Centropontine myelinolysis related to refeeding syndrome in an adolescent suffering from anorexia nervosa

Centropontine myelinolysis (CPM) is a rare neurologic disorder defined by symmetric demyelination in the central pons, mostly due to alcoholism, malnutrition, or water-electrolyte abnormalities. We report an unusual case of CPM likely due to hypophosphatemia, related to a refeeding syndrome in the context of mental anorexia. A 15-year-old girl with mental anorexia presented with hypophosphatemia in the following days of enteral refeeding, and then suffered from confusion, neurological signs, and typical MRI lesions of CPM. Hypophosphoremia may be considered as a causative agent in CPM related to refeeding syndrome. This clinical observation also highlights the importance of recognizing patients at high risk of refeeding syndrome to initiate a balanced nutrition with careful monitoring.     

Rhabdomyolysis in hypokalaemic periodic paralysis: a clue to the mechanism that terminates the paralytic attack?

Summary The changes in serum levels of myoglobin (Mb) and creatine kinase (CK) during a spontaneous attack of hypokalaemic periodic paralysis were studied. During paralysis, serum Mb and CK were normal. A rise in plasma potassium, resulting in clinical recovery, was associated with a simultaneous rise in serum Mb, and followed by a rise in serum CK. It is postulated that hypokalaemia might cause muscle ischaemia, which would result in an accumulation of free fatty acids (FFA) within the muscle cells. High concentrations of FFA may induce molecular changes and increase the permeability of the sarcolemma. This might be the mechanism by which potassium is released from muscle cells into the circulation and muscle membrane excitability is restored.     

Central pontine myelinolysis in severely burned patients: relationship to serum hyperosmolality

The rapid correction or over-correction of hyponatremia is believed by many to be the crucial factor in the causation of central pontine myelinolysis (CPM). Over a 17-year period we found CPM in 10 (7%) of the 139 burn patients examined postmortem but in only 10 (0.28%) of the 3,528 patients in the general autopsy population (p less than 0.001). Each of the burn patients with CPM had suffered a prolonged, nonterminal episode of extreme serum hyperosmolality, whereas most burn patients without CPM had not suffered such an episode. The histologic age of the lesions correlated with the duration of time between the hyperosmolar episode and death. Hypernatremia, hyperglycemia, and azotemia, alone or combined, accounted for the hyperosmolality. No single electrolyte or metabolic derangement was essential, as in at least one burn patient with CPM the serum sodium, glucose, or blood urea nitrogen was normal during the hyperosmolar episode. Hyponatremia was not present in any burn patient with CPM. We conclude that severely burned patients, like alcoholics, are especially susceptible to CPM, and that in burn patients with CPM there is a striking association with serum hyperosmolality. The data also suggest that the rapid correction of hyponatremia exerts its effects by causing an osmotic shift and not because of any specific property of the sodium ion.     

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.     

Association between rise in serum sodium and central pontine myelinolysis

Twelve hyponatremic patients with central pontine myeliolysis (CPM) showed a rise in serum sodium levels 3 to 10 days (mean, 6) prior to the development of CPM. The increase exceeded 20 mEq/L within 1 to 3 days and was then sustained for an additional 3 to 5 days. In addition, 11 of the 12 CPM patients achieved a sodium value of 147 mEq/L or greater during the period of sodium elevation. The rise in sodium frequently coincided with administration of saline solutions, diuretics, steroids, and lactulose. In contrast, 9 hyponatremic patients who did not have CPM showed sodium increases that were significantly less of slower (or both) following treatment of hyponatremia. Our findings suggest that CPM may be caused by a too rapid or excessive rise in serum sodium from a hyponatremic baseline.     

Neuropeptide Y counteracts the anorectic and weight reducing effects of ciliary neurotropic factor

Ciliary neurotrophic factor (CNTF), a cytokine of the interleukin-6 superfamily, has been shown to induce hypophagia and weight loss. Neuropeptide Y (NPY) and orexin are potent orexigenic signals in the hypothalamus. Anorexia, normally seen in response to infection, injury and inflammation, may result from diminished hypothalamic orexigenic signalling caused by persistently elevated cytokines, including CNTF. To test this hypothesis, we first examined the effects of chronic intracerebroventricular (i.c.v.) infusion of CNTF for 6-7 days on food intake and body weight as well as hypothalamic NPY and orexin gene expression in male rats. Subsequently, the effectiveness of NPY replacement to counteract the effects of CNTF by coinfusion of NPY and CNTF was evaluated. Chronic i.c.v. infusion of CNTF (2.5 microg/day) reduced body weight (14.3% vs control) at the end of 7 days. Food intake remained suppressed for 5 days postinfusion and subsequently gradually returned to the control range by day 7. Serum leptin concentrations in these rats were in the same range seen in control rats. Chronic i.c.v. infusion of higher doses of CNTF (5.0 microg/day) produced sustained anorexia and body weight loss (29% vs controls) through the entire duration of the experiment. This severe anorexia was accompanied by markedly suppressed serum leptin concentrations. Furthermore, CNTF infusion alone significantly reduced hypothalamic NPY gene expression (P < 0. 05) without affecting orexin gene expression. As expected, in fusion of NPY alone (18 microg/day) augmented food intake (191.6% over the initial control, P < 0.05) and produced a 25.1% weight gain in conjunction with a 10-fold increase in serum leptin concentrations at the end of the 7-day period. Interestingly, coinfusion of this regimen of NPY with the highly effective anorectic and body reducing effects of CNTF (5.0 microg/day) not only prevented the CNTF-induced anorexia and weight loss, but also normalized serum leptin concentrations and hypothalamic NPY gene expression. These results demonstrate that chronic central infusion to produce a persistent elevation of the cytokine at pathophysiological levels (a situation that may normally manifest during infection, injury and inflammation) produced severe anorexia and weight loss in conjunction with reduction in both serum leptin concentrations and hypothalamic NPY gene expression. Reinstatement of hypothalamic NPY signalling by coinfusion of NPY counteracted these CNTF-induced responses.     

Central Pontine Myelinolysis in a Patient with Hyperosmolar Hyperglycemia and Consistently Normal Serum Sodium

Introduction  

Central pontine myelinolysis (CPM) is almost always described in association with a disturbance in sodium homeostasis, most commonly rapid correction of chronic hyponatremia. It has only rarely been described in patients with disturbances of serum osmolality in the absence of abnormal serum sodium concentrations.     

Are disturbances in opioid and adrenergic systems involved in the hormonal dysfunction of anorexia nervosa?

Opioid peptides and catecholamines play an important role in the control of appetite, behaviour and hormonal secretion. To evaluate the role of the opioid and adrenergic systems in the hormonal dysfunction of anorexia nervosa (AN), we investigated the effects of naloxone and clonidine on serum GH, LH, FSH, β-endorphin, TSH, prolactin and cortisol concentrations in 35 women with AN.

Basal plasma β-endorphin concentrations were significantly lower than those in healthy controls. The response of β-endorphin to clonidine in the AN patients was increased, whereas the response of β-endorphin to naloxone was decreased.

Basal serum cortisol concentrations were significantly higher in the AN patients than that in the controls. There was significant increase in the cortisol response to naloxone in the controls but a lack of cortisol response to naloxone in the patients with AN.

Naloxone produced a significant increase in LH release in the controls during the luteal phase of the menstrual cycle, as well as in the majority of AN patients. Clonidine caused a diminution of LH in the controls and did not alter LH in the patients. After clonidine injection, a significant increase in GH release was observed in both groups of subjects. If these disturbances persist after normalization of body weight, it might suggest that altered opioid and adrenergic activity is an aetiological factor in the pathogenesis of anorexia nervosa.     

Central pontine myelinolysis

Summary Thirty-seven cases of central pontine myelinolysis (CPM) with miscellaneous underlying disorders were found in 1,000 consecutive autopsies, of which 636 brains were examined. The incidence of CPM in this study was 5.8%. The frequent underlying disorders were malignant neoplasms (43%), chronic pulmonary disease (27%), and chronic renal failure cases under dialysis treatment (14%). Fatty liver cirrhosis due to alcohol abuse was recognized in only one CPM case. In the present study, 78% of the CPM cases revealed either electrolyte disturbances or abnormal blood gas data, such as marked deviation of base excess and/or of serum pH in 62.5%, hyper- or hypochloremia (above 115 mEq/l, below 95 mEq/l) in 47%, hyper- or hyponatremia (above 150 mEq/l, below 130 mEq/l) in 25%, marked hypoxemia (less than 40 mmHg) in 12.5% and hypokalemia (below 3.0 mEq/l) in 9% of the CPM cases. The myelinolytic changes were localized in the basis pontis in 14 of 37 CPM cases and in the basis pontis and the cerebral and/or cerebellar white matter (extrapontine myelinolysis) in the remaining 23 cases. The extrapontine changes were also closely related to the electrolyte disturbances or the abnormal blood gas data. The results of this study suggest that myclin and oligodendrocytes in the basis pontis and cerebral and cerebellar white matter are vulnerable to abnormal levels of serum electrolytes and also to marked changes of the acid-base balance.     

Leptin, neuropeptide Y, and peptide YY in long-term recovered eating disorder patients.

BACKGROUND: Disturbances of leptin, neuropeptide Y (NPY), and peptide YY (PYY) have been found in women who are ill with anorexia or bulimia nervosa. It is not certain whether peptide disturbances are cause or consequence of eating disorders. METHODS: Plasma leptin and cerebrospinal fluid leptin, NPY, and PYY concentrations were measured in women who were recovered from anorexia or bulimia nervosa to determine whether alterations persisted after recovery. RESULTS: NPY, PYY, and leptin concentrations were similar across all diagnostic groups. CONCLUSIONS: Alterations in NPY, PYY, and serum leptin concentrations are probably secondary to pathological eating behaviors. Alterations of these peptides are unlikely to be trait-related disturbances that contribute to the etiology of eating disorders.     

Central pontine myelinolysis

Central pontine myelinolysis (CPM) was initially associated with alcoholism. Subsequently other factors, including rapid reversal of hyponatraemia and extreme serum hypoosmolality associated with severe burns, have been identified as other important factors in its pathogenesis. Extra-pontine lesions have also been described. CPM may be found at autopsy, either having been overlooked during life or as an incidental finding. Its precise incidence is not known but the ability to diagnose it during life has been helped by modern neuroimaging, particularly magnetic resonance imaging (MRI) of the brain stem. In the past the prognosis for CPM was thought to be invariably fatal. It is clear now that with the greater general awareness of the disorder and the ability to diagnose it during life that some degree of recovery is possible. However, the number who do recover and the degree of recovery is not known. We report a 40-year-old man who developed CPM presenting with quadriparesis and inability to speak and swallow. There were risk factors for CPM and the diagnosis was confirmed by MRI scanning. He made a complete recovery although he remains ataxic. We are reporting this case as we believe it is important to make clinicians aware of the potential for recovery of CPM. While no specific treatment has been shown to influence the degree and rate of recovery of the demyelination, the fact that the quadriplegia and bulbar paralysis can recover fully is of considerable importance. In particular, it means that when the diagnosis is made, complete and vigorous nursing and medical care is warranted.     

Biochemical abnormalities of the serum in anorexia nervosa

Biochemical analyses of sera from 27 patients with anorexia nervosa were performed and compared with those of normal female volunteers and other anorectic groups including patients who had undergone digestive tract surgery and patients with malignancies. There were significant increases in gamma-glutamyltranspeptidase, lactate dehydrogenase, glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, cholesterol, and amylase activity and significant decreases in total serum protein, blood sugar, albumin, globulins, and cholinesterase in anorexia nervosa patients compared with normal control subjects. At discharge, these values slightly improved. Similar alterations were also observed in two other anorectic groups. Compared with anorexia nervosa patients, the two other anorectic groups showed a severe reduction in the albumin level and increase in the globulin level. In two other anorectic groups cholesterol levels were lower, and in the malignancy group cholinesterase level was lower than in the anorexia nervosa patients. In anorexia nervosa patients, biochemical abnormalities in the serum were more frequent in total serum protein (93%), blood sugar (85%), and globulins (78%) than in other serum factors, such as blood urea nitrogen (15%), uric acid (15%), and alkaline phosphatase (7%). These results suggest that detection of biochemical abnormalities in the above-mentioned serum factors in routine analyses would be valuable in making an early diagnosis of anorexia nervosa from various anorectic disorders.     

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.     

Current perspectives on behavioural and cellular mechanisms of illness anorexia

Here we review our current understanding of the integration of immune, neural, metabolic and endocrine signals involved in the generation of anorexia during acute infection, with the focus on anorexia elicited by peripheral administration of bacterial lipopolysaccharide (LPS). We chose to limit this review to peripheral LPS-anorexia because the mechanisms underlying this response may also be valid for anorexia during other types of acute or chronic infections, with slight differences in the duration of anorexia, levels of circulating concentrations of pro-inflammatory cytokines and hypermetabolism. Evidence so far indicates that LPS-anorexia is a complex response beneficial to host defence that involves both peripheral and central action of pro-inflammatory cytokines, other immune factors, such as prostanoids, and neurotransmitters, such as serotonin. One interesting characteristic of LPS-anorexia is its sexual differentiation, an aspect mainly mediated by the gonadal hormone estradiol. Understanding the behavioural and molecular mechanisms of LPS-anorexia may even provide useful leads for identifying mechanisms of eating disorders in humans.     

Symptomatic hyponatraemia: can myelinolysis be prevented by treatment?

The treatment of hyponatraemia is controversial because of the risk of causing central or extrapontine myelinolysis (EPM). Rapid correction with hypertonic saline to a low normal sodium level has its proponents; others feel that slow correction to below normal sodium values is preventative. Most investigators feel that overcorrection should be avoided. It is not known whether the magnitude of serum sodium change is more important than the actual rate of correction. We present three patients with hyponatraemia ranging from 103 to 105 mmol/l who were corrected slowly with normal saline, corrected quickly with hypertonic saline, or rapidly overcorrected with hypertonic saline. All became comatose and died; all had EPM with or without central pontine myelinolysis (CPM). The rate of correction, the solution used, or the magnitude of correction did not seem to protect against demyelination. In a review of 67 reported CPM cases since 1983, no patients documented as having CPM or EPM by radiological studies or necropsy were treated with water restriction only. A group of 27 hyponatraemic patients treated only with water restriction and 35 with diuretic cessation alone did not develop CPM or EPM. This may be a reasonable approach to patients with symptomatic hyponatraemia and normal renal function.     

Current perspectives on behavioural and cellular mechanisms of illness anorexia

Here we review our current understanding of the integration of immune, neural, metabolic and endocrine signals involved in the generation of anorexia during acute infection, with the focus on anorexia elicited by peripheral administration of bacterial lipopolysaccharide (LPS). We chose to limit this review to peripheral LPS-anorexia because the mechanisms underlying this response may also be valid for anorexia during other types of acute or chronic infections, with slight differences in the duration of anorexia, levels of circulating concentrations of pro-inflammatory cytokines and hypermetabolism. Evidence so far indicates that LPS-anorexia is a complex response beneficial to host defence that involves both peripheral and central action of pro-inflammatory cytokines, other immune factors, such as prostanoids, and neurotransmitters, such as serotonin. One interesting characteristic of LPS-anorexia is its sexual differentiation, an aspect mainly mediated by the gonadal hormone estradiol. Understanding the behavioural and molecular mechanisms of LPS-anorexia may even provide useful leads for identifying mechanisms of eating disorders in humans.     

Hyponatremia with somnolence due to indapamide]

We report here an 83-year-old woman presenting with somnolence possibly induced by indapamide. She was diagnosed as having hypertension (180/110 mmHg), and 1 mg/day of indapamide was administered starting in October, 2002. Two months later, she complained of nausea, vomiting, and appetite loss and frequently fell down. On admission, she was hypotensive (90/54 mmHg). Neurologically, she was in a somnolent state (Japan Coma Scale 2-20), and showed brisk deep tendon reflexes of both upper limbs with bilateral Chaddock signs. Laboratory examination showed severe hyponatremia (115 mEq/l) and hypokalaemia (2.8 mEq/l). On brain MR imaging, there were no remarkable abnormalities, except for multiple lacunar infarctions. After the administration of indapamide was discontinued, her consciousness level and serum electrolytes immediately returned to normal levels. After a good effect for stroke prevention was reported, indapamide was widely prescribed in combination with angiotensin-converting enzyme (ACE) inhibitors, or angiotensin II receptor blocker (ARB) among the neurologists. We should keep in mind the risk of hyponatremia and hypokalaemia occurring in patients receiving indapamide, especially elderly women.     

被动应力刺激兔冈上肌腱急性断裂修复后腱-骨界面的组织学变化

背景：肩袖损伤治疗的方法很多，但是对其损伤修复机制仍不是非常清楚，尤其是对腱-骨特殊结构的损伤修复机制研究更少。 目的：通过建立兔冈上肌腱急性断裂术后被动应力刺激(CPM)训练实验动物模型，观察被动应力刺激对其腱-骨界面组织学变化的影响，探讨被动应力刺激在肩袖损伤术后康复中的作用。 方法：选取20只成年雄性新西兰白兔，随机选取2只处死作正常对照，余18只白兔建立双侧肩关节行冈上肌腱急性断裂重建模型。1周后拆除石膏，随机选取2只处死作模型对照。余16只白兔随机分为被动应力刺激组8只与非被动应力刺激组8只。被动应力刺激组建模后第2周开始训练；非被动应力刺激组正常笼养。分别于术后第2，4，6，8周训练结束每组分别各处死2只，取材行腱-骨界面大体及组织学观察。 结果与结论：建模后2周，与非被动应力刺激组比较，被动应力刺激组炎症反应较重，术后4周，被动应力刺激组炎症较前明显减轻，术后第6周，被动应力刺激组组织结构学显示成纤维细胞数量较非被动应力刺激组增多，且逐渐有序，术后8周，显示被动应力刺激组成纤维细胞较非被动应力刺激组明显增多，且形状及排列较后者更加有序。结果证实采用被动应力刺激(CPM)对兔冈上肌腱急性断裂重建后进行训练，能够促进其腱-骨修复，从而促进肩袖损伤功能恢复。     

Serum levels of S100B are decreased in chronic starvation and normalize with weight gain

S100B protein is mainly synthesized in glial cells and modulates the balance between cell proliferation and differentiation in neurons and glial cells. However, S100B is not CNS-specific since its production was detected in numerous non-cerebral tissues e.g. adipocytes. In this study we investigated the influence of chronic fasting and subsequent weight gain on serum levels of S100B in patients with anorexia nervosa. We found that nutritional status was an important factor influencing serum levels of S100B.