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Clinical Characteristics of Iranian Patients With HTLV-I Associated Myelopathy (HAM) *Dr Arami MA, MD ** Dr Kholghi Y, MD *Consultant neurologist of Milad hospital _Tehran **Consultant neurologist of Rasool-Akram hospital_Guilan_Rasht Abstract: Background: Human T lymphotropic virus type 1 myelopathy (HAM) that previously named tropical spastic paraparesis (TSP) is one of the major causes of infectious myelopathy in some area of the world. The epidemiology of the HAM in Iran is not clear in all geographic regions. This study explains some of clinical characteristics of a group of Iranian patients with HAM that referred from many provinces (against previous studies in Iran). Methods and materials: All suspected cases of HAM that referred to our hospitals from 2000 through 2006 and tested for HTLV-1 serology were reviewed. All selected patients with positive laboratory results were evaluated by expert neurologists. Brain and spinal cord MRI, EMG/NCV, somatosensory evoked potentials (SSEP) and CSF examinations were done for all patients. Past medical history and also demographic and clinical characteristics of patients were analyzed and compared with characteristics of patients of other countries. Results: Among 25 evaluated patients, females have been affected significantly more than males (64% against 36%) and the mean age at HAM onset was (33.3±14.6 y). The most common symptoms and signs were; spasticity and hyperreflexia (in all patients), lower limb paresthesia (68%), urinary complaints (92%), and lumbar pain (12%). Constipation was not frequent and the most common form of bladder involvement was neurogenic spastic bladder presented with frequency. Sensory level, pathologic cerebellar signs and tremor were detected in a few cases. Nearly all patients had breast feeding in their neonatal period but blood transfusion had been done in 5 cases (20%). Positive familial history of paraparesis was found only in 1 patient. Conclusions: Recently, HAM is frequently diagnosed in our country in a wide area. Special clinical and epidemiological characteristics could be studied and some preventive measures must be considered and the prime cause of female preponderance in middle or childbearing age could be obviated. Key words: Clinical Characteristics- Human T-Lymphotropic Virus Type-1 Associated Myelopathy (HAM)-Iranian patients. Introduction: In 1888, Strachan’s paper published on Jamaican peripheral neuritis. In 1956, Cruikshank described patients with spasticity (tropical spastic paraparesis, TSP) which he termed Jamaican neuropathy. In 1985, Gessain and colleagues, investigating the seroprevalence of HTLV-I among hematology patients and found that 59% of patients with tropical spastic paraparesis had anti-HTLV-I antibodies. In Japan, where adult T cell leukemia was first described in 1977 and associated with HTLV-I in 1981.Osame et al described the association of HTLV-I with a spastic paraparesis which they called HTLV-I associated myelopathy (HAM). While seronegative TSP has been described, by definition all patients with HAM are infected with HTLV-I.HTLV-I and the related virus, HTLV-II, are transmitted by sexual intercourse, especially from males to females. Parenterally through cellular blood products and the reuse of injecting equipment. From mother to child, predominantly through breast feeding. Although Europe is not an endemic area for HTLV-I infection, it is found among immigrants from high prevalence areas, their partners, and sporadically in the native population. HTLV-II is common among intravenous drug users in a number of European cities. There are three main hypotheses for Pathogenesis: 1. Direct toxicity 2. Autoimmunity 3. Bystander damage Direct toxicity hypothesis: HTLV-I infects glial cells in vivo, which then present HTLV-I antigens on their cell surface. Circulating CD8+ cytotoxic T cells specific for a HTLV-I antigen cross the blood–brain barrier, encounter the infected cell, and release cytokines which cause cell death. Autoimmune hypothesis: Glial cells “self” antigen is similar to a viral antigen. CD4+ helper cells encounter this viral antigen in the periphery and upon crossing the blood–brain barrier, mistake the glial cell for an infected cell triggering autoimmune activity with death of the glial cell. Alternatively, CD4+ “helper” cells which by chance recognize “self” antigen are stimulated to proliferate by infection with HTLV-I. The chance of infection of such a cell would be related to the infectious burden of virus. Bystander damage hypothesis: In this hypothesis, HTLV-I infected CD4+ and anti-HTLV-I specific CD8+ lymphocytes migrate across the blood–brain barrier, meet in the CNS and the innocent glial cells are damaged by cytokines released against the infected lymphocyte. Role of viral load for Pathogenesis: In cross sectional studies HTLV-I proviral load has been found to be at least 10-fold higher in patients with HAM/TSP than in carriers. In patients with TSP/HAM this viral burden was relatively constant over several months. In a prospective study HTLV-I proviral load, whether high or low, remained relatively constant over 2–3 years in most patients and carriers. Epidemiology: With an estimated 20 million people infected worldwide, HAM/TSP is Endemic in parts of Japan, South America, Africa, and the Caribbean, Iranian Jews. Asymptomatic in majority of individuals with approximately 1-5% of HTLV-I carriers developing disease 20-30yrs post infection. With a long clinical latency and low percentage of individuals who develop disease suggest that T-cell transformation occurs after a series of cellular alterations and mutations. At Risk Groups: • Intravenous drug abusers. • Immigrants from high-risk areas. • Often associated with co-infection with HIV. • Endemic in certain parts of the southeastern US (Native Amerindian population). Presentation of 25 Iranian cases of HTLV1 Associated Myelopathy (HAM) Loghman Hospital Tehran in 2000-2006 Descriptive Statistics N age age at onset YEARS TO Dx Severity Min 25 25 25 25 Max 20 23 1 1 65 60 20 4 Mean 46.24 38.32 7.30 3.20 Sex Distribution and rout of initial presenting features: Female = 64% Male = 36% LIMBS INVOLVMENT sex of patient male QUADRIPARESIS LOWER LIMBS female Clinical Characteristics of Patients in Iran: Clinical Characteristics of Patients in Peru : Imaging finding: CORD MRI FINDINGS BRAIN MRI FINDINGS HIGH SIGNAL LESIONS CORD ATROPHY NORMAL MRI OF SPINAL NORMAL MRI OF BRAIN Electrophysiological finding: Geographical Distribution of Disease (Province of Birthplace and Province of living): What is the most common Transmission pattern in Iran? • Infected blood products? • Sexual Transmission? • Breast feeding from infected mother? • IV abusing? • What about HIV and Hepatitis B Transmission in Iran? Route of Transmission: • All of our patients were breast-fed for >12 months. • Breast-feeding is probably the main route of HTLV-1 transmission? • Blood transfusion was the second route. Prevalence of infection in blood donors: • Saudi Arabia: 3/47426 (0.006%). • South America: 68/123,233 (0.05%). • Argentina: 40/19,426 (0.21%). • France: The overall prevalence is 0.039 per thousand. • Taiwan: 2311/3,701,087 (0.058%). • Caribbean Basin, Central Africa, and South Japan: greater than 1%. • Iran? Is screening for anti HTLV-I/II antibodies In Iran necessary and cost effective to prevent transmission through blood transfusions? Blood donors are routinely screened for HTLV-I/II in North America, several countries in Europe, Japan, Peru, and Taiwan. There are communications from other areas of endemicity that report a 16% decrease in HAM cases only 2 years after the implementation of blood donor screening. Summary of treatment options: Patients with more advanced disease, and possibly fixed deficits may not benefit from either anti-inflammatory or antiretroviral treatment. Although azidothymidine appears to have efficacy invitro against HTLV-I, it has not been clinically successful in the treatment of HAM. This may reflect the fact that neuronal injury in HAM may result from immunological attack by virus-specific cytotoxic T cells, rather than as a result of direct viral infection. Consistent with this model of pathogenesis is the suggestion that treatment with immunomodulatory agents including corticosteroids and interferon-a may be beneficial in HAM. Conclusion: • HAM is not rare in Iran. • Ham is not restricted to certain provinces like khorasan. • HAM is common between young females. • We don’t know the prevalence of infection. • We don’t know the effectiveness of blood screening. Recommendations: Screening, at least in high risk groups, could be considered in health programs. Urinary complaints were very prominent in our patients, so urologists and gynecologists must be alerted about HAM. According recent studies, all treatments are effective in first months/years of disease, so we must diagnose it as soon as possible.