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Re: Reply to both Letters to the Editor

The authors thank Cole et al. and von Giesen et al. for their interest in their article. After reviewing the literature concerning HHV-8 mentioned in Dr. Cole’s letter, this virus seems to be fairly common in the general population as most serologic studies suggest a global HHV-8 seroprevalence of 2% to approximately 10%. [1, 2] The overall seroprevalence of antibodies against HHV-8 for the blood donor population in Europe is 6.5% [range from different countries 4.5-8%,][3]usually higher than in North America. [2] Nonethe less an overall seroprevalence of 15% has been recently reported in Texas blood donors. [4] If the distribution of HHV-8 is compatible with a sexually transmitted agent, and increased with age, the HHV-8 seroprevalence among young men who have sex only with women (5%). [5] It is not that clear whether homosexuality, as suggested in the letter, could interfere in virus-associated ALS.

In von Giesen et al.’s observation of two male partners infected with the same HIV-1 strain and who developed for one an ALS syndome and for the other a syndrome combining cramps, fasciculations and brisk tendon reflexes are very interesting and add new evidence for HIV-1-associated ALS like disorder. [6] The hypothesis that particular HIV strains may be crucial for the development of an ALS syndrome could explain the scarcity of this neurologic complication. We completely aggree with their conclusions.

References:

1) Kedes DH, Operskalski E, Busch M, Kohn R, Flood J, Ganem D. The seroepidemiology of human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus): distribution of infection in KS risk groups and evidence for sexual transmission. Nature Med 1996;2:918-924.

2) Gao SJ, Kingsley L, Li M, et al. KSHV antibodies among Americans, Italians and Ugandans with and without Kaposi's sarcoma. Nat Med 1996;2:925-928.

3) Gambus G, Bourboulia D, Esteve A, et al. Prevalence and distribution of HHV-8 in different subpopulations, with and without HIV infection, in Spain. AIDS 2001;15:1167-1174.

4) Baillargeon J, Deng JH, Hettler E, et al. Seroprevalence of Kaposi's sarcoma-associated herpesvirus infection among blood donors from Texas. Ann Epidemiol 2001:7:512-518.

5) Diamond C, Thiede H, Perdue T, et al. Seroepidemiology of human herpesvirus 8 among young men who have sex with men. Sex Transm Dis 2001:28:176-183.

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Re: Reversible ALS-like disorder in HIV infection

Moulignier et al. recently had published [1] a series of six HIV-1 seropostitive (+) patients with a neurologic disorder mimicking amyotrophic lateral sclerosis (ALS). This disorder was reversible under HIV-1 specific highly active antiretroviral therapy (HAART), which suggested that HIV-1 itself might play a role in the neuropathogenesis. A similar case clearly responsive to HAAT has been published in the same issue. [2] This observation has prompted an editorial [3] in which a possible viral aetiology for ALS has been reviewed and newly debated.

In July 2001, a 44-year-old homosexual man was presented in our department. He was known to be HIV-1 (+) since 1991 (CDC stage B2 with history of herpes zoster, CD 4 cell count 430 cells/ul, plasma viral load 12.000 copies/ml).

He was naïve to any antiretroviral therapy and complained of ubiquitous fasciculations and muscle cramps. Fasciculations were observed in both quadriceps muscles. His deep tendon reflexes were brisk, but not exaggerated. The neurologic examination was otherwise normal.

Electroneurography excluded polyneuropathy and multifocal conduction block, electromyography revealed fasciculations not only in the quadriceps muscle, but also in the anterior tibial and the biceps brachii muscle, but no signs of active denervation. The history of the patient was remarkable in so far as his HIV-1 (+) partner had been diagnosed to suffer from ALS with its characteristic clinical and electrophysiological features. He first complained of fasciculations in May 2000, followed by progressive weakness and atrophy. The HIV-1 infection was diagnosed in April 2000 (CDC stage A2 CD 4 cell count 447 cells/ul, plasma viral load 21,857 copies/ml). Symptoms deteriorated progressively despite newly started HAART with zidovudine, lamivudine and nevirapine.

Sequence analysis form HIV reverse transcriptase and protease revealed that both patients showed HIV-1 subtype B and a sequence homology which is higher to each other compared to other HIV-strains. This implies infections with identical HIV-strains.

These cases suggest not only that viral quasispecies may indeed play a role in HIV-1 associated ALS like disorders, but also that the presence of defined HIV-1 strains may be a prerequisite for the later development of such a disease. This does not imply that other neuropathogenetic mechanisms are less important for the further course of the disease. Every patient presented with ALS like symptoms should be tested for HIV-1 because of a potential therapeutical option and HIV-1 viral quasispecies should be determine in HIV-1 (+) patients to identify possible preferential viral strains.

References:

1)Moulignier A, Moulonguet A, Pialoux G, Rozenbaum W. Reversible ALS- like disorder in HIV infection. Neurology 2001;57:995-1001.

2)MacGowan DJ, Scelsa SN, Waldron M. An AlS-like syndrome with new HIV infection and complete response to antiretroviral therapy. Neurology 2001;57:1094-1097.

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Re: Reversible ALS-like disorder in HIV infection

Two recent papers by Moulignier et al [1] and MacGowen et al [2] in Neurology present clinical and laboratory evidence of a probable increased incidence of amyotrophic lateral sclerosis (ALS) in patients infected by human immunodeficiency viruses (HIV)-1 and –2. Several possible mechanisms were suggested including direct neuronal damage, disease due to cytokine production and autoimmunity. The fact that symptoms and signs of ALS improved with antiretroviral therapy implied that the effect was specifically upon HIV induced disease. However, Kaposi’s sarcoma (KS) which now appears almost certainly to be due to human herpesvirus-8 (HIV- 8) also often disappears with antiretroviral therapy. It is more than passing interest that up to 35% of homosexual men with the acquired immunodeficiency syndrome demonstrates antibodies to HHV-8 [3], while they are present in less than 4% of US blood donors. [3]

We have recently had an opportunity to study HHV-8 antibody levels in five non-HIV+ patients with ALS. Two of five were women, one was black and all five had associated medical disorders including, monoclonal gammopathy, and lymphoma of the lung, scleroderma, osteoarthritis and hyperlipidemia. Their ages ranged from 70 to 81 years. Three ultimately dies of aspiration pneumonia.

Antibody titers as measured by indirect immunofluorescence using the BCP-1 cell line [4] were positive in all patients and ranged from 1:20 to 1:60. HHV-8 in blood by PCR was identified in only one patient.

The presence of HHV-8 antibody in all of our patients in this small study would suggest that this may also be the case in patients with AIDS and ALS. Since AIDS-related KS often improves with antiretroviral therapy, the improvement in ALS with such therapy may be due to an effect upon HHV- 8 as well.

Histopathologically, death of neurons in ALS is preceded by perikaryal shrinkage, the formation of webs of ubiquitin-positive threads [5] and axonal swellings staining for ubiquitin and alpha-synuclein. Over the years multiple causes of ALS have been invoked, particularly a viral etiology. The presence of a homologue of interleukin-6 in HHV-8 with 24.8% amino acid identity suggests that this viral cytokine could play a role in the pathogenesis of HHV-8 related diseases.

REFERENCES

1. Moulignier A, Moulonguet A, Pialoux G, Rezenbaum W. Reversible ALS -like disorder in HIV infection. Neurology 2001; 57: 995-1001.

2. MacGowen DLJ, Scelsa SN, Waldron M. An ALS-like syndrome with new HIV infection and complete response to antiretroviral therapy. Neurology 2001; 57: 1094-1097.

3. Gao S-J, Kingsley L, Li M, et al. KSHV antibodies among Americans, Italians and Ugandans with and without Kaposi’s sarcoma. Nature Med 1996; 2: 925-927.

4. Boshoff C, Gao S-J, Healey LE et al. Establishment of a KSHV positive cell line (BCP-1) from peripheral blood and characterizing its growth in vivo. Blood 1998; 91: 1671-1679.