Clinical manifestations

Presentation and course

Hyponatremic osmotic demyelination. 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 with the onset of myelinolysis. The clinical features vary, depending on whether the syndrome consists of central pontine myelinolysis, extrapontine myelinolysis, or both. Occasional cases are identified incidentally by neuroimaging obtained for other reasons (177).

The classical clinical presentation of central pontine myelinolysis includes progressive spastic quadriparesis, pseudobulbar palsy, and pseudobulbar affect (130).

Other symptoms may include lethargy, dysarthria, dysphagia, ophthalmoplegia, ataxia, nystagmus, oculomotor nerve palsy (109; 60), and various movement disorders, particularly parkinsonism and dystonia (136; 146; 10; 86).

Severe outcomes include the “locked-in” syndrome and death (85).

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 extrapyramidal signs have been described (39). Although not commonly affected by osmotic demyelination syndrome, the spinal cord has also been recognized as a site of extrapontine myelinolysis (66). These manifestations may occur with or without features of central pontine myelinolysis and may also occur in the same time frame.

Hypernatremic osmotic demyelination. Severe postpartum hypernatremia may present as an encephalopathy with rhabdomyolysis and diffuse white matter hyperintensities on MRI compatible with osmotic demyelination (112; 139; 21; 126; 11; 32; 160; 33; 71). Other causes of severe hypernatremia have also been associated with osmotic demyelination syndrome (see "Etiology and pathogenesis" section).

Prognosis and complications

The prognosis of osmotic demyelination syndrome is variable and probably depends on the size and severity of the demyelination in the central pons. Some affected individuals develop only 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. Some patients with extremely severe quadriparesis and inability to speak or swallow can make an essentially complete neurologic recovery over the course of weeks or months, whereas other similarly affected patients may have virtually no improvement. Aspiration and other complications associated with being paralyzed (eg, 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% had a favorable outcome at follow-up 2 years after diagnosis. Predictors of poor outcome were severe hyponatremia (< 115 mEq/L), hypokalemia, low Glasgow Coma Scale scores at presentation, and poor functional independence measure scores during hospitalization (72). 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%, compared with 45% in those without liver transplantation (P< 0.001) (147).

Diffusion tensor imaging may help clarify the prognosis for functional improvement following osmotic demyelination (88).

Clinical vignette

Case 1: Osmotic demyelination syndrome after correction of severe hyponatremia and hypokalemia in hyperemesis gravidarum (34). A 21-year-old woman was hospitalized for severe hyperemesis in the 10th week of gestation. At admission, she was restless and confused, with severe hyponatremia (serum sodium 107 mmol/L) and hypokalemia (serum potassium 1.1 mmol/L). Active and simultaneous correction of these imbalances caused an overly rapid increase in serum sodium levels (10 mmol/L in the first 6 hours and 17 mmol/L in the first 24 hours).

The isotonic saline solution was stopped and replaced by 5% dextrose solution infusion. However, her neurologic abnormalities worsened with the development of hypotonia, tremor, and involuntary muscle spasms.

The pons appeared normal on T2-weighted, FLAIR, and T1-weighted images. However, brain MRI revealed bilateral increased signal intensity of the lenticular nuclei, claustrum, and caudate nuclei on axial T2-weighted and FLAIR images. The T1-weighted images showed moderate hypointensity in the same nuclei.

These foci did not enhance with Gd-DTPA. The radiological features were consistent with the diagnosis of extrapontine osmotic demyelination syndrome.

Intravenous steroid administration was followed by progressive improvement of biochemical and clinical abnormalities. At discharge 20 days later, she could eat and walk with minimal external support. The patient delivered a healthy boy at 36 weeks of gestation by cesarean section, and at the 4-month follow-up evaluation, the child appeared to be healthy. Unfortunately, even with physical therapy, the mother achieved only mild improvement in her neurologic deficits.

Case 2: Development of parkinsonism in a patient with central pontine myelinolysis (10). A 69-year-old man with a long personal history of type II diabetes, hypertension, hypercholesterolemia, peripheral arterial obstruction, and depression had worked with glues and cement for about 40 years. He had no family history of neurologic diseases. In 2007, he was referred for evaluation of a 10-year history of severe daily headaches described as an “increasingly strange sensation of pain in the head." His medication history included clomipramine (for about 10 years), fluoxetine, several benzodiazepines (lorazepam, delorazepam, oxazepam), and olanzapine (for about 1 year). Cognitive function, cranial nerves, and upper and lower limb function were normal. Brain MRI disclosed a pontine lesion compatible with central pontine myelinolysis as well as multifocal cerebral ischemic lesions, attributable to his long history of hypertension and type II diabetes.

At age 71, asymmetric signs of parkinsonism (left-sided rigidity and bradykinesia) were noted during clinical evaluation. Levodopa/carbidopa was started, and the symptoms improved. A DaT-Scan SPECT revealed a moderate asymmetric reduction of pre-synaptic dopamine transporters in the right striatum.

The symptoms slowly worsened, and when the patient was last evaluated in 2019, the neurologic assessment showed hypomimia with stuttering and mild-moderate bilateral bradykinesia and rigidity, both more prominent on the left side. No rest tremor was present. He could only stand up from a chair with the help of his arms. His posture was moderately stooped without postural reflex impairment. His left foot did not clear the floor while walking. He had no sensory disturbances. He remained independent in activities of daily living and was almost independent in instrumental activities of daily living. He did not complain of daytime sleepiness, and a polysomnographic investigation showed no evidence of REM sleep behavioral disorder. Myocardial scintigraphy (123I-MIBG) was normal, with no evidence of cardiac adrenergic denervation. Satisfactory motor symptom control was achieved with low-dose levodopa/carbidopa.

Case 3: Osmotic demyelination syndrome in an alcoholic patient with rest tremor (06). A 49-year-old woman presented to an emergency department with 3 days of confusion, dysarthria, tremor, and imbalance. She had been discharged 6 days earlier from another hospital after an admission for alcohol withdrawal. She had returned to that facility twice the following week, complaining of progressive incoordination and weakness. Her husband had reported needing to carry her around the house. She denied alcohol consumption since her previous hospitalization.

Her examination was significant for horizontal gaze-evoked nystagmus, mild dysarthria, a resting tremor of both arms, and ataxia with heel-to-shin testing.

Post-contrast MRI of the brain showed enhancement of the pons with sparing of the corticospinal tracts and peripheral pontine fibers. These imaging findings have been described as a “trident sign” or “pig snout” due to their characteristic shape (73).

Case 4: Osmotic demyelination syndrome after transcatheter aortic valve replacement (TAVR) (70). A 64-year-old woman was admitted with a 2-month history of chest tightness, dyspnea, and fatigue, which had worsened in the 3 days prior to presentation. Auscultation revealed crackles in the lung fields, and systolic murmurs could be easily heard in the aortic area. Chest x-ray showed pulmonary edema, and transthoracic echocardiography showed severe aortic stenosis.

Her serum sodium was 135 mmol/L. Despite a diuretic, her symptoms worsened. She became hypotensive and unresponsive to dobutamine, prompting an emergency TAVR with extracorporeal membrane oxygenation support. Postoperatively, her urine output increased markedly, and serum sodium increased sharply from 140 to 172 mmol/L.

Because she remained unconscious, two CT scans were performed but these were unrevealing. MRI showed multiple lesions in the pons suggestive of osmotic demyelination syndrome.

Case 5: Stuttering subacute onset of osmotic demyelination syndrome confused with motor neuron disease and cerebrovascular disease (122). A 48-year-old man with no prior history of diabetes presented with complaints of generalized limb weakness and incoordination of about 1-month duration. No focal neurologic deficit was identified on examination, but his laboratory studies revealed a severely elevated blood glucose of 608 mg/dL with HgbA1c of 14.7%, a corrected sodium level of 133 mmol/L, and normal serum potassium of 3.8 mmol/L (122). T2-weighted MRI showed pontine hyperintensities on the initial imaging.

His hyperglycemia was treated, and he was discharged home on an oral hypoglycemic agent, but he was not compliant with this medication.

He was lost to follow-up until 2 months later when he again presented to an emergency room. He complained of several months of progressive symmetric generalized limb weakness, with a 1-month history of slurred speech, labile emotions, and uncontrollable laughter. Examination disclosed pseudobulbar palsy, quadriparesis, diffuse hyperreflexia, fasciculations in the right lower extremity, extensor plantar response, ataxia, and decreased vibration in the legs. He was wheelchair-bound. Laboratory data revealed hyperglycemia (serum glucose 391 mg/dL with HgbA1c 12.4%), normal serum sodium (136 mmol/L), and normal serum potassium (3.7 mmol/L). The initial working diagnosis was motor neuron disease because of the upper and lower motor neuron signs, but electromyography was inconsistent with this and instead showed a mild predominant sensory axonal length-dependent polyneuropathy. MRI of the brain showed an area of worsening signal hyperintensity in the central pons on T2-weighted and FLAIR sequences.

There was also restricted diffusion in the central pons on diffusion-weighted imaging with no apparent diffusion coefficient correlation. A subacute brainstem stroke was considered, but the pattern and central location of the pontine lesion with no apparent diffusion correlate were against a vascular etiology. With the central pontine location of the signal abnormalities and the specific imaging characteristics (T2-weighted signal intensity with restricted diffusion on DWI), he was diagnosed with central pontine myelinolysis.

Although he clinically improved with treatment of his hyperglycemia, his ataxia persisted. He was discharged to inpatient rehabilitation. At a follow-up clinic visit, he could ambulate unassisted, and his HgbA1c was 7%.

Case 6: Postpartum hypernatremia with extrapontine myelinolysis and rhabdomyolysis (33). A 29-year-old postpartum woman, G2P1A0, was brought to the emergency department in an unconscious state after a 4- or 5-day history of fever and decreased urine output. Nine days before this, she had an apparently uncomplicated full-term vaginal delivery. On examination, she had a fever of 104.6F (40.3C) and was tachycardic (144 beats per minute) but was normotensive (100/68 mmHg) without any vasopressors. She had no nuchal rigidity. Her Glasgow Coma Scale score was 7 (E2V1M4). She responded to painful stimuli by opening her eyes (without a verbal response) and normally flexing her limbs. Her pupils were equal and reactive to light. Plantar response was flexor. Based on her GCS score, she was intubated and placed on mechanical ventilation. Her provisional diagnosis was meningoencephalitis, so she was started on ceftriaxone 2 g intravenously twice a day.

CT of the brain was normal.

Laboratory studies showed severe hypernatremia (serum sodium 182meq/L), plasma hyperosmolality (439 mOsmol/kg, with normal values typically from 275 to 295 mOsm/kg), normal urine osmolality (782 mOsmol/kg), leukocytosis (total white blood cell count 16,680/mL), azotemia (blood urea nitrogen 171 mg/dL; serum creatinine 2.56 mg/ dL), and rhabdomyolysis (serum creatinine phosphokinase 475 IU; serum lactate dehydrogenase 1229 IU/L; urine myoglobin 1200 ng/mL). CSF biochemical studies and cell counts were normal. All cultures were sterile.

Intravenous administration of balanced crystalloids was started. A nasogastric tube was inserted, and free water replacement was started because the total free water deficit was calculated to be approximately 7.8 L. Serial monitoring of serum sodium was conducted using arterial blood gas analysis.

The rate of sodium correction was kept below 1 mEq/L/h. Over the next days, her serum sodium level dropped to 142 mEq/L. Sedation was stopped, and weaning trials were attempted. She could follow verbal commands by opening and closing her eyes and could identify her relatives by nodding her head. However, she was nearly quadriplegic, with muscle power between 1/5 to 2/5 in all four limbs.

MRI of the brain and spine revealed abnormal hyperintense signals involving the middle cerebellar peduncles, splenium of the corpus callosum, and posterior limb of the internal capsule.

FLAIR images revealed hyperintense signal and restricted diffusion along the corticospinal tract involving the centrum semiovale, corona radiata, posterior limb of the internal capsule, and crus cerebri, giving a "wine-glass" appearance on coronal images. Symmetrical signal changes also involved the middle cerebellar peduncles and the splenium of the corpus callosum. Gradient images showed microhemorrhages in the involved region.

The final diagnosis was postpartum hypernatremic encephalopathy with osmotic extrapontine myelinolysis and rhabdomyolysis (“rhabdomyelinolysis”).

Considering the bulbar involvement, she could not be readily extubated, so percutaneous tracheostomy was performed on day 12. She was then weaned from the ventilator. As she could not swallow semisolids, a percutaneous endoscopic gastrostomy was performed for long-term feeding.

She gradually improved while still in the intensive care unit. By the time of discharge to rehabilitation, she could sit with support, and her muscle power improved to grade 3/5 in the arms and grade 2/5 in the legs.

Biological basis

Etiology and pathogenesis

Central pontine myelinolysis is commonly associated with rapid correction of chronic hyponatremia but has been reported despite appropriate or even slow correction of hyponatremia (89; 99; 67; 140; 166; 129). Rapid correction of hyponatremia exerts its effects by causing an osmotic shift and not because of any specific property of the sodium ion per se (102).

Neurologic complications were noted in 8 patients whose serum sodium had been corrected by more than 12 mEq/liter per day (157). 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 < 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 neurologic complication (157). Of these 22 patients with neurologic complications, 14 (64%) were suspected of having central pontine myelinolysis. None of the 13 patients who were corrected slowly (< 12 mEq/liter per day) experienced a neurologic complication. Prospective MRI studies have also demonstrated the development of characteristic pontine lesions in patients treated for hyponatremia in whom the rate of correction of the hyponatremia was rapid (25).

Not all (or even a large proportion of) patients with a rapid increase in serum sodium develop osmotic demyelination syndrome. Consequently, other etiologic factors, including other electrolytes, may be operative. Hypokalemia appears to significantly impact the likelihood of developing osmotic demyelination syndrome (95; 92; 18; 37; 104). In a 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 (95). In some cases, hypokalemia may contribute to the development of osmotic demyelination syndrome by overcorrection of concomitant hyponatremia caused by potassium repletion without adequate free water replacement (18). Magnesium administration (131), hypophosphatemia (169), hyperammonemia (134; 165), diabetic ketoacidosis (148), the hyperosmolar hyperglycemic state (56; 61; 83; 74; 103; 31; 122; 178; 68; 105; 110; 143), and hypernatremia (102; 112; 139; 21; 57; 126; 11; 32; 160; 69; 124; 125; 79; 87; 171; 33; 44; 71), particularly the rapid development of hypernatremia (102; 70), may also contribute to the risk of developing osmotic demyelination syndrome.

Conventionally, rapid correction of chronic hyponatremia has been thought to cause glial swelling through osmosis, especially in the pons, leading eventually to myelinolysis and cell death. Unfortunately, because not all cases are readily explained by this mechanism, alternative pathophysiological explanations have been considered. For example, apoptosis has been considered an alternative pathophysiological mechanism, induced variously by osmotic stress, inadequate energy provision, and other factors (12).

Alcoholism has been the most commonly recognized etiologic factor for osmotic demyelination syndrome (02; 173; 115; 53; 59; 01; 109; 144; 51; 65; 38; 96; 135; 170; 07; 37; 116; 23; 42; 99; 101; 137; 30; 41; 43; 107; 17; 75; 94; 62; 04; 09; 67; 119; 128; 20; 45; 82; 87; 97; 121; 166; 36; 127; 52). Consideration of alcoholism as a risk factor for osmotic demyelination syndrome may be derived from the frequent occurrence of hyponatremia with alcoholism, especially with beer potomania (93; 111).

Diabetes insipidis may present with osmotic demyelination syndrome, including congenital nephrogenic diabetes insipidus presenting as osmotic demyelination syndrome in infancy (78) and accidental disruption of intranasal desmopressin treatment in patients with central diabetes insipidus after surgical treatment for a craniopharyngioma (22) or pituitary adenoma (181).

Hyperemesis gravidarum presents various severe electrolyte disturbances that can be associated with osmotic demyelination syndrome (92; 161; 16; 34; 08), including hyponatremia (34), hypokalemia (92; 161), or both (16; 08). In this setting, osmotic demyelination may be accompanied by Wernicke encephalopathy (161; 16).

In addition, burn patients (102) and patients undergoing liver transplantation (35; 63; 44) are particularly vulnerable to developing osmotic demyelination syndrome. Burn patients who develop osmotic demyelination syndrome have had extreme serum hyperosmolality, whereas most burn patients without osmotic demyelination have not. Hypernatremia, hyperglycemia, and azotemia, alone or combined, accounted for the hyperosmolality. Hyponatremia was not present in any burn patient with osmotic demyelination syndrome. Similarly, rapid changes in serum osmolality from ethylene glycol poisoning and its treatment can cause osmotic demyelination syndrome, independent of changes in serum sodium levels (05).

Severe postpartum hypernatremia may present as an encephalopathy with rhabdomyolysis and osmotic demyelination (112; 139; 21; 126; 11; 32; 160; 33; 71). Other causes of severe hypernatremia have also been associated with osmotic demyelination syndrome (57; 69; 124; 125; 79; 87; 171; 44), including frequent watery diarrhea in a patient treated with alternative medicine that included sodium chloride (57), a lactulose enema in a patient with chronic alcoholism (87), and extreme sodium intake in conjunction with restriction of fluid and food intake in an adolescent girl with an eating disorder (79).

Other proposed risk factors for osmotic demyelination syndrome include liver disease, malignancy, malnutrition, pregnancy or postpartum state, severe illness or sepsis, and adrenal insufficiency (142; 114; 49).

The pathological feature of osmotic demyelination syndrome is noninflammatory demyelination with relative sparing of neurons. 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 like that seen in the central pons (176; 55; 54). These extrapontine sites include the lateral geniculate bodies; the external, extreme, and internal capsules; the basal ganglia; the splenium of the corpus callosum; and the superior vermis of the cerebellum.

Animal models of central pontine myelinolysis have been developed in the dog and rat (77). In both animals, demyelination follows rapid correction of sustained, vasopressin-induced hyponatremia with hypertonic saline (76; 84). Rapid correction of chronic hyponatremia is much more likely to result in myelinolysis than similar correction of acute or rapid hyponatremia (118). Disruption of the blood-brain barrier may be important in the pathogenesis of osmotic demyelination syndrome (141). The role of organic osmolytes and brain amino acids in chronic hyponatremia and osmotic demyelination syndrome has not been defined (168; 91).

Myelinolysis in animals may also be induced by rapid hypernatremia (151). 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 (132). Rapid correction of hyponatremia triggers apoptosis in astrocytes, followed by loss of trophic communication between astrocytes and oligodendrocytes, secondary inflammation, microglial activation, and demyelination (48). A study using the rat model suggested that osmotic stress may cause protein aggregation and ubiquitination and that demyelination may be a consequence of proteostasis failure (proteostasis, or protein homeostasis, is the process that regulates proteins within the cell to maintain the health of both the cellular proteome and the organism itself) (46).

Epidemiology

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 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 (29; 54).

A study of 255 patients who presented to two large teaching hospitals between 2000 and 2007 with serum sodium <120 mmol/L found that inappropriately rapid correction of serum sodium (greater than 12 mmol/L over the first 24 hours) occurred in 37 patients (15%), with four patients developing osmotic demyelination (ie, 11% of those with inappropriately rapid correction) (170). Patients who developed osmotic demyelination were more likely to be younger, abuse alcohol (three of four patients), and have lower serum potassium levels.

A nationwide study in Sweden identified 83 individuals diagnosed with osmotic demyelination syndrome between 1997 and 2011 for an overall incidence of 0.61 per million person-years (04). Most cases were hyponatremic, with a medium sodium level of 104 mmol/L. All were chronically hyponatremic, and most were alcoholics. Patients with hyponatremia were treated mainly with isotonic saline and a minority with hypotonic fluids, with a median correction rate of 0.72 mmol/L/h; only six patients were corrected within the national treatment guidelines of less than or equal to 8 mmol/L/24h. At 3 months, most patients (60%) survived and became functionally independent, but 7% died.

Using hospital administrative records from a representative sample of US hospitals, osmotic demyelination syndrome was rare in a large cohort of 547,544 hospitalized patients with cirrhosis, with only 94 of these patients (0.02%) identified with the condition (20). In this cohort, alcohol-related cirrhosis, younger age, and female gender were associated with the disease.

In a single-center, retrospective chart review of 234 patients 18 years of age or older with at least one serum sodium <130 mEq/L during hospitalization, severe hyponatremia (serum sodium < 120 mEq/L) and history of alcohol use disorder were risk factors found to be associated with overcorrection of hyponatremia (127).

Prevention

Hyponatremic osmotic demyelination. In a single-center retrospective cohort study ("trohoc" study) of 50 patients admitted with initial serum sodium <125 mEq/L, overcorrection occurred in 14% (159); symptomatic hyponatremia at presentation and 3% saline were associated with overcorrection.

In a post hoc analysis of a multicenter, prospective randomized controlled study of 178 subjects with symptomatic hyponatremia (mean serum sodium level 118 mEq/L), overcorrection was defined as an increase in serum sodium level of more than 12 or 18 mEq/L within 24 and 48 hours, respectively (180). Twenty-one percent of the patients experienced hyponatremia overcorrection. Overcorrection was independently associated with initial severity of hyponatremia, chronic alcoholism, severe symptoms of hyponatremia, and severity of associated hypokalemia.

Because 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 is no adequate justification for using hypertonic saline to treat relatively asymptomatic or mildly symptomatic hyponatremia or to rapidly correct hyponatremia to levels above 120 to 125 mEq/liter in severe symptomatic hyponatremia. Hypertonic saline is reserved for patients with severe symptomatic hyponatremia; United States and European guidelines recommend treating severely symptomatic hyponatremia (ie, with signs of obtundation, coma, seizures, or cardiorespiratory distress) with bolus hypertonic saline to increase the serum sodium level by 4 to 6 mEq/L within 1 to 2 hours, but no more than 10 mEq/L within the first 24 hours; unfortunately, this approach exceeds the correction limit in 5% to 28% of patients (03).

In a 1993 review of 67 reported cases of osmotic demyelination syndrome since 1983, none documented by radiological studies or necropsy were treated with water restriction only (58). In a group of 27 hyponatremic patients treated only with water restriction and 35 with diuretic cessation alone, none developed osmotic demyelination syndrome. Consequently, water restriction or diuretic cessation may be a reasonable approach in patients with symptomatic hyponatremia and normal renal function.

Because patients with hyponatremia can rapidly correct even with normal saline, serum sodium should be measured every 4 hours to allow for fluid and electrolyte administration adjustments should serum sodium rise at a rate greater than 0.5 mEq/ml per hour. Sterns and colleagues suggested an even slower correction rate for chronic, severe hyponatremia, with a limit of 4 to 6 mEq/L/day increase in serum sodium (156). Separate professional organizations from the United States and Europe have published guidelines on the correction of hyponatremia. The limit, according to European guidelines, is 10 mmol/L per day (153; 154; 155). 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 (64). The use of desmopressin to limit water diuresis has become common as a means of preventing the overcorrection of severe hyponatremia (149; 98).

V2-receptor antagonists, or vaptans, are safe and effective for treating hypervolemic and normovolemic hyponatremia. A study using either 7.5 or 15 mg daily doses of tolvaptan in the emergency department for the 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 42% of patients, whereas 7.5 mg/day dosing did not cause any dangerous overcorrections. Osmotic demyelination was not observed in either group after 1 month of follow-up (26).

For patients with end-stage kidney disease on hemodialysis, there is a risk of correcting hyponatremia too rapidly during dialysis. One proposed method for preventing this is to use a dialysate with a sodium concentration of 130 mEql/L and limit blood flow to 50 mL/min (172).

Limited evidence suggests that minocycline may help prevent osmotic demyelination syndrome from water diuresis (163). In rat models, using urea to correct mild chronic hyponatremia has less risk than vasopressin antagonists or hypertonic saline (47).

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 the risk of too-rapid correction (13). Rapid intermittent bolus therapy did have a lower incidence of needing therapeutic relowering and possibly better efficacy, suggesting that this should be the preferred treatment for symptomatic hyponatremia (13).

Hypernatremic osmotic demyelination. Prevention includes early recognition and gradual correction of hypernatremia (< 10 mEq/L/day) by oral and intravenous free water (71).

Differential diagnosis

Confusing conditions

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.

Cases of central pontine myelinolysis have been confused with stroke (82; 122). For example, a 45-year-old alcoholic woman recently hospitalized for Wernicke encephalopathy presented with left hemiparesis and was initially suspected to have had a stroke (82). As part of a “code stroke” protocol, CT was performed, but the non-contrast brain CT and CT angiogram of the intracranial arteries were normal; however, a CT brain perfusion study demonstrated increased pontine blood flow. A subsequent MRI of the brain confirmed central pontine myelinolysis.

From an imaging perspective, there can sometimes be overlap with acute disseminated encephalomyelitis, metronidazole poisoning, and motor neuron disease (71). In acute disseminated encephalomyelitis, MRI abnormalities predominate in cerebral and cerebellar cortices, subcortical and parieto-occipital white matter, centrum semiovale, cerebellar peduncles, and brainstem; the lesions are typically large, asymmetric, and irregular in morphology. Metronidazole poisoning manifests after metronidazole intake for more than 2 weeks; brain MRI demonstrates abnormal symmetric hyperintensities in the cerebellum, cerebral white matter, and corpus callosum. In motor neuron disease, a similar imaging appearance is observed, particularly that of hypernatremic osmotic demyelination (81; 80), but the clinical presentation is one of relentless progression.

Diagnostic workup

Osmotic demyelination syndrome can sometimes be detected with computed tomography (167), but the sensitivity is low. MRI is the diagnostic modality of choice for demonstrating demyelination in the central pons, which is present in most patients with osmotic demyelination syndrome (40; 103; 143). Fairly typical early MRI findings of osmotic demyelination syndrome are shown in a 34-year-old woman with longstanding diabetes a 44-year-old diabetic man in the following figures.

Hypernatremic osmotic demyelination has different imaging characteristics on MRI than osmotic demyelination resulting from the too-rapid correction of hyponatremia. MRI abnormalities associated with hypernatremic osmotic demyelination include bilateral T2-weighted or FLAIR hyperintensities involving the corpus callosum (especially the splenium), the internal capsule, cerebellar peduncles, pons, and hippocampus, with restricted diffusion along the corticospinal tracts and in the splenium of the corpus callosum (71). The bilateral symmetric hyperintensities in the corticospinal tracts lead to a picture of a “wine glass” pattern of hyperintensities on coronal images, a pattern that has previously been described in amyotrophic lateral sclerosis and leukodystrophies (81; 139; 80; 160; 33; 71).

Subcortical white matter lesions can be present in osmotic demyelination syndrome, and their demonstration should be attempted with enhanced MRI (24); the co-occurrence of pontine and other enhancing subcortical lesions is very suggestive of osmotic demyelination syndrome, especially after rapid correction of hyponatremia.

Rarely, microhemorrhages may be seen with osmotic demyelination syndrome, possibly from osmotic-injury-induced endothelial damage (115; 71).

The serial progression of neurologic lesions disclosed by MRI can be appreciated in the case of a 51-year-old man who developed osmotic demyelination syndrome due to rhabdomyolysis and hyperosmolar hyperglycemic syndrome following cardiogenic shock (74).

MRI on day 10 revealed only symmetrical hyperintensity in the putamen and posterior limb of the internal capsule on DWI and FLAIR images.

MRI on day 16 revealed no changes in the findings except a loss of hyperintensity on DWI.

MRI on day 57 revealed symmetrical hyperintensity in the pons, cerebellar hemispheres, hippocampus, thalamus, and hypothalamus on FLAIR.

In another case of osmotic demyelination syndrome, a 44-year-old man with severe hyponatremia (100 mmol/L) was treated with sodium supplementation with 3% hypertonic saline and water restriction; he developed altered mental status with agitation, limb rigidity, bradykinesia, and dystonia on hospital day 2. Brain MRI FLAIR and T2-weighted images initially showed no significant abnormalities, whereas diffusion-weighted imaging showed symmetrical high-intensity lesions at the head of the caudate nucleus and putamen (86).

DWI on hospital day 12 showed that the previous caudate nucleus and putamen lesions had become more conspicuous, and a new high-intensity lesion involving the central pons was evident, consistent with central pontine myelinolysis.

There have been case reports of localized 18F-fluorodeoxyglucose uptake on PET and CT during active central pontine myelinolysis. The increased metabolism of attracted glial cells and macrophages as well as activated astrocytes during active disease are thought to be responsible for fluorodeoxyglucose uptake (133).

Management

No effective specific treatment for osmotic demyelination syndrome has been identified. Current management consists of general supportive care.

The rapid reinduction of hyponatremia has been proposed as a potential therapeutic maneuver. In a rat model, this approach reduced neurologic signs and symptoms suggestive of osmotic myelinolysis (152). Therapeutic relowering of serum sodium has not been evaluated in clinical trials. In several human cases, outcomes have been variable using this technique (150; 179; 120).

Other described potential therapeutic maneuvers based on results in rat models include the putatively protective effect of steroids (158; 106), myoinositol (145), and lovastatin (164) prior to the rapid correction of hyponatremia. Minocycline has also been examined in a rat model during the early phase of rapid sodium correction and has demonstrated protection from neurologic impairment and improved survival (162).

Anecdotal reports and small case series have been published of positive outcomes with intravenous immunoglobulin (108), plasma exchange (28; 50; 174; 175), and steroids (14) after the development of osmotic demyelination syndrome. The anecdotal failure of plasma exchange has also been reported (113). Such reports carry little evidentiary weight. Randomized, controlled clinical trials are needed to assess potential therapies adequately.

Special considerations

Pregnancy

To the extent that pregnant women are more likely to develop hyponatremia (eg, from hyperemesis gravidarum), pregnancy may carry an increased risk of osmotic demyelination syndrome (27). A woman with a twin pregnancy presented with central pontine myelinolysis and required emergency delivery to correct electrolyte and fluid balance, resulting in minimal sequelae for the mother (138); the twins were asymptomatic at 6 months of follow-up.

Liver disease

Hyponatremia is a common problem for patients with cirrhosis, and liver disease is a risk factor for 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 transplantation, higher positive intraoperative fluid balance, and postoperative hemorrhagic complications. Correction of hyponatremia prior to transplantation along with multidisciplinary management to carefully manage fluid and electrolytes during and after surgery are important to minimize the risk of osmotic demyelination syndrome in this vulnerable population (35).

Children

Osmotic demyelination is less common in children than in adults.

A review of 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 (15). There was no evident gender predisposition to osmotic demyelination in children. The highest prevalence was between ages 1 and 5 years. Sixty percent of affected children had a complete neurologic recovery. Although MRI is still preferred as the main diagnostic test, diffusion tensor imaging is more often used for prognostication. Other than supportive care, steroids and intravenous immunoglobulin are rarely used.