European Journal of Neurology 2014 doi:10.1111/ene.

12571

REVIEW ARTICLE

Central pontine and extrapontine myelinolysis: a systematic

review
T. D. Singh, J. E. Fugate and A. A. Rabinstein
Department of Neurology, Mayo Clinic, Rochester, MN, USA

Keywords: The purpose was to perform a systematic review of studies on central pontine and
central pontine extrapontine myelinolysis [forms of osmotic demyelination syndrome (ODS)] and
myelinolysis, define the spectrum of causes, risk factors, clinical and radiological presentations,
extrapontine and functional outcomes of this disorder. A thorough search of the literature was
myelinolysis, osmotic conducted using multiple databases (PubMed, Ovid Medline and Google) and bibli-
demyelination ographies of key articles to identify all case series of adult patients with ODS pub-
lished from 1959 to January 2013. Only series with five or more cases published in
Received 12 May 2014 English were considered. Of the 2602 articles identified, 38 case series were included
Accepted 1 August 2014 comprising a total of 541 patients who fulfilled our inclusion criteria. The most
common predisposing factor was hyponatremia (78%) and the most common pre-
sentation was encephalopathy (39%). Favorable recovery occurred in 51.9% of
patients and death in 24.8%. Liver transplant patients with ODS had a combined
rate of death and disability of 77.4%, compared with 44.7% in those without liver
transplantation (P < 0.001). ODS is found to have a good recovery in more than
half of cases and its mortality has decreased with each passing decade. Favorable
prognosis is possible in patients of ODS, even with severe neurological presentation.
Further research is required to confirm the differences found in liver transplant
recipients.

Osmotic demyelination syndrome (ODS) is an uncom-
mon neurological disorder caused by damage to the
myelin sheath of brain cells [1]. Central pontine my-
elinolysis (CPM) is the classical presentation, reflect-
ing greater susceptibility of pontine white matter
tracts, but extrapontine involvement (extrapontine
myelinolysis or EPM) is actually quite common.
Adams and colleagues first described CPM [2] in 1959
in a report of four patients with quadriplegia and
pseudobulbar palsy, all of whom were chronic alco-
holics or malnourished. Although the exact pathogen-
esis is still not known, a common trigger of
myelinolysis in clinical practice is rapid correction of
chronic hyponatremia [3,4], which has also been
shown to induce pathological changes in animal
models [5].
Osmotic demyelination syndrome (ODS) has tradi-
tionally been described in alcoholics [2,6–15], liver
transplant recipients [16–23] and in patients with rapid
osmolar shifts [4,8,11,24] (particularly with a precipi-
tous rise in serum sodium concentration). Yet multiple
Correspondence: A. A. Rabinstein, 200 First St SW – Mayo W8B,
Rochester, MN 55905, USA (tel.: 507-530-1036; fax: 507-266-4419;
e-mail: rabinstein.alejandro@mayo.edu).
other associations have been reported, including
severe hypophosphatemia [25,26,27] and hypokalemia
[27,28], diabetes mellitus [29–31], renal failure [32], he-
modialysis [32], hyperemesis gravidarum [33], anorexia
nervosa [34,35], Wilson disease [36], severe burns [14]
and systemic lupus erythematosus [37] amongst
others.
The clinical manifestations are variable. Classically
CPM presents with a biphasic course with initial sei-
zures or encephalopathy that may improve gradually
but are then followed by severe deterioration mani-
fested by dysarthria, dysphagia, oculomotor dysfunc-
tion and variable degrees of quadriparesis. Patients
with most severe cases may become locked-in, with
only preservation of vertical eye movements and
blinking. The increasing use of magnetic resonance
imaging (MRI), which is very sensitive for detecting
myelinolysis, has led to a greater recognition of mild
and even asymptomatic cases [15,38]. The typical
radiological findings on brain MRI are hyperintense
lesions in the central pons or associated extrapontine
structures on T2-weighted and fluid-attenuated inver-
sion recovery sequences with corresponding hypoin-
tensity on T1-weighted sequences.

© 2014 The Author(s)

European Journal of Neurology © 2014 EAN
2 T. D. Singh et al.
Initially ODS was thought to have a consistently
poor outcome because the diagnosis was only con-
firmed by necropsy [6–18]. However, contemporary
series have shown that good recovery from ODS is
not infrequent and total or near-total remission of
severe symptoms is possible [32,38–52]. This could be
attributed to more sensitive diagnosis with advanced
neuroimaging, greater recognition of the triggers of
ODS and improved intensive care treatment.
The literature on ODS has grown steadily in recent
years, but misconceptions persist. A systematic review
of studies on ODS published over the last five decades
was performed to define the spectrum of causes, risk
factors and predisposing conditions, clinical and
radiological presentations, and functional outcomes of
this disorder.
Methods
A thorough search of the literature was conducted to
identify all case series of adult patients with CPM and
ODS published from 1959 to January 2013. To iden-
tify the relevant studies multiple databases (PubMed,
Ovid Medline and Google) were searched using the
following terms: pontine myelinolysis, extrapontine
myelinolysis, and osmotic demyelination syndrome.
Eligible studies were those including adult patients
with a diagnosis of CPM, EPM or ODS confirmed by
imaging or pathological findings at necropsy. Only
series with five or more cases published in English
were included. The data were segregated into catego-
ries of cases diagnosed by necropsy and cases diag-
nosed radiologically. The cases diagnosed in liver
transplant recipients were analyzed separately because
it was the only associated condition with several spe-
cific case series reported.
Collected information included age, sex, serum
sodium levels and neurological symptoms at the time
of presentation (defined as the time of first hospital
evaluation), associated comorbidities, radiological or
necropsy findings, and final clinical outcome. Hypo-
natremia was defined as serum sodium concentration
lower than 135 mmol/l and severe hyponatremia as
serum sodium concentration lower than 120 mmol/l.
Disability was defined as inability to perform basic
activities of daily living. The outcome was calculated
based on the last follow-up reported in the studies.
Results are expressed using descriptive statistics.
The two-tailed Fisher’s exact test and chi-squared test
were used when appropriate to compare clinical char-
acteristics, distribution of demyelinating lesions, asso-
ciated conditions, and rates of death and disability
between liver transplant recipients and patients with-
out liver transplantation.
Results
Search results
A total of 2602 articles were identified by our initial
search. The distribution by search terms was pontine
myelinolysis (1489), extrapontine myelinolysis (952)
and osmotic demyelination syndrome (161). After
screening of the contents, 38 case series were found
that fulfilled our inclusion criteria: 10 case series
comprising 206 patients diagnosed at necropsy [6–
15], 20 case series with 276 patients diagnosed
radiologically [4,32,38–55] and eight case series with
59 patients who developed CPM, EPM or both
after liver transplantation who were diagnosed
radiologically (33 patients) [19–23] or by necropsy
(26 patients) [16–18]. This resulted in a total of 541
cases being included in our systematic review
(Tables S1, S2 and S3).
Necropsy studies
The studies in this category were published from
1964 to 1996. The mean age in this cohort was
49.1 years and 62.4% were men. More than two-
thirds (66.4%) were diagnosed with CPM, and about
a quarter of those had both CPM and EPM. There
was a small proportion of patients (6.2%) with only
EPM. Serum sodium was reported in only 105
(44.9%) patients. Three-quarters (74.3%) of the
patients had documented hyponatremia, including
23.8% in whom it was severe. On presentation, 50
(44.5%) had encephalopathy but only 7.1% were
comatose. Seizures were present in 12.5% of cases
whilst hemiparesis, ataxia and oculomotor signs were
all documented in <10% of cases. The majority of
patients (54.7%) had documented alcoholism; cirrho-
sis, malnutrition and cancer were the other main
associated conditions (Table 1).
Studies with radiological diagnosis
Studies were published from 1985 to January 2013.
A small proportion of cases also had pathological
confirmation (n = 8, 3.8%). Mean age was
50.6 years and 51.8% were men. More than half
had only CPM whilst 31.1% had both CPM and
EPM and 12.8% had only EPM. There were only
two studies that solely used computed tomography
(CT) scan for the diagnosis [4,54] whilst MRI was
used in 12 studies [19,21,22,28,30,32,38,40,42,44–46].
The rest of the studies used patients diagnosed on
both CT and MRI scans [4,20,23,39,41,43,47–
49,51,53–55]. Radiological findings of CPM/EPM
© 2014 The Author(s)
European Journal of Neurology © 2014 EAN
 Central pontine and extrapontine myelinolysis 3

Table 1 Patients with CPM or EPM distributed by method of diag- predominant associated condition (50.5%), followed
nosis distantly by cirrhosis and malnutrition.
Radiological
Necropsy diagnosis
(n = 234) (n = 307)
Studies on liver transplantation patients

n % n % Studies ranged from 1988 to 2009. The mean age of

these patients was 44.6 years and 77.5% were men.
Patient characteristics The majority of patients had CPM alone (78%), four
Age, years, mean 49.1 50.6
Male sex 116 62.4 156 51.8
(6.8%) had only EPM lesions and nine (15.3%) had
Sodium <120 mmol/l 25 23.8 126 58.9 both. Hyponatremia was documented in 66.7%
Sodium 121–135 mmol/l 53 50.5 45 21 patients but it was rarely severe (3.7%). Clinical pre-
Sodium >135 mmol/l 27 25.7 43 20.1 sentations included encephalopathy in 61.3% of
Lesional features patients, seizures in 48.9%, paresis in 29%. The main
CPM only 150 66.4 166 56.1
EPM only 14 6.2 38 12.8
associated condition was cirrhosis in 30.5%, and only
Both CPM and EPM 62 27.4 92 31.1 few patients (6.8%) had a history of alcoholism.
Restricted diffusion NA NA 30 45.5 Table 2 compares the clinical characteristics, associ-
Contrast enhancement NA NA 14 20.6 ated conditions and clinical outcomes of liver trans-
Clinical presentation plant recipients with radiological diagnosis of ODS
Encephalopathy 50 44.5 116 37.1
versus the rest of the patients with the same radiologi-
Seizures 14 12.5 75 24
Paresis 11 9.8 90 28.8 cal diagnosis. Compared with other patients with
Dysarthria 0 0 36 11.5 ODS, liver transplant patients were more frequently
Ataxia 9 8 45 14.4 men (P = 0.004), more likely to have only pontine
Oculomotor abnormalities 9 8 26 8.3 lesions (P = 0.005) and present with encephalopathy
Coma 8 7.1 44 14.1
Associated comorbidities
(P = 0.003), seizures (P < 0.001), and underlying cir-
Alcoholism 127 54.7 158 50.5 rhosis (P < 0.001). Meanwhile, severe hyponatremia
Cirrhosis 40 17.2 39 12.5 (P < 0.001) and alcoholism (P < 0.001) were less com-
Malnutrition 38 16.4 35 11.2 monly documented in liver transplant recipients.
Liver transplantation 30 12.9 43 13.7
Renal failure 26 11.2 25 8
Burns 9 3.9 1 0.3 Outcomes
Neoplasm 30 12.9 4 1.3
Clinical outcome The temporal distribution of clinical outcomes for all
Death NA NA 67 24.8 cases included in the analysis is shown in Fig. 1. Fig-
Disability NA NA 63 23.3 ure 2 shows this information exclusively for radiologi-
Recovery NA NA 140 51.9
cally diagnosed cases. Favorable outcome occurred in
Percentages are calculated based on the number of patients in whom more than half of all patients with radiological diag-
the specific variable was available. nosis and nearly one-quarter achieved good functional
recovery. However, the clinical outcome was worse in
liver transplant recipients (Table 2). Liver transplant
were detected by MRI in 253 (86.6%) patients and patients with ODS had a combined rate of death and
by CT scan in 17 (5.8%). CT and MRI scans were disability of 77.4% compared with 44.7% in those
both positive in 22 (7.6%) patients. Of the 63 without liver transplantation (P < 0.001).
patients in which diffusion-weighted sequences were
reported, 30 (45.5%) showed evidence of restricted
Discussion
diffusion. Contrast enhancement of the demyelinat-
ing lesions was noted in 14 of 68 patients (20.6%) This comprehensive review of the published experience
who had gadolinium administration. Serum sodium on ODS contains the largest collection of cases with
was reported in 214 (69.7%) patients. More than this disorder. It provides a perspective on the evolu-
two-thirds of the patients had documented hyponat- tion of our understanding of ODS and illustrates how
remia, which was severe in 58.9%. On presentation, it was dramatically impacted by the advent of modern
37.1% had encephalopathy and 14.1% were coma- imaging. When first recognized in necropsy cases,
tose. Paresis was noticed in approximately one-third CPM was thought to be exceptionally rare, difficult to
and seizures in one-quarter. Ataxia, dysarthria and recognize before death, and characteristically fatal
oculomotor signs were less common, but all were [7,24,56]. The development of CT and particularly
present in 10 20% of cases. Alcoholism was the MRI allowed the recognition of the true clinical and

© 2014 The Author(s)

European Journal of Neurology © 2014 EAN
4 T. D. Singh et al.

Table 2 Comparison between patients with

Liver liver transplantation and patients with
transplantation other associated conditions
(n = 59) Other (n = 482)

n % n %

Patient characteristics
Age, year, mean 44.6 51.4
Male sex 31 77.5 238 53.7
Sodium <120 mmol/l 2 3.7 149 56.2
Sodium 121–135 mmol/l 34 63 59 22.3
Sodium >135 mmol/l 12 22.2 57 21.5
Lesion location
CPM only 46 78 287 58.9
EPM only 4 6.8 48 9.9
Both CPM and EPM 9 15.3 152 31.2
Clinical presentation
Encephalopathy 19 61.3 146 34.4
Seizures 15 48.4 71 16.7
Paresis 9 29 98 23.1
Dysarthria 1 3.2 35 8.2
Ataxia 1 3.2 53 12.5
Oculomotor abnormalities 3 9.7 32 7.5
Coma 2 6.5 50 11.8
Associated comorbidities
Alcoholism 4 6.8 280 58.1
Cirrhosis 18 30.5 58 12
Malnutrition 0 0 73 15.1
Renal failure 8 13.6 43 8.9
Burns 0 0 10 2.1
Neoplasm 0 0 34 7.1
Clinical outcome*
Death 13 41.9 54 22.6
Disability 11 35.5 52 21.8
Recovery 7 22.6 133 55.6

Percentages are calculated based on the number of patients in whom the specific variable was
available. *Only among patients with radiological diagnosis.

Figure 1 Distribution of outcomes in

published cases of ODS over time.

© 2014 The Author(s)

European Journal of Neurology © 2014 EAN

Figure 2 Temporal distribution of pub-
lished cases of ODS diagnosed radiologi-
cally.
sub-clinical spectrum of the disease [40,45,53,55] and
facilitated research on its pathogenesis [4,54]. Thanks
to radiological diagnosis it is now known that the out-
come of ODS is neither as frequently fatal nor as uni-
formly disabling as previously considered. In fact, a
combined analysis of recent series that relied on radio-
logical diagnosis clearly indicates that full recovery is
possible and more than half of the patients with ODS
regain independent function [41,44,47–51]. The prog-
nosis may be less favorable in liver transplant recipi-
ents [20,22,23].
The clinical presentation can be quite variable.
Various degrees of encephalopathy is most common,
but coma occurred in less than 15% of cases. Focal
signs of pontine dysfunction are not present in
many cases, a fact that explains the difficulty with
ante-mortem diagnosis before neuroimaging became
widely available. Asymptomatic or very mildly
symptomatic cases can occur, but their incidence is
uncertain [48,53]. Meanwhile, even patients with
severe deficits at presentation can achieve good
recovery [49,51].
Rapid correction of chronic hyponatremia is the
most frequent predisposing factor for the development
of ODS [4,11,54]. Alcoholism [4,6–9,11–16,32,38–55],
cirrhosis [7,8,10–13,44,45], malnutrition [6,7,13,14,48–
52] and severe burns [14] are other associated condi-
tions, often present in combination with rapid rise in
serum sodium concentration [4,11,54]. This review
confirms and helps quantify these associations. At
least three-quarters of all reported cases had hyponat-
remia, which was severe (serum sodium concentration
<120 mmol/l) in more than half. Alcohol abuse was
documented in approximately half of all cases. These
© 2014 The Author(s)
European Journal of Neurology © 2014 EAN
Central pontine and extrapontine myelinolysis 5
associations have remained consistent over several
decades.
The current standard method for the diagnosis of
ODS is brain MRI. Pontine demyelination remains
the hallmark of the disease, but purely extrapontine
lesions were seen in 12.8% of our combined cohort
with radiological diagnosis and the combination of
pontine and extrapontine lesions is very common in
contemporary reports. Extrapontine lesions are most
often located in the midbrain, thalami and basal gan-
glia [48,49,52]. Pontine and extrapontine lesions can
exhibit restricted diffusion, but these changes do not
seem to facilitate earlier or more sensitive diagnosis
[52]. Contrast enhancement can also be noted in one-
fifth of cases. Lesion location, lesion volume, diffusion
restriction and contrast enhancement do not appear
to influence prognosis [48,49,52].
Liver transplant patients are known to be at risk
for developing ODS [20,22,23]. Our review suggests
some differences between cases of ODS in liver trans-
plant recipients compared with the rest of the cohort.
Male sex, demyelination restricted to the pons, presen-
tation with encephalopathy and seizures, and underly-
ing cirrhosis appear to be more common in these
patients, whilst severe hyponatremia and alcohol
abuse appear to be less frequent. Whether any of
these particular features or their combination may
help explain the differences in clinical outcome
deserves to be further studied.
Our review highlights the change in reported out-
comes of ODS over the last few decades. Although
formerly deemed to be almost invariably fatal or
severely disabling, ODS is actually compatible with
good recovery in more than half of cases. This is a
6 T. D. Singh et al.
very important message because some clinicians
remain unaware that favorable prognosis is possible
even in patients with severe neurological deficits, and
an overly pessimistic prognostication can lead to pre-
mature withdrawal of supportive therapy. Liver trans-
plant recipients with ODS may have worse chances of
recovery. Whether this is related to greater severity of
the demyelination or worse comorbidities remains
unclear. The pathophysiology of the disorder is
probably the same as in other cases, as suggested by
the comparable prevalence of hyponatremia, although
a heightened susceptibility to develop the complication
can be inferred by the lower severity of the hyponatre-
mia upon presentation.
Our study has several limitations. Given the lack
of sufficient detail in the published articles and the
large time span of our review, it was not possible to
collect individual patient data. Consequently, associa-
tions between various variables (e.g. degree of hypo-
natremia, alcoholism, MRI findings) and clinical
outcome could not be tested for. Although informa-
tion could only be collected on degree of hyponatre-
mia, hyponatremia per se is probably not a cause of
ODS and the chronicity and speed of correction of
this electrolyte disorder are crucial to the develop-
ment of demyelination [57]. However, information
was lacking on the chronicity and rapidity of correc-
tion of hyponatremia. Hyponatremia and ODS can
both produce encephalopathy and the clinical distinc-
tion can be very difficult. Our analysis was per-
formed on the basis of the information on
encephalopathy as provided in the individual studies.
Time to brain imaging from symptom onset was not
consistently reported and the frequency of radio-
graphic characteristics (restricted diffusion, contrast
enhancement) may be affected by time to imaging.
Outcomes in the different studies were often not
assessed using a standardized tool and length of fol-
low-up also varied. Nonetheless, the studies usually
provided enough information to determine whether
the patients had regained independence, and avail-
ability of longer follow-up would probably have
resulted in greater rates of functional recovery, thus
strengthening our main conclusion. The possibility
that the literature reviewed may be affected by publi-
cation bias cannot be ruled out. Case reports and
small case series with <5 patients were excluded to
reduce and minimize this potential bias. Lastly, the
number of patients with liver transplantation was
much smaller than the rest of the cohort used for
comparison. Consequently, the differences found in
liver transplant recipients require confirmation.
It is concluded that patients with ODS often
achieve a favorable recovery. Therefore, clinicians
should be cautious when estimating prognosis, and
aggressive supportive care and treatment of coexistent
diseases is justified even in patients with severe neuro-
logical deficits upon diagnosis of ODS.
Acknowledgement
None.
Disclosure of conflicts of interest
The authors declare no financial or other conflicts of
interest.
Supporting Information
Additional Supporting Information may be found in
the online version of this article:
Table S1. Necropsy studies.
Table S2. Radiological studies.
Table S3. Liver transplant series.
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© 2014 The Author(s)
European Journal of Neurology © 2014 EAN