Genetic Diagnosis in Neonatal Encephalopathy With Hypoxic Brain Damage Using Targeted Gene Panel Sequencing

Sangbo Lee,Se Hee Kim,Heung Dong Kim,Joon Soo Lee,Ara Ko,Hoon-Chul Kang 대한신경과학회 2024 Journal of Clinical Neurology Vol.20 No.5

Background and Purpose Neonatal encephalopathy (NE) is a neurological syndrome that presents with severe neurological impairments and complications. Hypoxic-ischemic encephalopathy is a major contributor to poor outcomes, being responsible for 50%–80% of admissions to neonatal intensive care units. However, some cases of NE accompanied by hypoxic brain damage cannot be solely attributed to hypoxia-ischemia. We aimed to identify diverse pathogenic genetic variations that may be associated with cases of NE accompanied by hypoxic brain damage rather than hypoxia-ischemia. Methods We collected data from 34 patients diagnosed with NE accompanied by hypoxic brain damage over a 10-year period. Patients with the following specific conditions were excluded: 1) premature birth (<32 weeks), 2) no history of hypoxic events, 3) related anomalies, 4) neonatal infections, 5) antenatal or perinatal obstetrical complications, 6) severe hypoxia due to other medical conditions, and 7) early death (within 1 week). A comprehensive review of clinical and radiological features was conducted. Results A genetic diagnosis was made in 11 (32.4%) patients, with pathogenic variants being identified in the following 9 genes: CACNA1A (n=2), KCNQ2 (n=2), SCN2A (n=1), SCN8A (n=1), STXBP1 (n=1), NSD1 (n=1), PURA (n=1), ZBTB20 (n=1), and ENG (n=1). No specific treatment outcomes or clinical features other than preterm birth were associated with the results of the genetic analyses. Personalized treatments based on the results of genetic tests were attempted, such as the administration of sodium-channel blockers in patients with KCNQ2 or SCN8A variants and the implementation of a ketogenic diet in patients with STXBP1 or SCN2A mutations, which demonstrated some degree of effectiveness in these patients. Conclusions Genetic analyses may help in diagnosing the underlying etiology of NE and concurrent hypoxic brain damage, irrespective of the initial clinical features.

허혈성 저산소증으로 유도한 신경 세포 소실시의 치상회 태상 섬유의 발아 유무에 대한 관찰

문한구(Han-Ku Moon),이은실(Eun Sil Lee),신손문(Son Moon Shin),박용훈(Yong Hoon Park) 대한소아신경학회 1998 대한소아신경학회지 Vol.6 No.1

목 적 : 측두엽 간질의 실험 동물이나 환자에서 흔히 관찰되는 해마 태상 섬유 발아는 해마에서의 세포 소실이 중요한 요인이며 세포 소실의 정도가 심할수록 발아의 정도는 증가한다고 알려져 있지만 미성숙 뇌를 허혈성 저산소증에 노출시켜 해마의 세포 소실을 유도하여도 태상 섬유 발아는 관찰할 수 없었다는 보고가 있다. 그러나 미성숙 뇌의 경우 여러 가지 손상에 대한 신경계의 변화는 성숙 뇌에서의 반응과 일치하지 않는 경우가 많다. 본 연구는 인간에 있어서 사춘기에 속하는 생후 4-5주 연령 및 성인기에 해당하는 생후 2개월 연령의 횐 쥐들을 허혈성 저산소증에 노출시켜 해마의 세포 손상을 유발한 후 해마 태상 섬유 발아 가 유도되는지 여부를 알고자 시행되었다. 방 법 : 생후 4-5주 및 2개월 연령의 Sprague-Dawley를 우측 경동맥 결찰 후 8%의 저농도 산소에 각각 90분, 50분동안 노출시켜 허혈성 저산소증을 유발한 뒤 2주 경과 후까지 생존한 생후 4-5주 연령군 (대조군 4마리, 실험군 5마리)과 2개월 연령군 (대조군 4마리, 실험 군 6마리) 횐 쥐의 뇌 조직을 추출하여 일부는 H & I 염색을 시행하여 해마내의 세포 손상을 확인하고 일부는 냉동절편 후 중금속 염색법인 Timm 염색을 시행하여 태상 섬유 발아 여부를 관찰하여 각 군의 대조군과 비교하였다. 결 과 : 4-5 주 및 2 개월 연령군에서 허혈성 저산소군의 H & I 염색한 해마에서 다양한 정도의 문 세포, 추체 세포들의 허혈성 저산소증에 의한 변화가 관찰되었다. 그러나 Timm 염색을 시행한 허혈성 저산소군(4-5 주 연령군 5례, 2개월 연령군 6례)의 우측 해마의 과립 세포 상부층의 Timm 염색 정도는 대조군과 비교하여 유의한 차이가 없었다. 결 론 : 연소 및 성숙 횐 쥐를 허혈성 저산소증에 노출시켜 해마의 세포 손상을 유발한 후 태상 섬유 발아가 유도되는 지를 관찰하였으나 대조군에 비해 유의한 차이를 찾을 수 없었다 이를 미루어 보아 해마의 발아는 단순히 세포 소실에 의한 2차적인 현상이 아닌 다른 요인이 관여할 것으로 추정된다. Purpose : Reorganization of mossy fiber terminals in the supragranular layer of the dentate has been found in hippocampi of human epileptics and animal models by Timm staining. Many studies have provided evidence that mossy fiber sprouting is strongly associated with neuronal loss. But the question of whether cell loss is necessary for stimulation of mossy fiber sprouting is remained to be answered. In this present study, we evaluated whether hippocampal mossy fiber sprouting is induced in damaged hippo- campus of the rats exposed to hypoxic-ischemic insults in juvenile and adult period. Methods : At ages of f-5 weeks and 2 months, the experimental rats were received procedure of right carotid artery unilateral ligation under anesthesia. After 3 hours of the recovery period, they were placed in an airtight 2000m1 chamber and exposed to a 8% oxygen-92% nitrogen mixture delivered at 5 liter/min for 90 minutes(juvenile) and 50 minutes(adult). After the recovery period, The animals were returned to cages and housed controls. 2 weeks later, rats of the control and hypoxic-ischemia group were tonesthetised and then perfused with sodium sulfide solution and fixed. 40 # m(for Timm stain) and 5#m(for H & I stain) coronary brain sections were obtained, stained with Timm method and H & I stain for the observation of the neuronal loss and supragranular Timm granules in the hippocampi. Results : Light microscopic examination of the brains from hypoxic-ischemic animals demonstrated ischemic changes of variable degrees in the hippocampal hilar and pyramidal cell layers. No supragranular mossy fiber sprouting were found in hippocampi of juvenile and adult rats with hypoxic-ischemic damages. Conclusion : These results implicated that hippocampal mossy fiber sprouting is not induced in the experimental hypoxic-ischemic encephalopathy of juvenile and adult rats, although cellular loss is found in hippocampus. Neuronal loss might be not necessary for the development of mossy fiber sprouting.

Increased intracranial pressure after massive blood loss -A case report-

박지현,전인구,손효정,곽미정 대한마취통증의학회 2010 Anesthesia and pain medicine Vol.5 No.2

A 4-year old boy with supravalvular ascending aortic stenosis underwent sliding aortoplasty. After cardiopulmonary bypass weaning, aorta suture site was torn accidentally and the patient was in hypovolemic shock. Emergency cardiopulmonary bypass was reinstituted and the aorta was repaired. After removal of the aortic clamp, bradycardia and hypertension were noted. We suspected increased intracranial pressure due to hypoxic brain damage after massive blood loss and the patient was treated to lower the intracranial pressure. Physicians should be aware of the significance of the hemodynamic change associated with increased intracranial pressure to prevent further neurologic damage.

저산소성 뇌손상 환자에서 전두엽 관리기능의 결손 단일 사례 연구

조영남,정재훈 대한재활치료과학회 2011 대한재활치료과학학회지 Vol.4 No.2

An Exploration of the Neural Network of Lance-Adams Syndrome: a Case Report

송지민,강원일,온석훈,정광익,Bashir Shahid,유우경 대한뇌신경재활학회 2021 뇌신경재활 Vol.14 No.1

Lance-Adams syndrome (LAS) is a rare neurological disorder that may occur after cardiopulmonary resuscitation. The LAS is usually caused by hypoxic changes. Neuroimaging studies show that the brain pathology of LAS patients is not uniform, and the pathophysiology of the myoclonus can vary from patient to patient. Our case study contributes to this etiological heterogeneity by neuroimaging and transcranial magnetic stimulation (TMS). In patients with rare brain conditions such as LAS, a combination of brain stimulation methods, such as TMS, and diffusion tensor imaging can provide insights into this condition's pathophysiology. These insights can facilitate the development of more effective therapies.

뇌량팽대에 제한확산을 보인 저산소뇌손상

김수정,이응석,오단아,이상원,박해인,계진성,유한별,윤혜원 대한신경과학회 2016 대한신경과학회지 Vol.34 No.4

Horizontal nystagmus with velocity-increasing waveforms in delayed post-hypoxic leukoencephalopathy: a case report

Jung Eugene,Lee Suk-Min,Choi Seo-Young,최광동 대한평형의학회 2024 Research in Vestibular Science Vol.23 No.3

Abnormal eye movements in unconscious patients serve as crucial diagnostic instruments, offering insights into the function of the central nervous system. Understanding these movements can aid in diagnosing the cause of unconsciousness, localizing brain lesions, and predicting outcomes. We report a patient who presented with spontaneous horizontal nystagmus unaffected by light in delayed post-hypoxic encephalopathy. Video-oculography showed exponentially increasing slow phases, with an amplitude ranging from 3° to 9° and a frequency of 0.5 Hz. Based on the results of oculography and neuroimaging, persistent horizontal nystagmus in our patient may be ascribed to an unstable neural integrator, possibly caused by disrupted cerebellar feedback mechanisms for horizontal gaze holding.

A Successful Treatment of Obesity Hypoventilation Syndrome Using Bi-level Positive Airway Pressure in a Patient With Hypoxic Brain Damage

홍유하,김한빛,송민준,모희정,임희진 대한수면연구학회 2022 Journal of sleep medicine Vol.19 No.1

We present the case of a 78-year-old female who experienced acute mental deterioration after vomiting. She showed severe hypercapnia without definite lung disease and hypoxic injury on brain image. After the acute period, she still had excessive daytime sleepiness, and the hypercapnia aggravated during the night. Polysomnography revealed severe obstructive sleep apnea, a sleep-related breathing disorder with a high apneahypopnea index of 60.2/h (mainly a hypopnea index of 59.0/h). She was diagnosed with combined obesity hypoventilation syndrome (OHS) and sleep-related breathing disorder, as the cause of daytime hypercapnia and excessive daytime sleepiness. Three months of successful bi-level positive airway pressure (BiPAP) therapy dramatically improved her daytime sleepiness and cognition. This case suggests that patients with OHS can be susceptible to hypoxic brain damage, and emphasizes the importance of the recognition and diagnosis of OHS and appropriate treatment with BiPAP therapy.

저산소성 뇌손상으로 오인된 비경련성 발작 지속증상

박형은(Hyung-Eun Park),조현지(Hyun-Ji Cho),김영도(Young-Do Kim) 대한임상노인의학회 2012 대한임상노인의학회지 Vol.13 No.4

Epileptic activity can cause regional vasogenic/cytotoxic edema that reflects hemodynamic and metabolic changes. However, extensive hemispheric involvements on magnetic resonance imaging (MRI) after status epilepticus (SE) were very rare. A 63-year-old man admitted to our hospital due to semicoma mental status duration about 10 hours. He had respiratory difficulty, so that he needs to care ventilator. MRI on 6th hospital day showed extensive high signal intensities on diffusion-weighted MRI (DWI) in both hemispheres resembling hypoxic brain lesions. Whereas, EEG showed epileptic discharges associated with generalized slowing waves. Follow-up MRI on 14th hospital day showed regression of previous brain lesions. Therefore, he was diagnosed as decreased mental status due to SE. This case reminded us that post-ictal MRI of SE might be ischemic lesion mimic. Therefore, we should consider DWI of cytotoxic edema after SE. 간질발작은 혈류역학성과 대사성 변화를 반영하는 혈관성/세포독성 부종의 원인이 될 수 있다. 하지만 발작지속증상이후에 광범위한 뇌실질의 변화를 뇌자기공명사진에서 보이는 경우는 매우 드물다. 63세 남자환자가 약 10시간 정도의 반혼수 상태로 내원하였다. 내원 6일째 찍은 뇌확산강조영상에서 저산소성 뇌손상과 비슷한 소견을 보였고, 뇌파에서는 전반적인 서파를 동반한 간질양파소견을 보였다. 내원 14일째 추적검사한 뇌자기공명사진상에서는 이전의 확산강조영상의 병변이 사라진 소견을 보였다. 따라서 발작후 뇌자기공명사진 소견은 저산소성 뇌손상과 같은 뇌병변 소견을 보일 수 있으므로 드물지라도 발작지속증상후 변화의 가능성도 고려해야 하겠다.

Comparison of Low Resolution Electromagnetic Tomography Imaging Between Subjects With Mild and Severe Obstructive Sleep Apnea Syndrome: A Preliminary Study

이현권,신현실,홍석찬,박두흠 대한신경정신의학회 2008 PSYCHIATRY INVESTIGATION Vol.5 No.1

Objective: The purpose of this study was to identify the regions of the brain associated with recurrent nocturnal chronic hypoxic episodes in patients with untreated obstructive sleep apnea syndrome (OSAS) using low-resolution electromagnetic tomography (LORETA) and quantitative electroencephalography (QEEG). Methods: Nocturnal polysomnograph (NPSG) and subsequent morning electroencephalograph (EEG) were measured in 20 subjects with OSAS. Mild (n=10 ages 39.5±12.1 years) and severe (n=10 ages 41.7±13.6 years) right-handed male OSAS subjects were selected by interview and questionnaires including the NPSG, Beck Depression Inventory, Beck Anxiety Inventory, Epworth Sleepiness Scale, and Pittsburgh Sleep Quality Index. The LORETA and QEEG were compared between the severe and mild OSAS groups by frequency bands (delta 1-3 Hz, theta 4-7 Hz, alpha 8-12 Hz, beta1 13-18 Hz, beta2 19-21 Hz, beta3 22-30 Hz, and total 1-30 Hz) made by spectral analysis during resting with the eyes closed. Results: The LORETA analysis showed decreased alpha activity at the right posterior cingulate gyrus (Brodmann area 23) in cases with severe OSAS compared to mild OSAS (p<0.05). For the QEEG, the absolute power of the alpha activity (8-12 Hz) was decreased in P3 (p=0.047), PZ (p=0.039) and O2 (p=0.04) in cases with severe OSAS compared to mild OSAS cases. The LORETA and QEEG analyses had similar results with regard to band, activation and location. Conclusion: The decreased activity of the alpha frequency in the right posterior cingulate gyrus, in patients with severe OSAS compared to those with mild OSAS, suggests that chronic repeated short-term hypoxia during sleep, in OSAS, could provoke cortical brain dysfunction associated with cognitive dysfunction such as memory and attention. Objective: The purpose of this study was to identify the regions of the brain associated with recurrent nocturnal chronic hypoxic episodes in patients with untreated obstructive sleep apnea syndrome (OSAS) using low-resolution electromagnetic tomography (LORETA) and quantitative electroencephalography (QEEG). Methods: Nocturnal polysomnograph (NPSG) and subsequent morning electroencephalograph (EEG) were measured in 20 subjects with OSAS. Mild (n=10 ages 39.5±12.1 years) and severe (n=10 ages 41.7±13.6 years) right-handed male OSAS subjects were selected by interview and questionnaires including the NPSG, Beck Depression Inventory, Beck Anxiety Inventory, Epworth Sleepiness Scale, and Pittsburgh Sleep Quality Index. The LORETA and QEEG were compared between the severe and mild OSAS groups by frequency bands (delta 1-3 Hz, theta 4-7 Hz, alpha 8-12 Hz, beta1 13-18 Hz, beta2 19-21 Hz, beta3 22-30 Hz, and total 1-30 Hz) made by spectral analysis during resting with the eyes closed. Results: The LORETA analysis showed decreased alpha activity at the right posterior cingulate gyrus (Brodmann area 23) in cases with severe OSAS compared to mild OSAS (p<0.05). For the QEEG, the absolute power of the alpha activity (8-12 Hz) was decreased in P3 (p=0.047), PZ (p=0.039) and O2 (p=0.04) in cases with severe OSAS compared to mild OSAS cases. The LORETA and QEEG analyses had similar results with regard to band, activation and location. Conclusion: The decreased activity of the alpha frequency in the right posterior cingulate gyrus, in patients with severe OSAS compared to those with mild OSAS, suggests that chronic repeated short-term hypoxia during sleep, in OSAS, could provoke cortical brain dysfunction associated with cognitive dysfunction such as memory and attention.