Central pontine myelinolysis

Introduction

Central pontine myelinolysis (CPM) is a neurological disorder characterized by severe damage to the myelin sheath surrounding nerve cells within the pons, a crucial region of the brainstem. While many cases of CPM are iatrogenic (resulting from medical treatment), the condition manifests through a range of neurological symptoms, including acute paralysis, dysphagia (difficulty swallowing), and dysarthria (difficulty speaking).

Illustration of the affected area in Central Pontine Myelinolysis.

Signs and symptoms

T2 weighted magnetic resonance scan image showing bilaterally symmetrical hyperintensities in caudate nucleus (small, thin arrow), putamen (long arrow), with sparing of globus pallidus (broad arrow), suggestive of extrapontine myelinolysis (osmotic demyelination syndrome)

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.

The classical clinical presentation is the progressive development of spastic quadriparesis, pseudobulbar palsy, and emotional lability (pseudobulbar affect), with other more variable neurological features associated with brainstem damage. These result from a rapid myelinolysis of the corticobulbar and corticospinal tracts in the brainstem.

In about ten per cent of people with CPM, extrapontine myelinolysis (EPM) is also found. In these cases symptoms of Parkinson's disease may be generated.

Causes

Loss of myelinated fibers at the basilar part of the pons in the brainstem (Luxol-Fast blue stain)

The most common cause is overly rapid correction of low blood sodium levels (hyponatremia). 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 of re-feeding syndrome, in the absence of hyponatremia.

It has also been known to occur in patients suffering withdrawal symptoms of chronic alcoholism. 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 the blood-brain barrier and cause abnormal thirst reception - in this scenario the CPM is caused by polydipsia leading to low blood sodium levels (hyponatremia).

In schizophrenic patients with psychogenic polydipsia, inadequate thirst reception leads to excessive water intake, severely diluting serum sodium. With this excessive thirst combined with psychotic symptoms, brain damage such as CPM may result from hyperosmolarity caused by excess intake of fluids, (primary polydipsia) although this is difficult to determine because such patients are often institutionalised and have a long history of mental health conditions.

It has been observed following hematopoietic stem cell transplantation.

CPM may also occur in patients prone to hyponatraemia affected by:

• Severe liver disease (e.g., cirrhosis)
• Liver transplant
• Alcoholism
• Hypokalemia
• People with serum sodium <105 mEq/L
• Severe burns
• Malnutrition
• Anorexia nervosa
• Severe electrolyte disorders
• HIV/AIDS
• hyperemesis gravidarum
• Hyponatremia due to peritoneal dialysis
• Wernicke encephalopathy

Pathophysiology

The currently accepted theory states that the brain cells adjust their osmolarities by changing levels of certain osmolytes like inositol, betaine, and glutamine in response to varying serum osmolality. In the context of chronic 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.

With correction of the hyponatremia with intravenous 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 CPM.

Diagnosis

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 by MRI typically demonstrates areas of hyperintensity on T2-weighted images.

Treatment

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 avoiding demyelination. 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. Alcoholic patients should receive vitamin supplementation and a formal evaluation of their nutritional status.

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 CPM 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.

Research has led to improved outcomes. Animal studies suggest that inositol reduces the severity of osmotic demyelination syndrome if given before attempting to correct chronic hyponatraemia. Further study is required before using inositol in humans for this purpose.

Prognosis

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. Recent data indicate that the prognosis of critically ill patients may even be better than what is generally considered, despite severe initial clinical manifestations and a tendency by the intensivists to underestimate a possible favorable evolution. 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. Permanent disabilities range from minor tremors and ataxia to signs of severe brain damage, such as spastic quadriparesis and locked-in syndrome. Some improvements may be seen over the course of the first several months after the condition stabilizes.

The degree of recovery depends on the extent of the original axonal damage.

Historical Overview

The condition was first identified and described in 1959. In the foundational paper, the authors presented four cases that resulted in fatal outcomes and detailed their autopsy findings. Historically, CPM was understood to predominantly affect individuals with alcoholism or malnutrition. The term "myelinolysis" was specifically chosen to emphasize the impact on the myelin, distinguishing this disorder from multiple sclerosis and other neuroinflammatory conditions, which are commonly referred to as ‘demyelination’ disorders.

Evolution of Terminology

Subsequent research after the initial discovery revealed that demyelination can occur outside of the pons (extrapontine) due to osmotic stress in other parts of the central nervous system. This broader perspective led to the adoption of the term Osmotic demyelination syndrome (ODS) to encompass both central pontine myelinolysis and extrapontine myelinolysis.

Pathogenesis and Presentation

Association with Hyponatremia

The majority of CPM and ODS cases are seen as a complication in patients being treated for significant hyponatremia (a low concentration of sodium in the blood). This disorder can stem from a wide array of underlying conditions that operate through diverse mechanisms. Specifically, CPM often arises due to a swift increase in blood tonicity after treatment, especially in individuals with long-standing, profound hyponatremia. These patients usually have developed intracellular adaptations to cope with the initial low tonicity, making them vulnerable to rapid changes in serum concentration.

Conclusion

Central pontine myelinolysis remains a critical concern in neurology, underscoring the necessity of careful and monitored medical treatments. While significant strides have been made since its discovery in the late 1950s, understanding the precise mechanisms, preventative strategies, and most effective treatments for CPM and ODS remains a vibrant area of medical research.

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