1. OSMOTIC DEMYELINATION SYNDROME Ubaidur Rahaman Senior Resident, Critical Care Medicine Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

2. Damned if we do, damned if we dontOh MS, Kim Hi, Carrol HJ.Recommendations for treatment of symptomatic hyponatremia. Nephron 1995;70:143-50 3. A 58-year-old male had been recently discharged from a ICU following a six day stay for treatment of hyponatremia, jaundice, and abnormal liver function tests. Four days later he presented to the local emergency department with agitation, delirium and altered level of consciousness. Physical examination demonstrated a jaundice, afebrile, normotension without cardiovascular, respiratory, abdominal or neurological abnormalities. Lab showed a normal complete blood count and electrolytes with minor elevation of total bilirubin and alkaline phosphatase. Within 48 hours he developed acute oropharyngeal dysphagia. 4. Unenhanced CT head focal hypoattenuation in the mid and dorsal ponsMRI brain abnormal low T1 and high T2 mexican hat shaped signal within the central pons with sparing of the corticospinal tracts ventrolaterally. Abnormal increased T2 signal was also demonstrated in the thalami and putamen bilaterally Restricted diffusion was noted in these corresponding regions with diffusion weighted imaging (DWI) Clinical and radiological findings were compatible with central pontine myelinolysis (CPM) and extrapontine myelinolysis (EPM) 5. HISTORICAL EVOLUTION 6. AMA Arch Neurol Psychiat 1959; 81:154172 Central pontine myelinolysis: a hitherto undescribed disease occurring in alcoholic and malnourished patients. Adams RD, Victor M, Mancall EL A series of 4 patients quadriparesis, pseudobulbar paralysis characteristic pattern of myelin loss confined within central pons. No evidence of inflammation ( differentiating from known demyelinating disease like multiple sclerosis) 3 patients were alcoholics, malnourished and chronically illAuthors called it "new disease" and termed it CENTRAL PONTINE MYELINOLYSIS 7. AMA Arch Neurol Psychiat 1959; 81:154172 Central pontine myelinolysis: a hitherto undescribed disease occurring in alcoholic and malnourished patients. Adams RD, Victor M, Mancall ELClassic histopathology of the pons in CPM showing a symmetrical, central bat-wing area of demyelination affecting most of the pontine base. Luxol-fast blue/PAS 8. Literature of previous 75 years revealed no case resembling CPM, clinically or pathologically.Adamsalcoholism abuse since ages, But CPM was newIOTROGENIC AGENTS detected in hospital setting only no patient admitted with symptoms of CPM, and proved to have such pathology at postmortem examination.1963 Aleu and Terry Co-incidence or Co relation 1950: the Plastic Revolution: Intravenous Fluid Therapy Corresponded with detection of CPM Messert and co-workers (1979) 9. 1966 More lesions identified and not localized to the Ponsbasal ganglia, thalamus, Gray-white junction of cerebral and cerebellar cortices, lateral geniculateMost of the cases occurred in chronic conditions such as liver disease, sepsis, burns, and cancer ie It occurred in presence of co-existing diseases/ conditions 10. 1977 Burcar et al15 casesAll hadHYPONATREMIA (S.Na: 96-130)Hyponatremia . ODS 11. 1977 Burcar et alLITERATURE REVIEWHyponatremiaODS80 cases, electrolytes documented in 30 cases; Hyponatremia: 12 cases.Rest 50 cases ( electrolytes not documented) Review of history for plausible conditions leading to hyponatremia ( compulsive water drinking, hemodialysis, SIADH, severe renal disease, diarrhea or vomiting, thyroid or adrenal disease)69 of 80 patients either had documented hyponatremia or plausible cause of hyponatremia 12. Tomlinson BE, Pierides AM, Bradley WG Central pontine myelinolysis. Two cases with associated electrolyte disturbance QJM. 1976;45:373-86.2 cases protracted vomiting and drowsinessHyponatremiasevere hyponatraemia (serum sodium 96100 mEq/l)ODS Correction of electrolyte abnormalities was accompanied by deterioration in the level of consciousness, quadriparesis, dysphasia and mutismPostmortem examination finding of CPM and EPM 13. 1979: Kevin Leslie Pathology resident at the University of Coloradobreakdown of BBB Autopsy of a Jaundiced patient with CPMstriking green discoloration Lesion in the ponsExit of albumin-bound bile pigment from blood stream into brain tissues.Blood derived MYELINOLYTIC factor Complements, immunoglobulinsSeveral reports of similar green discoloration of the pons in patients with CPM who had concurrent liver disease and jaundice 14. HYPONATREMIACORRECTION OF HYPONATREMIAOPENING OF BBBBLOOD DERIVED MYLENOLYTIC FACTORODS 15. Brightman 1973, Rapoport 1976BBB could be opened by intravenous Hypertonic saline Endothelial cell dehydration and shrinkage impairment of endothelial tight junctionsNeurosurgeons were using this strategy to deliver chemotherapeutic drugs that were impermeable to BBB 16. Why specific areas of brain affectedGray matter is 10 times rich in capillaries than white matter If some myelnotoxic factor is responsible for demyelination This factor would be enriched in GRAY matterwhile substrate MYELIN would be present in immediately adjacent WHITE matterAreas with rich admixture of GRAY and WHITE matter would be at greatest riskThese areas are PONS, thalamus, striatum 17. Why specific areas of brain affectedSketch of Human Pons close admixture of white matter bundles within gray matter 18. Blood derived MYELINOLYTIC factor 19. I wonder whether CPM is due to osmotic stress? Scott VendenBerg, first year Pathology ResidentOne morning in 1979 while preparing to review the histology of a case of CPM, I mentioned our recent studies on the potential role of hyponatremia. In a nonchalant manner Scott said I wonder whether CPM is due to osmotic stress?. I was not exactly sure what Scott had in mind when he uttered that phrasebut that was a quintessential moment as this comment immediately crystallized all of the disjointed facts into a logical mechanism, potentially explaining the pathogenesis of CPMMichael D. Norenberg Central Pontine Myelinolysis: historical and mechanistic considerations Metab Brain Dis. 2010;25:97-106 20. Neurology ResidentNorenberg MD, Leslie KO, Robertson AS. Association between rise in serum sodium and central pontine myelinolysis. Ann Neurol. 1982;11:128-35. 15 case of CPMComparable groupRise in S.Na of 20-30meq/L over 3-10 days before symptoms appearedwith similar degree of hyponatremia, which was corrected slowly, did not develop CPMKleinschmidt-DeMasters BK, Norenberg MD. Rapid correction of hyponatremia causes demyelination: relation to central pontine myelinolysis Science 1981;211:1068-70. Rats made hyponatremic with vasopressin and water injection S.Na corrected with hypertonic salineDemyelinating lesions were observed in midbrain, thalamus and straitum. But not in Pons ( in rats pons consists totally of white matter) 21. 1982: Norenberg Case reportNormonatremic ( S.Na-139) patient with hepatic encephalopathy Treated with lactuloseOn Day10, S.Na increased to 171 meq/LPatient became restless and confused and died on D20Histopathology showed demyelinating lesion in centre of pontine base 22. HYPONATREMIACORRECTION OF HYPONATREMIARapid correction of HyponatremiaOPENING OF BBBBLOOD DERIVED MYLENOLYTIC FACTORODSOSMOLALITY DIFFERENCE 23. 1984:NORENBERG Rapid correction of hyponatremia in Patient with short duration hyponatremia ( hours to few days), did not develop CPM. But those with longer duration ( 1 week or longer), developed CPM.Michael D. Norenberg, Rebecca E. Papendick Chronicity of hyponatremia as a factor in experimental myelinolysis Annals of Neurology 1984;15(6): 544547 Rats hyponatremic for 1 day compared with another group hyponatremic for 3 days 3-day hyponatremic rats developed more numerous and more severe demyelinative lesions than the 1-day rats 24. HYPONATREMIACORRECTION OF HYPONATREMIARapid correction of HyponatremiaOPENING OF BBBBLOOD DERIVED MYLENOLYTIC FACTOROSMOLALITY DIFFERENCEODS DURATION OF HYPONATREMIA Chronicity 25. Nephrol Dial Transplant (1993) 8: 644-646Central pontine myelinolysis secondary to frequent and rapid shifts in plasma glucose in a diabetic haemodialysis patient N. Esforzado, E. Poch, C. Cardenal, J. Lopez-Pedret, L. Revert22 years female, case of DM type 1 with CKD History of frequent rapid change in glucose Admitted with depression of consciousness and difficulty in swallowing. Afebrile, hemodynamically stable. Neurological examinationL bilateral Babinski sign with a reduced gag reflex. The rest of the physical examination was unremarkable. Investigation revealed glucose 684mg/dl, BUN 78mg/dl, Na 130 mmol/L, K 5.1 mmol/L, serum osmolality 302 mOsm/kg CSF and toxicology screening negative MRI brain suggestive of CPM 26. Clin Neuropathol. 1989 Nov-Dec;8(6):284-8. Lateral pontine and extrapontine myelinolysis associated with hypernatremia and hyperglycemia. McComb RD, Pfeiffer RF, Casey JH, Wolcott G, Till DJ.A woman presented in hyperosmolar diabetic coma with hypernatremia (169 mEq/l) and hyperglycemia (954 mg/dl).Plasma sodium rapidly increased to 188 mEq/l before gradually returning to normal She remained obtunded and died 21 days laterAutopsy showed widespread, symmetrical demyelination involving subcortical white matter, corpus callosum, anterior commissure, external, and internal capsules, fornix, thalamus, cerebellum, and lateral pons. 27. Neurocrit Care. 2009;11(2):251-4 Central pontine myelinolysis in a patient with hyperosmolar hyperglycemia and consistently normal serum sodium Burns JD, Kosa SC, Wijdicks EF.A 93 year-old-man developed marked gait ataxia 2 days after the diagnosis and treatment of hyperosmolar hyperglycemiaCalculated S.OSM on admission was 344 mOsm/kg and fell to 300 mOsm/Kg over 20 h. Serum sodium concentration stayed between 137 and 140 mEq/l throughout the admission.MRI symmetric lesion in the central pons consisting of increased T2 signal intensity and restricted diffusion, consistent with CPM. 28. J Child Neurol 2009 24: 884Osmotic Demyelination Syndrome as a consequence of Treating Hyperammonemia in a Patient With Ornithine Transcarbamylase Deficiency Javier F. Cardenas, MD, and John B. Bodensteiner, MD7-year-old female patient with a 1-year history of psychiatric outbursts presented to the emergency department with a prolonged episode of confusion, hallucinations, and agitation.Lab showed elevated blood ammonia- 253 mmol/L, SGOT-296 U/L, SGPT- 496 U/L, S. sodium- 142 mmol/L.Presumptive diagnosis of ornithine transcarbamylase deficiency was made treated with sodium benzoate and sodium phenylacetate and responded quickly, with ammonia levels reaching 33 mmol/L within 24 hours. 10 days later, she began to have an unsteady gait, uncoordinated arm movements, and dysarthia MRI brain demonstrated T2-weighted hyperintensities in the central pons and the sublentiform white matter, bilaterally. 29. Rapid change in Osmolality without change in S.Na has been reported to led to ODS In Post liver transplant patients Dialysis disequilibrium syndrome Treatment of hyperammonemic patients Correction of hypernatremia and hyperglycemiaREAL CULPRIT OSMOLALITY CHANGE 30. Clin Neurol Neurosurg. 1995 Nov;97(4):340-3. Central pontine myelinolysis following 'slow' correction of hyponatremia. Pradhan S, Jha R, Singh MN, Gupta S, Phadke RV, Kher V.2 patients chronic renal failure admitted in a stuporous state due to hyponatremia118 122 126 133 Over consecutive 4 daysRate of correction:118 122 125 129 Over consecutive 4 daysBoth developed CPM during the hospital stay despite slow and judicious correction of hyponatremia. 31. Renal failure and administration of exogenous urea Prevented myelinolysis following rapid correction of experimental hyponatremia Soupart 2000. 32. PATHOPHYSIOLOGY 33. Electrolyte Composition of Body Fluid Compartments 34. Na is the most abundant molecule in ECF Na is the most osmotically active molecule ( Osmolytes) in ECF Contribution of Gluc and BUN is 5 mOsm/LS. Osm ( mOsm/kg of water) (2*[Na] + [Glucose/18] + [BUN/2.8] (Na in meq/L, Glucose in mg/dL, BUN in mg/dL)Osmotic pressure and osmolality determines distribution of fluid in body compartments 35. INTRACELLULAR COMPARTMENTINORGANIC OSMOLYTESORGANIC OSMOLYTES Glycine Taurine Creatine Myoinositol 36. OSMOLALITYSerum 280-295 mOsm/kg 37. Real story in critically ill patientsS. Osm = 2* (140) + 90/18 + 5/2.8 = 280 + 5 + 1.7 = 286.7S. Osm = 2* (145) + 180/18 + 60/2.8 = 290 + 10 + 21 = 321 38. HYPO OSMOLALITY HYPONATREMIA 39. Osmolality difference between intracellular and extracellualar compartmentInitially GLIAL cells selectively swell have selective AQP channelsAfter 24 to 48 hoursEnergy dependent of extrusion of solute and water from cells Restoration of cell volume this compensatory mechanism is complete bye 48 hours. Hence working definition of acute vs chronic hyponatremiaJoshua D. King, Mitchell H. Rosner. Osmotic demyelination syndrome. Am J med sci 2010:339;6 40. Cell adapted to decreased osmolalityRapid correction of osmolalityOsmolality difference between two compartments Water exits from cellsDisruption of BBBExposure of glial cells to cytokines, complementsCell dehaydrationDemyelination and apoptosisAxonal shear injuryJoshua D. King, Mitchell H. Rosner. Osmotic demyelination syndrome. Am J med sci 2010:339;6 41. Cell adapted to decreased osmolalityRapid correction of osmolalityNeed for Increased production of organic osmolytesOsmolality difference between two compartmentsUpregulation of Na K ATPase channelsSignificant Metabolic StressPatient vulnerable to energy deprivation- Alcoholics, MalnutritionFailure to respond to these changes Failure to regulate cellular volume Joshua D. King, Mitchell H. Rosner. Osmotic demyelination syndrome. Am J med sci 2010:339;6 42. brain reclaims organic osmolytes more slowly during correction of hyponatremia than it loses them during the onset of hyponatremia; this slow recovery of osmolytes appears to play an important role in the pathogenesis of iatrogenic brain damage. Several lines of evidence in experimental models support this conclusion (1) brain regions that are most susceptible to myelinolysis are the slowest to reclaim lost osmolytes (2) uremia, which is protective against myelinolysis, is associated with a more rapid recovery of brain organic osmolytes after correction of hyponatremia (3) exogenous administration of the organic osmolyte, myoinositol, during correction of hyponatremia rapidly restores brain myoinositol levels and decreases the number and severity of demyelinating lesions in the brain.Richard H. Sterns, Sagar U. Nigwekar, John Kevin Hix, The Treatment of Hyponatremia Semin Nephrol 29:282-299 43. Chronic hyponatremiaLoss of organic osmolytes is moreFollowing rapid correction Synthesis and accumulation of organic omolytes into cells takes about 5 days This is compensated by accumulation of inorganic osmolytes in higher amountInorganic osmolytes bind to proteins and denature them and destroy normal protein structure and function iof cells 44. Joshua Johnstone, Arumugam JayakumarOsmotically stressed endothelial cells in culture release a factor that is lytic to cultured oligodendrocytes. 45. Effect of co existing other electrolyte and metabolic disturbances increased risk of ODS HYPOKALEMIA Concomitant hypokalemia potentiates osmolality difference between intracellular and extracellular compartment Na is corrected more rapidly, when hypokalemia is corrected along with hyponatremia Increased activity of NaKATPaseHypophosphatemia Pi is required for synthesis of two organic osmolytes, phosphocreatine and glycerolphosphorylcholine 46. Effect of co existing other electrolyte and metabolic disturbancesUREMIA Protective effect In azotemic rats, Brain myoinositol ( organic osmolyte) levels increased more quickly during rapid correction of hyponatremia 47. J Neurol Neurosurg Psychiatry 2003;74:353355 Central pontine myelinolysis associated with hypokalaemia in anorexia nervosa T Sugimoto, T Murata, M Omori, Y Wada 48. DISEASES ASSOCIATED WITH ODSAlcoholism Malnutrition Post liver transplant Prolonged diuretic use Psychogenic polydypsia Burns Post pituitary surgery Post surgery: urological, gynecological 49. LIVER DISEASE AND ORTHOTROPIC LIVER TRANSPLANTATIONOften associated hyponatremia Malnourished decreased intracellular myo ionositol level Reduced myo ionositol level has been documented in these patients Cultured astrocytes treated with ammonia show reduced myo ionositol levels. Ammonia impairs uptake of myo ionositol by astrocytes. Other organic osmolytes ( taurine, glycerophosphorylcholine) are reduced in patients with hepatic encephalopathy 50. INCIDENCENot exactly known because of paucity of studies Majority of pathologically diagnosed cases are clinically asymptomatic Largest autopsy series: 0.25-0.5% prevalence in general population Majority were undiagnosedAlcoholics and liver transplant have much higher rate on pathological examination Liver transplant patient 10% (on autopsy)Josua D. King, Mitchell H. Rosner Osmotic Demyelination Syndrome Am J Med Sciences 2010;339(6) 51. CLINICAL MANIFESTATION Patient presenting with encephalopathy or seizures from hyponatremia Hyponatremia corrected Patient impvrovesFew days later (1 to 7 days) Patient presents withDysarthria, dysphagia, flaccid quadriaparesis later becoming spastic Pupillary abnormality and EOM palsy Locked in syndrome 52. CLINICAL MANIFESTATION Psychiatric and behavioral changes Movement disorders Mutism, parkinsonism, dystonia, catatoniaIn EPM variety of clinical features can be seen to evolve Patient progressing from spastic paraparesis with postural limb tremors and myoclonic jerks to a parkinsonian picture with choreoathetosis and finally into a permanent parkinsonian state with dystoniaParkinsonism dominated clinical picture with signs of pyramidal dysfunction which resolved over four months, being replaced by transient retrocollis and oromandibular dystonia and a permanent focal dystonia of arm with spasmodic dysphonia.These movement disorders are easily controlled with dopaminergic drugs 53. IMAGING MRI:imaging of choice Hyperintense lesion on T2 weighted Hypointense lesion on T1 weighted DWI might have capability of detecting lesion undetectable on T2TIMING Timing of appearance may be delayed MR image typically are normal at the onset of symptoms and become positive after approximately 2 weeks If diagnosis remains likely: repeat imaging at 10-14 days may reveal lesion 54. LESIONS OF ODS Pons Cerebellum Lateral geniculate body External capsule Hippocampus Putamen Cerebral cortex/ subcortex Thalamus Caudate nucleus Claustrum Internal capsule Midbrain Internal medullary lamella Mamillary body Medulla oblongata 55. MICROSCOPYDegeneration and loss of oligodendrocytes with preservation of axons unless lesion is advanced 56. RELATIVE PROPORTIONS OF CPM AND EPMCPM 1/2CPM + EPM 3/5EPM 2/5 57. TREATMENT Prevention Judicious correction of Hyponatremia Selective vasopressin receptor antagonis For euvolumic or hypervolumic hyponatremia Corticosteroids Used to mitigate severity of ODS ? Stabilization of BBB Timing of administration not well determined Myoinositol Improve mortality in rats with rapid correction of hyponatremia Plasmapheresis Appeared beneficial in series of 4 patients with ODS ? Reduction in inflammatory mediators and preservation of BBB 58. TREATMENT Re induction of Hyponatremia in chronic hyponatremic rats who had roughly 30 meq/L change in S.serum Na in 12 hours Reinduction of mild hyponatremia reduced both neurological manifestation and mortlaity from 100% to 6% Kidney Int. 2009 Sep;76(6):614-21 Re-induction of hyponatremia after rapid overcorrection of hyponatremia reduces mortality in rats. Gankam Kengne F, Soupart A, Pochet R, Brion JP, Decaux GCase reports showing improvement in neurological symptoms after re induction of hyponatremia Oya S, Tsutsumi K, Ueki K, et al. Reinduction of hyponatremia to treat central pontine myelinolysis. Neurology 2001;57:19312 Soupart A, Ngassa M, Decaux G. Therapeutic relowering of the serum sodium in a patient after excessive correction of hyponatremia. Clin Nephrol 1999;51:383 6 59. CORRECTION OF HYPONATREMIAMortality associated with hyponatremia and slow correctionRisk of ODS and associated morbidity and mortalityDamned if we do, damned if we dont Oh MS, Kim Hi, Carrol HJ. Recommendations for treatment of symptomatic hyponatremia. Nephron 1995;70:143-50Nutritional status of patient plays a part, impairing ability to generate organic osmoles. At present we can not assess this ability, and so it is not really possible to determine a threshold rate of change that can be guaranteed to be universally safe. Recommendations for safe rate of Na rise are based on animal models and published series of CPM R J Martin, Central pontine and extrapontine myelinolysis: the osmotic demyelination syndromes 60. SUGGESTED MAXIMUM CORRECTION OF HYPONATREMIA 61. Rate of correctionSymptomatic or Acute hyponatremia1-2 meq/L/h ( 10-12 meq/L/day)(change >0.5 meq/L/h or onset in < 48 hours)Chronic hyponatremia (Change over > 48 hours or unknown duration)Increased risk of CPM as adaptive mechanism has occuredGOAL of Correction0.5 meq/L/h ( 8-10 meq/L/day)120-130 meq/L Lower in patients with s.Na1012 mmol/L/day.Asymptomatic hyponatremia 0.5 mmol/L/h 63. Crit Care Med. 2012 Mar;40(3):970-2. Long-term outcome of patients hospitalized in intensive care units with central or extrapontine myelinolysis Louis G, Megarbane B, Lavou S, Lassalle V, Argaud L, Poussel JF, Georges H, Bollaert PE.Retrospective observational study, unfavorable outcome- modified Rankin Scale score >3 or death 36 patients with CPM or EPM treated in 2000-2010 31 (86%) patients were alcoholics and 33 (92%) presented with hyponatremia Mechanical ventilation was required in 32 (89%) patientsAt 1-yr follow-up, 11 (31%) died 14 (56%) survivors recovered to Rankin score 1.EOLS (withheld) in 11 (31%) patients Severe cerebral motor disability was the most frequently cited reason. However, five of them were still alive at 1 yr with Rankin score 1 for four of them 64. Crit Care Med. 2012 Mar;40(3):970-2. Long-term outcome of patients hospitalized in intensive care units with central or extrapontine myelinolysis Louis G, Megarbane B, Lavou S, Lassalle V, Argaud L, Poussel JF, Georges H, Bollaert PE.No statistical difference between 18 (50%) patients with a favorable outcome and 18 (50%) patients with an unfavorable outcome with regard to severity of illness,recovery is Possible BUT unpredictable on the basis of clinical presentationThe prognosis of critically ill patients with central or extrapontine myelinolysis is better than thus far thought despite initial severe clinical manifestations.Regarding the high rate of decisions to withhold life-supporting therapies, the probability of a favorable outcome might be underestimated by intensivists 65. KEY POINTSConsider ODS in a patient who has failed to recover as expected after a severe illness requiring intravenous fluid In a patient manifesting psychiatric symptoms after such an illness, even if imaging is negative Na rise need not be in excess of 10 mmol/l/day for condition to develop. There may be no safe limit for the rate of rise of Na. Prognosis is not uniformly bad MRI changes may be delayed MRI severity is not prognosticR J Martin Central Pontine and Extrapontine Myelinolysis: The Osmotic Demyelination Syndrome J Neurol Neurosurg Psychiatry 2004;75 66. With some people solitariness is an escape not from others but from themselves. For they see in the eyes of others only a reflection of themselves Eric Hoffer 67. MODIFIED RANKIN SCORE0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent and requiring constant nursing care and attention 6 Dead