Very early meningoencephalopathy associated with the intraoperative use of OKT3 in renal retransplant

Meningoencefalopatia precoce associada com o uso intraoperatório de OKT3 em transplante renal

CLINICAL/SCIENTIFIC NOTE

Very early meningoencephalopathy associated with the intraoperative use of OKT3 in renal retransplant

Meningoencefalopatia precoce associada com o uso intraoperatório de OKT3 em transplante renal

Juliana Bohn Assmann^I; Vivian Fontana^I; Henry M. Pansard^II; Maria Beatriz Cardoso Ferreira^III; Marino Muxfeldt Bianchin^IV

^IMedical Student, Hospital de Clínicas de Porto Alegre, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre RS, Brazil

^IIMD, Division of Nephrology, Hospital Universitário, Universidade Federal de Santa Maria, Santa Maria RS, Brazil

^IIIMD, PhD, Adjunct Professor, Department of Pharmacology, Universidade Federal do Rio Grande de Sul, Porto Alegre RS, Brazil

IVMD, PhD, Adjunct Professor, Department of Internal Medicine, Division of Neurology, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande de Sul, Porto Alegre RS, Brazil. Authors are supported by CNPq and FAPERGS.

Muromonab CD3 (murine monoclonal antibody towards the cluster of differentiation 3 antigen; OKT3) is a murine IgG_2a monoclonal antibody from the OKT series that specifically reacts with the epsilon chain of the CD3 molecular complex on the surface of circulating T lymphocytes. OKT3 can be used as a treatment for acute allograft rejection episodes and as "rescue" therapy for steroid-resistant allograft rejection^1-7. OKT3 can also be used during the perioperative period as induction therapy in sequential immunosuppressive regimens. Recently, OKT3 has elicited renewed interest due to its capacity to induce immune tolerance. This aspect will probably lead to the revaluation of OKT3 role for organ transplants¹.

We report a patient who received intraoperative inductive OKT3 in renal retransplant to improve graft viability. The patient developed a very early aseptic OKT3-related meningoencephalopathy that complicated her management during the immediate postoperative period. We were unable to find in literature such early onset of meningoencephalopathy associated with use of OKT3.

CASE

A 26-year old female with end-stage renal failure of undefined cause was admitted for cadaveric renal retransplant. She was on hemodialysis since 1990 and underwent to an unsuccessful renal transplantation in 1993.

Short before surgery hemodialysis was optimized in order to minimize CRS. Surgery started 19:00. Midazolam (15 mg) was used as anesthetic premedication. General anesthesia was induced with etomidate (0.2 mg/kg), sulfentanil (1 mg/kg) in bolus followed by atracurium (0.5 mg/kg) that was repeated every 30 minutes. She received epidural analgesia with bipuvocaine plus dimorphine. Anesthesia was maintained with O₂/N₂O [1:1] and isofluorane (concentration up to 1%) under controlled mechanical ventilation. Patient was monitored according with ASA recommendations. Inductive immunosuppressive therapy (sequential therapy) was applied through intravenous intraoperative use of 500 mg of methylprednisolone, followed by 5 mg OKT3 one hour later. These drugs were used before allograft perfusion. The surgery ended at about 23:00 h and all surgical and anesthetic procedures occurred without abnormalities. At about 01:15 h the patient presented fever (37.6ºC). During the next hours her body temperature ranged from 37.6 to 38.5ºC, while arterial pressure was stable, and arterial oxygen saturation ranged from 97% to100%, with O₂ administered through a Venturi mask. Since recovery from anesthesia was quite delayed, blood tests were ordered and she was admitted into the intensive care unit, where she was seen by a neurologist.

Upon this first neurological evaluation she showed response only to vigorous physical stimuli. She presented nuchal rigidity and had miotic pupils, but normal oculocephalic reflexes. Generalized hypertonia was evident and deep tendon reflexes were briskly symmetrical. Bilateral Babinski's sign was present. At this time urea was 94 mg/dL, creatinine was 5.5 mg/dL, hemoglobin was 9.4 g/dL, hematocrit was 26.7%. Other blood tests were all within normal range. CT scans revealed mild brain swelling. A lumbar tap was performed. The CSF aspect was mildly yellowish and opening pressure was 330 mmH₂O. Protein was 90 mg/dL, glucose was 75mg/dL, and white blood cell count was 386 cells/mm³ (92% neutrophils, 8% mononuclear). Gram stain of the CSF and cultures were all negative. In spite of lack in literature of complications associated with intraoperative use of OKT3, we suspected of aseptic meningitis and encephalopathy related to the use of intraoperative OKT3 and decided not to administer any antibiotic therapy. During the subsequent two days the patient was managed only with supportive care. Her consciousness level gradually improved and the patient showed progressive recovery of muscle strength followed by normalization of her neurological exam. OKT3 was not discontinued and it was used for 10 days (2.5 mg/kg/day iv), associated to methylpredisolone (250 mg iv/day) that was used for 2 days after transplantation and then replaced by prednisone. Azathioprine was initiated during the third postoperative day because of neurological complications. Cyclosporine was delayed and initiated during the 7^th postoperative day when creatinine level was 3 mg/dL. No further complication occurred and her kidney transplant was highly successful. No abnormal neurological deficit was observed at later neurological evaluations.

DISCUSSION

Aseptic meningitis and encephalopathy are considered complications of OKT3 use and it has been described earlier. The time for the occurrence of the first symptoms of OKT3-related meningoencephalopathy is variable. The syndrome is usually evident after 72 hours⁸. Eventually it may appear as early as during the first day of OKT3 use or as late as 30 days after the first exposure to OKT3⁹. However, we were not able to find in medical literature a very early onset impairing recovery from anesthesia as reported here.

The mechanisms involved in CNS adverse effects have not yet been completely elucidated. OKT3-induced T-cell activation with cytokines release⁸, brain edema caused by capillary leakiness, cross-reaction of OKT3 with surface antigens shared by lymphocytes and CNS cell, and alteration in blood viscosity are all possible mechanisms involved¹⁰. Usually CNS signs and symptoms subside without specific interventions and without the need to discontinue OKT3 administration. However, CNS adverse effects can be severe enough to require discontinuation of OKT3 and to produce potentially hazardous neurological abnormalities¹¹.

Cadaveric renal transplantation, delayed graft function and diabetes have all been reported to be associated with OKT3-induced meningoencephalopathy¹². In our case, pharmacological interaction of OKT3 with other drugs used during intraoperative period may have facilitated the development of meningoencephalopathy. Thus, identifying a potential pharmacological interaction of OKT3 with drugs used for anesthesia, as well as other additional intraoperative risk factors for the development of this syndrome would permit the optimization of the intraoperative use of OKT3, not only for kidney transplant but also for other types of transplants.

Like us, other authors have also reported diagnostic problems caused by perioperative use of OKT3¹¹. Thus, in spite of its rarity, early postoperative CRS-related meningoencephalopathy must be considered as a possible differential diagnosis in all cases of abnormal anesthesia recovery or in those cases of early aseptic menigoencephalopathy seen in transplanted patients who receive intraoperative or perioperative OKT3.

Received 14 May 2008. Accepted 22 July 2008.

Dr. Marino Muxfeldt Bianchin – Serviço de Neurologia / Hospital de Clínicas de Porto Alegre - Rua Ramiro Barcelos 2350 - 90035-903 Porto Alegre RS - Brasil. E-mail: [e-mail]

• 1. Chatenoud L. CD3-specific antibody-induced active tolerance: from bench to bedside. Nature Rev Immunol 2003;3:123-132.
• 2. Chatenoud L, Bluestone, JA. CD3-specific antibodies: a portal to the treatment of autoimmunity. Nature Rev Immunol 2007;7:622-632.
• 3. Webster A, Pankhurst T, Rinaldi F, Chapman JR, Craig JC. Polyclonal and monoclonal antibodies for treating acute rejection episodes in kidney transplant recipients. Cochrane Database Systematic Rev 2008.
• 4. Kirk AD. Induction Immunosupression. Transplantation 2006;82:593-602.
• 5. Loertscher R. The utility of monoclonal antibody therapy in renal transplantation. Transplant Proc 2002;34:797-800.
• 6. Henry ML, Pelletier RP, Elkhammas EA, Bumgardner GL, Davies EA, Ferguson RM. A randomized prospective trial of OKT3 induction in the current immunosuppression era. Clin.Transplant 2001;15:410-414.
• 7. Brock MV, Borja MC, Ferber L, et al. Induction therapy in lung transplantation: a prospective, controlled clinical trial comparing OKT3, anti-thymocyte globulin, and daclizumab. J Heart Lung Transplant 2001;20:1282-1290.
• 8. Jeyarajah DR, Thistlethwaite JR Jr. General aspects of cytokine-release syndrome: timing and incidence of symptoms. Transplant Proc 1993;25:16-20.
• 9. Adair JC, Woodley SL, Oconnell JB, Call GK, Baringer JR: Aseptic-meningitis following cardiac transplantation: clinical characteristics and relationship to immunosuppressive regimen. Neurology 1991;41:249-252.
• 10. Pradier O, Abramowicz D, Capel P, Goldman M. Procoagulant properties of Okt3 at the monocyte level: inhibition by pentoxifylline. Transplant Proc 1993;25:39-40.
• 11. Pittock SJ, Rabinstein AA, Edwards BS, Wijdicks EFM. OKT3 neurotoxicity presenting as akinetic mutism. Transplantation 2003;75:1058-1060.
• 12. Shihab FS, Barry JM, Norman DJ. Encephalopathy following the use of Okt3 in renal-allograft transplantation. Transplant Proc 1993;25:31-34.

Publication Dates

• Publication in this collection
  15 Oct 2008
• Date of issue
  2008