Osmotic demyelination syndrome(ODS)

1.Previous name#

• Central pontine myelinolysis; 不過因為involve範圍不只pons, 另外也可以不involve pons, 所以目前改叫ODS

2.Pathogenesis of ODS#

• Chronic hyponatremia的brain adaption:see hyponatremia-S/S-adaptation; 由於chronic hyponatremia時brain的osmolytes變少, acute correction of hyponatremia會使brain decreases size a lot(因為osmolytes resynthesis/reuptake by brain不快), decrease size a lot會導致demyelination(真正機制未知, 不過推測 1.shrinkage BV endothelial cells導致BBB打開而使lymphocytes, complement, cytokines...可過BBB==>damage brain, demyelination; 2.hyponatremia回復時Na/K大量進入brain cells with loss of water before osmolytes repletion可能damage to astrocyte, disruption in the function of myelin-producing oligodendrocytes, release of inflammatory cytokines, and activation of microglia)

3.Risk factors#

• 多發生在chronic(>2天, brain才會代償; <1天rapid correction多不會發生ODS; 但除非history很明確, 有時候很難知道是不是<1天), severe(Na<120; 尤其<105) with rapid correction of hyponatremia; 不過Na 120-129 with slower correction rate也有發生的案例, 但Na 120-129大多發生在correction rate is very high[(如severe liver disease s/p liver transplantation) or (DI Tx with DDAVP complicated with hyponatremia then DC abruptly) or (corrected SIADH) or (corrected true hypovolemia(導致ADH被suppress)) or (DC thiazide)], autocorrection(hyponatremia原因被解決)是導致給予IVF算Na公式不準的最主要原因(多因為ADH被suppressed而排出diluted urine使serum Na level↑↑↑)
  • Daily correction rate比hour correction rate重要得多; hour correction rate太快但daily correction rate WNL則多不會ODS
    • 矯正速率標準(依歐洲ESICM/ESE/ERA-EDTA指引〔PMID 24569125〕與Sterns專家共識〔PMID 25551526〕)：
      • 一般風險：目標上升 4-8 mmol/L/d；安全上限 <10 mmol/L in 24hrs (<18 mmol/L in 48hrs)
      • 高風險(Na≦105、hypokalemia、alcoholism、malnutrition、advanced liver disease)：目標 4-6 mmol/L/d；嚴格上限 ≦8 mmol/L in 24hrs (<14-16 mmol/L in 48hrs)〔PMID 26735146〕
      • if overcorrection, 應即刻給予 D5W 合併 DDAVP 進行救援降鈉(但acute hyponatremia則不用re-lowering SNa, 因為不太會ODS)
        • vs. Hypernatremia; hypernatremia overcorrection不須re-raising(因為IICP risk不大, 見前述-Adaptation)
• Other risk factors:Malnutrition, alcoholism, liver disease, hypokalemia(感覺就是本來osmo就不夠的病人)
• Overly rapid correction of hyponatremia by HD in ESRD Pt似乎不太會ODS, 可能是因為1.urea也被洗掉的關係(雖然urea是ineffective osmo, 但是brain和blood的urea平衡比water慢, 所以在urea被rapidly reduced時, urea仍算是brain的relatively effective osmo) 2.Azotemia會刺激brain reuptake organic osmolytes

4.S/S#

• involve很多地方, 尤其pons, corticospinal/corticobulbar tract; dysarthria, dysphagia, paraparesis or quadriparesis(可locked-in syndrome), movement disorders/parkinsonism, behavioral disturbances, disorientation, confusion, lethargy, seizures, coma...
• Usually delayed for 2-6 days after rapid correction and often irreversible or only partially reversible(見下圖)
  • 

Neurologic symptoms of osmotic demyelination syndrome (ODS) typically occur two to six days after correction of the hyponatremia. In this patient, severe hyponatremia was corrected too quickly (23 mEq/L in 48 hours), and coma developed two days later. The serum sodium was quickly reviewed and then slowly corrected. Neurologic symptoms improved, which may have been due to relowering of the serum sodium or may have represented spontaneous resolution.

5.Diagnosis#

• MRI(但不一定看得到(may not be positive for as long as 4W), 所以一開始MRI(-)不能排除ODS); 不過用DWI看似乎可earlier detection

6.Prevention#

• Correction rate同§3(見上): 一般風險 <10 mmol/L/24hrs (<18 mmol/L/48hrs)；高風險 4-6 mmol/L/d (上限 ≦8 mmol/L/24hrs, <14-16 mmol/L/48hrs)〔PMID 26735146〕; monitor Na Q2-3hrs, record I/O
  • Preventive strategy
    • 可能會因為autocorrection而correction rate too rapid的Pts考慮prophylactic使用3% saline(15-30ml/hr)+DDAVP(1-2(4)ug Q6-8H for 1-2 days)以免因為water diuresis Na上升太快
  • Reactive strategy
    • 發現initial Tx後有water diuresis or correction rate trend看起來會超過limit(>8mM/24hrs), 則補D5W or 可↓Tx with DDAVP use(以DDAVP控制unwanted urinary water losses防autocorrection〔PMID 26735146〕; 用DDAVP可Q4-6H check Na即可; 若沒有用, 則難以預期Na==>Q2-3H recheck)
  • Rescue strategy (意外過度矯正之救援降鈉)
    • 超過矯正速率上限即為醫療急症，應立即停止升鈉點滴，給予 DDAVP 阻斷內源水利尿，並輸注 D5W 重新回降血鈉：
      • DDAVP 1-2 $\mu$g (可至 4 $\mu$g) IV/SC Q6-8H ＋ D5W 3-6 ml/kg/hr 輸注，Q2H 追蹤血鈉；目標以每小時回降 1 mmol/L 速度將血鈉拉回安全上限範圍內(24小時淨升 <8-10 mmol/L, 48小時 <14-16 mmol/L)〔PMID 26735146〕
      • 達成目標後停用 D5W，但維持 DDAVP 避免反彈性利尿
        • 舉例:原Na 115mM->127mM/16hrs->則於接下來8hrs內↓4mM使首日淨升降至8mM，並保持48hrs<16mM
    • 輔助藥物之實證分級：Minocycline (動物實驗顯示抑制小膠質細胞活化與發炎介質)、Steroid (Dexamethasone)、Myoinositol 補充，均僅存於動物模型階段，缺乏人體 RCT 實證，臨床指引未建議常規使用；預防核心唯一具備一級實證者為嚴格控制升鈉速率與過度矯正時之 D5W+DDAVP 救援降鈉。

7.Tx of established ODS#

• Unknown goal(no well evidence), uptodate:suggest lower Na to 48hrs goal(↑<16mM)
  • 下降的方法如同上述rescue strategy, with ↓1mM/hr to goal
  • 舉例:原Na 100mM->130mM->則↓14mM with ↓1mM/hr to goal(如上圖)

8.Prognosis#

• Initial severity 不影響 prognosis：文獻與世代研究顯示，發病初期神經學症候嚴重度（即使呈現四肢癱瘓、昏迷）或最低血鈉值，與長期神經預後無直接線性相關；在積極多專科支持與復健治療下，許多病人在 2-3 個月後仍有顯著功能恢復，切勿過早放棄治療。
• 要aggressive Tx if ODS(+), 且要觀察>6-8W才能斷定irreversible(因為有些人可recover after prolonged periods)