Topiramate as a Disease Altering Therapy for CSPN

隐源性感觉性周围神经病（CSPN）影响5%-10%的40岁以上的人，导致 由于疼痛、感觉丧失、不平衡和跌倒相关损伤导致生活质量降低。CSPN是一个重要的 患者发病的原因，对此不存在改变疾病的治疗。临床上与早期糖尿病相似 神经病变，其特征在于优先损伤小轴突，并经常导致突出的感觉神经病变。 丧失和神经性疼痛。小轴突的损伤反映在表皮内神经纤维密度的降低 （IENFD）。虽然CSPN的确切病因尚不清楚，可能是多因素的， 表明肥胖、血脂异常和胰岛素抵抗/前驱糖尿病（代谢综合征）与 CSPN风险。CSPN患者发生代谢综合征和糖尿病前期患者的风险增加 CSPN的风险增加。肥胖和血脂异常也会显著增加神经病变的风险 在糖尿病患者中。动物模型支持肥胖和糖尿病前期葡萄糖水平 失调引起神经病。越来越多的文献表明，运动可以改善神经再生 容量，导致IENFD增加，并改善CSPN患者的神经性疼痛， 糖尿病前期累积起来，这些数据支持代谢综合征与神经病变相关的假设 风险，CSPN可能是可逆的，积极的代谢管理可能是一种有效的策略， 促进神经再生并改善患者症状。然而，目前可用的生活方式干预措施 由于依从性差和必要的摩擦， 行为改变开发更好的药理学方法是一个主要的优先事项。最近的数据表明 电压门控钠通道功能的获得在CSPN和其他常见形式的 神经病变托吡酯是治疗CSPN的有效方法。这种抗惊厥药的临床试验 药物治疗糖尿病神经病变提示疼痛和生活质量的改善， 周围神经功能，包括感觉测试和IENFD。托吡酯具有多种潜在的 神经保护作用。它在本研究中提出的剂量下诱导显著的体重减轻，并且还改善了 胰岛素抵抗这些影响在肥胖患者中最大。托吡酯也阻断电压门控 钠离子通道它已被广泛研究用于治疗癫痫和偏头痛， 安全且耐受良好。几项研究表明，神经性疼痛的潜在益处与 糖尿病神经病变小型研究表明，托吡酯治疗不仅可以改善疼痛， 改善QOL，优先影响小纤维功能的测量，包括IENFD的增加。 来自糖尿病动物模型的数据也支持其潜在的治疗功效。虽然托吡酯具有 多种潜在作用机制（体重减轻、胰岛素敏感性改善、钠通道调节）， 事实上，每一个都将有望在CSPN中受益， 纤维损伤是CSPN的特征，支持其作为疾病改变疗法的进一步评价。的 托吡酯治疗CSPN（TopCSPN）研究将125名CSPN患者随机分配至托吡酯每日100 mg或 匹配的安慰剂。治疗将持续24个月。IENFD和诺福克生活质量-糖尿病神经病变 （NQOL-DN）将是共同主要结局指标。TopCSPN研究的一个主要次要目标是 评价IENFD和其他常用的神经病变替代指标的临床意义。 CSPN研究的结果有望立即影响患者护理，并促进未来的外周 神经病临床试验。

Cryptogenic sensory peripheral neuropathy (CSPN) affects 5-10% of those over 40 years old, resulting in reduced quality of life due to pain, sensory loss, imbalance, and fall related injuries. CSPN is a significant cause of patient morbidity, for which there exists no disease altering therapy. Clinically similar to early diabetic neuropathy, it is characterized by preferential injury to small axons, and frequently results in prominent sensory loss and neuropathic pain. Injury to small axons is reflected in reduced intraepidermal nerve fiber density (IENFD). While the precise etiology of CSPN is unknown, and likely multifactorial, accumulating evidence indicates that obesity, dyslipidemia, and insulin resistance/prediabetes (metabolic syndrome) are linked to CSPN risk. Patients with CSPN have an elevated risk of metabolic syndrome and patients with prediabetes have an elevated risk of CSPN. Obesity and dyslipidemia also significantly increase the risk of neuropathy among diabetic patients. Animal models support the hypothesis that obesity and prediabetic levels of glucose dysregulation cause neuropathy. A growing literature suggests that exercise improves nerve regenerative capacity, results in increased IENFD and improves neuropathic pain among patients with CSPN and prediabetes. Cumulatively, these data support the hypothesis that metabolic syndrome is linked to neuropathy risk, CSPN is potentially reversible, and aggressive metabolic management may be an effective strategy to enhance nerve regeneration and improve patient symptoms. However, currently available lifestyle interventions are very difficult to employ in a clinical setting due to poor compliance and attrition from the necessary behavioral changes. Development of better pharmacologic approaches is a major priority. Recent data suggest that gain of function in voltage gated sodium channels plays a role in CSPN and other common forms of neuropathy. Topiramate is a promising therapeutic approach to CSPN. Clinical trials of this anticonvulsant agent in diabetic neuropathy suggest improvement in pain and quality of life, and also in measures of peripheral nerve function including sensory testing and IENFD. Topiramate has multiple potentially neuroprotective effects. It induces significant weight loss at the dose proposed in this study, and also improves insulin resistance. These effects are greatest among obese patients. Topiramate also blocks voltage gated sodium channels. It has been extensively studied for the treatment of epilepsy and migraine and is generally safe and well tolerated. Several studies suggest a potential benefit for neuropathic pain associated with diabetic neuropathy. Small studies suggest topiramate therapy not only results in improved pain, but also improves QOL and preferentially impacts measures of small fiber function, including an increase in IENFD. Data from animal models of diabetes also support its potential therapeutic efficacy. While topiramate has multiple potential mechanisms of action (weight loss, improved insulin sensitivity, sodium channel modulation), the fact that each would be expected to have benefit in CSPN and its potential to differentially impact small fiber injury, which is characteristic of CSPN, support its further evaluation as a disease altering therapy. The Topiramate for CSPN (TopCSPN) Study will randomize 125 CSPN patients to 100 mg of topiramate daily or matched placebo. Treatment will last 24 months. IENFD and the Norfolk Quality of Life – Diabetic Neuropathy (NQOL-DN) will be co-primary outcome measures. A major secondary goal of the TopCSPN study is to evaluate the clinical meaning of IENFD and other commonly employed surrogate measures of neuropathy. The results of the CSPN Study promise to immediately impact patient care and facilitate future peripheral neuropathy clinical trials.