history of present illness
The patient is a male in his late 30s with a past medical history of alcohol abuse and hypertension who presented to the emergency department (ED) with a chief complaint of urinary incontinence and altered mental status. His symptoms started 18 days ago when he first noticed gait problems. He presented to the ED on day seven of symptoms, at which point his gait abnormalities worsened and he had associated seizures. At that time, he had an ataxic broad-based gait and fell backwards while walking. He was hyponatremic with a sodium of 109 and had a witnessed seizure in the ED. He was given hypertonic saline and admitted to the medical intensive care unit (MICU) for further management. His sodium was gradually corrected at a rate of 4-6 mEq per day. On hospital day three he left against medical advice (AMA); his sodium that morning was 126 and he continued to have an ataxic gait but was able to ambulate 30 steps unassisted.
He was seen in another ED 13 days after his initial presentation for ataxia and confusion and was diagnosed with alcohol withdrawal syndrome and discharged with a lorazepam taper. He presented to the ED again on day 18 of symptoms with worsening mental status and was no longer able to ambulate or perform his activities of daily living (ADLs). At this time, the patient’s mental status deteriorated to the point that he could answer simple questions but could not provide any additional history.
Past Medical History: Alcoholism, hypertension
Past Surgical History: None
Medications: Folic acid, thiamine, multivitamin, metoprolol, lisinopril-hydrochlorothiazide, lorazepam
Allergies: No known
Vitals T 97.7° HR 62 RR 12 BP 157/104 SaO2 100%
Physical Exam: The patient appears well nourished but disheveled. He is alert and oriented to person, place, and time. His speech is delayed but he is able to answer simple questions. Extraocular movements show vertical and horizontal nystagmus with roving eye movements. The remainder of his cranial nerve exam is normal. He has normal strength in bilateral upper and lower extremities, and his sensation to light touch is grossly intact. His reflexes are normal throughout with down going Babinski bilaterally. His finger to nose testing is slow with dysmetria bilaterally but worse on the right. He has slow rapid alternating movements. He is unable to take a step unsupported. He has no asterixis in his upper extremities. The rest of his exam is unremarkable.
WBC: 5.2 Hgb: 12.1 Hct: 33.9 Plt: 206
Na: 137 K: 4.4 Cl: 100 HCO3: 28 BUN: 14 Cr: 1.03 Glucose: 92
AST/ALT: 33/28 Total bilirubin: 0.6 NH3: 83 Folic acid: 24.8 Vitamin B12: 1,430
Urine drug screen: Positive for benzodiazepines
Chest X-ray: Normal Noncontrast CT Head: Normal
The patient was given intravenous thiamine, folic acid, and a multivitamin for presumed Wernicke’s encephalopathy. He was admit-ted to medicine and started on high dose thiamine replacement. He went on to develop pseudobulbar affect on hospital day one with inappropriate emotional lability, and neurology evaluated the patient. An MRI was performed and was consistent with osmotic demyelination syndrome (ODS, previously referred to as central pontine myelinolysis) and severe cerebral and cerebellar volume loss. A representative image of the patient's MRI is shown below.
The patient was unlikely to have neurologic benefit from reducing sodium levels to previous state given the amount of time that had elapsed since correction. He received five treatments of plasmapheresis with improvement in his symptoms. He was discharged on hospital day 17 with significant improvement in his dysmetria and gait. He was able to ambulate with minimal assistance and complete ADLs with minimal difficulty.
Sodium is the primary determinant of serum tonicity. When the concentration of sodium in the serum decreases, water traverses the blood brain barrier and enters brain cells in an attempt to maintain isotonicity with the surrounding environment. This movement of water causes the cells to swell, and this triggers several protective mechanisms which attempt to maintain normal cell volume. Within minutes, the increased intracranial pressure and hydrostatic force pushes interstitial fluid into the cerebrospinal fluid. Cellular edema activates channels within the cell membrane releasing potassium, chloride, taurine, glutamate, aspartate, myoinositol, and other osmotic solutes into the interstitial space. As these osmotic substances pass into the surrounding interstitial fluid, water follows, allowing brain cells to remain isotonic with their surrounding environment with-out large increases in intracellular water or cell volume. Substantial intracellular osmolyte depletion and fluid shifts occur within the first 24 hours, and full adaptation is complete within 48 hours.
When hyponatremia is corrected, the serum sodium increases and extracellular tonicity begins to rise. Brain cells must once again adapt to a now relatively hypertonic environment. Inorganic ions such as sodium, potassium, and chloride now move back into the depleted cells. Further adaptation relies on the transport and synthesis of organic osmolytes within the cells, however this process takes much longer.[2,3] When replenishment of organic intracellular osmolytes cannot keep up with the rate of rise in serum tonicity, fluid shifts from the intracellular environment into the interstitial fluid in an attempt to maintain isotonicity. The shift of inorganic ions into the cell coupled with the shift of free water out of the cell results in cell shrinkage and intracellular hypertonicity.[2,3] These cause cellular damage and apoptosis. Astrocytes and oligodendrocytes are particularly susceptible to these changes, and death of these cells ensues within 24 hours leading to the development of ODS.[1,4,5] Several studies have demonstrated that the pons is the slowest region of the brain at restoring intracellular organic osmolytes, making this area of the brain most susceptible to demyelination.[6,7]
ODS includes the more common central pontine myelinolysis (CPM), as well as extrapontine myelinolysis (EPM), which occurs in addition to CPM in approximately 10% of cases. Osmotic demyelination syndrome typically presents two to six days following overcorrection or rapid correction of hyponatremia.[1,9,10,11] Patients typically present with a multiphasic history initially with acute decompensation due to significant hyponatremia followed by a brief recovery phase as the patient becomes normonatremic. Patients who develop ODS then further decompensate after this brief recovery period. The initial symptoms of ODS include dysarthria, dysphagia, and pseudobulbar palsy due to involvement of the corticobulbar tracts. Late symptoms include flaccid paralysis that becomes spastic due to involvement of the corticospinal tracts, diplopia, disorientation, confusion, altered mentation, seizures, coma, and locked in syndrome.[1,9,10] Osmotic demyelination can extend into other sites including the cerebellum, lateral geniculate, external capsule, hippocampus, putamen, cerebral cortex, thalamus, and caudate nucleus. EPM can lead to movement disorders including catatonia and parkinsonism, as well as behavioral and psychiatric disorders.[1,9] The prognosis of ODS varies wildly from no residual deficit to profound neurologic deficits and even death due to complications of the disease. In general, the deficits associated with ODS are typically permanent and severe.
ODS is more common in patients with a serum sodium <120, particularly in those who are chronically hyponatremic. Patients with liver disease, especially liver transplant patients, have been shown to be at a significantly increased risk of ODS. One study demonstrated the incidence of CPM in liver transplant patients to be up to 30%.[12,13,14] Although this predisposition is not entirely understood, it is believed to be because this patient population frequently has concomitant hyponatremia and malnourishment, making them ill-equipped to replenish the osmolytes necessary to combat fluctuations in serum tonicity.
Due to the wide range of symptoms that may be present in ODS, it can be difficult to distinguish from other disorders. Patients with ODS often present with normal sodium, and if the emergency physician is not aware that the patient has been previously hyponatremic this diagnosis can be missed. In such cases, the diagnosis must be suspected based on physical exam and history, as emergency physicians are unlikely to order a diagnostic MRI without significant clinical suspicion. Some key risk factors that should raise clinical suspicion of ODS are chronic alcohol abuse, chronic ma-nutrition, liver disease, or liver transplant. Recent history of acute illness from which the patient recovered and then subsequently decompensated again is extremely suspicious for ODS, particularly in a patient with significant risk factors.
Differential and Diagnosis
The differential diagnosis of ODS includes intracranial hemorrhage, acute ischemic stroke, Wernicke’s encephalopathy, acute intoxication, and various metabolic derangements. Intracranial hemorrhage and ischemic stroke often present with focal neurologic deficits and acute onset as opposed to the subacute presentation of ODS.
One method to treat ODS as mentioned in the patient case is to re-lower serum sodium levels if repletion is occurring too rapidly if within a reasonable period. Several animal studies have demonstrated improved outcomes following re-lowering of the serum sodium even when symptoms of ODS were already present.[30,31] Soupart et al. demonstrated complete neurologic recovery in an elderly female with hyponatremia whose serum sodium was over-corrected in the first 24 hours and subsequently re-lowered. Similar findings have been demonstrated in several other studies.[33,34] One method to re-lower the serum sodium is to administer 2-4 mcg of desmopressin IV every 8 hours with repeated 3mL/kg boluses of D5W. The sodium should be checked after the administration of each D5W infusion and should be continued until the serum so-dium has been re-lowered to a level beneath the therapeutic goal. Re lowering of the serum sodium has a greater therapeutic effect when initiated earlier, and no therapeutic effect has been demonstrated when initiated more than 24 hours after the onset of ODS symptoms. Other therapies can be used when treating a patient further into their course of illness.
Some animal model studies have suggested that glucocorticoids may improve outcomes in ODS by preventing blood brain barrier (BBB) disruption, limiting BBB permeability, and reducing the number of MRI detectable lesions.[35,36,37] However, re-lowering serum sodium has been shown to be more effective in improving outcomes of ODS, and the efficacy of glucocorticoids in humans has not been demonstrated and therefore is not currently a recommended treatment.[23,32,35]
Plasmapheresis is an additional therapy which is beginning to be utilized for the treatment of ODS. The proposed mechanism for this therapy is that plasmapheresis may remove myelin toxic sub-stances.[38,39] Several studies have demonstrated significant improvement in patients with ODS after multiple sessions of plasmapheresis, even when therapy is initiated several days after the onset of symptoms.[38,39,40] The regimens in these studies vary drastically from daily treatments to biweekly treatments, and a total of anywhere from 6-10 treatments. Unfortunately, no unified recommendation exists for implementation of this therapy as the data is limited to a few case studies. However, the case reports available demonstrate promise for plasmapheresis as a treatment strategy for ODS, even when treatment is initiated over 24 hours after onset of symptoms and the patient’s serum sodium has already been re-lowered with no improvement.
ODS is a demyelinating disease that most commonly develops after iatrogenic rapid correction of hyponatremia, although it can be seen in other disease states with rapid increases in serum tonicity. Patients who develop ODS have a delayed symptom onset and frequently present with spastic paralysis, dysarthria, dysphagia, movement disorders, mood and behavior disturbances, with symptoms ranging from alteration in mental status to seizures, coma, or locked in syndrome. Prevention requires careful correction of hyponatremia, with regular monitoring throughout the therapeutic course. Once overcorrection has occurred within the first 24 hours and symptoms of ODS have set in, appropriate treatment involves re-lowering of the serum sodium. Plasmapheresis has a limited amount of data but has been shown to improve outcomes and should be considered in the management of ODS.
authored by meaghan frederick, m.d.
posted by matthew scanlon, m.d.
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