutely altered patient with neurologic findings, cranial computed tomography is indicated to rule out space-occupying lesions, and vessel imaging may be considered in the appropriate patients to rule out acute vascular diseaseas needed. Electroencephalogram (EEG) may also be useful if there is concern for non-convulsive status epilepticus.
Treatment
The first step in the treatment of suspected acyclovir toxicity involves the assessment of whether the patient’s current dosage is appropriate for their level of underlying kidney function, and whether there are indications for its continuation. For those with chronic kidney disease, dosages often need to be reduced, and in other cases, complete cessation is indicated. Patients exhibiting mild toxicity can generally be treated symptomatically. Nausea and vomiting may be treated with antiemetics; headache with standard migraine therapies. Acyclovir-induced renal failure may be treated with volume repletion with intravenous fluid therapy and loop diuretics in an attempt to flush out obstructing crystal depositions . Though the use of these therapies are more theoretical in nature given the lack of robust literature on the topic, they have generally been well-tolerated. Patients with CNS depression should have an airway assessment performed early on during their course. Seizures should be aborted with standard antiepileptics. For those with significant neurotoxic symptoms, hemodialysis is indicated and has been shown to be highly effective in returning patients back to their neurologic baseline. Some reports describe removal of 30-60% of the drug after a single four-hour hemodialysis session. Although this may have a profound effect on neurotoxic symptoms, hemodialysis has not been shown to alter outcomes of acyclovir renal toxicity. [12] Additionally, peritoneal dialysis is not an effective means for removing acyclovir from the blood and has no role in management of acyclovir toxicity.
Summary
Patients undergoing acyclovir or valacyclovir therapy with underlying chronic kidney disease are particularly at risk for developing acyclovir-induced neurotoxicity. Symptoms of toxicity can develop precipitously and may prove difficult to differentiate from viral encephalitis. Despite recent advances in biomarkers associated with acyclovir-associated neurotoxicity, the diagnosis remains clinical. Discontinuation of acyclovir, coupled with hemodialysis when indicated, has been shown to significantly improve symptoms and outcomes. This case highlights the caution needed in both prescribing and dosing acyclovir in patients with underlying renal impairment.
AUTHORED BY Jonathan Chuko, MD
Editing by the Annals of B Pod Editors
References
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