Stefanou Maria-Ioanna, Panagiotopoulos Evangelos, Palaiodimou Lina, Bakola Eleni, Smyrnis Nikolaos, Papadopoulou Marianna, Moschovos Christos, Paraskevas George P, Rizos Emmanouil, Boutati Eleni, Tzavellas Elias, Gatzonis Stylianos, Mengel Annerose, Giannopoulos Sotirios, Tsiodras Sotirios, Kimiskidis Vasilios K, Tsivgoulis Georgios
Second Department of Neurology, National and Kapodistrian University of Athens, School of Medicine, "Attikon" University Hospital, Athens, Greece.
Department of Neurology & Stroke, Eberhard-Karls University of Tuebingen, Tuebingen, Germany.
EXCLI J. 2024 Nov 27;23:1463-1486. doi: 10.17179/excli2024-7885. eCollection 2024.
Since the outbreak of the COVID-19 pandemic, there has been a global surge in patients presenting with prolonged or late-onset debilitating sequelae of SARS-CoV-2 infection, colloquially termed long COVID. This narrative review provides an updated synthesis of the latest evidence on the neurological manifestations of long COVID, discussing its clinical phenotypes, underlying pathophysiology, while also presenting the current state of diagnostic and therapeutic approaches. Approximately one-third of COVID-19 survivors experience prolonged neurological sequelae that persist for at least 12-months post-infection, adversely affecting patients' quality of life. Core neurological manifestations comprise fatigue, post-exertional malaise, cognitive impairment, headache, lightheadedness ('brain fog'), sleep disturbances, taste or smell disorders, dysautonomia, anxiety, and depression. Some of these features overlap substantially with those reported in post-intensive-care syndrome, myalgic encephalomyelitis/chronic fatigue syndrome, fibromyalgia, and postural-orthostatic-tachycardia syndrome. Advances in data-driven research utilizing electronic-health-records combined with machine learning and artificial intelligence have propelled the identification of long COVID sub-phenotypes. Furthermore, the evolving definitions reflect the dynamic conceptualization of long COVID in both research and clinical contexts. Although the underlying pathophysiology remains incompletely elucidated, neuroinflammatory responses, endotheliopathy, and metabolic imbalances, rather than direct viral neuroinvasion, are implicated in neurological sequelae. Genetic susceptibility has also emerged as a potential risk factor. While major limitations remain with existing definitions, collaborative strategies to standardize diagnostic approaches are needed. Current therapeutic paradigms advocate for multimodal approaches, integrating pharmacological and non-pharmacological interventions along with comprehensive rehabilitation programs. Although preliminary evidence of therapeutic efficacy has been provided by a number of clinical trials, methodological constraints limit the generalizability of this evidence. Preventive measures, notably vaccination, have proven integral for reducing the global burden of long COVID. Considering the healthcare and socioeconomic repercussions incurred by long COVID worldwide, international collaborative initiatives are warranted to address the remaining challenges in diagnosing and managing patients presenting with neurological sequelae. See also the graphical abstract(Fig. 1).
自新冠疫情爆发以来，全球范围内感染严重急性呼吸综合征冠状病毒2（SARS-CoV-2）后出现长期或迟发性衰弱后遗症的患者激增，通俗地称为“长新冠”。这篇叙述性综述提供了关于“长新冠”神经学表现的最新证据的更新综合内容，讨论了其临床表型、潜在病理生理学，同时还介绍了诊断和治疗方法的现状。大约三分之一的新冠幸存者经历长期的神经后遗症，这些后遗症在感染后至少持续12个月，对患者的生活质量产生不利影响。核心神经学表现包括疲劳、运动后不适、认知障碍、头痛、头晕（“脑雾”）、睡眠障碍、味觉或嗅觉障碍、自主神经功能障碍、焦虑和抑郁。其中一些特征与重症监护后综合征、肌痛性脑脊髓炎/慢性疲劳综合征、纤维肌痛和体位性直立性心动过速综合征中报告的特征有很大重叠。利用电子健康记录结合机器学习和人工智能进行的数据驱动研究取得进展，推动了“长新冠”亚表型的识别。此外，不断演变的定义反映了“长新冠”在研究和临床背景下的动态概念化。尽管潜在的病理生理学仍未完全阐明，但神经炎症反应、内皮病变和代谢失衡，而非直接的病毒神经侵袭，与神经后遗症有关。遗传易感性也已成为一个潜在的风险因素。虽然现有定义仍存在重大局限性，但需要采取协作策略来规范诊断方法。当前的治疗模式提倡多模式方法，将药物和非药物干预与综合康复计划相结合。尽管一些临床试验提供了治疗效果的初步证据，但方法学限制限制了该证据的普遍性。预防措施，特别是疫苗接种，已被证明对减轻全球“长新冠”负担至关重要。考虑到“长新冠”在全球范围内对医疗保健和社会经济造成的影响，有必要开展国际合作倡议，以应对诊断和管理出现神经后遗症患者方面的剩余挑战。另见图1的图形摘要。
