Alternating hemiplegia

Alternating hemiplegia of childhood is a rare neurodevelopmental disorder in which recurrent episodes of hemiplegia alternate between the two sides of the body, beginning before 18 months of age and accompanied by developmental delay, dystonia and often epilepsy.儿童交替性偏瘫是一种罕见神经发育障碍，反复的偏瘫发作在身体两侧交替出现，起病于 18 月龄前，并伴发育迟缓、肌张力障碍，且常合并癫痫。

Most cases are caused by dominant variants in ATP1A3, the gene encoding the neuron-specific sodium-potassium pump alpha-3 subunit, and the attacks are typically relieved by sleep.多数病例由 ATP1A3 显性变异所致，该基因编码神经元特异性钠钾泵 α3 亚基，发作常在睡眠后缓解。

Terminology and classification

• The eponym-free name alternating hemiplegia of childhood was adopted to distinguish the disorder from the adult brainstem syndrome of crossed hemiplegia, which is also called alternating hemiplegia.采用儿童交替性偏瘫这一非人名命名，是为与成人脑干的交叉性偏瘫相区分，后者亦称交替性偏瘫。
• In adult neurology, alternating or crossed hemiplegia means ipsilateral cranial nerve palsy with contralateral limb weakness from a unilateral brainstem lesion, exemplified by Weber and Foville syndromes.在成人神经病学中，交替性或交叉性偏瘫指单侧脑干病变所致同侧颅神经麻痹伴对侧肢体无力，以 Weber 与 Foville 综合征为代表。
• ICD-11 release 2025-01 places the hemiplegic pattern under MB53.0, alternating hemiplegia, within the MB53 hemiplegia block, and ICD-10 uses G81.9 when the pattern is recorded without further specification.ICD-11 2025-01 版将偏瘫型归入 MB53 偏瘫区块下的 MB53.0 交替性偏瘫，ICD-10 在未进一步说明时使用 G81.9。
• The childhood disease has its own registry identity as ORPHA:2131 and MONDO:0016241, and it is flagged as rare and Orphanet-rare in the Monarch ontology.该儿童疾病在登记系统中具有独立身份 ORPHA:2131 与 MONDO:0016241，并在 Monarch 本体中标记为罕见与 Orphanet 罕见。
• It belongs to the ATP1A3-related neurological disorders, together with rapid-onset dystonia-parkinsonism and CAPOS syndrome, which share the gene but not the phenotype.它属于 ATP1A3 相关神经系统疾病，与快速起病的肌张力障碍-帕金森综合征及 CAPOS 综合征同属一基因谱系但表型不同。
• Interoperability anchors include DOID 0050635, MeSH C536589, GARD 0000011, NORD 758, MedGen 90925, NCIt C35261, SNOMED CT 230466004 and UMLS C0338488.互操作锚点包括 DOID 0050635、MeSH C536589、GARD 0000011、NORD 758、MedGen 90925、NCIt C35261、SNOMED CT 230466004 与 UMLS C0338488。
• The most discriminating phenotypes are coded as HP:0001263 for global developmental delay and HP:0001250 for seizure, both of which are common but not universal.最具鉴别力的表型编码为全面发育迟缓 HP:0001263 与癫痫发作 HP:0001250，二者常见但并非普遍存在。

History

• Verret and Steele reported the first series in 1971, describing eight children with recurrent alternating hemiplegia that began in infancy and resembled complicated migraine.Verret 与 Steele 于 1971 年报告首个病例系列，描述八名婴儿期起病的反复交替性偏瘫患儿，表现类似复杂性偏头痛。
• Aicardi and colleagues defined the clinical criteria in the 1980s and 1990s, fixing onset before 18 months, alternating attacks and relief by sleep as the diagnostic core.Aicardi 及其同事在 1980 至 1990 年代确立临床标准，把 18 月龄前起病、交替发作与睡眠后缓解确定为诊断核心。
• The migraine hypothesis dominated early thinking, and many children were treated as atypical migraine until the non-progressive but persistent motor and cognitive deficits were recognised.偏头痛假说早期占主导，许多患儿按非典型偏头痛治疗，直到人们认识到其非进展却持续存在的运动与认知缺损。
• In 2012 two independent groups reported heterozygous ATP1A3 mutations in most patients, establishing a molecular diagnosis and a shared mechanism with rapid-onset dystonia-parkinsonism.2012 年两个独立团队报告多数患者存在 ATP1A3 杂合突变，确立了分子诊断，并揭示其与快速起病肌张力障碍-帕金森综合征共享机制。
• Genotype-phenotype studies then showed that the same gene causes CAPOS syndrome and that some variants produce overlapping or intermediate phenotypes, revising the earlier one-gene-one-disease model.随后的基因型-表型研究显示同一基因可致 CAPOS 综合征，部分变异产生重叠或中间表型，修正了早期的一基因一病模型。
• The observation that attacks disappear during sleep, known since the earliest descriptions, remains unexplained and is now a target for studies of state-dependent pump function.自最早描述起即知发作在睡眠中消失，这一现象至今未获解释，现已成为状态依赖性泵功能研究的靶点。
• International consensus diagnostic criteria were published in 2021, incorporating genetic testing and separating classic from atypical presentations.2021 年发表国际共识诊断标准，纳入基因检测并将经典型与非典型表现分开。

Epidemiology

• Orphanet classifies the disease as rare with a point prevalence below 1 per 1,000,000, and fewer than 1,000 patients have been described worldwide.Orphanet 将该病归为罕见，点患病率低于每 100 万 1 例，全球已描述患者不足 1000 例。
• Estimates from national cohorts suggest a birth incidence of roughly 1 in 1,000,000, although milder ATP1A3 phenotypes are probably undercounted.来自国家队列的估计提示出生发病率约为百万分之一，但较轻的 ATP1A3 表型很可能被低估。
• Males and females are affected equally, consistent with autosomal dominant inheritance without sex linkage.男女受累比例相等，符合无性别连锁的常染色体显性遗传。
• Onset is by definition before 18 months, and most children have their first attack before 6 months, often in the first weeks of life.按定义在 18 月龄前起病，多数患儿首次发作在 6 月龄前，常在出生后最初数周内出现。
• About three quarters of patients carry a pathogenic ATP1A3 variant, and most of these variants arise de novo, so parental testing is usually normal.约四分之三的患者携带致病性 ATP1A3 变异，其中多数为新发变异，因此父母检测通常正常。
• There is no geographic or ethnic predilection, and cases have been reported from Europe, North America, East Asia, South Asia and Latin America.该病无地域或种族倾向，欧洲、北美、东亚、南亚与拉丁美洲均有病例报告。
• Data sources are Orphanet, national rare-disease registries and the international patient registry maintained by the Alternating Hemiplegia of Childhood Foundation.数据来源包括 Orphanet、各国罕见病登记，以及交替性偏瘫基金会维护的国际患者登记。
• Heath-economic burden is driven by lifelong care, recurrent hospital admissions and rehabilitation rather than by premature mortality, and formal cost studies are lacking.卫生经济负担主要来自终身照护、反复住院与康复，而非过早死亡，正式的疾病成本研究仍缺如。

Pathophysiology

• ATP1A3 encodes the alpha-3 catalytic subunit of the sodium-potassium ATPase, which is expressed mainly in neurons and extrudes three sodium ions for two potassium ions per ATP.ATP1A3 编码钠钾 ATP 酶 α3 催化亚基，主要表达于神经元，每水解一分子 ATP 泵出三个钠离子并泵入两个钾离子。
• Loss of pump activity raises intracellular sodium, impairs calcium clearance through the sodium-calcium exchanger and destabilises membrane excitability in motor circuits.泵活性下降使细胞内钠升高，损害钠钙交换体对钙的清除，并使运动环路的膜兴奋性失稳。
• Studies in patient-derived neurons and knock-in mice show impaired synaptic transmission and altered cerebellar and basal ganglia function, which fits the dystonia and ataxia of the phenotype.患者来源神经元与敲入小鼠研究显示突触传递受损及小脑与基底节功能改变，与表型中的肌张力障碍和共济失调相符。
• The basis of alternation between hemispheres is unknown, and proposed explanations include asymmetric pump reserve, spreading depression and state-dependent thalamocortical gating.两侧半球交替受累的机制未知，候选解释包括泵储备不对称、扩散性抑制与状态依赖性丘脑皮质门控。
• Sleep-related relief suggests that the attack depends on a wakefulness-linked metabolic or ionic state that is reset during sleep.睡眠相关缓解提示发作依赖某种与觉醒相关的代谢或离子状态，并在睡眠中被重置。
• The disorder is not neurodegenerative, and imaging is usually normal or shows non-specific atrophy, so structural lesions must not be expected.该病并非神经退行性，影像通常正常或仅见非特异性萎缩，因此不应期待结构性病变。
• Trigger factors such as stress, excitement, fatigue, water exposure and changes in temperature are reported by most families and are thought to act on the same unstable excitability threshold.多数家庭报告应激、兴奋、疲劳、接触水与温度变化等触发因素，被认为作用于同一不稳定的兴奋性阈值。

Clinical features

• Hemiplegic attacks last from minutes to days, alternate sides within a single episode or between episodes, and frequently begin with abnormal posturing or tremor.偏瘫发作持续数分钟至数日，可在同一次发作内或发作之间交替侧别，常以异常姿势或震颤起病。
• Attacks are often relieved by sleep, a feature so characteristic that its absence should prompt reconsideration of the diagnosis.发作常在睡眠后缓解，这一特征极为典型，若缺失应重新考虑诊断。
• Dystonia, choreoathetosis, ataxia and abnormal eye movements occur both during and between attacks and accumulate into a fixed motor disorder.肌张力障碍、舞蹈手足徐动、共济失调与眼球运动异常在发作期与间歇期均可出现，并累积为固定的运动障碍。
• Developmental delay and intellectual disability affect the majority, and speech is often the most affected domain, with expressive language lagging motor milestones.发育迟缓与智力障碍影响多数患者，言语常为受影响最重的领域，表达性语言落后于运动里程碑。
• Epilepsy occurs in roughly half of patients and may precede the first hemiplegic attack, which can delay recognition of the underlying disorder.约半数患者合并癫痫，且可先于首次偏瘫发作出现，从而延误对基础疾病的识别。
• Autonomic features during attacks include sweating, flushing, pupillary change and altered respiratory pattern, and they support an organic rather than functional cause.发作期自主神经表现包括出汗、潮红、瞳孔改变与呼吸节律变化，支持器质性而非功能性病因。
• Complications include injury during falls, aspiration during severe attacks, status dystonicus, scoliosis and feeding difficulty, and each requires proactive surveillance.并发症包括跌倒受伤、严重发作时误吸、肌张力障碍持续状态、脊柱侧弯与喂养困难，均需主动监测。
• Neonatal presentations may mimic seizures or sepsis, and a history of paroxysmal abnormal movements in the first weeks of life should raise the possibility.新生儿期表现可类似惊厥或败血症，出生后数周内出现阵发性异常运动的病史应提示本病。

Diagnosis

• The 2021 international consensus criteria require onset before 18 months, recurrent hemiplegic attacks involving both sides, and paroxysmal or permanent neurological abnormalities not explained by another disorder.2021 年国际共识标准要求 18 月龄前起病、累及两侧的反复偏瘫发作，以及不能用其他疾病解释的阵发性或持续性神经异常。
• ATP1A3 sequencing confirms the diagnosis in about three quarters of patients, and deletion and duplication analysis is added when sequencing is negative.ATP1A3 测序可在约四分之三的患者中确诊，测序阴性时应加做缺失与重复分析。
• Video-electroencephalography during an attack helps separate hemiplegic attacks from postictal Todd paresis, and interictal epileptiform activity supports comorbid epilepsy.发作期视频脑电图有助于区分偏瘫发作与癫痫后 Todd 麻痹，发作间期癫痫样活动支持合并癫痫。
• Brain magnetic resonance imaging is performed to exclude structural causes and is usually normal, while magnetic resonance angiography excludes moyamoya disease.脑磁共振用于排除结构性病因且通常正常，磁共振血管成像则用于排除烟雾病。
• The differential diagnosis includes hemiplegic migraine, moyamoya disease, alternating hemiplegia from brainstem lesions, epilepsy with Todd paresis, stroke and mitochondrial disease.鉴别诊断包括偏瘫型偏头痛、烟雾病、脑干病变所致交替性偏瘫、癫痫伴 Todd 麻痹、卒中与线粒体病。
• Alternating hemiplegia of childhood is distinguished from hemiplegic migraine by onset before 18 months, fixed interictal deficits and the absence of a typical migraine aura.儿童交替性偏瘫与偏瘫型偏头痛的区分点在于 18 月龄前起病、发作间期固定缺损与缺乏典型偏头痛先兆。
• Brainstem crossed hemiplegia is distinguished by ipsilateral cranial nerve palsy, adult onset and an identifiable lesion on imaging, none of which belongs to the childhood disease.脑干交叉性偏瘫以同侧颅神经麻痹、成年起病与影像可见病变相区分，这些均不属于该儿童疾病。
• Diagnostic delay is common because attacks are mistaken for seizures or migraine, and many patients wait years before genetic testing is requested.诊断延误常见，因为发作被误认为癫痫或偏头痛，许多患者等待数年才被送检基因。

Management

• Flunarizine, a calcium channel blocker, is the most used preventive drug, reported to shorten attacks and reduce severity in about half of treated patients.钙通道阻滞剂氟桂利嗪是最常用的预防药物，据报告可使约半数患者的发作缩短并减轻严重程度。
• Topiramate, other antiepileptics and ketogenic diet have been tried with inconsistent benefit, and none is supported by a randomised controlled trial.托吡酯、其他抗癫痫药与生酮饮食均曾试用，获益不一致，且无一项获得随机对照试验支持。
• Trigger avoidance, including avoidance of overheating, sudden cold water exposure and excessive excitement, is recommended by families and specialist centres.避免过热、突然接触冷水与过度兴奋等触发因素，受到家庭与专科中心的推荐。
• Epilepsy, dystonia and spasticity are treated symptomatically with standard antiepileptic, anticholinergic and botulinum toxin approaches.癫痫、肌张力障碍与痉挛状态按症状治疗，采用标准抗癫痫药、抗胆碱能药与肉毒毒素方案。
• Multidisciplinary rehabilitation includes physiotherapy, speech and language therapy, occupational therapy and orthotic management for gait and posture.多学科康复包括物理治疗、言语治疗、作业治疗以及针对步态与姿势的矫形器管理。
• Nutritional support, gastrostomy when aspiration is recurrent, and scoliosis surveillance are part of long-term care in severe cases.营养支持、反复误吸时行胃造瘘以及脊柱侧弯监测，是重症患者长期照护的组成部分。
• Genetic counselling should explain autosomal dominant inheritance, the high proportion of de novo variants and a 50 per cent recurrence risk for an affected parent.遗传咨询应说明常染色体显性遗传、新发变异比例高，以及受累父母所生子女 50% 的再发风险。
• Prenatal testing is possible once the familial variant is known, and preimplantation genetic testing has been used in affected families.已知家系变异后可行产前检测，受累家庭亦有使用胚胎植入前遗传学检测的报道。
• Prognosis for survival is generally good, but motor disability, intellectual impairment and epilepsy persist, and most adults need supported living or supervision.生存预后总体良好，但运动残疾、智力障碍与癫痫持续存在，多数成人需要支持性居住或监护。

Research and controversies

• The mechanism by which attacks alternate between hemispheres remains the central unsolved question, and no model fully reproduces the human pattern.发作在两侧半球间交替的机制仍是核心未解问题，尚无模型能完整再现人类表现。
• Whether flunarizine truly modifies the disease or only reduces attack severity is disputed, because trials are open-label and outcome measures vary between centres.氟桂利嗪究竟改变疾病进程还是仅减轻发作严重程度存在争议，因为试验多为开放标签且各中心结局指标不一。
• Trials of ketamine and of NMDA receptor modulation are based on the excitability model, and early reports are limited to small case series.氯胺酮与 NMDA 受体调节试验基于兴奋性模型，早期报告仅限于小规模病例系列。
• Antisense oligonucleotide and gene-replacement strategies are in preclinical development for ATP1A3 disorders, but delivery to the central nervous system remains unsolved.针对 ATP1A3 疾病的反义寡核苷酸与基因替代策略处于临床前开发阶段，但中枢神经系统递送仍未解决。
• Patient organisations, led by the Alternating Hemiplegia of Childhood Foundation, drive registry building and natural-history studies, which are essential because cohorts are small.以交替性偏瘫基金会为首的患者组织推动登记建设与自然史研究，这在队列规模小的背景下至关重要。