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Central pontine myelinolysis: Insight into

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DOI: 10.4103/2455-5568.196871

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IJAM Journal of
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 Images in Academic Medicine

Central pontine myelinolysis: Insight into pathogenesis,

in the absence of hyponatremia
Mark William Fegley, Amitoj Singh1, Santo Longo2, Shree Gopal Sharma3, Sudip Nanda1
Departments of Family Medicine, 1Internal Medicine and 2Pathology, St. Luke’s University Health Network, Bethlehem, Pennsylvania,
3
Department of Pathology, University of Arkansas, Fayetteville, Arkansas, USA

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.

Key Words: Central pontine myelinolysis, hyper‑osmolar, hyponatremia, hypo‑osmolar

Address for correspondence:

Dr. Sudip Nanda, Department of Internal Medicine, St. Luke’s University Hospital Network, 801 Ostrum Street, Bethlehem, Pennsylvania 18015, USA.
E‑mail: sudip.nanda@sluhn.org
Received: 27.12.2015, Accepted: 29.01.2016

INTRODUCTION CASE REPORT

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.
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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
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DOI: How to cite this article: Fegley MW, Singh A, Longo S, Sharma SG,
10.4103/2455-5568.196871 Nanda S. Central pontine myelinolysis: Insight into pathogenesis, in the
absence of hyponatremia. Int J Acad Med 2016;2:249-52.

© 2016 International Journal of Academic Medicine | Published by Wolters Kluwer - Medknow 249
 Fegley, et al.: Central pontine myelinolysis insight into pathogenesis
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].
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]
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
250 International Journal of Academic Medicine | July-December 2016 | Vol 2 | Issue 2
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.
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.
 Fegley, et al.: Central pontine myelinolysis insight into pathogenesis

Table 1: Differential diagnosis of magnetic resonance imaging brainstem lesions

Etiology MRI findings
Glioma Hypointense mass on T1‑weighted images. High‑intensity signal on T2‑weighted and proton density images. Low‑grade
tumors often appear homogenous where as high‑grade tumors are often heterogeneous with central necrosis
Metastasis In general, hypointense on T1‑weighted images and increased signal intensity on T2‑weighted and proton density
images. Isolated brainstem lesions are unusual and are typically present in other locations
Other tumors Hamartoma, teratoma, epidermoid, and lymphoma will have various patterns on T1‑weighted and T2‑weighted images
Infarction Hypointense on T1‑weighted images. Hyperintense on T2‑weighted images. There is often an associated mass effect
and vague contrast enhancement resembling features of neoplasm
Multiple sclerosis Hypointense on T1‑weighted images. Hyperintense on T2‑weighted images. Typically similar areas of demyelination
will be seen elsewhere in the brain
Central pontine myelinolysis A central region of hypointensity on T1‑weighted images and hyperintensity on T2‑imagning in the pons. In extreme
cases, lesions can extend into the tegmentum, midbrain, thalamus, internal capsule, and cerebral cortex
Syringobulbia Central mass of cerebrospinal fluid density (hypointense on T1‑weighted images; hyperintense T2‑weighted images)
lying in and usually enlarging the medulla. Sharply defined margins and no contrast enhancement
Granuloma/abscess Types of abscess include tuberculosis, sarcoidosis, and infection. Appearance mimics a neoplasm and biopsy often
required for definitive diagnosis
MRI=Magnetic resonance imaging

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]

Treatment of hyponatremia involves gentle correction

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
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
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

International Journal of Academic Medicine | July-December 2016 | Vol 2 | Issue 2 251

 Fegley, et al.: Central pontine myelinolysis insight into pathogenesis
Table 2: Summary of etiological factors of central pontine
myelinolysis and pathogenesis
Etiology Pathogenesis
Chronic Hyponatremia, upregulation of vasopressin receptors,
alcoholism lack of glucose or glycogen, excess production of free
radicals, deranged nitric acid metabolism
Hypokalemia Decreased concentration of Na‑K ATPase
Nephrogenic Hypokalemia
diabetes
insipidus
Cirrhosis Decreased organic osmolytes, metabolic stress, lack of
glucose or glycogen, free radical production, release of
glutamate and increased apoptosis
Liver No definite mechanism; possible mechanism mentioned
transplantation under cirrhosis, other possible cause may be sepsis,
metabolic disorders, hepatic encephalopathy,
decreased organic osmolytes, hypoxia, cyclosporine
toxicity and extent of pretransplant liver dysfunction
Acute May be deficiency of δ‑amino levulinic acid, heme
intermittent deficiency, reversible vasospasm, hyponatremia
porphyria
Hyponatremia Leads to cell swelling‑rapid corrections leave insufficient
time for adaptive mechanism (such as osmolyte
synthesis) to come into play resulting in cell death
Malnutrition May be decreased glucose stores in glial cells, electrolyte
and metabolic imbalances, decreased organic osmolytes
Burn Electrolyte imbalance, rapid correction of hyponatremia
Hyperglycemia High glucose load in the extracellular fluid and shift to
hyperosmolar state
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
252 International Journal of Academic Medicine | July-December 2016 | Vol 2 | Issue 2
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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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