Acta Pædiatrica ISSN 0803-5253
REGULAR ARTICLE
Osmotic demyelination syndrome associated with hypophosphataemia: 2 cases and a review of literature Jessica Turnbull1, Daniel Lumsden1, Ata Siddiqui2, Jean-Pierre Lin1, Ming Lim (
[email protected])1 1.Children’s Neurosciences, Evelina Children’s Hospital, King’s Health Partners AHSC, London, UK 2.Department of Neuroradiology, King’s Health Partners AHSC, London, UK
Keywords Central pontine myelinolysis, Extrapontine myelinolysis, Hyponatraemia, Hypophosphataemia, Osmotic demyelination syndrome Correspondence Dr Ming Lim MRCP, PhD, Children’s Neurosciences, Evelina Children’s Hospital @ Guy’s and St Thomas’ NHS Trust, King’s Health Partners Academic Health Science Centre, Westminster Bridge Road, London SE1 7EH, UK. Tel: 020 7188 4002 | Fax: 020 7188 0851 | Email:
[email protected] Received 19 November 2012; accepted 18 December 2012. DOI:10.1111/apa.12143
ABSTRACT Aim: Central and extrapontine myelinolysis are collectively known as osmotic demyelination syndrome. This encephalopathic illness has been well documented in the adult literature, occurring most commonly in the context of chronic alcoholism, correction of hyponatraemia and liver transplantation. Aetiology and outcome in the paediatric population are less well understood. Methods: Two cases of osmotic demyelination syndrome occurring in children with transient severe hypophosphataemia during the course of their illness are presented. Both had very different neurological outcomes, but the changes of central and extrapontine myelinolysis were apparent on neuroimaging. Sixty-one cases in the paediatric literature were then reviewed. Results: We summarize aetiology and outcome in paediatric cases of osmotic demyelination syndrome and postulate a role for hypophosphataemia as a contributing factor in the development of these sometimes devastating conditions. Conclusion: Hypophosphataemia may contribute to the risk of developing osmotic demyelination syndrome in at-risk paediatric patients and further study of this association should be undertaken.
INTRODUCTION Central pontine myelinolysis and extrapontine myelinolysis (CPM and EPM) are collectively known as Osmotic Demyelination Syndrome (ODS). They are rare causes of encephalopathic illness that may result in motor, psychiatric and behavioural disorders. ODS occurs in association with chronic alcoholism (39%), correction of hyponatraemia (21.5%), liver transplantation (17%) (1) and less commonly in burns (2), systemic lupus erythematosus (SLE) (3), porphyria (4), cytomegalovirus (CMV) hepatitis (5) and anaphylactic shock (6). The clinical course of CPM or EPM often takes the form of a transient period of encephalopathy, with initial recovery prior to a second phase of neurological deterioration hours to days later. Clinical features reflect the areas of demyelination, with dysarthria and dysphagia due to corticobulbar involvement, and ensuing flaccid and then spastic quadriparesis due to corticospinal tract involvement; the main feature of CPM. A locked-in syndrome may
Key notes
Abbreviations CMV, cytomegalovirus; CPM, central pontine myelinolysis; CT, computed tomography; EPM, extrapontine myelinolysis; MRI, magnetic resonance imaging; ODS, osmotic demyelination syndrome; SLE, systemic lupus erythematosus.
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also occur in more severe cases (7). In EPM, movement and behavioural disorders may occur including dystonia, parkinsonism, ataxia and catatonia, corresponding to the areas of myelinolysis such as the basal ganglia, cerebellum and cortex (7). Neuroimaging in CPM characteristically reveals a symmetrical lesion within the pons, equidistant from the floor of the fourth ventricle and ventral surface of the pons, typically sparing the outer rim. Lesions are hyperintense on T2-weighted magnetic resonance imaging (MRI) and of low attenuation on computed tomography (CT). Diffusionweighted imaging may be useful for detection of early lesions, and it is known that imaging changes may be delayed by more than a week after the onset of clinical signs
Osmotic demyelination syndrome is an encephalopathic illness with a wide range of presumed causative factors including electrolyte disturbance. The risk factors for development of this rare condition are not fully understood. Hypophosphataemia is known to cause a range of neurological symptoms and may contribute to the risk of developing osmotic demyelination syndrome.
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(8,9). Extrapontine lesions are usually symmetrically distributed (10,11) and have been described in the cerebellum, lateral geniculate body, hippocampus, putamen, caudate nucleus, thalamus, external and extreme capsules, cerebral cortex and spinal cord (12). Interestingly, a recent series of 8 adult cases found all 8 to have symmetrical changes in the corpora striatum, and only 25% to have co-existent CPM (13). A previous review of 58 adult cases found 27 to be confined to the pons, 18 to have pontine and extrapontine involvement and 13 to be solely extrapontine (14). Prognosis varies, a series of 44 adult patients with CPM found that of survivors, one-third recovered completely, one-third had partial recovery with independent living and one-third remained dependent. The severity of initial imaging findings did not correlate with clinical findings or subsequent outcome (15). Reports within the paediatric literature remain scarce and causative factors within this population are still poorly understood. Here we report two cases of osmotic demyelination in paediatric patients presenting with recent weight loss, and, in addition to osmotic sodium shifts, also demonstrated transient severe hypophosphataemia during the course of their illness. We review the literature of paediatric cases reported and postulate a role for hypophosphataemia as a risk factor in the development of these sometimes devastating conditions.
CASE DESCRIPTION Case 1 A 13-year-old girl presented with vomiting, lethargy and anorexia have been unwell for 3 weeks. On assessment at her local hospital she was found to have a fluctuating level of consciousness and diffuse weakness. Plasma sodium was 119 mmol/L, which was gradually corrected to 134 mmol/ L over the next 5 days. Her clinical state failed to improve despite this, prompting a referral to our centre. On day 12 she developed a profound flaccid paralysis with loss of brainstem reflexes and a locked-in syndrome requiring intubation and ventilation. On review of her imaging (day 6 and day 19), which revealed signal changes in her medulla oblongata and base of the 3rd ventricle, thalami and chiasm, an inflammatory demyelinating syndrome was initially considered and she underwent intensive immunotherapy comprising high dose intravenous corticosteroids, intravenous immunoglobulins and subsequently plasma exchange. At 3 weeks of illness there was no convincing evidence of recovery (eye opening and minimal facial expression only). Repeat neuroimaging on day 42 demonstrated extensive signal change in the central pons and long tracts in the mid brain and pons (Fig. 1). At this stage, a disclosure of a recent unexplained weight loss of 6.5 kg was ascertained, prior to her onset of symptoms. A revised diagnosis of
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Figure 1 Top row (A–C) – Axial T2-weighted MRI images at the level of the lower thalami, pons and medulla showing high signal in the paramedian thalamic and hypothalamic region (white arrows in A), within the central pons (dashed arrow in B) and in the medulla (black arrow in C). Bottom row (D–F) showing follow up MRI images with shrinkage of the lesions and residual gliosis.
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an osmotic demyelination syndrome was considered. Additionally, prior investigations had not revealed an infective, inflammatory or metabolic cause for encephalopathy. During this period, plasma sodium had risen from 119 mmol/L (day 1) to 179 mmol/L (day 22) at a rate not exceeding 0.6 mmol/L/hr and normalized to 144 mmol/L by day 26. The maximal rate of fall of plasma sodium was 1.1 mmol/L/h over days 23 to 24. Plasma phosphate was 1.5 mmol/L (normal range 1.0–1.8 mmol/L) on admission to our hospital before it fell to 0.8 mmol/L by day 12, and then fluctuated and reached a nadir of 0.4 mmol/L by day 26. Plasma phosphate had risen back to normal at 1.3 mmol/L by day 33. Gradual neurological improvement followed over 6 months, and on discharge for further rehabilitation she had regained some power in all four limbs and slow speech through a tracheostomy-speaking valve. After 2 years on an intensive rehabilitative programme, she had only mild bulbar symptoms of dysarthria and dysphagia and central hypopnoea, currently not requiring treatment. Case 2 A 12-year-old girl was found unresponsive at home and brought in to her local hospital where coma secondary to diabetic ketoacidosis was diagnosed. During the preceding 6 months she had been symptomatic with lethargy, poly-
dipsia and polyuria. Weight loss of approximately 12 kg was noted. At presentation she was profoundly acidotic, (pH 6.85, HCO3 4.4 mmol/L, CO2 1.3 kPa) and required ventilation due to a depressed level of consciousness. A high CRP and imaging of her mastoids suggested the infective aetiology likely to have triggered this diabetic decompensation, which was optimally treated with intravenous cefotaxime. Her initial blood glucose was 25.5 mmol/L, corrected plasma sodium 139 mmol/L and plasma potassium 3.5 mmol/L. Corrected plasma sodium increased to a maximum of 166.4 mmol/L (rise of 0.8 mmol/L/h) over the next 32 h. Serum phosphate on admission was 0.9 mmol/L, but fell to 0.2 mmol/L by day 2, increasing to 0.7 mmol/L after correction with a phosphate infusion the same day and was within normal range at 1.3 mmol/L by day 8. Due to a protracted encephalopathy persisting despite adequate correction of her biochemical derangements, an MRI brain was performed, demonstrating T2 high signal change in the corpora striatum and sub-insular region, with restricted diffusion in the external capsule bilaterally, consistent with myelinolysis (Fig. 2). Over the next 48 h, her conscious level improved, facilitating transfer to the paediatric ward where she was discharged with no neurological sequelae on day 9, and on a basal bolus regime of insulin for her diabetes. Repeat MRI
Figure 2 Top row showing axial T2-weighted image, diffusion weighted image (DWI) and apparent diffusion coefficient (ADC) map which demonstrate symmetrical mildly increased T2 signal in the lentiform nuclei and external capsules bilaterally with some diffusion restriction along the lateral margins (solid arrows). There is also some hazy increased signal in the internal capsules (dashed arrow). Corresponding follow-up images (bottom row) show complete resolution of the changes.
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brain on follow-up after 2 months showed complete resolution of the acute changes (Fig. 2). Single centre review of neuroimaging changes with sodium derangements Following our index Case 1 we sought to review whether MRI changes consistent with ODS could be identified in children admitted with sodium derangements. MRI brain scans of children admitted to the intensive care unit over a 6-month period (September 2005–March 2006) who had suffered hypo- or hypernatraemia during the course of their illness were reviewed. We identified 18 cases with disturbed plasma sodium levels; 7 hyponatraemic (minimum Na 120– 131 mmol/L), 8 hypernatraemic (maximum Na 151– 187 mmol/L) and 3 both hypo- and hypernatraemic (range 126–163 mmol/L, 127–155 mmol/L and 119–179 mmol/ L) in whom brain imaging was undertaken at a median of 5 days (range 1–135 days) after onset of sodium derangement. Only in our index Case 1 were changes consistent with CPM/EPM alone, highlighting the need for a better understanding of risk factors for developing this sometimes devastating condition (16).
DISCUSSION Our two cases experienced osmotic demyelination during the course of severe illnesses associated with electrolyte disturbance including profound hypophosphataemia. To evaluate the aetiology and outcome of osmotic demyelination syndromes in children, we performed a review of the literature (Medline 1950-present, Embase 1980-present) using the search terms ‘central pontine myelinolysis,’ ‘extrapontine myelinolysis,’, ‘extra-pontine myelinolysis,’, ‘osmotic demyelination’ and ‘osmotic demyelination syndrome.’. Sixty-one cases referring to children (
