Central pontine myelinolysis after liver transplantation

Eight adults and 3 children out of 85 patients who had neuropathologic examination after death following orthotopic liver transplantation showed central pontine myelinolysis (CPM). Four patients also had extrapontine myelinolysis. Eight patients had significant serum sodium changes. In 5, the fluctuation occurred perioperatively and 4 had a clinical picture consistent with CPM, although no patient had this as an antemortem diagnosis. We emphasize the role of hepatic dysfunction as a cause of CPM and recommend careful monitoring of electrolytes in the perioperative period of patients undergoing liver transplantation.     

Central pontine myelinolysis after hepatic transplantation]

We report two cases of central pontine myelinolysis (CPM) following liver transplantation. The incidence may well be underestimated as in the past the diagnosis of CPM was based on postmortem findings. Malnutrition, poor clinical condition, encephalopathy are common features of transplanted patients developing CPM. The clinical course is characterized by a biphasic pattern; after normal recovery from anesthesia, there is a subsequent and gradual deterioration in the neurological state. The complex syndrome associates loss of consciousness, flaccid quadriplegia and pseudobulbar palsy. Among the many factors suspected of inducing CPM, a rapid correction of natremia (> 12 mmole/l/day) seems most probable. With regards to liver transplantation, CPM presents rather specific problems. Delaying transplantation to correct hyponatremia carries a risk of severe hepatic encephalopathy. On the other hand, the intraoperative compensation of blood losses with high sodium content blood products tends to induce an abrupt rise in sodium serum concentration. Moreover, renal capacity to excrete sodium is often impaired, due to hepatic insufficiency and surgical procedure. Transplantation should not be delayed, but as infusion of large amounts of sodium cannot be avoided (fresh frozen plasma, human albumin, red blood cells), natremia may be controlled by continuous veno-venous hemofiltration with low sodium content substitution fluids.     

Neurologic complications of pediatric liver transplantation

The neurologic complications of 24 children, ages 5 months to 18 years, following orthotopic liver transplantation at the Indiana University hospitals are reported. Biliary atresia (14 patients) was the most common cause for orthotopic liver transplantation. Three children died. Seventeen children (70%) had no neurologic deficit on follow-up 6 months or longer after transplantation. Eleven children (46%), including 4 of 16 patients (25%) who had received OKT3, had neurologic complications. Seven children (29%) had newonset seizures; 4 of these patients had status epilepticus. Two children had intracranial hemorrhage. Seizures occurred later in children than in adults following orthotopic liver transplantation and were not associated with poor prognosis. Longer term follow-up is indicated to assess subtle, cognitive deficits following liver transplantation in children.     

Cyclosporin-associated akinetic mutism and extrapyramidal syndrome after liver transplantation.

Three patients developed akinetic mutism on the third day after the introduction of intravenous cyclosporin A, given for immunosuppression after liver transplantation. One patient in addition developed a florid orofacial dyskinesia, which resolved completely, as did the akinetic mutism, after withdrawal of cyclosporin. In these patients the time course of the akinetic mutism and extrapyramidal syndrome, which developed in the absence of any other identifiable cause, suggests cyclosporin A was the precipitating factor. Subsequently, two of the patients showed signs of pseudobulbar palsy with abnormalities in the pons on MRI scanning, suggesting central pontine myelinolysis (CPM). None of the patients had experienced significant fluctuations in serum sodium or other risk factors for central pontine myelinolysis and the exact relationship to the earlier cyclosporin related mutism was not clear.     

Central pontine myelinolysis and abnormalities in serum sodium

Central pontine myelinolysis (CPM) was found at autopsy in 21 of 220 consecutive patients with chronic liver disease. It showed the same incidence in chronic nonalcoholic as in chronic alcoholic liver disease but did not occur in acute liver disease. No patients had clinical symptoms of CPM, although 15 had encephalopathy. The lesion was active in 13 and inactive in 8. Laboratory data was incomplete in 2 patients with active and 8 with inactive CPM. Of 11 closely monitored patients with active CPM, 6 had a rapid rise in serum sodium of at least 8 meq/l per day, sustained for 5 or more days, and preceding death by 8-21 days; the other 5 showed no rise during 15-64 days prior to death. All patients with a large, rapid, sustained rise in serum sodium showed CPM at autopsy, but half of those with active CPM showed no such sodium changes even though closely monitored.     

Neurological complications after cadaveric and living donor liver transplantation

Problems related to the central nervous system have a major impact on survival and quality of life. The aim of this retrospective study was to evaluate the incidence of neurological complications after liver transplantation (LT), including both cadaveric and living donor liver transplantation. Between April 2001 and March 2004 174 patients (120 cadaveric liver transplantations, 54 living donor transplantations) were admitted to our intensive care after liver transplantation. Of the transplanted patients 24.7% developed neurological complications. These patients’ stay in the intensive care (14.2 ± 17.2 days) was much longer than that of all admitted patients (8.4 ± 10.5 days, p < 0.05). The most common neurological complications were encephalopathy (72.1%) and seizures (11.6 %). The incidence of neurological complications in living donor liver transplanted patients was significantly lower than in cadaveric transplantation patients (20.4% vs 26.7 %). The cold ischemia time in living donor transplanted patients was significantly shorter in comparison with cadaveric transplanted patients (215 ± 119.3 vs. 383.7 ± 214.7). The survival rate after liver transplantation of patients with neurological complications was lower than that of patients without, but not significantly different (79.1 % vs. 82.4%, p > 0.05). The incidence of neurological symptoms was found to be similar between the patients treated with cyclosporine (25%) and tacrolimus (23.8 %) in this study. In conclusion, there was a high incidence of neurological complications after LT, prolonging the patients’ stay in intensive care significantly. The major neurological manifestation in our patients was encephalopathy followed by seizures. Living donor liver transplantation was associated with a significantly lower incidence of neurological complications compared with patients who had received a cadaveric graft. This might be due to the good quality of the organ and the much shorter cold ischemia time of the graft when the donor was alive.     

The Course And Prognostic Factors Of Familial Amyloid Polyneuropathy After Liver Transplantation

Familial amyloid polyneuropathy (FAP) associated with mutations of the transthyretin (TTR) gene is the most common type of FAP, a devastating disease causing death within 10 years after the first symptoms. Because most of the amyloidogenic mutated TTR is secreted by the liver, transplantation is widely used to treat these patients, but long-term quantitative evaluation of the effects of liver transplantation on the progression of the neuropathy are not available. We have treated 45 patients with symptomatic TTR-FAP, including 43 with the Met30 TTR gene mutation, and report on the results of periodic evaluation of markers of neuropathy in 25 of them, who have been followed for more than 2 years after liver transplantation (mean follow-up 3 years). The overall survival rates at 1 and 5 years were 82 and 60%, respectively. Urinary incontinence and a low Norris score at liver transplantation were associated with poorer outcome. The motor score stabilized in seven of 11 patients (64%) with mild sensorimotor neuropathy (walking unaided) and in two of the eight patients (25%) with severe sensorimotor deficit (walking with aid) at liver transplantation. In five other patients, deterioration of motor deficit occurred only within the first year after liver transplantation, but was progressive after this interval in two patients. None of the six patients with pure sensory neuropathy developed motor loss and superficial sensory loss remained unchanged. Two years after liver transplantation, the rate of myelinated axon loss in nerve biopsy specimens was markedly lower in seven transplanted patients (0.9/mm(2) of endoneurial area/month) than in non-transplanted patients (70/nm(2) of endoneurial area/month). Symptoms of dysautonomia and quantitated cardiocirculatory autonomic tests remained unchanged. In all patients, serum mutated TTR decreased to 2.5% of pre-liver transplantation values and remained at this level during follow-up. We presently recommend liver transplantation in FAP patients at onset of first symptoms and exclusion of those with a Norris score below 55 and/or with urinary incontinence.     

Value of plasmapheresis in hepatic encephalopathy

Plasmapheresis is used for treating the complications of liver failure. We performed plasmapheresis on 6 children with hepatic encephalopathy resulting from acute hepatic failure and prospectively assessed its effects on neurologic and electrophysiologic (electroencephalography and evoked potentials) function. Clinical improvement was observed in 3 of 6 patients; changes in the serum ammonia value or the results of initial electrophysiologic tests did not predict the patient response. Two patients underwent transplantation after neurologic improvement was produced by plasmapheresis; however, despite plasmapheresis, 4 patients progressed to brain death. Our data demonstrate that plasmapheresis may transiently improve the encephalopathy of acute hepatic failure but is not curative alone. Therefore, plasmapheresis may be a useful adjunct in the treatment of liver failure, potentially improving the pretransplantation status of the patient.     

肝移植相关心理问题分析

肝移植是治愈终末期肝病的有效方法,但由于移植本身的特殊性及经济状况等原因,移植给患者带来了巨大的心理压力。文章分析了肝移植患者移植前及移植后存在的心理问题,证实了移植前患者除了有躯体不适外,还存在由原发病所致的不同程度的精神社会功能缺损及生活质量水平下降导致的心理障碍;移植后主要为忧郁、过分乐观、放纵的心理。探讨了缓解肝移植相关问题的思路和对策,得出结论：对患者进行心理疏导,满足患者需求心理,帮助患者了解肝移植知识有助于减轻患者心理压力,使患者积极配合医疗并接受移植。     

Normal diffusion-weighted MRI during the acute stage of central pontine myelinolysis

Central pontine myelinolysis (CPM) is rare demyelinating disorder characterized by loss of myelin in the center of the basis pontis. The clinical features of CPM vary depending on the involved areas. Diffusion-weighted imaging (DWI) is thought to be useful for early detection during the acute phase, but its utility in this context has not been investigated thoroughly. We report the case of a CPM patient with normal initial DWI findings even at 1 week after symptom onset. To the best of our knowledge, no such cases of CPM have previously been reported.     

Hepatocerebral mitochondrial DNA depletion syndrome caused by deoxyguanosine kinase (DGUOK) mutations

BACKGROUND: Autosomal recessive mutations in deoxyguanosine kinase (DGUOK) have been identified in the hepatocerebral form of mitochondrial DNA (mtDNA) depletion syndrome. OBJECTIVES: To describe the clinical spectrum of DGUOK-related mtDNA depletion syndrome in 6 children and to summarize the literature. RESULTS: We identified pathogenic mutations in DGUOK in 6 children with the hepatocerebral form of mtDNA depletion syndrome. We describe the clinical, neuroradiologic, histologic, and genetic features in these children. All children showed severe hepatopathy, while involvement of other organs (skeletal muscle and brain) was variable. We identified 5 novel mutations (1 of them in 2 children) and 2 previously described mutations. Three different mutations affected the initial methionine, suggesting a mutational hot spot. One of our patients underwent liver transplantation; pathologic findings revealed (in addition to diffuse hepatopathy) a hepatocellular carcinoma, implying a possible link between mtDNA depletion syndrome and tumorigenesis. CONCLUSION: We studied 12 children with infantile hepatoencephalopathies and mtDNA depletion syndrome and found pathogenic DGUOK mutations in 6, suggesting that this gene defect is a frequent but not an exclusive cause of the hepatic form of mtDNA depletion syndrome.     

Impact of aging on the progression of neuropathy after liver transplantation in transthyretin Val30Met amyloidosis

Introduction: Information related to the long‐term follow‐up of neuropathy in patients with familial amyloid polyneuropathy after liver transplantation is still scarce. Methods: We describe the neuropathic features of 3 patients with the transthyretin Val30Met mutation. Each patient underwent liver transplantation at an early stage of neuropathy, as indicated by the absence of motor dysfunction and relative preservation of myelinated fibers in sural nerve biopsy specimens. Results: Although the patient with late‐onset disease (at age 60 years) presented with the least amount of amyloid deposition, he had neuropathic progression after liver transplantation. An older early‐onset (at age 40 years) patient reported a slight exacerbation of both somatic and autonomic neuropathic symptoms 10 years after transplantation. However, the younger early‐onset (at age 28 years) patient did not exhibit characteristics suggestive of neuropathy 7 years after transplantation. Conclusion: Aging may determine the progression of neuropathy after liver transplantation. Muscle Nerve, 2012     

Reversible Cytotoxic Edema in TPN‐Related Hepatic Encephalopathy

Hepatic encephalopathy (HE) is an uncommon complication of total parenteral nutrition (TPN). Cytotoxic edema has not been reported in children with TPN‐related HE. We describe a case of TPN‐related HE presenting with diffuse cytotoxic edema which reversed after liver transplantation.     

Autonomic and peripheral neuropathy in endstage liver disease and following liver transplantation

Severe chronic liver disease may be associated with a peripheral somatic and an autonomic neuropathy. There are only a limited number of reports on the incidence and features of these neuropathies. In addition the effects of liver transplantation on these neuropathies have not been well studied. We examined peripheral somatic and autonomic nerve function in 42 patients with endstage liver disease prior to transplantation and also examined the effect of liver transplantation on these neuropathies in 14 patients. Peripheral somatic neuropathy (93%) and autonomic neuropathy (50%) were common in patients with endstage liver disease and were more frequent than previously reported. Abnormalities improved in some patients after liver transplantation, particularly if there was return of normal hepatic function.     

乙肝病毒相关肝病患者肝移植后外周血单个核细胞及肝组织中乙型肝炎病毒cccDNA的检测

背景：肝移植后受者体内绝大部分病毒负荷被清除,植入新肝后其复发性肝炎病原体从肝外进入肝内的途径及其复制规律目前尚无定论。 目的：检测肝移植前后外周血单个核细胞和肝组织中乙型肝炎病毒cccDNA及血清中乙型肝炎病毒DNA的表达。 方法：采用淋巴细胞分离液从乙肝病毒相关终末期肝病37例患者外周血中分离出单个核细胞,采用荧光定量PCR检测肝移植前后及移植后乙肝复发3个时期外周血单个核细胞和肝组织中cccDNA及血清乙型肝炎病毒DNA表达。 结果与结论：肝移植前,单个核细胞cccDNA阳性12例,肝组织cccDNA阳性6例,检出率分别为32%和16%,单个核细胞、肝组织中cccDNA拷贝范围分别为(3.028~6.508)×104,(4.158~6.234)×104 拷贝/mL。肝移植后,单个核细胞cccDNA阳性1例,无血清乙型肝炎病毒DNA检测阳性病例。6例肝移植后乙肝复发病例中外周血单个核细胞cccDNA阳性4例,肝组织活检cccDNA阳性1例,6例血清乙型肝炎病毒 DNA均为阳性。提示乙肝病毒相关终末期肝病患者肝移植后乙肝复发途径可能是残留乙肝病毒在外周单个核细胞中以cccDNA为模板复制,然后再迁移到肝脏。     

Neurosurgical complications of pediatric orthotopic liver transplantation

Liver transplantation is the only definitive treatment of end-stage liver disease. The University of Nebraska began its hepatic transplantation program in July 1985. Since that time, 43 children and 48 adults have undergone orthotopic liver transplantation (OLTx) with survival rates to date of 79.1% and 79.2%, respectively. Eight children developed complications of neurosurgical interest (18.6% incidence). Hemorrhagic complications were the most frequent. Neurosurgical salvage was achieved in five patients, but delayed complications of the transplant caused the death of two of these children. Two survivors are functioning well at home and in kindergarten, one child is doing well but is still hospitalized, and one child is vegetative. Aggressive management of life-threatening CNS problems is thus appropriate in this population. The authors review the pathophysiology of these complications, as well as potential pitfalls in their management.     

丙型肝炎病毒阳性受者肾移植后的安全性分析

背景：对于丙肝病毒阳性患者接受肾移植后安全性的问题是目前大家关注的热点。 目的：丙型肝炎病毒感染者接受肾移植后临床观察及处理对策。 方法：纳入22例患者,肾移植前肝炎病毒RNA均为阳性,其中14例患者肝功能轻度升高。移植后定期检测患者的肝、肾功能,积极防治可能的排斥反应。主要观察患者一般情况、肝、肾功能、肝炎病毒基因学情况及死亡率。 结果与结论：移植后随访6~36个月,20例患者移植后4周~6个月内出现不同程度的肝功能异常,予护肝治疗后肝功能均恢复正常,1例移植后HCV-RNA 阳性患者,因自行改变抗排斥方案于移植后1.5年出现严重的肝功能衰竭而死亡;4例患者移植后应用干扰素和利巴韦林治疗,HCV-RNA转阴,其余18例患者HCV-RNA均呈阳性,需长期护肝治疗。表明,对丙肝病毒阳性受者,移植后应进行严格的随访,出现肝功能异常时,及时采取相应处理和护肝治疗。     

Central pontine myelinolysis presenting as isolated sixth nerve palsy in third trimester of pregnancy

A 30-year-old primigravida presented with isolated left sixth nerve palsy at 38 weeks gestation. Her MRI showed a lesion consistent with central pontine myelinolysis (CPM). Extensive investigations did not reveal any secondary cause for the CPM. She recovered spontaneously in 2 weeks with complete resolution of her MRI changes. To our knowledge, this is the first report of CPM occurring in third trimester in the absence of identifiable secondary causes and of CPM presenting as an isolated sixth nerve palsy. We discuss the reported causes of CPM in pregnancy, possible pathophysiologic mechanisms involved and the anatomic basis of the unique clinical presentation of sixth nerve palsy in our case.     

Neuromuscular complications associated with liver transplantation

We studied neuromuscular complications in a cohort of 520 patients with liver transplantation. Perioperative mononeuropathy developed in 9 patients. The peroneal nerve, radial nerve, and cutaneous branch of the femoral nerve were affected in 2 patients each. Two patients had herpes zoster-associated radiculopathy, and 1 patient had Horner's syndrome. Recovery was good in most patients. In 7 patients, severe quadriplegia complicated the perioperative course. In 5 patients, electrophysiologic studies suggested acute necrotic myopathy, and muscle biopsy specimens showed evidence of rhabdomyolysis in 1 patient. Outcome in survivors was good, all recovering completely. We conclude that neuromuscular complications in liver transplantation are uncommon (less than 1%) and do not significantly contribute to morbidity. Mononeuropathies may have iatrogenic perioperative causes, and rhabdomyolysis may be an important cause of generalized muscle weakness after liver transplantation. © John Wiley & Sons, Inc.     

Central pontine myelinolysis.

Central pontine myelinolysis (CPM) is a demyelinating disease of the pons often associated with demyelination of other areas of the central nervous system (CNS). The term 'osmotic demyelinization syndrome' is used for pontine and extrapontine myelinolysis. In this paper, we are concerned with CPM although the extrapontine one is based on the same pathogenesis. Both share the diagnostic methods, and their prevention and therapy are the same. The etiology and pathogenesis of this disorder are unclear and will be discussed. However, almost all cases of CPM are related to severe diseases. Chronic alcoholism is still the most common underlying condition of CPM patients. In the literature, 174 cases of CPM have been reported in alcoholics since 1986, which is equivalent to an incidence of 39.4%. Likewise, 95 cases of CPM following the correction of hyponatremia have been documented since 1986 (21.5%). The role of hyponatremia and its correction will be outlined in the discussion of the pathogenesis of CPM. The third largest group of CPM cases are liver transplant patients (17.4%), with the development of CPM being attributed to the immunosuppressive agent cyclosporine in particular. Depending on the involvement of other CNS structures, the clinical picture can vary considerably. The large-scale introduction of magnetic resonance imaging has increasingly facilitated the antemortem diagnosis of CPM, although the radiological findings lag behind and do not necessarily correlate with the clinical picture. As yet, there is no specific therapy of choice. A number of therapeutic approaches have been tested and although they have not been compared with regard to their rate of success, they have all led to a substantial improvement in the prognosis of CPM.