| Abstract|| |
A 51-year-old man, who received a living related transplant from his wife and anti-thymocyte globulin (ATG) as induction therapy, developed delayed graft function after transplantation. One day after he received an i.v. dose of ganciclovir, the patient developed hallucinations, confusion and agitation, which worsened the following day. CTscan of the brain and cerebrospinal fluid were unremarkable. Ganciclovir-induced encephalopathy was considered the most likely reason for the patient's neurological condition, since he recovered completely a few days after discontinuation of this drug. Since anti-CMV prophylactic treatment is now widely used after transplantation, a high index of suspicion is required to diagnose ganciclovir (or acyclovir) induced neurotoxicity.
Keywords: Confusion, Transplantation, Ganciclovir
|How to cite this article:|
Hussein MM, Mooij JM, Al Malki N, Ali Idriss D. Confusion and Agitation after a Recent Kidney Transplantation. Saudi J Kidney Dis Transpl 2008;19:446-9
|How to cite this URL:|
Hussein MM, Mooij JM, Al Malki N, Ali Idriss D. Confusion and Agitation after a Recent Kidney Transplantation. Saudi J Kidney Dis Transpl [serial online] 2008 [cited 2020 Jan 18];19:446-9. Available from: http://www.sjkdt.org/text.asp?2008/19/3/446/40509
| Introduction|| |
Confusional state in patients after recent transplant surgery can be multifactorial that include neurotoxicity with cytomegalovirus (CMV) prophylaxis with drugs such as acyclovir, ganciclovir, valganciclovir and valcyclovir. ,,,,,,,,,,
We present a case of severe confusion and agitation one to two days after giving one dose of oral valganciclovir and one dose of intravenous (i.v.) ganciclovir, which resolved completely after discontinuation of the antiviral medication. To make the diagnosis, a high index of suspicion will be needed, and timely discontinuation or dose reduction might prevent further deterioration.
| Case Report|| |
A 51-year-old man with end-stage renal disease of uncertain etiology (shrunken kidneys of around 5-6 cm in size), and diabetes mellitus controlled on diet only, was on maintenance hemodialysis for the last 5 years in another hospital.
In August 2006, the patient was referred to our hospital for possible kidney transplantation from his wife. His pre-operative investigations revealed atrial fibrillation with a ventricle rate of around 80 per minute. Echocardiogram revealed an ejection fraction of 40-45%, moderate aortic regurgitation and moderate mitral regurgitation with moderate pulmonary hypertension. Coronary angiography illustrated normal coronary arteries. Patient was started on advice of the cardiologist on warfarin as oral anticoagulant, bisoprolol as a beta-blocker, and digoxin.
Laboratory investigations included markers of active hepatitis that all were negative. The investigations of the donor were all normal. Cytotoxic crossmatch with the donor was negative, and panel reactive antibodies (PRA) of the recipient was negative. Both recipient and donor were seropositive for CMV-IgG.
Three days before transplantation the patient was switched to heparin, which was discontinued 10 hours before surgery. Two days prior to the transplantation, the patient was started on immunosuppressive medications that included cyclosporine, prednisone, and mycophenolate mofetil (MMF).
On December 17, 2006, the patient underwent transplantation that was complicated by delayed graft dysfunction, most likely due to hemodynamic instability during the operation, and it required daily hemodialysis.
On the 1st post operative day, cyclosporine was discontinued and patient was started on anti-thymocyte globulin (ATG) with a dose of 1.5 mg/kg i.v. daily over 6 hrs. After the first 3 doses, it was reduced to 0.75 mg/kg in view of thrombocytopenia.
On the 3 rd postoperative day, anti- CMVprophylaxis was initiated. The patient received one dose of valganciclovir 450 mg orally, followed the next day by ganciclovir i.v. in a dose of 1.25 mg/kg BW every 48 hours, the recommended dose for patient's degree of creatinine clearance.
On the 5 th post-operative day, the patient became confused, hallucinating and agitated pulling out his i.v. lines. The blood pressure was 160/80 mm Hg, temp 37°C, and 24-h urine output 211 ml. Laboratory investigations revealed hemoglobin (Hgb) of 7.5 g/dl, white blood cell count (WBC) of 4.4 x 10 9 /l, and platelets count 104 x 10 9/l. Blood chemistry showed serum sodium of 129 mmol/L, potassium: 5.5 mmol/L, bicarbonate: 14 mmol /L, blood urea nitrogen (BUN) 42 mmol/L, creatinine 924 µmol/L, and arterial blood gas (ABG): pH 7.30, pCO2 23 mm Hg, pO2 65 mm Hg. Chest X-ray (CXR) illustrated pulmonary congestion. A plain computerized tomography (CT) scan of the brain revealed normal findings.
On the 6 th post operative day, the patient was stuperous, but arousable and oriented to person, place, and time. He remained afebrile with blood pressure 135/74 mmHg, heart rate 110 per minute, and clear chest on auscultation. There were no focal neurological signs and no neck stiffness. Laboratory investigations revealed Hgb of 7.7 g/dl, WBC of 7.7 x 10 9 /L, and platelets 119 x 10 9 /L. Serum sodium was 126 mmol/L, potassium 5.5 mmol/L, chloride 96 mmol/L, bicarbonate 11 mmol/L, blood glucose level was 4.8 mmol/L, BUN 49.9 mmol/l, serum creatinine 1076 µmol/L, corrected serum calcium 1.98 mmol/L, lactic acid 0.7 mmol/l, and ABG that included pH 7.13, pCO 2 35 mm Hg, HCO 3 13 mmol/L, and O2 96% on 2 liters of oxygen by nasal canula. The CXR was normal, and blood culture revealed no growth. Repeat CT-scan of the brain did not show any new changes, a lumbar puncture revealed clear, colorless cerebrospinal fluid with a white cell count 2 per mm 3 , protein 189 mg/L and glucose 3.3 mmol/L. Later that day, the patient's condition deteriorated further, and he had to be intubated and ventilated. A metabolic and/or drug-related cause of the conusion and decreased level of consciousness was suspected. Because of its probable neurotoxicity, ganciclovir was discontinued, however, its serum levels were not measured. In addition, ATG treatment was also withheld.
Over the next few days, there was a gradual improvement in the neurological condition of the patient. His mental status improved completely and he could be extubated on the 11 th postoperative day. The urine output increased to around 1.5 liters per day, but the patient remained dialysis dependent. A transplant biopsy was performed in a later stage, which revealed tubular necrosis with calcium oxalate deposits without signs of rejection.
| Discussion|| |
Low level of consciousness post renal transplantation can be due to one or a combination of several factors such as he use of analgesics and/or sedatives, circulatory failure, respiratory insufficiency, sepsis, metabolic acidosis, hypo-and hyperglycemia, hyponatremia, and central nervous system (CNS) insults.
Our patient initially recovered well from the anesthesia, and for the first three days postoperatively his mental status was normal. However, since the 4 th post operative day the patient became more drowsy and confused, agitated and hallucinating, together with worsening of the respiratory function, so that the patient had to be re-intubated again.
Several factors may have contributed to this process including fluid overload that resulted in hyponatremia, metabolic acidosis due to graft dysfunction, CNS insult, medication side effects, and respiratory failure.
However, these parameters could not explain the patient's condition completely, as the hyponatremia was mild (from 129 to 126 mmol/L), the symptoms started before the acidosis became prominent, and CT-scan of the brain was unremarkable. The use of monoclonal antibody anti-CD3 (OKT3), and possibly also of the polyclonal ATG has been occasionally associated with aseptic meningitis,  however, cerebrospinal fluid findings were negative.
At present, ganciclovir or valganciclovir are routinely used post-solid organ transplantations in any case of CMV-seropositive donor and/or recipient to prevent CMV infection and disease. , This is especially needed when the patient receives induction therapy with polyclonal antibodies, as there is an increased risk of CMV-disease in these cases.
Neuropsychiatric side effects of ganciclovir and related compounds such as acyclovir and valacyclovir have been frequently reported, especially in patients with renal dysfunction. ,,,,, The symptoms sometimes occur one day after stating the anti-viral treatment, , while in our patient they developed 1-2 days after initiating it. The symptoms may vary from nightmares and hallucinations to agitation and delirium that may progress to coma. , However, the process is usually reversible upon withdrawal of the drug. High levels of the metabolite 9-carboxymethoxymethylguanine (CMMG) in patients receiving acyclovir may cause the neurological side effects.  In a reported case on a patient with acyclovir-associated coma, generalized slowing of the rhythm of electroencephalogram (EEG) was found. 
Although a serum level ganciclovir might have been helpful in the diagnosis,  the above considerations strongly suggested that our patient suffered from ganciclovir-induced encephalopathy. The contributions of other factors, although unlikely, could not be excluded.
Eventually, the patient's mental condition recovered fully in a few days after discontinuation of the drug, although the renal function did not improve, and patient remained on dialysis.
With the wide use of anti-CMV prophylactic treatment after solid organ transplantation, it is important to pay attention to the neurological side effects of ganciclovir and acyclovir, which occur mainly in cases of renal dysfunction, even when the dose is adjusted to the degree of renal impairment according to the manufacturer's guidelines. 
As mentioned earlier, the symptoms may occur as early as one day after initiation of treatment. ,
As patients after recent transplantation surgery may often develop confusion and agitation, a high index of suspicion is required to diagnose ganciclovir or acyclovir neurotoxicity during course of therapy.  Timely discontinuation of these medications or dose reduction might prevent further deterioration.
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Magdi M Hussein
Department of Nephrology and Dialysis, Al Hada Armed Forces Hospital, P.O. Box 1347, Taif