Osmotic demyelination syndrome

-Dr. Sachin A Adukia

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

‘‘…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’.

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.

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.

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

Pathophysiology

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 rapidcorrection of hyponatremia.

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 availabilityAyus 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.

Disorders of solute metabolism

Associated with alterations in cellular volume control.

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 ODSHowever 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

Clinical features

Appear 2 to 6 days after rapid correction of sodiumInclude:

Central pontine myelinolysis (CPM) Extra pontine myelinolysis (EPM) Movement disorders in EPM

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’’

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

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

Radiological differential diagnosis of CPM

General imaging differential considerations include: demyelination - multiple sclerosis (MS) infarction from basilar perforators can be central pontine neoplasms - astrocytomas

Management

PreventionRe-lowering Serum SodiumSupportive careExperimental therapies

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

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 urineRafat 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.

Supportive care

VentilatorPhysiotherapy and Neuro-rehabAnti-Parkinsonism drugs

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.

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.

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.

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