Central pontine myelinolysis and the osmotic demyelination syndromes: an open and shut case?

Central pontine myelinolysis and extrapontine myelinolysis are collectively called the osmotic demyelination syndromes. Despite being described in 1959, there are several aspects of the disorder that remain an enigma. Animal models and neuroimaging techniques have allowed us to understand the condition better. From being a universally fatal disorder that was diagnosed post mortem, increased awareness, neuroimaging techniques and supportive care have enabled us to make the diagnosis ante-mortem. This has also led to a significant drop in associated mortality. The aim of this review is to highlight the clinical spectrum, neuroimaging findings, and recent developments.

Lack of astrocytes hinders parenchymal oligodendrocyte precursor cells from reaching a myelinating state in osmolyte-induced demyelination.

Demyelinated lesions in human pons observed after osmotic shifts in serum have been referred to as central pontine myelinolysis (CPM). Astrocytic damage, which is prominent in neuroinflammatory diseases like neuromyelitis optica (NMO) and multiple sclerosis (MS), is considered the primary event during formation of CPM lesions. Although more data on the effects of astrocyte-derived factors on oligodendrocyte precursor cells (OPCs) and remyelination are emerging, still little is known about remyelination of lesions with primary astrocytic loss. In autopsy tissue from patients with CPM as well as in an experimental model, we were able to characterize OPC activation and differentiation. Injections of the thymidine-analogue BrdU traced the maturation of OPCs activated in early astrocyte-depleted lesions. We observed rapid activation of the parenchymal NG2+ OPC reservoir in experimental astrocyte-depleted demyelinated lesions, leading to extensive OPC proliferation. One week after lesion initiation, most parenchyma-derived OPCs expressed breast carcinoma amplified sequence-1 (BCAS1), indicating the transition into a pre-myelinating state. Cells derived from this early parenchymal response often presented a dysfunctional morphology with condensed cytoplasm and few extending processes, and were only sparsely detected among myelin-producing or mature oligodendrocytes. Correspondingly, early stages of human CPM lesions also showed reduced astrocyte numbers and non-myelinating BCAS1+ oligodendrocytes with dysfunctional morphology. In the rat model, neural stem cells (NSCs) located in the subventricular zone (SVZ) were activated while the lesion was already partially repopulated with OPCs, giving rise to nestin+ progenitors that generated oligodendroglial lineage cells in the lesion, which was successively repopulated with astrocytes and remyelinated. These nestin+ stem cell-derived progenitors were absent in human CPM cases, which may have contributed to the inefficient lesion repair. The present study points to the importance of astrocyte-oligodendrocyte interactions for remyelination, highlighting the necessity to further determine the impact of astrocyte dysfunction on remyelination inefficiency in demyelinating disorders including MS.

Temporal evolution of the trident and piglet signs of osmotic demyelination syndrome.

Central pontine myelinolysis (CPM) is a potentially-devastating complication of rapid osmolar shifts, classically attributed to overlyaggressive correction of chronic hyponatremia. Magnetic resonance imaging (MRI) allowed earlier diagnosis of CPM, but most importantly, it has revealed that the odds of good functional recovery are surprisingly high. A trident shaped pontine lesion is a typical finding in CPM (the trident sign). The "piglet sign" is a much less well-known radiologic finding in CPM. Due to the rarity of CPM, very little has been published on the evolution of these MRI findings. We present a case of CPM in an alcoholic young man, and describe the temporal evolution of both the trident and piglet signs on MRI in CPM.

Desmopressin acetate (DDAVP)-associated hyponatremia and brain damage: a case series.

BACKGROUND: Desmopressin (DDAVP) is typically prescribed for central diabetes insipidus, von Willebrands disease and for enuresis. DDAVP-associated hyponatremia is a known complication of DDAVP therapy. The currently recommended treatment for this condition calls for discontinuing DDAVP as part of the initial therapy. This recommendation could lead to a water diuresis and potentially over-correction of the serum sodium. METHODS: The 15 patients in this case series developed symptomatic DDAVP-associated hyponatremia and were admitted to acute care hospitals. Thirty-eight percent presented with symptomatic hyponatremia and 62% developed symptomatic hyponatremia due to concomitant DDAVP and hypotonic intravenous fluid administration during a hospital stay. Group 1 patients (n = 13) were treated by withholding DDAVP and providing intravenous saline. Group 2 patients (n = 2) were treated by continuing DDAVP and providing DDAVP and intravenous hypertonic saline. RESULTS: Among Group 1 patients, in whom DDAVP was withheld as initial management of DDAVP-associated hyponatremia (n = 13), the mean change in serum sodium in the first 2 days of treatment was 37.1 ± 8.1 mEq/L. The ultimate outcome in this group was death in 23%, severe brain damage in 69% and moderate brain damage in 8%. In Group 2 patients, in whom DDAVP was continued (n = 2) as part of the initial management strategy, the mean change in serum sodium was 11.0 ± 0 mEq/L in the first 2 days. The ultimate outcome was survival without neurological sequelae in both cases. CONCLUSIONS: Discontinuing DDAVP in a patient with symptomatic DDAVP-associated hyponatremia can lead to rapid correction of the serum sodium and resultant severe neurological injury. In contrast, continuing the medication while correcting DDAVP-associated hyponatremia may lead to better outcomes by avoiding over-correction of the serum sodium. Thus, an alternative approach that we propose is to continue DDAVP as part of the initial management of this disorder.

Osmotic myelinolysis with malignant cerebellar edema occurring after DDAVP-induced hyponatremia in a child.

Central pontine myelinolysis (CPM) and extrapontine myelinolysis (EPM) are dire neurological disorders, characterized by severe damage to the myelin sheath of neurons, which typically result from rapid correction or overcorrection of systemic hyponatremia. For many years, both conditions have been considered universally fatal, though survivors have been reported more recently. Pediatric cases are rare. We present a 13-year-old boy with panhypopituitarism secondary to repair of a nasofrontal encephalocele in infancy, managed on long-term corticosteroid, deamino arginine vasopressin and thyroid hormone. He presented with severe hyponatremia (116 mEq/l), which during correction rapidly and unexpectedly increased to 176 mEq/l, resulting in profoundly impaired consciousness. Brain imaging revealed multiple bilateral changes in the basal ganglia, thalamus, pons and cerebral white matter, consistent with both CPM and EPM. Malignant cerebellar edema necessitated emergent suboccipital craniectomy, with subsequent improvement in level of consciousness and imaging postoperatively. However, he succumbed to acute cardiorespiratory arrest 8 weeks later. Nine similar cases from the literature are reviewed.

Central pontine myelinolysis after liver transplantation: is sodium the only villain? Case report.

BACKGROUND AND OBJECTIVES: Critically ill patients frequently develop neurologic symptoms, which frequently become a clinical challenge. Described approximately 50 years ago, pontine neuronal demyelination is a pathologic change associated with neurologic and psychiatric problems after liver transplantation. The objective of this report was to present a case of central pontine myelinolysis diagnosed after liver transplantation and to discuss its pathophysiology. CASE REPORT: A 29 years old female patient underwent liver transplantation for fulminant hepatic failure. Postoperatively, she developed neurologic symptoms characteristic of the Locked In Syndrome and the MRI showed changes compatible with central pontine myelinolysis. The patient did not develop dramatic changes in sodium plasma levels, which is frequently incriminated as the causal agent, and improved considerably within a few weeks. CONCLUSIONS: The etiology of central pontine myelinolysis is multifactorial, and special attention should be given to the group of patients at greater risk, such as those with sudden changes in the plasma levels of sodium, liver transplantation, chronic alcoholics, and malnourished. It is important to recognize that osmotic demyelination can develop in patients with low, normal, or elevated plasma levels of sodium, indicating the contribution of other trigger factors.

(99m)Tc-TRODAT-1 and (123)I-IBZM SPECT studies in a patient with extrapontine myelinolysis with parkinsonian features.

Osmotic demyelination syndrome can result from the rapid correction of hyponatremia, and is categorized by central pontine myelinolysis and extrapontine myelinolysis (EPM). Magnetic resonance imaging (MRI) is currently the most useful modality for visualizing EPM lesions. However, MRI is unable to delineate the severity of involvement in the nigrostriatal dopaminergic pathway. The authors describe the case of a 48-year-old woman who developed isolated EPM with predominantly right-sided parkinsonian symptoms after rapid correction of hyponatremia. MRI revealed symmetrical demyelinating lesions in the bilateral striatum without central pontine involvement. (99m)Tc-TRODAT-1 and (123)I-iodobenzamide ((123)I-IBZM) single-photon emission computed tomography (SPECT) images showed unequally decreased uptake in the bilateral striatum. Treatment with carbidopa/levodopa improved the clinical parkinsonian symptoms. (99m)T(C)-TRODAT-1 and (123)I-IBZM SPECT images provide presynaptic and postsynaptic molecular information of the nigrostriatal dopaminergic pathway. The lesions demonstrated in the (99m)T(C)-TRODAT-1 and (123)I-IBZM SPECT images show higher correlation with the severity of clinical features in EPM than MRI, and the modalities may be useful in the evaluation of patients with parkinsonian symptoms.

Osmotic myelinolysis syndrome after treatment of severe deamino arginine vasopressin-associated hyponatraemia: pitfalls in emergency medicine.

Hyponatraemia is among the more common electrolyte abnormalities encountered in the ED. Both the primary disturbance and its correction can result in life-threatening neurological sequelae. Osmotic myelinolysis syndrome is one such complication and is associated with the rapid correction of hyponatraemia. The present case report describes the mechanism of severe hyponatraemia in a patient taking deamino arginine vasopressin, and the subsequent development of both central pontine and extrapontine myelinolysis after rapid correction of sodium levels. Implications for the emergency management of such patients are discussed.

Central pontine myelinolysis.

The case is described of a 46 year old female alcoholic, presenting with confusion, jaundice and reduced level of consciousness. The patient was hyponatraemic on admission and despite gradual correction of serum sodium the patient deteriorated neurologically. Magnetic Resonance Imaging scan of the brain revealed characteristic findings of Central Pontine Myelinolysis (CPM). We provide an overview of the first published cases of CPM. The clinical and pathological features of CPM are described. No specific therapy has been shown to improve outcome; current literature advocates supportive management. Identification of patients at risk and gradual correction of hyponatraemia is recommended.

Overlapping features of extrapontine myelinolysis and acquired chronic (non-Wilsonian) hepatocerebral degeneration.

Central pontine myelinolysis (CPM, osmotic demyelination syndrome) and acquired chronic hepatocerebral degeneration (ACHD) both occur in patients with liver failure, but are not thought to be caused by similar etiopathogenic mechanisms despite the fact that occasional patients exhibit both disorders. In our autopsy practice we have recently encountered three patients with the pontine lesions of acute or subacute osmotic demyelination syndrome, coupled with superimposed non-Wilsonian ACHD. All three patients had well-documented rapid elevations in serum sodium proximate to their demise, as well as terminal liver failure. A close intermingling and juxtaposition of lesions with severe demyelination and macrophage breakdown [thought to represent extrapontine myelinolysis (EPM)] to those with vacuolization of myelin but no cellular reaction or myelin loss (ACHD) was noted within some of the same anatomic areas. Particular overlap was seen in lesions at the cerebral cortical gray-white junction and in pencil fibers of the striatum. In these areas it was difficult to be certain whether the lesions were due to EPM or ACHD. We concluded that there was a synergism between the two disorders and raise the possibility that there may be factors common to both disorders that lead to similar anatomic sites for involvement.

Mechanisms and therapy of osmotic demyelination.

Central pontine myelinolysis (CPM) is a rare but serious demyelinative disease that is associated with rapid correction of chronic hyponatremia. Disruption of the blood-brain barrier (BBB) following a rapid increase in serum sodium concentration is considered to play a critical role in the pathogenesis of osmotic demyelination. We investigated the protective effect of dexamethasone (DEX) on osmotic demyelination in rats. After rapid correction of chronic hyponatremia, rats displayed serious neurologic impairments and demyelinative lesions were observed in various brain regions. Conversely, DEX-treated rats exhibited minimal neurologic impairments and demyelinative lesions were rarely seen in the brain. A marked extravasation of endogenous immunoglobulin G and Evans blue dye were observed in the brains of rats that did not receive DEX, indicating disruption of the BBB, but this was not observed in DEX-treated rats. These results indicate that DEX is effective in preventing osmotic demyelination by inhibiting BBB disruption, and suggest that DEX might be useful for the prevention of CPM in clinical practice.

Decreased striatal dopamine transporter binding in a patient with extrapontine myelinolysis.

We describe the case of a 61-year-old woman who developed extrapontine myelinolysis (EPM) with parkinsonism. Decreased striatal dopamine transporter binding assessed by [(123)I]N-(3-iodopropen-2-yl)-2beta-carbomethoxy-3beta-(4-chlorophenyl) tropane and single photon emission computed tomography ([(123)I]IPT) SPECT) were observed in the patient, suggesting that osmotic injury causes the demyelination of nigrostriatal dopaminergic neurons and that such injury may be involved in the pathogenesis of EPM with parkinsonism.

Evidence for a role for apoptosis in central pontine myelinolysis.

We have performed an immunocytochemical study of autopsy material from five cases of central pontine myelinolysis (CPM) and five age and sex-matched control subjects with the aim of exploring the possible involvement of apoptotic mechanisms in oligodendrocytes in this condition. We searched for immunoreactivity of glial cells for the apoptotic-related markers death receptor (DR) 3, Bax and Bak, the anti-apoptotic marker Bcl-2 and the cell cycle marker Ki-67. The latter marker was studied because it is known that entry of cells into the cell division cycle can trigger apoptosis if it does not result in mitosis. In CPM there was marked up-regulation of expression of the myelination-related enzyme carbonic anhydrase isoenzyme II and also markedly increased expression of Ki-67 in nuclei of glial cells of all types but particularly those of cells morphologically resembling oligodendrocytes. Despite this, there was no clear increase in density of such cells in CPM. The pro-apoptotic markers Bax, Bak and DR3 were all modestly increased in glial cell cytoplasm in CPM, while there was no change in expression of Bcl-2, which was only sparsely detected in glial cells both in controls and cases of CPM. The ratio of pro- to anti-apoptotic factors would appear from this evidence to have altered in favour of apoptosis in glial cells, most of which had the appearance of oligodendrocytes and many of which expressed Ki-67. We interpret this preliminary study as favouring apoptosis as a mechanism of oligodendrocytic death in CPM. Further study of this mechanism in CPM may lead to identification of factors that could reduce or prevent this rare but serious and often fatal disease.

A case of central pontine and extrapontine myelinolysis with early hypermetabolism on 18FDG-PET scan.

We report a 63 year-old woman who developed central pontine and extrapontine myelinolysis after rapid correction of hyponatremia. Lesions on brain MRI showed hypermetabolism on 18FDG-PET scan in the early stage of the disease and became hypometabolic on the follow-up scan. We suggest that active microglia and astrocytes are the main cause of the increased glucose metabolism.