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Imbalance and lower limb tremor in chronic inflammatory demyelinating polyradiculoneuropathy 慢性炎性脱髓鞘性多根神经病变的失衡和下肢震颤
IF 3.8 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-06-14 DOI: 10.1111/jns.12574
Matthew Silsby, Con Yiannikas, Alessandro F. Fois, Karl Ng, Matthew C. Kiernan, Victor S. C. Fung, Steve Vucic

Background and Aims

Imbalance is a prominent symptom of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Although upper limb tremor in CIDP is described, lower limb tremor has not been assessed. The aim of this study was to determine whether lower limb tremor was present in CIDP and assess potential relationships with imbalance.

Methods

This was a cross-sectional observational study of prospectively recruited consecutive patients with typical CIDP (N = 25). Clinical phenotyping, lower limb nerve conduction and tremor studies, and posturography analyses were performed. The Berg Balance Scale (BBS) divided CIDP patients into those with “good” and “poor” balance.

Results

Lower limb tremor was evident in 32% of CIDP patients and associated with poor balance (BBSTremor 35 [23–46], BBSNo Tremor 52 [44–55], p = .035). Tremor frequency was 10.2–12.5 Hz with legs outstretched and on standing, apart from four patients with a lower frequency tremor (3.8–4.6 Hz) while standing. Posturography analysis revealed a high-frequency spectral peak in the vertical axis in 44% of CIDP patients (16.0 ± 0.4 Hz). This was more likely in those with “good” balance (40% vs. 4%, p = .013).

Interpretation

Lower limb tremor is present in one third of CIDP patients and is associated with poor balance. A high-frequency peak on posturography is associated with better balance in CIDP. Lower limb tremor and posturography assessments could serve as important biomarkers of balance in a clinical setting.

背景与目的失衡是慢性炎症性脱髓鞘性多根神经病变(CIDP)的一个突出症状。虽然对CIDP的上肢震颤进行了描述,但下肢震颤尚未得到评估。本研究的目的是确定下肢震颤是否存在于CIDP中,并评估其与失衡的潜在关系。方法前瞻性连续招募典型CIDP患者(N = 25)进行横断面观察性研究。临床表型,下肢神经传导和震颤研究,以及姿势分析。伯格平衡量表(BBS)将CIDP患者分为“良好”和“差”两组。结果32%的CIDP患者下肢震颤明显,并伴有平衡不良(bbs震颤35 [23-46],BBSNo震颤52 [44-55],p = 0.035)。除了4名站立时震颤频率较低(3.8-4.6 Hz)的患者外,双腿伸展和站立时震颤频率为10.2-12.5 Hz。体位照相分析显示44%的CIDP患者在纵轴处出现高频频谱峰(16.0±0.4 Hz)。这在那些“良好”平衡的人身上更有可能发生(40%对4%,p = 0.013)。解释:三分之一的CIDP患者存在下肢震颤,并伴有平衡能力差。姿势照相的高频峰值与CIDP中更好的平衡有关。下肢震颤和体位学评估可以作为临床平衡的重要生物标志物。
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引用次数: 2
EGR2 gene-linked hereditary neuropathies present with a bimodal age distribution at symptoms onset EGR2基因相关的遗传性神经病在症状发作时呈现双峰年龄分布
IF 3.8 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-06-12 DOI: 10.1111/jns.12572
Andoni Echaniz-Laguna, Cécile Cauquil, Jean-Baptiste Chanson, Céline Tard, Lucie Guyant-Marechal, Thierry Kuntzer, Ioana Maria Ion, Anne-Sophie Lia, Jérôme Bouligand, Vianney Poinsignon

Background

Mutations in the Early-Growth Response 2 (EGR2) gene cause various hereditary neuropathies, including demyelinating Charcot–Marie-Tooth (CMT) disease type 1D (CMT1D), congenital hypomyelinating neuropathy type 1 (CHN1), Déjerine–Sottas syndrome (DSS), and axonal CMT (CMT2).

Methods

In this study, we identified 14 patients with heterozygous EGR2 mutations diagnosed between 2000 and 2022.

Results

Mean age was 44 years (15–70), 10 patients were female (71%), and mean disease duration was 28 years (1–56). Disease onset was before age 15 years in nine cases (64%), after age 35 years in four cases (28%), and one patient aged 26 years was asymptomatic (7%). All symptomatic patients had pes cavus and distal lower limbs weakness (100%). Distal lower limbs sensory symptoms were observed in 86% of cases, hand atrophy in 71%, and scoliosis in 21%. Nerve conduction studies showed a predominantly demyelinating sensorimotor neuropathy in all cases (100%), and five patients needed walking assistance after a mean disease duration of 50 years (47–56) (36%). Three patients were misdiagnosed as inflammatory neuropathy and treated with immunosuppressive drugs for years before diagnosis was corrected. Two patients presented with an additional neurologic disorder, including Steinert's myotonic dystrophy and spinocerebellar ataxia (14%). Eight EGR2 gene mutations were found, including four previously undescribed.

Interpretation.

Our findings demonstrate EGR2 gene-related hereditary neuropathies are rare and slowly progressive demyelinating neuropathies with two major clinical presentations, including a childhood-onset variant and an adult-onset variant which may mimic inflammatory neuropathy. Our study also expands the genotypic spectrum of EGR2 gene mutations.

早期生长反应2 (EGR2)基因突变可导致多种遗传性神经病变,包括脱髓鞘性沙科-玛丽-图斯病(CMT) 1D型(CMT1D)、先天性低髓鞘神经病变1型(CHN1)、dsamjerine - sottas综合征(DSS)和轴突性CMT (CMT2)。方法在本研究中,我们确定了2000年至2022年间诊断为EGR2杂合突变的14例患者。结果平均年龄44岁(15 ~ 70岁),女性10例(71%),平均病程28年(1 ~ 56岁)。发病年龄为15岁前9例(64%),35岁后4例(28%),26岁1例无症状(7%)。所有有症状的患者均有足弓足和下肢远端无力(100%)。86%的患者出现下肢远端感觉症状,71%的患者出现手部萎缩,21%的患者出现脊柱侧凸。神经传导研究显示所有病例(100%)主要为脱髓鞘感觉运动神经病变,5例患者在平均病程50年(47-56年)(36%)后需要行走辅助。3例患者被误诊为炎症性神经病变,经免疫抑制药物治疗多年后才得到纠正。2例患者表现出额外的神经系统疾病,包括Steinert's肌强直性营养不良和脊髓小脑性共济失调(14%)。发现了8个EGR2基因突变,其中包括4个以前未描述过的突变。解释。我们的研究结果表明,EGR2基因相关的遗传性神经病是一种罕见的缓慢进展的脱髓鞘性神经病,有两种主要的临床表现,包括儿童期发病的变体和成人发病的变体,可能模仿炎症性神经病。我们的研究也扩大了EGR2基因突变的基因型谱。
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引用次数: 0
CYBA allelic variants are associated with severity and recovery in Guillain–Barré syndrome CYBA等位基因变异与格林-巴-巴综合征的严重程度和恢复有关
IF 3.8 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-06-08 DOI: 10.1111/jns.12571
Andreas Törnell, Nina Lagerström, Natalia Mossberg, Roberta Kiffin, Helen Farman, Jan Lycke, Oluf Andersen, Markus Axelsson, Kristoffer Hellstrand, Anna Martner

Background and Aims

Guillain–Barré syndrome (GBS) is a rare, acute neuropathy characterized by ascending muscle weakness. Age, axonal GBS variants, and antecedent Campylobacter jejuni infection are associated with severe GBS, but the detailed mechanisms of nerve damage are only partly explored. Pro-inflammatory myeloid cells express NADPH oxidases (NOX) that generate tissue-toxic reactive oxygen species (ROS) that are implicated in neurodegenerative diseases. This study analyzed the impact of variants of the gene encoding the functional NOX subunit CYBA (p22phox) on acute severity, axonal damage, and recovery in adult GBS patients.

Methods

Extracted DNA from 121 patients was genotyped for allelic variation at rs1049254 and rs4673 within CYBA using real-time quantitative polymerase chain reaction. Serum neurofilament light chain was quantified by single molecule array. Patients were followed for severity and motor function recovery for up to 13 years.

Results

CYBA genotypes linked to reduced formation of ROS, i.e. rs1049254/G and rs4673/A, were significantly associated with unassisted ventilation, shorter time to normalization of serum neurofilament light chain and shorter time to regained motor function. Residual disability at follow-up was confined to patients carrying CYBA alleles associated with high formation of ROS.

Interpretation

These findings implicate NOX-derived ROS in GBS pathophysiology and CYBA alleles as biomarkers of severity.

背景和目的吉兰-巴勒综合征(GBS)是一种罕见的急性神经病变,以上升肌无力为特征。年龄、轴突GBS变异和先前的空肠弯曲杆菌感染与严重的GBS有关,但神经损伤的详细机制仅被部分探索。促炎髓细胞表达NADPH氧化酶(NOX),产生与神经退行性疾病有关的组织毒性活性氧(ROS)。本研究分析了编码功能性NOX亚基CYBA (p22phox)的基因变异对成人GBS患者急性严重程度、轴突损伤和康复的影响。方法提取121例患者的DNA,采用实时定量聚合酶链反应对CYBA中rs1049254和rs4673等位基因变异进行基因分型。采用单分子阵列法定量血清神经丝轻链。随访患者的严重程度和运动功能恢复长达13年。结果与ROS形成减少相关的CYBA基因型rs1049254/G和rs4673/A与无辅助通气、较短的血清神经丝轻链正常化时间和较短的运动功能恢复时间显著相关。随访时的残障局限于携带与ROS高形成相关的CYBA等位基因的患者。这些发现暗示GBS病理生理和CYBA等位基因中nox衍生的ROS是严重程度的生物标志物。
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引用次数: 0
Nodes of Ranvier in health and disease 朗维耶淋巴结在健康和疾病中的作用
IF 3.8 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-06-05 DOI: 10.1111/jns.12568
Yael Eshed-Eisenbach, Peter J. Brophy, Elior Peles

Action potential propagation along myelinated axons depends on the geometry of the myelin unit and the division of the underlying axon to specialized domains. The latter include the nodes of Ranvier (NOR), the paranodal junction (PNJ) flanking the nodes, and the adjacent juxtaparanodal region that is located below the compact myelin of the internode. Each of these domains contains a unique composition of axoglial adhesion molecules (CAMs) and cytoskeletal scaffolding proteins, which together direct the placement of specific ion channels at the nodal and juxtaparanodal axolemma. In the last decade it has become increasingly clear that antibodies to some of these axoglial CAMs cause immune-mediated neuropathies. In the current review we detail the molecular composition of the NOR and adjacent membrane domains, describe the function of different CAM complexes that mediate axon-glia interactions along the myelin unit, and discuss their involvement and the underlying mechanisms taking place in peripheral nerve pathologies. This growing group of pathologies represent a new type of neuropathies termed “nodopathies” or “paranodopathies” that are characterized by unique clinical and molecular features which together reflect the mechanisms underlying the molecular assembly and maintenance of this specialized membrane domain.

沿着有髓鞘轴突的动作电位传播取决于髓鞘单位的几何形状和潜在轴突向特殊结构域的划分。后者包括兰维尔结(NOR)、位于结两侧的节旁结(PNJ)以及位于节间致密髓鞘下方的邻近的颈旁区。这些结构域中的每一个都包含一种独特的轴珠粘附分子(CAM)和细胞骨架支架蛋白组成,它们共同指导特定离子通道在淋巴结和颈旁轴上的位置。在过去的十年里,越来越清楚的是,针对其中一些轴突CAM的抗体会导致免疫介导的神经病变。在目前的综述中,我们详细介绍了NOR和相邻膜结构域的分子组成,描述了介导髓鞘单元轴突-神经胶质相互作用的不同CAM复合物的功能,并讨论了它们在外周神经病理中的参与和潜在机制。这一不断增长的病理组代表了一种新型的神经病理学,称为“多巴胺”或“副多巴胺”,其特征是独特的临床和分子特征,这些特征共同反映了分子组装和维持这一特殊膜结构域的机制。
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引用次数: 0
The autoimmune vulnerability of the node of Ranvier Ranvier淋巴结的自身免疫易感性
IF 3.8 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-06-05 DOI: 10.1111/jns.12570
Luis Querol, Emilien Delmont, Cinta Lleixà

The nodes of Ranvier (NoR) are essential domains for nerve conduction and their disruption plays a key role in the pathophysiology of immune-mediated neuropathies. Our understanding of the specialized nodal regions and the immune mechanisms that affect them is growing and has led to the update of peripheral neuropathy classification to include the autoimmune nodopathies, defined by the site of the autoimmune attack. Autoantibodies directed against molecules of the nodal region (as neurofascin-140/186, neurofascin-155, contactin-1, contactin-associated protein 1, contactin-associated protein 2, gangliosides, LGI4, or myelin-associated glycoprotein), macrophage-induced paranodal demyelination, and phenotypic changes of the nodal domains of Schwann cells have been identified as key mechanisms in the pathogenesis of the autoimmune neuropathies. This review explores the current knowledge of the autoimmune vulnerability of the NoR, including the underlying mechanisms leading to dysfunction in the diverse autoimmune disorders.

Ranvier淋巴结(NoR)是神经传导的重要区域,其破坏在免疫介导的神经病变的病理生理中起着关键作用。我们对特殊淋巴结区域和影响它们的免疫机制的理解正在增长,并导致周围神经病变分类的更新,包括自身免疫结节病,由自身免疫攻击部位定义。针对结区分子的自身抗体(如神经束蛋白140/186、神经束蛋白155、接触蛋白1、接触蛋白相关蛋白1、接触蛋白相关蛋白2、神经节苷、LGI4或髓鞘相关糖蛋白)、巨噬细胞诱导的旁结脱髓鞘以及雪旺细胞结域的表型改变已被确定为自身免疫性神经病变发病的关键机制。这篇综述探讨了目前对NoR自身免疫性易感性的认识,包括导致各种自身免疫性疾病功能障碍的潜在机制。
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引用次数: 1
Autoimmune nodo-paranodopathies 10 years later: Clinical features, pathophysiology and treatment 10年后自身免疫性淋巴结副病:临床特征、病理生理和治疗
IF 3.8 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-06-05 DOI: 10.1111/jns.12569
Antonino Uncini

Background and Aims

Autoimmune neuropathies are classified, on the basis of pathophysiology, as demyelinating or axonal. The term nodo-paranodopathy, introduced in 2013 to better categorize the neuropathies with antiganglioside antibodies and later expanded to include neuropathies with antibodies to nodal and paranodal axoglial complexes, characterizes disorders in which the nodal region is critical in the pathogenesis. These neuropathies, although presenting electrophysiologic demyelinating features do not show pathologic evidence of segmental demyelination, or, although being classified as axonal, can show reversible nerve conduction failure and rapid recovery contrary with the communal concept of an axonal neuropathy.

Methods

In this personal view is reported, with a splitting approach, an update on autoimmune nodo-paranodopathies, classified according to the domains of peripheral nerve fiber, the target antigens and the antibody class and subclass involved. The clinical features, the electrophysiologic findings, the results of the immunopathological and ultrastructural studies, the pathophysiology and treatment are also described.

Results and Interpretation

The nodo-paranodopathy category integrates the clinical classification of autoimmune neuropathies and expands the traditional dichotomous demyelinating and axonal classification. It helps to a better systematization pointing to the domain and target antigens of the autoimmune process, it resolves conflicting pathologic and electrophysiologic findings, reconciles the contradiction that axonal neuropathies may be rapidly reversible, avoids taxonomical confusion and possible misdiagnoses. Finally this categorization, through the identification of the specific antibody and its prevalent class and subclass, clarifies the pathophysiological mechanisms and addresses to a more targeted therapeutic approach.

背景和目的基于病理生理学,自身免疫性神经病分为脱髓鞘性和轴突性。2013年,为了更好地对含有抗神经节苷脂抗体的神经病进行分类,引入了“淋巴结-副神经节病”这一术语,后来扩大到包括含有针对淋巴结和副神经节轴胶质复合物抗体的神经病,这一术语描述了淋巴结区域在发病机制中起关键作用的疾病。这些神经病变,虽然表现出电生理脱髓鞘特征,但没有表现出节段性脱髓鞘的病理证据,或者,虽然被归类为轴突性,但可以表现出可逆的神经传导障碍和快速恢复,这与轴突性神经病变的普遍概念相反。方法根据周围神经纤维、靶抗原、所涉及的抗体类别和亚类别对自身免疫性结节-副病理进行分类,采用分裂方法报道自身免疫性结节-副病理的最新进展。并对其临床特点、电生理表现、免疫病理及超微结构检查结果、病理生理及治疗进行了叙述。结果与解释结节-副神经病变分类整合了自身免疫性神经病变的临床分类,扩展了传统的脱髓鞘和轴突分类。它有助于更好地系统化指出自身免疫过程的域和靶抗原,它解决了相互矛盾的病理和电生理发现,调和了轴突神经病变可能迅速可逆的矛盾,避免了分类混乱和可能的误诊。最后,通过鉴定特异性抗体及其流行类和亚类,这种分类澄清了病理生理机制,并提出了更有针对性的治疗方法。
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引用次数: 0
Recruiting for an International Rare Disease Clinical Trial Readiness Study during the COVID-19 pandemic: Challenges and solutions COVID-19大流行期间招募国际罕见病临床试验准备研究:挑战和解决方案
IF 3.8 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-06-04 DOI: 10.1111/jns.12559
Katy Eichinger, Steffen Behrens-Spraggins, Janet E. Sowden, Davide Pareyson, Mary M. Reilly, Steven S. Scherer, Michael E. Shy, David N. Herrmann, the ACT-CMT Study Group
The Accelerate Clinical Trials in
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引用次数: 0
Toxic medications in Charcot–Marie–Tooth patients: A systematic review Charcot-Marie-Tooth患者的毒性药物:系统回顾
IF 3.8 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-05-30 DOI: 10.1111/jns.12566
Guido Cavaletti, Katherine Forsey, Paola Alberti

Background and Aims

Several widely used medications, with a relevant efficacy profile, are toxic to the peripheral nervous system and an even larger number of agents are suspected to be neurotoxic. There are concerns about the use of these drugs in patients with Charcot–Marie–Tooth disease (CMT), a hereditary motor and sensory neuropathy. This review provides evidence-based updated recommendations on this clinically relevant topic.

Methods

A systematic review of the available studies/reports written in English was performed from July to September 2022 including in the search string all reported putative neurotoxic drugs.

Results

The results of our systematic review provide evidence-based support for the statement that use of vincristine, and possibly paclitaxel, can occasionally induce an atypical, and more severe, course of drug-related peripheral neurotoxicity in CMT patients. It is therefore reasonable to recommend caution in the use of these compounds in CMT patients. However, no convincing evidence for a similar recommendation could be found for all other drugs.

Interpretation

It is important that patients with CMT are not denied effective treatments that may prolong life expectancy for cancer or improve their health status if affected by non-oncological diseases. Accurate monitoring of peripheral nerve function in CMT patients treated with any neurotoxic agent remains mandatory to detect the earliest signs of neuropathy worsening and atypical clinical courses. Neurologists monitoring CMT patients as part of their normal care package or for natural history studies should keep detailed records of exposures to neurotoxic medications and support reporting of accelerated neuropathy progression if observed.

背景和目的一些广泛使用的药物,具有相关的疗效,对周围神经系统有毒性,甚至更多的药物被怀疑是神经毒性的。这些药物在患有腓骨肌萎缩症(CMT)(一种遗传性运动和感觉神经病变)患者中的应用令人担忧。本综述就这一临床相关主题提供了基于证据的最新建议。方法对2022年7月至9月已有的英文研究/报告进行系统回顾,检索字符串中包括所有报道的推定神经毒性药物。结果本系统综述的结果为以下观点提供了证据支持:长春新碱,可能还有紫杉醇,在CMT患者中偶尔会诱发非典型的、更严重的药物相关周围神经毒性病程。因此,建议在CMT患者中谨慎使用这些化合物是合理的。然而,没有令人信服的证据表明类似的建议适用于所有其他药物。重要的是,CMT患者不应被拒绝接受有效的治疗,这些治疗可能延长癌症的预期寿命,或改善非肿瘤疾病患者的健康状况。在接受任何神经毒性药物治疗的CMT患者中,准确监测周围神经功能仍然是必要的,以发现神经病变恶化的早期迹象和非典型临床病程。作为常规护理包或自然史研究的一部分,神经科医生监测CMT患者时,应详细记录神经毒性药物的暴露情况,并支持观察到的神经病变加速进展的报告。
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引用次数: 1
Clinical features of a family with late-onset distal hereditary motor neuropathy harboring p.Pro39Leu variant of HSPB1 携带HSPB1 p.Pro39Leu变异的迟发性远端遗传性运动神经病家族的临床特征
IF 3.8 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-05-30 DOI: 10.1111/jns.12567
Hiroya Naruse, So Okubo, Atsushi Sudo, Jun Mitsui, Takashi Mikata, Hiroyuki Ishiura, Shinichi Morishita, Shoji Tsuji, Tatsushi Toda

Background and Aims

Pathogenic variants of HSPB1, the gene encoding the small heat shock protein 27, have been reported to cause autosomal dominant distal hereditary motor neuropathy (dHMN) type II and autosomal dominant Charcot–Marie-Tooth (CMT) disease with minimal sensory involvement (CMT2F). This study aimed to describe the clinical features of patients in a family with late-onset dHMN carrying the Pro39Leu variant of HSPB1.

Methods

Whole-exome sequence analysis identified a heterozygous pathogenic variant (Pro39Leu) of HSPB1 in the proband. The presence of the HSPB1 Pro39Leu variant in two affected individuals was confirmed using direct nucleotide sequence analysis.

Results

Both patients exhibited distal muscle weakness with lower extremity predominance and no obvious sensory deficits, leading to a clinical diagnosis of late-onset dHMN. Nerve conduction studies (NCSs) revealed a subclinical complication of sensory disturbance in one of the patients. The clinical and electrophysiological findings of patients with the HSPB1 Pro39Leu variant in this study and previous reports are summarized.

Interpretation

This study suggests that the clinical spectrum of patients carrying HSPB1 Pro39Leu variants, especially the disease onset, might be broader than expected, and HSPB1 variants should be considered in patients diagnosed with late-onset dHMN. Furthermore, patients with dHMN may have concomitant sensory deficits that should be evaluated using NCSs.

背景和目的编码小热休克蛋白27的HSPB1基因的致病性变异已被报道导致常染色体显性远端遗传性运动神经病变(dHMN) II型和常染色体显性夏科-玛丽-图斯病(CMT)伴最小感觉受累(CMT2F)。本研究旨在描述携带HSPB1 Pro39Leu变异体的迟发型dHMN家族患者的临床特征。方法先证者HSPB1基因杂合致病变异(Pro39Leu)的全外显子组序列分析。HSPB1 Pro39Leu变异存在于两个受影响的个体中,通过直接核苷酸序列分析证实。结果两例患者均表现为下肢远端肌无力为主,无明显感觉障碍,临床诊断为迟发性dHMN。神经传导研究(NCSs)显示一个亚临床并发症的感觉障碍的一个病人。本文总结了本研究和以往报道的HSPB1 Pro39Leu变异患者的临床和电生理结果。本研究提示携带HSPB1 Pro39Leu变异体的患者的临床谱,尤其是发病谱可能比预期的更广,在诊断为晚发型dHMN的患者中应考虑HSPB1变异体。此外,dHMN患者可能伴有感觉缺陷,应使用ncs进行评估。
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引用次数: 0
Caspr1 antibodies autoimmune paranodopathy with severe tetraparesis: Potential relevance of antibody titers in monitoring treatment response Caspr1抗体自身免疫性副病伴严重四全:抗体滴度监测治疗反应的潜在相关性
IF 3.8 3区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-05-29 DOI: 10.1111/jns.12565
Lorenzo Bresciani, Alessandro Salvalaggio, Elisa Vegezzi, Andrea Visentin, Andrea Fortuna, Mariagiulia Anglani, Mario Cacciavillani, Stefano Masciocchi, Silvia Scaranzin, Miryam Carecchio, Andrea Martinuzzi, Matteo Gastaldi, Chiara Briani

Aim

Nodopathies and paranodopathies are autoimmune neuropathies associated with antibodies to nodal–paranodal antigens (neurofascin 140/186 and 155, contactin-1, contactin-associated protein 1 [Caspr1]) characterized by peculiar clinical features, poor response to standard immunotherapies (e.g., intravenous immunoglobulins, IVIg). Improvement after anti-CD20 monoclonal antibody therapy has been reported. Data on Caspr1 antibodies pathogenicity are still preliminary, and longitudinal titers have been poorly described.

Methods

We report on a young woman who developed a disabling neuropathy with antibodies to the Caspr1/contactin-1 complex showing a dramatic improvement after rituximab therapy, mirrored by the decrease of antibody titers.

Results

A 26-year-old woman presented with ataxic-stepping gait, severe motor weakness at four limbs, and low frequency postural tremor. For neurophysiological evidence of demyelinating neuropathy, she was diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy and treated with IVIg without benefit. MRI showed symmetrical hypertrophy and marked signal hyperintensity of brachial and lumbosacral plexi. Cerebrospinal fluid showed 710 mg/dL protein. Despite intravenous methylprednisolone, the patient progressively worsened, and became wheelchair-bound. Antibodies to nodal–paranodal antigens were searched for by ELISA and cell-based assay. Anticontactin/Caspr1 IgG4 antibodies resulted positive. The patient underwent rituximab therapy with slow progressive improvement that mirrored the antibodies titer, measured throughout the disease course.

Conclusions

Our patient had a severe progressive course with early disability and axonal damage, and slow recovery starting only a few months after antibody-depleting therapy. The close correlation between titer, disability, and treatment, supports the pathogenicity of Caspr1 antibodies, and suggest that their longitudinal evaluation might provide a potential biomarker to evaluate treatment response.

目的淋巴结病变和副淋巴结病变是与淋巴结-副淋巴结抗原(神经束蛋白140/186和155,接触蛋白1,接触蛋白相关蛋白1 [Caspr1])抗体相关的自身免疫性神经病变,其临床特征特殊,对标准免疫疗法(如静脉注射免疫球蛋白,IVIg)反应差。抗cd20单克隆抗体治疗后改善已有报道。关于Caspr1抗体致病性的数据仍然是初步的,纵向滴度的描述也很差。方法:我们报告了一位患有Caspr1/contactin-1复合物抗体的年轻女性,她在接受美罗华治疗后出现了显著的改善,抗体滴度下降。结果1例26岁女性患者表现为步态共济失调,四肢严重运动无力,伴有低频体位性震颤。由于脱髓鞘神经病变的神经生理学证据,她被诊断为慢性炎症性脱髓鞘性多根神经病变,并接受IVIg治疗,但没有效果。MRI显示臂丛、腰骶丛对称性肥大,信号明显增高。脑脊液显示蛋白710 mg/dL。尽管静脉注射甲基强的松龙,患者病情仍逐渐恶化,并成为轮椅。采用酶联免疫吸附试验(ELISA)和细胞法寻找结旁抗原抗体。抗接触蛋白/Caspr1 IgG4抗体阳性。患者接受了利妥昔单抗治疗,进展缓慢,反映了整个疾病过程中测量的抗体滴度。结论该患者病程严重,早期残疾,轴突损伤,抗体消耗治疗数月后恢复缓慢。滴度、致残性和治疗之间的密切相关性支持了Caspr1抗体的致病性,并提示其纵向评估可能为评估治疗反应提供潜在的生物标志物。
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Journal of the Peripheral Nervous System
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