Central pontine and extrapontine myelinolysis: a rare and fatal complication after liver transplantation

Central pontine myelinolysis (CPM) may be more prevalent after liver transplantation (OLT). Central pontine and extrapontine myelinolysis (CPEM) is rare. The occurence of CPM may be associated with hyponatremia, a rapid rise in serum sodium concentrations, postoperatively increased plasma osmolality, and the duration of the operation. Only 1 patient had abnormal sodium levels before LT. No abnormalities were detected in immunosuppressive drug blood levels. The aim of this paper was to report our experience with CPEM among LT patients.     

Central pontine and extrapontine myelinolysis in an infant associated with the treatment of craniopharyngioma: case report

A 3-year-old girl presented with osmotic demyelination syndrome after undergoing uneventful neuroendoscopic cystostomy for a growing cystic suprasellar craniopharyngioma following microscopic subtotal resection 1 year previously. Endocrinopathy had well been controlled by hormone replacement therapy and administration of 1-amino-8-d-arginine-vasopressin with serum sodium concentration within the normal range. She presented generalized seizure and fever on postoperative day 7, with hyponatremia beginning on postoperative day 4 and deteriorating despite frequent correction. The serum sodium concentration began to fluctuate on the same day, in the range 111-164 mEq/l, which lasted for 2 weeks, refractory for intense management. Her body temperature also fluctuated between hypo- and hyperthermia not correlated with serum inflammatory markers. Her conscious disturbance progressively deteriorated with spastic paraparesis. T(2)-weighted magnetic resonance (MR) imaging taken on postoperative day 19 revealed hyperintense areas in the pons, external capsule, bilateral thalami, and basal nuclei, which had not been recognized before, suggesting osmotic demyelination syndrome causing central pontine and extrapontine myelinolysis. MR imaging taken on postoperative days 230 and 360 showed some diminished lesions but others persisted and resulted in a cavity. The patient's depressed conscious level did not improve. Suprasellar craniopharyngioma with long-standing hypothalamic dysfunction may be associated with severe osmotic demyelination syndrome even after less invasive surgery, so serum sodium derangement after surgery should be promptly corrected even if only subtle signs are present.     

Fellows’ Forum in Dialysisedited by Mark A. Perazella: Does Uremia Protect against the Demyelination Associated with Correction of Hyponatremia during Hemodialysis? A Case Report and Literature Review

Rapid correction of chronic hyponatremia is known to cause demyelination syndromes, which are attributed to the rapid shift of water out of the brain. In uremic patients with hyponatremia, depending on the dialysate sodium concentration and delivered Kt/V, serum sodium levels may be rapidly corrected inadvertently during the hemodialysis (HD) session. It is not known whether uremic patients are as susceptible to the development of demyelination as patients with normal renal function. Since urea diffuses slowly across the blood-brain barrier, it can act as an effective osmole between plasma and the brain if levels are changed abruptly. During HD, blood urea levels drop suddenly and significantly and cerebral edema may develop (dialysis disequilibrium syndrome). This effect may counteract the fluid shift out of the brain during correction of hyponatremia. Therefore, theoretically, uremic patients may be less prone to develop demyelination. We present a patient with renal failure whose hyponatremia was corrected rapidly during HD to illustrate the potential problem. The patient tolerated rapid correction of hyponatremia without sustaining any neurologic damage. We performed a literature search looking for similar case reports and reviewed the scientific evidence behind the above hypothesis.     

Pontine and extrapontine myelinolysis following liver transplantation. Relationship to serum sodium

The relationship between central pontine myelinolysis (CPM) and extrapontine myelinolysis (EPM) and serum sodium changes in the setting of orthotopic liver transplantation (OLT) is examined. Postmortem examination of 14 patients with end-stage liver disease who underwent liver transplantation revealed CPM in four, of which three also had EPM. A retrospective review of clinical and laboratory data was performed on all patients. There were marked perioperative rises (21-32 mEq/L) in the serum sodium concentration in all four patients who developed myelinolysis. In contrast, the largest increase in sodium in patients without demyelination was 16 mEq/L. We conclude that perioperative rises in the serum sodium concentration increase the risk of myelinolysis. CPM and EPM should be considered if the patient develops mental status changes or focal neurological deficits several days after OLT.     

Minocycline protects against neurologic complications of rapid correction of hyponatremia

Osmotic demyelination syndrome is a devastating neurologic condition that occurs after rapid correction of serum sodium in patients with hyponatremia. Pathologic features of this injury include a well-demarcated region of myelin loss, a breakdown of the blood-brain barrier, and infiltration of microglia. The semisynthetic tetracycline minocycline is protective in some animal models of central nervous system injury, including demyelination, suggesting that it may also protect against demyelination resulting from rapid correction of chronic hyponatremia. Using a rat model of osmotic demyelination syndrome, we found that treatment with minocycline significantly decreases brain demyelination, alleviates neurologic manifestations, and reduces mortality associated with rapid correction of hyponatremia. Mechanistically, minocycline decreased the permeability of the blood-brain barrier, inhibited microglial activation, decreased both the expression of IL1α and protein nitrosylation, and reduced the loss of GFAP immunoreactivity. In conclusion, minocycline modifies the course of osmotic demyelination in rats, suggesting its possible therapeutic use in the setting of inadvertent rapid correction of chronic hyponatremia in humans.     

Central and extrapontine myelinolysis in a patient in spite of a careful correction of hyponatremia

We report the case of a 54-year-old alcoholic female patient who was hospitalized for neurologic alterations along with a severe hyponatremia (plasma Na+: 97 mEq/l). She suffered from potomania and was given, a few days before admission, a thiazide diuretic for hypertension. A careful correction of plasma Na+ levels was initiated over a 48-hour period (rate of correction < 10 mEq/l/24h) in order to avoid brain demyelination. After a 2-day period of clinical improvement, her neurologic condition started to deteriorate. By the 5th day of admission, she became tetraplegic, presented pseudobulbar palsy, ataxia, strabism, extrapyramidal stiffness and clouding of consciousness. Scintigraphic and MRI investigations demonstrated pontine and extrapontine lesions associated with Gayet-Wernicke encephalopathy. After correction of ionic disorders (hyponatremia, hypokaliemia) and vitamin B (thiamine) deficiency, the patient almost completely recovered without notable disabilities. This case illustrates that profound hyponatremia, in a paradigm of slow onset, can be compatible with life. It also demonstrates that demyelinating lesions, usually considered as a consequence of a too fast correction of hyponatremia, may occur despite the strict observance of recent guidelines. There is increasing evidence to suggest that pontine swelling and dysfunction may sometimes occur in alcoholic patients even in absence of disturbance in plasma Na+ levels. It is therefore of importance, while managing a hyponatremic alcoholic patient, to identify additional risk factors (hypokaliemia, hypophosphoremia, seizure-induced hypoxemia, malnutrition with vitamin B deficiency) for brain demyelination and to correct them appropriately.     

A proposed approach to the dialysis prescription in severely hyponatremic patients with end-stage renal disease

Patients with renal failure and severe hyponatremia present a therapeutic dilemma. Conventional hemodialysis is necessary to correct blood chemistries and volume overload, yet it may raise serum sodium (Na) too quickly, potentially resulting in osmotic demyelination syndrome. We present the case of a patient who presented with renal failure requiring dialysis and also with a serum Na of 112 mEq/l. Using a dialysate Na concentration of 130 mEq/l and by limiting the blood flow to 50 ml/minute, we were able to raise her serum Na by only 2 mEq/l/hour during her hemodialysis treatment and thus control both the rate and total change in the patient's serum Na.     

Hypercalcemia and acute renal failure caused by production of parathyroid hormone-related protein from renal cell carcinoma

A 69-year-old male patient was diagnosed with right-sided renal cell carcinoma and humoral hypercalcemia of malignancy caused by an excessive production of parathyroid hormone-related protein. The hypercalcemia led to acute tubular necrosis, so the patient had to be put on hemodialysis. The renal failure was accompanied by hyponatremic encephalopathy. Rapid correction of the hyponatremia might have initiated central pontine myelinolysis.     

Central pontine myelinolysis after orthotopic liver transplant-a rare complication

Central pontine myelinolysis is a rare but devastating cause of morbidity and mortality after orthotopic liver transplant. The exact cause of central pontine myelinolysis is uncertain. However, rapid correction of hyponatremia has been described as a major factor. We describe a patient with central pontine myelinolysis after orthotopic liver transplant in the absence of significant hyponatremia. Although rapid correction of hypernatremia has been reported in association with central pontine myelinolysis, to our knowledge, in this case, where the serum sodium went from normal to hypernatremic, later diagnosis of central pontine myelinolysis in a postliver transplant setting is unique. We also discuss factors that may contribute to the development of central pontine myelinolysis after orthotopic liver transplant and its pathophysiology.     

Astrocytes are an early target in osmotic demyelination syndrome

Abrupt osmotic changes during rapid correction of chronic hyponatremia result in demyelinative brain lesions, but the sequence of events linking rapid osmotic changes to myelin loss is not yet understood. Here, in a rat model of osmotic demyelination syndrome, we found that massive astrocyte death occurred after rapid correction of hyponatremia, delineating the regions of future myelin loss. Astrocyte death caused a disruption of the astrocyte-oligodendrocyte network, rapidly upregulated inflammatory cytokines genes, and increased serum S100B, which predicted clinical manifestations and outcome of osmotic demyelination. These results support a model for the pathophysiology of osmotic brain injury in which rapid correction of hyponatremia triggers apoptosis in astrocytes followed by a loss of trophic communication between astrocytes and oligodendrocytes, secondary inflammation, microglial activation, and finally demyelination.     

Apparent diffusion coefficient map based on diffusion-weighted magnetic resonance imaging is useful in diagnosing the brainstem variant of reversible posterior leukoencephalopathy syndrome with uremia

A 54-year-old Japanese man entered our hospital for investigation of appetite loss. His blood pressure was 201/113 mmHg, and laboratory findings revealed renal failure and hyponatremia. On physical examination, disorientation and dysarthria were observed. Hemodialysis was performed the same day. Magnetic resonance imaging (MRI) after hemodialysis revealed swelling of the brainstem and a high signal intensity on fluid-attenuated inversion recovery (FLAIR) imaging, similar to findings of central pontine myelinolysis (CPM), which is generally irreversible. However, on an apparent diffusion coefficient (ADC) map based on diffusion-weighted MRI, higher signal intensity was observed in the area of the high signal intensity on FLAIR imaging, which is not seen in CPM. The abnormal neurological symptoms improved within a few days, and MRI findings also normalized. We diagnosed the lesion as the brainstem variant of reversible posterior leukoencephalopathy syndrome (RPLS) with uremia. ADC map was very useful in diagnosing RPLS with uremia.     

Diuretic-associated hyponatremia

Soon after their introduction in 1957, thiazide diuretics became a recognized cause of hyponatremia. Thiazides may be the sole cause and they may exacerbate hyponatremia in patients with disorders that cause the syndrome of inappropriate antidiuretic hormone secretion. Although thiazides do not inhibit the ability to concentrate the urine, they impair diluting ability in several ways: inhibition of sodium and chloride transport at cortical diluting sites; stimulation of vasopressin release; reduction of glomerular filtration and enhanced proximal water reabsorption, which reduce delivery to the distal diluting sites; and, possibly, a direct effect on water flow in the collecting duct. Water retention caused by impaired water excretion combined with cation depletion may result in severe hyponatremia. Thiazides should be avoided in frail elderly patients with chronically high water intake or in others who depend on the excretion of maximally dilute urine to maintain fluid balance, such as patients with psychogenic polydipsia or heavy beer drinking. Inadvertent rapid correction of hyponatremia is common in thiazide-induced hyponatremia because the ability to dilute the urine is restored when the diuretic is discontinued and volume deficits are repaired. Hypokalemia, which often is present, increases the susceptibility to osmotic demyelination syndrome and replacement of potassium deficits contributes to the increase in serum sodium concentration.     

我国肝移植受者继发中枢神经系统脱髓鞘疾病回顾性分析

目的探讨我国肝移植受者继发中枢神经系统脱髓鞘疾病（DDCNS）的发病情况、临床表现及影响预后的相关因素。方法利用PubMed、中国知网和万方数据库检索2000—2011年中国（不包括港澳台地区）肝移植受者继发DDCNS相关病例报道,进行回顾性分析。结果纳入2000—2011年12家移植中心发表的13篇文献,共报道44例肝移植受者继发DDCNS。围手术期低钠血症纠正过快及术前存在肝性脑病史者分别占全部病例的77.4%和45.2%,与术后神经系统症状出现时间相关（P〈0.05）;合并感染及肾衰竭者分别占71.0%和38.7%,与临床结局有关（P〈0.05）。结论肝移植受者继发DDCNS与围手术期低钠血症纠正过快及术前存在肝性脑病有关。感染和肾衰竭等并发症影响患者预后,需要临床医师重视。     

Postoperative hyponatremia in children: pathophysiology, diagnosis and treatment

OBJECTIVES: To review the current data on pathophysiology, causes and management of postoperative hyponatremia in children. DATA SOURCES AND EXTRACTION: The Pubmed database was searched for articles, combined with references analysis of major articles on the field. DATA SYNTHESIS: The incidence of postoperative hyponatremia has been evaluated at 0.34% and its mortality significant. Postoperative hyponatremia is triggered by the diminished renal ability to excrete free water, due to antidiuretic hormone release. Inappropriate secretion of antidiuretic hormone is frequently seen after spine, cardiac and neurosurgery but can occur even after minor surgery. In this context, the infusion of hypotonic fluids represents a strong risk factor for developing hyponatremia. Other causes of hyponatremia are represented by extrarenal fluid losses, cerebral salt wasting syndrome, desalination phenomenon, adrenal insufficiency or some medications. Preventive treatment is essential and based on prohibition of hypotonic fluids infusion and the use of isotonic fluids infusions, maintenance of a normal total blood volume, the observance of the good practice recommendations for fluid infusion in children, and frequent blood and urine sodium concentration determinations in patients at risk for developing hyponatremia. Hyponatremic encephalopathy requires an emergent management, consisting in respiratory care and hypertonic sodium chloride infusion. Chronic hyponatremia is most often asymptomatic and the main neurological risk factor is represented by a too rapid correction of plasma sodium, which may lead to centropontine myelinolysis.     

Utility of Tolvaptan in the Perioperative Management of Severe Hyponatremia During Liver Transplantation: A Case Report

Severe hyponatremia can complicate the pretransplantation management of patients with decompensated cirrhosis while they await liver transplantation. Before the liver transplant, it is critical to correct severe hyponatremia to an appropriate level to reduce the risks of perioperative complications such as central pontine myelinolysis, cerebral edema, and seizures. Vasopressin receptor antagonists, and in particular tolvaptan, offer a therapeutic modality that can correct severe refractory hyponatremia in a timely and predictable manner before liver transplantation. In this case report, we describe a patient with decompensated cirrhosis and severe hyponatremia in whom administration of tolvaptan led to an optimal correction of preoperative severe hyponatremia and allowed for successful liver transplantation with no associated postoperative complications. In light of the increasing pretransplantation disease severity and higher risk of severe hyponatremia, the use of tolvaptan in the pretransplant period may gain increasing importance as a therapeutic intervention for maintaining peritransplant sodium homeostasis.     

Rapid (24-hour) reaccumulation of brain organic osmolytes (particularly myo-inositol) in azotemic rats after correction of chronic hyponatremia

It was recently demonstrated that renal failure and exogenous urea prevent myelinolysis induced by rapid correction of experimental hyponatremia. To determine why elevated blood urea levels favorably affect brain tolerance to osmotic stress, the changes in brain solute composition that occur when chronic hyponatremia is rapidly corrected were studied in rats with or without mercuric chloride-induced renal failure. After 48 h of hyponatremia, the brains of azotemic and nonazotemic animals became depleted of sodium, potassium, and organic osmolytes. Twenty-four hours after rapid correction of hyponatremia, the brains of animals without azotemia remained depleted of organic osmolytes, with little increase in myo-inositol or taurine contents above those observed in animals with uncorrected hyponatremia; brain electrolytes were rapidly reaccumulated, increasing the brain sodium content to a level 17% higher than values for normonatremic control animals. In contrast, within 2 h after correction of hyponatremia, brain myo-inositol contents in azotemic rats returned to control levels and brain taurine levels were significantly higher than those in azotemic animals with uncorrected hyponatremia (16.5 versus 9 micromol/g dry weight). There was no "overshooting" of brain sodium and water contents after rapid correction in the azotemic animals. Rapid reaccumulation of brain organic osmolytes after correction of hyponatremia could explain why azotemia protects against myelinolysis.     

Central pontine myelinolysis following rapid correction of hyponatremia in an alcoholic

An alcoholic patient presented with profound hyponatremia of uncertain etiology. Despite partial correction of hyponatremia within 24 hours, central pontine myelinolysis (CPM) ensued and the patient subsequently died. The optimal rate of correction of severe, symptomatic hyponatremia has not yet been elucidated.     

Minocycline prevents osmotic demyelination syndrome by inhibiting the activation of microglia

Rapid correction of chronic hyponatremia can lead to osmotic demyelination syndrome (ODS), a severe demyelination disease. The microglia that accumulate in the demyelinative lesions may play a detrimental role in the pathogenesis of ODS by producing proinflammatory cytokines, suggesting that they may be a target for therapeutic intervention. Here, we investigated whether minocycline, a selective and potent inhibitor of microglial activation, could protect against ODS in rats. We induced hyponatremia by liquid diet feeding and dDAVP infusion. Rapid correction of the hyponatremia 7 days later resulted in neurologic impairment with severe demyelinative lesions. Activated microglia accumulated at the site of demyelination. Treatment with minocycline within 24 hours of rapid correction, however, was protective: rats exhibited minimal neurologic impairment, and survival improved. Histologic analysis showed that minocycline inhibited demyelination and suppressed the accumulation of microglia at the site of demyelination. Real-time RT-PCR and immunohistochemical analyses showed that minocycline inhibited the activity of microglia and the expression of inflammatory cytokines (e.g. IL-1β, inducible nitric-oxide synthase, and TNF-α), monocyte chemoattractant protein-1, and matrix metalloproteinase-12 in microglia. These results demonstrate that minocycline can protect against ODS by inhibiting the activation and accumulation of microglia at the site of demyelinative lesions, suggesting its possible use in clinical practice.     

Therapeutic relowering of the serum sodium in a patient after excessive correction of hyponatremia.

BACKGROUND: Inappropriate correction of chronic hyponatremia could lead to major neuropathological sequelae. In man, the risk of brain myelinolysis increases strikingly when correction of the serum sodium exceeds 10-15 mEq/l/24 h. No treatment is actually available for this iatrogenic brain injury. However, recent experimental data showed that rapid reinduction of the hyponatremia greatly reduces the incidence of brain damage and death in case of serum sodium overshooting. SUBJECTS AND METHODS: We tested this rescue manoeuver in a 71-year-old woman with nausea, confusion and severe (SNa 106 mEq/l) chronic hyponatremia related to thiazides. It was associated with hypokalemia (SK: 3.2 mEq/l). RESULTS: Treatment with isotonic saline produced inappropriately high SNa correction level of +21 mEq/l after the first 24 h. After initial improvement, the neurological status deteriorated after 72 h. Rapid reinduction of the hyponatremia was then ordered. Administration of hypotonic fluids (by oral and i.v. route) combined with dDAVP induced a prompt decline in the SNa (-16 mEq/l/14 h) with a final gradient of correction of deltaSNa +9 mEq/l. This manoeuver was well tolerated without untoward effects. The natremia then progressively normalized and the patient completely recovered without neurological sequelae. CONCLUSION: Hypotonic fluids may be safely administered to decrease the natremia after excessive correction of hyponatremia for potential prevention of myelinolysis.