CENTRAL PONTINE MYELINOLYSIS AND CYCLOSPORINE NEUROTOXICITY FOLLOWING LIVER TRANSPLANTATION

Abstract

In a recent series of 44 liver transplants we identified both extrapontine myelinolysis (EPM)-characteristic of cyclocosporine neurotoxicity-and central pontine myelinolysis (CPM) in 5 recipients posttransplant. An additional 2 recipients had EPM only posttransplant. MRIs performed in 4 asymptomatic recipients were normal. Large perioperative shifts in serum sodium, hypomagnesemia, and high cyclosporine levels may play a role in the development of these lesions, although the evidence from this study is inconclusive. In addition to supportive care, dilantin was started in patients who had seizures; aggressive magnesium replacement was initiated for hypomagnesemia, and cyclosporine levels were reduced in all patients. All patients demonstrated a slow steady recovery and all but 2 are home at the time of writing. CPM may be more prevalent than previously appreciated following liver transplantation, although its prognosis may not be as dismal.

Between April and December 1994, 44 patients received primary liver transplants at our center. All transplants were performed without venous bypass in an otherwise standardized manner as previously described⁽¹⁾. Patients who developed abnormal neurologic symptoms posttransplant underwent complete neurologic evaluation including magnetic resonance imaging (MRI)^* of the head.

The neurologic findings that prompted further investigation included impaired mentation in all seven patients, with markedly decreased levels of consciousness in five; tonic-clonic seizures in three; severe ataxia in one; marked impairment of motor function in four, with classic“locked-in” syndrome in one (Table 1). In four patients, the occurrence of dramatic neurologic events (seizures in three, “locked-in” syndrome in one) prompted aggressive diagnostic workups and led to relatively early diagnoses at 7, 7, 10, and 14 days posttransplant. All patients who had seizures were started on dilantin. In the other three patients, symptoms were less dramatic, and diagnoses were made much later (43, 66, and 76 days). Two liver recipients developed neurologic complications (Fig. 1B) posttransplant and had evidence of extrapontine myelinolysis (EPM) only on MRI. Clinically, the most significant difference between these patients and those with both central pontine myelinolysis (CPM) and EPM was that the patients that also had CPM had significantly decreased levels of consciousness.

Lumbar punctures (LPs) were performed in four of the symptomatic patients because of a clinical suspicion of meningitis. Three had normal cerebrospinal fluid (CSF), while the fourth had positive CSF findings and required a total of five LPs before candidal meningitis was diagnosed. This was treated successfully with intravenous amphotericin B.

Electroencephalography was performed in five of the symptomatic patients. Two had diffuse findings consistent with metabolic encephalopathy, while focal epileptiform activity (one, left frontal temporal region; 1, parieto-occipital region) was found in the three patients who had seizures.

With MRI, five patients had abnormal signal intensity within the pons as well as subcortical white matter in bilateral parieto-occipital regions. The extent of pontine abnormality was variable and did not correlate with the severity of neurologic deficits. Two patients with indistinguishable CPM had different clinical settings: one (Fig. 1) had the“locked-in” syndrome, and the other (Fig. 2) had less-severe manifestations; however, the only patient with abnormal signal extending into both thalami was “locked-in” clinically(Fig. 1). Extensive parieto-occipital white matter changes were evident in two patients. Only one patient had both severe CPM and severe EPM (Fig. 2). To rule out the possibility that these lesions were not present in all liver transplant recipients as a consequence of end-stage liver disease, MRIs were performed pretransplant and posttransplant in four consecutive, but otherwise unremarkable, liver recipients. None of the asymptomatic group had MRI evidence of either CPM or EPM.

Pretransplant hyponatremia (<135 mmol/L) was present in four of the five symptomatic patients with CPM and EPM, one of the two with EPM only, and two of the four asymptomatic patients, and was either fully or partially corrected perioperatively. The average increase in serum sodium perioperatively in the symptomatic patients with CPM and EPM was 9.8±9.9 mmol/L/48 hr, with the most extreme shift being 25 mmol over 48 hr (Table 1A). Sodium shifts were less dramatic in the patients with EPM only(5.0±1.4 mmol/L) and the asymptomatic patients (4.8±5.7 mmol/l).

Postoperative hyponatremia and hypernatremia were noted an average of 3.8 days and 4.6 days per patient, respectively. Despite this, only one patient had a significant shift in serum sodium outside the perioperative period(i.e., >48 hr posttransplant) with an increase of 11 mmol/L (146-157 mmol/L) occurring over 48 hr. This shift was chronologically associated with a dramatic neurologic deterioration and development of a “locked-in” syndrome. Since her serum sodium had not been low, this shift did not occur as a result of correcting hyponatremia-a more typical scenario preceding CPM.

Pretransplant hypomagnesemia (<0.72 mmol/L) was noted in four of five patients who developed CPM and EPM posttransplant (Table 1A), and was less prevalent in both the EPM only group(Table 1B) and the asymptomatic group(Table 1C). Posttransplant, magnesium levels were monitored daily, and hypomagnesemia, identified an average of 12.8 times per patient in the symptomatic patients, was treated with i.v. boluses of magnesium sulfate. Some of the seizures observed may have been directly related to hypomagnesemia.

Pretransplant hypocholesterolemia (<4.0 mmol/L) was identified and was measured in all patients (Table 1).

Following transplantation, all patients received cyclosporine-based induction immunosuppression. The period of study coincided with the establishment of a new immunosuppressive induction protocol. In the previous protocol, OKT3 was given for the first 7 days posttransplant, and intravenous cyclosporine was initiated at posttransplant day 5 and converted to oral cyclosporine over the next few days. With the new protocol, OKT3 was not given, and intravenous cyclosporine was initiated immediately posttransplant with oral dosing being started the following day. Although target cyclosporine trough levels (radioimmunoassay) were the same with both protocols-(300-400 ng/ml for days 1-14; 250-350 ng/ml for weeks 3 and 4; 150-250 ng/ml for months 2-6; and 100-200 ng/ml for months 6-12)- obtaining such levels early, when the blood/brain barrier and central nervous system (CNS) are still recovering from hepatic encephalopathy, may potentiate neurotoxicity.

Furthermore, at least one patient received the Neoral (Sandoz Canada) preparation of cyclosporine that is associated with higher peak levels and earlier achievement of target trough levels than regular cyclosporine⁽²⁾. Another patient received the regular cyclosporine preparation while the other three were randomized to receive either Neoral or regular cyclosporine. Since this study is ongoing, the identity of the drug each patient received will not be known until the code is broken.

The mean trough cyclosporine level in the symptomatic patients with CPM and EPM prior to diagnosis was 357±151 ng/ml. When cyclosporine neurotoxicity was diagnosed, doses were reduced, and the mean level was decreased to 234±132 ng/ml for the remainder of the hospital stay. The mean cyclosporine level prior to diagnosis was slightly lower in the two patients with EPM only (294±98 ng/ml) and was reduced to 235±90 ng/ml following diagnosis. Although the mean, in-hospital cyclosporine levels in the asymptomatic group (376±129 ng/ml) were higher than either symptomatic group, this is misleading since their short posttransplant hospital stays included the period when higher cyclosporine levels are routinely sought. Over all, adjustments for cyclosporine levels that were too high or too low were necessary an average of 15.2 and 11.8 times per patient, respectively, posttransplant during their hospitalization.

All symptomatic patients had prolonged recovery times compared with the asymptomatic patients as reflected by their length of stay in hospital(Table 1), however, at the time of this writing, three of five with CPM and EPM are functioning well at home, and two patients are slowly recovering in hospital. One of them, who developed the“locked-in” syndrome and was given little chance of recovery, is now ambulatory, orientated, and enrolled in a rehabilitation program. The second patient remaining hospitalized, who was set back by candidal meningitis and a fall in hospital, is also ambulatory and orientated. Despite her striking MRI findings, many of this patient's symptoms may have been due to meningitis. Both the symptomatic patients with EPM only are functioning well at home.

The incidence of CPM, prior to the introduction of MRI, was likely underestimated as the diagnosis was based on postmortem findings^(3,4). Liver transplant recipients constitute a high-risk group for developing CPM^(3-6). CPM also occurs in nontransplant patients. Alcoholics are at higher risk for developing this lesion⁽⁷⁾. Only one patient in our series was alcoholic and, in keeping with our policies, was abstinent for at least 6 months pretransplant.

Although the exact etiology of this potentially fatal lesion is unclear, it has commonly been associated with rapid correction of hyponatremia⁽⁶⁾. Other factors have also been implicated, including cyclosporine ^{(5, 8, 9)}. Although CPM has characteristically been associated with an irreversible“locked-in” syndrome and a high mortality rate, this probably occurs in only a minority of cases ^{(5, 9)}. Therefore, with the development of MRI technology, CPM and other demyelinating CNS lesions are easier to identify antemortem ⁽¹⁰⁾.

Cyclosporine neurotoxicity occurs in an many as 30% of liver transplant recipients ^{(11, 12)}. It has also been reported in renal, cardiac, and bone marrow transplants. The typical radiologic appearance is that of extrapontine demyelination, represented by areas of hyperintense signaling seen in T2-weighted images of the cerebral cortex on MRI. Several factors may contribute to these lesions including elevated levels of cyclosporine metabolites, hypocholesterolemia ⁽¹²⁾, hypomagnesemia ⁽¹³⁾, high-dose steroids⁽¹⁴⁾, reduced hepatic cytochrome P450 activity⁽¹⁵⁾, and elevated serum endothelin⁽¹¹⁾ levels, although the mechanism of injury is unclear. Clinical features include seizures, confusion, disorientation, headache, anorexia, nausea, vomiting, agitation, psychosis, cortical blindness, ataxia, speech and motor disturbances, paralysis and coma.

Several similarities lead one to believe that cyclosporine neurotoxicity and central pontine myelinolysis may share a common etiology in these patients. First, both lesions are commonly seen in liver transplant patients and may coexist, as evidenced by this study and others^{(3, 8, 11)}. Second, they are both demyelinating lesions and have similar histopathology^{(4, 8)}. Third, the clinical presentations of the two lesions often overlap ^{(3, 5, 9, 12)}. Finally, both lesions are potentially reversible as is reported by this study and others ^{(11, 16)}.

In summary, clinical and radiologic evidence of neurotoxicity are not infrequent after liver transplantation. Central pontine myelinolysis and cyclosporine neurotoxicity are both part of this spectrum. Neurotoxicity is associated with prolonged hospitalization as well as significant patient morbidity and mortality. The MRI is currently the best modality available to identify these lesions and if unusual neurologic symptoms develop posttransplant, it should be performed early. The etiology of these lesions remains unclear. Abnormalities in magnesium, sodium, and cholesterol may play a role but were not consistent findings in this study. Although the patients with both CPM and EPM had higher trough cyclosporine levels than those with EPM only, patient numbers were too low for any meaningful statistical analysis. Nevertheless, reduction of cyclosporine levels was associated with gradual clinical improvement in all symptomatic patients. Since better absorption is obtained with the Neoral formulation, more elaborate monitoring such as peak cyclosporine level determination, or area under the curve analysis may be necessary to better correlate neurotoxicity to drug exposure. Conversion to FK506 may not be beneficial in this situation since it is associated with a similar spectrum of neurologic complications⁽¹⁷⁾. Hence, in addition to judiciously correcting electrolyte abnormalities, it is recommended that cyclosporine levels be reduced in these patients. Although CPM is generally considered to be a rare complication with a grave prognosis, this study indicates that in liver transplant recipients it may be more prevalent than previously appreciated but less lethal.

Figure 1: Female patient (57 years old) with fulminant hepatic failure of unknown etiology. A sudden decrease in level of consciousness occurred on posttransplant day 10 with development of a “locked-in” syndrome. Axial T2-weighted images (TR 2800 TE80) showed confluent hyperintense signal centrally in pons (A) and bilateral thalami (B).

Figure 2: Female patient (59 years old) with cirrhosis secondary to hepatitis C. Focal seizures involving her left arm began 2 weeks posttransplant. Axial T2-weighted images (TR 2800 TE80) revealed abnormal signals in pons (A) as well as parieto-occipital regions (B).