Characteristics and clinical course of myoclonus in Cavalier King Charles Spaniels
查理士王小猎犬肌阵挛的特征和临床过程

1 INTRODUCTION 1 引言

Myoclonus is an involuntary, shock-like movement of a muscle or group of muscles, occurring as a result of sudden increased contraction (positive myoclonus) or cessation of contraction (negative myoclonus).¹ The sudden and brief nature of myoclonic movements, typically resulting in movement of the affected body part, helps to distinguish it from other involuntary movements such as tremor or dyskinesia. Numerous methods have been used to classify myoclonus in humans according to body distribution (focal, multifocal, segmental or generalized), etiology (physiologic, essential, epileptic or symptomatic), or presumed neural generator based on electrophysiological testing (cortical, subcortical, segmental or peripheral).² Myoclonus also may be described as spontaneous, action-related or reflex depending on the presence and nature of provoking factors.
肌阵挛是指肌肉或肌肉群因收缩突然增强（正性肌阵挛）或收缩突然停止（负性肌阵挛）而出现的一种不自主的、类似于休克的运动。¹ 肌阵挛运动具有突发性和短暂性，通常会导致受影响的身体部位移动，这有助于将其与震颤或运动障碍等其他不自主运动区分开来。根据身体分布（局灶性、多灶性、节段性或全身性）、病因（生理性、本质性、癫痫性或症状性）或根据电生理学测试推测的神经发生器（皮质、皮质下、节段或外周），有许多方法用于对人类肌阵挛进行分类。² 肌阵挛也可描述为自发性、动作相关性或反射性，这取决于诱发因素的存在和性质。

Myoclonus associated with epileptic seizures, or progressive myoclonic epilepsies (PMEs), occur in veterinary medicine and include neuronal glycoproteinosis (Lafora disease [LD]),^{3, 4} neuronal ceroid lipofuscinosis,⁴ juvenile myoclonic epilepsy of Rhodesian Ridgeback dogs,^{4, 5} and audiogenic reflex seizures in cats.⁶ In addition, myoclonus may be observed in aging dogs alongside epileptic seizures of unknown origin.⁷ Non-epileptic forms of myoclonus occur in dogs with distemper,⁸ often a constant repetitive myoclonus affecting the limb and facial muscles, and in hereditary hyperekplexia reported in Irish Wolfhounds,⁹ Spanish Greyhounds,¹⁰ and Miniature Australian Shepherds.¹¹ Myoclonus also may be toxin or drug-induced,² as has been reported secondary to gabapentin toxicity.¹²
与癫痫发作相关的肌阵挛或进行性肌阵挛癫痫（PMEs）在兽医学中时有发生，包括神经元糖蛋白病（拉弗拉病 [LD]）、^{3, 4} 神经细胞类脂膜炎、⁴ 罗得西亚脊背犬幼年肌阵挛性癫痫、^{4, 5} 和猫的听觉反射性癫痫发作。⁶ 此外，在衰老的狗身上可能会观察到肌阵挛和不明原因的癫痫发作。⁷ 犬瘟热患者会出现非癫痫形式的肌阵挛、⁸ 常常是影响四肢和面部肌肉的持续重复性肌阵挛、据报道，爱尔兰猎狼犬、⁹ 西班牙灰猎犬也患有遗传性肌阵挛、¹⁰ 和迷你澳大利亚牧羊犬。¹¹ 肌阵挛也可能是毒素或药物引起的、² 如继发于加巴喷丁毒性的报道。¹²

A recent retrospective study described myoclonus in aged CKCS, in which the abnormal episodes consisted predominantly of rapid eye blinking and head nodding with variable extension to the thoracic limbs.¹³ An association with epilepsy was speculated, because 9/39 dogs also suffered ≥1 generalized tonic-clonic seizures (GTCS).
最近的一项回顾性研究描述了老年 CKCS 的肌阵挛，其中异常发作主要包括快速眨眼和点头，并可延伸至胸肢。¹³ 由于 9/39 的犬只≥1 次全身强直-阵挛发作（GTCS），因此推测这与癫痫有关。

The aim of our questionnaire-based study was to collect information regarding myoclonus in CKCS, to further assess the phenotypic features and natural clinical course, as well as explore a potential link to generalized epileptic seizures.
我们的问卷调查研究旨在收集有关 CKCS 肌阵挛的信息，进一步评估其表型特征和自然临床过程，并探索其与全身性癫痫发作的潜在联系。

2 MATERIALS AND METHODS 2 材料和方法

3 RESULTS 3 结果

3.2 Questionnaire responses
3.2 问卷答复

All dogs experienced multiple episodes of myoclonus per day. A word cloud summarizing the freehand description of the episodes by the caregivers is depicted in Figure 1. In most dogs, the frequency of the episodes was reported to increase (18/27) or remain unchanged (6/10) since onset, although in 3 dogs the frequency decreased. The severity of the episodes often was reported to increase (15/27) or remain unchanged (11/26), although in 1 dog the severity decreased.
所有狗狗每天都会经历多次肌阵挛发作。图1中的词云总结了护理人员对发作的自由描述。据报告，大多数狗的发作频率自发病以来有所增加（18/27）或保持不变（6/10），但有 3 只狗的发作频率有所下降。据报告，发作的严重程度通常会增加（15/27）或保持不变（11/26），但有 1 只狗的严重程度有所下降。

Myoclonic episodes usually involved the head (25/27), whereas forelimbs (13/27), facial features (12/27), hindlimbs (8/27), back and abdomen (7/27) and neck (7/27) also were variably affected.
肌阵挛发作通常涉及头部（25/27），而前肢（13/27）、面部特征（12/27）、后肢（8/27）、背部和腹部（7/27）以及颈部（7/27）也会受到不同程度的影响。

The episodes most often occurred spontaneously or at rest (25/27). Only 3 respondents identified possible triggers of the episodes including stress (2/3), touch (2/3), excitement (1/3) and sudden movement (1/3). Eight respondents believed the episodes had negatively affected the quality of life of the dog.
发作最常发生在自发或休息时（25/27）。只有 3 位受访者指出了可能的诱发因素，包括压力（2/3）、触摸（2/3）、兴奋（1/3）和突然移动（1/3）。有 8 位受访者认为癫痫发作对狗狗的生活质量造成了负面影响。

Diagnostic investigations consisted of blood tests (8), magnetic resonance imaging (MRI) of the brain (7), and cerebrospinal fluid analysis (3). Reported findings and comorbidities included mitral valve disease (12), Chiari-like malformation (7), syringomyelia (6), keratoconjunctivitis sicca (5), and otitis media with effusion (2). Thirteen dogs were receiving medication for comorbidities, most commonly gabapentin or pregabalin for Chiari-like malformation and syringomyelia in 6 dogs, pimobendan for mitral valve disease in 3 dogs, and cyclosporine for keratoconjunctivitis sicca in 3 dogs.
诊断检查包括血液化验（8 例）、脑部磁共振成像（7 例）和脑脊液分析（3 例）。报告的检查结果和合并症包括二尖瓣疾病（12 例）、奇异畸形（7 例）、鞘膜积液（6 例）、角膜结膜炎（5 例）和中耳炎伴渗出（2 例）。有 13 只狗正在接受治疗合并症的药物，其中最常见的是加巴喷丁或普瑞巴林，用于治疗 6 只狗的琪阿瑞样畸形和鞘膜积液；3 只狗正在接受治疗二尖瓣疾病的匹莫班丹；3 只狗正在接受治疗角结膜炎的环孢素。

Medical management of the myoclonic episodes was attempted in 8 dogs. Levetiracetam (LEV) was prescribed for 6 dogs. In 4 of these dogs, the episodes completely stopped after initiation of treatment, whereas in 2 dogs there was partial improvement. Regardless, 5/6 dogs were reported to have a later progressive increase in the frequency and severity of myoclonic episodes. The perceived duration of effect of LEV generally was not stated. Two dogs received prednisolone, 1 in addition to gabapentin; in both dogs the episode frequency and severity decreased.
对 8 只狗尝试了肌阵挛性发作的药物治疗。其中 6 只狗服用了左乙拉西坦（LEV）。其中 4 只狗的肌阵挛发作在接受治疗后完全停止，2 只狗的肌阵挛发作得到部分改善。尽管如此，据报告，5/6 的狗肌阵挛性发作的频率和严重程度后来逐渐增加。LEV的疗效持续时间一般没有说明。两只狗接受了泼尼松龙治疗，其中一只狗在接受加巴喷丁治疗的同时还接受了泼尼松龙治疗；这两只狗的发作频率和严重程度都有所下降。

Generalized epileptic seizures were reported in 4 dogs. In 2 dogs, the onset of myoclonus preceded the onset of seizures by 20 and 22 months (seizure onset of 10 years, and 11 years 10 months, respectively). One dog began having seizures at 1 year of age and was diagnosed with idiopathic epilepsy; myoclonus first occurred 8 years later. In 1 dog, the seizures and myoclonic episodes were reported to have the same age of onset (8 years). In the latter 2 cases, the caregivers reported effective control of generalized seizures using zonisamide and phenobarbitone, respectively.
据报告，有 4 只狗出现了全身性癫痫发作。两只狗的肌阵挛发病时间分别比癫痫发作时间早 20 个月和 22 个月（癫痫发作时间分别为 10 年和 11 年 10 个月）。一只狗在 1 岁时开始出现癫痫发作，被诊断为特发性癫痫；肌阵挛在 8 年后首次出现。据报道，有一只狗的癫痫发作和肌阵挛发作的发病年龄相同（8 岁）。在后两个病例中，护理人员报告说，他们分别使用唑尼沙胺和苯巴比妥有效控制了全身性癫痫发作。

Fifteen dogs had displayed changes in behavior since experiencing the myoclonic episodes, in their caregiver's opinion. These changes included a perceived desire to stay close to the caregiver (7), being less playful (6), being more restless (4), sleeping more (3), a perceived desire to be on their own (2) and aggression towards people (1). No such changes were reported for 12 dogs.
在护理人员看来，15 只狗在经历肌阵挛发作后行为发生了变化。这些变化包括：认为自己想靠近照顾者（7 只）、不太爱玩耍（6 只）、更不安分（4 只）、睡得更多（3 只）、认为自己想独处（2 只）和对人有攻击性（1 只）。有 12 只狗没有出现这种变化。

4 DISCUSSION 4 讨论

Most CKCS experienced daily episodes of spontaneous myoclonus affecting predominantly the head, with variable involvement of the thoracic limbs, facial features, pelvic limbs, back, abdomen, and neck. There was a tendency for increasingly frequent and severe myoclonic episodes over time, both in dogs that received medical treatment and those that did not. Provoking factors only rarely were identified, such as touch, stress, excitement, and sudden movement. The most frequent descriptive terms used by caregivers are depicted in Figure 1. This clinical phenotype is broadly consistent with that described previously.¹³ However, in the current cohort, GTCS were reported slightly less commonly (4/27 rather than 9/39). The rarity of provoking factors contrasts with some progressive myoclonic epilepsies described in veterinary medicine such as LD and feline audiogenic reflex seizures (FARS), in which reflex myoclonus in response to light and sound is a prominent feature.
大多数 CKCS 每天都会发作自发性肌阵挛，主要累及头部，胸部四肢、面部特征、骨盆四肢、背部、腹部和颈部也会受到不同程度的影响。随着时间的推移，接受治疗和未接受治疗的犬只肌阵挛发作的频率和严重程度都有增加的趋势。很少发现诱发因素，如触摸、压力、兴奋和突然移动。图1描述了护理人员最常使用的描述性术语。¹³ 不过，在目前的队列中，GTCS 的报告略少（4/27 而不是 9/39）。诱发因素的罕见程度与兽医学中描述的一些进行性肌阵挛癫痫（如LD和猫听源性反射性癫痫（FARS））形成鲜明对比，后者对光和声音的反射性肌阵挛是一个突出特征。

Most dogs were reported to have displayed changes in behavior since the onset of myoclonic episodes (18/27). These changes most often involved being more attached to and dependent on the caregiver and less playful, although 3 dogs had a preference to be on their own and 2 tended to display aggression to other dogs. Restless or obsessive behavior, excessive sleepiness and perceived loss of memory also were identified. A similar spectrum of behavioral changes is commonly reported as a manifestation of progressive cognitive decline in dogs with LD. In Miniature Wirehaired Dachshunds with LD, late clinical signs (>3 years after onset) included dementia defined as disorientation and memory loss with or without altered sleep/wake cycle and anxiety, loss of house training, and aggression towards people or dogs.³ Similarly, Beagles with LD exhibited staring into space, decreased stress resistance, increased noise sensitivity, separation anxiety, decreased playfulness, reclusiveness, loss of house training, attachment to the caregiver, and aggression towards people or dogs.¹⁴
据报告，自肌阵挛发作以来，大多数狗狗的行为都发生了变化（18/27）。这些变化最常见的是更加依恋和依赖照护者，玩耍性降低，但有 3 只狗喜欢独处，有 2 只狗倾向于攻击其他狗。此外，还发现了不安或强迫行为、过度嗜睡和记忆力减退等症状。类似的一系列行为变化通常被报告为患有 LD 的狗狗认知能力逐渐下降的一种表现。在患有痴呆症的迷你线毛腊肠犬中，晚期临床症状（发病后 >3 年）包括痴呆症，即迷失方向和记忆力减退，伴有或不伴有睡眠/觉醒周期改变、焦虑、失去家教以及对人或狗的攻击行为。³ 同样，患有痴呆症的比格犬表现出凝视空间、抗压能力下降、对噪音的敏感性增加、分离焦虑、玩耍能力下降、孤僻、失去家训、对照料者的依恋以及对人或狗的攻击性。¹⁴

In a previous study,¹³ only 2/39 CKCS showed signs of cognitive dysfunction consisting of staring into space, being less interactive with the caregiver, aimlessly wandering, and anxiety. It was speculated that these signs may not have been directly related to the myoclonus, and could correlate with a historical diagnosis of idiopathic epilepsy in both dogs. Similarly, 2 dogs in our study had idiopathic epilepsy, of which 1 was reported to have behavioral changes. In contrast, however, most CKCS (18/27) developed signs consistent with cognitive dysfunction.¹⁵ Overall, dogs with behavioral changes were generally older (median age, 145 months) and had experienced the myoclonic episodes for longer (median, 25 months) than those without behavioral changes (median age, 129.5 months; median duration, 18.5 months). Although it cannot be excluded that some behavioral changes may have been related to concurrent age-related health problems such as undiagnosed orthopedic conditions, this finding lends support to the possibility of an underlying neurodegenerative disorder involving cognitive decline alongside progressive myoclonus.
在之前的一项研究中，¹³ 只有 2/39 的 CKCS 表现出认知功能障碍，包括凝视空间、与看护人的互动减少、漫无目的地游荡和焦虑。据推测，这些症状可能与肌阵挛没有直接关系，可能与这两只狗曾被诊断为特发性癫痫有关。同样，在我们的研究中，有两只狗患有特发性癫痫，其中一只据报告有行为变化。然而，与此形成鲜明对比的是，大多数 CKCS（18/27）都出现了与认知功能障碍一致的症状。¹⁵ 总体而言，与无行为变化的犬只相比，有行为变化的犬只年龄普遍较大（中位年龄为 145 个月），肌阵挛发作的时间也较长（中位时间为 25 个月）（中位年龄为 129.5 个月；中位持续时间为 18.5 个月）。虽然不能排除某些行为改变可能与并发的与年龄相关的健康问题（如未确诊的骨科疾病）有关，但这一发现支持了潜在的神经退行性疾病的可能性，即在进行性肌阵挛的同时出现认知功能下降。

Ten dogs were prescribed medication for myoclonus. Eight dogs with behavioral changes were prescribed medication, as opposed to only 2 dogs without behavioral changes. This difference could suggest that medication was more likely to be offered, or accepted, for dogs that displayed behavioral abnormalities alongside the myoclonus. However, in most cases it was not possible to determine the exact nature of the clinical signs at the time of the first prescription, which is one limitation of our study. Although an adverse influence of medication on behavior cannot be ruled out, most dogs reported to have behavioral changes did not receive any medication (10/18).
10 只狗接受了肌阵挛药物治疗。其中，8 只有行为变化的狗获得了药物治疗，而只有 2 只没有行为变化的狗获得了药物治疗。这种差异可能表明，对于那些在肌阵挛的同时还表现出行为异常的犬只，更有可能提供或接受药物治疗。不过，在大多数情况下，我们无法确定首次处方时临床症状的确切性质，这也是我们研究的局限性之一。虽然不能排除药物对行为的不良影响，但大多数报告有行为变化的犬只都没有接受任何药物治疗（10/18）。

Levetiracetam was the most commonly prescribed medication. It has a unique mechanism of action among the more frequently used anti-seizure drugs (ASD). By binding to synaptic vesicle glycoprotein 2A (SV2A) LEV is believed to inhibit presynaptic calcium channels and decrease neurotransmitter release.¹⁶ Levetiracetam is considered a useful ASD in the treatment of myoclonic seizures in both humans and animals, with high response rates reported in several veterinary epileptic syndromes in which myoclonus is a prominent feature, including LD.^{17, 18} For example, in Rhodesian Ridgebacks with juvenile myoclonic epilepsy, treatment with LEV resulted in significant reduction in frequency and intensity of myoclonic and absence seizures on video-electroencephalogram.⁵ In another study of FARS, in which myoclonus is a hallmark feature, all 28 cats that were treated with LEV showed a >50% decrease in seizure frequency.¹⁹ Half of the cats achieved complete seizure freedom.
左乙拉西坦是最常用的处方药。在较常用的抗癫痫药物（ASD）中，它具有独特的作用机制。通过与突触小泡糖蛋白2A（SV2A）结合，LEV被认为可以抑制突触前钙通道，减少神经递质的释放。¹⁶ 左乙拉西坦被认为是治疗人类和动物肌阵挛发作的一种有效ASD，据报道，它对以肌阵挛为显著特征的几种兽医癫痫综合征（包括LD）的反应率很高。^{17, 18} 例如，在患有幼年肌阵挛性癫痫的罗得西亚脊背犬中，使用 LEV 治疗可显著降低视频脑电图上肌阵挛和失神发作的频率和强度。⁵ 在另一项以肌阵挛为特征的FARS研究中，接受LEV治疗的28只猫的癫痫发作频率均下降了50%以上。¹⁹ 半数猫完全摆脱了癫痫发作。

All dogs that received LEV showed a positive response initially, including complete cessation of myoclonic episodes in half of the dogs (4/8). However, later recurrence of myoclonus was common, progressing in frequency in severity and necessitating dose increases of LEV in some dogs. The specific period of time for which the effect of LEV lasted generally was not stated, other than the owners usually described any subsequent worsening as slow or gradual. This trend has been reported in dogs with LD¹⁸ and idiopathic epilepsy.^20-22 One explanation is a possible preliminary effect observed as the development of functional tolerance to LEV with chronic use. This phenomenon has been demonstrated in rat models of epilepsy, in which the anticonvulsant effect of LEV decreased with repeated administration despite no change in plasma concentrations.^{23, 24} Similar effects have been observed in both dogs²⁰ and people^{25, 26} with refractory epilepsy. Alternative, or perhaps concurrent, reasons for decreasing seizure control may include an initial placebo effect or recall bias by the owners, natural progression or fluctuation of the epilepsy, pharmacokinetic alterations such as would occur with poor caregiver compliance, or other mechanisms of acquired drug resistance.²⁷ Given the tendency for natural progression of the myoclonic syndrome described in both treated and untreated CKCS in our cohort, it is possible that the loss of effect of LEV over time is at least partly reflective of an underlying neurodegenerative process. It also suggests that use of LEV is unlikely to prevent progression of the disease but can provide effective relief of clinical signs in the early stages. Caregivers of affected dogs should be made aware of this possibility at the outset.
所有接受 LEV 治疗的狗最初都表现出了积极的反应，包括半数狗（4/8）的肌阵挛发作完全停止。然而，肌阵挛后来复发的情况很常见，频率和严重程度不断增加，有些狗不得不增加 LEV 的剂量。LEV效果持续的具体时间通常没有说明，但狗主人通常会将随后的恶化描述为缓慢或逐渐的。这种趋势在患有LD¹⁸ 和特发性癫痫的狗中也有报道。^20-22 一种解释是，长期使用 LEV 可能会产生初步效应，即对 LEV 产生功能性耐受。这种现象已在大鼠癫痫模型中得到证实，在这些模型中，尽管血浆浓度没有变化，但随着重复给药，LEV 的抗惊厥效果会下降。^23、24 在狗²⁰ 和人^{25 中也观察到类似的效果、26} 难治性癫痫。癫痫发作控制率下降的其他原因或并发原因可能包括最初的安慰剂效应或药主的回忆偏差、癫痫的自然进展或波动、药代动力学改变（如护理人员依从性差时出现的改变）或其他获得性耐药机制。²⁷ 鉴于在我们的队列中，接受治疗和未接受治疗的 CKCS 患者的肌阵挛综合征都有自然进展的趋势，因此随着时间的推移，LEV 的疗效减退可能至少部分反映了潜在的神经退行性过程。这也表明，使用LEV不太可能阻止疾病的发展，但可以有效缓解早期阶段的临床症状。患病犬的护理人员应从一开始就意识到这种可能性。

The main limitations of our study are its retrospective nature and relatively small sample size. In particular, the number of dogs that underwent diagnostic investigation and medical treatment was low and the approach not standardized, and additional prospective case series ideally would be required to establish firm conclusions regarding outcomes. As with most questionnaire-based studies, recall by the participants may have included inaccuracies and been subject to bias.
我们研究的主要局限性在于其回顾性和相对较小的样本量。特别是，接受诊断检查和治疗的犬只数量较少，而且治疗方法也没有标准化，因此理想情况下需要更多的前瞻性病例系列才能就治疗结果得出确切结论。与大多数基于问卷调查的研究一样，参与者的回忆可能存在不准确之处，也可能存在偏差。

5 CONCLUSION 5 结束语

Myoclonus in CKCS tends to increase in frequency and severity with increasing age. The proportion of dogs that had concurrent GTCS was low. Later-onset behavioral changes suggestive of cognitive decline are commonly reported. Although the number of dogs prescribed medication was relatively low, there often was an initial positive response to LEV followed by later deterioration. These findings support the possibility of an underlying neurodegenerative process.
随着年龄的增长，CKCS 肌阵挛的发生频率和严重程度都会增加。并发 GTCS 的犬只比例较低。后期出现的行为变化提示认知能力下降的报告很常见。虽然给狗狗开药的数量相对较少，但它们对 LEV 的最初反应往往是积极的，但后来情况恶化。这些发现支持了潜在神经退行性过程的可能性。

CONFLICT OF INTEREST DECLARATION
利益冲突声明

Authors declare no conflict of interest.
作者声明无利益冲突。

OFF-LABEL ANTIMICROBIAL DECLARATION
标签外抗菌剂声明

Authors declare no off-label use of antimicrobials.
作者声明未在标签外使用抗菌药物。

INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE (IACUC) OR OTHER APPROVAL DECLARATION
机构动物护理和使用委员会（IACUC）或其他批准声明

Authors declare no IACUC or other approval was needed.
作者声明无需 IACUC 或其他批准。

HUMAN ETHICS APPROVAL DECLARATION
人类伦理批准声明

Authors declare human ethics approval was not needed for this study.
作者声明，本研究无需人道伦理批准。