osmotic demyelination syndrome central pontine myelinolysis extrapontine myelinolysis

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

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hyponatremia, hypoosmolality, rapid correction

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OSMOTIC DEMYELINATION SYNDROMEUbaidur Rahaman Senior Resident, Critical Care Medicine Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

Damned if we do, damned if we dont

Oh MS, Kim Hi, Carrol HJ.

Recommendations for treatment of symptomatic hyponatremia.Nephron 1995;70:143-50

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.

Unenhanced CT head focal hypoattenuation in the mid and dorsal pons

MRI 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)

HISTORICAL EVOLUTION

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 ill

Authors called it "new disease" and termed it CENTRAL PONTINE MYELINOLYSIS

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

Classic 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

Literature of previous 75 years revealed no case resembling CPM, clinically or pathologically.

Adams

alcoholism abuse since ages, But CPM was new

IOTROGENIC AGENTSdetected in hospital setting onlyno 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)

1966More lesions identified and not localized to the Pons

basal ganglia, thalamus, Gray-white junction of cerebral and cerebellar cortices, lateral geniculate

Most 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

1977 Burcar et al

15 cases

Hyponatremia . ODS

All had

HYPONATREMIA (S.Na: 96-130)

1977 Burcar et al

Hyponatremia

LITERATURE REVIEW

ODS

80 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

Tomlinson BE, Pierides AM, Bradley WGCentral pontine myelinolysis. Two cases with associated electrolyte disturbance QJM. 1976;45:373-86.

2 casesprotracted vomiting and drowsiness severe hyponatraemia (serum sodium 96100 mEq/l)

Hyponatremia

ODSCorrection of electrolyte abnormalities was accompanied by deterioration in the level of consciousness, quadriparesis, dysphasia and mutism

Postmortem examination finding of CPM and EPM

1979: Kevin LesliePathology resident at the University of Colorado

breakdown of BBB Autopsy of a Jaundiced patient with CPMExit of albumin-bound bile pigment from blood stream into brain tissues.

striking green discoloration Lesion in the pons

Blood derived MYELINOLYTIC factorComplements, immunoglobulins

Several reports of similar green discoloration of the pons in patients with CPM who had concurrent liver disease and jaundice

HYPONATREMIA

CORRECTION OF HYPONATREMIA

OPENING OF BBB

BLOOD DERIVED MYLENOLYTIC FACTOR

ODS

Brightman 1973, Rapoport 1976

BBB could be opened by intravenous Hypertonic saline Endothelial cell dehydration and shrinkage impairment of endothelial tight junctions

Neurosurgeons were using this strategy to deliver chemotherapeutic drugs that were impermeable to BBB

Why specific areas of brain affected

Gray 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 matter

while substrate MYELIN would be present in immediately adjacent WHITE matter

Areas with rich admixture of GRAY and WHITE matter would be at greatest risk

These areas are PONS, thalamus, striatum

Why specific areas of brain affected

Sketch of Human Pons close admixture of white matter bundles within gray matter

Blood derived MYELINOLYTIC factor

I wonder whether CPM is due to osmotic stress?Scott VendenBerg, first year Pathology Resident

One 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 CPM

Michael D. Norenberg Central Pontine Myelinolysis: historical and mechanistic considerations Metab Brain Dis. 2010;25:97-106

Neurology Resident

Norenberg MD, Leslie KO, Robertson AS. Association between rise in serum sodium and central pontine myelinolysis. Ann Neurol. 1982;11:128-35. 15 case of CPM Rise in S.Na of 20-30meq/L over 3-10 days before symptoms appeared Comparable group with similar degree of hyponatremia, which was corrected slowly, did not develop CPM

Kleinschmidt-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 saline

Demyelinating lesions were observed in midbrain, thalamus and straitum. But not in Pons ( in rats pons consists totally of white matter)

1982: NorenbergCase report

Normonatremic ( S.Na-139) patient with hepatic encephalopathy Treated with lactulose

On Day10, S.Na increased to 171 meq/L

Patient became restless and confused and died on D20

Histopathology showed demyelinating lesion in centre of pontine base

HYPONATREMIA

CORRECTION OF HYPONATREMIA

Rapid correction of Hyponatremia

OPENING OF BBB OSMOLALITY DIFFERENCE

BLOOD DERIVED MYLENOLYTIC FACTOR

ODS

1984:NORENBERGRapid 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

HYPONATREMIA

CORRECTION OF HYPONATREMIA

Rapid correction of Hyponatremia

OPENING OF BBB OSMOLALITY DIFFERENCE

BLOOD DERIVED MYLENOLYTIC FACTOR

ODS DURATION OF HYPONATREMIA Chronicity

Nephrol Dial Transplant (1993) 8: 644-646

Central pontine myelinolysis secondary to frequent and rapid shifts in plasma glucose in a diabetic haemodialysis patientN. Esforzado, E. Poch, C. Cardenal, J. Lopez-Pedret, L. Revert

22 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

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 later

Autopsy showed widespread, symmetrical demyelination involving subcortical white matter, corpus callosum, anterior commissure, external, and internal capsules, fornix, thalamus, cerebellum, and lateral pons.

Neurocrit Care. 2009;11(2):251-4 Central pontine myelinolysis in a patient with hyperosmolar hyperglycemia and consistently normal serum sodiumBurns JD, Kosa SC, Wijdicks EF.

A 93 year-old-man developed marked gait ataxia 2 days after the diagnosis and treatment of hyperosmolar hyperglycemia

Calculated 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.

J Child Neurol 2009 24: 884

Osmotic Demyelination Syndrome as a consequence of Treating Hyperammonemia in a Patient With Ornithine Transcarbamylase DeficiencyJavier F. Cardenas, MD, and John B. Bodensteiner, MD

7-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.

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 hyperglycemia

REAL CULPRIT OSMOLALITY CHANGE

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 hyponatremia

118 122 126 133 Over consecutive 4 days

Rate of correction:

118 122 125 129 Over consecutive 4 days

Both developed CPM during the hospital stay despite slow and judicious correction of hyponatremia.

Renal failure and administration of exogenous urea Prevented myelinolysis following rapid correction of experimental hyponatremiaSoupart 2000.

PATHOPHYSIOLOGY

Electrolyte Compositionof Body Fluid Compartments

Na is the most abundant molecule in ECF Na is the most osmotically active molecule ( Osmolytes) in ECFContribution of Gluc and BUN is 5 mOsm/L

S. 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

INTRACELLULAR COMPARTMENT

INORGANIC OSMOLYTES

ORGANIC OSMOLYTES Glycine Taurine Creatine Myoinositol

OSMOLALITY

Serum 280-295 mOsm/kg

Real story in critically ill patients

S. Osm = 2* (140) + 90/18 + 5/2.8 = 280 + 5 + 1.7 = 286.7

S. Osm = 2* (145) + 180/18 + 60/2.8 = 290 + 10 + 21 = 321

HYPO OSMOLALITY HYPONATREMIA

Osmolality difference between intracellular and extracellualar compartment

Initially GLIAL cells selectively swell have selective AQP channels

After 24 to 48 hours

Energy dependent of extrusion of solute and water from cells Restoration of cell volumethis compensatory mechanism is complete bye 48 hours. Hence working definition of acute vs chronic hyponatremia

Joshua D. King, Mitchell H. Rosner. Osmotic demyelination syndrome. Am J med sci 2010:339;6

Cell adapted to decreased osmolality

Rapid correction of osmolality

Osmolality difference between two compartments Water exits from cells

Disruption of BBB

Cell dehaydration

Exposure of glial cells to cytokines, complements Axonal shear injury

Demyelination and apoptosis

Joshua D. King, Mitchell H. Rosner. Osmotic demyelination syndrome. Am J med sci 2010:339;6

Cell adapted to decreased osmolality

Rapid correction of osmolality Osmolality difference between two compartments

Need for Increased production of organic osmolytes Upregulation of Na K ATPase channels

Significant Metabolic Stress

Patient vulnerable to energy deprivation- Alcoholics, Malnutrition

Failure to respond to these changes Failure to regulate cellular volumeJoshua D. King, Mitchell H. Rosner. Osmotic demyelination syndrome. Am J med sci 2010:339;6

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

Chronic hyponatremia

Loss of organic osmolytes is more

Following rapid correction Synthesis and accumulation of organic omolytes into cells takes about 5 days This is compensated by accumulation of inorganic osmolytes in higher amount

Inorganic osmolytes bind to proteins and denature them and destroy normal protein structure and function iof cells

Joshua Johnstone, Arumugam Jayakumar

Osmotically stressed endothelial cells in culture release a factor that is lytic to cultured oligodendrocytes.

Effect of co existing other electrolyte and metabolic disturbances increased risk of ODSHYPOKALEMIA 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 NaKATPase

HypophosphatemiaPi is required for synthesis of two organic osmolytes, phosphocreatine and glycerolphosphorylcholine

Effect of co existing other electrolyte and metabolic disturbances

UREMIA Protective effect In azotemic rats, Brain myoinositol ( organic osmolyte) levels increased more quickly during rapid correction of hyponatremia

J Neurol Neurosurg Psychiatry 2003;74:353355 Central pontine myelinolysis associated with hypokalaemia in anorexia nervosa T Sugimoto, T Murata, M Omori, Y Wada

DISEASES ASSOCIATED WITH ODS

Alcoholism Malnutrition Post liver transplantProlonged diuretic use Psychogenic polydypsia Burns Post pituitary surgery Post surgery: urological, gynecological

LIVER DISEASE AND ORTHOTROPIC LIVER TRANSPLANTATION

Often 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

INCIDENCE

Not 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 undiagnosed

Alcoholics 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)

CLINICAL MANIFESTATIONPatient presenting with encephalopathy or seizures from hyponatremia Hyponatremia corrected Patient impvroves

Few days later (1 to 7 days)Patient presents with

Dysarthria, dysphagia, flaccid quadriaparesis later becoming spastic Pupillary abnormality and EOM palsy Locked in syndrome

CLINICAL MANIFESTATIONPsychiatric and behavioral changes Movement disorders Mutism, parkinsonism, dystonia, catatonia

In 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 dystonia

Parkinsonism 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

IMAGING MRI:imaging of choiceHyperintense lesion on T2 weighted Hypointense lesion on T1 weighted DWI might have capability of detecting lesion undetectable on T2

TIMINGTiming 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

LESIONS OF ODSPons Cerebellum Lateral geniculate body External capsule Hippocampus Putamen Cerebral cortex/ subcortex Thalamus Caudate nucleusClaustrum Internal capsule Midbrain Internal medullary lamella Mamillary body Medulla oblongata

MICROSCOPY

Degeneration and loss of oligodendrocytes with preservation of axons unless lesion is advanced

RELATIVE PROPORTIONS OF CPM AND EPM

CPM 1/2

CPM + EPM 3/5

EPM 2/5

TREATMENTPrevention 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

TREATMENT Re induction of Hyponatremiain 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 G

Case reports showing improvement in neurological symptoms after re induction of hyponatremiaOya 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

CORRECTION OF HYPONATREMIARisk of ODS and associated morbidity and mortality

Mortality associated with hyponatremia and slow correction

Damned if we do, damned if we dontOh MS, Kim Hi, Carrol HJ. Recommendations for treatment of symptomatic hyponatremia. Nephron 1995;70:143-50

Nutritional 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

SUGGESTED MAXIMUM CORRECTION OF HYPONATREMIA

Rate of correction

Symptomatic or Acute hyponatremia(change >0.5 meq/L/h or onset in < 48 hours)

1-2 meq/L/h ( 10-12 meq/L/day)

Chronic hyponatremia(Change over > 48 hours or unknown duration)

Increased risk of CPM as adaptive mechanism has occured

0.5 meq/L/h ( 8-10 meq/L/day)

GOAL of Correction

120-130 meq/L Lower in patients with s.Na1012 mmol/L/day.

Asymptomatic hyponatremia0.5 mmol/L/h

Crit Care Med. 2012 Mar;40(3):970-2. Long-term outcome of patients hospitalized in intensive care units with central or extrapontine myelinolysisLouis 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%) patients

At 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

Crit Care Med. 2012 Mar;40(3):970-2. Long-term outcome of patients hospitalized in intensive care units with central or extrapontine myelinolysisLouis 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 presentation

The 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

KEY POINTS

Consider 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 prognostic

R J Martin Central Pontine and Extrapontine Myelinolysis: The Osmotic Demyelination Syndrome J Neurol Neurosurg Psychiatry 2004;75

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 themselvesEric Hoffer

MODIFIED RANKIN SCORE

0 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