SEMINARS IN NE:UROl,OGY-VOI.UMI;.

12, N O . 4 DEC;EMHER I992

Cutaneous Manifestations of Human Immunodeficiency Virus Infection

Of patients infected with the human imrnunodeficiency virus (HIV), half will experience clinically detectable neurologic disease during the course of their illness, and 80% will have neuropathologic abnormalities at autopsy.' Essentially all persons with HIV disease have abnormalities of the skin, the mucous membranes, or both, during the course of their prolonged illness. An awareness of the cutaneous changes that occur in HIV disease may help the neurologist to evaluate referred patients, because of the coexistence of neurologic and cutaneous nlanifestations in HIV-infected patients. Cutaneous findings that may facilitate the diagnosis of' the neurologic presentation include those occurring in the infectious syndromes of syphilis, herpes simplex virus types 1 and 2, varicella-zoster virus, Cryptococcus neoformans, Coccidioides immitis, Histoplasma capsulatum, Candida albicans, and mucormycosis as well as tumors such as Kaposi's sarcoma (KS). In this article we review the skin diseases associated with HIV infection that may assist the neurologist in identifying individuals at risk for HIV-associated neurologic disorders.

EPIDEMIOLOGY According to the World Health Organization, the number of reported cases with acquired immunodeficiency syndrome (AIDS), through January 1992, exceeds 418,000 worldwide, with almost 10,000,000 individuals infected by HIV. In the United States, approximately 1,000,000 persons are now HIV-infected, of whom more than 200,000 have developed AIDS and nearly 130,000 have died from the disease (Table 1).

Classified as a lentiretrovirus, HIV is highly adapted for human T lymphocytes, possessing an intricate array of regulatory proteins for subverting cellular functions. Two distinct types of HIV have been reported: H IV- 1 , which causes nearly all of HIV infection in the United States and Europe, and HIV-2, which is essentially confined to West Africa and has a less aggressive course than HIV1-associated AIDS. HIV is present in blood, semen, vaginal secretions, breast milk, cutaneous exudates, and saliva. Transmission of the virus occurs in circumstances that promote the exchange of blood, blood products, or other bodily fluids containing the virus or cells infected by the virus. Three modes of HIV transmission have been identified: ( I ) sexual intercourse, either through homosexual contact, which accounts for the majority of cases in the United States, Europe, and other developed countries, or through heterosexual contact, which is predorninant in developing countries; (2) parenteral transmission, which occurs in intravenous drug users; in transfusion and transplant recipients; and, very rarely, in health care workers through accidental exposure to HIV by needle stick; and (3) perinatal transmission. Certain behaviors have been also associated with increased rates of HIV transmission, such as having a large number of sexual partners, sexual contact with individuals who are in a high-risk group for HIV infection, or traumatic sexual practices (anal intercourse, penile or vaginal abrasions). Sexually transmitted diseases, particularly those with ulcerative genital lesions, have also been reported to increase HIV transmission. Finally, the virulence of the virus strain, the viral load of the

Department or Dermatology, Division of Llermatology, New England Deaconess Hospital; and Harvard Medical School, Boston, Massachusetts. Copyright O 1992 by Thicme Medical Publishers, Inc., 381 Park Avenue South, New York, N Y 10016. All rights reserved.

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Alexander J. Stratzgos, M.D., Richard Allen Johnson, M.D.C.M., and Jeffrey S. Dover, M .L)., F.R.C.P.(C)

SEMINAKS IN NEUKOLOGY

VOLUME 12. NUMHEK 4 DRCEII~HRR1992

oped AIDS within 1 1 years after being i n f e ~ t e d . ~ Progression to clinical disease (AIDS-related complex [AKC], AIDS) is associated with increased Number Location rates of replicatiorl of HIV in the cells, increased 1,000,000 North America viral burden, and a dramatic reduction of CD4 >1,000,000 Latin America cells. 500,000 Western Europe 20,000 Eastern Europe ARC is characterized by fever, weight loss, ca50,000 North Africa chexia, night sweats, persistent diarrhea, general6,500,000 Sub-Saharan Africa >1,000,000 ized lymphadenopathy, oropharyngeal candidiasis, South and Southeast Asia 30,000 Australia herpes zoster, and oral hairy leukoplakia (OHL). Abnormal laboratory findings include anemia, Total >10,100,000 leukopenia, thrombocytopenia, reduced CD4 to CD8 ratio, reduced blastogenesis, and cutaneous anergy. All patients with ARC progress to AIDS, infecting partner, and the level of immune re- an event that is defined by the occurrence of opsponse to viral exposure may influence the likeli- portunistic infections, KS, and K-cell lymphomas. Encephalopathy, myelopathy, or peripheral neuhood of transmission. ritis resulting from the direct viral infection of neural tissue (macr-ophages, microglial cells), can be the first manifestations of HIV infection and is NATURAL HISTORY OF HUMAN usually seen in patients with scvcrc inlrnunodefiIMMUNODEFICIENCY VIRUS INFECTION ciency. HIV infection is characterized by a progresT h e spectrum of skin diseases associated with sive course, with an initial period of latency HIV infection is broad and includes disorders that and profound terminal immunodeficiency. HIV- commonly present in appareritly healthy persons induced immunodeficiency results from dysfunc- as well as lesions that occur only in those who have tion and, eventually, destruction of the hclper/in- HIV-induced immunosuppression. Certain disducer T-lymphocytes (CD4 lymphocytes) that have orders appear in the early stages 01' HIV-induced an instrumental role in orchestrating virtually all immunodeficiency, whereas others present in immunologic responses. Other cells that have t~ccri patients with profound immunosuppression. T h e found to be affected directly by HIV include mac- mucocutaneous findings that the Centers for Disrophages, B lymphocytes, promyelocytes, oligo- ease Control (CDC) have established for the diagdendrocytes, astrocytes, and cells of the renal and nosis of AIDS are listed in Table 2. gastrointestinal epithelium. Langerhans (:ells of 'l'he cutaneous ant1 mucous membrane rnanithe mucosa and the skin can be also infected by the festations of HIV infection have the following sigvirus and become sites of HIV replication. nificance: (1) they rriay be the earliest sign of HIV Primary HIV infection is asymptomatic in the infection, (2) they indicate the progression of the majority of individuals; however, in 10 to 20% of disease from the asymptomatic to the synlplomatic cases, syrnptornatic illness occurs that rcsernbles stage, (3) they differ in frequency and type from mononucleosis or aseptic meningitis. Symptoms in- skin disorders that present in the gcrlcral populacl~idefever, malaise, anorexia, headache, arthral- tion, (4) they can be causes of considerable morbidgias, myalgias, and abdominal pain. In up to 75% of symptomatic primary infections, a nonspecific viral exanthem or urticaria occurs. A wide rarigc of neurologic manifestations, including meningoTable 2. AIDS-Defining Mucocutaneous encephalitis,' rnyelopathy,:' peripheral neuropathy, Signs (CDC) and Guillain-Barre s y n d r ~ r n e ,has ~ been docuIn individuals with unknown HIV status and no other cause of mented during pri~naryHIV infection. immunodeficiency Candidiasis of the esophagus, trachea, bronchi, or lungs After primary infection, HJV infection be(not oropharyngeal candidiasis alone) comes latent. During this phase, the virus is preCryptococcosis with hematogenous dissemination to the sent within the infected cells without expressing skin Persistent herpes simplex virus mucocutaneous ulcer (lastany reproductive or virulent activity. Generalized, ing more than 1 month) asymptomatic lymphadenopathy can occur during Kaposi's sarcoma in a patient younger than 60 years this period in the absence of other symptoms. T h e In HIV-seropositive individuals Coccidioidomycosis; histoplasmosis with hematogenous duration of latency varies among risk groups and dissemination to the skin routes of transmission. In a cohort of homosexual Kaposi's sarcoma at any age men in San Francisco, approxirnately 50% devel-

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Table 1. Geographic Distribution of HIV Infection in Adults (WHO Data--January, 1992)

ity and contribute to the mortality of HIV infection, (5) the mucocutaneous site of involvement may serve as a portal of entry for life-threatening infections, and (6) the skin lesions can help in the early recognition of a systemically disseminated infection. The morphology of HIV-related cutaneous lesions depends not only on the nature of the causative microorganism, but on the host response, which may be greatly altered. This fact, in combination with a broader range of infections occurring in the susceptible HIV-infected host, results in a far longer list of alternative diagnoses for a particular lesion than in an immunocompetent host.

COMPLICATIONS OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION WITH BOTH MUCOCUTANEOUS AND NEUROLOGIC MANIFESTATIONS Complications of HIV infection with mucocutaneous and neurologic nlariifcstations are listed in Table 3. SYPHILIS

T h e interaction of syphilis and HIV infection has become an increasingly complex problem. The incidence of syphilis has increased anlong the heterosexual population during he past Sew years. Syphilitic genital ulcers can be an important cofactor for acquiring HIV infcctiorl and have been associated with an increased risk for- HIV transmission. Coexistent HIV infection and syphilis may rnodify the clinical course of syphilis. The immune dysfunction that is associated with HIV infection may alter the usual antibody response to Treponerna pallidurn, rcsultirig in falsc-negative serologic tests, despite the existence of' active infection. T h e degree of immunocompromise may alter the clinical manifestations of' syphilis, with rapid pro-

Table 3. Complications of HIV Disease with both Neurologic and Cutaneous Manifestations Bacterial infections Syphilis Viral infections Herpes simplex virus infections Varicella-zostervirus infections Cytomegalovirus infections Deep fungal infections Cryptococcosis Histoplasmosis Coccidioidomycosis Parasitic infections Toxoplasmosis Neoplasms Kaposi's sarcoma

gression to the later stages of the disease, susceptibility to the development of neurologic complications, involvement of many organs, and reduced response to the standard therapeutic methods. In most HIV-infected persons with syphilis (95% of cases), however, the disease follows a typical clinical course. T h e clinical presentation of primary and secondary syphilis is identical with that in the normal host, although, occasionally, the extent and number of chancres are greater.' Progression to advanced stages of the disease and, especially, neurosyphilis can occur very rapidly, with the late sequelae of syphilis presenting less than 6 months after primary infection, despite administration of the CDC-recommended the rap^.^ Neurosyphilis presents with a wide range of neurologic findings and may be manifested as asymptomatic infection, acute aseptic meningitis, meningovascular syphilis, or parenchymal neurosyphilis. T h e classic forms of parenchymal disease, such as tabes dorsalis and general paresis, have not been reported in HIVinfected patients, possibly because of the shorter latency period of the syphilitic infection. The most corrinion findings include hemiparesis, pure motor hemiplegia, unilateral facial palsy, and neurosensory hearing 1 0 ~ sA. ~severe necrotizing encephalitis resulting from massive treponemal invasion of the brain has been described in an HIV-infected person."~yphiIitic eye disease can also occur, with uveitis and optic neuritis presenting more commonly in the early stages of syphilis, whereas chorioretinitis and optic nerve atrophy with blind~less occur in the advanced stages of the disease. Because immune function is abnormal, interpretation of serologic tests for syphilis may present certain difficulties. Since both false-negative and hlse-positive results can occur in this patient population, the diagnosis of syphilis is optimally confirmed by dark-field examination and skin biopsy of' cutaneous lesions. In addition, specific immunofluorescent or immunoperoxidase staining of the pathologic specimens is helpful for the definite diagnosis. The diagnosis of neurosyphilis is based on cerebrospinal fluid (CSF) findings of cells, elevated protein concentration, and a positive Venereal Disease Research Laboratory (VDRL) test ofs the CSF. However, if the CSF VDRL is negative, the diagnosis is complicated by the lack of other reliable diagrlostic tests arid the difficulty of distinguishing between neurosyphilis and the neurologic conlplications of HIV itself. CSF examination is indicated in HIV-infected patients with neurologic symptoms or psychologic dysfunction, with a diagnosis of latent syphilis of more than 1-year duration and with early syphilis that does not respond to treatment or with titers of antitreponemal anti- 301

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SKIN DISEASES ASSOCIATED WITH HIV-STRATIGOS, JOIINSON, DOVER

bodies that increase, or fail to decrease fourfold, within 6 months after initiation of therapy. Clinical management of HIV-infected patients with syphilis should be based on penicillin regimens, according to the therapeutic guidelines that the CDC has issued. However, recent studies have reported the isolation of T. pallidum from the CSF of HIV-infected patients who had already completed standard penicillin therapy for early syphilis."' This indicates that therapy appropriate for neurosyphilis should be given to any immunocompromised individual coinfected with HIV and syphilis, regardless of the apparent clinical stage of syphilis. Close follow-up, with repeated clinical and nontreponemal serologic examination (VDRL rapid plasma reagin) after treatment is necessary in these patients, and they should be followed longer if there are questions about the adequacy of their clinical or serologic response. For patients with neurosyphilis, CSF examination is recommended at 6-month intervals until the findings have stabilized. VIRAL INFECTIONS

Cutaneous viral infections, which are commonly seen in HIV disease, are mainly caused by herpes, papilloma, and pox viruses. These viral agents can produce significant morbidity in HIV-infected individuals; they result in chronic, widespread infections. Recent studies have demonstrated that Epstein-Barr virus (EBV) and cytomegalovirus (CMV) can cause immunosuppression, accelerating the HIV-induced immunologic deterioration. Herpesviruses also appear to induce the expression of HIV, playing an important role in progression of HIV infection from the latent to the productive disease. '

Herpes Simplex Virus Infection

Herpes simplex virus (HSV) types 1 and 2 infections occurring in the setting of HIV disease usually, present as reactivation of the latent virus; the most common sites of presentation are, in order of frequency, perianal, genital, orofacial, and digital. T h e severity of recurrent disease correlates to the degree of HIV-related immunodeficiency. In the early stages of HIV disease, the course of HSV infection is unremarkable; it is characterized by the development of vesicles and pustules on an erythematous base, which rupture leaving erosions and ulcerations that heal by reepithelialization in 7 to 14 days. As immune suppression advances, HSV lesions may recur or fail to heal, forming chronic herpetic ulcers, which may become confluent, A

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V O L U M E 12, N U M B E R 4 DECEMBER 1992

Figure 1. Chronic herpetic ulcer of the penis in a patient with HIV infection.

forming large, painful lesions (Fig. 1). Herpes simplex virus infection may also involve the oropharynx and esophagus and cause severe odynophagia. Very few cases of acute herpetic encephalitis in patients with HIV disease have been described. HSV-1 causes a subacute encephalitis with lethargy, ataxia, and seizures and is associated with a diffuse involvement of the brain tissue. Disseminated HSV-2 infection may result in a hemorrhagic encephalitis involving the temporal lobes and the limbic system, or can even affect the spinal cord, causing a necrotizing myelitis in patients with AIDS." Herpetic lesions usually respond well to systemic treatment with acyclovir. Persistent, unresponsive, chronic herpetic ulcers indicate the presence of an acyclovir-resistant strain of the virus, which can be effectively treated with vidarabine or trisodium phosphonoformate."

Varicella-Zoster Virus Infection

Early in the AIDS epidemic, herpes zoster in young homosexual men was recognized as a marker of the underlying immunodeficiency. Zoster is associated with impaired cellular immunity occurring in patients with leukemia, lymphoma, and iatrogenic immunosuppression. It results from reactivation of a latent varicella-zoster virus (VZV) infection in the dorsal root ganglion. T h e possibility of coexisting, undetected HIV infection should be considered in all individuals who present with herpes zoster. In developed countries, homosexual

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S E M I N A R S I N NEURO1,OGY

men under the age of 50 years, presenting with zoster, have a probability of more than 50% of being HIV-infected, the incidence being seven times higher than in such men who are uninfected.'" Zoster occurs in the setting of moderate H IVinduced immunodeficiency and may precede the presentation of OHL and oropharyngeal candidiasis. In a group of 112 HIV-infected homosexual men with zoster who were followed for 6 years, 23% developed AIDS within 2 years, 46% within 4 years, and 73% within 6 years.'"n HIV-infected patients with roster, a poor prognosis for the HIV infection is correlated with the extent of dermatoma1 involvement, the severity of pain, and the involvement of cervical or cranial dermatomes. Zoster presents as a cluster of painful vesicles on an erytheniatous base, located in one or, in sorne cases, additional dermatomes. Occasionally, the dermatomal eruption may be bullous, hemorrhagic, necrotic, and accompanied by severe pain. In HIV-infected individuals, roster can recur within the same dermatome or disseminate hematogenously from the original dermatome to other cutaneous sites. Systemic disserriiriation of VZV with the developmen~of pneumonitis and hepatitis usually occurs in patients with profound irnn~unodeficiency. CNS manifestations associated with VZV infection include enceqhalornyelitis, trigeminal encephalitis, leukoencephalitis, cerebral vasculopatliy, and herpes zoster ophthalmicus. Intravenous acyclovir and rccombinant interferon-alpha-2 have been used for the treatment of disseminated disease, and corticosteroids have been indicated for the prevention of postherpetic neuralgia. Despite the severity of acute zoster infection in HIV-infected individuals, the incidence of postherpetic neuralgia seems to be decreased, probably because of the young age of most of the patients.

Cytomegalovirus Infection T h e majority of HIV-seropositive individuals harbor latent CMV infection, and reactivation of CMV is a major cause of mortality and morbidity in this group. Approximately 90% of patients with AIDS present with CMV infection and u p to 25% of them experience life-threatening complications. CMV is transmitted sexually but may also be acquired perinatally or by contact with infected secretions or blood products. Severe involvement of the eye, gastrointestinal tract, and pulmonary system can result as the infection proceeds from the initial latent phase to the reactivation stage in the

immunocompromisctl host. CMV chorioretinitis leads to visual field cuts and visual loss and is the most important cause of blindness in AIDS, occurring in 5 to 10% of' patients with AIDS. CMV pneumonitis and gastrointestinal disorders such as hepatitis, colitis, and esophagitis occur in 5% of cases. Although CMV is not considered to be a neurotropic virus, it has been isolated and identified in brain tissue or CSF. A subacute encephalitis caused by CMV that can occur in patients with AIDS is characterized by personality changes, headaches, and somnolence. CMV myelitis, presenting with lower extremity weakness, spasticity, and bladder and bowel symptoms, has been also described. Specific CMV-induced skin lesions have not been identified in HIV-infected individuals. Although the presence of CMV has been demonstrated in biopsy specimens of mucocutaneous lesions, the role of the virus in their pathogenesis has not yet been defined. CMV-related oral and perianal ulceratioris have been reported in patients with AIDS and CMV infection of the gastrointestinal tract.15 DEEP FUNGAL INFECTIONS

The incidence of systemic mycoses (cryptococcosis, histoplasmosis, coccidioidomycosis, and sporotrichosis) is increased in HIV-infected patients; cutaneous lesions may represent the first sign of disseminated disease.

Cryptococcosis Primary infection with C. neoformans initially occurs as an asymptomatic pulmonary infection. In severely immunocon~promisedhosts reactivation of the latent infection may occur and be followed by dissemination to the meninges, skin, and other organs. Cryptococcosis, the second most common opportunistic infection in HIV-infected individuals, occurs in 5% of patients with AIDS.'" Cryptococcal meningitis presents with symptoms such as headache (in more than 70% of cases), fever (60 to 80%), stiff neck (20 to 30%), photophobia (20%), malaise, nausea, vomiting (40 to 70%), and findings that include confusion, personality changes, loss of memory, cranial nerve palsies, and seizures (4 to 8%). Skin involvement is seen in 10% of HIV-infected patients with cryptococcosis and may precede or occur simultaneously with the central nervous system (CNS) infection. The lesions appear most commonly on the head and neck; they include painless, erythematous, or hyperpigmented papules that may progress to

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SKIN DISEASES ASSOCIATED W I T H HIV-STRATIGOS,JOHNSON, DOVER

nodules o r ulcers. T h e most characteristic skin manifestation is multiple papules on the face, which resemble molluscum contagiosum (MC) but usually lack the umbilication o r keratin plug seen in that condition (Fig. 2).15 Other reported cutaneous findings of cryptococcal infection include erythematous macules, necrotic o r keratinplugged papules and nodules, pustules, folliculitis, acneiform lesions, vegetative plaques, and herpeslike vesiculations." Common

Cutaneous manifestations of human immunodeficiency virus infection.

SEMINARS IN NE:UROl,OGY-VOI.UMI;. 12, N O . 4 DEC;EMHER I992 Cutaneous Manifestations of Human Immunodeficiency Virus Infection Of patients infecte...
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