Osmotic Demyelination Syndrome (ODS)



  • Osmotic Demyelination Syndrome Predominantly Occurs in Patients with Severe Hyponatremia (Na ≤120 mE/L) Which Has Been Present for >2-3 Days (Ann Intern Med, 1987) [MEDLINE] (J Am Soc Nephrol, 1994) [MEDLINE] (J Med, 2013) [MEDLINE] (Acta Neurol Scand, 2019) [MEDLINE]
    • This is Due the Fact that This is the Period of Time Required for Cerebral Adaptation to Occur
    • However, Some Cases of Osmotic Demyelination Syndrome Occur with Serum Sodium Concentrations >120 mEq/L and Slower Rates of Hyponatremia Correction, Suggesting Individual Variability
      • Osmotic Demyelination Syndrome Occurring in Patients with Serum Sodium >120 mEq/L is Generally Observed in the Following Subsets of Patients
        • Patients with Advanced Liver Disease and Moderate Hyponatremia in Whom Serum Sodium Levels Increase After Liver Transplant (Hepatology, 2009) [MEDLINE]
        • Patients with Diabetes Insipidus Who Have Developed Moderate Hyponatremia as a Complication of Desmopressin Therapy and Subsequently Have Their Desmopressin Discontinued (with a Resulting Water Diuresis)

Factors Related to Risk

Low-Risk Groups for Osmotic Demyelination Syndrome

  • Hyponatremic Patients with Self-Induced Water Intoxication (Runners, Psychotic Patients with Severe Polydipsia, Ecstasy Users, etc)
    • These Patients Have Not Had Adequate Time for Brain Cells to Expel Osmotic Substances
  • Patients with Mild-Moderate Hyponatremia (Serum Sodium >120 mEq/L)
    • Since Almost All Patients Who Develop Osmotic Demyelination Syndrome Initially Presented with a Serum Sodium ≤120 mEq/L

Risk Factors Which Increase the Risk of Osmotic Demyelination Syndrome (Clin J Am Soc Nephrol, 2018) [MEDLINE] (Acta Neurol Scand, 2019) [MEDLINE]

  • General Comments
    • Risk Factors May Increase the Risk of Developing Osmotic Demyelination Syndrome with Lesser Degrees of Hyponatremia and/or with Slower Rates of Hyponatremia Correction
  • Alcohol Abuse (see Ethanol)
    • In a Large Study of MRI-Documented Osmotic Demyelination Syndrome Cases, 70% of the Patients Had an Alcohol Use Disorder (Acta Neurol Scand, 2019) [MEDLINE]
  • Hypokalemia (see Hypokalemia)
    • In a Large Study of MRI-Documented Osmotic Demyelination Syndrome Cases, 68% of the Patients Had Hypokalemia (Acta Neurol Scand, 2019) [MEDLINE]
  • Hypophosphatemia (see Hypophosphatemia): possible risk factor
  • Liver Disease (see Cirrhosis)
  • Malnutrition (see Malnutrition)
  • Serum Sodium ≤105 mEq/L
    • The Majority of Osmotic Demyelination Syndrome Cases Occur in Patients with Serum Sodium ≤105 mEq/L (Ann Intern Med, 1987) [MEDLINE] (J Am Soc Nephrol, 1994) [MEDLINE] (J Med, 2013) [MEDLINE] (Acta Neurol Scand, 2019) [MEDLINE]
    • Patients Who Have More Severe Hyponatremia at Initial Presentation Have Greater Degree of Cerebral Depletion of Organic Osmotically-Active Solutes (Predominantly Myoinositol, Glutamate, and Glutamine) During Cerebral Adaptation to the Hyponatremia and Generally Tend to Experience a Greater Increase in the Serum Sodium During Treatment (Clin J Am Soc Nephrol, 2007) [MEDLINE]
  • Chronic Hyponatremia (Duration ≥2 Days)
    • Animal Studies Indicate that Osmotic Demyelination Syndrome Does Not Occur When Hyponatremia of <1 Day Duration is Rapidly Corrected (Kidney Int, 1989) [MEDLINE] (J Neuropathol Exp Neurol, 2006) [MEDLINE]
    • However, if Hyponatremia Persists for >2-3 Days, Osmotic Demyelination Syndrome Occurs When the Hyponatremia is Rapidly Corrected (J Neuropathol Exp Neurol, 2006) [MEDLINE]
    • Importantly, While the Duration of Hyponatremia is Critical, it is Frequently Not Known at the Time of the Patient’s Presentation
      • For This Reason, if the Duration is Unknown, the Duration of Hyponatremia Should Be Presumed to Be Chronic (≥2 Days Duration) to Avoid Rapidly Correcting Hyponatremia

Protective Factors Which Decrease the Risk of Osmotic Demyelination

  • Elevated Blood Urea Nitrogen (BUN) in the Setting of Renal Failure




  • The Serum Sodium Concentration is the Primary Determinant of the Serum Tonicity (Also Referred to as the “Effective Serum Osmolality”)
    • Hypotonic Hyponatremia Causes Water to Move Across the Blood-Brain Barrier into the Brain (Increasing Brain Water Content and Predominantly, Astrocyte Swelling)
      • Severe Hyponatremia Can Result in Cerebral Edema (and Consequent Neurologic Manifestations)
    • In Response to Hyponatremia, the Brain Adapts to Decrease the Cerebral Volume Back Toward Normal by Exporting Osmotically-Active Organic Solutes (Predominantly Myoinositol, Glutamate, and Glutamine) from Astrocytes, Which Starts Immediately After the Development of Hyponatremia and is Complete within 2 Days
      • Because the Brain is Able to Adapt to Hypotonicity, Hyponatremia Which Develops Over >2-3 Days is not Associated with the Development of Cerebral Swelling (and is Extremely Unlikely to Cause Cerebral Edema and Herniation) (Kidney Int, 1990) [MEDLINE]
    • In the Setting of Chronic Hyponatremia, Cerebral Adaptations Make the Brain Vulnerable to Rapid Hyponatremia Correction-Associated Osmotic Demyelination
      • Osmotically-Active Organic Solutes (Predominantly Myoinositol, Glutamate, and Glutamine) Cannot Be Quickly Replaced Back into the Brain When the Brain Volume Starts to Shrink During the Rapid Correction of Hyponatremia

Relationship of Rate of Correction to the Risk of Osmotic Demyelination

  • Case Series Examining the Use of 3% Saline to Treat Hyponatremic Encephalopathy in the ED Setting (Am J Kidney Dis, 2015) [MEDLINE]
    • Baseline Mean Serum Sodium was 114.1 ± 0.8 (SEM) mEq/L
      • Mean 3 hr Serum Sodium Correction to 117.9 ± 1.3
      • Mean 12 hr Serum Sodium Correction to 121.2 ± 1.2
      • Mean 24 hr Serum Sodium Correction to 123.9 ± 1.0 (Delta of Approximately 10 mEq/L in the First 24 hrs)
      • Mean 48 hr Serum Sodium Correction to 128.3 ± 0.8 mEq/L
    • No Cases of Osmotic Demyelination were Observed
  • Large Cohort Studies Indicate that Correction of Hyponatremia <5 mEq/L Per Day are Not Associated with the Development of Neurologic Complications (Mayo Clin Proc, 2015) [MEDLINE]
  • Retrospective Cohort Study of Risk Factors for Rapid Correction of Hyponatremia (Clin J Am Soc Nephrol, 2018) [MEDLINE]: n = 1,490 patients admitted with serum sodium <120 mEq/L
    • Median Change in Serum Sodium at 24 hrs was 6.8 mEq/L (Interquartile Range, 3.4-10.2)
    • Rapid Correction of Hyponatremia Occurred in 41% of Patients
    • Risk Factors Associated with Rapid Correction
      • Younger Age
      • Female Sex
      • Schizophrenia
      • Lower Charlson Comorbidity Index
      • Lower Presentation Serum Sodium
      • Urine Sodium <30 mEq/L
    • Risk Factors Associated with Lower Risk of Rapid Correction
      • Prior Hyponatremia
      • Outpatient Aldosterone Antagonist Use
      • Treatment at an Academic Center
    • Approximately 88% of Patients with Incident Osmotic Demyelination Had a Documented Episode of Rapid Correction of Hyponatremia (with Serum Sodium Increase >8 mEq/L Over 24 hrs)

Anatomic Distribution of Osmotic Demyelination

  • While Central Pontine Demyelination is One Manifestation of Osmotic Demyelination Syndrome, it Does Not Always Involve the Pons and it May Be More Diffuse (NEJM, 1986) [MEDLINE] (Ann Intern Med, 1987) [MEDLINE] (Kidney Int, 1990) [MEDLINE] (J Am Soc Nephrol, 1994) [MEDLINE]


Brain Magnetic Resonance Imaging (MRI) (see Brain Magnetic Resonance Imaging)

  • Standard Part of Diagnostic Evaluation
    • In a Study of Osmotic Demyelination Syndrome, 51% of Patients Had Central Pontine Demyelination Only, 45% of Patients Had Both Central Pontine Demyelination and Extrapontine Demyelination, and 4% of Patients Had Extrapontine Demyelination Only (Acta Neurol Scand, 2019) [MEDLINE]
    • However, Brain MRI May Not Become Positive Until as Long as 4 wks After the Onset of Neurologic Symptoms
      • Earlier Detection May Be Possible with Newer MRI Techniques, Such as Diffusion-Weighted Imaging

Clinical Manifestations

Time Course

  • Delayed Onset of Symptoms Occurs Approximately 2-6 Days After the Rapid Sodium Correction Event

Neurologic Manifestations


Use of Desmopressin (see Desmopressin)

  • Canadian Retrospective Observational Study of Use of Desmopressin During the Correction of Hyponatremia (Am J Med, 2018) [MEDLINE]: n = 1,450
    • Desmopressin (DDVAP) was Used in 17.5% of Cases (However, Most Cases Received it as Part of a “Reactive” Strategy (in Which DDAVP was Administered After a Change in Plasma Sodium within Correction Limits)
    • There was Lower Mortality Rate in the Desmopressin Group (3.9% vs 9.4%), Although This was Likely Affected by Confounding

Avoidance of Rapid Correction of Hyponatremia

  • Maintain a Maximum Rate of Correction of Hyponatremia Correction of ≤8 mEq/L in the First 24 hrs (J Am Soc Nephrol, 2012) [MEDLINE] (Clin J Am Soc Nephrol, 2018) [MEDLINE]


Supportive Care

Respiratory Support

Re-Lowering of the Serum Sodium

  • Recommended that the Serum Sodium Be Lowered to a Level Just Below the Initial 48 hr Serum Sodium Target (i.e. to <16 mEq/L Above the Initial Target Serum Sodium)
    • The 48 hr Target is the Most Practical to Implement Since Osmotic Demyelination Syndrome General Presents 2-6 Days After the Rapid Sodium Correction Event
  • Clinical Efficacy
    • In a Rat Model of Rapid Sodium Correction, Re-Lowering the Serum Sodium was Associated with Improved Survival (J Neuropathol Exp Neurol, 1996) [MEDLINE]
    • Limited Human Case Reports Suggest that Re-Lowering the Serum Sodium May Be Beneficial (Clin Nephrol, 1999) [MEDLINE] (Neurology, 2001) [MEDLINE] (N Z Med J, 2005) [MEDLINE] (Curr Opin Nephrol Hypertens, 2010) [MEDLINE]
  • Procedure
    • Start Either Hypotonic Intravenous Fluids (D5W, etc) or Desmopressin within Hours of the Onset of Neurologic Symptoms
      • While the Optimal Timing of Re-Lowering is Unclear, it is Recommended to Start Re-Lowering as Soon as Possible

Investigational Therapies

Plasmapheresis (see Plasmapheresis)

  • There are Case Series Describing the Effectiveness of Plasmapheresis in Osmotic Demyelination Syndrome (Lancet, 1999) [MEDLINE] (J Neurol, 2005) [MEDLINE] (Transpl Int, 2008) [MEDLINE]


Symptoms are Frequently Irreversible

  • General Comments
    • Determination that the Neurologic Manifestations are Irreversible Should Be Delayed for Approximately 6-8 wks (NEJM, 1986) [MEDLINE] (J Neurol, 1999) [MEDLINE] (Crit Care Med, 2012) [MEDLINE]
  • Study of Outcome of Osmotic Demyelination Syndrome (J Neurol, 1999) [MEDLINE]: n = 44
    • Authors Observed that Patients with Osmotic Demyelination Survive if the Secondary Complications (Aspiration Pneumonia, Ascending Urinary Tract Infection, Deep Venous Thrombosis/Pulmonary Embolism) Can Be Avoided
  • French Retrospective Study of the Prognosis of Osmotic Demyelination Syndrome in Critically Ill Patients (Crit Care Med, 2012) [MEDLINE]: n = 36
    • Population: 86% of patients were alcoholics and 92% presented with hyponatremia
    • At 1 yr Follow-Up, 31% of Patients Had Died and 56% (Survivors) Returned to Rankin Score ≤1
    • Life-Supporting Therapy was Withheld in 31% of Patients (Mainly Due to Severe Cerebral Motor Disability)
    • Recovery is Possible and Unpredictable Based on Clinical Presentation
    • Chronic Alcohol Abuse was Less Frequent in Patients with a Favorable Outcome, as Compared to Patients with an Unfavorable Outcome (72% vs 100%] p = 0.04)
  • Large Retrospective Swedish Nationwide Study of Osmotic Demyelination Syndrome (Acta Neurol Scand, 2019) [MEDLINE]: n = 83
    • 40% of Patients Died or Were Functionally Impaired at 3 mos
    • 60% of Patients were Functionally Independent (Although Some Had Persistent Mild Symptoms