Updated March 2004

Key to Abbreviated Terms Within Guidelines

I. INTRODUCTION

The purpose of these guidelines is to help the medical provider correctly diagnose the symptoms and signs of neurologic complications that may be found in HIV-infected patients. Detection is essential for proper management of these disorders, and appropriate referral to a specialist should be made when necessary. Appendix A provides a summary of neuromuscular complications of HIV. Opportunistic infections involving the central nervous system are covered in Infectious Diseases Associated With HIV Infection.

With high morbidity and mortality rates, neurologic disorders are among the most frequent and devastating complications of HIV infection. Frequently, neurologic disorders negatively impact patients’ quality of life and their adherence to medical treatment.

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II. HIV-ASSOCIATED DEMENTIA

Recommendations:

When patients with HAD present with accompanying depression, mania, psychosis, behavioral disturbance, or substance use, primary care clinicians should refer for psychiatric consultation to assist in psychopharmacologic treatment and management.

Clinicians should use standardized tools to stage HAD.

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A. Presentation

Symptoms of HAD may be subtle, especially in the early stages. Symptoms are highly variable, ranging from subtle cognitive and motor impairments to profound dementia (see Table 1).

The effects of drug or alcohol intoxication and withdrawal in chronic substance users can mimic HIV dementia. A careful substance use history, possibly supplemented with urine drug screening, should be obtained.

B. Diagnosis

Recommendations:

The following tests should be performed to exclude other possible etiologies of cognitive dysfunction:

• vitamin B₁₂ and folate levels
• serum syphilis screen (rapid plasma reagin or venereal disease research laboratory test)
• serum cryptococcal antigen
• thyroid function tests

Cerebrospinal fluid testing to exclude other central nervous system infections that may cause cognitive dysfunction, such as neurosyphilis, cytomegalovirus encephalitis, tuberculous meningitis, and cryptococcal meningitis, should be performed when clinically indicated.

Clinicians should obtain neuroimaging in patients with cognitive dysfunction.

Clinicians should refer patients to a neuropsychologist for detailed neuropsychological evaluation when the presentation is not typical and differentiation from pseudodementia secondary to depression is necessary.

There are no pathognomonic tests diagnostic of HIV dementia, because it is a diagnosis of exclusion. Investigations are performed to exclude other treatable causes of cognitive dysfunction and to add support to the diagnosis (see Table 2).

1. Neurologic Examination and Testing

In early stages of HAD, findings from the neurological examination are often normal or, if abnormalities are present, they are few and subtle. Diffuse hyperreflexia may develop. Frontal release signs, particularly glabellar tap and snout reflex, may be present in approximately one fourth of patients.¹

When early-stage HAD is suspected, the usual screening tests used for cognitive disorders are of limited value, including abbreviated forms of the mental status examination. Although not effective for identifying early-stage cognitive dysfunction, the following tests have been used to identify and stage HAD:

• HIV Dementia Scale: screens for the memory deficits and psychomotor slowing that is typical of HIV dementia; takes approximately 5 minutes to administer
• Modified HIV Dementia Scale: designed specifically for use by non-neurologists

Adaptations of the Trail making A and B subtests of the Halstead-Reitan neuropsychological battery have been used to track a patient’s progress; however, the results should be interpreted by a neuropsychologist. The Memorial Sloan Kettering (MSK) scale is used for assessing severity (see Appendix B); it combines the functional impact of both cerebral (dementia) and spinal cord dysfunction (myelopathy). The two entities can be separated and staged independently.

2. Neuropsychological Testing

Neuropsychological tests may be an important adjunct to the neurological evaluation, especially in providing support for the diagnosis and following the course and response to treatment of HAD. This testing may include tests for recall memory, psychomotor speed, attention, recognition memory and language. The neuropsychological tests useful in confirming the diagnosis of HAD are those that assess psychomotor speed and verbal and non-verbal learning. The micro-neurologic version of the AIDS Clinical Trials Group neurologic assessment consists of four quantitative components: 1) timed gait, 2) finger tapping in the dominant hand, 3) grooved pegboard, and 4) digit symbol. These tests can be used in a clinical or research setting to serially assess functions characteristically affected in HAD.

3. Blood Tests

The following blood tests should be obtained: vitamin B₁₂ and folate levels, serum syphilis screen [rapid plasma reagin (RPR) or venereal disease research laboratory test (VDRL)], serum cryptococcal antigen, and thyroid function tests.

4. Lumbar Puncture

CSF findings are non-specific and include mildly elevated protein and mild lymphocytic pleocytosis. CSF testing to exclude other CNS infections that may cause cognitive dysfunction, such as neurosyphilis, cytomegalovirus (CMV) encephalitis, tuberculous meningitis, and cryptococcal meningitis, should be performed. Early studies,^2-4 particularly in the pre-HAART era, indicate that CSF HIV viral load correlates with severity of cognitive dysfunction, particularly in patients whose CD4 count is <200 cells/mm³. In patients with CD4 counts >200 cells/mm³, the diagnostic utility of HIV viral load is less clear, because CSF viral load levels generally parallel those in plasma, with CSF approximately 1 to 2 logs less than plasma.¹ In one study, elevated HIV viral load in the CSF of >200 copies/mL predicted subsequent progression to neuropsychologic impairment.⁵ Other sources, however, suggest that CSF HIV viral load may no longer be a reliable marker of CNS neurocognitive dysfunction. In addition, CSF HIV viral load may increase in the presence of other CNS infections, such as toxoplasmosis or cryptococcal meningitis.¹ At this time, measurement of viral load in CSF is predominantly a research tool, rather than routine standard of care.

5. Neuroimaging Studies

a. Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) is preferable to computed tomography (CT) because of higher spatial and contrast resolution, and its multiplanar capacity. MRI better delineates tissue compartments and neuroanatomic structures. Atrophy and parenchymal lesions are better depicted in terms of specific affected brain structures (cortical vs. subcortical, gray matter vs. white matter, lobar vs. generalized). In addition, MRI does not involve ionizing radiation.

The principal MRI finding in HIV dementia, apart from atrophy, consists of symmetrical white matter hyperintensity on T2-weighted and proton-density and fluid attenuated inversion recovery (FLAIR) images, without mass effect or enhancement. There is an association between the severity of HIV dementia and the degree of cerebral atrophy, as quantified by MRI. Non-contrast and contrast-enhanced MRI study should be performed. See Appendix C for sample radiologic images.

b. Computed Tomography

Brain CT continues to play an important role in evaluating HIV-infected patients with cognitive dysfunction because of its convenience, widespread availability, and lower cost in comparison to MRI. Both non-contrast and contrast-enhanced study should be performed to screen for the presence of opportunistic infections, neoplasms, and other focal brain lesions.

The most frequent CT finding in HIV-infected patients is cerebral atrophy. Cerebral atrophy and ventricular enlargement correlate with the degree of immunosuppression and stage of infection. The presence of atrophy, however, does not necessarily equate with the presence of dementia because atrophy may also occur in non-demented HIV-infected individuals. The second most frequent finding on CT scan is the presence of low-attenuation, bilateral, symmetrical, predominantly subcortical parenchymal lesions, without mass effect or enhancement.

c. Magnetic Resonance Spectroscopy and Positron Emission Tomography

Magnetic resonance spectroscopy (MRS) has increasing utility in evaluation of HIV dementia. Three primary metabolic markers in MRS have been investigated in HIV dementia:

• N-acetyl aspartate (NAA)—indicator of neuronal function
• Myoinositol—a glial cell product
• Choline—found in high concentrations in glial cells and correlates with cell membrane injury, turnover, and glial cell activation

NAA is reduced in HIV dementia, whereas myoinositol and choline levels are elevated. These MRS patterns correlate with the degree and severity of cognitive dysfunction in HIV dementia. This modality may not be readily available and is presently used primarily in research settings.

Positron emission tomography (PET) has been studied in small series of HIV-infected individuals with dementia. This modality has shown hypermetabolism in subcortical areas in early HIV dementia, and progression to hypometabolism in both cortical and subcortical areas in late stages.⁶ These abnormalities have been shown to normalize with administration of ARV therapy.⁷ Like MRS, this modality is primarily a research tool and may not be readily available.

C. Treatment

Recommendations:

When patients receiving HAART present with symptoms of HAD, clinicians should assess the efficacy of the HAART regimen.

When patients not receiving HAART present with symptoms of HAD, clinicians should initiate HAART (see Antiretroviral Therapy).

Two types of treatment may be considered in the management of HAD: ARV therapy and pharmacologic treatment of symptoms. Pharmacologic agents that are aimed at secondary mechanisms of HAD are currently under research.

1. Antiretroviral Therapy

Early, small studies have shown that HAART that includes drugs that penetrate the blood-brain barrier, particularly zidovudine, lead to improvement and, at the very least, to a partial return of functioning in patients previously diagnosed with HAD. However, more recent data suggest that HAART that achieves viral suppression, independently of its theoretical ability to efficiently cross the blood-brain barrier, improves patients’ cognitive performance.⁸ Therefore, it is probable that if viral load is suppressed systemically, it will be suppressed in the CNS. Accordingly, the prevailing goal may be to use an ARV regimen that is most effective in viral suppression, rather than a regimen that is superior only in crossing the blood-brain barrier. Future research may help elucidate the optimal ARV regimens for treatment of HAD.

2. Pharmacologic Treatment of Symptoms

Patients with HAD may also benefit from psychotropic medications used to target specific symptoms, such as psychomotor slowing, agitation, depression, and psychosis. Such therapies are best administered under the guidance of a psychiatrist who is experienced with HIV infection, particularly because many of these agents have pharmacologic interactions with ARV drugs. Neuroprotective agents, such as memantine, nimodipine, lexipafant, and selegiline, are being studied in clinical research trials for potential use as adjunctive medications for HIV dementia.

The reader should refer to the New York State Department of Health AIDS Institute’s Mental Health Care for People With HIV Infection: HIV Clinical Guidelines for the Primary Care Practitioner for further information on managing patients with HAD.

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III. HIV-ASSOCIATED MYELOPATHY

A. Presentation

HIV-associated myelopathy is a major source of morbidity in HIV-infected patients. It is sometimes termed vacuolar myelopathy, based on pathological findings within the spinal cord. Symptoms of HIV-associated myelopathy usually develop insidiously over months. Urinary urgency and frequency are often the first symptoms. Erectile dysfunction is a common early symptom in men. There are many other reasons for impotence in the setting of AIDS, but HIV-associated myelopathy should be a consideration. Lower extremity weakness may develop in the setting of myelopathy, although lower extremity stiffness (spasticity) may be a more prominent symptom than weakness, resulting in gait difficulty. Patients may also have numbness and paresthesias in the lower extremities that are rarely severe. Involvement of the arms is usually minimal at presentation because myelopathy typically involves the thoracic spinal cord initially.

Neurological examination may reveal a combination of the following findings:

• Lower extremity weakness (paraparesis), spasticity (increased tone), or both
• Increased thresholds of vibration and proprioception, with a positive Romberg sign
• Pain and temperature sensation are usually preserved, unless there is superimposed peripheral neuropathy
• Hyperactive deep tendon reflexes, particularly the patellar, with bilateral ankle clonus
• Extensor plantar responses (Babinski sign)
• Scissoring, stiff gait with impaired tandem
• In advanced cases, patients may be wheelchair-bound and unable to ambulate

The presence of a discrete sensory level and spine tenderness or back pain are evidence against the diagnosis of HIV-associated myelopathy and should lead to investigation of alternative causes of spinal cord disease.

B. Diagnosis

Recommendations:

In the differential diagnosis for HIV-associated myelopathy, clinicians should exclude other treatable conditions that could cause spinal cord disease, particularly compressive lesions and other infectious or neoplastic etiologies.

Clinicians should obtain the following blood tests in patients with suspected HIV-associated myelopathy:

• serum RPR or VDRL
• toxoplasma antibodies
• cryptococcal antigen
• vitamin B₁₂ level
• HTLV I/II antibodies

Clinicians should obtain neuroimaging studies of the spinal cord in all patients who present with suspected spinal cord disease.

The diagnosis of HIV-associated myelopathy is largely clinical and is based on the slow progression of symptoms, typical findings on neurological examination, and exclusion of other causes of spinal cord disease. The clinician may obtain CSF analysis and electrophysiologic studies to evaluate suspected spinal cord disease.

The diagnosis of HIV-associated myelopathy is one of exclusion. The differential diagnosis of HIV-associated myelopathy is extensive and includes the following infections of the spinal cord:

• human T-lymphotropic virus type I or II (HTLV I/II)
• cytomegalovirus (CMV)
• herpes simplex virus type 2
• toxoplasmosis
• tuberculosis
• syphilis
• metabolic (B₁₂ deficiency)
• neoplastic diseases (particularly lymphoma)
• degenerative disease (cervical spondylosis with cervical cord compression)

1. Blood Tests

The following blood tests should be obtained in all patients: serum RPR or VDRL, serum toxoplasma antibodies, serum cryptococcal antigen, vitamin B₁₂ level, and HTLV I/II antibodies.

2. Lumbar Puncture

CSF studies often reveal nonspecific findings in the setting of HIV infection, such as mild pleocytosis (5-10 cells/mm³) and mild protein elevation. CSF pleocytosis >30 cells/mL should raise suspicion of other causes and should lead to additional CSF studies.

3. Neuroimaging Studies

Imaging of the spine is important to exclude extradural compressive or intramedullary lesions causing myelopathy. MRI of the spine, with and without contrast, is preferable. MRI findings in HIV-associated myelopathy may be normal or nonspecific, including mild atrophy of the spinal cord or areas of increased signal on T2-weighted images.

4. Electrophysiologic Studies

Somatosensory evoked potentials (SSEP) provide an objective physiological measure of spinal cord dysfunction, particularly in cases in which there is superimposed peripheral neuropathy. Prolongation of the tibial nerve central conduction time correlates with the clinical diagnosis of myelopathy. SSEP can be used to diagnose subclinical or asymptomatic myelopathy and to follow disease progression. The combination of SSEP with NCV/ EMG studies may separate myelopathic from neuropathic components of disease.

C. Treatment

Recommendation:

Clinicians should prescribe symptomatic therapy to patients with HIV-associated myelopathy.

No definitive treatment is available for HIV-associated myelopathy. Symptomatic treatment is indicated for patients with spasticity and urinary dysfunction.

The efficacy of HAART on this disorder is unknown. One study showed a beneficial response to zidovudine (10 mg/kg),⁹ whereas another reported no benefit from zidovudine.¹⁰ The use of different combinations of ARV agents was ineffective in preventing the onset of myelopathy.¹¹ Supplementation with vitamin B₁₂ is ineffective in improving the symptoms or delaying the progression of this condition.¹²

Animal and human data indicate that HIV-associated myelopathy may be caused by metabolic mechanisms, particularly methionine deficiency. A pilot study using high doses of oral L-methionine led to improvement in clinical and electrophysiologic features of the disease in an open-label clinical trial.¹³ A double-blind, placebo-controlled study using methionine to treat AIDS-associated myelopathy has completed accrual with results forthcoming.

Uncontrolled clinical experience has not shown any benefit from corticosteroids and intravenous immunoglobulin (IVIG).¹⁴ An open-label pilot trial of IVIg in the treatment of this condition is underway.

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IV. PERIPHERAL NEUROPATHY

Figure 1 provides an algorithm for the management of peripheral neuropathy in an HIV-infected patient.

A. Distal Symmetric Polyneuropathy

1. Presentation

Paresthesias, dysesthesias, and/or numbness occur symmetrically in both feet, later ascending to the ankles and bilateral forelegs, and may, in advanced cases, involve fingers and hands; the distribution is termed as “stocking and glove.” Distal pain, often described as sharp, stabbing or burning, may become excruciating. A number of scales are available to grade pain intensity, including the Visual Analog Scale (VAS) and Gracely pain scale. Deep tendon reflexes are reduced or absent symmetrically in the lower extremities; ankle jerks are usually absent or reduced bilaterally. Pinprick, temperature, and vibration sensation are diminished in a stocking and glove distribution. Joint position sense (proprioception) loss and significant objective muscle weakness are atypical in distal symmetric polyneuropathy (DSP), and its presence should suggest either a central type of sensory loss (e.g., myelopathy) or another type of neuropathy (i.e., inflammatory demyelinating polyneuropathy, mononeuropathy multiplex).

DSP may be caused or exacerbated by concomitant diabetes mellitus, alcoholism, or the use of dideoxynucleoside class of ARV agents (didanosine, zalcitabine, stavudine). ARV-associated DSP is clinically indistinguishable from HIV-associated DSP, except in its response to ARV dose reduction or drug withdrawal.

2. Diagnosis

Recommendations:

Clinicians should obtain blood tests to screen for diabetes and vitamin B₁₂ deficiency in the evaluation of a patient with suspected distal symmetric polyneuropathy.

Clinicians should refer patients with more complex suspected or proven peripheral neuropathy syndromes to a neurologist to assist with the diagnosis and management.

Figure 1: Algorithm for Management of Peripheral Neuropathy in an HIV-Infected Individual

* The clinician should consider obtaining EMG/NCV studies. † The clinician should consider obtaining muscle and nerve biopsies.

a. Blood Tests

Blood studies should be performed to exclude other causes of DSP (e.g., glucose, B₁₂). Other laboratory evaluation is usually not necessary.

b. Electrophysiological Studies

Nerve conduction studies (NCS) and electromyography (EMG) are usually not necessary in the clinical diagnosis of typical DSP. NCS reveal absence or reduction of sural nerve amplitudes. Less commonly, reduced sensory or motor amplitude of the median or ulnar nerves are found. EMG may show active or chronic denervation with reinnervation in distal muscles of the lower extremities. NCVs and EMG studies are of great value in the diagnosis of HIV-associated non-DSP neuropathies.

c. Nerve Biopsy

Nerve biopsy is rarely necessary in DSP, except in atypical cases. Sural nerve biopsy usually reveals degeneration of myelinated and unmyelinated axons, with associated sparse to moderate inflammatory infiltrates.

d. Skin Biopsy

Skin biopsy with epidermal nerve fiber density studies is currently used in the research setting to provide a minimally invasive marker of peripheral nerve integrity.

3. Treatment and Management

Recommendations:

Clinicians should provide pain control for distal symmetric polyneuropathy, which is achieved by a careful, systematic, and stepwise evaluation of the patient’s response to available analgesic agents (see Figure 2).

Clinicians should initiate mild analgesics, including acetaminophen, aspirin, or other non-steroidal anti-inflammatory agents, with or without adjunctive agents (e.g., anticonvulsants, antidepressants, topical agents), as the first line of therapy for pain control.

Clinicians should use narcotic analgesia when pain control is not achieved by first line and adjunctive measures.

Clinicians should refer patients to a pain management specialist when adequate pain control cannot be achieved.

In cases of ARV therapy-associated DSP, the decision to discontinue a neurotoxic ARV drug is not automatic and should only be made after carefully weighing the risks and benefits of virologic control versus neuropathic symptom control.

In addition to mild analgesics, adjunctive analgesic medications may also be used for pain control. These include tricyclic antidepressants, such as amitriptyline or desipramine, and anticonvulsants, such as gabapentin and lamotrigine. Amitriptyline is generally initiated at 10 to 25 mg at night, and slowly titrated to 100 to 150 mg/day. Lamotrigine is initiated at 25 mg every other day and titrated to 200 mg bid over 6 to 8 weeks to avoid rash. Gabapentin is initiated at 300 mg tid and titrated to 2400 to 3600 mg/day. Topical anesthetics may also be used, such as lidocaine patch or gel or capsaicin. Narcotic analgesics are often necessary to control pain in severe cases. The WHO analgesic treatment algorithm for cancer pain (see Figure 2) can be used as a guide to the treatment of HIV-associated peripheral neuropathy.

The efficacy of various modalities has been studied in randomized clinical trials. Treatment with Peptide T, amitriptyline, mexiletine, and acupuncture did not significantly improve pain versus placebo.^15-18 Mexiletine was associated with a higher frequency of dose-limiting adverse advents. Patients who received lamotrigine experienced less average daily pain and a lesser degree of worst pain as measured by a modified Gracely pain scale.¹⁹ Patients who received nerve growth factor (2 doses) experienced improvement of pain as measured by the Gracely pain scale and clinician and patient assessment of global improvement, although it did not show evidence of nerve regeneration.²⁰

Successful HAART may have a beneficial effect on non-ARV-associated DSP. A pilot study has shown improvement in quantitative thermal testing results in patients followed up prospectively after initiation of HAART.²¹ In cases of ARV-associated DSP, ARV dose reduction or substitution of a less neurotoxic ARV, without sacrificing virologic control, may be sufficient to alleviate symptoms. In cases in which alternative non-neurotoxic ARV agents are not available due to resistance or toxicity, and substitution is not possible without jeopardizing virologic control, symptomatic analgesic treatment while continuing the neurotoxic ARV may be appropriate.

Figure 2: The WHO Analgesic Treatment Algorithm

Used with permission from J Pain Symptom Manage, Vol 6, Grond S, Zech D, Schug SA, et al, Validation of World Health Organization guidelines for cancer pain relief during the last days and hours of life, pp 411-422, 1991.22

B. Inflammatory Demyelinating Polyneuropathy

1. Presentation

Acute inflammatory demyelinating polyneuropathy (IDP) often occurs early in the course of HIV infection, particularly during seroconversion. It causes rapidly progressive weakness, with minor sensory symptoms and generalized areflexia. Chronic IDP symptoms and signs are similar to acute IDP, except that chronic IDP is more slowly progressive (>6 weeks), has a more protracted course, and may be monophasic or relapsing. There have been recent reports of IDP associated with lactic acidosis or symptomatic hyperlactatemia, leading to death in several patients. Most of these patients were receiving nucleoside analogues, particularly stavudine.

2. Diagnosis

Recommendation:

Clinicians should perform lumbar puncture and EMG/NCV in patients with suspected IDP.

a. Blood Studies

Blood studies should include serum lactate and bicarbonate to screen for hyperlactatemia.

b. Lumbar Puncture

Lumbar puncture generally reveals a markedly elevated CSF protein level in IDP. Lymphocytic pleocytosis (10-50 cells/mm³) is more marked in HIV-infected patients with acute IDP than in non-infected patients with acute IDP. In patients with CD4 counts <100 cells/mm³, CSF should be assayed for CMV by polymerase chain reaction (PCR).

c. Electrophysiologic Studies

EMG/NCVs show markedly decreased motor and sensory nerve conduction velocity, conduction block, prolonged distal latencies, reduced compound muscle action potential (CMAP) amplitudes, reduced sensory nerve action potential (SNAP) amplitudes, and reduced motor unit recruitment, proportional to the degree of weakness. These findings are consistent with demyelination.

3. Treatment

Recommendations:

Clinicians should initiate immunomodulating therapy, such as corticosteroids, high-dose intravenous immunoglobulin (2.0 gm/kg divided over 2-5 days), or plasmapheresis (4-5 exchanges), for patients with HIV-associated IDP.

When IDP is associated with symptomatic hyperlactatemia or lactic acidosis, clinicians should immediately discontinue ARV therapy, especially NRTIs.

In advanced HIV infection, anti-CMV therapy may be indicated in collaboration with the appropriate specialist.

C. Mononeuropathy Multiplex

1. Presentation

Mononeuropathy multiplex is relatively rare in comparison to other neuropathies associated with HIV infection. Mononeuropathy multiplex (MM) is characterized clinically by multifocal motor and sensory nerve abnormalities. These abnormalities have an asymmetric distribution and may include involvement of cutaneous nerves, mixed nerves, nerve roots, and cranial nerves. Examples are sensory abnormalities in patchy areas of the trunk and extremities, foot drop, and facial palsy. Tendon reflexes are preserved in uninvolved areas. Extensive nerve involvement may rapidly progress to include multiple cranial nerves. The occurrence of MM is bimodal. The first peak occurs early in the course of HIV infection, when CD4 cell counts are >200 cells/mm³, with a limited distribution of deficits. The second peak occurs in advanced immunosuppression, with CD4 counts of 50 to 100 cells/mm³ or less.

2. Diagnosis

Recommendation:

Clinicians should establish the diagnosis and etiology of mononeuritis multiplex based on neurologic consultation, electrophysiologic studies, and/or nerve biopsy.

a. Lumbar Puncture

CSF is usually abnormal in HIV-associated MM. However, findings are nonspecific and include elevated protein and mild mononuclear pleocytosis. In MM occurring in late-stage AIDS, CSF PCR for CMV determination should be obtained.

b. Electrophysiologic Studies

Electrophysiologic studies are helpful in patients with MM, and generally show asymmetric reduction in amplitudes of CMAP and SNAP, with mild reduction in NCV. EMG shows evidence for denervation and neuropathic motor unit recruitment patterns.

c. Nerve Biopsy

Nerve biopsy findings range from axonal degeneration with or without endoneural and epineural perivascular inflammatory infiltrates in early-onset MM, to numerous polymorphonuclear infiltrates with mixed axonal and demyelinative lesions in late-onset MM. Vasculitis has been noted in several cases.²³ In some cases of late-onset MM, CMV inclusions are detected in peripheral nerve.

3. Treatment

Recommendations:

Clinicians should observe patients with early-onset MM because it may spontaneously resolve within weeks to several months.

Clinicians should initiate HAART in patients with late-onset MM occurring in advanced HIV infection.

Early MM may resolve spontaneously within weeks to several months. In cases of delayed or incomplete recovery, corticosteroids, plasmapheresis, or intravenous immunoglobulins may be indicated.

D. Progressive Polyradiculopathy

1. Presentation

Progressive polyradiculopathy (PP) occurs most commonly in advanced HIV infection when CD4 cell counts decrease to <50 cells/mm³. PP is characterized clinically by the rapid onset of radiating pain and paresthesias in a cauda equina distribution (peringuinal and lower extremities), followed by signs of progressive involvement of multiple nerve roots, usually lumbar and sacral. Clinical signs include flaccid paraparesis, sphincter dysfunction (e.g., urinary retention), and lower extremity areflexia. With the advent of HAART, the incidence of PP, particularly PP due to CMV, has markedly decreased.

2. Diagnosis

Recommendation:

Clinicians should establish the diagnosis of progressive polyradiculopathy based on neurologic consultation, spinal MRI, CSF analysis, and electrophysiologic studies.

a. Neuroimaging Studies

Contrast-enhanced MRI of the lumbar spine may reveal increased T2 signal of cauda equina and enhanced, thickened, and clumped lumbosacral roots.

b. Lumbar Puncture

CSF should be assayed for CMV PCR, varicella-zoster virus (VZV) PCR, VDRL, and cytology. In CMV polyradiculopathy, lumbar puncture generally reveals marked polymorphonuclear pleocytosis (mean, 651 ± 1053 X 10⁶ cells/mm³), elevated protein (mean, 2.28 ± 1.78 g/L), and hypoglycorrhachia (mean CSF:plasma glucose ratio, 0.48 ± 0.17). For most of the other etiologies mentioned, CSF reveals predominantly lymphocytic pleocytosis.

c. CMV Polymerase Chain Reaction

CMV is the major cause of PP in patients with HIV/AIDS, although less common causes include neurosyphilis and lymphomatous meningitis. CMV detection by PCR analysis of CSF has a sensitivity of 92% and specificity of 94% in CMV-associated PP.^24-26

d. Electrophysiologic Studies

EMG studies show reduced number of motor units and abnormal spontaneous activity in weak muscles. Nerve conduction velocities are only mildly abnormal.

3. Treatment

Recommendations:

Clinicians should promptly initiate anti-CMV therapy for improvement of symptoms and/or stabilization of signs in progressive polyradiculopathy secondary to CMV.

Clinicians should initiate or optimize HAART in patients with progressive polyradiculopathy.

PP secondary to CMV has 100% mortality when effective antiviral treatment is not given.

Combination therapy with ganciclovir and foscarnet may provide efficacy, but no controlled data are available to support this. The low incidence of CMV PP has precluded accrual of patients for a controlled trial.

Therapy appropriate for specific etiologies (such as penicillin for syphilitic radiculopathy, acyclovir for zoster radiculitis, radiotherapy and/or chemotherapy for lymphomatous radiculitis) should be given once there is clear evidence for it.

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V. MYOPATHY

A. Presentation

HIV-associated myopathy presents with slowly progressive weakness of proximal muscles. Typical complaints include difficulty in lifting the arms above the head, standing up from a seated position, and climbing stairs. Myalgia (muscle aches, pain) is common and may be present in 25% to 50% of cases, although this is a non-specific symptom in HIV infection.²⁷ Neurological examination reveals symmetric weakness of proximal muscles of the extremities and neck flexors. Deep tendon reflexes are intact unless there is superimposed peripheral neuropathy or myelopathy.

B. Diagnosis

Recommendations:

Clinicians should use CPK determinations combined with EMG and/or muscle biopsy to confirm the diagnosis of HIV-associated myopathy.

Clinicians should consider referring patients to a neurologist or rheumatologist to confirm and manage HIV-associated myopathy.

1. Serum Creatine Phosphokinase

Creatine phosphokinase (CPK) levels are usually elevated to a moderate degree, with a median level of approximately 500 IU/L. Muscle trauma, including vigorous exercise and intramuscular injections, should be excluded as possible causes of increased CPK.

2. Electromyography

EMG is sensitive and specific in the diagnosis of myopathy. Findings show muscle irritability with abnormal spontaneous activity and myopathic features.

3. Muscle Biopsy

Muscle biopsy reveals myofiber atrophy, often with associated inflammatory infiltrates. Some authors have reported mitochondrial abnormalities, attributable to zidovudine or other nucleoside analogue toxicity.

C. Treatment

Although corticosteroids may provide benefit in HIV myopathy, they should be used with caution because of their immunosuppressant effects. Intravenous immunoglobulin may be an alternative option without risk of immunosuppression, although there is only limited reported experience in the setting of HIV myopathy. Some patients with myopathy improve when zidovudine or other nucleoside ARV drugs are discontinued, but most do not. This is likely because most patients have an underlying immune-mediated myopathy caused by HIV infection itself.

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VI. HIV-ASSOCIATED NEUROMUSCULAR WEAKNESS SYNDROME (HANWS)

A. Presentation

The Food and Drug Administration (FDA) and several case series have reported a “rapidly ascending neuromuscular weakness syndrome,” associated with lactic acidosis syndrome in HIV-infected patients.^28-30 In the majority of these patients, dramatic motor weakness developed over days to weeks (resembling Guillain-Barre syndrome) and led to respiratory failure and death in several patients. Diagnostic information in a limited number of cases revealed evidence of severe axonal neuropathy. Systemic symptoms included nausea, vomiting, weight loss, abdominal distention, hepatomegaly, and lipoatrophy. From FDA surveillance, 22 of 25 patients developed this syndrome in association with stavudine therapy; however, muscle weakness worsened even after discontinuation of ARV therapy.

The neurologic manifestations of this syndrome are not well elucidated. They are predominantly that of a rapidly progressive sensorimotor polyneuropathy, associated with areflexia. In a few cases, it may be a subacutely progressive proximal muscle weakness, with elevated serum CK, consistent with a myopathic process. A retrospective review of a series of 55 HIV-infected patients with new-onset weakness either acute (1-2 weeks) or subacute (>2 weeks), affecting either the lower extremities or both the lower and upper extremities, has been undertaken. In this review, the cases were classified as possible HANWS when confounding conditions were present or when comprehensive neuromedical evaluation was not completed; probable HANWS when neuromedical evaluation to exclude confounding causes of weakness was documented; and definite HANWS when electrophysiologic or pathologic confirmation of neuromuscular pathology was available.³¹ There were 55 cases identified: 17 possible, 15 probable, and 23 definite. In the definite cases with documented serum lactate level, 17 of 20 patients had elevated levels (mean, 8.4 mmol/L), and 9 had metabolic acidosis (mean HCO³ = 12.9 meq/L; median pH = 7.1). Stavudine was the most commonly used ARV agent (44 of 55 cases). In 14 cases, the onset of neurological symptoms lagged significantly after discontinuation of ARV therapy. Of 36 patients with documented follow-up, 14 required intubation, and 9 died.

B. Diagnosis

Recommendations:

Clinicians should exclude other possible causes of weakness by performing a complete neurologic examination and obtaining blood tests.

Clinicians should consult with a neurologist for evaluation and management of patients with suspected HANWS.

1. Neurological Examination and Blood Tests

A complete neurological examination should be performed and blood tests obtained to evaluate for other confounding causes of weakness (e.g., stroke, myelopathy, myasthenia gravis, hypokalemia). The following serum levels should be determined:

• Serum lactate level, which may be elevated more than twice the upper limit of normal
• Serum bicarbonate and arterial pH, which may be decreased
• Serum CPK, which may be elevated

2. Electrophysiology

EMG-NCV is an essential tool for evaluating HANWS. A severe axonal neuropathy is seen in most patients, but demyelinating features may be seen admixed or in isolation. In a few cases, myopathic features may be noted.

3. Nerve and Muscle Biopsy

Nerve and muscle histology is another important tool for evaluating patients with HANWS. Mitochondrial studies with morphology assessment and mitochondrial DNA (mtDNA) quantification may be needed to further elucidate the role of mitochondrial toxicity in this syndrome.

C. Treatment

Recommendations:

Clinicians should discontinue the use of NRTIs in patients with HANWS.

For patients with HANWS, clinicians should initiate systemic treatment for lactic acidosis syndrome and supportive treatment for the neurologic component in a monitored setting.

In the reported cases, patients were treated with a variety of agents both for lactic acidosis syndrome and neuromuscular weakness. For the latter, agents such as corticosteroids, intravenous immunoglobulins, vitamins (B₁, B₁₂), and plasmapheresis were used. There is not enough data to make any conclusive recommendation regarding which agent should be used for treatment. There is some suggestion that tapering of the offending ARV agent may be needed, but there is not enough data to make any conclusive recommendation.

Systemic management of the lactic acidosis syndrome and adequate supportive treatment in a monitored environment are imperative.

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APPENDIX A

APPENDIX B

APPENDIX C

Figure C-1: MRI Images

MRI images (A, axial FLAIR; B and C axial and coronal T2 sequences) showing symmetrical, bilateral, and diffuse signal in the white matter.