Epileptlform Electroencephalographc Abnormahties in Liver Transplant Recipients 2. K. Wstolek, MD," A. J. Aksamit, MD," R. J. Ellingson, MD,t F. W. Sharbrough, MD," B. F. Westmoreland, MD," R. F. Pfeiffer, MD,? R. E. Steg, MD,? and P. C . de Groen, MDS
We retrospectively studied patients who had undergone orthotopic liver transplantation and who also had electroencephalography to determine whether epileptiform changes were associated with a poor neurological outcome. Study groups were 36 patients who died after transplantation (141 electroencephalograms) and underwent neuropathological examination, 11 who died (18 electroencephalograms) but did not have autopsy, and a third group of 34 (62 electroencephalograms) who remained alive. Epileptiform activity was seen in electroencephalograms of 14 of the patients who died (11 from the autopsy group) and in 2 of those who remained alive. All had multiple epileptiform abnormalities and clinical or subclinical seizures. The incidence of epileptiform activity after orthotopic liver transplantation was fivefold higher in the nonsurvivors. Serious cerebral structural changes were found in 10 of the 11 patients who underwent autopsy. Epileptiform activity in the electroencephalograms of patients who had undergone orthotopic liver transplantation indicates a poor prognosis. It should alert the clinician to investigate further for potentially treatable causes. Wszolek ZK, Aksamit AJ, Ellingson RJ, Sharbrough F W , Westmoreland BF, Pfeiffer RF, Steg RE, de Groen PC. Epileptiform electroencephalographic abnormalities in liver transplant recipients. Ann Neurol 1991;30:37-41
Advances in surgical techniques, better methods of tissue preservation, and use of cyclosporine and other immunosuppressive agents explain an increase in the use of orthotopic liver transplantation (OLT) for treatment of end-stage liver disease, hlminant hepatic failure, neoplasm, or metabolic or congenital abnormalities (1-13). Many patients who undergo OLT suffer from various neurological complications, with mental status changes and seizures being the most frequent [S, 14-20). Electroencephalography (EEG) is one of the diagnostic tests used. Most often, generalized slowing of cerebral activity, characteristic of metabolic/toxic encephalopathy, is found (15, 2 11. Epileptiform activity, focal o r generalized, may indicate a more serious structural abnormality requiring appropriate medical or surgical therapy. To test the hypothesis that epileptiform changes on the EEG predict structural brain disease and a poor neurological outcome, we retrospectively studied patients who underwent OLT and who had EEGs. The study groups were patients who died after undergoing OLT and had a postmortem neuropathological evaluation (Group l), patients who died but did not have a postmortem examination (Group 2), and patients who remained alive after undergoing OLT (Group 3). In
each group of patients, we assessed the type and frequency of epileptiform activity and its relationship to neurological outcome, and in Group 1 we correlated EEG findings with neuropathological abnormalities.
From the *Department of Neurology, and $Division of Gastroenterolom and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, MN, and tSection of Neurology, University of Nebraska Medical Center, Omaha, NE.
Received Oct 1, 1990, and in revised form Jan 14, 1991. Accepted for publication Jan 30. 1991.
Material and Methods Between March 1, 1985, and September 30, 1989, 173 adults (age 17 years or older) underwent 209 OLTs at the Mayo Clinic (Rochester, MN). Between July 1, 1985, and September 30, 1989, 187 adults (age 17 years or older) underwent 220 OLTs at the University of Nebraska Medical Center (Omaha, NE). The total number of adult patients who underwent this surgery at both centers was 360, and they underwent 429 OLTs. The two centers used approximately the same surgical approach, similar preoperative diagnostic criteria, and similar postoperative care. The referral area includes not only the Midwest region but also both national and international sources. Sixty-nine patients died; 31 died at the Mayo Clinic and 38 died at the University of Nebraska Medical Center. Only 36 patients (age range, 21-62 years; mean age, 43 years; 18 men) in the two centers had both EEG and neuropathological evaluation. They served as study Group 1. Thirty-six patients had 52 OLTs; 2 1 patients underwent only one OLT each, 14 underwent two each, and 1 patient underwent three OLTs. Survival times after the first transplantation ranged from 2 to
Address correspondence to D r Aksamit, Mayo Clinic, 200 First Street SW, Rochester, M N 55905.
Copyright 0 1991 by the American Neurological Association
37
422 days (mean, 84 days). Among these patients, 141 EEGs were recorded using the International 10-20 Electrode Systern and multiple bipolar and referential montages. Alerting procedures were performed routinely. Hyperventilation was done whenever possible. The EEGs were classified according to the Mayo EEG Classification System {22}. The brains of patients who underwent autopsy were fixed in 10% buffered formalin. Both gross and microscopic examinations were performed. Tissue sections were stained with Lux01 fast blue and hemaroxylin-eosin, and the Bielschowsky silver reaction or other appropriate stains were used according to particular requirements. Microbiological and viral studies were done if clinicopathologically indicated. Study Group 2 was composed of 11 patients (age range, 19-66 years; mean age, 40 years; S men) with EEG recordings who died but did nor undergo autopsy. Eleven patients had 20 OLTs: 4 patients underwent one OLT each, 6 underwent two each, and 1 patient underwent four OLTs. Survival times after the first transplantation ranged from 7 to 1,461 days (mean, 285 days). These patients had 18 EEGs recorded. Study Group 3 consisted of 34 adults (age range, 18-61 years; mean age, 43 years; 19 men) who underwent OLT at the Mayo Clinic, had EEGs, and remained alive. This group included all possible patients who sarisfied these criteria. Thirty-four patients had 39 OLTs: 30 patients underwent one OLT each, 3 underwent two each, and 1 patient underwent three OLTs. The intervals between the first OLT and September 30, 1989 (the cutoff date of the study) ranged from 10 to 1,400 days (mean, 733 days). These patients had 62 EEGs recorded.
Results O f the total of 69 patients at both centers who died, 47 had EEGs (Groups 1 and 2): 45 (95.796) had o n e or more abnormal EEGs, and 1 4 (29.8%) had EEGs with epileptiform abnormalities. Among the 34 patients who remained alive (Group 3), 25 (73.5%) had one or more abnormal EEGs showing nonspecific changes and 4 (11.8%) had EEGs with epileptiform activity. O n e patient from Group 3 , however, had a chronic preexisting seizure disorder and another had transient epileptiform activity (periodic lateralizing epileptiform discharges) after acute head trauma complicated by hyponatremia before undergoing OLT but only nonepileptiform and normal EEGs after OLT. If these 2 patients are excluded, the incidence of postOLT epileptiform activity in Group 3 is 5.9971. N o n e of the patients in Groups 1 and 2 had preexisting epilepsy or EEG epileptiform activity before OLT. Thus, the incidence of epileptiform abnormahty was fivefold higher among the nonsurvivors than among the survivors who had EEGs ( p < 0.001). Of the 47 patients who died and had EEGs, 36 underwent autopsies (Group 1). Neuropathological findings are presented in Table 1, and the types of EEG abnormalities are presented in Table 2. Of these 36 patients, 35 had one or more abnormal EEGs; 11
38 Annals of Neurology
Vol 30 N o 1 July I991
Table 1 . Neuropathological Findings in 36 OLT Patients Who Had EEGJ
Finding
Patients (n)
Intracranial hemorrhage (parenchymal, subdural, or subarachnoid) Ischemic/anoxic encephalopathy Cerebral edema Infectious changes Pontine and extrapontine myelinolysis Cortical infarctions Normal brain
19
OLT = orthotopic liver transplantation; EEGs
12
11 8 7 1
7 =
electroencephalo-
grams.
Table 2. Abnormulities Observed in One or More EEGsafrom 36 OLT Patients Who Had NeuropathologicalExaminations
EEG Abnormality Nonspecific mild to moderate generalized slowing Severe generalized slowing (delta) Generalized suppression Typical and atypical triphasic waves Interictal spikes and sharp waves Focal Generalized Electrographic seizure discharges Focal subclinical Focal clinical Generalized clinical Status epilepticus Asymmetry Others
Patients With Epileptiform Activity (n = 11)
Patients Without Epileptiform Activity (n = 25)
8
20
8
16
6 4
14
10
...
6 4 11
... ...
7
...
... ... 2 2
‘Tocal number of EEGs was 136.
EEGs = electroencephalograms; OLT = orthotopic liver cransplantation.
(30.5%) exhibited epileptiform abnormality. O n e of the 36 patients had one normal pre-OLT EEG and o n e normal post-OLT EEG; h e was among the 7 patients with normal brains at autopsy. O n e patient had one normal EEG and 1 had two normal EEGs; both subsequently had several abnormal EEGs wirh epileptiform activity. The other 136 EEGs from these patients were abnormal (see Table 2 j. Detailed clinical, EEG, and pathological data o n the 11 patients who underwent autopsy and whose EEGs showed epileptiform abnormalities are presented in
Table 3. Clinical, EEG, and Pathological Data for 11 OLT Patients with Epileptifm Changes on EEG
Survival Time after OLT (days)
Time (in days) Between OLT" and the First EEG with Epileptiform Activity
Clinical Presentation on the Day of EEG
Age (yr)l Sex
OLT Number"
1
331M
A
64
All2
Coma, focal seizures
Severe, generalized slowing; bilateral independent PLEDs
CPM, ischemic changes, laminar cortical necrosis
2
24/M
A
56
A153
Coma, postcardiac arrest, generalized seizures
Diffuse anoxiclischemic changes
3
23/F
A C
169 145 120
CIS0
Generalized suppression; generalized spikes, seizure discharges Severe, generalized slowing; focal spikes, subclinical seizure discharges
A128
Obtundation, generalized seizure
Severe, generalized slowing, sharp waves
Intracerebral hemorrhages, encephalitis with microglial nodules
Coma, increased intracranial pressure, focal seizure
Severe, generalized slowing; focal sharp waves, seizure discharges
Cerebral edema, extensive laminar comcal necrosis
Coma, hemiparesis, focal seizures
Frequent subclinical and clinical seizure discharges Severe, generalized slowing; generalized seizure discharges Triphasic waves, focal spikes, partial status epilepticus Focal sharp waves, subclinical scizurc discharges Generalized suppression; generalized sharp waves, status epilepticus Focal sharp waves, seizure discharges
Subdural hematoma and cerebral hemorrhages Cerebral edema, multiple cerebral hemorrhages
Patient
B
Coma, no clinical seizures
4
25lF
A
53
5
36lF
A H
21
Bl1
A
116
A139
A
B
42 16
B/ 1
6
38lF
7
52lF
36
Coma, generalized seizures
8
53/F
A
29
A15
Confusion, cbnic activity
9
53lF
A
48
A16
Confusion, hemiparesis
10
561M
A B
43 11
B19
A
51
A118
11
62lF
Coma, generahzed seizures
Lethargy, intermittent seizures
EEG Abnormalioes
Neuropathological Correlations
CPM, EPM, tuberculorna
CPM, EPM, focal subarachnoid hemorrhages CPM, EPM, laminar cortical necrosis Severe cerebral edema with herniation, scattered neuronal necrosis Mild cerebral edema, no herniation
'The letter designations are as follows: A is the first OLT, B is the second OLT, and so on.
EEG = electroencephalographic; OLT = orthotopic liver transplantation; CPM = central pontine myelinolysis; EPM = extrapontine myelinolysis; PLEDs = periodic lateralizing epileptiform discharges.
Table 3. All experienced clinical or subclinical seizures. Of the 11 patients, 4 had central pontine myelinolysis (CPM), and 3 of those also had extrapontine myelinolysis. Three of the 4 patients who developed CPM (Patients 3, 8, and 9 in Table 3 ) have been previously described 1231. In addition, 2 had anoxic changes, 1 suffered bilateral subarachnoid hemorrhages, and 1 had a tuberculoma. Thus, all patients with CPM and epileptiform activity had other coexisting pathological abnormalities. Anoxic changes were found in 5 patients, in-
cluding 2 with CPM. Hemorrhagic lesions were found in 3 patients, including 1 with CPM and 1 with probable viral encephalitis. One patient showed only mild edema. EEG findings in these patients demonstrated various epileptiform activities, including focal and generalized spikes and sharp waves, periodic lateralized epileptiform discharges, focal subclinical seizures, and focal and generalized clinical seizures (see Tables 2 , 3). Of the 11 patients who died but did not undergo autopsy (Group 2), 3 had epileptiform abnormalities. Wszolek e t al: Epileptiform EEG Abnormalities
39
One of the 3 had seizures. The deaths were attributed to multiple factors, including anoxia and bacterial and fungal infections. Two survivors (Group 3) exhibited post-OLT epileptiform abnormalities. One was a 41year-old man who became confused on postoperative day 13. An EEG obtained 6 hours later revealed status epilepticus characterized by generahzed sharp and slow waves, moderate generalized delta slowing, and atypical triphasic waves. Further diagnostic evaluation demonstrated a hyponatremia of 127 mEq/L and Ldsteria sp. meningitis. Two additional EEGs obtained on postoperative days 14 and 2 9 did not show epileptiform activity. At 1,370 days after his only OLT, he exhibited residual right hemiparesis and impaired mentation but no seizures (on phenytoin). The other patient was an 18-year-old woman who had transplantation for chronic active hepatitis with cirrhosis in whom a spontaneous right temporoparietal intracerebral hemorrhage developed that required surgical evacuation on postoperative day 8. Five days later, she became confused and the first EEG was obtained. The recording revealed right temporoparietocentral spikes in addition to the expected focal delta activity and asymmetry over the right parietocentrotemporal region. She developed hepatic artery thrombosis, and a second OLT was performed 19 days later. She recuperated well but again became confused 53 days later. The EEG obtained at this time showed right cerebral hemisphere periodic lateralizing epileptiform discharges, right centrotemporoparietal delta activity, and asymmetry. Similar EEG changes were present on recordings 2 , 12, and 23 days later. She required chronic anticonvulsant therapy. A persistent right temporal spike focus was documented on recordings 212, 383, and 544 days after her intracerebral hemorrhage.
Discussion Comparison of these different groups of patients with OLT suggests that epileptiform activity in the EEG indicates a poor prognosis. Among our patients, the incidence of epileptiform abnormalities was fivefold higher among the patients who died than among those who survived. Of the patients who had epileptiform activity, all either died (14 patients) or had permanent neurological disorders (2 patients). Of the 11 patients who underwent autopsy, 10 had a variety of serious structural abnormalities. EEG findings are mentioned in only a few reports describing neurological abnormalities after’ OLT. Adams and associates f19J reviewed findings on 52 patients. Seventeen had neurological complications. EEGs were recorded in 8 patients. Epileptiform activity was reported in 2 patients (in 1 before OLT), both of whom died; EEG findings were not well described in the other 6 patients, all of whom died. Estol and colleagues f17) described 21 adult patients who had sei40 Annals of Neurology Vol 30 No 1 July 1991
zures after OLT and died and underwent autopsies. Sixteen had EEGs. Clinical seizures were recorded in 9 patients with appropriate EEG seizure patterns. Interictal EEGs showed no epileptiform abnormalities in 7 patients, including triphasic waves in 1, burstsuppression patterns in 2, moderate generalized slow abnormalities in 3, and mild slowing in 1. All 21 patients had multiple neuropathological lesions at autopsy, in general agreement with our findings. Vogt and co-workers [ l 5 ) described 19 patients who underwent 21 OLTs, 8 of whom developed seizures postoperatively. EEGs were recorded in 6, demonstrating “diffuse encephalopathy” in 5 and bilateral epileptiform activity in 1 of the 5. This patient died (no autopsy). Because of the differences in sampling procedures and reporting methods, meaningful comparison of these fragmentary results with our data is not possible. Mental status changes ranging from confusion or lethargy to coma are common after OLT and were the most common indication for EEG in our series. All of our patients who showed epileptiform abnormalities presented in this manner. Epileptogenic processes, however, are not the only cause of mental status changes. Others include liver rejection, cyclosporine neurotoxicity, and systemic complications such as infection, coagulopathy, renal dysfunction, hypertension, and electrolyte imbalances. These are most often characterized by generalized nonspecific slow abnormality, but occasionally by suppression or asymmetries. Wesunoreland and colleagues f2 1J discussed the EEG findings in cydosporine-induced neurotoxicity. They described 5 patients who developed encephalopathy with multiple neurological findings, including altered level of consciousness, seizures, and cortical blindness, 3 of whom were previously described by de Groen and associates Cl6). The EEGs in all 5 showed generahzed slowing, in addition to focal slowing in 3 patients and asymmetry in 3 patients; however, none of them showed an epileptiform pattern. These 5 patients are included in Group 3 of the present study. Little is known about generation of epileptiform discharges in such complicated clinical situations in which metabolic, electrolyte, and toxic alterations are superimposed on structural changes. It is possible that electrical irritability involving excitatory neurotransmitters or neuronal membrane alterations may add to the gross structural damage we observed [24]. We emphasize that our study represents a review that has limitations. Further prospective analysis is certainly needed. We conclude that epileptiform abnormdties in the EEG after OLT are associated with serious, often irreversible, brain damage. The presence of epileptiform abnormalities should alert the clinician to investigate further for potentially treatable causes, such as infectious and hemorrhagic complications. Although the ab-
sence of epileptiform activity does not exclude serious underlying abnormality, nonepileptiform changes are less frequently of dire consequence. Therefore, the presence of epileptiform abnormalities on the EEG usually indicates significant underlying neuropathological changes. We thank Dr Byers W. Shaw,Jr, and Dr R. Patrick Wood for helping to make their patients available to us and Susan L.Robinson for her excellent secretarial assistance.
References 1. Scharschmidt BF. Human liver transplantation: analysis of data on 540 patients from four centers. Hepatology 1984;4(suppl 1):95S-lOlS 2. Rolles K, Williams R, Neuberger J. Calne R. The Cambridge and King’s College Hospital experience of liver transplantation, 1968- 1983. Hepatology 1984;4(suppl 1):50s-5 5 S 3. Van Thiel D H . Liver transplantation. Pediatr Ann 1985;14: 474-480 4. Bismuth H, Casting D, Ericzon BG, et al. Hepatic transplantation in Europe: first report of the European Liver Transplant Registry. Lancet 1987;2:674-676 5. Polson RJ, Rolles K, Calne RY, et al. Reversal of severe neurological manifestations of Wilson’s disease following onhotopic liver transplantation. Q J Med 1987;64:685-691 6. Stanl TE, Iwatsulu S, Van Thiel DH, et al. Evolution of liver transplantation. Hepatology 1982;2:614-636 7. Starzl TE, Klintmalm GBG, Porter KA, et al. Liver transplantation with use of cyclosporin A and prednisone. N Engl J Med 1981;305:266-269 8. Waller RR. Liver transplantation at Mayo-initial deliberations. Mayv Clin Proc 1989;64:82-83 9. Krom RAF, Wiesner RH, Rettke SR, et al. The first 100 liver transplantations at the Mayo Clinic. Mayo Clin Proc 1987;64: 84-94 10. Starzl TE, Demevis AJ, Van Thiel D. Liver transplantation (first of two parts). N Engl J Med 1989;321:1014-1092
11. Stanl TE, Demetris AJ, Van Thiel D. Liver transplantation (second of two parts). N Engl J Med 1989;321:1092-1099 12. Markus BH, Dickson ER, Grambsch PM, et al. Efficacy of liver transplantation in patients with primary biliary cirrhosis. N Engl J Med 1989;320:1709-1713 13. Burroughs AK, BiGini M, McCormick PA, Roues K. Liver transplantation and primary biliary cirrhosis. Postgrad Med J 1987;65:553-558 14. Starzl TE, Schneck SA, Mazzoni G, et at. Acute neurological complications after liver transplantation with particular reference to intraoperative cerebral air embolus. Ann Surg 1978; 187:236-240 15. Vogt DP, Lederman RJ, Carey WD, Broughan TA. Neurologic complications of liver transplantation. Transplantation 1988; 45: 1057-106 1 16. de Groen PC, Aksamit AJ, Rakela J, et al. Central nervous system toxicity after liver transplantation: the role of cyclosporine and cholesterol. N Engl J Med 1987;317:861-866 17. Estol CJ, Lopez 0, Brenner RP, Martinez AJ. Seizures after liver transplantation: a clinicopathologic study. Neurology 1989;39:1297- 1301 18. Martinez AJ, Estol C , Faris AA. Neurologic complications of liver transplantation. Neurol Clin 1988;6:327-348 19. Adams DH, Ponsford S, Gunson B, et al. Neurological complications following liver transplantation. Lancet 1987;1:949-95 1 20. Estol CJ, Faris AA, Martinez AJ, Ahdab-Barmada M. Central pontine myelinolysis after liver transplantation. Neurology 1989;39:493-498 21. Westmoreland BF, de Groen P, Aksamit AJ. The EEG in cyclosporine neurotoxicity. Electroencephalogr Clin Neurophysiol 1989;73:66P (Abstract) 22. Department of Neurology and Department of Physiology and Biophysics, Mayo Clinic and Mayo Foundation. Clinical examinations in Neurology. 5th ed. Philadelphia: WB Saunders, 1981:278-299 23. Wszolek ZK, McComb RD, Pfeiffer RF, et al. Pontine and extrapontine myelinolysis following liver transplantation. Transplantation 1989;48:1006- 1012 24. Brenner RP, Schaul N. Periodic EEG patterns: classification, clinical correlation, and pathophysiology. J Clin Neurophysiol 1990;7:249-267
Wszolek et al: Epileptiform E E G Abnormalities
41
We retrospectively studied patients who had undergone orthotopic liver transplantation and who also had electroencephalography to determine whether epileptiform changes were associated with a poor neurological outcome. Study groups were 36 patients who died after transplantation (141 electroencephalograms) and underwent neuropathological examination, 11 who died (18 electroencephalograms) but did not have autopsy, and a third group of 34 (62 electroencephalograms) who remained alive. Epileptiform activity was seen in electroencephalograms of 14 of the patients who died (11 from the autopsy group) and in 2 of those who remained alive. All had multiple epileptiform abnormalities and clinical or subclinical seizures. The incidence of epileptiform activity after orthotopic liver transplantation was fivefold higher in the nonsurvivors. Serious cerebral structural changes were found in 10 of the 11 patients who underwent autopsy. Epileptiform activity in the electroencephalograms of patients who had undergone orthotopic liver transplantation indicates a poor prognosis. It should alert the clinician to investigate further for potentially treatable causes. Wszolek ZK, Aksamit AJ, Ellingson RJ, Sharbrough F W , Westmoreland BF, Pfeiffer RF, Steg RE, de Groen PC. Epileptiform electroencephalographic abnormalities in liver transplant recipients. Ann Neurol 1991;30:37-41
Advances in surgical techniques, better methods of tissue preservation, and use of cyclosporine and other immunosuppressive agents explain an increase in the use of orthotopic liver transplantation (OLT) for treatment of end-stage liver disease, hlminant hepatic failure, neoplasm, or metabolic or congenital abnormalities (1-13). Many patients who undergo OLT suffer from various neurological complications, with mental status changes and seizures being the most frequent [S, 14-20). Electroencephalography (EEG) is one of the diagnostic tests used. Most often, generalized slowing of cerebral activity, characteristic of metabolic/toxic encephalopathy, is found (15, 2 11. Epileptiform activity, focal o r generalized, may indicate a more serious structural abnormality requiring appropriate medical or surgical therapy. To test the hypothesis that epileptiform changes on the EEG predict structural brain disease and a poor neurological outcome, we retrospectively studied patients who underwent OLT and who had EEGs. The study groups were patients who died after undergoing OLT and had a postmortem neuropathological evaluation (Group l), patients who died but did not have a postmortem examination (Group 2), and patients who remained alive after undergoing OLT (Group 3). In
each group of patients, we assessed the type and frequency of epileptiform activity and its relationship to neurological outcome, and in Group 1 we correlated EEG findings with neuropathological abnormalities.
From the *Department of Neurology, and $Division of Gastroenterolom and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, MN, and tSection of Neurology, University of Nebraska Medical Center, Omaha, NE.
Received Oct 1, 1990, and in revised form Jan 14, 1991. Accepted for publication Jan 30. 1991.
Material and Methods Between March 1, 1985, and September 30, 1989, 173 adults (age 17 years or older) underwent 209 OLTs at the Mayo Clinic (Rochester, MN). Between July 1, 1985, and September 30, 1989, 187 adults (age 17 years or older) underwent 220 OLTs at the University of Nebraska Medical Center (Omaha, NE). The total number of adult patients who underwent this surgery at both centers was 360, and they underwent 429 OLTs. The two centers used approximately the same surgical approach, similar preoperative diagnostic criteria, and similar postoperative care. The referral area includes not only the Midwest region but also both national and international sources. Sixty-nine patients died; 31 died at the Mayo Clinic and 38 died at the University of Nebraska Medical Center. Only 36 patients (age range, 21-62 years; mean age, 43 years; 18 men) in the two centers had both EEG and neuropathological evaluation. They served as study Group 1. Thirty-six patients had 52 OLTs; 2 1 patients underwent only one OLT each, 14 underwent two each, and 1 patient underwent three OLTs. Survival times after the first transplantation ranged from 2 to
Address correspondence to D r Aksamit, Mayo Clinic, 200 First Street SW, Rochester, M N 55905.
Copyright 0 1991 by the American Neurological Association
37
422 days (mean, 84 days). Among these patients, 141 EEGs were recorded using the International 10-20 Electrode Systern and multiple bipolar and referential montages. Alerting procedures were performed routinely. Hyperventilation was done whenever possible. The EEGs were classified according to the Mayo EEG Classification System {22}. The brains of patients who underwent autopsy were fixed in 10% buffered formalin. Both gross and microscopic examinations were performed. Tissue sections were stained with Lux01 fast blue and hemaroxylin-eosin, and the Bielschowsky silver reaction or other appropriate stains were used according to particular requirements. Microbiological and viral studies were done if clinicopathologically indicated. Study Group 2 was composed of 11 patients (age range, 19-66 years; mean age, 40 years; S men) with EEG recordings who died but did nor undergo autopsy. Eleven patients had 20 OLTs: 4 patients underwent one OLT each, 6 underwent two each, and 1 patient underwent four OLTs. Survival times after the first transplantation ranged from 7 to 1,461 days (mean, 285 days). These patients had 18 EEGs recorded. Study Group 3 consisted of 34 adults (age range, 18-61 years; mean age, 43 years; 19 men) who underwent OLT at the Mayo Clinic, had EEGs, and remained alive. This group included all possible patients who sarisfied these criteria. Thirty-four patients had 39 OLTs: 30 patients underwent one OLT each, 3 underwent two each, and 1 patient underwent three OLTs. The intervals between the first OLT and September 30, 1989 (the cutoff date of the study) ranged from 10 to 1,400 days (mean, 733 days). These patients had 62 EEGs recorded.
Results O f the total of 69 patients at both centers who died, 47 had EEGs (Groups 1 and 2): 45 (95.796) had o n e or more abnormal EEGs, and 1 4 (29.8%) had EEGs with epileptiform abnormalities. Among the 34 patients who remained alive (Group 3), 25 (73.5%) had one or more abnormal EEGs showing nonspecific changes and 4 (11.8%) had EEGs with epileptiform activity. O n e patient from Group 3 , however, had a chronic preexisting seizure disorder and another had transient epileptiform activity (periodic lateralizing epileptiform discharges) after acute head trauma complicated by hyponatremia before undergoing OLT but only nonepileptiform and normal EEGs after OLT. If these 2 patients are excluded, the incidence of postOLT epileptiform activity in Group 3 is 5.9971. N o n e of the patients in Groups 1 and 2 had preexisting epilepsy or EEG epileptiform activity before OLT. Thus, the incidence of epileptiform abnormahty was fivefold higher among the nonsurvivors than among the survivors who had EEGs ( p < 0.001). Of the 47 patients who died and had EEGs, 36 underwent autopsies (Group 1). Neuropathological findings are presented in Table 1, and the types of EEG abnormalities are presented in Table 2. Of these 36 patients, 35 had one or more abnormal EEGs; 11
38 Annals of Neurology
Vol 30 N o 1 July I991
Table 1 . Neuropathological Findings in 36 OLT Patients Who Had EEGJ
Finding
Patients (n)
Intracranial hemorrhage (parenchymal, subdural, or subarachnoid) Ischemic/anoxic encephalopathy Cerebral edema Infectious changes Pontine and extrapontine myelinolysis Cortical infarctions Normal brain
19
OLT = orthotopic liver transplantation; EEGs
12
11 8 7 1
7 =
electroencephalo-
grams.
Table 2. Abnormulities Observed in One or More EEGsafrom 36 OLT Patients Who Had NeuropathologicalExaminations
EEG Abnormality Nonspecific mild to moderate generalized slowing Severe generalized slowing (delta) Generalized suppression Typical and atypical triphasic waves Interictal spikes and sharp waves Focal Generalized Electrographic seizure discharges Focal subclinical Focal clinical Generalized clinical Status epilepticus Asymmetry Others
Patients With Epileptiform Activity (n = 11)
Patients Without Epileptiform Activity (n = 25)
8
20
8
16
6 4
14
10
...
6 4 11
... ...
7
...
... ... 2 2
‘Tocal number of EEGs was 136.
EEGs = electroencephalograms; OLT = orthotopic liver cransplantation.
(30.5%) exhibited epileptiform abnormality. O n e of the 36 patients had one normal pre-OLT EEG and o n e normal post-OLT EEG; h e was among the 7 patients with normal brains at autopsy. O n e patient had one normal EEG and 1 had two normal EEGs; both subsequently had several abnormal EEGs wirh epileptiform activity. The other 136 EEGs from these patients were abnormal (see Table 2 j. Detailed clinical, EEG, and pathological data o n the 11 patients who underwent autopsy and whose EEGs showed epileptiform abnormalities are presented in
Table 3. Clinical, EEG, and Pathological Data for 11 OLT Patients with Epileptifm Changes on EEG
Survival Time after OLT (days)
Time (in days) Between OLT" and the First EEG with Epileptiform Activity
Clinical Presentation on the Day of EEG
Age (yr)l Sex
OLT Number"
1
331M
A
64
All2
Coma, focal seizures
Severe, generalized slowing; bilateral independent PLEDs
CPM, ischemic changes, laminar cortical necrosis
2
24/M
A
56
A153
Coma, postcardiac arrest, generalized seizures
Diffuse anoxiclischemic changes
3
23/F
A C
169 145 120
CIS0
Generalized suppression; generalized spikes, seizure discharges Severe, generalized slowing; focal spikes, subclinical seizure discharges
A128
Obtundation, generalized seizure
Severe, generalized slowing, sharp waves
Intracerebral hemorrhages, encephalitis with microglial nodules
Coma, increased intracranial pressure, focal seizure
Severe, generalized slowing; focal sharp waves, seizure discharges
Cerebral edema, extensive laminar comcal necrosis
Coma, hemiparesis, focal seizures
Frequent subclinical and clinical seizure discharges Severe, generalized slowing; generalized seizure discharges Triphasic waves, focal spikes, partial status epilepticus Focal sharp waves, subclinical scizurc discharges Generalized suppression; generalized sharp waves, status epilepticus Focal sharp waves, seizure discharges
Subdural hematoma and cerebral hemorrhages Cerebral edema, multiple cerebral hemorrhages
Patient
B
Coma, no clinical seizures
4
25lF
A
53
5
36lF
A H
21
Bl1
A
116
A139
A
B
42 16
B/ 1
6
38lF
7
52lF
36
Coma, generalized seizures
8
53/F
A
29
A15
Confusion, cbnic activity
9
53lF
A
48
A16
Confusion, hemiparesis
10
561M
A B
43 11
B19
A
51
A118
11
62lF
Coma, generahzed seizures
Lethargy, intermittent seizures
EEG Abnormalioes
Neuropathological Correlations
CPM, EPM, tuberculorna
CPM, EPM, focal subarachnoid hemorrhages CPM, EPM, laminar cortical necrosis Severe cerebral edema with herniation, scattered neuronal necrosis Mild cerebral edema, no herniation
'The letter designations are as follows: A is the first OLT, B is the second OLT, and so on.
EEG = electroencephalographic; OLT = orthotopic liver transplantation; CPM = central pontine myelinolysis; EPM = extrapontine myelinolysis; PLEDs = periodic lateralizing epileptiform discharges.
Table 3. All experienced clinical or subclinical seizures. Of the 11 patients, 4 had central pontine myelinolysis (CPM), and 3 of those also had extrapontine myelinolysis. Three of the 4 patients who developed CPM (Patients 3, 8, and 9 in Table 3 ) have been previously described 1231. In addition, 2 had anoxic changes, 1 suffered bilateral subarachnoid hemorrhages, and 1 had a tuberculoma. Thus, all patients with CPM and epileptiform activity had other coexisting pathological abnormalities. Anoxic changes were found in 5 patients, in-
cluding 2 with CPM. Hemorrhagic lesions were found in 3 patients, including 1 with CPM and 1 with probable viral encephalitis. One patient showed only mild edema. EEG findings in these patients demonstrated various epileptiform activities, including focal and generalized spikes and sharp waves, periodic lateralized epileptiform discharges, focal subclinical seizures, and focal and generalized clinical seizures (see Tables 2 , 3). Of the 11 patients who died but did not undergo autopsy (Group 2), 3 had epileptiform abnormalities. Wszolek e t al: Epileptiform EEG Abnormalities
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One of the 3 had seizures. The deaths were attributed to multiple factors, including anoxia and bacterial and fungal infections. Two survivors (Group 3) exhibited post-OLT epileptiform abnormalities. One was a 41year-old man who became confused on postoperative day 13. An EEG obtained 6 hours later revealed status epilepticus characterized by generahzed sharp and slow waves, moderate generalized delta slowing, and atypical triphasic waves. Further diagnostic evaluation demonstrated a hyponatremia of 127 mEq/L and Ldsteria sp. meningitis. Two additional EEGs obtained on postoperative days 14 and 2 9 did not show epileptiform activity. At 1,370 days after his only OLT, he exhibited residual right hemiparesis and impaired mentation but no seizures (on phenytoin). The other patient was an 18-year-old woman who had transplantation for chronic active hepatitis with cirrhosis in whom a spontaneous right temporoparietal intracerebral hemorrhage developed that required surgical evacuation on postoperative day 8. Five days later, she became confused and the first EEG was obtained. The recording revealed right temporoparietocentral spikes in addition to the expected focal delta activity and asymmetry over the right parietocentrotemporal region. She developed hepatic artery thrombosis, and a second OLT was performed 19 days later. She recuperated well but again became confused 53 days later. The EEG obtained at this time showed right cerebral hemisphere periodic lateralizing epileptiform discharges, right centrotemporoparietal delta activity, and asymmetry. Similar EEG changes were present on recordings 2 , 12, and 23 days later. She required chronic anticonvulsant therapy. A persistent right temporal spike focus was documented on recordings 212, 383, and 544 days after her intracerebral hemorrhage.
Discussion Comparison of these different groups of patients with OLT suggests that epileptiform activity in the EEG indicates a poor prognosis. Among our patients, the incidence of epileptiform abnormalities was fivefold higher among the patients who died than among those who survived. Of the patients who had epileptiform activity, all either died (14 patients) or had permanent neurological disorders (2 patients). Of the 11 patients who underwent autopsy, 10 had a variety of serious structural abnormalities. EEG findings are mentioned in only a few reports describing neurological abnormalities after’ OLT. Adams and associates f19J reviewed findings on 52 patients. Seventeen had neurological complications. EEGs were recorded in 8 patients. Epileptiform activity was reported in 2 patients (in 1 before OLT), both of whom died; EEG findings were not well described in the other 6 patients, all of whom died. Estol and colleagues f17) described 21 adult patients who had sei40 Annals of Neurology Vol 30 No 1 July 1991
zures after OLT and died and underwent autopsies. Sixteen had EEGs. Clinical seizures were recorded in 9 patients with appropriate EEG seizure patterns. Interictal EEGs showed no epileptiform abnormalities in 7 patients, including triphasic waves in 1, burstsuppression patterns in 2, moderate generalized slow abnormalities in 3, and mild slowing in 1. All 21 patients had multiple neuropathological lesions at autopsy, in general agreement with our findings. Vogt and co-workers [ l 5 ) described 19 patients who underwent 21 OLTs, 8 of whom developed seizures postoperatively. EEGs were recorded in 6, demonstrating “diffuse encephalopathy” in 5 and bilateral epileptiform activity in 1 of the 5. This patient died (no autopsy). Because of the differences in sampling procedures and reporting methods, meaningful comparison of these fragmentary results with our data is not possible. Mental status changes ranging from confusion or lethargy to coma are common after OLT and were the most common indication for EEG in our series. All of our patients who showed epileptiform abnormalities presented in this manner. Epileptogenic processes, however, are not the only cause of mental status changes. Others include liver rejection, cyclosporine neurotoxicity, and systemic complications such as infection, coagulopathy, renal dysfunction, hypertension, and electrolyte imbalances. These are most often characterized by generalized nonspecific slow abnormality, but occasionally by suppression or asymmetries. Wesunoreland and colleagues f2 1J discussed the EEG findings in cydosporine-induced neurotoxicity. They described 5 patients who developed encephalopathy with multiple neurological findings, including altered level of consciousness, seizures, and cortical blindness, 3 of whom were previously described by de Groen and associates Cl6). The EEGs in all 5 showed generahzed slowing, in addition to focal slowing in 3 patients and asymmetry in 3 patients; however, none of them showed an epileptiform pattern. These 5 patients are included in Group 3 of the present study. Little is known about generation of epileptiform discharges in such complicated clinical situations in which metabolic, electrolyte, and toxic alterations are superimposed on structural changes. It is possible that electrical irritability involving excitatory neurotransmitters or neuronal membrane alterations may add to the gross structural damage we observed [24]. We emphasize that our study represents a review that has limitations. Further prospective analysis is certainly needed. We conclude that epileptiform abnormdties in the EEG after OLT are associated with serious, often irreversible, brain damage. The presence of epileptiform abnormalities should alert the clinician to investigate further for potentially treatable causes, such as infectious and hemorrhagic complications. Although the ab-
sence of epileptiform activity does not exclude serious underlying abnormality, nonepileptiform changes are less frequently of dire consequence. Therefore, the presence of epileptiform abnormalities on the EEG usually indicates significant underlying neuropathological changes. We thank Dr Byers W. Shaw,Jr, and Dr R. Patrick Wood for helping to make their patients available to us and Susan L.Robinson for her excellent secretarial assistance.
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