Objectives: Seizure is a common complication after liver transplant and has been reported to occur in up to 42% of patients in different case series. Multiple factors can trigger seizures, including immunosuppressive toxicity, sepsis, metabolic imbalance, and structural brain lesions. The aim of this retrospective study was to evaluate seizure types and associated factors in adult liver transplant patients.

Materials and Methods: We retrospectively evaluated the medical records of 142 adult patients who received a liver transplant between 2005 and 2013. We recorded demographic data, immuno­suppressive treatment, seizure type, cause, recurrence, and treatment.

Results: Of the 146 patients, 23 (15.7%) had a seizure after the liver transplant. This group included 10 females and 13 males, with ages ranging between 18 and 63 (39.9 ± 14.8 y). Generalized tonic-clonic seizures were the most common, occurring in 20 patients (87%). We observed complex partial seizure and status epilepticus in 1 and 2 patients. Immunosuppressive drug-related seizure occurred in 8 patients (34.8%) with normal drug blood levels, and all but 1 of these patients experienced seizure within the first week after transplant. Multiple factors (26.1%), metabolic imbalance (17.4%), structural lesion (13%), and sepsis (8.7%) were the other factors identified as underlying conditions.

Conclusions: In conclusion, seizure occurred in a significant proportion of patients who underwent liver transplant. Immunosuppressive drugs were the most common factor associated with seizure occurrence and drug cessation prevented seizure recurrence.

Key words : Seizure, Liver transplant, Seizure cause, Immunosuppressive drug toxicity

Introduction

Postoperative neurologic complications can occur in liver transplant (LT) patients, with seizure being the second most common.^1-4 Although the seizure rate has decreased in recent studies, previous case series reported seizure prevalence rates as high as 42%.^5,6 There are various causative factors underlying seizures, including immunosuppressive drug toxicity, metabolic disturbance, infection, and structural brain lesions.⁶ Generalized seizures are the most common type in this patient population.^6,7 It is difficult to establish accurate reasons for seizures in LT patients because multiple factors may influence their onset; therefore, the aim of this retrospective study was to evaluate seizure type and associated factors in adult LT patients.

Materials and Methods

We retrospectively evaluated the medical records of 142 adult patients who underwent LT between 2005 and 2013 at Baskent University hospital. Of these, 23 experienced seizures after LT. We recorded their demographic data, immunosuppressive treatment, seizure type, immunosuppressive drug level at the time of seizure, cause, recurrence, and seizure treatment.

The possible seizure causative factors considered were immunosuppressive drug toxicity, metabolic disturbance, infection, and structural lesion. Causative factors were determined by performing extensive evaluations in all 23 patients, including neurologic examinations and blood tests for metabolic disturbance, infection, and drug levels. Brain imaging for structural lesions and electro­encephalography was performed if available. Patients were considered to have immuno­suppressive drug toxicity if there was no other possible explanation for seizure onset rather than drugs, even the drug level within normal limits. The possible cause was classified as multifactorial in patients who had 2 or more precipitating factors at the time of seizure onset. Seizure type was determined based on clinical observations.

Statistical analyses
Statistical analyses were performed with SPSS software (version 11.0 for Windows, SPSS, Inc, Chicago, IL, USA). Data are expressed as percentages for categorical variables and as means ± SD for continuous variables.

Results

Of the 142 patients who underwent LT, 23 (15.7%) experienced postoperative seizure. Among the 23 patients, there were 10 females and 13 males with ages ranging between 18 and 63 years (39.9 ± 14.8). The liver tissue was from a living donor in 19 cases (82.6%) and a deceased donor in 4 cases (17.4%). The indications for LT and the patients’ clinical findings are listed in Table 1.

Of the 23 patients, 20 (87%) had generalized tonic-clonic seizures, 2 (8.7%) had status epilepticus, and 1 (4.3%) had a complex partial seizure. We determined that immunosuppressive drug-related seizure (34.8%) was the most common etiology, followed by multifactorial cause (26.1%). Immunosuppressive drug levels in all 23 patients were within therapeutic ranges at the time of seizure onset. Patient 23 was determined to have multifactorial cause because at the time of brain magnetic resonance imaging, which showed lesions compatible with posterior reversible leuko­encephalopathy syndrome, she also had acute renal failure and malignant hypertension. In 4 patients (17.4%), metabolic disturbance was established as an underlying cause; 1 had hypoglycemia, 1 had hypocalcemia, and the other 2 had elevated liver enzyme levels. Structural lesions were detected in 3 patients (13%). Two had air embolisms due to catheter removal, and 1 of these patients also had a subacute ischemic infarct in a posterior brain region. The third patient had a residual lesion following a cryptococcal brain abscess. Seizures in 2 patients (8.7%) were related to sepsis.

Twelve patients (52.2%) had recurrent seizure. We found that seizures due to structural lesions and multifactorial causes tended to be recurrent (100% and 83.3%), whereas most drug-related seizures were single episodes (75%).

We preferred to prescribe levetiracetam as an antiepileptic drug for most patients (12/23, 52.2%). Diphenylhydantoin was administered to 4 patients (17.4%) and propofol to 2 patients (8.7%) with refractory status epilepticus. Five patients were not treated with antiepileptic drugs.

Discussion

Seizure is a common complication after LT.^1,7,8 The reported incidence of seizure ranges from 2.8% to 42% in different case series,⁶ although recent publications have stated that the incidence of seizure in transplant patients tends to decrease over time.^5,8

Generalized seizure was the most common type in both our study and the majority of published case series.^6,7 Only 1 study reported a higher frequency of partial seizure.⁹ The determination of seizure type is based on clinical observations and electro­encephalography findings when available. It is difficult to determine the true incidence of focal and secondary generalized seizures because they can easily be overlooked.^6,7 For that reason, the rates of focal seizures may be higher than reported. Convulsive and nonconvulsive status epilepticus are also rare in transplant patients.^6,7 Nonconvulsive status epilepticus should be considered in patients with impaired consciousness, and electro­encephalography is a useful diagnostic tool in these cases.¹⁰

Seizure in LT patients typically occurs in the early postoperative period.^6,9 One study described a bimodal distribution of seizure occurrence: within the first week and between 5 and 16 weeks after transplant.⁶ We did not observe a bimodal distribution in the present series, but the majority of our patients experienced seizures within the first 4 weeks after LT.

It is important to establish seizure cause to plan the best treatment. Various factors such as immunosuppressive drug toxicity, metabolic factors, infection, and structural lesions may precede seizure in LT patients.^6,9,11 The diagnostic evaluations should consist of extensive examinations including blood tests for metabolic parameters and immuno­suppressive drug levels, electro­encephalography, and neuroimaging to accurately identify the underlying factor(s).⁷ Brain magnetic resonance imaging is the recommended modality to assess for structural abnormalities that cause seizure as in the general population.⁷ Cerebrospinal fluid examination is also suggested in patients with suspected central nervous system infection.⁷ Immunosuppressive drug toxicity is the main causative factor in the literature describing seizure in LT patients.^6,7,9,11 Immunosuppressive drug-related seizures may occur independently or in association with posterior reversible leukoencephalopathy syndrome, even in patients on therapeutic drug levels.^12,13 In these patients, reducing the dosage or changing drugs are the recommended treatment approaches.⁷ In our study group, the most common causative factor was immunosuppressive drugs, and the blood levels of these drugs were within normal ranges at the time of seizure in all 8. Two of these patients also had hyperintense lesions in parieto-occipital regions on T2-weighted and fluid-attenuated inversion recovery magnetic resonance images, which was compatible with posterior reversible leukoencephalopathy syndrome.

Seizure recurrence was associated with the underlying cause. Seizures that develop as a result of immunosuppressive drug toxicity or metabolic factors such as electrolyte imbalance or hypo­glycemia do not usually recur if treatment is promptly administered.¹⁴ Conversely, seizure due to other factors such as organ rejection, sepsis, or cerebrovascular disease has a poor prognosis.⁹

Medical treatment of seizure is an important issue in LT patients, but no randomized controlled trials have tested antiepileptic drugs in this population. Pharmacokinetic properties are important to consider when selecting an appropriate drug to treat seizures.¹⁴ Some antiepileptic drugs such as carbamazepine, oxcarbazepine, phenobarbital, and diphenylhydantoin may reduce the blood levels of cyclosporine, tacrolimus, and steroids.^14,15 The newer antiepileptic drugs, especially levetiracetam, are recommended as a first-line therapy in LT patients.^14,16

In conclusion, seizure is a common complication after LT. Preventive approaches such as close control of metabolic parameters and immunosuppressive drug levels may reduce seizure frequency in these patients. In seizures do occur, prompt treatment should be administered according to the underlying factor(s). If necessary, levetiracetam is the recom­mended first-line antiepileptic drug to prevent seizure recurrence.

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