HIV-Associated Neuromuscular Syndromes

Chinese Version

Derek J.R.W. Williams, RPA-C,, Nilay R. Shah, M.D., David M. Simpson, M.D.

 

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.

               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).

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.

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.

               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.

               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).

               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.

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.

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.

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).

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).

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.

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).

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.

               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).

               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).

               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.

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).

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.

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.

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.

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.

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).

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).

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.

               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).

               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.

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.

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.

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).

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).

 

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. 

Figure 3.  The World Health Organization three-step analgesic ladder

 

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