osmotic deyelination syndrome

CPM, EPM, osmotic deyelination syndrome, correction of sodium

1. Osmotic demyelination syndrome -Dr. Sachin A Adukia

2. History 1959- Victor and Adams first described central pontine myelinolysis clinical findings- quadriparesis , pseudobulbar paralysis Pathology - myelin loss confined within the central pons was felt as a sequela of alcoholism or malnutrition 1962 - recognised that lesions can occur outside the pons :- extrapontine myelinolysis ( EPM ). 1976- Tomlinson – suggested link with rapid correction of sodium in hyponatraemic patients was established 1981: Kleinschmidt - DeMasters and Norenberg conclusively demonstrated a link between ODS and rapid correction of hyponatremia

3. ‘‘… whenever a patient who is gravely ill with alcoholism and malnutrition or a systemic medical disease develops confusion, quadriplegia, pseudobulbar palsy, and pseudo coma (‘ locked-in syndrome’) over a period of several days, one is justified in making a diagnosis of central pontine myelinolysis ’.

4. Controversy in nomenclature 1962- extrapontine myelinolysis (EPM ) may also occur hence broader term- Osmotic demyelination syndrome. But as per Victor and Adams: location of principal lesion is given  neurological consequences of the lesion can be deduced. term “ demyelination” avoided so as to distinguish this condition in which myelin loss occurs without obvious inflammatory infiltrate from inflammatory nature of MS .

5. Pathology Predominantly - basis pontis , sparing the tegmentum may extend up to midbrain, very rarely down to medulla Pathologically , loss of myelin sheath with relative sparing of axons and neurons in sharply demarcated lesion absence of an inflammatory infiltrate in these lesions Reason for localisation within this region: this is a region of maximal admixture of grey and white matter elements Similarly lesions of EPM are seen in similar regions of grey–white apposition.

6. Epidemiology Rare disease , frequency not known. Majority of pathologically diagnosed ODS cases are clinically asymptomatic Largest autopsy series :- prevalence of 0.25% to 0.5 % in a general population, majority were not diagnosed premortem Populations, such as alcoholics and liver transplant have higher rates of ODS Liver transplant pts- postmortem rate of ODS 10%. Peak incidence in adults aged 30 to 60 years Male preponderance , ? Higher alcoholism in this age group

7. Pathophysiology

8. Role of organic osmolytes Hyponatremia – causes loss of osmotically active, protective, organic osmolytes within few hours to days of hyponatremia Glycine , taurine , myoinositol , glutamate, glutamine from astrocytes However , not as quickly replaced when brain volume begins to shrink due to correction of hyponatremia As a result, brain volume falls below normal with rapid correction of hyponatremia .

9. Factors which may increase risk of acute hyponatremia encephalopathy Estrogen inhibits Na-K- ATPase pump Thus ODS is more common in women of childbearing age Arginine vasopressin decreased cerebral perfusion and decrease ATP availability for ion exchange Hypoxia limits ATP availability Ayus JC, Achinger SG, Arieff A. Brain cell volume regulation in hyponatremia : role of sex, age, vasopressin and hypoxia. Am J Physiol Renal Physiol 2008;295:F619 –24.

10. Disorders of solute metabolism Associated with alterations in cellular volume control.

11. Duration of Hyponatremia to cause ODS Brain damage does not occur when hyponatremia < 1 day duration is rapidly corrected If persists for > 2 to 3 days same treatment results in ODS However duration is often not known. Thus , assume that pt. has chronic hyponatremia unless the history suggests acute water intoxication . marathon runners psychotic patients users of ecstasy

12. Clinical features Appear 2 to 6 days after rapid correction of sodium Include: Central pontine myelinolysis (CPM ) Extra pontine myelinolysis (EPM) Movement disorders in EPM

13. Central pontine myelinolysis (CPM) Biphasic clinical course , initially encephalopathic or seizures from hyponatraemia , then recovering rapidly as normonatraemia is restored deteriorate several days later .- Manifested by s/o CPM dysarthria and dysphagia (secondary to corticobulbar fibre involvement), a flaccid quadriparesis ( corticospinal tract) later becomes spastic hyperreflexia and bilateral Babinski signs if tegmentum of pons is involved pupillary , oculomotor abnormalities apparent change in conscious level -‘‘ locked-in syndrome ’’

14. Diagnosis Clinical suspicion any patient presenting with new-onset neurological symptoms with a recent rapid increase in serum sodium. postliver transplant other risk factors listed Diagnosis clinico -radiological no role for tissue examination

15. Typical MRI lesions Trident shaped / spreading bushfire pattern in central pons Signal characteristics of affected region include: T1:  mildly or moderately hypointense T2:  hyperintense, sparing the periphery and  corticospinal tracts FLAIR :  hyperintense DWI:  hyperintense ADC:  signal low or signal loss T1 C+ ( Gd ):  usually there is no enhancement Radiologic findings do not improve over time , despite complete or nearly complete clinical recovery

16. Radiological differential diagnosis of CPM General imaging differential considerations include: demyelination - multiple sclerosis (MS) infarction from basilar perforators can be central pontine neoplasms - astrocytomas

17. Management Prevention Re-lowering Serum Sodium Supportive care Experimental therapies

18. Prevention Rate of sodium correction to avoid ODS < 10 to 12 mEq /L per 24 hours < 18 mEq /L in 48 hours Presence of other risk factors require slower rates- max 8 mEq /L per 24 hrs Some may have risk factors and have urgent symptoms of hyponatremia necessitating immediate correction, such as seizures or obtundation Generally, most life-threatening manifestations of hyponatremia will abate with a 5% rise in serum sodium Subsequent correction  no more than 8 to 12 mEq /L per 24 hours Geoghegan P, Harrison AM, Thongprayoon C, et al. Sodium Correction Practice and Clinical Outcomes in Profound Hyponatremia . Mayo Clin Proc 2015; 90:1348

19. Re-lowering Serum Sodium Goals of therapy Rate of lowering sodium is 1 meq /L per hour Target a rate of correction of < 8 meq /L in any 24-hour period and < 16 meq /L in any 48-hour period. D5%, 6 mL /kg lean body weight , infused over 2 hours . lowers Serum sodium by approximately 2 meq /L infusion should be repeated until the therapeutic goal dDAVP , 2 mcg intravenously or subcutaneously q6h can be increased to 4 mcg in those who do not respond dDAVP is continued, even after D5W infusions have ceased, to prevent serum sodium from rising again d/t excretion of dilute urine Rafat C, Schortgen F, Gaudry S, et al. Use of desmopressin acetate in severe hyponatremia in the intensive care unit. Clin J Am Soc Nephrol 2014; 9:229 Oya S, Tsutsumi K, Ueki K, Kirino T. Reinduction of hyponatremia to treat central pontine myelinolysis . Neurology 2001; 57:1931.

20. Supportive care Ventilator Physiotherapy and Neuro -rehab Anti-Parkinsonism drugs

21. Investigational therapies Minocycline minocycline crosses BBB  inhibits microglial activation  reducing microglial production of inflammatory cytokines no available data in humans Dexamethasone - no available data in humans myoinositol  Exogenous myoinositol rapidly restores the brain myoinositol content to normal levels no available data in humans Plasmpheresis ?? Spontaneous rapid clinical recovery Zhu S, Stavrovskaya IG, Drozda M, et al. Minocycline inhibits cytochrome c release and delays progression of ALS in mice. Nature 2002; 417:74 . Sugimura Y, Murase T, Takefuji S, et al. Protective effect of dexamethasone on osmotic-induced demyelination in rats. Exp Neurol 2005; 192:178 Saner FH, Koeppen S, et al. Treatment of central pontine myelinolysis with PLEX / IVIg in liver transplant patient. Transpl Int 2008; 21:390.

22. Prognosis 25 % develop severe, incapacitating neurological disease requiring lifelong support Variable persistent paralysis severe ataxia Bulbar symptoms Less common- persistence of cognitive/ beahvioural symptoms Menger H, Jorg J. Outcome of central pontine and extrapontine myelinolysis (n 44). J Neurol 1999;246:700 –5.

23. References Martin RJ. Central pontine and extrapontine myelinolysis : the osmotic demyelination syndromes. Journal of Neurology, Neurosurgery & Psychiatry . 2004 Sep 1;75( suppl 3):iii22-8 . King JD, Rosner MH. Osmotic demyelination syndrome. Am J Med Sci . 2010 Jun 1;339(6):561-7 . Uptodate website- 2017

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