HIV相关的神经肌肉疾病

 

Derek J.R.W. Williams, RPA-C

New York State AIDS Institute,

Nicholas A. Rango HIV Clinical Scholar

Mount Sinai Medical Center

New York, NY

 

Nilay R. Shah, MD

Resident in Neurology

Mount Sinai Medical Center

New York, NY

 

David M. Simpson, MD

Professor of Neurology

Director of Neuro-AIDS Research Program

& Clinical Neurophysiology Laboratories

Mount Sinai Medical Center

One Gustave Levy Place; Box 1052

New York, NY 10029

Phone: 212-241-8748

Fax: 212-987-3301

Email: david.simpson@mssm.edu

 

译者： 柳青 医学博士 理学博士

             北京协和医院 神经科科

             北京市东城区帅府园1号

             100730

 

 

INTRODUCTION

               There is a wide spectrum of neurological complications associated with human immunodeficiency virus-1 (HIV) infection that are related either directly to HIV, to opportunistic infections, or to medications used in the treatment of the disease. These neurological disorders can range from asymptomatic to disabling conditions. In this chapter we will discuss the peripheral neuropathies associated with HIV disease, including distal symmetric polyneuropathy, inflammatory demyelinating polyneuropathy, progressive polyradiculopathy, mononeuropathy multiplex, and autonomic neuropathy.

前言

        人类免疫缺陷病毒感染后会出现很多神经系统症状，可以由于HIV直接感染导致，也可以由于机会性感染或药物治疗而引发。这些神经系统症状可以很轻微甚至无症状，也可以很重甚至致残。本章将讨论HIV感染相关的周围神经病，包括远端对称性多发性神经病、炎症性脱髓鞘性多发性神经病、进展性多神经根病、多发性单神经病和自主神经病。

               While peripheral neuropathy is usually not life threatening, the associated pain and discomfort can severely impact a patient's quality of life. Virtually all clinicians working with HIV-infected individuals will encounter patients with peripheral neuropathy. Unfortunately, these neuropathies are often overlooked or misdiagnosed (62). This is due to several factors, including the insidious onset of symptoms, the fact that peripheral neuropathy can be masked by other neurological disorders, and the possibility that neuropathy might be eclipsed by other serious conditions, that are frequently present in advanced acquired immunodeficiency syndrome (AIDS).

        虽然周围神经病并不会致命，但是它所产生的疼痛和不适却会严重影响病人的生活质量。事实上，与HIV感染病人有接触的临床医生都会遇到出现周围神经病变的病人。然而，这些神经系统病变常被忽视或误诊(62)。其原因在于这类疾病常症状隐袭，或是易被其他神经系统疾病所掩盖，在艾滋病晚期也可能因为并存的其他严重疾病状态而被忽视。

 

EPIDEMIOLOGY

               Among the many conditions that can affect the nervous system of the HIV infected patient, peripheral nerve disorders are the most common complications (52, 37, 6, 67). Peripheral neuropathies occur in up to 35% of patients with AIDS (68). while they are less common in patients with less advanced HIV disease. Table 1 lists the major neuromuscular syndromes associated with HIV infection.

               The progression of HIV disease is associated with an increase in the incidence of neuropathic symptoms (61). Other factors that increase the risk of peripheral neuropathy include the degree of immunosuppression, as reflected by reduced CD4 lymphocyte count, increased plasma HIV viral load, increasing age, poor nutritional status, and the presence of other chronic medical conditions (16, 70). Furthermore, with the prolonged survival of AIDS patients, attributable to highly active antiretroviral therapy (HAART), it is likely that more patients will develop peripheral neuropathy.

流行病学和发病机制

        在HIV感染后出现的众多神经系统疾病中，周围神经病变是最常见的合并症(52, 37, 6, 67)，在艾滋病病人中的发生率可达35%，而在HIV感染早期没有那么普遍。表1列举了HIV感染相关的主要神经肌肉病变。

        随着HIV的进展，神经病症状发生率逐渐增加(61)。其他可能增加周围神经病变发生的因素还包括免疫抑制的程度（可由CD4淋巴细胞计数衡量），血浆高HIV病毒载量，年龄增长，不良营养状况，及是否存在其它慢性疾病等情况(16, 70)。而且，随着HAART治疗的应用，艾滋病人的生存时间将不断延长，将有越来越多的病人出现周围神经病。

 

Distal Symmetrical Polyneuropathy

               Distal symmetric polyneuropathy is the most common form of peripheral neuropathy in HIV infection. Clinical and electrophysiological studies indicate that distal symmetric polyneuropathy is present in 17%-75% of patients with AIDS (8, 72), and may be detected pathologically at autopsy in nearly all cases (34). While the etiology of HIV-associated distal symmetric polyneuropathy is unknown, (61) there are a number of theories proposing mechanisms for the disorder.

远端对称性多神经病

        远端对称性多神经病是HIV感染者最常见的周围神经病变形式。临床和电生理研究表明远端对称性多发性神经病在17%-75%艾滋病病人中出现(8, 72)，而尸体解剖发现在几乎所有的病例均可发现病理学上的改变(34)。虽然有众多学说探讨HIV相关远端对称性多发性神经病发生机制(61)，但病因仍不清楚。

               HIV has been postulated to cause distal symmetric polyneuropathy, based on results of HIV culture from sural nerve homogenates in several patients (25, 38) and of retroviral-like inclusions in myelinated nerve fibers of the sural nerve (7). This theory has been challenged since subsequent studies involving greater numbers of patients have been unable to identify HIV antigens or retroviral-like elements in peripheral nerve (33). Additionally, the absence of CD4 specific receptors in peripheral nerve argues against direct infection with HIV (59). The gp120 glycoprotein of HIV virus may have a role as a co-factor in the pathogenesis of distal symmetric polyneuropathy (5). Cytokines, such as tumor necrosis factor-alpha and interleukin-1 may contribute to the pathogenesis of distal symmetric polyneuropathy, due to interaction with nerve growth factor (75, 35). Cytomegalovirus (CMV) has also been speculated to be a cause of distal symmetric polyneuropathy. Although CMV inclusions or antigens have been found on pathologic examination of peripheral nerve specimens in some AIDS patients (58). It is generally associated with other forms of AIDS-associated peripheral neuropathies, as discussed below, and is an unlikely cause of distal symmetric polyneuropathy.

        HIV可能导致远端对称性多发性神经病，已经从数位病人的腓肠神经匀浆物中培养出HIV(25, 38)，并且在腓肠神经的有髓纤维发现了逆转录病毒样包涵体(7)。但是在后续试验中，大量病例中并未发现周围神经中存在HIV抗原或逆转录病毒样成分，因此上述理论受到质疑(33)。而鉴于周围神经缺乏CD4特异性抗体则进一步挑战了HIV直接感染产生远端对称性多发性神经病的理论(59)。HIV病毒的gp120糖蛋白可能作为一个共同因子参与发病(5)。肿瘤坏死因子和白介素-1等细胞因子可能通过与神经生长因子的相互作用而参与该病的发生(75, 35)。巨细胞病毒(CMV)也被认为是远端对称性多神经病的发病原因之一。虽然在艾滋病人周围神经的病理标本中检测到了巨细胞病毒包涵体或抗原(58)，但通常认为CMV感染会导致其它形式的艾滋病相关的周围神经病（如下），而非远端对称性多发性神经病。

               Early studies reported impaired absorption or low serum levels of vitamin B12 in patients with HIV-associated distal symmetric polyneuropathy, with improvement of symptoms in some patients who received parenteral treatment with supplemental vitamin B12 (40). However most studies have concluded that there is only a rare association of B12 deficiency with distal symmetric polyneuropathy (56, 71). Furthermore, vitamin B12 abnormalities are often seen in HIV infected patients without distal symmetric polyneuropathy (27, 55).

        早期研究曾报道出现HIV相关的远端对称性多发性神经病病人中有吸收不良或低血清维生素B12水平现象，并且当静脉途径补充了维生素B12后患者相应临床症状有所改善(40)。然而，此后大部分试验证明维生素B12缺乏与远端对称性多发性神经病关系甚微(56, 71)，而且，维生素B12异常在感染了HIV却不伴有远端对称性多发性神经病的病人中十分常见(27, 55)。

               Neurotoxins such as vincristine (32), dapsone (50, 1), thalidomide (51, 53), and isoniazid (INH), especially without pyridoxine supplementation (29), may cause distal symmetric polyneuropathy. Most importantly, certain antiretrovirals used in the treatment of HIV infection are neurotoxic. The dideoxynucleoside analogue reverse transcriptase inhibitors (NRTI) didanosine (ddI), zalcitabine (ddC), and stavudine (d4T), are established causes of distal symmetric polyneuropathy (49, 48, 65). The neurotoxicity of antiretrovirals is dose-related, and is increased in patients with advanced immunosuppression. When hydroxyurea is used in combination with ddI or d4T, the incidence of distal symmetric polyneuropathy increases (48). While the mechanism of antiretroviral neurotoxicity is not clearly established, the drugs' effect on mitochondrial DNA (mtDNA) gamma polymerase, as established in vitro and in animal models, may partly explain its effects on peripheral nerves (15). Reports of decreased serum levels of acetyl-carnitine in patients with antiretroviral-associated distal symmetric polyneuropathy provide further support for a mitochondrial mechanism (28) although other studies have found normal carnitine levels in the majority of subjects with HIV neuropathy, irrespective of antiretroviral exposure (66). While a mitochondrial pathogenesis has been speculated to underlie various antiretroviral-related toxicities, including neuropathy and lipodystrophy, further proof in humans is required.

        神经毒性物质如长春新碱(32)、氨苯砜(50, 1)、沙利度胺(51, 53)和异烟肼等，尤其当没有同时补充维生素B6时，将导致远端对称性多发性神经病。而针对HIV的治疗中很多药物都具有神经毒性。已经证明脱氧核苷类似物逆转录酶抑制剂(NRTT) 去羟肌苷(ddI), 扎西他宾(ddC)和司坦夫定(d4T) 可以导致远端对称性多发性神经病(49, 48, 65)。这些药物的神经毒性呈剂量相关，并且对免疫抑制晚期的患者毒性作用越发明显。联合应用羟基脲和ddI或d4T治疗将增加远端对称性多发性神经病的发生率(48)。虽然抗逆转录病毒类药物导致远端对称性多发性神经病具体机制仍不清楚，但在体外和动物模型中发现这些药物可以影响线粒体DNAγ聚合酶，该理论可以从一个侧面解释药物对周围神经的作用(15)。而这类病人中血清乙酰卡尼汀的低水平则进一步支持了线粒体受累学说(28)，虽然也有研究表明不管是否接受了逆转录病毒类药物治疗(66)，有HIV神经病表现的大部分病人血清卡尼汀水平是正常的。因而，虽然通常认为线粒体参与的发病机制（包括神经病和脂质代谢异常）是抗逆转录病毒药物导致远端对称性多发性神经病的原因，但这一理论仍需更多证据支持。

 

Inflammatory Demyelinating Polyneuropathy

               Inflammatory demyelinating polyneuropathy is often the first manifestation of HIV disease, when CD4 counts are relatively high (12). Autoimmune mechanisms are likely responsible for inflammatory demyelinating polyneuropathy in such immunocompetent patients. CMV may cause inflammatory demyelinating polyneuropathy in the late stages of HIV through direct infection of peripheral nerve.(47) While inflammatory demyelinating polyneuropathy appears to be a relatively uncommon complication in HIV infection, its prevalence is unknown.

炎症性脱髓鞘性多神经病

        当CD4细胞计数在相对较高水平时，炎症性脱髓鞘性多发性神经病常常是HIV感染后的首发症状(12)。在这类免疫功能尚正常的病人中，自身免疫是炎症性脱髓鞘性多发性神经病的发病机制。在HIV感染后期巨细胞病毒（CMV）可以通过直接感染周围神经而产生炎症性脱髓鞘性多发性神经病的症状(47)。炎症性脱髓鞘性多发性神经病在HIV感染中相对少见，其发病率尚不明确。

Progressive Polyradiculopathy

               CMV infection is the most common cause of progressive polyradiculopathy in AIDS. As in other CMV-related complications, progressive polyradiculopathy generally occurs in individuals with advanced HIV infection, i.e. CD4 counts < 50 cells/µL, and in conjunction with associated AIDS-defining opportunistic infections (24). In the current era of HAART, in populations that can access these therapies, CMV polyradiculopathy is a rare complication, although its frequency may increase in patients failing antiretroviral regimens.

进展性多神经根病

          巨细胞病毒感染是艾滋病病人中进展性多神经根病最常见的病因。像其它巨细胞病毒相关的并发症一样，进展性多神经根病多发生在HIV感染晚期，比如当CD4细胞计数< 50 个/µl时，并且常与其他艾滋病的机会感染并发(24)。在接受HAART治疗的人群，CMV导致进展性多神经根病变得相对较少，但在没有抗逆转录病毒治疗的人群中发生率会增高。

 

Mononeuropathy Multiplex

               Like inflammatory demyelinating polyneuropathy, mononeuropathy multiplex may occur early in the course of HIV infection, when CD4 counts are greater than 200 cells/µL (64). Similarly, when mononeuropathy multiplex occurs late in the course of HIV infection, CMV is an important cause (58). Diffuse interstitial lymphocytic syndrome, a Sjögren-like disorder associated with HIV, is a rare cause of mononeuropathy multiplex and other peripheral neuropathies (31).

多发性单神经病

        像炎症性脱髓鞘性多神经病一样，多发性单神经病在HIV感染早期如CD4细胞计数大于200 个/µl时即可发生(64)。同样的，在HIV感染晚期，CMV感染是多发性单神经病的常见病因(58)。弥漫性间质性淋巴细胞增多症，即与HIV感染相关的干燥综合征样疾病，是多发性单神经病及其他周围神经病的病因之一(31)。

 

Autonomic Nervous System

               Involvement of the autonomic nervous system has been reported in otherwise asymptomatic HIV-infected patients, although it is more common in advanced HIV disease (74).

自主神经系统

        自主神经症状虽然在HIV感染晚期更常见，但在无症状的HIV感染病人中也有报道(74)。

DIFFERENTIAL DIAGNOSIS

               The various forms of HIV-associated neuropathy can be differentiated primarily on the basis of the distribution of the peripheral nerves involved and the physiology of peripheral nerve dysfunction. These findings are discussed below under the heading Clinical Manifestations.

鉴别诊断

        不同形式的HIV相关神经病基本上可以通过受累周围神经的分布和功能受累情况进行区别。这些表现在下面的临床表现这节中有进一步讨论。

RISK FACTORS

               Diabetes mellitus (14, 18) and alcohol abuse (45) are among the most common causes of distal symmetric polyneuropathy in patients not infected by HIV. These conditions, as well as injection drug use (10) can lead to nutritional deficiencies that may also cause or exacerbate distal symmetric polyneuropathy. One such nutritional disorder, common in patients with AIDS, is wasting syndrome. However, the role of wasting syndrome in the pathogenesis of distal symmetric polyneuropathy is unclear because, while excessive weight loss is common in patients that develop distal symmetric polyneuropathy, it is also commonly present in those without distal symmetric polyneuropathy (68). Metabolic abnormalities, including insulin resistance and lipid abnormalities, are commonly present in HIV infection, and may increase the risk of HIV neuropathy. Some predictors of distal symmetric polyneuropathy are increasing age, prior history of peripheral neuropathy or an AIDS-defining condition, a low CD4 cell count (usually < 100 cells/mm3) and increased HIV viral load (16, 70).

危险因素

        糖尿病(14, 18)和酗酒(45)是非HIV感染人群中发生远端对称性多发性神经病最常见的原因。除此之外还有静脉吸毒(10)可导致营养缺陷，从而引起或加重远端对称性多发性神经病。消耗综合征是艾滋病病人中比较常见的一种营养缺陷性表现，它在远端对称性多发性神经病发生过程中所起的作用尚不明确。体重急剧下降的病人可以出现远端对称性多发性神经病，也可以不出现(68)。代谢性异常，包括胰岛素抵抗及脂质代谢异常，在HIV感染病人中常见，而且可以增加发生HIV相关神经病的风险。此外，还有一些因素可以预测远端对称性多发性神经病的发生，如老龄，既往存在的周围神经病，或艾滋病缺陷状态，低CD4细胞计数（通常< 100 个/ul），及HIV病毒载量的增加(16, 70)。

 

CLINICAL MANIFESTATIONS

Signs and Symptoms

Distal Symmetric Polyneuropathy: The most common initial symptoms of distal symmetric polyneuropathy are numbness and dysesthesias in the distal lower extremities that can ascend to above the ankles. The upper extremities can become involved later in a similar pattern, starting distally. The symptoms are typically symmetrical. Pain associated with distal symmetric polyneuropathy is often described as burning, and can reach an intensity that may cause patients to alter their gait so as to avoid undue pressure on the soles of their feet. Patients may report that even the lightest contact with socks or bed sheets elicits pain. Muscle weakness is usually not a major symptom of distal symmetric polyneuropathy, and if it occurs, appears only late in the disease (78). Symptoms typically have an insidious onset, except when distal symmetric polyneuropathy is related to antiretroviral drugs, in which symptoms may appear more rapidly.

临床表现

症状和体征

        远端对称性多发性神经病：远端对称性多神经病最常见的首发症状是远端肢体的麻木和感觉异常，平面可以发展至踝以上。上肢远端随病情发展也可以相同模式出现远端起始的症状。症状通常是对称出现的，疼痛多呈烧灼样，并且由于疼痛剧烈可以导致病人的步态变化从而尽可能避免脚底承重。病人常诉即使是与袜子或床单的轻微接触也会引发疼痛。肌无力通常不是远端对称性多发性神经病的主要表现，如果发生也多在晚期(78)。症状出现通常较为隐袭，但如果是抗逆转录病毒药物相关的远端对称性多发性神经病，其症状出现则相对较迅速。

               The most common objective findings of distal symmetric polyneuropathy are depressed or absent reflexes in the ankles relative to the knees (50, 51, 41, 76). Occasionally, hyperactive knee reflexes are present together with depressed ankle reflexes when there is concurrent myelopathy and neuropathy (23).

        远端对称性多神经病客观查体中最常见的表现为踝反射减低或消失，而膝反射相对保留较好(50, 51, 41, 76)。有时因为同时存在脊髓病和周围神经病，可以见到膝反射亢进而踝反射减低并存的现象(23)。

               Temperature and pinprick sensation are decreased in a stocking and glove distribution, vibratory thresholds are increased and joint position sensation remains relatively normal (42) (Table 2). Objective muscle weakness is generally limited to intrinsic muscles of the feet (50, 51).

        温度觉和针刺觉减退呈手套袜套样分布，震动觉的阈值会升高但关节位置觉相对正常(42) (表 2)。客观的肌无力通常仅限于足部肌肉(50, 51)。

               The clinical presentation of distal symmetric polyneuropathy is usually distinct enough so that the diagnosis can be made based on history and neurological examination. However, a review of data from AIDS Clinical Trial Group (ACTG) Protocol 175 revealed that even experienced clinical investigators often misdiagnosed distal symmetric polyneuropathy (62). For example, focal peripheral nerve symptoms due to radiculopathy from lumbar disc disease or carpal tunnel syndrome may be mistaken for distal symmetric polyneuropathy. It is important to adhere to strict diagnostic criteria for distal symmetric polyneuropathy in order to arrive at a correct diagnosis. In complicated cases with atypical features, referral to a neurologist experienced in HIV disease should be sought.

        远端对称性多神经病的临床表现通常很特异，通过病史和神经系统检查多可确诊。然而，研究数据显示(ACTG 175)，即使是很有经验的临床工作者也常常误诊远端对称性多发性神经病(62)。比如，将腰间盘疾病或腕管综合征导致的局灶性周围神经症状误诊为远端对称性多发性神经病。因此严格遵循远端对称性多发性神经病的诊断标准从而获得正确的诊断是至关重要的。对有不典型表现的复杂病例，建议请有相关经验的神经科医生会诊。

Inflammatory Demyelinating Polyneuropathy: The clinical features of inflammatory demyelinating polyneuropathy in HIV-infected patients resemble those of HIV-negative patients (73, 21). HIV-associated inflammatory demyelinating polyneuropathy can manifest in acute and chronic forms. Patients with the acute form of inflammatory demyelinating polyneuropathy (AIDP) present with rapidly progressing ascending weakness and mild sensory symptoms. The chronic form is characterized by a slower progression of weakness and may be either monophasic or relapsing. Facial nerve weakness and other cranial nerve findings are frequently present. Neurological examination reveals generalized muscle weakness, mild sensory loss, and areflexia (11).

炎症性脱髓鞘性多神经病：HIV感染病人的炎症性脱髓鞘性多神经病与HIV阴性病人的临床症状相似(73, 21)。HIV相关炎症性脱髓鞘性多发性神经病可以为急性和慢性病程。急性炎症性脱髓鞘性多发性神经病表现为迅速进展的上升性无力和轻微的感觉症状。慢性炎症性脱髓鞘性多发性神经病的病人肌无力进展缓慢，可以发作一次或多次。面神经及其他颅神经问题也经常出现，神经系统查体常发现全身肌无力，轻度的感觉障碍和腱反射缺失(11)。

 

Progressive Polyradiculopathy: Progressive polyradiculopathy presents with lower extremity weakness, pain and rapidly progressive weakness in the cauda equina distribution. Urinary retention or incontinence is frequently present. Patients exhibit flaccid paraparesis and mild sensory loss of the lower extremities.

进展性多神经根病：表现为下肢无力、疼痛和迅速进展的马尾神经支配区的肌无力。尿潴留或尿失禁也经常出现。可以有下肢的轻瘫及轻微的感觉缺失。

Mononeuropathy Multiplex: Characteristic findings in mononeuropathy multiplex include multifocal motor and sensory abnormalities involving cranial nerves, nerve roots or peripheral cutaneous or mixed nerves (46). Typical signs include focal weakness, wrist drop (radial nerve palsy) or foot drop (peroneal neuropathy). The asymmetric, multifocal peripheral and cranial nerve lesions may occur in the setting of fever, cachexia and CSF pleocytosis.

多发性单神经病：多发性单神经病的典型表现包括脑神经、神经根或周围皮神经或混合神经在内的多灶性运动和感觉异常(46)。出现局灶性的无力、腕下垂（桡神经瘫）或足下垂(腓总神经病变)。这种不对称的多发周围神经或颅神经病变可合并发热、恶异质及脑脊液淋巴细胞增多。

 

Autonomic Dysfunction: Autonomic nervous system involvement in AIDS is characterized by orthostatic hypotension (74), syncope, dizziness and in severe cases, cardiorespiratory arrest (22). Variations in heart rate are measured in response to the Valsalva maneuver and deep breathing, while blood pressure changes are noted in relation to sustained handgrip and standing up.

自主神经病：艾滋病的自主神经系统受累主要表现为体位性低血压(74)，晕厥，眩晕，在一些严重病例，可以出现心跳呼吸停止(22)。通过Valsalva运动和深呼吸时可触发心率变化，而持续握手和站立则会出现血压变化。

 

RADIOGRAPHIC MANIFESTATIONS

               Radiologic techniques are generally not part of the current standard of care in the diagnosis and management of most peripheral neuropathies. MRI of the lumbar spine in patients with progressive polyradiculopathy may reveal contrast-enhancement of the cauda equina, due to inflammatory changes associated with CMV infection.

影像学表现

        目前周围神经病的诊断和治疗通常并不借助于影像学检查手段。对于进展性多神经根病的患者，腰椎的核磁共振成像可能发现增强的马尾神经，提示巨细胞病毒感染相关的炎症性改变。

DIAGNOSIS

Approach to Diagnosis

               The major HIV-associated neuropathies are distinguished and characterized by specific signs, symptoms and areas of the body that they affect in Figure 1. The diagnosis of distal symmetric polyneuropathy is predominantly clinical, established with comprehensive history and neurological examination. The diagnosis of distal symmetric polyneuropathy can be confirmed by nerve conduction studies, which show small or absent sural and other sensory nerve action potentials and mild abnormalities in motor nerve conduction studies (41). However, these are rarely necessary outside of the research setting. In patients with inflammatory demyelinating polyneuropathy, nerve conduction studies are necessary and reveal evidence of primary demyelination. In mononeuropathy multiplex and progressive polyradiculopathy, nerve conduction studies and electromyography (EMG) show evidence of axonal pathology in the distribution of the focal peripheral nerve lesions or cauda equina. Electrophysiological studies are helpful in distinguishing the axonal lesions of mononeuropathy multiplex from the primarily demyelinating pathology seen in inflammatory demyelinating polyneuropathy. Autonomic dysfunction may be diagnosed with tilt table studies, measuring change in blood pressure and heart rate, and quantitative sudomotor axon reflex testing (QSART) in the forearm and foot (20).

诊断

诊断方法

        HIV相关的神经病变可以通过特异性的症状、体征及受累部位而确诊(图1)。远端对称性多发性神经病以临床诊断为主，通过全面的病史和神经系统检查而确立。该病的诊断可以由神经传导速度检查所证实，可以发现腓肠神经和其他感觉神经动作电位变小或消失，运动神经传导也可有轻度异常(41)。然而，这些检查目前主要用于科研、临床上并非必需。在炎症性脱髓鞘性多发性神经病的病人，神经传导和肌电图检查是必要的，可以发现脱髓鞘的证据。在多发性单神经病和进展性多神经根病的病人，神经传导和肌电图检查可以发现局部周围神经或马尾神经轴索损伤的证据。电生理检查有助于鉴别多发性单神经病的轴索损伤和炎症性脱髓鞘性多发性周围神经病原发性的髓鞘损伤。自主神经功能障碍可以通过倾斜试验中测量血压和心律变化，以及定量测量前臂和足部的排汗反射试验帮助诊断。

INVASIVE DIAGNOSTIC TESTS

               The level of immunosuppression is an important diagnostic criterion in determining the form and etiology of neuropathy for which a patient is at risk. The next step in the diagnosis of selected patients with peripheral neuropathy involves nerve conduction studies and EMG, as discussed above. The indications for nerve conduction studies, EMG, nerve biopsy and as cerebrospinal fluid analysis is based primarily on the clinician's suspicion of which disease entity may be responsible for the patient's symptoms.

               Sural nerve biopsy in mononeuropathy multiplex may reveal necrotizing arteritis, or primary CMV infection. Cerebrospinal fluid (CSF) analysis is indicated in certain forms of peripheral neuropathy. In inflammatory demyelinating polyneuropathy, the CSF reveals increased protein, as in HIV-negative patients (21). CSF pleocytosis is helpful in distinguishing patients with HIV infection, since CSF is usually acellular in HIV-negative patients with inflammatory demyelinating polyneuropathy. In later stage AIDS patients with inflammatory demyelinating polyneuropathy, mononeuropathy multiplex, or progressive polyradiculopathy, polymerase chain reaction (PCR) assay of CSF may reveal the presence of CMV DNA (19).

有创检查

        在评价病人可能出现的神经病的形式和病因时，免疫抑制的程度是个很重要的诊断指标。正如上面讨论的一样，诊断周围神经病其次步骤是神经传导和肌电图的检查。只有当临床医生怀疑病人可能为上述神经病的时候，进行神经导速度检查、肌电图、神经活检及脑脊液分析才有意义。

        多发性单神经病的腓肠神经活检可能发现坏死性动脉炎，或原发性的巨细胞病毒感染。特定的周围神经病脑脊液分析有不同的意义。炎症性脱髓鞘性多发性神经病脑脊液可以发现与HIV阴性病人相同的蛋白升高(21)。脑脊液淋巴细胞增多可以鉴别HIV感染与否，HIV阴性的炎症性脱髓鞘性多发性神经病病人，脑脊液通常无细胞。而相对晚期的艾滋病病人，当出现炎症性脱髓鞘性多发性神经病、多发性单神经病或进展性多神经根病时，通过脑脊液的聚合酶链式反应(PCR)检测可以发现巨细胞病毒DNA(19).

MANAGEMENT

Distal Symmetric Polyneuropathy

(Please refer to Figure 2: Algorithm for management of HIV-associated peripheral neuropathy)

               Current treatment for distal symmetric polyneuropathy is primarily symptomatic. The first step should be to treat other factors contributing to the neuropathy, including the correction of any metabolic and nutritional abnormalities. In patients receiving a potentially neurotoxic drug, dose reduction or discontinuation of that agent should be considered. However, if the neurotoxic medication is an important part of the antiretroviral regimen, particularly if alternatives are limited, the drug may be continued while other management options are attempted. Once the decision is made to withdraw a neurotoxic antiretroviral, the patient should be informed that they may experience a "coasting period" of 4-8 weeks that is characterized by increased neuropathic symptoms. In some instances, resolution of symptoms of distal symmetric polyneuropathy may take up to 16 weeks (9). It is not clear whether the objective signs of neurotoxic neuropathy are completely reversible, since long term follow-up studies have not been reported.

治疗

远端对称性多神经病

（参照图2：治疗HIV相关周围神经病的原则）

        目前对远端对称性多神经病的治疗都是对症治疗。首先要治疗导致神经病的其他原因，包括纠正代谢和营养异常。对于正在接受有潜在神经毒性药物治疗的病人，应该考虑减量或终止该种药物。然而，如果产生神经毒性的药物是抗逆转录病毒治疗的一部分，尤其当替代药物有限时，需要继续应用该药物的同时寻求其他治疗办法。一旦决定终止某种有神经毒性的抗逆转录病毒药物，应该告知病人可能在4-8周内的神经症状将有所加重。有些病例中远端对称性多神经病将需要经过16周方能停止(9)。目前因为缺乏长期随访研究的报道，并未证实这种客观的神经功能缺损是完全可逆的。

               Analgesics are the most common treatment modality for painful distal symmetric polyneuropathy. Up to 85 percent of patients with AIDS-related pain are undertreated for their pain (13). Guidelines established by the World Health Organization to manage cancer pain (36) may be adapted to treat HIV-associated distal symmetric polyneuropathy, as shown in Figure 3. This approach identifies different levels of pain and uses sequentially increasing doses of analgesic medications, in conjunction with adjuvant therapy, to treat pain. Patients with mild pain may respond sufficiently to non-opioid analgesics, such as acetaminophen and non-steroidal anti-inflammatory agents. With increasing levels of pain, mild opioids such as acetaminophen with codeine and adjuvant agents can be used. Common adjuvant analgesic agents used to treat distal symmetric polyneuropathy include tricyclic antidepressants such as amytriptyline, antiarrhythmics like mexiletine, and anticonvulsants such as lamotrigine and gabapentin (77). However ACTG Protocol 242 revealed that amitriptyline or mexiletine were not superior to placebo in the reduction of pain associated with AIDS-associated distal symmetric polyneuropathy (39). A small placebo-controlled clinical trial revealed preliminary evidence that lamotrigine is effective in the treatment of distal symmetric polyneuropathy (63). Results of large multicentered study of lamotrigine is under analysis. Lidoderm® gel, a 5% preparation of topical lidocaine (17) which was recently approved by the Food and Drug Administration (FDA) for the treatment of post-herpetic neuralgia, is under investigation in the treatment of HIV-associated distal symmetric polyneuropathy (26). While complementary therapies are often used in the treatment of painful distal symmetric polyneuropathy, a controlled trial did not demonstrate that acupuncture was effective in reducing the pain associated with AIDS-associated distal symmetric polyneuropathy (60).

        对远端对称性多发性神经病出现的疼痛常需通过麻醉类药物缓解。约85%的艾滋病相关性疼痛需要止痛治疗(13)。世界卫生组织制定的针对癌症性疼痛的三阶梯疗法可以适用于HIV相关的远端对称性多发性神经病，如图3所示。这个治疗方案根据不同程度的疼痛在辅助治疗的同时给予顺序性递增剂量的麻醉药物控制疼痛。轻度疼痛的病人使用非阿片类药物控制疼痛就足够了，如对乙酰氨基酚和非甾体抗炎药。随着疼痛程度的加重，温和的阿片类药物如加可待因和佐剂的对乙酰氨基酚。在远端对称性多发性神经病的治疗中常用的佐剂包括三环类抗抑郁药，抗心律失常药如美西率，以及抗惊厥药如拉莫三嗪和加巴喷丁(77)。但是ACTG 242研究指出拉莫三嗪和加巴喷丁与对照组相比并不能减轻艾滋病相关的远端对称性多发性神经病(39)。一个小型安慰剂对照临床试验得到的初步结果表明拉莫三嗪对远端对称性多发性神经病有效(63)。关于拉莫三嗪的多中心试验结果尚在分析中。利多卡因凝胶，即5%的用于表面麻醉利多卡因(17)，继被食品和药物管理委员会(FDA)批准为疱疹后神经痛的治疗后，它是否适用于HIV相关的远端对称性多发性神经病治疗正在研究中(26)。对照研究试验并未显示针灸对于缓解艾滋病相关的远端对称性多发性神经病有效(60)。

               Recombinant human nerve growth factor (rhNGF) is a pathogenesis-based therapy that has been studied in the treatment of distal symmetric polyneuropathy. NGF is a trophic factor expressed in the developing and damaged peripheral nervous system (54). In animal studies, NGF prevents the occurrence of chemotherapy-related neuropathy (3). Phase II clinical trials of rhNGF in patients with neuropathy associated with HIV and diabetes mellitus revealed subjective and objective improvement of neuropathic features (44, 4). However, larger phase III studies in diabetes mellitus did not demonstrate efficacy compared to placebo. Future development of NGF for the treatment of peripheral neuropathy is uncertain.

        在远端对称性多发性神经病的治疗中应用重组人神经生长因子（rhNGF）治疗是种针对病因的治疗。NGF为周围神经系统生长和受损过程中表达的营养因子(54)。动物实验表明，NGF可以预防化疗相关的神经病(3)。以HIV和糖尿病已有神经病变的病人为研究对象的rhNGF II期临床试验发现，rhNGF可以从主观和客观上改善受损的神经功能(44, 4)。然而，针对糖尿病病人的规模更大的III期试验却并未证实rhNGF优于安慰剂。因此，NGF未来的应用前景尚不确定。

Inflammatory Demyelinating Polyneuropathy

               The approach to treating an HIV-infected patient with inflammatory demyelinating polyneuropathy does not significantly differ from the therapeutic regimen used in HIV-uninfected patients. Case studies have shown that corticosteroids may be effective in the treatment of inflammatory demyelinating polyneuropathy associated with HIV infection (21). Although prednisone may effectively treat the chronic form of inflammatory demyelinating polyneuropathy (CIDP), discontinuation of treatment may result in relapse of the disease. While corticosteroids may be safely used in HIV-infected patients and other severely immunocompromised individuals, corticosteroid use could further aggravate immunosuppression, and place the patient at increased risk for opportunistic infections such as Pneumocystis carinii pneumonia. HIV-infected patients with inflammatory demyelinating polyneuropathy have also responded to treatment with plasmapheresis or intravenous immunoglobulin (IVIg) (21). Plasmapheresis generally requires 5 to 6 treatment sessions over 10 - 14 days. Because of the large fluid shifts and greater technical difficulty associated with intravenous access, patients are often hospitalized for this treatment. Intravenous immunoglobulin may be given on an outpatient basis after a patient has safely received this therapy without complications. In HIV-infected individuals, high dose intravenous immunoglobulin may be given as 2 gm/kg dose divided over two to five days, and may be repeated at 4 - 6 week intervals.

炎症性脱髓鞘性多发性神经病

        治疗HIV感染病人的炎症性脱髓鞘性多发性神经病与非HIV感染病人的方案相似。病例研究表明激素可能对HIV感染病人的炎症性脱髓鞘性多发性神经病有效(21)。泼尼松可以治疗慢性炎症性脱髓鞘性多发性神经病，但停用后可能出现病情复发。虽然泼尼松治疗HIV感染的病人及其他有严重免疫抑制的情况的个体较为安全，但是它同时可能进一步加重免疫抑制状态，并且增加病人机会性感染如卡氏肺孢子虫肺炎的可能。血浆置换或静脉输注人免疫球蛋白治疗对HIV感染病人的炎症性脱髓鞘性多发性神经病也可有疗效(21)。血浆置换通常需要5-6次治疗，约10-14天。由于涉及大量输液等操作，通常需要住院完成治疗。而如果病人曾经接受过免疫球蛋白治疗而无合并症，则可适用于非住院病人。HIV感染的个体，可以给予总量2gm/kg的大剂量静脉免疫球蛋白治疗，分2-5天完成，间隔4-6周后可重复治疗。

 

Progressive Polyradiculopathy

               An important aspect of treatment of progressive polyradiculopathy is its early diagnosis in order to minimize or prevent irreversible nerve root necrosis. In patients with advanced immunosuppression, especially when PCR of CSF reveals CMV DNA, therapy is targeted at CMV infection with medications including ganciclovir, foscarnet, or cidofovir singly or in combination (2). A prospective trial of the treatment of CMV-associated neurologic diseases in HIV-infected individuals (ACTG Protocol 305) was suspended due to the low number of individuals with clinical CMV infection in the current era of HAART.

进展性多神经根病

        进展性多神经根病的治疗中较为重要的是早诊断从而减小或防止不可逆性神经根坏死。当病人免疫抑制较严重时，尤其是脑脊液中PCR发现巨细胞DNA，治疗上主要应用针对巨细胞病毒感染包括无环鸟苷或膦甲酸，或西多福韦单药或联合治疗(2)。关于HIV感染个体巨细胞病毒相关神经病治疗的前瞻性试验(ACTG 305研究)由于HAART领域临床CMV感染例数过少而被迫中止。

 

Mononeuropathy Multiplex

               In the early form of HIV-associated mononeuropathy multiplex, the peripheral nerve lesions often spontaneously remit within months (69). When patients have incomplete recovery, immunomodulatory therapy may be used (43). As in the treatment of inflammatory demyelinating polyneuropathy, corticosteroids, plasmapheresis and high-dose intravenous immunoglobulins are options. Roullet et al. demonstrated improvement in 14 of 15 patients treated with either ganciclovir or foscarnet in late-stage HIV patients, in whom mononeuropathy multiplex was associated with CMV infection (57).

多发性单神经病

        在HIV相关的多发性单神经病的早期，周围神经病变在数月内常可自发缓解(69)。当病人不能完全康复时，可以开始免疫调节治疗(43)。与炎症性脱髓鞘性多发性神经病治疗相似，类固醇激素、血浆置换和大剂量免疫球蛋白治疗均可选择。Roullet等报道应用无环鸟苷或膦甲酸治疗晚期HIV病人15例中14例有效，这些病人的多发单神经病与巨细胞病毒感染相关(57)。

 

Autonomic Nervous System

               Abnormalities in the autonomic nervous system are treated with specific targeting of the dysfunction identified. Life-threatening cardiac dysrhythmias, sphincter dysfunction and syncope can all be effectively treated. Therapeutic options include supportive care with fluid and electrolyte management, discontinuation of drugs that may cause autonomic impairment, and the use of antiarrhythmic agents and fludrocortisone (30).

自主神经病

        自主神经系统异常的病人多根据受累部位给予特异的靶向性治疗。威胁生命的心律失常，括约肌功能障碍，及晕厥等都可以有良好的治疗效果。治疗的选择包括补充水和电解质的支持疗法，停止可能引起自主神经功能异常的药物，应用抗心律失常药物及服用氟氢可的松(30)。

 

Tables and Figures

Table 1.  Major HIV-Associated Neuromuscular Syndromes

Table 2.  Neurologic Signs for DSP Diagnosis

Figure 1. The four major HIV-associated  neuropathies can be distinguished by signs, symptoms and the areas of  the body that they affect. Adapted from Wulff, Simpson, "Neuromuscular Complications of HIV-1 Infection" Seminary in Neurology 1999; 19(2):157-164.

Figure 2.  Algorithm for management of HIV-associated peripheral neuropathy. 

 

 

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