DÄ internationalArchive35-36/2019Central Pontine Myelinosis and Osmotic Demyelination Syndrome

Review article

Central Pontine Myelinosis and Osmotic Demyelination Syndrome

Dtsch Arztebl Int 2019; 116: 600-6. DOI: 10.3238/arztebl.2019.0600

Lambeck, J; Hieber, M; Dreßing, A; Niesen, W

Background: Osmotic demyelination syndrome (ODS), which embraces central pontine myelinolysis (CPM) and extrapontine myelinosis (EPM), is often underdiagnosed in clinical practice, but can be fatal. In this article, we review the etiology, pathophysiology, clinical features, diagnosis, treatment, and prognosis of ODS.

Methods: Pertinent publications from the years 1959 to 2018 were retrieved by a selective search in PubMed.

Results: The most common cause of ODS is hyponatremia; particular groups of patients, e.g., liver transplant recipients, are also at risk of developing ODS. The pathophysiology of ODS consists of cerebral apoptosis and loss of myelin due to osmotic stress. Accordingly, brain areas that are rich in oligodendrocytes and myelin tend to be the most frequently affected. Patients with ODS often have a biphasic course, the first phase reflecting the underlying predisposing illness and the second phase reflecting ODS itself, with pontine dysfunction, impaired vigilance, and movement disorders, among other neurological abnormalities. The diagnostic modality of choice is magnetic resonance imaging (MRI) of the brain, which can also be used to detect oligosymptomatic ODS. The current mainstay of management is prevention; treatment strategies for manifest ODS are still experimental. The prognosis has improved as a result of MRI-based diagnosis, but ODS can still be fatal (33% to 55% of patients either die or remain permanently dependent on nursing care).

Conclusion: ODS is a secondary neurological illness resulting from a foregoing primary disease. Though rare overall, it occurs with greater frequency in certain groups of patients. Clinicians of all specialties should therefore be familiar with the risk constellations, clinical presentation, and prevention of ODS. The treatment of ODS is still experimental at present, as no evidence-based treatment is yet available.

LNSLNS

Osmotic demyelination syndrome (ODS) was first described in 1959 by Adams and Victor, who reported “pontine myelinolysis” in alcoholic patients (1). On pathophysiological considerations, and as an increasing number of manifestation sites in addition to the pons were detected, central pontine myelinolysis (CPM) and extrapontine myelinolysis (EPM) were combined into “osmotic demyelination syndrome”. Exact epidemiological data are still lacking, as there is not always a clear distinction between ODS and a prior or underlying disease. Furthermore, ODS is not always detected radiologically. As a result, the introduction of magnetic resonance imaging (MRI) led to increasing incidences of ODS, with the demonstration of oligosymptomatic as well as asymptomatic manifestations. Overall, ODS accounts for 0.4% to 0.56% of all neurological admissions to tertiary referral hospitals and 0.06% of all medical hospital admissions (24). MRI-based studies describe incidence of 0.3% to 1.1%. In contrast, at-risk groups show incidence of 9.5%, with rates of 9.8% to 29% after liver transplantation (5). A 2015 clinical study found a 2.5% incidence of ODS among patients in intensive care units (6).

ODS usually manifests itself between the ages of 30 and 50 years; 51.8% to 77.0% of patients are men, and 23% to 48.2% have had a liver transplant (6, 7). Early studies found that the syndrome was localized mostly at the pontine in 67% of the cases, was strictly extrapontine for 6%, and had a mixed location in 27%. More recent, MRI-based studies have resulted in a shift to EPM (with CPM in 40% to 56% of cases, pure EPM in 13% to 35%, and mixed in 23% to 31%). This manifests as myelinolysis in the basal ganglia (especially in the striatum; 34%), cerebellar white matter (33% to 55%), thalamus, or hippocampus (68).

Etiology

Etiologically, there are a large number of underlying causes and relevant comorbidities. Common to all is the development of ODS as a result of a severe prior disease or its treatment. While most of the early publications (up to the mid-1980s) described chronic alcohol use and alcohol withdrawal as the decisive comorbidities (>40%), more recent work as well as some of the older work describes foregoing hyponatremia as the most common cause, occurring in 30% to 78% of cases (710). Severe hyponatremia (serum sodium levels <120 mmol/L) is often present, in around 47% of cases; however, the majority of cases have additional concomitant cofactors, each of which alone can trigger ODS (8). In summary, almost any electrolyte imbalance can be the cause. Severe hypokalemia is especially important as a sole determining factor as well as a cofactor, particularly for patients in intensive care units (6, 11).

Another common etiological factor is liver transplantation (LTx), for which the most relevant cofactor is hyponatremia (67%, but severe in only 3.7%). Further risk factors for LTx (12) are described in the eSupplement.

Pathophysiology

Histopathological basis

In pathological sections as well as in imaging, ODS occurs in typical locations. These have a characteristic histological structure (eSupplement) and are characterized by symmetrical expression. Histopathologically, there is noninflammatory demyelination with concurrent preservation of neurons and associated axons. In addition, there is a loss of oligodendrocytes, mainly due to apoptosis, and a significant infiltration of myelin-degrading macrophages (13, 14).

Pathophysiology in hyponatremia and correction of hyponatremia

The most common cause of ODS is hyponatremia. However, despite the osmotic stress not every patient who has hyponatremia develops ODS. Simply expressed, the only patients at risk for ODS are those who have experienced chronic hyponatremia (e.g., duration >48 h, or progression at a rate <0.5 mmol/h [15]) and correction of hyponatremia. The background for this is the sequential changes during the regulation of cell volume: a decisive role for transition from acute to chronic hyponatremia is played by the removal of inorganic and organic osmolytes from cells, with subsequent normalization of cell volume. The same process occurs during correction of extracellular sodium without rapid regeneration of osmolytes, leading to a decrease in the cell volume along the osmotic gradient, with consecutive cell death (16, 17) (Figure 1, eSupplement).

Pathophysiology of hyponatremia
Pathophysiology of hyponatremia
Figure 1
Pathophysiology of hyponatremia

Clinical

Clinical course

ODS is highly variable in its clinical manifestation. In contrast, its time course is characteristic and central to diagnosis. The triggering factor precedes demyelination and its symptoms by 1 to 14 days. A symptom-free or stable clinical interval is then followed by ODS-induced secondary deterioration (8, 15). The symptoms usually correlate with the site of manifestation, differentiated into pontine and extrapontine. The most common clinical manifestations (CPM and EPM) are encephalopathies, characterized by vigilance disorders, qualitative impairment of consciousness, delirium, and disorders of drive, memory, and concentration, among others. The course can also be oligosymptomatic or asymptomatic (18).

Central pontine myelinolysis

If the pons and the corticospinal and bulbar tracts are affected in CPM, patients present with frequent encephalopathies and signs of damage to the brainstem. With corticobulbar pathway involvement, patients are affected by dysarthria and dysphagia (3.2% to 11.5% of ODS cases) (8). If the corticospinal tracts are affected, initially flaccid and later spastic tetrapareses of varying severity appear (in 9.8% to 28.8% of cases) (8). If tegmental lesions are present, ocular and pupillary motility may also be affected (about 8% of all ODS) (8). In severe cases, the symptoms may even lead to locked-in syndrome (15). Severe disorders of consciousness occur in 6.1% to 14% of cases (8).

Extrapontine myelinolysis and movement disorders

Improvements in MRI have revealed numerous extrapontine sites of demyelination syndromes. As a result of demyelination of the basal ganglia, a wide range of characteristic extrapyramidal motor symptoms have been found, including dystonia, myoclonus, rigor, akinesia, and tremor (5, 18). The course of movement disorders in EPM is often biphasic. Early onset of extrapyramidal symptoms is followed by a second peak that often involves choreoathetoses or dystonia (4, 19). Little is known about the rates of occurrence of the individual symptoms. In a small case series of patients with EPM, 60% had extrapyramidal motor symptoms (4). Much less frequently described (8–14% of cases) are ataxias, generally as part of a cerebellar syndrome with lesions of the cerebellar peduncles (8, 20).

Neurobehavioral disorders

Recent case series and case reports have described the occurrence of cognitive deficits associated with ODS. Lesions can be found in the area of the cortex (cortical laminar necrosis) or at the transition between gray and white matter (21). Cognitive symptoms include frontal dysfunctions (e.g., problem-solving, planning what to do, drive, impulse control, and emotional control), concentration disorders, and psychiatric disorders (such as depressive or manic syndromes, emotional lability, catatonia, and mutism). A further group of patients (12–24%) presents with epileptic seizures that persist longer than potential epileptic seizures in the acute phase of hyponatremia (8, 22).

In summary, the presumptive diagnosis of ODS is usually based first on the clinical picture and course. The following factors suggest the presence of ODS: biphasic clinical course, initial electrolyte imbalance or other risk factors, and the appearance of pontine or extrapyramidal symptoms after 1 to 14 days.

Factors that do not support a suspected diagnosis of ODS are symptom onset during the phase of electrolyte imbalance, cortical symptoms, and lateralizing symptoms (Table).

Common clinical symptoms by site of manifestation and syndrome classification (4, 20, 24)
Common clinical symptoms by site of manifestation and syndrome classification (4, 20, 24)
Table
Common clinical symptoms by site of manifestation and syndrome classification (4, 20, 24)

Diagnosis

A suspected diagnosis of ODS or, more specifically, CPM should be based on the presence of risk factors and a compatible clinical course. Suspicion is confirmed by MRI demonstration of demyelination sites, typically localized in pons, cerebellum, lateral geniculate body, thalamus, and external and extreme capsules. Damage to the brainstem can be detected by electrophysiological diagnostics as supportive evidence. No correlation can be made between diagnostic findings and clinical outcome, due to insufficient research data (22, 23).

Laboratory diagnostics: triggering factors

The principal predisposing factors are electrolyte disturbances (especially rapid correction of a chronic hyponatremia), chronic alcohol abuse, and malnutrition, as well as previous LTx. Therefore, a suspected diagnosis of ODS should be supplemented or completed by the appropriate laboratory diagnostics and medical history. The laboratory parameters to be examined are serum sodium, serum potassium, and liver values, as well as parameters for evaluation of the nutritional status (e.g., vitamin B12, methylmalonic acid, folic acid, and phosphate in serum). If possible, the previous course should be evaluated, especially with regard to serum electrolyte values.

Imaging

As a rule, MRI is more sensitive than computed tomography for detecting the typical demyelination lesions as a morphological correlate of ODS (3, 24). MRI is also successful in providing evidence for milder courses of disease. This has significantly improved assessment of the prognosis of ODS, as diagnosis is no longer restricted to autopsy-verified ODS after a fatal outcome.

MRI: course and sequences

Demyelination sites show hyperintensity in T2-weighted and T2 fluid-attenuated inversion recovery (FLAIR) sequences, and hypointensity in T1-weighted sequences (3, 25). The sensitivity of diffusion-weighted imaging (DWI) is unclear. On the one hand, early DWI changes without T2 or T2 FLAIR demarcation have been described (26). On the other hand, some studies have shown that DWI lesions as well as T1, T2, or T2-FLAIR lesions were detectable (24, 27). Accordingly, DWI, T2, and T2 FLAIR sequences should be considered equivalent for purposes of detection (27, 28).

Likewise, no clear recommendations can be made with regard to the optimal timing of MRI imaging. Positive MRI findings can sometimes be present as early as the first day after onset of symptoms (27, 28). However, cases have also been reported where the MRI findings were initially inconspicuous and first pointed to the diagnosis at a follow-up examination (24, 27).

In general, in the case of an early (<7 days) inconspicuous MRI examination, follow-up imaging should be carried out 1 to 2 weeks later (3). MRI alone is insufficient for assessment of the prognosis, as neither initial lesion size nor changes in size during the course correlate reliably with clinical outcome (23, 24).

Cranial computed tomography

Cranial computed tomography (CCT) can also be used to confirm clinical ODS, but has significantly lower sensitivity than MRI (initial detection rate: 25% to 28.5%) (3, 28). The rate of positive CCT findings increases over the course of development, although the detection rate does not match that of MRI (28). In contrast, however, CCT imaging is faster than MRI and is ubiquitously available. This makes it especially useful for swift exclusion of differential diagnoses. If the CCT findings are inconspicuous, however, ODS cannot be ruled out at either an early or a late stage.

Nuclear medicine

Nuclear medicine methods contribute more to the pathophysiological understanding than to confirmation of the diagnosis. For instance, based on metabolic analysis by means of 18F-FDG-PET scanning, an early focal hypermetabolism was described that showed partial reversal towards hypometabolism over the course of disease (29). To evaluate the nigrostriatal dopaminergic system in EPM, 99mTc-TRODAT-1 and 123I-IBZM SPECT can be used. With this method, bilateral reduced uptake of metabolites in the striatum, corresponding to ODS lesions, has been observed (30).

Electrophysiology

Although electrophysiological diagnostics may allow ODS to be detected, especially in the case of a pontine or other brainstem lesion, they do not provide consistent, specific findings. Indeed, not even a correlation with the current clinical symptoms or the outcome has been consistently described.

Therapy

General

The small low amount of evidence on treatment of overt ODS is based purely on case reports and small case series. A preventive approach in hypo- and hypernatremia of varying severity is better documented. Important issues for prevention are diagnostic determination of the cause of electrolyte derangement (and, where appropriate, treatment of the causative underlying disease) as well as the acuity of derangement and the associated symptoms.

Prevention

The severity of the initial electrolyte imbalance and the rapidity of its correction appear to play a critical role. In severe hyponatremia (<20 mmol/L), ODS incidence is significantly reduced by very slow correction of sodium, limited to <0.5 mmol/L per hour and <12 mmol/L per day (31). For hyponatremia (>120 mmol/L), the rate of sodium correction does not seem to be quite as decisive (15). In the case of severe hyponatremia with relevant neurological symptoms, infusion of a hypertonic solution of 3% sodium chloride should be considered (32). In contrast, if neurological symptoms are not present, increasing the serum sodium with respect to the cause of hyponatremia is of primary importance. For raising the serum sodium levels, the infusion rate and amount can be calculated according to the limits given in the Box.

Calculation of adequate sodium correction with specified limits
Calculation of adequate sodium correction with specified limits
Box
Calculation of adequate sodium correction with specified limits

The goal of every treatment for hyponatremia is initially to achieve euvolemia and then to attain balanced osmolality. If hypokalemia is also present, it must be treated first (33). It is important to closely monitor the levels of sodium and potassium as well as osmolality in serum and urine. If there is significant derangement, monitoring should be done every hour. In addition, fluid intake should be limited and reliably balanced.

Depending on the cause of the hyponatremia, another potential approach is the use of vasopressin antagonists to enhance elimination of water without concomitant loss of electrolytes. The selective V2 receptor antagonist tolvaptan has been approved for this indication (34). Due to the associated risks and a lack of outcome data (35), however, the use of this antagonist is reserved for severe refractory cases after careful consideration. The risks include danger of overcorrection, onset of hyperkalemia, and dangers associated with an initially critical, highly frequent monitoring of electrolyte and volume status (Figure 2).

Preventive measures to avoid osmotic demyelination syndrome
Preventive measures to avoid osmotic demyelination syndrome
Figure 2
Preventive measures to avoid osmotic demyelination syndrome

Clinical manifestation

It should first be noted that in a significant proportion of cases, good spontaneous remission occurs (3). The described treatment options all have a low level of evidence and can only be characterized as experimental. Animal studies have shown that overly rapid sodium correction has a myelinotoxic-inflammatory component. Based on animal experiments, case reports and small case series have tested early treatment with dexamethasone (36), plasmapheresis, and/or immunoglobulins (37, 38), among others, with unanimous reports of rapid positive outcomes. However, whether this was a consequence of the respective therapeutic measure or merely the spontaneous course (independent of treatment) remains an open question.

Minocycline is another interesting substance with anti-inflammatory and anti-apoptotic effects for which data exist for other demyelinating diseases, such as multiple sclerosis. Among other effects, it inhibits the activation of microglial cells. In animal models, minocycline has been shown to have a protective effect against the development of ODS after rapid sodium correction for chronic hyponatremia (39). Furthermore, in experimental studies and case reports, reinduction of hyponatremia after initial excessively rapid correction for sodium showed higher rates of prolonged survival (40).

Prognosis

While studies up to the mid-1980s reported mortality of 90% to 100%, more recent work describes a much better prognosis, with a good outcome in about 33% to 50% of cases. About 24% to 39% of patients reach restitutio ad integrum; another 16% to 34% are self-sufficient in all activities of daily life (5, 23, 24). In contrast, approximately 33% to 55% of patients will require some care, be fully dependent on care, or die. Predictors of a poor outcome are severe hyponatremia of <114 mmol/L, hyponatremia with concomitant hypokalemia, and a notable reduction in vigilance. LTx patients who have clinically noticeable symptoms have the worst outcome: ODS is a relevant outcome factor, with mortality of 63% (LTx with ODS) versus 13% (LTx without ODS) and a morbidity/mortality rate of >77% (8, 12).

The currently more favorable prognosis is due to several factors, including earlier detection of ODS by MRI, the considerable progress achieved by modern intensive care medicine (such as more precise fluid and electrolyte management, among other things), and a more detailed pathophysiological understanding. Patients benefit from improved care programs and early rehabilitative measures in intensive care. A large proportion of patients improve early in the disease course. As significant improvements have also been reported in the long term, after up to 4 years, the prognosis of ODS remains open for a long time (5).

The change in the prognosis of ODS over the years has also been significantly affected by the greater use of MRI-based diagnostics in oligosymptomatic/asymptomatic patients. Furthermore, recent work in the MRI era has revealed a significantly higher proportion of patients with predominant EPM and extrapyramidal motor symptoms. In contrast to the severe motor deficits of CPM, these are amenable to symptomatic dopaminergic treatment, which yields good response rates (15).

Outlook

Despite the continuing significant proportion of patients with a poor outcome, overall the prognosis of ODS has improved due to various factors. A significant amount of improvement can also be expected in the long term.

Conflict of interest statement
The authors declare that no conflict of interest exists.

Manuscript received on 30 July 2018, revised version accepted on
29 May 2019

Translated from the original German by Dr. Veronica A. Raker.

Corresponding author
Dr. Wolf-Dirk Niesen
Klinik für Neurologie und Neurophysiologie
Universitätsklinikum Freiburg
Breisacher Str. 64
79106 Freiburg, Germany
wolf-dirk.niesen@uniklinik-freiburg.de

Cite this as:
Lambeck J, Hieber M, Dreßing A, Niesen WD: Central pontine myelinosis and osmotic demyelination syndrome. Dtsch Arztebl Int 2019; 116: 600–6. DOI: 10.3238/arztebl.2019.0600

Supplementary material

eSupplement:
www.aerzteblatt-international.de/19m0600

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*1Shared first authors
*2Shared senior authors
Department of Neurology and Neurophysiology, University Medical Center Freiburg, Germany:
Dr. med. Johann Lambeck, Dr. med. Maren Hieber,
Dr. med. Andrea
Dreßing, Dr. med. Wolf-Dirk Niesen
Calculation of adequate sodium correction with specified limits
Calculation of adequate sodium correction with specified limits
Box
Calculation of adequate sodium correction with specified limits
Pathophysiology of hyponatremia
Pathophysiology of hyponatremia
Figure 1
Pathophysiology of hyponatremia
Preventive measures to avoid osmotic demyelination syndrome
Preventive measures to avoid osmotic demyelination syndrome
Figure 2
Preventive measures to avoid osmotic demyelination syndrome
Key messages
Common clinical symptoms by site of manifestation and syndrome classification (4, 20, 24)
Common clinical symptoms by site of manifestation and syndrome classification (4, 20, 24)
Table
Common clinical symptoms by site of manifestation and syndrome classification (4, 20, 24)
1.Adams RD, Victor M, Mancall EL. Central pontine myelinolysis. Arch Neurol Psychiatry 1959; 81: 154–72 CrossRef
2.Bhoi KK, Pandit A, Guha G, et al.: Reversible parkinsonism in central pontine and extrapontine myelinolysis: a report of five cases from India and review of the literature. Neurol Asia 2007; 12: 101–9.
3.Kallakatta RN, Radhakrishnan A, Fayaz RK, Unnikrishnan JP, Kesavadas C, Sarma SP: Clinical and functional outcome and factors predicting prognosis in osmotic demyelination syndrome (central pontine and/or extrapontine myelinolysis) in 25 patients. J Neurol Neurosurg Psychiatry 2011; 82: 326–31 CrossRef MEDLINE
4.de Souza A, Desai PK: More often striatal myelinolysis than pontine? A consecutive series of patients with osmotic demyelination syndrome. Neurol Res 2012; 34: 262–71 CrossRef MEDLINE
5.de Souza A: Movement disorders and the osmotic demyelination syndrome. Parkinsonism Relat Disord 2013; 19: 709–16 CrossRef MEDLINE
6.Rao PB, Azim A, Singh N, Baronia AK, Kumar A, Poddar B: Osmotic demyelination syndrome in Intensive Care Unit. Indian J Crit Care Med 2015; 19: 166–9 CrossRef MEDLINE PubMed Central
7.Berlit P: Die zentrale pontine Myelinolyse. Nervenarzt 1986; 57: 624–33.
8.Singh TD, Fugate JE, Rabinstein AA: Central pontine and extrapontine myelinolysis: a systematic review. Eur J Neurol 2014, 21: 1443–50 CrossRef MEDLINE
9.Lampl C, Yazdi K. Central pontine myelinolysis. Eur Neurol 2002; 47: 3–10 CrossRef MEDLINE
10.Burcar PJ, Norenberg MD, Yarnell PR: Hyponatriemia and central pontine myelinolysis. Neurology 1977; 27: 223–6 CrossRef MEDLINE
11.Sugimoto T, Murata T, Omori M, Wada Y: Central pontine myelinolysis associated with hypokalaemia in anorexia nervosa. J Neurol Neurosurg Psychiatry 2003; 74: 353–5 CrossRef MEDLINE PubMed Central
12.Morard I, Gasche Y, Kneteman M et al.: Identifying risk factors for central pontine and extrapontine myelinolysis after liver transplantation: A case–control study. Neurocrit Care 2014; 20: 287–95 CrossRef MEDLINE
13.Alleman AM: Osmotic demyelination syndrome: central pontine myelinolysis and extrapontine myelinolysis. Semin Ultrasound CT MR 2014; 35: 153–9 CrossRef MEDLINE
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