Central pontine myelinolysis
Other names	Osmotic demyelination syndrome, central pontine demyelination
Axial fat-saturated T2-weighted image showing hyperintensity in the pons with sparing of the peripheral fibers, the patient was an alcoholic admitted with a serum Na of 101 treated with hypertonic saline, he was left with quadriparesis, dysarthria, and altered mental status
Specialty	Neurology
Causes	Alcoholism,malnutrition

Central pontine myelinolysis (CPM) is a neurological condition involving severe damage to themyelin sheath ofnerve cells in thepons (an area of the brainstem). It is predominatelyiatrogenic (treatment-induced), and is characterized by acute paralysis,dysphagia (difficulty swallowing),dysarthria (difficulty speaking), and other neurological symptoms.

Central pontine myelinolysis was first described as a disorder in 1959. The original paper^[1] described four cases with fatal outcomes, and the findings on autopsy. The disease was described as a disease ofalcoholics andmalnutrition.^[2] 'Central pontine' indicated the site of the lesion and 'myelinolysis' was used to emphasise that myelin was affected. The authors intentionally avoided the term 'demyelination' to describe the condition, in order to differentiate this condition from multiple sclerosis and other neuroinflammatory disorders.^[3]

Since this original description, demyelination in other areas of the central nervous system associated with osmotic stress has been described outside the pons (extrapontine).^[4]Osmotic demyelination syndrome (ODS) is the term used for both central pontine myelinolysis and extrapontine myelinolysis.^[5]

Central pontine myelinolysis, and osmotic demyelination syndrome, present most commonly as a complication of treatment of patients with profoundhyponatremia (lowsodium), which can result from a varied spectrum of conditions, based on different mechanisms. It occurs as a consequence of a rapid rise inserumtonicity following treatment in individuals with chronic, severe hyponatremia who have made intracellular adaptations to the prevailing hypotonicity.^[6][7]

Symptoms depend on the regions of the brain involved. Prior to its onset, patients may present with the neurological signs and symptoms of hyponatraemic encephalopathy such as nausea and vomiting, confusion, headache and seizures. These symptoms may resolve with normalisation of the serum sodium concentration. Three to five days later, a second phase of neurological manifestations occurs correlating with the onset of myelinolysis. Observable immediate precursors may include seizures, disturbed consciousness, gait changes, and decrease or cessation of respiratory function.^[8][9]

The classical clinical presentation is the progressive development of spasticquadriparesis,pseudobulbar palsy, and emotional lability (pseudobulbar affect), with other more variable neurological features associated with brainstem damage. These result from a rapid myelinolysis of thecorticobulbar andcorticospinal tracts in the brainstem.^[10]

In about ten per cent of people with central pontine myelinolysis, extrapontine myelinolysis is also found. In these cases symptoms ofParkinson's disease may be generated.^[2]

The most common cause is overly-rapid correction of low blood sodium levels (hyponatremia).^[11] Apart from rapid correction of hyponatraemia, there are case reports of central pontine myelinolysis in association with hypokalaemia, anorexia nervosa when feeding is started, patients undergoing dialysis and burn victims. There is a case report of central pontine myelinolysis occurring in the context ofrefeeding syndrome, in the absence of hyponatremia.^[3]

It has also been known to occur in patients suffering withdrawal symptoms of chronicalcoholism.^[2] In these instances, occurrence may be entirely unrelated to hyponatremia or rapid correction of hyponatremia. It could affect patients who take some prescription medicines that are able to cross theblood-brain barrier and cause abnormal thirst reception - in this scenario the central pontine myelinolysis is caused bypolydipsia leading to low blood sodium levels (hyponatremia).^{[citation needed]}

Inschizophrenic patients withpsychogenic polydipsia, inadequate thirst reception leads to excessive water intake, severely diluting serum sodium.^[12] With this excessive thirst combined with psychotic symptoms, brain damage such as central pontine myelinolysis^[13] may result fromhyperosmolarity caused by excess intake of fluids, (primary polydipsia) although this is difficult to determine because such patients are ofteninstitutionalised and have a long history of mental health conditions.^[14]

It has been observed followinghematopoietic stem cell transplantation.^[15]

Central pontine myelinolysis may also occur in patients prone to hyponatremia affected by:

• Severe liver disease (e.g.,cirrhosis)
• Liver transplant^[16][17][18]
• Alcoholism
• Hypokalemia
• People with serum sodium <105 mEq/L
• Severe burns^[19][20]
• Malnutrition
• Anorexia nervosa^[21][22][23]
• Severe electrolyte disorders
• HIV/AIDS
• hyperemesis gravidarum^[24][25]
• Hyponatremia due toperitoneal dialysis
• Wernicke encephalopathy^[26]

The currently accepted theory states that the brain cells adjust theirosmolarities by changing levels of certain osmolytes likeinositol,betaine, andglutamine in response to varying serum osmolality. In the context ofchronic low plasma sodium (hyponatremia), the brain compensates by decreasing the levels of these osmolytes within the cells, so that they can remain relatively isotonic with their surroundings and not absorb too much fluid. The reverse is true in hypernatremia, in which the cells increase their intracellular osmolytes so as not to lose too much fluid to the extracellular space.^[27]

With correction of the hyponatremia withintravenous fluids, the extracellular tonicity increases, followed by an increase in intracellular tonicity. When the correction is too rapid, not enough time is allowed for the brain's cells to adjust to the new tonicity, namely by increasing the intracellular osmoles mentioned earlier. If the serum sodium levels rise too rapidly, the increased extracellular tonicity will continue to drive water out of the brain's cells. This can lead to cellular dysfunction and central pontine myelinolysis.^[28][29]

It can be diagnosed clinically in the appropriate context, but may be difficult to confirm radiologically using conventional imaging techniques. Changes are more prominent on MRI than on CT, but often take days or weeks after acute symptom onset to develop. Imaging byMRI typically demonstrates areas of hyperintensity on T2-weighted images.^[30]

To minimise the risk of this condition developing from its most common cause, overly rapid reversal of hyponatremia, the hyponatremia should be corrected at a rate not exceeding 10 mmol/L/24 h or 0.5 mEq/L/h; or 18 mEq/L/48hrs; thus potentially avoiding demyelination^[29] although ODS can still occur with rises in osmolality within recommended ranges. No large clinical trials have been performed to examine the efficacy of therapeutic re-lowering of serum sodium, or other interventions sometimes advocated such as steroids or plasma exchange.^[29]Alcoholic patients should receive vitamin supplementation and a formal evaluation of their nutritional status.^[31][32]

The effect of therapeutic saline, in particular hypertonic saline, is often implicated in rapid rises in serum Na and osmolality when treating patients with hyponatraemia. The effect of saline is twofold. There is an initial redistribution/dilution that rarely causes an unsafe rise in Na/osmolality.

The rise in serum sodium due to redistribution alone can be estimated from the following equation.

${\displaystyle {\text{Na}}_{\text{final}}=\frac{({\text{Na}}_{\text{serum}}\times \text{ECF})+({\text{Na}}_{\text{infusate}}\times V_{\text{infusate}})}{\text{ECF}+V_{\text{infusate}}}}$

Where Na_serum is the concentration of the patient's plasma sodium, ECF is an estimate of extracellular water in litres (approximately body weight in kg x 0.2 for males and body weight x 0.17 for females), Na_infusate is the sodium concentration of the IV fluid and V_infusate is the volume of the IV fluid in litres. For a 100kg man with a plasma Na of 105mmol/L given 300mLs of 2.7% saline (462mmol of Na) the final dilution of plasma sodium would only be 110mmol/L.

${\displaystyle \frac{(105\times 20)+(462\times 0.3)}{20+0.3}=110.3}$

This initial 5mmol/L rise is usually sufficient to stabilise the patient's acute neurological deterioration due to cerebral oedema. Note that it is a rise in osmolality that is the treatment aim rather than Na itself - however for simplicity the Na is used as a measure of the osmolality and the osmolar rise will be roughly twice the Na rise. Direct measurement of osmolality would be preferable but the turnaround time in most hospital laboratories is too long to be useful so serum Na is used and therapeutic targets are set against this.

However after the initial rise from this mixing of 300mLs of 2.7% saline with the patients blood there is an osmotic load (Na⁺ + Cl^-) of 277mOsmol/kg available to the kidneys. With this load the patient could then potentially produce a water diuresis of up to 7L (277 / 40). 40mOsmol/Kg is approximately the most dilute the urine can be in humans. This secondary water diuresis (sometimes termed aquaresis) usually happens in the subsequent 24 hours in patients at risk - usually in patients initially suffering from a relativeantidiuresis the cause of which has been reversed (such as urinary obstruction, medication side effects orpotomania). Patients with an antidiuresis in which the cause persists (such assmall cell lung cancer or due to drug side effects that are long lasting or have not been stopped) are less prone to aquaresis.

It is this secondary water diuresis that can cause a very rapid rise in serum sodium, sometimes greater then 2mmol/L/hr which can lead to ODS. Physicians treating patients at high risk of ODS should both measure plasma Na every 3-4 hours and also the urine output for at least 24 hours. If a brisk diuresis does occur (>2mL urine per kg body weight per hour) prophylacticdesmopressin (4mg 8 hourly IV) can be given to limit free water clearance. If the patient does overshoot the recommended rise 5% dextrose in water can be given to bring the Na level back down to target levels.

Once osmotic demyelination has begun, there is no cure or specific treatment. Care is mainly supportive. Alcoholics are usually given vitamins to correct for other deficiencies. The favourable factors contributing to the good outcome in central pontine myelinolysis without hyponatremia were: concurrent treatment of all electrolyte disturbances, early intensive care unit involvement at the advent of respiratory complications, early introduction of feeding including thiamine supplements with close monitoring of the electrolyte changes and input.^[3]

Research has led to improved outcomes.^[33] Animal studies suggest thatinositol reduces the severity of osmotic demyelination syndrome if given before attempting to correct chronichyponatraemia.^[34] Further study is required before using inositol in humans for this purpose.^[35]

Though traditionally the prognosis is considered poor, a good functional recovery is possible. All patients at risk of developing refeeding syndrome should have their electrolytes closely monitored, including sodium, potassium, magnesium, glucose and phosphate.^[3]Recent data indicate that the prognosis of critically ill patients may even be better than what is generally considered,^[36] despite severe initial clinical manifestations and a tendency by the intensivists to underestimate a possible favorable evolution.^[37]While some patients die, most survive and of the survivors, approximately one-third recover; one-third are disabled but are able to live independently; one-third are severely disabled.^[38] Permanent disabilities range from minor tremors andataxia to signs of severe brain damage, such asspastic quadriparesis andlocked-in syndrome.^[39] Some improvements may be seen over the course of the first several months after the condition stabilizes.^{[citation needed]}

The degree of recovery depends on the extent of the original axonal damage.^[28]

• MedPix Images of Osmotic Myelinolysis

• Demyelinating diseases of CNS
• Electrolyte disturbances

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