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:
central pontine myelinolysis, extrapontine myelinolysis, osmotic demyelination Received 12 May 2014 Accepted 1 August 2014
The purpose was to perform a systematic review of studies on central pontine and extrapontine myelinolysis [forms of osmotic demyelination syndrome (ODS)] and define the spectrum of causes, risk factors, clinical and radiological presentations, and functional outcomes of this disorder. A thorough search of the literature was conducted using multiple databases (PubMed, Ovid Medline and Google) and bibliographies of key articles to identify all case series of adult patients with ODS published from 1959 to January 2013. Only series with five or more cases published in English were considered. Of the 2602 articles identified, 38 case series were included comprising a total of 541 patients who fulfilled our inclusion criteria. The most common predisposing factor was hyponatremia (78%) and the most common presentation 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 uncommon neurological disorder caused by damage to the myelin sheath of brain cells [1]. Central pontine myelinolysis (CPM) is the classical presentation, reflecting 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 alcoholics or malnourished. Although the exact pathogenesis 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 traditionally 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 precipitous 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: [email protected]).
© 2014 The Author(s) European Journal of Neurology © 2014 EAN
other associations have been reported, including severe hypophosphatemia [25,26,27] and hypokalemia [27,28], diabetes mellitus [29–31], renal failure [32], hemodialysis [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 seizures or encephalopathy that may improve gradually but are then followed by severe deterioration manifested by dysarthria, dysphagia, oculomotor dysfunction 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 inversion recovery sequences with corresponding hypointensity on T1-weighted sequences.
2
T. D. Singh et al.
Initially ODS was thought to have a consistently poor outcome because the diagnosis was only confirmed 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 identify 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 categories of cases diagnosed by necropsy and cases diagnosed radiologically. The cases diagnosed in liver transplant recipients were analyzed separately because it was the only associated condition with several specific 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. Hyponatremia 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 characteristics, distribution of demyelinating lesions, associated conditions, and rates of death and disability between liver transplant recipients and patients without 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 twothirds (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
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:
central pontine myelinolysis, extrapontine myelinolysis, osmotic demyelination Received 12 May 2014 Accepted 1 August 2014
The purpose was to perform a systematic review of studies on central pontine and extrapontine myelinolysis [forms of osmotic demyelination syndrome (ODS)] and define the spectrum of causes, risk factors, clinical and radiological presentations, and functional outcomes of this disorder. A thorough search of the literature was conducted using multiple databases (PubMed, Ovid Medline and Google) and bibliographies of key articles to identify all case series of adult patients with ODS published from 1959 to January 2013. Only series with five or more cases published in English were considered. Of the 2602 articles identified, 38 case series were included comprising a total of 541 patients who fulfilled our inclusion criteria. The most common predisposing factor was hyponatremia (78%) and the most common presentation 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 uncommon neurological disorder caused by damage to the myelin sheath of brain cells [1]. Central pontine myelinolysis (CPM) is the classical presentation, reflecting 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 alcoholics or malnourished. Although the exact pathogenesis 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 traditionally 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 precipitous 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: [email protected]).
© 2014 The Author(s) European Journal of Neurology © 2014 EAN
other associations have been reported, including severe hypophosphatemia [25,26,27] and hypokalemia [27,28], diabetes mellitus [29–31], renal failure [32], hemodialysis [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 seizures or encephalopathy that may improve gradually but are then followed by severe deterioration manifested by dysarthria, dysphagia, oculomotor dysfunction 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 inversion recovery sequences with corresponding hypointensity on T1-weighted sequences.
2
T. D. Singh et al.
Initially ODS was thought to have a consistently poor outcome because the diagnosis was only confirmed 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 identify 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 categories of cases diagnosed by necropsy and cases diagnosed radiologically. The cases diagnosed in liver transplant recipients were analyzed separately because it was the only associated condition with several specific 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. Hyponatremia 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 characteristics, distribution of demyelinating lesions, associated conditions, and rates of death and disability between liver transplant recipients and patients without 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 twothirds (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
