Hemophilia and other coagulation disorders: neurologic aspects
Jun. 20, 2022
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Spastic quadriparesis, pseudobulbar palsy, and pseudobulbar affect occurring several days following a rapid rise in serum osmolality are the classical signs of osmotic demyelination syndrome. The author reviews the classic clinical signs and pathophysiology of osmotic demyelination syndrome and includes updates from literature on methods of prevention and potential future treatment options for this infrequent, but preventable, iatrogenic disease.
• All patients with severe hyponatremia receiving intravenous fluids should have serum sodium measured every 4 hours in order to allow for adjustments in fluid administration, if serum sodium should rise at a rate greater than 0.5 mEq/ml per hour.
• The use of desmopressin to limit water diuresis during correction of severe hyponatremia should be considered for prevention of overcorrection.
• Vaptans have been shown to be efficacious and safe in the treatment of hypervolemic and normovolemic hyponatremia.
• Patients with severe hyponatremia and concomitant hypokalemia are at greater risk for developing osmotic demyelination syndrome, and a slower correction than 12 mEq/ml in a 24-hour period should be considered.
• After development of signs or symptoms of osmotic demyelination syndrome, treatment should be mainly supportive, as no large clinical trials have been performed to examine the efficacy of therapeutic relowering of serum sodium, steroids, plasma exchange, or IVIG.
The original description of osmotic demyelination syndrome was by Adams, Victor, and Mancall in 1959 (01). During their studies of the neuropathology of alcoholism, they recognized a peculiar and unique demyelination occurring in the central pons of 4 individuals with alcoholism and malnutrition. They labeled this disorder “central pontine myelinolysis.” Since this original description, demyelination in other areas of the central nervous system associated with osmotic stress has been described encouraging the use of the more general term “osmotic demyelination syndrome” rather than the more restrictive term “central pontine myelinolysis” (45; 38).
The clinical syndrome of osmotic demyelination develops in hospitalized patients several days after a rapid rise in serum sodium (characteristically greater than 12 mEq/ml in a 24-hour period, although cases have been described with slower rates of correction).
Prior to the onset of osmotic demyelination, patients may present with the neurologic signs and symptoms of hyponatremic encephalopathy. These symptoms resolve with normalization of the serum sodium concentration. Three to 5 days later, a second phase of neurologic manifestations occurs correlating with the onset of myelinolysis. The clinical features vary, depending on whether the syndrome consists of central pontine myelinolysis, extrapontine myelinolysis, or both.
The classical clinical presentation of central pontine myelinolysis (osmotic demyelination syndrome) is progressive, spastic quadriparesis, pseudobulbar palsy, and pseudobulbar affect (45).
Other symptoms may include dysarthria, dysphagia, ophthalmoplegia, ataxia, nystagmus, and cranial nerve III palsy (24). Severe cases can result in a “locked-in” syndrome or death (31).
The clinical features of extrapontine myelinolysis vary depending on the location of the lesions, and may include altered mental status, emotional lability, akinetic mutism, gait disturbance, and myoclonus. Movement disorders, including parkinsonism, dystonia, and other extra-pyramidal signs have been described (15). Although not commonly affected by osmotic demyelination syndrome, the spinal cord has also been recognized as a site of extrapontine myelinolysis (26). These manifestations may occur with or without features of central pontine myelinolysis and may also occur in the same time frame.
The prognosis of osmotic demyelination syndrome is variable. Many patients may develop subclinical lesions in the pons that are later noted on an MRI obtained for other reasons or are noted as an incidental finding on autopsy. The prognosis is likely dependent on the size and severity of the demyelination in the central pons. Patients with extremely severe quadriparesis and inability to speak or swallow (such as described in the clinical vignette above) can make an essentially complete neurologic recovery over the course of weeks or months. Other similarly affected patients may have virtually no improvement. Aspiration and the other complications associated with being paralyzed, such as deep venous thrombosis and decubitus ulcers, are among the frequent complications of osmotic demyelination syndrome.
One study of 25 patients with osmotic demyelination syndrome found that 46% of patients had a favorable outcome at follow up 2 years after diagnosis. Severe hyponatremia (< 115 mEq/L), hypokalemia, low GCS scores at presentation, and poor functional independence measure (FIM) scores during hospitalization predicted a poor outcome (27). A review of 38 case series comprising a total of 541 patients revealed that liver transplant patients with osmotic demyelination syndrome have a combined rate of death and disability of 77.4%, compared with 44.7% in those without liver transplantation (P< 0.001) (52).
Diffusion tensor imaging also holds some theoretical promise in understanding the prognosis for functional improvement following osmotic demyelination (32).
A 60-year-old man developed a “viral syndrome” characterized by nausea and vomiting for 8 days. He had been on a thiazide diuretic for mild hypertension. He had no other significant prior medical problems. When he presented to the emergency department, his serum sodium was 105 mEq/ml. He was admitted to the hospital with a diagnosis of dehydration and hyponatremia. He was treated with intravenous normal saline. The next day his serum sodium was 127 mEq/ml. The patient was noted to be lethargic on day 4. On day 5, the patient was noted to be weak in all 4 extremities. The patient also developed speech and swallowing difficulties over the next day. He was also diagnosed as being depressed because of frequent spontaneous crying spells. The patient was transferred to another medical facility for neurologic evaluation 20 days after his admission to the initial hospital. Neurologic examination revealed a severe spastic quadriparesis. He was unable to ambulate. He could not speak or swallow, and a feeding gastrostomy had already been placed. He followed all commands appropriately using eye movements, blinking, head nods, and slight voluntary foot movements. He displayed frequent, brief easily-evoked crying episodes. Clinically, he displayed a severe spastic quadriparesis, pseudobulbar palsy, and pseudobulbar affect. Head CT scan was normal (MRI was not yet available). Over the next several months, his neurologic function slowly returned to normal.
The initial suggestion that an "electrolyte imbalance may be a contributing factor" in the development of central pontine myelinolysis was made by Berry and Olszewski (07). In 1969 Paguirigan and Lefken made the interesting observation that acute cases of central pontine myelinolysis only developed in hospitalized patients who were being hydrated (44). Leslie and colleagues (34) noted that in 12 cases of acute central pontine myelinolysis, there had been a recent rapid rise of serum sodium in each patient and suggested that central pontine myelinolysis "is an iatrogenic disorder that in most cases is caused by a rapid correction of serum sodium rather than by hyponatremia per se." The factors that led to the appearance of the disorder during the 1950s were the introduction of diuretics, the liberal use of intravenous fluids, and the ability to rapidly measure serum electrolytes (45).
Neurologic complications were noted in 8 patients whose serum sodium had been corrected by more than 12 mEq/liter per day (58). Conversely, uncomplicated recoveries were noted in patients in whom hyponatremia was corrected more slowly than by 12 mEq/liter per day. In a literature review of 80 patients with severe hyponatremia (serum sodium less than 106 mEq/liter), enough detail was reported in 51 patients to determine a maximal rate of correction of serum sodium. In 39 of 51 patients who were corrected rapidly (more than 12 mEq/liter per day), 22 (58%) had some type of neurologic complication (58). Of these 22 patients with neurologic complications, 14 (64%) were suspected of having central pontine myelinolysis. Of the 13 patients who were corrected slowly (less than 12 mEq/liter per day), none experienced a neurologic complication. Prospective magnetic imaging studies have now also demonstrated the development of characteristic pontine lesions in patients treated for hyponatremia in whom the rate of correction of the hyponatremia was rapid (09).
Not all (or even a large proportion of) patients with a rapid increase of their serum sodium will develop osmotic demyelination syndrome. Consequently, other factors may be important, including other electrolytes. Hypokalemia is thought to have a significant impact on the likelihood of developing osmotic demyelination syndrome. In 1 study of published reports of patients with central pontine myelinolysis in whom initial values of sodium and potassium were given, all patients who developed central pontine myelinolysis were initially hypokalemic (36). The role of hypokalemia in development of osmotic demyelination syndrome may be related to the risk of overcorrection of concomitant hyponatremia caused by potassium repletion without adequate free water replacement (06). Magnesium administration has been implicated in a report of 1 patient with central pontine myelinolysis (46). Hypophosphatemia may also contribute to the risk of developing osmotic demyelination syndrome (64). Hyperosmolar hyperglycemic state has also been described in association with osmotic demyelination (23).
Central pontine myelinolysis has been reported to occur in spite of slow correction of hyponatremia (33). Patients undergoing liver transplantation are particularly vulnerable to develop osmotic demyelination syndrome (14).
Patients who develop hypernatremia rapidly are also at risk of osmotic demyelination syndrome (39).
The pathological feature of osmotic demyelination syndrome is noninflammatory demyelination with relative sparing of neurons and axons. This demyelination is most frequently seen in the central pons. Noninflammatory demyelination has also been described in other areas of the central nervous system where there is also an admixture of gray and white matter as is seen in the central pons (68; 22; 21). These extrapontine sites include the lateral geniculate bodies, the external, extreme, and internal capsules, the basal ganglia, splenium of the corpus callosum, and the superior vermis of the cerebellum.
Animal models of central pontine myelinolysis (29) have been developed in the dog and rat. In both animals, demyelination follows rapid correction of sustained, vasopressin-induced hyponatremia with hypertonic saline (28; 30). Rapid correction of chronic hyponatremia is much more likely to result in myelinolysis (42). Disruption of the blood-brain barrier may be important in the pathogenesis of osmotic demyelination syndrome (50). The role of organic osmolytes and brain amino acids in chronic hyponatremia and osmotic demyelination syndrome has not been defined (63; 35).
Myelinolysis in animals may also be induced with rapid hypernatremia (55). Myelinolysis occurs in areas of the brain characterized by an extensive admixture and apposition of gray and white matter. The topography of oligodendrocytes may play a role; oligodendrocytes in vulnerable areas are predominantly located within adjacent gray matter, rather than within the white matter bundles. Because gray matter is much more vascular than white matter, oligodendrocytes in this location may be more vulnerable to serum osmotic shifts (47). Rapid correction of hyponatremia triggers apoptosis in astrocytes, which is followed by loss of trophic communication between astrocytes and oligodendrocytes, secondary inflammation, microglial activation, and demyelination (19). Work in a rat model has suggested that osmotic stress may cause protein aggregation and ubiquitination, and that demyelination may be a consequence of proteostasis failure (17).
Definitive epidemiological information concerning the incidence of osmotic demyelination syndrome does not exist. However, following its original description in 1959, many additional cases of central pontine myelinolysis were reported suggesting that osmotic demyelination syndrome was not a rare disorder. Moreover, it also quickly became evident that not all cases of central pontine myelinolysis were associated with alcoholism or malnutrition, suggesting that osmotic demyelination syndrome could occur in any condition associated with rapid shifts in serum osmolality. A relatively high frequency of small “subclinical” lesions has been noted in pathological series (13; 21). A study of 255 patients who presented to 2 large teaching hospitals between 2000 and 2007 with serum sodium less than 120 mmol/L found that inappropriately rapid correction of serum sodium (> 12 mmol/L over the first 24 hours) occurred in 37 patients (15%), with 4 patients (11%) developing osmotic demyelination. Patients who developed osmotic demyelination were more likely to be younger, abuse alcohol (3 of 4 patients), and have lower serum potassium levels (65).
A nationwide study in Sweden identified 83 individuals diagnosed with osmotic demyelination syndrome between 1997 and 2011 for an overall incidence rate of 0.611 per million person/years (02). Most cases were hyponatremic with a medium sodium level of 104 mmol/L, all of which were chronic, and the majority alcoholics. Hyponatremic patients were treated mainly with isotonic saline and a minority with hypotonic fluids with a median correction rate of 0.72 mmol/L/h, although only 6 patients were corrected within the national treatment guidelines of less than or equal to 8 mmol/L/24h. At 3 months, most patients (60.2%) survived and became functionally independent, whereas 7.2% died.
The prevalence of osmotic demyelination syndrome from a large cohort of 547,544 hospitalized patients with cirrhosis revealed the condition to be very rare, with only 94 patients (0.02%) identified with the condition. Among this population, alcohol-related cirrhosis, younger age, and female gender were more commonly associated with the disease (08).
Because chronic hyponatremia is less likely to produce neurologic symptoms and rapid correction of chronic hyponatremia is more likely to produce osmotic demyelination syndrome, a judicious approach to the correction of chronic hyponatremia is strongly recommended. There appears to be no justification for using hypertonic saline to treat relatively asymptomatic hyponatremia or to rapidly correct hyponatremia to levels above 120 to 125 mEq/liter in symptomatic hyponatremia. Because patients with hyponatremia can rapidly correct even with normal saline, serum sodium should be measured every 4 hours in order to allow for adjustments in fluid administration to be made should serum sodium rise at a rate greater than 0.5 mEq/ml per hour. Sterns and colleagues have suggested an even slower correction rate for chronic, severe hyponatremia, with a limit of 4 to 6 mEq/L/day increase in serum sodium (57). Guidelines have been published by separate professional organizations from the United States and Europe on the correction of hyponatremia. The limit according to European guidelines is 10 mmol/L per day. The United States guidelines are more specific, with a limit of 10 to 12 mmol/L per day with an additional recommended maximum correction of 8 mmol/L per day in cases where there is a high risk of osmotic demyelination syndrome, such as in patients with hypokalemia, alcoholism, malnutrition, or liver disease (25). The use of desmopressin to limit water diuresis has also come into favor as a means of preventing overcorrection of severe hyponatremia (53; 37).
V2-receptor antagonists, or vaptans, have been shown to be safe and effective for treatment of hypervolemic and normovolemic hyponatremia. A study using either 7.5 or 15 mg daily doses of tolvaptan in the emergency department for treatment of moderate to severe euvolemic or hypervolemic hypernatremia in 23 patients revealed that 15 mg/day dosing resulted in a dangerous overcorrection (> 12 mEq/L/24 h) in 41.7% of patients, whereas 7.5 mg/day dosing did not cause any dangerous overcorrections. No cases of osmotic demyelination syndromes were observed in either group after 1 month of follow up (10).
For patients with end-stage kidney disease on hemodialysis, hyponatremia presents a unique challenge due to the risk of overcorrection during dialysis. One proposed method for preventing too rapid of an increase in serum sodium in these patients is to use a dialysate with sodium concentration of 130 mEql/L and limit blood flow to 50 mL/min (66).
Limited evidence suggests that minocycline may be helpful in preventing osmotic demyelination syndrome from water diuresis, and the use of urea for correction of mild chronic hyponatremia has less risk of pathologic change in rat models in comparison to vasopressin antagonists or hypertonic saline (61; 18).
A prospective, multicenter, open-label, randomized clinical trial of 178 adult patients with symptomatic hyponatremia comparing continuous infusion versus rapid intermittent bolus therapy with hypertonic saline revealed that both approaches were effective and safe, with no difference in overcorrection risk (03). Rapid intermittent bolus therapy did have a lower incidence of needing therapeutic relowering and possibly better efficacy, suggesting that this is the preferred treatment of symptomatic hyponatremia (03).
In the appropriate clinical situation and with the classical clinical signs and symptoms, there is little difficulty in arriving at the diagnosis of osmotic demyelination syndrome. However, myelinolysis often occurs in the setting of critical illness, and symptoms may be masked in mechanically ventilated patients receiving paralytics or sedatives or in patients with an underlying metabolic or hypoxic encephalopathy.
MRI is the diagnostic modality of choice for demonstrating demyelination in the central pons that is present in the vast majority of patients with osmotic demyelination syndrome (16).
CT can occasionally demonstrate the lesion in the central pons, but is seldom helpful at the time of initial clinical symptoms.
There have been case reports of localized 18F-fluorodeoxyglucose uptake on positron emission tomography/computed tomography during active central pontine myelinolysis. It is hypothesized that the increased metabolism of attracted glial cells and macrophages as well as activated astrocytes during active disease are responsible for fluorodeoxyglucose uptake (48).
Effective treatment for osmotic demyelination syndrome has not been defined. Current management consists of general supportive care. The rapid reinduction of hyponatremia has been proposed as a potential therapeutic maneuver and has shown a reduction in neurologic signs and symptoms suggestive of osmotic myelinolysis in rats (56). Furthermore, several case reports describe this same technique with variable outcome (54; 69; 43). Therapeutic relowering of serum sodium, however, has not been evaluated in clinical trials. Other described potential therapeutic maneuvers include the protective effect of steroids (59; Murase et al 2006), myoinositol (51), and lovastatin (62) prior to the rapid correction of hyponatremia in rats. Minocycline has also been examined during the early phase of rapid correction and has demonstrated protection from neurologic impairment and improved survival in a rat model (60).
Case reports with positive outcomes with intravenous immunoglobulin (IVIG) (40), plasma exchange (12; 20; 67), and steroids (04) after development of osmotic demyelination syndrome have been reported. However, failure of plasma exchange has also been reported, demonstrating the need for randomized, controlled human clinical trials. to evaluate for effective therapies (41).
To the extent that pregnant women are more likely to develop hyponatremia, such as from hyperemesis gravidarum, pregnancy may carry an increased risk of osmotic demyelination syndrome (11). Few case reports exist; however, a report of a twin pregnancy presenting with central pontine myelinolysis required emergency delivery in order to correct electrolyte and fluid balance, resulting in minimal sequelae for the mother whereas the twins were asymptomatic at 6 months of follow-up (49).
Hyponatremia is a common problem for patients with cirrhosis, and liver disease is also identified as a risk for developing osmotic demyelination syndrome. For patients with end-stage liver disease undergoing transplantation, risk factors for developing osmotic demyelination syndrome include severe pretransplant hyponatremia, the magnitude of change of serum sodium during transplant, higher positive intraoperative fluid balance, and postoperative hemorrhagic complications. It has been suggested that correction of hyponatremia prior to transplant, along with multidisciplinary management to carefully manage fluid and electrolytes during and after surgery are important for minimizing the risk of osmotic demyelination syndrome in this vulnerable population (14).
Osmotic demyelination is less common in children than in adults. A review of all reported pediatric cases of osmotic demyelination syndrome in available English literature revealed that about half present with central pontine myelinolysis, a third with isolated extrapontine myelinolysis, and the remaining with combined central and extrapontine myelinolysis. The review suggests that there is no gender predisposition to osmotic demyelination, the highest prevalence occurred between ages 1 to 5 years, and 60% of children had a complete neurologic recovery. Although MRI is still preferred as the main diagnostic test, diffusion tensor imaging is more often being used for prognostication. Other than supportive care, steroids and intravenous immunoglobulin were used rarely, with optimism that these treatments are potentially helpful, although there remains a lack of controlled studies supporting the effectiveness of these treatments (05).
Nicholas J Beimer MD
Dr. Beimer of the University of Michigan has no relevant financial relationships to disclose.See Profile
Douglas J Lanska MD FAAN MS MSPH
Dr. Lanska of the University of Wisconsin School of Medicine and Public Health, the Medical College of Wisconsin, and IM Sechenov First Moscow State Medical University has no relevant financial relationships to disclose.See Profile
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