Liver transplants are the final therapeutic option for patients with irreversible end-stage liver disease or acute hepatic failure in whom conventional medial ther- apy has been ineffective. Since the initiation of liver transplants in the 1960s, this procedure has been per- formed with increasing frequency and as a result, relat- ed medical and surgical complications have become more common (1).
Although the incidence of liver-transplant-related complications has decreased markedly lately due to re- cent improvements in surgical techniques and post-op- erative care, central nervous system (CNS) complica- tions account for much of the morbidity and mortality following liver transplants (2). The reported incidence of CNS involvement varies widely from 9.7% to 42% (3, 4).
Familiarity with the frequency and imaging features of neurological complications is especially important to ra- diologists when interpreting the imaging studies of liver transplant patients, as early diagnosis has a very impor- tant role in initiating appropriate treatment. A series of pathology reports dealing with neurological complica- tions following liver transplants have been published.
However, only a few of these reports have described imaging findings.
In this review, of a total of 498 liver transplant recipi- ents, 21 patients (4%) were found to have abnormal ra- diological findings in the central nervous system follow- ing their liver transplant. The radiological findings of a spectrum of neurological complications following liver transplant are illustrated and described here, as well as their corresponding clinical correlations (Table 1).
Focal Hemorrhagic or Occlusive Complication
Eleven (n=11, 52.4%) of the 21 patients were affected by intracranial hemorrhage (n=7) and/or cerebral in-
Neurological Complications Following Liver
Transplant: A Pictorial Review of Radiological and Clinical Findings1
Young Kyung Lee, M.D., Ji Hoon Shin, M.D., Sang Joon Kim, M.D.,
Deok Hee Lee, M.D., Ho Kyu Lee, M.D., Choong Gon Choi, M.D., Dae Chul Suh, M.D.
Neurological complications are a rare but important and significant source of infor- mation about morbidity and mortality in liver transplant patients. Based on the clinical and radiological findings of 21 patients, neurological complications were categorized into five main groups; focal hemorrhagic or occlusive complications (n=11); diffuse hypoxic-ischemic injury (n=3); hypertensive encephalopathy (n=1); central pontine or extra-pontine myelinolysis (n=4); and infection (n=2). Neurological manifestations varied according to the location of the lesion, although seizures were the most com- mon manifestation. In this pictorial review, we illustrate the radiological findings, fo- cusing on MR and CT images, of a spectrum of neurological complications following liver transplants, as well as their clinical correlations.
Index words :Central nervous system Liver transplant
Neurological complication
1Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine
Received April 28, 2005 ; Accepted June 20, 2005
Address reprint requests to : Ji Hoon Shin, M.D., Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Poongnap-dong, Songpa-gu, Seoul 138-736, Korea.
Tel. 82-2-3010-4400 Fax. 82-2-476-4719 E-mail: [email protected]
farction (n=4) of varying types and sizes. Hemorrhages included five cerebral or cerebellar hematomas and two subdural hematomas. One patient had a pontine infarc- tion (Fig. 1), and three patients had cerebral infarctions, but no source of the emboli was detected.
Hemodynamic instability during the peri- or post-op- erative periods in the setting of unrecognized carotid or intracranial occlusive disease or embolic occlusion sec- ondary to heart or deep vein problems, can result in oc- clusive cerebrovascular complications (5). Intra-opera- tive air embolisms associated with the use of venous by- pass have been described (6), but have now become a
relatively rare complication.
Intracranial hemorrhages may be intraparenchymal (Fig. 2), subdural (Fig. 3) or subarachnoid, and can be isolated or a combination of the three. Coagulopathy,
Fig. 1. A 36-year-old man with acute pontine ischemic change or infarction four months after living-related liver transplant due to fulminant toxic hepatitis.
Unenhanced CT scans show poorly defined low density (ar- row) in the central pons. This patient died as a result of the pontine infarction.
Fig. 3. A 55-year-old woman with a subacute subdural hematoma three months after living-related liver transplant due to cirrhosis of the liver.
Unenhanced CT scan shows a high-density subdural hematoma in the left cerebral convexity. Subfalcian herniation is also noted.
Fig. 2. A 33-year-old man with right frontal lobe intracerebral hemorrhage one week after living-related liver transplant due to fulminant toxic hepatitis.
Unenhanced CT scans show high-density hemorrhage (arrow) in the right frontal lobe. There is a mild edema surrounding the hematoma and moderate mass effect. This patient died four days after the CT scan was performed.
Table 1. Neurological Complications According to the Primary Clinical Manifestation in a Series of 21 Cases
Neurological complication Primary Clinical Manifestation (Number of cases) Intracranial hemorrhage (n=7) Seizure (2)
Mental change (2) Neurological deficit (3) Occlusive infarction (n=4) Mental change (2)
Neurological deficit (1) Nonspecific headache (1)
Hypoxic-ischemic Seizure (2)
encephalopathy (n=3) Nonspecific headache (1) Hypertensive encephalopathy (n=1) Nonspecific headache (1) Central pontine myelinolysis (n=3) Mental change (3) Extra-pontine myelinolysis (n=1) Seizure (1)
Neurocysticercosis (n=1) Nonspecific headache (1) CNS tuberculosis (n=1) Fever (1)
secondary to liver failure, unstable blood pressure con- trol, and co-existent CNS infection can also lead to in- tracranial hemorrhages.
The prevalence of cerebral infarctions following ortho- topic liver transplants (OLT) have been reported with an incidences ranging from 3.6% to 18% in autopsied pa- tients (2, 7, 8). Intracranial hemorrhages have been re- ported in 7% to 24% of autopsied liver transplant recipi- ents and are strongly associated with high patient mor- tality (2, 7, 8).
In some cases, there are multiple hemorrhages and in- farctions of the neocortex with no apparent etiology (1).
Usually these kinds of occlusive or hemorrhagic compli- cations carry poor prognoses.
Diffuse Hypoxic Ischemic Injury
Diffuse hypoxic ischemic encephalopathies with vary- ing degrees of severity were seen in three patients (14.3%). None of the patients with hypoxic ischemic le- sions had any previous record of clinical episodes of car- dio-respiratory arrest, but most had experienced some level of hypotension during the peri- or post-operative period.
Hypoxic ischemic damage ranged from a mild injury to a few susceptible foci to widespread and severe change with evidence of cortical laminar necrosis (7). A hypoxic-ischemic insult is the result of global rather
Fig. 4. A 51-year-old woman with a hypoxic-ischemic injury one week after an orthotopic liver transplant due to cirrhosis of the liver.
CT scans one week after the liver transplant show diffuse low density of both basal ganglia and thalami.
Fig. 5. A 29-year-old man with hypertensive encephalopathy four days after living-related liver transplant due to cirrhosis of the liver.
Unenhanced CT scans show high-density hemorrhage with a surrounding edema in both parietal lobes.
A B
Fig. 6. A 48-year-old man with central pontine myelinolysis ten days after an orthotopic liver transplant due to cir- rhosis of the liver. The pre-operative serum sodium level was 118 mEq/L, but it rapidly corrected to 142 mEq/L immediately following surgery. These MR images are compatible with central pontine myelinolysis with the clinical background of rapid sodium correc- tion. This patient gradually improved.
A, B. T2-weighted MR images show high-signal intensity, thus indicating the spared corticospinal tract in the brainstem.
than focal brain injury (8). Severely generalized cerebral edemas ensue 24 to 48 hours following a liver transplant and are seen as diffuse low-density on CT images and as abnormal signal intensity at the vascular watershed zones, cortical areas, and deep gray matter, including basal ganglia and thalami, on MR images (Fig. 4).
Hypertensive Encephalopathy
Hypertensive encephalopathies usually occur during the early post-operative period. Seizures are the most frequently encountered symptom without evidence of intracranial bleeding. These hypertensive seizures have been attributed to vascular spasms or a breakdown of the auto regulation of cerebral blood flow resulting in an ischemia and/or edema (9).
The fluid requirements and coagulopathy during the surgical procedure and cyclosporine and steroid therapy during post-operative management result in post-opera- tive hypertension, which is responsible for the appear- ance of CNS hemorrhage.
Hypertensive encephalopathies commonly occur in the parieto-occipital area (Fig. 5). Hemodynamic and he- mostatic control during the immediate post-operative period, although not always easy, can help to eliminate these potentially fatal complications (3).
Central Pontine and Extra-pontine Myelinolysis
Four patients (19.0%) were affected by demyelination, with a pattern characteristic of central pontine (Fig. 6) and extra-pontine (Fig. 7) myelinolysis.
The incidence of central and extra-pontine myelinoly- sis following liver transplants is still unclear. However, central and extra-pontine myelinolysis were found in 10-30% of patients who died following their liver trans- plant (2).
Although its etiology is unknown, central pontine myelinolysis (CPM) is associated with rapid correction of prolonged hyponatremia (6). The appropriate rate of correction is still unknown, but it has been suggested that serum-sodium levels should not increase by more
A B
Fig. 7. A 48-year-old man with ex- trapontine myelinolysis one month af- ter an orthotopic liver transplant due to cirrhosis of the liver.
A. T1-weighted MR image shows high signal intensity in both globus palli, suggesting a hepatic encephalopathy.
B-D. FLAIR (B, C, D) MR images show high-signal intensity (arrows) in the right thalamus, the right occipital lobe, and the central pons. This patient grad- ually improved.
C D
than 0.5 mEq/L per hour (4). Central and extra-pontine myelinolysis are also associated with rapid correction of broad fluctuations in plasma glucose levels or of blood cyclosporin levels (1, 5, 10).
CPM may cause progressive quadriplegia resulting in loss of speech and swallowing. Seizures or frank comas may hint to extra-pontine involvement. This clinical fea- ture is often clouded by toxic, metabolic or ischemic en- cephalopathy, thus obscuring the diagnosis of CPM (6).
In our case, CPM had not been suspected on clinical grounds.
Extra-pontine sites, such as the putamen, caudate nu- clei, midbrain, thalami, and subcortical white matter, have also been reported to be areas of myelination.
Extra-pontine myelinolysis (EPM) usually affects white matter tracts, but most patients experience gradual clini- cal and radiological resolution to a variable extent (10).
In EPM, CT images show non-enhancing areas of low attenuation, while these foci appear as areas of in- creased signal on T2-weighted MR images (11).
Careful peri-operative fluid management specifically related to sodium and glucose levels may reduce the risk of CPM and EPM (12).
Infection
Two patients displayed evidence of CNS infection, one with tuberculosis (Fig. 8) and the other with neuro- cysticercosis (Fig. 9).
Infection is a serious complication of human organ transplants and accounts for a post-transplant mortality rate of up to 80% (1). Immunosupression, required to avoid graft rejection, renders a patient more vulnerable to bacterial, fungal, viral, and protozoal opportunistic
A B C
D E F
Fig. 8. A 38-year-old man with CNS Tuberculosis two years after living-related liver transplant.
A-D. Contrast-enhanced CT (A, B) and Gadolinium-enhanced T1-weighted (C, D) MR images show multi-focal, tiny enhancing nodules in both cerebral hemispheres.
E, F. T2-weighted MR images show multi-focal high-signal intensity of the multiple tiny nodules.
microorganisms. The difficulty of post-transplant thera- peutic management is in keeping an adequate balance in the host defense mechanism (13).
CNS infections were documented in 34% of one large autopsy series (5). Most infections occur in the first two months following a liver transplant and are commonly manifested as either meningitis or meningoencephalitis.
Viral (Cytomegalovirus (CMV), Herpes simplex or zoster, Epstein Barr), bacterial (Listeria, E.coli, tubercu- losis, cysticercosis), and fungal (cryptococcosis, as- pergillosis) infections can involve the CNS. Bacteria are known to be the most common cause of clinically signif- icant infections following liver transplants (1). However, a recent investigation using in situ hybridization clearly demonstrated a significantly higher frequency of CMV genomic material in brain tissue from OLT patients than in aged-matched immunocompetent controls (89% vs.
23%) (14). Encephalopathic patients following OLT
showed unusually prominent degrees of CMV hy- bridization (14).
Disseminated fungal infections or abscesses due to Cryptococcus, Aspergillosis or Candida, are frequently seen in liver transplant patients, especially in the first month following a transplant, with a reported incidence of between 4% and greater than 40% (14, 15). These or- ganisms usually cause disseminated systemic infections and are frequently fatal. Contrast-enhanced CT scans show multi-focal enhancing nodules or peripheral rim enhancing nodules in both cerebral hemispheres, and T2-weighted MR images show multi-focal high-signal in- tensities.
Conclusion
Neurological complications are not uncommon in the immediate post-operative period following liver trans-
A B
Fig. 9. A 51-year-old man with neuro- cyticercosis three weeks after living-re- lated liver transplant. Cysticercosis was confirmed on an enzyme-linked im- munosorbent assay (ELISA) test.
A, B. Gadolinium-enhanced T1-weight- ed MR images show multi-focal, rim- enhancing, small nodules (arrows) in the right frontal lobe, both occipital lobes and in the left insular cortex.
C, D. T2-weighted MR images show the high-signal intensity of the lesions (arrow) in the left insular cortex and in both occipital lobes. Low-signal intensi- ty and a marked edema surrounding the area of active inflammation are not- ed in the lesion involving the right frontal lobe.
C D
plants and are associated with high mortality. These complications can be caused by numerous factors (8).
Understanding the common radiological findings of neurological complications following liver transplants is important for both early recognition and intensive treat- ment.
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대한영상의학회지 2005;53:1-7
간이식후 신경학적 합병증: 방사선학적 소견1
1울산대학교 의과대학 서울아산병원 영상의학과
이영경・신지훈・김상준・이덕희・이호규・최충곤・서대철
간 이식 후 신경학적 합병증은 드물게 발생 하지만 간 이식 후의 환자의 이환율과 사망률에 중요한 원인이다. 간 이식 후 신경학적 합병증이 발생한 21명의 환자를 임상적 소견과 방사선학적 소견을 바탕으로 분류하였다. 이 중11예에서 국소 출혈성 또는 폐색성 합병증으로, 3예에서 미만성 허혈성 손상으로, 1예에서 고혈압성 뇌병증으로, 4예에서 중심 성 뇌교 및 뇌교외 수초용해증(Central pontine or extra-pontine myelinolysis)으로, 2예에서 감염으로 진단되었다.
간 이식 후 신경학적 합병증 환자에서 병변의 위치가 다양함에도 불구 하고 발작이 가장 흔한 임상 증상 이었다. 본 연 구에서는 우리 저자들은 간 이식 후 신경학적 합병증에 대해 임상적인 소견과 연관되어 다양한 자기 공명 영상(MR)과 전산화 단층 촬영(CT)의 소견을 보여 주고자 한다.
