Pain is the second most prevalent symptom in HIV/AIDS after fever and increases in severity with advancing disease. In a study of more than 500 ambulatory patients from Sloan Kettering Cancer Center in New York City, significant persistent pain in the preceding two weeks was seen in 25-30% of patients in early stage HIV, increasing to 50% in ambulatory patients with full blown AIDS. Hospitalized patients had a prevalence rate of around 50-60%, with 60-70% in a hospice setting reporting pain. On an analog pain scale (0=no pain, 10=worst pain), the average pain was reported as 5.7 and the worst pain averaged 7.2.
The most common pain syndromes are abdominal pain (26%), peripheral neuropathy (25%), throat pain (20%), HIV-related headache (17%), HIV-unrelated headaches(with the usual prevalence rates for migraine, tension-type, and migraine with aura as in the general population, AZT-induced headache (16%), arthralgias (5%), herpes zoster (5%) and back pain (5%). These totals sum to more than 100% for the obvious reason that many sufferers have more than one condition.
Not surprisingly, HIV/AIDS pain may be nociceptive, neuropathic, inflammatory, mixed, or psychogenic. Nociceptive pain may be cutaneous, visceral, and deep somatic or headache- related. Cutaneous causes include Kaposi‚Äôs sarcoma and oral cavity pain. Visceral causes include tumors, gastritis, pancreatitis, infection, and biliary tract disorders. Deep somatic pain includes arthralgias, back pain, and myopathies. Headache disorders include HIV-related conditions, such as meningitis, encephalitis, or neoplasm; HIV-unrelated manifestations, such as migraine and tension-type headaches; and iatrogenic occurrences, such as AZT therapy.
Nearly one half of pain in HIV/AIDS is neuropathic pain, which spares no part of the nervous system. Pain may result from direct viral infections, infection with secondary pathogens, or be a side effect of drug therapy (neurotoxic).Central or peripheral manifestations and, particularly, painful peripheral neuropathies, generally follow the stage of HIV. Knowledge about the stage of the disease is imperative in the diagnosis of painful conditions as they vary by stage.
In the acute or seroconversion phase, mononeuritis multiplex and acute demyelinating polyneuropathy (ADP) or the Guillain-Barre syndrome predominate. In the latent phase, where the patient is asymptomatic with CD4 and T lymphocytes are more than 500/cubic mm, ADP and chronic demyelinating polyneuropathy (CIDP) generally appear. In the transition phase, with 200-500 CD4 cells, herpes zoster and mononeuritis multiplex appear,
In the late phase, with less than 200 CD4 cells, sensory neuropathy, autonomic neuropathy, cytomegalovirus (CMV) polyradiculopathy, severe mononeuritis multiplex, mononeuropathies associated with aseptic meningitis, mononeuropathies secondary to lymphomatous meningitis, and Nucleoside toxicity are most common.
Opportunistic Neuropathies and Radiculopathies
Herpes zoster may cause an HIV- related radiculopathy and HIV itself can cause a lumbosacral poly radiculopathy with asymmetric leg weakness involving proximal and distal muscles, flaccid paraparesis, hypo or areflexia, sacral and lower extremity sensory loss, and sphincter disturbances, such as urinary retention. The symptoms develop over a period of 1 to 6 weeks. Cytomegalovirus may also cause a polyradiculopathy, which occurs in approximately 2% of patients with a CD4 cell count of 50 cells or less. The patient typically presents with radiating, low back pain, progressive areflexic paraparesis, and distal sensory loss. Two thirds of patients complain of urinary difficulties, including hesitancy or retention. Weakness is typically more prominent than sensory loss. Anticytomegalovirus therapy with ganciclovir, foscarnet, or a combination of both drugs, is imperative because of the rapid progression of these symptoms. In one study of patients with AIDS and acute lumbosacral polyradiculopathy, 15 of 23 patients had cytomegalovirus infection and treatment with ganciclovir was followed by stabilization. Oral acyclovir is usually effective in herpes zoster radiculitis.
Radiculopathy has also been associated with primary CNS lymphoma with lymphomatous meningitis, syphilis, lymphoma, vasculitis, toxoplasmosis, tuberculosis, and herpes zoster as well as HIV itself.
Bilateral brachial plexopathy with severe pain has been described at disease onset.
Commonly occurring cranial mononeuropathies are facial nerve palsies, with less frequent involvement of cranial nerves II, V, and VIII. Bilateral facial nerve palsies have also been reported with HIV infection, most commonly occurring at the time of seroconversion, but also when the AIDS stage of the disease is reached, possibly secondary to opportunistic infection or lymphoma. Herpes zoster, neurosyphilis, and hepatitis C have been associated with facial nerve palsies and should be excluded.
The clinical pattern of mononeuritis multiplex is that of simultaneous or sequential involvement of individual major peripheral nerves in different limbs, resulting in the often abrupt onset of symptoms in variable distributions. This syndrome may develop early or late in the course of HIV infection.
The neuropathy symptoms may be accompanied by weight loss, myalgias, and leg tenderness. Systemic manifestations, though less frequent, include renal failure, skin rash, testicular pain, arthritis, or hypertension. The erythrocyte sedimentation rate is usually elevated, and patients may be positive for hepatitis B surface antigen. Mononeuritis multiplex may also occur in association with vasculitis, involving small vessels with neutrophilic inflammatory vascular disease. A milder form of mononeuritis multiplex is associated with a pathological picture of perivasculitis, in which there are perivascular inflammatory cells but no vasonecrosis or fibrosis, with the neuropathy following a more benign course.¬†Cryoglobulinemia, frequently associated with hepatitis B and C, may cause vasculitis, resulting in mononeuritis multiplex in patients with HIV.
Peripheral neuropathy in HIV-infected patients may present as a distal sensory polyneuropathy, with symmetrical numbness, tingling, burning, or pain in the feet or hands without motor weakness. The two most common causes are toxic neuropathy from medications (usually stavudine, didanosine, or both) or HIV itself. Other causes or contributing factors include alcoholism, thyroid disease, vitamin B12 deficiency, syphilis, or diabetes mellitus, including diabetes caused by protease inhibitors. In drug-induced neuropathy, early interruption of the offending agent gradually leads to complete resolution of symptoms.
A sensorimotor polyneuropathy may develop due to angiocentric infiltration by CD8 cells and vascular mural necrosis. In one series of 12 patients with diffuse infiltrative lymphocytosis syndrome and peripheral neuropathy, all had a sicca syndrome and multivisceral involvement. Four patients had an asymmetrical and eight had a symmetrical neuropathy. Nerve biopsy showed marked angiocentric CD8 infiltrates without mural necrosis and with abundant HIV p24 protein in macrophages. Improvement with AZT was seen in 6 out of 6 patients, and steroids were beneficial in 4 out of 5 patients. Two patients developed a primary B-cell lymphoma.
In later stages of HIV infection (when patients have less than 50 CD4 cells), cytomegalovirus may result in a rapidly progressive multifocal neuropathy. This neuropathy may be confirmed by demonstration of cytomegalovirus in the CSF by polymerase chain reaction accompanied by an elevated protein level and predominantly polymorphonuclear pleocytosis. Characteristic nerve biopsy findings include multiple foci of endoneurial necrosis, inflammatory infiltrates of mononuclear and polymorphonuclear cells, and cytomegalovirus inclusions in endothelial cells of endoneurial capillaries, with surrounding inflammation.
A predominantly sensory, distal symmetric polyneuropathy is the most common peripheral manifestation seen in HIV-1 infection and typically has been reported to occur in later stages of the disease. In the era of HAART therapy, comorbidities not dependent on immunologic or virologic status are increasingly being recognized to be important in the pathogenesis of distal symmetric polyneuropathy, such as vitamin B12 deficiency, substance abuse, complications of medications, and diabetes.
Electrophysiologic findings are largely axonal although demyelinating features have been described to a lesser degree. Pathologic features include axonal degeneration of long axons in distal regions. Axonal damage follows the “dying back” pattern of degeneration, with a reduction in the density of both small and large myelinated fibers. Small fiber nerve damage may be assessed by skin biopsy with quantification of the epidermal nerve fiber density. A decreased epidermal nerve fiber density is associated with greater pain intensity and higher HIV plasma RNA levels, and qualitative changes (such as focal swellings) may precede development of symptomatic distal symmetric polyneuropathy. Occasionally, the HIV virus may be cultured from the CSF of affected individuals.
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