Received: 25 June 2019 | Revised: 16 July 2019 | Accepted: 20 July 2019

DOI: 10.1111/ane.13150

ORIGINAL ARTICLE

Incidence of osmotic demyelination syndrome in Sweden: A

nationwide study

Hildur Aegisdottir1 | Charith Cooray2,3 | Karin Wirdefeldt2,4 | Fredrik Piehl2,3 |

Olafur Sveinsson1,2

1
Department of Neurology, The National
University Hospital of Iceland, Reykjavik, Objective: To report the incidence rate of osmotic demyelination syndrome (ODS),
Iceland associated risk factors, treatment, and long‐term outcomes in a nationwide cohort.
2
Department of Neurology, Karolinska
Methods: We conducted a retrospective study of individuals diagnosed with central
University Hospital, Stockholm, Sweden
3
Department of Clinical
pontine myelinolysis (ICD‐10 code G37.2) in the Swedish National Patient Register
Neuroscience, Karolinska Institutet, during 1997‐2011.
Stockholm, Sweden
4
Results: During the study period, we identified 83 individuals with ODS, 47 women
Department of Medical Epidemiology
and Biostatistics, Karolinska Institutet, and 36 men. Median age at diagnosis was 55 years. The incidence rate of ODS for
Stockholm, Sweden the entire study period was 0.611 (95% CI: 0.490‐0.754) per million person‐years and
Correspondence increased during the study period from 0.271 (95% CI: 0.147‐0.460) in 1997‐2001
Olafur Sveinsson, Department of Neurology, to 0.945 (95% CI: 0.677‐1.234) individuals per million person‐years in 2007‐2011.
Karolinska University Hospital, 171 76,
Stockholm, Sweden. Most cases (86.7%) were hyponatremic with a median sodium level at admission of
Email: olafur.sveinsson@sll.se 104 mmol/L. All hyponatremic cases were chronic. The cause of hyponatremia was
multifactorial, including drugs (56.9%), polydipsia (31.9%), and vomiting or diarrhea
(41.7%). A majority of patients (69.9%) were alcoholics. Hyponatremic patients were
predominantly treated with isotonic saline (93.1%) and only 4.2% with hypotonic flu‐
ids. The median correction rate was 0.72 mmol/L/h. Only six patients were corrected
in accordance with national guidelines (≤8 mmol/L/24/h). At three months, 7.2% had
died and 60.2% were functionally independent (modified Rankin Scale 0‐2).
Interpretation: We found an increasing incidence during the study period, which
could partly be explained by increased access to magnetic resonance imaging. ODS
occurs predominantly in patients with extreme chronic hyponatremia which is cor‐
rected too fast with isotonic saline. Most patients survived and became functionally
independent.

KEYWORDS
central pontine myelinolysis, incidence, modified Rankin Scale, osmotic demyelination
syndrome

1 | I NTRO D U C TI O N
Osmotic demyelination syndrome (ODS) is a neurologic disorder char‐
acterized by myelin sheath degradation in various areas of the brain,
Fredrik Piehl and Olafur Sveinsson are shared last authorship.
the usual affected site being the central basal pons (central pontine
myelinolysis) but sometimes involving other areas, for example the
basal ganglia, thalami, and cerebellum (extrapontine myelinolysis).1,2
The condition was first described by Adams et al in 1959, in autopsied
pontine tissue of four alcoholic and malnourished patients.3 ODS was

342 | © 2019 John Wiley & Sons A/S. wileyonlinelibrary.com/journal/ane Acta Neurol Scand. 2019;140:342–349.
Published by John Wiley & Sons Ltd
AEGISDOTTIR et al. | 343

previously believed to be universally fatal.3-5 In the last four decades,
it has become clear that many patients survive ODS and that it can be
at least partly reversible.6-8 ODS has thus shifted from being mainly
a pathological diagnosis at autopsy to a radiological one, as especially
magnetic resonance imaging (MRI) shows the characteristic pontine
or extrapontine lesions of demyelination.9,10
The most commonly described underlying cause is an overly
rapid correction of hyponatremia,11 which has been observed both
in the clinical setting and in controlled animal trials.9,11-17 The exact
mode by which the correction of hyponatremia causes ODS is still
unknown, but osmotic imbalance between the blood and brain cells
is believed to be an underlying mechanism.18,19 Organic osmolytes
travel through the glial cell membrane slower than electrolytes,
and they are released into the blood in a state of chronic hypona‐
tremia.18,19 When the hyponatremia is corrected, osmolyte reac‐
cumulation in the cell is delayed, causing acute osmotic imbalance
and subsequent cell death and myelin degradation.18-21 However,
various predisposing factors have been described including other
electrolyte disturbances such as hypokalemia, hypernatremia, alco‐
holism, malnutrition, and liver failure.17,22-26 The incidence of ODS is
unknown, and larger case series are rare. The aim of this nationwide
study was to determine the incidence, causes, clinical presentation,
and prognosis of ODS in Sweden.
radiologic signs of ODS (Figure 1). The rate of sodium correction was
calculated from patient records. We determined the fastest correction
rate in mmol/L/h in each case, which had to be calculated over a mini‐
mum of 8 hours. Chronic hyponatremia was defined to have developed
>48 hours.28
2.2 | Rating of symptoms
For the estimation of the level of consciousness at admission, the pa‐
tients’ score on the Glasgow Coma Scale (GCS) was extracted from
records and categorized into two groups: those with 14‐15 (mild en‐
cephalopathy) and those with 13 or lower (moderate or severe en‐
cephalopathy). The modified Rankin Scale (mRS) was used to rate
the patients’ functional outcome at 3 months after the diagnosis of
ODS. Patients with mRS 0‐2 were classified as being functionally in‐
dependent and patients with mRS 3‐6 as functionally dependent. To
rate the severity of acute ODS symptoms at diagnosis, an ODS symp‐
tom severity scale was developed (Table 1). As in the mRS, patients
were rated from 0‐6 according to the level of their acute disability,
but without ADL assessment as that is usually not considered in the
acute setting. A similar rating of ODS symptoms was conducted in a
review of pediatric ODS cases by Ranger et al. 29

2 | M E TH O DS

2.1 | Data collection

All patients diagnosed
This study was approved by the ethical committee in Stockholm,
with ODS in the Swedish
Sweden. The Swedish National Patient Register (SNPR) contains Patient Register between
all patients hospitalized (with total national coverage from 1987) 1997 and 2011 (n = 111)
or managed in hospital‐based ambulatory care (since 2001) in
Sweden. 27 Each individual's outpatient visit or hospital discharge
Missing or
diagnosis (ICD code) is linked with their unique personal identifica‐ Neurological disorder incomplete data
tion number. We retrieved Patient Register records for all individuals other than ODS (n = 5)
with a diagnosis of central pontine myelinolysis (ICD‐10 code G37.2, -Cerebrovascular No mention of ODS
n = 111) between January 1, 1997 and December 31, 2011. disease (n = 5) (n = 5)
After receiving information from the National Patient Register, we -Multiple sclerosis
requested medical records from the respective hospitals. Demographic (n = 1)
and clinical information, including radiologic findings, treatment, and -Olivopontocerebellar
outcome, were obtained from medical records through a structured atrophy (n = 1) Diagnosis of ODS
unclear (n = 2)
questionnaire. Central pontine myelinolysis or ODS was defined as -Other neurological
symptoms and radiologic signs (preferably MRI) corresponding to disorder (n = 5)
pontine or extrapontine myelinolysis. For five patients, there was no
or missing information in the medical records and for another five pa‐
tients, there were clear clerical errors regarding the ICD code (Figure 1).
In all, 101 records were evaluated independently by two of the authors Patients with ODS after chart review
(n = 87)
(HA and OS). If there was disagreement, diagnoses were assigned by
consensus between the two. Patients deemed more likely to have
other neurological disorders (n = 12) and patients who did not have
Patients diagnosed within the
a definite ODS diagnosis (n = 2) were excluded. Four of the remaining specified study period (n = 83)
patients received the diagnosis outside the study period. The remain‐
ing 83 patients were included in the cohort, all of which had clinical and FIGURE 1 Patient selection flowchart
344 | AEGISDOTTIR et al.

ODS symptom severity scale
No neurologic symptoms
Very mild symptoms of ODS
without significant disability
Mild paresis or walking
instability
Limb paresis and/or bulbar
symptoms and/or extrapy‐
ramidal symptoms
Complete limb paresis/tetra‐
plegia and/or seizures and/
or impaired consciousness
Locked‐in state/coma
Dead
TA B L E 1 Osmotic demyelination
Modified Rankin Scale
syndrome (ODS) symptom severity
0 No symptoms 0 scale and the modified Rankin Scale for
1 No significant disability. Able to carry out all 1 comparison
usual activities, despite some symptoms
2 Slight disability. Able to look after own affairs 2
without assistance, but unable to carry out all
previous activities
3 Moderate disability. Requires some help, but 3
able to walk unassisted
4 Moderately severe disability. Unable to attend 4
to bodily needs without assistance or unable to
walk unassisted
5 Severe disability. Requires constant nursing care 5
and attention, bedridden
6 Dead 6

TA B L E 2 Incidence rate of ODS in Sweden during 1997‐2011 3 | R E S U LT S

Incidence rate (95%
Time period Cases/person‐yearsa CI)b 3.1 | Incidence
1997‐2011 83/135 810 0.611 (0.490‐0.754) The incidence rate of ODS during the entire study period was 0.611
1997‐2001 12/44 325 0.271 (0.147‐0.460) (95% CI: 0.490‐0.754) individuals per million person‐years (Table 2).
2002‐2006 28/44 990 0.622 (0.422‐0.888) The incidence rate increased during the study period from 0.271

2007‐2011 43/46 495 0.945 (0.677‐1.234) (95% CI: 0.147‐0.460) per million person‐years in 1997‐2001 to
0.622 (0.422‐0.888) per million person‐years in 2002‐2006, and fi‐
Abbreviations: CI, 95% confidence interval, ODS, osmotic demyelinat‐
nally to 0.945 (95% CI: 0.677‐1.234) individuals per million person‐
ing syndrome.
a
Million person‐years. years in 2007‐2011.
b
Average yearly incidence rate per 1 000 000 individuals.

3.2 | Demography, clinical characteristics,

2.3 | Statistical analysis
Population data for the estimation of incidence were obtained
from Statistics Sweden (www.scb.se). The incidence rate of ODS
was calculated as the number of incident ODS cases during the
period January 1, 1997 to December 31, 2011 divided by the total
number of person‐years at risk (estimated by summing up the
mid‐year census population of each year) and was reported per
1 000 000 person‐years with 95% confidence interval. In addi‐
tion, we calculated incidence rate separately for the time periods
1997‐2001, 2002‐2006, and 2007‐2011. Associations between
dependent and independent variables were univariately presented
as odds ratios with accompanying 95% confidence intervals (cal‐
culated using a logistic regression framework). The dependent
variable analyzed was poor functional outcome, defined as a
mRS 3‐6. Hyponatremia was defined as having a serum sodium of
<135 mmol/L. The independent variables studied were hypona‐
tremia ≤110 mmol/L vs hyponatremia >110 mmol/L, Symptom
severity scale 4‐6 vs 0‐3, sodium correction rate >0.5 mmol/L/h
vs ≤0.5 mmol/L/h, hypokalemia at admission ≤3.5 mmol/L vs
>3.5 mmol/L and GCS at admission ≤13 vs GCS at admission >13.
Statistical analysis was performed in Stata® statistical software.
treatment, and outcome
During the study period, we identified 83 individuals with ODS.
There were no patients with recurrent disease. There was a slight
predominance of females (n = 47, 56.6%) (Table 3). The median age
at diagnosis was 55 years (Inter Quartile Range, 48‐61). No children
with ODS were detected. The majority of cases (n = 72, 86.7%) were
hyponatremic. In the hyponatremic group, the median sodium level
at admission was 104 mmol/L (IQR 99.5‐110.5) (Table 3). All hypona‐
tremic cases were judged to be chronic. There were three hyperna‐
tremic patients with a median sodium at admission of 162 mmol/L
(range 150‐180). Four patients were normonatremic at admission
and in another four cases, sodium levels at admission were unknown.
In all these eight cases, a known predisposing factor was present
(alcoholism, n = 8, liver failure, n = 1, lung cancer, n = 1). The median
potassium level at admission was 3.1 mmol/L (IQR 2.6‐3.7) (normal
value 3.5‐4.6 mmol/L). In five cases, it was unknown. There were
56 (67.5%) individuals with hypokalemia, with a median potassium at
admission of 3.0 mmol/L (Table 3).
A majority (n = 58; 69.9%) of the patients were alcoholics.
Other comorbidities can be seen in Table 3. Although most pa‐
tients (n = 68; 81.9%) were encephalopathic at admission, only 19
(22.9%) had a GCS of 13 or lower. Six patients (7.2%) presented
AEGISDOTTIR et al. | 345

TA B L E 3 Patients demography and clinical characteristics TA B L E 4 Hyponatremic treatment, symptoms and outcome

Demographics (n = 83) Hyponatremic treatment (n = 72)

Sex (females) 47 (56.6%) Isotonic 67 (93.1%)

Average age at diagnosis (range) 54.5 (22‐83) Hypotonic 3 (4.2%)
Comorbid diseases (n = 83) Hypertonic 1 (1.4%)
Alcoholism 58 (69.9%) No fluids 1 (1.4%)
Systemic hypertension 40 (48.2%) Symptoms & clinical findings (n = 83)
Psychiatric disorder other than alcoholisma 20 (24.1%) Symptoms at admission
Endocrinological diseaseb 13 (15.7%) Encephalopathy 68 (81.9%)
Renal failure 6 (7.2%) Seizures 6 (7.2%)
Tumor 3 (3.6%) GCS 13 or lower 19 (22.9%)
Known liver disease 2 (2.4%) Symptoms at ODS diagnosis
Sodium at admission (n = 83) Bulbar symptoms 73 (88.0%)
Hyponatremia (<135 mmol/L) 72 (86.7%) Dysarthria/dysphagia 71 (85.5%)
Sodium ≤ 110 mmol/L among hypona‐ 54 (75.0%) Limb paresis 65 (78.3%)
tremic patients (n = 72) Locked‐in state 10 (12.0%)
Sodium >110 mmol/L among hypona‐ 18 (25.0%) Median score on the ODS symptom severity 3 (2‐5)
tremic patients (n = 72) scale
Median sodium among hyponatremic 104 mmol/L (IQR ODS symptom severity scale (0‐3) 63 (75.9%)
patients (n = 72) 99.5‐110.5)
ODS symptom severity scale (4‐6) 20 (24.1%)
Hypernatremia (>146 mmol/L) 3 (3.6%)
Radiology (n = 83)
Normonatremia (135‐146 mmol/L) 4 (4.8%)
Only CPM 42 (50.6%)
Unknown 4 (4.8%)
Both CPM and EPM 37 (44.6%)
Potassium at admission (n = 83)
Only EPM 4 (4.8%)
Median potassium at admission 3.1 mmol/L (IQR
2.6‐3.7) Outcome at three months (n = 83)

Hypokalemia (≤3.5 mmol/L) 56 (67.5%) ADL independent (modified Rankin Scale, 0‐2) 50 (60.2%)

Median potassium among hypokalemic 3.0 mmol/L (IQR ADL dependent (modified Rankin Scale, 3‐6) 33 (39.8%)
patients (n = 56) 2.3‐3.2) Extrapyramidal rigidity 8 (9.6%)
Unknown 5 (6.0%) Dead 6 (7.2%)
Cause of hyponatremia (n = 72) Abbreviations: ADL, Activities of Daily Living; CPM, central pontine
Drugs 41 (56.9%) myelinolysis; EPM, extrapontine myelinolysis; ODS, Osmotic demyelina‐
tion syndrome.
Antidepressants 11 (15.3%)
Diuretics 35 (48.6%)
Polydipsia 23 (31.9%) or diarrhea in 30 (41.7%). The hyponatremic patients were mostly
Vomiting or diarrhea 30 (41.7%) treated with isotonic saline (n = 67; 93.1%); only three (4.2%) were

Abbreviation: IQR, Inter Quartile Range.

a
Depression (14), psychosis (4), anxiety disorder (3).
b
Diabetes mellitus type 2 (6), Thyroid disease (3), Addison's disease (2),
Diabetes insipidus (1), Conn's disease (1).
with or had seizures around the time of admission (Table 4). When
diagnosed with ODS, the majority (n = 73; 88.0%) had bulbar symp‐
toms, primarily dysarthria/dysphagia (n = 71; 85.5%). Furthermore,
65 (78.3%) had limb paresis at diagnosis and ten (12.0%) were in a
locked‐in state.
The cause of hyponatremia was mostly multifactorial (Table 3).
Drugs (n = 41; 56.9%), including diuretics (n = 35; 48.6%) and anti‐
depressants (n = 11; 15.3%), were common. Polydipsia contributed
as a cause of hyponatremia in 23 (31.9%) individuals and vomiting
treated with hypotonic fluids (Table 4). The median fastest correc‐
tion rate among the hyponatremic patients was 0.72 mmol/L/h
(IQR 0.56‐1.05 mmol/L/h), corresponding to a median correc‐
tion rate of 17.16 mmol/L over 24 hours. Only six were corrected
below ≤8 mmol/L/24 h (national guidelines),30 the remaining were
corrected faster. None of the 19 individuals with a sodium level
at admission below 100 mmol/L were corrected ≤0.5 mmol/L/h.
The three hypernatremic patients were all treated with hypotonic
fluids and the median correction rate was 0.54 mmol/L/h (range
0.42‐0.83 mmol/L/h).
Three patients were diagnosed with computerized tomography
(CT) and 80 with MRI. Half of the patients (n = 42; 50.6%) had
only central pontine myelinolysis, 4 (4.8%) had only extrapontine
myelinolysis, and 37 (44.6%) had both pontine and extrapontine
myelinolysis (Table 4). There were no patients with cerebellar
346 | AEGISDOTTIR et al.
extrapontine lesions or hemorrhages. At three months, 6 (7.2%)
individuals had died, all directly from ODS or complications related
to ODS. Fifty patients (60.2%) were functionally independent
(mRS 0‐2) at three months (Table 4). At three months, 8 (9.6%) in‐
dividuals had extrapyramidal rigidity, of which all had both central
pontine and extrapontine myelinolysis as visualized on MRI. Five
of them were treated with levodopa and one also with deep‐brain
stimulation.
Having hyponatremia under ≤110 mmol/L at admission (n = 54)
was not associated with an unfavorable outcome (functional depen‐
dency) compared to those with hyponatremia >110 mmol/L (n = 18)
(OR 0.59 [0.20‐1.73]). A score between 4 and 6 on the Symptom
severity scale predicted a worse outcome (OR 3 [1.06‐8.46]). The
following variables were not associated with a worse outcome; so‐
dium correction above 0.5 mmol/L/h (OR 0.51 [0.15‐1.71]), having
hypokalemia at admission (OR 0.78 [0.29‐2.10]) or having GCS at 13
or below at admission (OR 1.13 [0.40‐3.21]).
4 | D I S CU S S I O N
We report the first incidence study and the largest population‐based
clinical series of ODS to our knowledge. Interestingly, the incidence
increased markedly over the study period. We have no clear expla‐
nation for this, but one factor could be that the introduction of MRI
has allowed diagnosing premortal and milder cases, as well as those
with extrapontine affection. Specifically, diffusion‐weighted imag‐
ing (DWI) has proved useful in early diagnosis of the disease but a
DWI signal need not be present and does not necessarily precede
10,31
a lesion on T1 and T2 imaging. Heightened awareness among
physicians and expanded access to specialist neurologic examination
and diagnosis might also play a role in the increasing incidence.
The Swedish Patient Register allows full coverage of all hospital
diagnoses during the study period and due to the nature of ODS
most patients should be hospitalized. However, our incidence is
most likely an underestimate since we only had access to records
where the patient had been diagnosed with central pontine myelin‐
olysis. As autopsy series indicate, a number of cases will most prob‐
ably go unrecognized,3,5 and some cases might be asymptomatic.32
Since access to MRI throughout Sweden was high during the obser‐
vation period, it is likely that cases not detected here were those
with milder symptoms, in which a clinical suspicion of ODS was not
raised. Although the information content of the patient records var‐
ied, most patients had extensive records, especially during care at
intensive care units. Long‐term outcomes were available from reha‐
bilitation clinics.
Most of our patients presented with the classic biphasic
12,17,33
course. On presentation, they were commonly lethargic,
confused, and disoriented, had malaise and general weakness, but
very few were severely encephalopathic. An initial improvement
was seen after hydration treatment, followed by deterioration a few
days later with signs of ODS. Despite most patients having severe
hyponatremia, only 22.9% had GCS 13 or lower, and only 7.2% had
seizures on admission. These relatively mild symptoms might be ex‐
plained by the fact that all hyponatremic cases were chronic. Acute
hyponatremia at the same level (median 104 mmol/L) would be ex‐
pected to cause coma and seizures more frequently.19
The medical records indicated that most treating physicians were
aware of the ODS risk and took this into consideration when aim‐
ing at a sodium correction rate under 8‐12 mmol/L/24 h. However,
controlling the rate of correction often proved to be a challenge.
For example, stopping a diuretic frequently caused an inadvertent
rapid increase in sodium levels. In other cases, a relatively rapid in‐
crease was deemed necessary due to ongoing seizures or reduced
consciousness.
Over the years, the cutoff of rate of sodium increment in 24 hours,
at which the correction of chronic hyponatremia is deemed safe, has
varied significantly. Animal studies have showed clinical evidence
of myelin loss at above 16 mmol/L/24 h.19 However, due to diffi‐
culties in appreciating symptom manifestations in animals as well as
nonsensitive diagnostic techniques, these results may be difficult to
directly transfer to humans. Moreover, animals do not have predis‐
posing factors such as alcoholism, liver disease, or hypokalemia. The
increments of ≤10‐12 mmol/L/24 h that are generally considered to
be safe are based on an assumption of no concomitant hypokalemia
or alcoholism.19 As known from previous reports, and also from 12
of our cases, ODS can even occur after a slow rate of serum so‐
dium correction (<12 mmol/L over a 24‐hour period).19 All these
individuals had extreme hyponatremia and only six were corrected
≤8 mmol/L/24 h which are the Swedish national guidelines.30 These
guidelines also recommend water restriction as first‐line treatment
in euvolemic patients, which was very seldomly done.
The appropriate correction rate likely varies between patients,
but a conservative regime is to aim for a slow correction rate, es‐
pecially in long‐standing hyponatremia, and in absence of life‐
threatening encephalopathy or seizures. A majority (93.1%) of the
hyponatremic patients received an intravenous isotonic sodium
chloride solution. Although too few cases were included here, an al‐
ternative approach would be to treat with hypotonic solutions such
as 5% glucose or fluid restriction only in addition to correcting un‐
derlying factors. Importantly, the patient's volume status and dura‐
tion of hyponatremia must be assessed in each case to establish the
most appropriate treatment.33
Correction of hypernatremia has also been reported to cause
myelinolysis in humans.34 Rapidly reversing a hyper‐osmolar state
might cause similar osmotic stress in brain cells as in the correction
of hyponatremia, but through the delayed release of osmolytes, as
opposed to delayed reaccumulation.35 ODS has also been described
as a consequence of the development of hypernatremia alone and
not its correction,36 with support from animal experiments.37 We
had three hypernatremic cases, of which two were corrected too
fast. However, one of these three patients already had symptoms
of ODS when presenting with hypernatremia. A second patient al‐
ready had dysphagia on presentation before the hypernatremia was
corrected, later developing tetraparesis. In these cases, it is possi‐
ble that the development of ODS was due to a rapid rise of serum
AEGISDOTTIR et al.
sodium from a hyponatremic or normonatremic state. In either way,
it can be assumed that ODS in the setting of hypernatremia is ex‐
tremely uncommon.
ODS has occasionally been described to occur independently of
hypo‐ or hypernatremia. Most of these patients have suffered from
38
underlying diseases such as alcoholism and liver failure or AIDS.
We observed four normonatremic cases and four cases where so‐
dium levels were not documented at admission. All these patients
had alcoholism, often in combination with other predisposing fac‐
tors. Some of these patients could possibly have had hyponatre‐
mia before serum sodium was initially measured and self‐corrected
with fluid and food intake as well as cessation of alcohol intake. For
example, three individuals had been in psychiatric clinics or prison
due to alcohol abuse, without blood samples being taken. However,
undiagnosed hyponatremia in these cases remains a speculation.
Nevertheless, it is likely that additional susceptibility factors such as
malnourishment apart from solely hyponatremia and its rapid cor‐
rection can trigger underly ODS.
In most cases, the cause of ODS was a combination of predis‐
posing and precipitating factors. The difference between the two
is not always clear but we consider comorbid diseases such as alco‐
holism and liver disease to be predisposing factors and rapid correc‐
tion of hyponatremia, a precipitating factor. ODS could otherwise
occur repeatedly in the same individual, which does not occur to our
knowledge, even if the comorbid diagnoses are still present. A defi‐
nite conclusion on the effect of these factors on the risk of ODS
would however require a control group of patients with a history of
treated hyponatremia and no subsequent ODS, which was not pres‐
ent in this study. In line with the previous literature, alcoholics were
a majority (69.9%) among the cases. Patients with alcoholism and
liver failure may lack a supply of glucose or glycogen, exacerbated by
thiamine deficiency which itself decreases glucose uptake.40 Some
authors have advocated more active treatment with vitamins and
glucose to prevent ODS in hyponatremic patients, especially those
who are predisposed to malnutrition.40
Extrapontine myelinolysis (EPM) was present in half of our cases,
but only four individuals had such signs without a pontine lesion. In
some case series, this proportion has been higher.17 We speculate
that the treating physicians might have had a difficulty in formalizing
the diagnosis if imaging was not indicative of a pontine lesion, par‐
ticularly since the disorder is named “Central pontine myelinolysis”
(CPM) in the ICD classification system. In fact, the earliest case in
our cohort with EPM exclusively was from 2006. All EPM lesions
were diagnosed on MRI, not CT, indicating that the earliest cases
of EPM had possibly been missed. The incidence of EPM without
signs of CPM might therefore be underreported and contribute to
the lower incidence during the first half of the study period. In all
our extrapontine cases except one, the lesions involved the basal
ganglia or thalamus.
At three months follow‐up, eight patients in our cohort had doc‐
umented extrapyramidal symptoms and parkinsonian features. All
had both a pontine and extrapontine affection on MRI. Five were
treated with levodopa and one also with deep‐brain stimulation.
| 347
Interestingly, the four patients with only EPM, and no pontine lesion,
had ODS symptom severity scores of 3‐4 (the mean score among the
entire cohort being 3), but all were functionally independent at three
months (mRS scores 1‐2). This might indicate a better prognosis for
this group, but due to small number of individuals this finding should
39
be interpreted with some caution.
Case reports have shown promising use of corticosteroids,38
intravenous immunoglobulins (IVIG),41 or plasmapheresis42 when
symptoms of ODS have already begun to emerge. In our cohort, only
one patient received IVIG treatment (none with corticosteroids or
plasmapheresis). Therefore, no conclusions can be drawn from this
study about their efficacy.
Given that ODS was previously a postmortem diagnosis, the con‐
dition was believed to be uniformly fatal. In concordance with other
case series and case reports, our study demonstrated that a large
majority (92.8%) of those who develop ODS survive with the help of
supportive treatment, and many become functionally independent.
Therefore, a decision to withhold care based on the false assumption
that the condition is fatal, should not be made. The introduction of
MRI has allowed for diagnosing milder cases, as well as patients with
extrapontine affection.
Even though we found an association between a higher score
on the ODS symptom severity scale with a worse outcome, we
observed that outcome at three months varied considerably and
could not always be predicted from the acute state. Cases of a
locked‐in state were an exception, as 90% of those patients were
either very dependent on physical support or had died at 3 months.
Other studies published in the last 20 years emphasize favorable
outcomes in 50%‐67% of patients with ODS.6-8 In our study, 60.2%
were functionally independent at three months. We could not
show that extremely low sodium (≤110 mmol/L), hypokalemia, or
GCS ≤ 13 at presentation predicted a poorer outcome as reported
previously.17
5 | CO N C LU S I O N
During the study period, the incidence of ODS increased stead‐
ily and approached one case per million inhabitants per year to‐
ward the end of the period. We suspect that increased access to
MRI and raised awareness of ODS could partly explain this, rather
than a true increase in ODS incidence. The majority of ODS cases
were hyponatremic and the median sodium value at admission
was extremely low (104 mmol/L), which indicates that ODS occurs
predominantly in extreme hyponatremia. Furthermore, almost all
were corrected faster than recommended. As described in the lit‐
erature, a large proportion of cases were alcoholics. As opposed
to older literature, most patients survived and over 50% became
functionally independent. Many questions remain unanswered,
and there is an evident need for further studies, including case‐
control studies, to study risk factors, where individuals with ODS
and hyponatremia are compared to individuals with a similarly se‐
vere hyponatremia who do not develop ODS.
348 | AEGISDOTTIR et al.
AC K N OW L E D G M E N T S
The authors have no acknowledgements.
C O N FL I C T O F I N T E R E S T
HA, CC, and KW have no conflicts of interest to report. FP has re‐
ceived research grants from Biogen, Genzyme, Merck KGaA, and
Novartis, and fees for serving as Chair of DMC in clinical trials with
Parexel, all outside the submitted work. OS has received grants from
GSK, Biogen, personal fees from Biogen and UCB, all outside the
submitted work.
AU T H O R ' S C O N T R I B U T I O N S
All authors contributed substantially (a) to the conception or design
of the work; or the acquisition, analysis, or interpretation of data for
the work; (b) to the drafting of the work or revising it critically for
important intellectual content; (c) to the final approval of the version
to be published. All authors agree to be accountable for all aspects
of the work.
DATA AVA I L A B I L I T Y S TAT E M E N T
All data relevant to this study are contained within the manuscript.
Anonymized data will be shared by request from any qualified
investigator.
ORCID
Olafur Sveinsson https://orcid.org/0000-0002-4507-2935
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How to cite this article: Aegisdottir H, Cooray C, Wirdefeldt
K, Piehl F, Sveinsson O. Incidence of osmotic demyelination
syndrome in Sweden: A nationwide study. Acta Neurol Scand.
2019;140:342–349. https​://doi.org/10.1111/ane.13150​