Acute kidney injury and acyclovir-associated encephalopathy after administration of valacyclovir in an elderly person with normal renal function

Abstract Introduction: Acyclovir (ACV)-associated encephalopathy is related to an increase in plasma levels of 9-carboxymethoxymethylguanine, an ACV metabolite, and is often reported in patients with renal dysfunction. We report a case of ACV-associated encephalopathy with rapid progression of renal dysfunction after oral administration of valacyclovir (VACV) and review literature of previous ACV-associated encephalopathy cases. Patient concerns: An 88-year-old man was diagnosed with herpes zoster. VACV (3000 mg/day) treatment was initiated. Serum creatinine (Cr) level was 0.80 mg/dL. However, irritability, memory impairment, and decreased responsiveness occurred after 3 days. The Cr level was 6.76 mg/dL on admission. Diagnosis: He was diagnosed with ACV-associated encephalopathy with acute kidney injury. Interventions: VACV was discontinued, hemodialysis was initiated on the day of admission, and then the signs and symptoms improved approximately 72 hours after the admission. Conclusion: Worsening of renal function and encephalopathy should be a focus when using VACV or ACV, regardless of age and original renal function. Acute kidney injury and ACV-associated encephalopathy may particularly occur in the elderly even when renal function is normal. Therefore, regular monitoring of renal function and consciousness is necessary during VACV treatment.


Introduction
Acyclovir (ACV) associated encephalopathy is a very rare case induced by ACV and valacyclovir (VACV), a prodrug of ACV. [1] Rashiq et al reported that several neuropsychiatric symptoms, such as consciousness disturbance, tremor, and myoclonus, usually occur within 2 days of administering VACV. [1] Hallucination frequently occurs in addition to consciousness disturbance and involuntary movements. [1][2][3] However, headache, fever, convulsions, and focal symptoms are rare. [2] Abnormalities in cerebrospinal fluid examinations or head computed tomography (CT)/magnetic resonance imaging are generally not observed, and symptoms disappear 48 to 72 hours after discontinuing ACV. However, dialysis may be necessary. [4] ACV-associated encephalopathy is related to an increase in plasma levels of 9-carboxymethoxymethylguanine, a metabolite of ACV, and is often reported in patients with renal dysfunction. [5] However, there are few reports of the onset of ACVassociated encephalopathy in patients in whom renal dysfunction was not indicated. [4] Here, we report a case of ACV-associated encephalopathy with the rapid progression of renal dysfunction after oral VACV administration, although serum creatinine (Cr) levels were normal. In addition, we report a review of previous ACV-associated encephalopathy cases.

Case report
An 88-year-old man who could independently perform activities of daily living visited the hospital with a primary complaint of consciousness disturbance. The patient had a history of radical resection for prostate cancer (T1c N0 M0, stage I). His history of varicella-zoster infection was unknown. A painful vesicular eruption appeared in the right axilla 8 days before admission, and he visited a nearby clinic the following day. The Cr level was 0.80 mg/dL. He was consequently diagnosed with herpes zoster. Thus, VACV administration (3000 mg/d) was initiated. Pregabalin (75 mg/d) and mecobalamin (1500 mg/d) were also administered for analgesic purposes without the concomitant use of nonsteroidal anti-inflammatory drugs. The patient experienced pain that led to reduced food intake and dehydration. He urinated about 4 times daily. Also, irritability, memory impairment, and decreased responsiveness occurred after 3 days, and the patient was admitted to our hospital for emergency treatment due to exacerbated symptoms.
Physical findings on admission were as follows: E3V3M6 on the Glasgow Coma Scale, body temperature of 35°C, blood pressure of 110/60 mm Hg, pulse rate of 60 beats/min, respiratory rate of 20 breaths/min, and oxygen saturation level of 96% (room air). The patient had xerostomia. Herpes zoster scarring on the right upper limb (TH-1/TH-2 areas) was noted in the extremities. Furthermore, examination of meningeal irritation symptoms showed no neck stiffness, negative Kernig sign, and negative Brudzinski sign. The diameter/light reflex of the pupils was 2+/2+. Myoclonus was observed with no clear paralysis. Hematologic examination results were as follows: white blood cell, 6530/mL; C-reactive protein, 1.07 mg/dL; blood urea nitrogen, 58.4 mg/dL; Cr, 6.76 mg/dL; and blood glucose, 91 mg/dL ( Table 1). The urine sediment showed muddy brown casts of epithelial cells, indicating acute tubular necrosis. Cerebrospinal fluid test results revealed an initial pressure of 13 cm H 2 O, cell count of 71/mL (mononuclear cell count, 70/mL), protein level of 147 mg/dL, and glucose level of 48 mg/dL (Table 2). However, blood, urine, and cerebrospinal fluid cultures were negative.
The hemodynamics were maintained, but ultrasound showed that the inferior vena cava collapsed, suggesting dehydration. Abdominal CT revealed no obstruction, and postrenal renal failure was ruled out. The maximum diameter of the kidney was 62 mm on the right and 65 mm on the left, and there was no prominent renal swelling. However, urinary retention of about 250 mL in the bladder was observed. Moreover, head magnetic resonance imaging did not reveal any findings suggestive of encephalitis. Table 3 shows the comparison of ACV-associated encephalopathy and varicella zoster virus encephalitis. [6,7] Our elderly patient had taken VACV for a sufficient period and was thus suspected to have ACV-associated encephalopathy based on the absence of fever, stiff neck, and headache, and normal imaging findings. The clinical course is shown in Fig. 1. VACV was discontinued, hemodialysis was initiated from the day of admission to day 3, and then the signs and symptoms improved approximately 72 hours after the admission. The Glasgow Coma Scale score was 14 points, and hemodialysis was discontinued on hospital day 4. The plasma concentration of ACV level at the time of examination, which was discovered later, was markedly elevated (34.6 mg/mL), and results of polymerase chain reaction analysis of the cerebrospinal fluid were negative for herpes simplex virus and varicella zoster virus DNA. The plasma concentration of ACV level was <0.5 mg/mL (normal range <2.0) when the consciousness level became normal on day 10 of hospitalization. Negative blood, urine, and cerebrospinal fluid cultures ruled out bacterial consciousness disorder. Furthermore, the consciousness level did not improve immediately after the dialysis on day 1; however, it improved after the dialysis was performed for 3 days. Therefore, the consciousness disorder due to uremia was ruled out. Thus, a definitive diagnosis of ACVassociated encephalopathy was made based on the patient's course. The increase in cell count in the cerebrospinal fluid could have been due to the effects of ACV-associated encephalopathy, although this finding was atypical.  Subsequently, ambulatory discharge was possible on hospital day 35 without any sequelae.

Search strategy
The terms "acyclovir neurotoxicity" or "acyclovir encephalopathy" were searched in the MEDLINE database. Fifty-one cases have existed in the literature since 1988. Among those 51 cases, 35 reported acyclovir neurotoxicity when limited to the English and Japanese literature.

Discussion
We report a case of ACV-associated encephalopathy with rapid progression of renal dysfunction after oral VACV administration despite normal serum Cr levels (0.80 mg/dL). The patient experienced pain that led to reduced food intake and dehydration. Moreover, the use of VACV, which has a high oral bioavailability and a long plasma half-life, caused renal dysfunction, leading to ACV-associated encephalopathy. Furthermore, as shown in Table 4, ACV-associated encephalopathy may occur even under normal renal function or prophylactic administration of antiviral drugs. ACV-associated encephalopathy is commonly observed in patients with impaired renal function but may develop even when renal function is normal. [1] Two mechanisms of ACV-induced acute kidney injury exist. One is renal dysfunction due to dehydration and the use of nonsteroidal anti-inflammatory drugs, as well as tubular obstruction due to ACV itself, [5] and the other is renal dysfunction caused by a direct mechanism of ACV aldehyde. [6] The serum ACV level increases due to dysuria when renal dysfunction occurs, which further exacerbates renal dysfunction and causes ACV-associated encephalopathy. [8] Elderly people are prone to dehydration and potentially impaired renal function. The aforementioned mechanism causes acute renal damage and a tendency for the onset of ACV-associated encephalopathy. Moreover, VACV is a prodrug of ACV and has better gastrointestinal absorption than ACV. Consequently, the oral bioavailability of ACV is 10% to 20% (54.2% for VACV), and its serum half-life is approximately 5 times longer. Hence, VACV is simpler to administer than ACV because the number of doses is smaller and characteristically tends to result in increased serum levels. [1] In total, 43 cases of ACV-associated encephalopathy have been reported in 35 studies. A summary of the literature review is presented in Table 4. The age range of the patients with ACVassociated encephalopathy was from 0.5 to 88 years (mean age, 55.0 years; median age, 62 years). Among the patients, 24 (55.8%) were aged ≥60 years, and 6 (13.9%) were aged 18 years. The sex ratio was almost equal (18 females and 24 males [55.8]; 1 unknown). ACV-associated encephalopathy occurred following the treatment of herpes zoster in 27 cases (62.7%), treatment of herpetic simplex in nine cases (20.9%), and for the purpose of suppressing the onset of virus associated with chemotherapy in 5 cases (11.6%).
ACV-associated encephalopathy occurred in 24 patients (55.8%) using oral medication only. The administered antiviral agent was ACV in 37 cases (86.0%). The duration of antiviral administration was known in 40 patients, and the time of onset was 1 to 36 days (median, 4 days). Moreover, an NSAID was concomitantly used in only 2 patients (4.7%).
Many patients had an underlying disease, especially 27 dialysis patients (62.7%; 22 undergoing hemodialysis and 5 undergoing peritoneal dialysis). However, 4 patients (9.3%) had no underlying disease, and the presence of the underlying disease was unknown in 4 patients (9.3%).   Patel J et al [13] 63 Man
Yes HD Unknown Unknown Unknown 17 Hoskote SS et al [21] 52 Man

Anti-CMV prophylaxis
Oral GCV (5 Yang HH et al [28] 70 Man Chevret L et al [29] 0.5 Woman Prevention Intravenous ACV (2) Serum ACV concentration was measured in 21 of 43 cases (48.8%). The serum concentration of 9-carboxymethoxymethylguanine was measured in only 1 case (case 28). VACV is a prodrug of ACV, which becomes ACV in the blood; thus, there were no cases with VACV concentration measurement.
For many patients, the precritical serum Cr levels were unknown, and in 2 patients (4.7%), the levels were <1.0 mg/dL. Moreover, serum Cr levels at the time of onset were often unknown. The serum Cr level at the time of onset, when known, was elevated except in 1 patient, a 7-year-old child (0.3 mg/dL).
In conclusion, based on our case findings, it is important to focus on the worsening of renal function and encephalopathy when using VACV or ACV regardless of age and original renal function. Acute kidney injury and ACV-associated encephalopathy may particularly occur in the elderly even when renal function is normal. Therefore, regular monitoring of renal function and consciousness is necessary.
Author contributions