Central pontine myelinolysis: Insight into pathogenesis, in the absence of hyponatremia

Mark William Fegley; Amitoj Singh; Santo Longo; Shree Gopal Sharma; Sudip Nanda

doi:10.4103/2455-5568.196871

IMAGES IN ACADEMIC MEDICINE

Year : 2016 | Volume : 2 | Issue : 2 | Page : 249-252

Central pontine myelinolysis: Insight into pathogenesis, in the absence of hyponatremia

Mark William Fegley¹, Amitoj Singh², Santo Longo³, Shree Gopal Sharma⁴, Sudip Nanda²
¹ Department of Family Medicine, St. Luke's University Health Network, Bethlehem, Pennsylvania, USA
² Department of Internal Medicine, St. Luke's University Health Network, Bethlehem, Pennsylvania, USA
³ Department of Pathology, St. Luke's University Health Network, Bethlehem, Pennsylvania, USA
⁴ Department of Pathology, University of Arkansas, Fayetteville, Arkansas, USA

Date of Submission	27-Dec-2015
Date of Acceptance	29-Jan-2016
Date of Web Publication	28-Dec-2016

Correspondence Address:
Sudip Nanda
Department of Internal Medicine, St. Luke's University Hospital Network, 801 Ostrum Street, Bethlehem, Pennsylvania 18015
USA

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/2455-5568.196871

Abstract

Central pontine myelinolysis (CPM) is a well-recognized iatrogenic complication of rapid correction of chronic hyponatremia. Dehydration of the brain and shrinkage of the oligodendrocyte cause separation of the myelin sheath from the axons. This damage can cause the full clinical spectrum of CPM. We report a patient with pseudohyponatremia, diabetes with hyperglycemia, hepatitis C-induced liver cirrhosis, malnutrition, and hypokalemia who developed CPM. The patient had not used insulin for 3 days during which he became hyperglycemic. After reinstitution of his insulin treatment, he developed clinical signs and radiological evidence of CPM. We review the cerebral adaptive mechanisms for the prevention of cellular shrinkage and CPM. This will help identify patient population who are at an increased risk of developing CPM in the absence of hyponatremia.
The following core competencies are addressed in this article: Patient care, medical knowledge.

Keywords: Central pontine myelinolysis, hyper-osmolar, hyponatremia, hypo-osmolar

How to cite this article:
Fegley MW, Singh A, Longo S, Sharma SG, Nanda S. Central pontine myelinolysis: Insight into pathogenesis, in the absence of hyponatremia. Int J Acad Med 2016;2:249-52

How to cite this URL:
Fegley MW, Singh A, Longo S, Sharma SG, Nanda S. Central pontine myelinolysis: Insight into pathogenesis, in the absence of hyponatremia. Int J Acad Med [serial online] 2016 [cited 2022 Oct 2];2:249-52. Available from: https://www.ijam-web.org/text.asp?2016/2/2/249/196871

Introduction

Central pontine myelinolysis (CPM) is a demyelinating disease of the central nervous system, most critically affecting the pons. It is commonly perceived to result from the rapid correction of hyponatremia. We report CPM in a diabetic with hyperglycemia, hypokalemia and hepatitis C-induced cirrhosis who unexpectedly developed the disease despite no true hyponatremia. We review various cerebral adaptive mechanisms and review risk factors for CPM.

Case Report

A 59-year-old diabetic male with cirrhosis and history of alcohol use presented with drowsiness, disorientation, slurred speech, dysphagia, and ambulatory dysfunction which had progressively worsened over 3 days. His HbA1c was 10.3%, which correlates to an average glucose of approximately 250 mg/dl. His maintenance regimen had been 30 units of glargine insulin daily, and 5 units of aspartate insulin with each meal. Seven days before the presentation, he had run out of insulin and for 3 days, his blood sugars were above 450 mg/dl. The blood sugar fell to 100 mg/dl within 1 day of restarting glargine insulin.

Examination, on admission, revealed stable vitals, icteric sclera, arousable with reduced attention span, dysarthria, dysphagia, reduced muscle bulk with increased tone, exaggerated reflexes, extensor plantar, and spastic gait. The serum sodium was 130 mmol/L (corrected sodium 136 mmol/L by Katz and 138 mmol/L by Hiller), potassium 3.3 mmol/L, and albumin 2.6 g/dl. Liver dysfunction was evident by a total bilirubin of 3.2 mg/dl and chronically elevated aspartate transaminase and alanine transaminase at 2–3 times upper normal limit. These were very similar to out-patient test from about 6 months back. Urine was negative for ketones. Magnetic resonance imaging (MRI) of the brain revealed a characteristic “bat wing” lesion in the pons on fluid-attenuated inversion-recovery and T2-weighted images [Figure 1].

Figure 1: Magnetic resonance imaging brain: A central, well-circumscribed region of high signal intensity within the pons measuring 1.7 cm × 1.4 cm seen on axial T2-weighted image

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Discussion

CPM is a devastating neurologic disease which occurs due to demyelination of the nerve cells at the mid pons. Signs and symptoms include confusion, lethargy, dysarthria, dysphagia, tremor, and profound bilateral weakness that may progress to spastic quadriplegia and “locked in syndrome.” A full differential of brain stem lesions is discussed in [Table 1].^[1] MRI provides definitive diagnosis. A central region of hypointensity on T1-weighted images and hyperintensity on T2-weighted imagining in the pons known as the “bat wing” lesion or “trident sign” [Figure 1].^[1]

Table 1: Differential diagnosis of magnetic resonance imaging brainstem lesions

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The mechanism of CPM is well studied. Both gray and white matters form a significant portion of the central part of the pons. In this location, the axons and glial cells are contained in a tight grid arrangement, which limits their capacity to swell. In the hypo-osmolar state, the glial cells adapt by losing osmolytes into the extracellular space, leaving the cell with abundant cytosolic water. When osmolar correction ensues, there is shrinkage of the glial cells by loss of intracellular water to the extracellular fluid.

There is a strong association between CPM and hyponatremia that is related to the rapid correction of chronic hyponatremia.

Cerebral adaptive mechanisms come into play to lessen neural cell swelling and damage. Within 1–3 h of hyponatremia, the swollen cerebral cells increase the interstitial pressure, causing interstitial fluid to flow into the cerebrospinal fluid. Starting 3 h after the onset of hypotonicity, there is a loss of intracellular potassium. Over the next 72 h, there is a loss of intracellular glutamate, taurine, myo-inositol, and glutamine.^[2] The reverse occurs when extracellular osmolarity is corrected [Figure 2]. Intracellular volume is normalized by electrolytes moving into the cell and the intracellular synthesis of organic osmoles.

Figure 2: A normal brain cell showing forces that work with osmolar changes. When extracellular sodium concentration falls water moves into the cell. The cell tries to limit its swelling by losing K⁺ and organic molecules such as taurine and others. When extracellular osmolality is restored, water moves out while K⁺ moves in and organic moles are synthesizemoles are synthesizemoles are synthesized

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Intracellular acquisition or loss of electrolytes and synthesis or loss of organic osmoles are reversed depending on osmolarity of extracellular fluid. Our patient had a combination of factors that limited his ability to control intracellular osmolarity: (a) The catabolic state of cirrhosis, malnutrition, sepsis, and metabolic disorders significantly impairs the synthesis of organic osmolytes.^[3] The role of organic osmoles is well-studied in rat models and is of great significance.^[4] His serum albumin and liver function enzymes did attest to reduced synthetic liver function and malnutrition. (b) Hypokalemia limits the amount of potassium that can move into the cell. It causes dysfunction of the sodium-potassium (Na ⁺-K ⁺) pump [Figure 2].^[5] CPM in diabetics with hypokalemia and malnutrition in the absence of hyponatremia is well documented.^[6],[7] When blood sugar suddenly plummets so does cerebral intracellular sugar. To prevent the cells from sudden shrinkage, potassium has to move into the cells and intracellular organic osmoles have to be synthesized. Both of these were limited by his existing preconditions.

His corrected sodium levels were at the lower limit of normal. Low normal sodium can result from advanced liver disease, syndrome of inappropriate antidiuretic hormone secretion, malnutrition, and adrenocortical insufficiency. Our patient had a history of alcoholism but had not been drinking in the preceding months. Alcohol blocks anti-diuretic hormone action resulting in upregulation of vasopressin receptors. These upregulated receptors coupled with malnutrition that accompanies chronic alcoholism, lead to hyponatremia.^[5] Once again, this was not causative in him as his sodium really did not change throughout the clinical course.

Conditions associated with CPM include chronic alcoholism (40%), rapid correction of hyponatremia (20%), postliver-transplantation (17%), cirrhosis (5%) and hyperglycemia, azotemia, hypernatremia, and rapid normalization of hypophosphatemia. Other causes are listed in [Table 2].^[8]

Table 2: Summary of etiological factors of central pontine myelinolysis and pathogenesis

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Treatment of hyponatremia involves gentle correction of the sodium level so that the cerebral adaptive mechanisms are not overwhelmed in over aggressive correction. The most recent European guidelines recommend a limit of sodium correction not exceed 10 mmol/L in 24 h and 18 mmol/L in 48 h. If this limit is exceeded, the guidelines recommend enacting measures to lower sodium levels back to within these limits. An exception is hyponatremia associated with cerebral edema and seizures. Sodium corrections as high as 4–5 mmol/L/h is recommended until one of the following occurs: The patient becomes asymptomatic, serum sodium reaches 120–125 mmol/L, or the plasma sodium has increased by 20 mmol/L.^[9]

Hyponatremia remains the most common electrolyte abnormality among inpatients; thousands are treated with different protocols and have varying rates of sodium correction. A very small minority go on to develop CPM. Harris et al. were unable to identify a lower limit of sodium infusion or an absolute magnitude of sodium correction that would consistently and accurately preclude the development of CPM.^[9],[10] This points at major roles played by other electrolytes and organic osmoles in either accentuating or attenuating the risk of developing CPM.

We suggest special considerations be taken in patients with underlying liver disease, malnutrition, and hypokalemia. Potassium and phosphate need to be corrected simultaneously with correction of blood sugar, to help cerebral adaptive mechanisms of osmolar changes. In addition, if there is true hyponatremia which merits correction, a much more gradual correction should be enacted.

Conclusion

Historically, CPM was described when chronic hyponatremia was rapidly corrected. Our patient developed CPM just from aggressive correction of blood sugar in the absence of true hyponatremia. He was deficient in potassium and organic osmoles from his underlying cirrhosis, and this limited his cerebral adaptive mechanisms. Patients with underlying liver disease, malnutrition, and hypokalemia are at increased risk of developing CPM when their blood sugar is corrected. A more comprehensive correction of potassium, phosphate should be incorporated to correction of blood sugar to prevent this debilitating complication.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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