Delayed Encephalopathy Research Articles

Hyperbaric oxygen therapy mobilized circulating stem cells and improved delayed encephalopathy after acute carbon monoxide poisoning with up-regulation of brain-derived neurotrophic factor.

Background Delayed encephalopathy (DE) is the most severe complication after acute carbon monoxide (CO) poisoning, which seriously affects the outcome of patients and leads to a high disability rate. Prior studies have shown that hyperbaric oxygen (HBO2) therapy is therapeutic for DE due to reducing immune-mediated neuropathology and thus improving cognitive performance. Methods In our present perspective study, five DE patients were treated regularly with HBO2 therapy. The mini-mental state examination (MMSE) and Barthel index (BI) were intermittently collected during their hospitalization for mental and physical status evaluation, the peripheral bloods were serially sampled to determine the concentration changes of circulating stem cells, as well as corresponding BDNF and neural markers. Results MMSE and BI showed series of improvements after multiple HBO2 therapies. The CD34+/CD90+ and CD34+/CD133+ dual positive cells, which were categorized as circulating stem cells, were observed an overall up-regulation since the beginning of the DE onset upon the application of HBO2 therapy. Characteristic neurotrophin BDNF, neural markers such as nestin and synaptophysin (SYP) were also up-regulated after exposure of HBO2. Conclusion The application of HBO2 therapy is of significance in improving the cognition of DE patients, along with mobilized circulating stem cells. We primarily infer that the CD34+/CD90+ and CD34+/CD133+ cells were mobilized by HBO2 exposure and have played a positive role in cognition improvement on DE patients by up-regulation of BDNF, nestin and SYP. The altering amount of circulating stem cells mobilized in peripheral blood could be a potential marker on predicting the outcome of DE.

Carbon monoxide poisoning–induced delayed encephalopathy accompanies decreased microglial cell numbers: Distinctive pathophysiological features from hypoxemia–induced brain damage

Carbon monoxide (CO) causes not only acute fatal poisoning but also may cause a delayed neurologic syndrome called delayed encephalopathy (DE), which occasionally occurs after an interval of several days to several weeks post-exposure. However, the mechanisms of DE have not been fully elucidated. This study aimed to clarify the pathophysiology of CO–induced DE and its distinctive features compared with hypoxemic hypoxia. Rats were randomly assigned to three groups; the air group, the CO group (exposed to CO), and the low O2 group (exposed to low concentration of O2). Impairment of memory function was observed only in the CO group. The hippocampus tissues were collected and analyzed for assessment of CO–induced changes and microglial reaction. Demyelination was observed only in the CO group and it was more severe and persisted longer than that observed in the low O2 group. Moreover, in the CO group, decreased in microglial cell numbers were observed using flow cytometry, and microglia with detached branches were observed were observed using immunohistochemistry. Conversely, microglial cells with shortened branches and enlarged somata were observed in the low O2 group. Furthermore, mRNAs encoding several neurotrophic factors expressed by microglia were decreased in the CO group but were increased in the low O2 group. Thus, CO–induced DE displayed distinctive pathological features from those of simple hypoxic insults: prolonged demyelination accompanying a significant decrease in microglial cells. Decreased neurotrophic factor expression by microglial cells may be one of the causes of CO–induced DE.

長期的な高圧酸素療法が社会復帰に奏効したと思われる間歇型一酸化炭素中毒の1例(A case of delayed encephalopathy after recovery from acute carbon monoxide poisoning through repetitive hyperbaric oxygen therapy)

間歇型一酸化炭素（carbon monoxide: CO）中毒は遅発性脳症（delayed encephalopathy: DE）とも呼ばれ，治療法は確立されておらず，重度の後遺症を残す症例も多い。DEに対し，長期的な高圧酸素療法（hyperbaric oxygen therapy: HBOT）を施行し，社会復帰を得た症例を経験したので報告する。症例は30歳の女性。家族が自宅ガレージに駐車後エンジンを停止するのを忘れており，翌日上階室内で意識消失しているところを発見された。来院時，GCS 8の意識障害を認め，CO–Hb 32%で急性CO中毒と診断した。気管挿管を実施し，100%平圧酸素投与と48時間の脳低温療法を施行した。CTで淡蒼球の低吸収化，MRIで前頭葉大脳白質に高信号を認めた。その後第19病日までに意識は元の状態まで回復したが，第32病日に突然，無表情となり不隠行動と失禁がみられ，第35病日に立位や嚥下が困難となり，意思疎通も不能となった。DEを発症したと考え，2.0気圧，60分間でHBOTを開始した。3か月間で計60回行ったところ，徐々に神経所見が改善し，大きな後遺症を残すことなく退院となり社会復帰した。DEに対するHBOTの有効性を示す大規模研究はないが，本症例では長期的なHBOTが著効した印象が強く，重度のDEにおいて症状が進行しても長期治療すべき症例があると考えられた。 Delayed encephalopathy (DE) after acute carbon monoxide (CO) poisoning is a disease with a poor prognosis. There is no established treatment for DE, and no evidence that hyperbaric oxygen therapy (HBOT) is beneficial in DE. A 30–year–old female presented with severe CO poisoning. She was found unconscious and her carboxyhemoglobin level on admission was 32%. She was admitted to the intensive care unit, and immediately treated with mechanical ventilation with normobaric oxygen and brain hypothermia therapy. She regained consciousness 19 days later, and returned to her normal activities. However, 13 days later she became restless and developed incontinence. Her neurologic state began to deteriorate rapidly, progressing to akinetic mutism over the next week and finally she became less communicative. She was diagnosed with DE after CO intoxication. HBOT was conducted every day at 2.0 absolute atmosphere (ATA), each session lasting 60min, and gradual and progressive clinical improvement was observed. Her condition gradually improved over the next three months and she regained independence in her activities of daily living. She also showed significant improvement in neurocognitive function. HBOT appears useful in treating DE patients. 倫理規定に関する事項は次の通りである。 ①倫理委員会が審査・承認すべき事項には該当しない。 ②個人情報保護に基づき，匿名化している。 ③患者および家族より論文の掲載に関して同意を得ている。 急性一酸化炭素（carbon monoxide: CO）中毒の経過において，数日から数週間後に見当識障害，認知機能障害，運動失調，無言無動などの特徴的な神経症状が出現する症例があり，間歇型CO中毒，あるいは遅発性脳症（delayed encephalopathy: DE）と呼ばれる。急性CO中毒の10～30%に発症すると報告 1されているが，明確な治療方法は確立されておらず，重度の後遺症を残す症例も多い。また，DEの発生は遅発性のため，急性期施設である救命救急センターにおいて救急医が経験する機会は少ない。 今回，救命救急センター入院中にDEを発症し，長期的な高圧酸素療法（hyperbaric oxygen therapy: HBOT）を施行し，完全に社会復帰した症例を経験したので報告する。 患 者：30歳の女性。対人恐怖症があり，自宅2階で十数年間ひきこもり生活をしていた。その他既往歴なし。7月某日，自室の直下にある1階ガレージでシャッターを閉めたまま家族が車のエンジンを停止し忘れた。24時間後に自室のソファ上で意識がない状態で発見されて救急搬送となった。 来院時現症：意識レベルJCS II–30，GCS 8（E2V2M4），心拍数138/分，血圧133/90mmHg，呼吸数22/分，SpO2 97%（リザーバーマスク酸素10L/min投与下）。嘔吐痕と失禁を認めた。搬入時の動脈血ガス分析はCO–Hb 32%であり急性CO中毒と診断した。高乳酸血症（乳酸値10.3mmol/L）を伴う代謝性アシドーシスを合併していた。血液検査所見は白血球数高値のほか，高アミラーゼ血症，高CPK血症を認めた（Table 1）。 来院後経過（Fig. 1）：意識障害と誤嚥による呼吸不全のため気管挿管を実施し，頭部CT検査を行ったところ脳腫脹を認めたため，ICU入室後に48時間の脳低温療法（35℃）を施行した。急性期CO中毒に対して，乳酸値が正常化するまで，100%酸素を約40時間投与した。誤嚥性肺炎は抗菌薬投与と人工呼吸管理で改善した。従命反応可能なレベル（GCS：E4VtM6）まで意識が改善したため，第12病日に気管チューブを抜去したが仮性球麻痺を認め，第13病日に誤嚥防止のため気管切開術を施行した。第19病日に意識清明となり，第30病日には仮性球麻痺も改善し，気管切開チューブを抜去した。その後リハビリテーションを継続していたが，第32病日に突然，失禁，無表情，不隠行動，不随意運動が出現した。その後症状は悪化し，立位困難，嚥下障害，無言無動を呈し，意思疎通ができなくなった。症状からDEを発症したと考え，第35病日よりHBOTとステロイドパルス療法を開始した。HBOTは2気圧（ATA）60分間を1日1回平日に施行した。ステロイドパルス療法はmethylprednisolone 1gを3日間投与した。嚥下障害に対して胃瘻造設を施行し経腸栄養を行った。その後HBOT施行20回目に従命反応が出現し，22回目には発語を認めた。27回目で意識清明となり，経口摂取が可能となった。29回目で排尿が自立し，43回目で歩行が可能となった。症状の改善効果が固定したと判断するまで，HBOTは合計60回，3か月間実施した。退院前の高次脳機能検査ではmini–mental status examination（MMSE）＝25，Wechsler adult intelligence scale（WAIS）–III＝（全検査IQ69，言語性IQ85，動作性IQ59）と若干の低下は認めたが，入院から4か月後に独歩退院となった。 Clinical course from admission to discharge. ＜経過中の検査所見＞ 頭部CT：第4病日に来院時にはなかった両側淡蒼球の濃度低下が出現し，その所見は退院まで変化が認められなかった（Fig. 2）。 Brain CT series, brain MRI series and brain SPECT series. 頭部MRI（FLAIR，DWI）：第7病日に撮像された頭部MRIでは両側の淡蒼球と前頭葉の深部白質に高信号を呈した。DE発症直前の第29病日ではさらに白質病変が拡大したが，第92病日のMR–FLAIR画像では前頭葉の軽度萎縮を認める一方，深部白質の高信号病変は縮小した（Fig. 2）。 SPECT（123I–IMP脳血流シンチグラム)：初回（第36病日）のSPECTでは全般的な脳血流低下を認めたが，第62病日の両前頭葉の局在的な血流低下を経て，第92病日には左前頭葉と左側頭葉内側領域に明らかな血流改善を認めた（Fig. 2）。 脳波検査：第62病日の脳波では全般性の持続性低振幅徐波が認められ，重度のびまん性脳症を示唆した。第92病日の脳波における前頭部の律動性δ波と第121病日の脳波における持続性不規則徐波は前頭葉の脳機能低下を示唆したが，同時にα帯域の後頭部優位律動が徐々に回復しており，SPECTの変化にも一致した（Fig. 3）。 Electroencephalogram series. DEはCO暴露数日から数週間の意識清明期（lucid interval）後に，異常行動，人格変化，高次脳機能障害などの精神神経症状や歩行障害，パーキンソニズムなどの運動機能障害を来すことにより診断される。病理学的には大脳白質のミエリンやオリゴデンドログリアの損傷による脱髄性白質脳症といわれており 2，機序は酸素欠乏後の酸素再供給に伴う活性酸素発生や免疫系の関与を指摘されている 3。 DEは急性CO中毒の10～30%に発症するとされており，発症予測因子の研究では，Pepeら 4は初期の意識レベルGCS 8以下（オッズ比7.15）と搬入時白血球数10,000/µL以上（オッズ比3.31）の症例で有意に発症率が増加していたと報告しており，Parkinsonら 5のMRIを使用した研究においては，DE発症には大脳白質病変が必発であると報告している。一方で淡蒼球病変の有無はDE発症に関与しないとされている。本症例では初期の意識レベルGCS 8以下，搬入時白血球数10,000/µL以上，MRIの大脳白質病変すべての発症予測因子を満たしていた。本症例でDE発症の可能性が高かったことを考えると，発症を念頭に置いた経過観察が必要であったが，一方で発症時期については数日から数週間と幅があり，どの程度の経過観察期間が必要かに関して明確な基準はない。近年のDEに対してHBOTを施行した症例の検討で，予後良好群は，若年，意識清明期が長い，肺炎の合併がない，最も状態が悪化したときのADLが悪くないことを報告しているが，予後良好群の平均間歇期間は25.9±6.5日であった 6。いつまで急性期病院で経過観察すべきかの議論は別として，発症予測因子がある場合には1か月程度はDEを発症する可能性を考えた経過観察が必要であろう。 DE発症予防に対する急性期治療の効果についても明確ではない。CO中毒に対する急性期のHBOTは，DEを予防するという報告 7がある一方，平圧療法と比較して1か月後の社会復帰率やDEの予防効果に差はないとする報告 8もあり，議論の分かれるところである。当施設では人工呼吸管理中の患者は安全を考慮して急性期のHBOTは施行せず，平圧高濃度酸素療法を行っている。また，Kamijoら 9は急性CO中毒に脳低温療法を施行した症例報告により脳低温療法はDEを予防する可能性があることを示唆しているが，本症例では脳低温療法を施行したものの，DEを発症した。DE予防のための急性期脳低温療法に関しては今後の検討が必要と考えられる。 DE発症後のHBOTの有効性に関しては，RCTを含めた大規模研究は施行されておらず，未だ定説は得られていないが，長期間施行することで有効とする報告 10もある。DE自体は自然回復するのか不明であるが，我々の経験した症例ではHBOT 20回目から神経学的な回復がみられ，画像所見も改善を認めたため，HBOTが非常に効果的であった印象がある。本症例のようにADLや認知機能が著しく低下しても，諦めずに長期間のHBOTを試みる価値があると考えられる。HBOTの実施期間に関しては明確な基準はないが，本症例を経験して，土居らの報告 11のように症状が固定したと判断するまで長期的に続けるべきという意見に賛同する。HBOTのDEに対する機序は，大脳灰白質にある神経細胞が残存しているうちに，白質にある髄鞘の再生を促進するとともに，神経細胞自体に保護的作用を発揮すると推測される。本症例では20回ごとに治療効果判定と継続判断を行った。ステロイドパルス療法もDEの改善に効果的な可能性が示唆されており 12，oligodendrocyteの保護あるいは分化を促進することで髄鞘の再生を促す機序，あるいはステロイドの各種抗炎症作用によるといわれているが，本症例での有効性については不明であった。また早期のリハビリテーションも重要である。 本症例では経時的に画像検査を施行することができ，HBOTの治療効果を視覚的に確認し得た。CT所見はHBOT後の変化はみられなかったが，MRI所見は若干の改善傾向を認めた。SPECTでDE発症時に前頭葉の血流低下が認められることが報告 13されているが，本症例では頻回のHBOT後に著明な血流改善所見を認めた。SPECTでの脳血流の変化から脳細胞代謝や脳細胞機能低下は不可逆的ではなく，HBOTにより改善しうることが示唆された。本症例でHBOTによりMRI，SPECT，および脳波所見の改善を認めたため，HBOT継続判断には臨床症状にこれらの検査所見も加えて，検査所見の改善傾向を認めるうちは治療を継続すべきと考える。 重度のDEにおいても神経学的な回復を見込める症例も存在するため，複数回のHBOTの適応を積極的に検討すべきである。その適応や継続の判断には神経生理学的検査や脳画像診断は有用である。搬入時昏睡の重症例やDE発症リスクをもつ患者に対しては危険性を十分に説明し厳重な経過観察をすべきである。 本論文に関連して開示すべき利益相反はない。

Callosal damage and cognitive deficits in chronic carbon monoxide intoxication: A diffusion tensor imaging study

PurposeTo evaluate the correlation between microstructural damage in the corpus callosum (CC) and the cognitive performance of patients with or without delayed encephalopathy (DE) after carbon monoxide (CO) intoxication in the chronic stage. MethodsDiffusion tensor imaging (DTI) was performed more than 6months after CO intoxication for 10 patients with DE and 10 patients without DE recruited from out-patient clinics, as well as for 15 normal controls (NCs). Using a probabilistic tractography method to parcel the CC based on fiber projections to cortical connectivity patterns, the DTI indices were calculated in the CC subregions and further correlated with cognitive performance. ResultsThe DE group exhibited significantly lower fractional anisotropy (FA) and higher radial diffusivity (RD) values in the prefrontal, premotor, primary motor, primary sensory, parietal, and occipital CC subregions than did the NCs. The DE group also exhibited significantly lower FA values in the prefrontal and premotor subregions than did the non-DE group. Lower FA and higher RD values in the CC subregions were associated with poorer scores on the symbol search test. ConclusionsCO intoxication may cause lower FA and higher RD in the CC subregions, with subsequent cognitive impairment. This finding suggests that selective CC damage after CO intoxication is more profound in patients with DE.

Structural and cognitive deficits in chronic carbon monoxide intoxication: a voxel-based morphometry study

BackgroundPatients with carbon monoxide (CO) intoxication may develop ongoing neurological and psychiatric symptoms that ebb and flow, a condition often called delayed encephalopathy (DE). The association between morphologic changes in the brain and neuropsychological deficits in DE is poorly understood.MethodsMagnetic resonance imaging and neuropsychological tests were conducted on 11 CO patients with DE, 11 patients without DE, and 15 age-, sex-, and education-matched healthy subjects. Differences in gray matter volume (GMV) between the subgroups were assessed and further correlated with diminished cognitive functioning.ResultsAs a group, the patients had lower regional GMV compared to controls in the following regions: basal ganglia, left claustrum, right amygdala, left hippocampus, parietal lobes, and left frontal lobe. The reduced GMV in the bilateral basal ganglia, left post-central gyrus, and left hippocampus correlated with decreased perceptual organization and processing speed function. Those CO patients characterized by DE patients had a lower GMV in the left anterior cingulate and right amygdala, as well as lower levels of cognitive function, than the non-DE patients.ConclusionsPatients with CO intoxication in the chronic stage showed a worse cognitive and morphologic outcome, especially those with DE. This study provides additional evidence of gray matter structural abnormalities in the pathophysiology of DE in chronic CO intoxicated patients.

The investigation on the correlation between plasma D-dimer with delayed encephalopathy in patients with acute carbon monoxide poisioning

Objective To investigate the correlation between plasma D-dimer with delayed encephalopathy (DE) in patients with acute carbon monoxide poisioning(ACOP).Methods According to the severity of disease,100 patients with ACOP were divided into mild group (27 cases),moderate group (31 cases),severe group (42cases).And depending on whether DE occured,all patients were divided into DE group(20 cases) and no DE group (80 cases).4 venous blood samples were obtained separately from each subject in 1,7,14 days after their admission to hospital by using latex immunoturbidimetry.The levels of blood plasma D-dimer of patients in each group were detected by immune turbidimetry and analyzed,1th,7th and 14th day after admission.Results The plasma D-dimer level of the mild group at different time points was in the normal range,and the difference was not statistically significant(all P ＞ 0.05) ;The plasma D-dimer level of the severe group and moderate group was significantly higher than that of the mild group(all P ＜0.01),and it reached a peak in one week(7 days),and showed a downward trend after two weeks(14 days).The DE all occurred in the moderate and severe group.The plasma D-dimer levels of the DE group were higher than those of no DE group from admission to the 7 th and 14 th day (all P ＜ 0.01).Conclusion The dynamic monitoring plasma D-dimer is helpful in assessing to the severity and prognosis of ACOP,and could surpport positive clinical significance for the prevention and treatment of DE. Key words: Acute disease; Carbon monoxide poisoning

Elevated S100B level in cerebrospinal fluid could predict poor outcome of carbon monoxide poisoning

Objective S100B is a calcium-binding protein produced by astroglia in the brain and has been used as a marker of neuronal damage after brain trauma. We investigated the utility of S100B in cerebrospinal fluid (CSF) measured during the early phase of carbon monoxide (CO) poisoning in predicting the subsequent clinical course. Methods The study included 31 patients who were admitted to the hospital with loss of consciousness following CO poisoning. S100B levels were measured by enzyme-linked immunosorbent assay in CSF, and serum samples collected simultaneously within 24 hours and on the fourth day after CO exposure. All patients were followed for at least 3 months and divided into 3 groups based on the clinical course: persistent vegetative state (PVS), delayed encephalopathy (DE), and complete recovery with no complications (NC). Results During the 3-month period, 3 patients developed PVS, 5 developed DE, and 23 were classified as NC. The mean S100B levels in the CSF within 24 hours after CO exposure were higher in the PVS group (9.25 ng/mL) than in the DE (2.03 ng/mL) and NC groups (1.86 ng/mL). However, the mean serum S100B levels were not elevated in the 3 groups (0.21, 0.59, and 0.16 ng/mL, respectively). Conclusion Early elevation of S100B in CSF after CO poisoning could be a suitable predictor of subsequent development of PVS.

The early elevation of interleukin 6 concentration in cerebrospinal fluid and delayed encephalopathy of carbon monoxide poisoning

Objective This study was designed to investigate whether interleukin 6 (IL-6) in cerebrospinal fluid (CSF) in the early phase of carbon monoxide (CO) poisoning can be a predictive marker of delayed encephalopathy (DE). Methods Nine patients with CO poisoning were included in the study. Cerebrospinal fluid was sampled within 24 hours of the last exposure to CO, on hospital day 4, and once a week for at least 1 month to determine IL-6 and myelin basic protein concentrations. All patients were followed at least 3 months. Results Three patients demonstrated significant early IL-6 elevation in CSF, normal IL-6 level in CSF on day 4, and significant delayed myelin basic protein elevation in CSF. The 2 patients with the highest early IL-6 elevation in CSF developed DE. Interleukin 6 in serum was not related to DE. Conclusion Interleukin 6 in CSF at the early phase of CO poisoning may be a predictive marker of DE.

Lactate as a prognostic factor in carbon monoxide poisoning: a case report

Carbon monoxide (CO) poisoning results in various neuropsychological impairments, including delayed encephalopathy (DE) and death. However, factors related to these outcomes are unknown. A group suicide was attempted by 3 young people--a 31-year-old man (patient 1), a 21-year-old woman (patient 2), and a 20-year-old man (patient 3)--by burning charcoal in a closed car. At the emergency department, hypotension and hyperthermia were severe in patient 1, moderate in patient 2, and absent in patient 3, although all the patients were comatose. The initial serum lactate levels were 75.1 mg/dL in patient 1, 41.9 mg/dL in patient 2, and 26.3 mg/dL in patient 3, although the carboxyhemoglobin levels were approximately equal in all the patients. Hyperbaric oxygen therapy (HBOT) was immediately initiated and continued for 10 days in all the cases; however, the outcomes of these patients varied considerably. Patient 1 remained comatose and died on day 31 because of central diabetes insipidus after shock. Patient 2 recovered from coma and was discharged; however, she was rehospitalized for DE on day 45 and recovered completely after another 10-day HBOT. Patient 3 gained consciousness and recovered completely with no sequelae during the 1-year follow-up. From these cases, we can consider that the initial blood lactate may correlate with the patient outcomes and prove to be a useful prognostic factor. Thus, we should particularly consider elevated lactate levels in CO poisoning.

Risk Factors of Development of Delayed Encephalopathy following Acute Carbon Monoxide Poisoning

Delayed encephalopathy (DE) is a poorly predictable outcome following acute carbon monoxide (CO) poisoning. In order to define the risk factors of DE in patients with acute CO poisoning and improve prevention, 207 cases of acute CO poisoning were observed during the acute stage and followed up for 3 months: 27 (13%) developed DE. Statistical analyses of 97 factors present in the acute stage showed 6 to be statistically significant risk factors for the devel opment of DE. These were: age > 40 years, occupation involved mental work, previous hypertension, coma at the acute stage lasting 2-3 days, longer persis tence of dizziness and fatigue after regaining consciousness, and being men tally stimulated during the recovery stage of acute CO poisoning. Based on these six factors, a logistic regression equation for predicting the probability of DE in individual patients with acute CO poisoning has been established.