Autoimmune limbic encephalitis associated with antibodies to components of the voltage‐gated potassium channel complex (VGKCC‐Ab‐LE) often leads to focal hippocampal atrophy and persistent episodic memory impairment (Butler et al., 2014; Loane et al., 2019). In an interesting study of 7 VGKCC‐Ab‐LE patients with hippocampal damage, Lad, Mullally, Houston, Kelly, and Griffiths (2019) reported (a) impaired recall, in the face of preserved recognition memory, as disclosed by the Doors and People Test (DPT; Baddeley, Emslie, & Nimmo‐Smith, 1994). This was interpreted as consistent with frameworks attributing recollection processes to hippocampal function (Yonelinas, 2002); (b) impairment of autobiographical (“episodic”) memory in the face of preserved personal semantic memory, without temporal gradient (Autobiographical Memory Interview—AMI; Kopelman, Wilson, & Baddeley, 1989). This was interpreted as inconsistent with systems consolidation accounts (Squire, Genzel, Wixted, & Morris, 2015) and dovetails with reports on temporally ungraded retrograde amnesia post‐VGKCC‐Ab‐LE (Chan, Henley, Rossor, & Warrington, 2007). Given the rarity of VGKCC‐Ab‐LE, it is important to examine the replicability of such dissociations employing the same tests and patient selection criteria.

In a recent paper, we reported on the brain abnormalities underlying anterograde amnesia in a large cohort of VGKCC‐Ab‐LE patients (n = 24) (Loane et al., 2019). Our patients scored lower than healthy controls (CTRs) in verbal/visual recall and verbal recognition. However, the selection criteria employed by Lad et al. (2019) were different, highlighting the possibility that an appropriate subset of our cohort would replicate their findings. Among those criteria were: (a) structural MRI conducted >1 year post‐acutely; (b) atrophic hippocampi and spared parahippocampal gyri in the stable chronic phase. However, the definition of atrophy was based on visual inspection. In contrast, the data we reported in Loane et al. (2019) allow us to apply this criterion in a more precise fashion, since we had conducted gold‐standard manual volumetry of medial temporal lobe structures; (c) VGKCC‐Ab level > 1,000 pmol/L at diagnosis. This value is very high relative to commonly used cut‐offs [100 pmol/L (Celicanin et al., 2017; Zuliani et al., 2007); 150 pmol/L (Barajas, Eric Collins, Cha, & Geschwind, 2010); 400 pmol/L (Irani et al., 2010; Vincent et al., 2004)]; (d) a clinical phenotype consistent with LGI1‐LE. While the paper relied on neurological assessment to determine the presence of an “LGI1‐type,” our data allow us to select cases that tested positive exclusively for LGI1‐Ab.

We first identified four patients with LGI1‐Ab‐LE, focal hippocampal atrophy [right and/or left hippocampus: z < −1.96 relative to a group of 48 age‐matched CTRs (Argyropoulos et al., 2019), reflecting significant volume reduction (p < .05); right/left entorhinal/perirhinal/parahippocampal cortex volumes: z > −1.29], assessed > 1 year post‐symptom onset (“HPC patients”). Consistent with the post‐acute profile of our cohort as a whole (Loane et al., 2019), these patients showed preserved semantic memory and language, visuospatial, motor, and executive function. Since Lad et al. (2019) had employed age‐ and sex‐matched CTRs on an individual basis, we compared our 4 male HPC patients with the 26 male CTRs of our study (patients' age at assessment: mean = 63.43; SD = 8.99 years; male CTRs' age: mean = 60.20; SD = 10.06 years; patients vs. male CTRs: t = −0.60, p = 0.551). We also conducted comparisons against population means, wherever available, in order to enhance the generalizability of our findings.

Unlike Lad et al. (2019), HPC patients showed clearly impaired verbal recognition, along with impaired delayed verbal recall (Table 1). Regarding retrograde amnesia, they showed impairment in both autobiographical and personal semantic memory. However, their impaired personal semantic memory was driven by their low scores in the recent epoch: they showed no evidence of personal semantic memory impairment for childhood or early adulthood, but impairment for recent events. On the contrary, patients showed impaired autobiographical memory for events in all three periods assessed (childhood, early adulthood, recent events).

Given that our different findings could potentially be attributed to the lower sample size, we then (a) included another 3 LGI1‐Ab‐LE cases that satisfied all criteria above except for the fact that: 1 patient had been assessed 1 year [instead of >1 year as in Lad et al. (2019)] post‐symptom onset, and another 2 had presented with acute VGKCC‐Ab levels < 1,000 pmol/L (but still >400 pmol/L; “HPC₂ patients”); consistent with (Loane et al., 2019), no negative correlation was observed, even at trending levels, between the acute VGKCC‐Ab levels and DPT/AMI scores or right/left hippocampal volumes across those 7 HPC₂ patients (all rhos/ps, −0.234 ≤ rho ≤ 0.580; p ≥ .228); (b) identified another 5 (1 female) LGI1‐Ab‐LE patients with no atrophy in the hippocampus or the parahippocampal gyrus (“HPC‐intact”)—all 5 patients showed intact semantic memory, language, executive, motor, and visuospatial function. We iterated the comparisons on the DPT and the AMI between these groups and all 39 CTRs (male and female) reported in Loane et al. (2019) (age at assessment: CTRs: mean = 60.86; SD = 11.61 years; HPC₂: mean = 62.32; SD = 12.76 years; HPC‐intact: mean = 67.81; SD = 9.56; all comparisons: |t| < 1.29, p > .2). We tested the prediction that HPC₂ patients would show selective recall deficits along with impaired autobiographical but spared personal semantic memory, whereas HPC‐intact patients would show little evidence for retrograde/anterograde amnesia.

Our comparisons revealed a very different pattern: both HPC₂ and HPC‐intact patients showed impaired visual and/or verbal recall, but HPC₂ patients also showed impaired verbal recognition (Figure 1a). HPC₂ patients scored lower in both autobiographical and personal semantic memory than CTRs, as did HPC‐intact patients (Figure 1b). Nevertheless, impaired personal semantic memory was driven by low scores in the recent epoch only. Moreover, patients' low scores in the recent epoch for both autobiographical and semantic memories should not be attributed to retrograde amnesia, since the recent epoch largely overlapped with the postmorbid period. The selective impairment in autobiographical aspects of remote memory shown in Lad et al. (2019) may thus not be inconsistent with our findings.

Overall, our data show that focal hippocampal atrophy after VGKCC‐Ab‐LE does not necessarily cause selective deficits in recall memory. Instead, impairment may extend to certain types of recognition memory, as observed in cases of more dense amnesia following hippocampal damage (e.g., Manns & Squire, 1999). Custom‐made behavioral paradigms that quantify the contributions of familiarity and recollection in recognition memory following focal damage within the medial temporal lobes should be employed instead (e.g., Argyropoulos et al., 2020; Bowles et al., 2007), ideally for distinct material types. For instance, the hippocampus may enhance verbal recognition by activating pre‐existing associations with (and thus enriching contextual memory for) each verbal memorandum, hence increasing the probability of its successful recognition (Bird & Burgess, 2008). Individual differences in the extent to which HPC patients rely on familiarity to perform in recognition memory tasks pre‐ and, a fortiori, post‐morbidly should also be taken into account. However, anterograde and retrograde amnesia may occur post‐VKGCC‐Ab‐LE in the absence of hippocampal/parahippocampal atrophy. We propose that the interpretation of memory deficits reported here and in Lad et al. (2019) should also take into account structural/functional abnormalities in the extended hippocampal system (Bubb, Kinnavane, & Aggleton, 2017), in line with Argyropoulos et al. (2019) and Loane et al. (2019). Across our patient cohort, overall memory scores (DPT) were a function of reduced interhippocampal and corticohippocampal resting‐state functional connectivity (Figure 1c). Likewise, remote autobiographical memory (AMI) impairment was a function of thalamic volume reduction (Figure 1d). We thus believe that assessment of network abnormalities that may follow hippocampal damage is crucial to resolve debates about the neural basis of anterograde and retrograde amnesia. Since the profile of small patient groups with “focal” hippocampal amnesia may readily be biased by the idiosyncratic features of each study, we call for cross‐center studies that employ a broad range of neuropsychological tests to assess episodic memory and also capitalize on the variability of hippocampal damage and symptom severity across larger cohorts.

与电压门控钾通道复合物 (VGKCC-Ab-LE) 成分抗体相关的自身免疫性边缘系统脑炎通常会导致局灶性海马萎缩和持续性情景记忆障碍（Butler 等人，2014 年；Loane 等人，2019 年）。在一项对 7 名患有海马损伤的 VGKCC-Ab-LE 患者进行的有趣研究中，Lad、Mullally、Houston、Kelly 和 Griffiths（2019 年）报告说（a）面对保留的识别记忆，如 Doors 和人员测试（DPT；Baddeley、Emslie 和 Nimmo-Smith，1994 年）。这被解释为与将回忆过程归因于海马功能的框架一致（Yonelinas，2002); (b) 面对保留的个人语义记忆，没有时间梯度，自传（“情节”）记忆受损（自传记忆访谈-AMI；Kopelman, Wilson, & Baddeley, 1989）。这被解释为与系统整合账户不一致（Squire、Genzel、Wixted 和 Morris，2015 年），并且与 VGKCC-Ab-LE 后暂时未分级的逆行性遗忘症的报告相吻合（Chan、Henley、Rossor 和 Warrington，2007 年）。鉴于 VGKCC-Ab-LE 的罕见性，使用相同的测试和患者选择标准来检查这种分离的可重复性很重要。

在最近的一篇论文中，我们报告了一大群 VGKCC-Ab-LE 患者（n = 24）（Loane 等人，2019 年）的顺行性遗忘症的大脑异常。我们的患者在语言/视觉回忆和语言识别方面的得分低于健康对照 (CTR)。然而，Lad 等人采用的选择标准。( 2019 ) 不同，突出了我们队列中适当的子集复制他们发现的可能性。这些标准包括：(a) 急性后 1 年以上进行的结构性 MRI；（ b ）在稳定慢性期萎缩的海马和幸免的海马旁回。然而，萎缩的定义是基于目视检查。相比之下，我们在 Loane 等人报告的数据。( 2019) 允许我们以更精确的方式应用这个标准，因为我们已经对内侧颞叶结构进行了黄金标准的手动体积测量；(c) 诊断时 VGKCC-Ab 水平 > 1,000 pmol/L。相对于常用的临界值 [100 pmol/L（Celicanin 等人，2017 年；Zuliani 等人，2007 年），该值非常高；150 pmol/L（Barajas、Eric Collins、Cha 和 Geschwind，2010 年）；400 pmol/L（Irani 等人，2010 年；Vincent 等人，2004 年）]；(d) 与 LGI1-LE 一致的临床表型。虽然该论文依靠神经学评估来确定“LGI1 型”的存在，但我们的数据使我们能够选择仅对 LGI1-Ab 测试呈阳性的病例。

我们首先确定了四名 LGI1-Ab-LE 局灶性海马萎缩患者 [右侧和/或左侧海马： 相对于一组 48 名年龄匹配的 CTR，z < -1.96（Argyropoulos 等人，2019 年），反映了显着的体积减少( p  < .05); 右/左内嗅/鼻周/海马旁皮质体积：z  > -1.29]，评估 > 1 年症状发作后（“HPC 患者”）。与我们整个队列的急性期后概况一致（Loane 等人，2019 年），这些患者表现出保留的语义记忆和语言、视觉空间、运动和执行功能。由于 Lad 等人。( 2019) 在个体基础上采用了年龄和性别匹配的 CTR，我们将 4 名男性 HPC 患者与我们研究的 26 名男性 CTR 进行了比较（评估时患者的年龄：平均值 = 63.43；SD = 8.99 岁；男性 CTR 的年龄：平均值 = 60.20；SD = 10.06 年；患者与男性 CTR：t = -0.60，p = 0.551）。我们还对可用的人口平均值进行了比较，以增强我们发现的普遍性。

与 Lad 等人不同。（2019 年），HPC 患者表现出明显的语言识别障碍，以及延迟的语言回忆障碍（表 1）。关于逆行性遗忘症，他们在自传和个人语义记忆方面都表现出损害。然而，他们受损的个人语义记忆是由他们在最近时期的低分造成的：他们没有表现出童年或成年早期个人语义记忆受损的证据，但最近发生的事件受损。相反，患者在评估的所有三个时期（童年、成年早期、近期事件）都表现出对事件的自传体记忆受损。

鉴于我们的不同发现可能归因于较小的样本量，然后我们 (a) 纳入了另外 3 例满足上述所有标准的 LGI1-Ab-LE 病例，但以下事实除外： 1 名患者接受了 1 年的评估 [而不是> 1 年，如 Lad 等人所述。( 2019 )] 症状后发作，另外 2 名急性 VGKCC-Ab 水平 < 1,000 pmol/L（但仍 >400 pmol/L；“HPC ₂患者”）；与（Loane 等人，2019 年）一致，即使在趋势水平上，急性 VGKCC-Ab 水平与 DPT/AMI 评分或这 7 名 HPC ₂患者（所有 rhos/ p s, -0.234 ≤ rho ≤ 0.580; p ≥ .228)；(b) 确定了另外 5 名（1 名女性）LGI1-Ab-LE 患者海马或海马旁回没有萎缩（“HPC 完好”）——所有 5 名患者都表现出完整的语义记忆、语言、执行、运动和视觉空间功能。我们迭代了这些组与 Loane 等人报告的所有 39 个 CTR（男性和女性）之间 DPT 和 AMI 的比较。（2019 年）（评估年龄：CTR：平均值 = 60.86；SD = 11.61 岁；HPC ₂：平均值 = 62.32；SD = 12.76 岁；HPC 完整：平均值 = 67.81；SD = 9.56；所有比较：| t | < 1.29，p  > .2）。我们测试了 HPC ₂的预测患者会表现出选择性回忆缺陷以及自传体受损但个人语义记忆受损，而 HPC 完好的患者几乎没有逆行/顺行性遗忘的证据。

我们的比较揭示了一种非常不同的模式：HPC ₂和 HPC 完好患者都表现出视觉和/或语言回忆受损，但 HPC ₂患者也表现出语言识别受损（图 1a）。HPC ₂患者在自传体和个人语义记忆方面的得分低于 CTR，HPC 完整患者也是如此（图 1b）。然而，受损的个人语义记忆仅在最近的时期由低分驱动。此外，近期患者在自传体和语义记忆方面的低分不应归因于逆行性遗忘症，因为最近的时期在很大程度上与病后时期重叠。Lad 等人显示的远程记忆自传方面的选择性损害。( 2019) 因此可能与我们的发现不一致。

总体而言，我们的数据显示 VGKCC-Ab-LE 后局灶性海马萎缩不一定会导致回忆记忆的选择性缺陷。相反，损伤可能会扩展到某些类型的识别记忆，如在海马损伤后更严重的健忘症的情况下所观察到的（例如，Manns & Squire，1999 年）。应改用定制的行为范式，量化熟悉度和回忆在内侧颞叶内局灶性损伤后的识别记忆中的贡献（例如，Argyropoulos 等人，2020 年；Bowles 等人，2007 年）)，非常适合不同的材料类型。例如，海马体可以通过激活与每个口头备忘录的预先存在的关联（从而丰富上下文记忆）来增强口头识别，从而增加其成功识别的可能性（Bird & Burgess, 2008）。在某种程度上个体差异，其HPC患者依靠熟悉的识别记忆任务进行预处理和，更不用说，后病态也应考虑在内。然而，在没有海马/海马旁萎缩的情况下，VKGCC-Ab-LE 后可能会发生顺行和逆行健忘症。我们建议此处和 Lad 等人报告的记忆缺陷的解释。( 2019) 还应考虑扩展海马系统的结构/功能异常 (Bubb, Kinnavane, & Aggleton, 2017 )，与 Argyropoulos 等人的观点一致。（2019 年）和 Loane 等人。( 2019）。在我们的患者队列中，总体记忆评分 (DPT) 是海马间和皮质海马静息状态功能连接减少的函数（图 1c）。同样，远程自传体记忆 (AMI) 损伤是丘脑容积减少的函数（图 1d）。因此，我们认为，评估海马损伤后可能出现的网络异常对于解决有关顺行性和逆行性遗忘症的神经基础的争论至关重要。由于具有“局灶性”海马失忆症的小患者群体的概况很容易受到每项研究的特殊特征的偏见，我们呼吁进行跨中心研究，采用广泛的神经心理学测试来评估情景记忆并利用可变性较大队列的海马损伤和症状严重程度。