Herbert B. Newton, MD, FAAN
DESCRIPTION
Neuromuscular (NM) complications are common in patients with HIV infection and AIDS, potentially affecting nerve roots, peripheral nerves, and muscles. The etiology of these disorders is variable and may result from direct effects of HIV infection, damage from inflammatory processes and cytokine production, opportunistic infections and neoplasms, metabolic abnormalities, and toxic effects of HIV therapy.
EPIDEMIOLOGY
Incidence/Prevalence
- Approximately 10–40% of patients with HIV-1 and AIDS develop some form of NM complication. The most common complication is distal symmetric polyneuropathy (DSP), which is diagnosed in 20–30% of patients. Asymptomatic HIV-1-infected patients can also be affected and have an incidence between 2% and 20%, as shown by detailed neurophysiological testing. NM complications are decreasing in HIV patients because of HAART therapy.
- All races affected; most common in Caucasians and blacks. Any age can be affected; most common between 20 and 40 years of age. Both sexes can be affected; most often diagnosed in males.
RISK FACTORS
Diagnosis of HIV infection, low CD4 counts (i.e., less than 100/µL), and lack of antiretroviral therapy.
Genetics
Genetic factors have not been identified.
GENERAL PREVENTION
Use of HAART therapy.
PATHOPHYSIOLOGY/ETIOLOGY
- Etiology depends on specific syndrome. In early stages of HIV-1 infection, NM complications are caused by immune dysregulation. Acute and chronic forms of inflammatory demyelinating polyradiculoneuropathy (AIDP, CIDP) and vasculitic neuropathy are thought to occur by this mechanism. In AIDP and CIDP, an autoimmune process develops which results in damage to peripheral nerve myelin (i.e., myelin antibodies). Vasculitic neuropathy appears to be caused by deposition of HIV-1 antibody/antigen immune complexes into blood vessel walls.
- DSP and autonomic neuropathy usually occur in the middle and late stages of HIV-1 infection. Although the etiology of DSP remains unclear, it does not appear to be caused by direct infection of nerves by HIV-1.
- During late stages opportunistic infections and neoplasms can directly involve nerve roots and peripheral nerves. The most common infection is cytomegalovirus (CMV), which can involve the nerve roots (i.e., polyradiculopathy) and/or peripheral nerves (i.e., mononeuropathy multiplex). Other less common infections include herpes zoster ganglionitis, syphilitic radiculopathy, and tuberculous polyradiculopathy. Lymphoma can directly invade nerve roots and cause polyradiculopathy after spreading to the spinal meninges. Infrequently, neuropathies can develop in patients with vitamin B6 and/or vitamin B12 deficiencies.
- Toxic neuropathies can arise in a dose-dependent manner from therapy for HIV-1, in particular the antiretroviral dideoxynucleotide analogues didanosine (ddI), zalcitabine (ddC), and stavudine (d4T). The neuropathy may result from damage to cellular mitochondria caused by inhibition of mitochondrial DNA-γ polymerase.
- Myopathies can develop as a result of HIV-1 infection or from toxicity of antiretroviral therapy. Productive HIV-1 infection has not been demonstrated in myofibers. Zidovudine is also implicated as a cause of myopathy and appears to damage myofiber mitochondria, resulting in “ragged-red fibers” and other evidence of dysfunction. The mechanism is through inhibition of mitochondrial DNA-γ polymerase.
- Rarely, opportunistic infections can directly involve muscle and present as a myopathy, such as toxoplasmosis or CMV.
HISTORY
- Patients with DSP usually complain of distal, symmetric numbness, paresthesias, and dysesthesias of the legs and feet that develops over weeks to months; upper extremities can become affected in late stages of disease. Typically, the pain is most severe on the soles of the feet. Light touch and pressure often exacerbate the pain. On examination, most patients have loss of reflexes at the ankles and a distal-to-proximal gradient to pinprick, cold, and vibration; muscle weakness and atrophy are usually mild or absent. Toxic neuropathies from HIV-1 therapy have signs and symptoms similar to DSP.
- HIV-1-related AIDP and CIDP have a similar clinical presentation to the idiopathic neuropathies. The patient notes either a rapid (i.e., weeks; AIDP) or slow (i.e., months; CIDP) onset of progressive weakness in two or more limbs, generalized areflexia, and mild sensory loss. Muscle atrophy may be noted in patients with long-standing disease.
- Patients with autonomic neuropathy complain of fainting, orthostatic dizziness, impotence, diminished sweating, diarrhea, and urinary dysfunction. In addition, cardiac conduction abnormalities may occur.
- The various forms of polyradiculopathy present with progressive lower extremity and sacral paresthesias, flaccid paraparesis, areflexia, sensory loss, and urinary dysfunction.
- Mononeuropathy multiplex is characterized by multifocal, asymmetric, dysfunction of cutaneous nerves, mixed nerves, and nerve roots that often presents with wrist drop, foot drop, facial palsy, and other focal neuropathic signs.
- Patients with myopathy complain of slowly progressive, generalized proximal muscle weakness that initially affects activities such as arising from a chair or climbing stairs. Myalgias are noted in 25–50% of patients. Reflexes are preserved and sensory function remains intact.
PHYSICAL EXAM
Varies depending on specific syndrome.
DIAGNOSTIC TESTS AND INTERPRETATION
Lab
Initial Lab Tests
The most important tests will consist of blood counts (including CD4 counts, to determine stage of HIV infection), infectious cultures of appropriate tissues (e.g., CMV), and serum antibody titers of various infectious agents. Serum creatine kinase levels are moderately elevated (450–500 U/L) in patients with myopathy. Other specific tests may be helpful in certain cases, such as Venereal Disease Research Laboratory test (VDRL) and vitamin B6 and vitamin B12 levels.
Imaging
Initial Approach
MRI and CT have limited diagnostic value.
Diagnostic Procedures/Other
- Lumbar puncture is often helpful and should at least include routine CSF studies, bacterial/fungal antigens, cytology, CSF bacterial/viral/fungal cultures, smear and culture for acid-fast bacilli, and VDRL. The CSF cell count always demonstrates a pleocytosis (20–50 mononuclear cells) in patients with HIV-1-related AIDP and CIDP (usually hypocellular in HIV-negative cases). Patients with CMV mononeuropathy multiplex and polyradiculopathy have an elevated CSF protein and mononuclear cell pleocytosis.
- Electromyography and nerve conduction testing are helpful for diagnosis. In DSP, the findings are consistent with a distal, symmetrical sensory more than motor, axonal neuropathy, with evidence for acute and chronic partial denervation and reinnervation of muscles. A similar pattern is seen with toxic neuropathies. AIDP and CIDP demonstrate slowed motor nerve conduction velocities consistent with demyelination, as well as conduction block. Myopathy shows typical myopathic findings of early, polyphasic motor unit potentials, positive sharp waves, and fibrillation potentials.
- Autonomic function testing may be helpful to define the presence and extent of autonomic neuropathy.
Pathological Findings
Will vary depending on the specific NM complication involved, affecting various peripheral nerves or muscle as outlined above.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis is extensive and includes any non-HIV-related disease with a similar presentation affecting the nerve roots, peripheral nerves, or muscles.
MEDICATION
First Line
All patients should be evaluated for HAART, since this may prevent or abrogate the direct and indirect effects of HIV on nerve roots, peripheral nerves, and muscles. All other drug decisions have to be individualized to the specific NM complication of each patient.
ADDITIONAL TREATMENT
General Measures
Antiretroviral therapy should be maximized, if possible (i.e., HAART). All systemic infections should be diagnosed and treated. Medications that could contribute to a myopathic or neuropathic process (e.g., zidovudine, ddC) should be reviewed and possibly discontinued as a therapeutic trial.
Additional Therapies
Treatment for DSP is symptomatic and consists of a combination of tricyclic antidepressants, selected serotonin reuptake inhibitors, carbamazepine, gabapentin, lamotrigine, and topical agents (i.e., capsaicin). Toxic neuropathies receive similar treatment to DSP and may improve after cessation of the offending drug. Patients with AIDP and CIDP may respond to plasmapheresis or IV immunoglobulin, similar to HIV-negative patients. Therapy for autonomic neuropathy consists of fludrocortisone, antiarrhythmic agents, and management of fluids and electrolytes. CMV polyradiculopathy and mononeuropathy multiplex may respond to ganciclovir. HIV myopathy may respond to a course of prednisone (60 mg/day). Zidovudine myopathy should be treated with reduced dosage or cessation of the drug.
SURGERY/OTHER PROCEDURES
Biopsy of involved nerve roots, peripheral nerves, or muscles may be helpful for definitive diagnosis.
IN-PATIENT CONSIDERATIONS
Admission Criteria
Patients are generally admitted for acute neurological changes related to the specific neuropathic or myopathic process. The most common causes for admission include focal extremity weakness, generalized weakness, progressive proximal weakness, and exacerbation of extremity pain. Patients with persistent neurological deficits should be considered for rehabilitation.
Discharge Criteria
Varies.
FOLLOW-UP RECOMMENDATIONS
Varies.
Patient Monitoring
Follow-up of neurological status will be required. This is particularly true for conditions that require long-term therapy, such as distal painful neuropathy or infectious NM complications (e.g., CMV).
PATIENT EDUCATION
PROGNOSIS
The course and prognosis for many of the neuropathies and myopathies mentioned above is quite poor, since the majority occur in patients with low CD4 counts and advanced disease. However, in some cases, treatment may lead to stabilization or improvement. Infectious complications caused by specific agents may respond to appropriate therapies such as CMV polyradiculopathy or mononeuropathy multiplex, syphilitic radiculopathy, or tuberculous polyradiculopathy. Toxic myopathies and neuropathies may improve if the offending agent is discontinued at an early stage.
COMPLICATIONS
Varies.
