The Microbiologist asked where the patient had been born and after ringing the ward to find out the Neurologist reported that the patient had actually been born and spent her childhood in the Caribbean.
The Neurologist looked at the Microbiologist expectantly thinking they were going to add more to that question.
“Errrrr. Tropical what?” asked the Neurologist after a moment when nothing more was forth coming.
“Human T Lymphotrophic Virus infection causing TSP, also known as HTLV Associated Myelopathy or HAM” clarified the Microbiologist.
“Oh, but that’s incredibly rare, textbook rare… but I didn’t think of that” answered the Neurologist, “it could be though. Gosh that would be a very clever diagnosis to make. How do you test for that? Can you test for that?!”
“Sure, send us some blood and CSF and we’ll see what we can do.”
What is Human T Lymphotrophic Virus?
Human T Lymphotrophic Virus (HTLV) was the first retrovirus discovered, in the USA back in 1980 by Poiesz et al. before the better known retrovirus Human Immunodeficiency Virus (HIV). HTLV is a single-stranded RNA virus in the Retroviridae family. HTLV and HIV are very similar however rather than killing T cells HTLV causes them to proliferate.
It is estimated that up to 20 million people Worldwide are infected with HTLV however only 5% of these people develop disease. It was in Jamaica where the first cases of Tropical Spastic Paraparesis (TSP) were reported by H. Strachan in 1888 and where the first epidemic outbreak of TSP was published in 1918 by H.H. Scott. HTLV is endemic in Southern Japan (as high as 30% of the population), the Caribbean (5%), South America, Melanesia, Papua New Guinea, the Middle East, and in West, Central, and Southern Africa. In the UK and USA the prevalence is less than 1%.
How does infection with HTLV present?
HTLV causes two typically fatal diseases; one a form of cancer and the other a neurological condition:
- Adult T cell Leukaemia/Lymphoma (ATL)
- HTLV-1 Associated Myelopathy (HAM) also known as Tropical Spastic Paraparesis (TSP)
Which type of disease develops is strongly linked to the way HTLV is acquired. If HTLV is acquired through breast feeding it causes ATL; if it is acquired through direct inoculation through sexual intercourse, sharing needles or blood transfusion it causes HAM/TSP. It is incredibly rare for someone to have both disease presentations. I find this very weird as HTLV is the only virus I can think of where the mode of acquisition influences the presentation. Usually the presentation of a virus is unrelated to the way the virus was acquired, once you have the virus it presents in the same way however you got it, for example HIV can be acquired from breast feeding, sexually, by needlestick injury and even through splashing of body fluids into eyes but the patient still goes on to develop AIDS.
ATL usually occurs 20-30 years after the initial infection. Patients have very high CD4 T cells (compared to the very low CD4 T cells seen in HIV). These T cells are not very effective and so these patients are immunosuppressed despite the high levels of cells. About 50% of HTLV associated ATL follows a very aggressive course with cancer cells invading other body tissues, allowing opportunistic infections to occur such as pneumocystis pneumonia (PCP). The average length of survival is only 6 months. Even with the more chronic forms of ATL cancers survival is only 2-5 years.
HTLV infection leads to cancer more commonly than any other known virus; for example Human Papilloma Virus causing cervical cancer or Hepatitis B Virus causing hepatocellular cancer.
The neurological signs of HAM/TSP can occur 4-30 years after the initial infection. Patients develop progressive weakness of the legs with hyperreflexia and changes in sensation as well as often back pain, loss of bladder control, urinary and faecal incontinence. The arms are not affected and cognitive function remains unchanged. Symptoms progress slowly but most patients are wheelchair bound within 20 years.
How does HTLV cause cancer OR HAM/TSP?
HTLV doesn’t cause cancer in the same way as most other viral causes, by producing oncogenes (mutated cellular genes that then trigger abnormal growth). Instead HTLV produces viral proteins that change the function of human cell proteins; these new cellular proteins then trigger cell proliferation and cancer.
The neurological conditions HTLV-1 Associated Myelopathy (HAM) and TSP on the other hand are thought to be autoimmune in origin. The host’s immune response generates antibodies against the virus which are then thought to start to attack the central nervous system.
How is HTLV infection diagnosed?
ATL is usually diagnosed by Haematologists looking at blood films because the abnormal T cells are distinctive. Whereas HAM/TSP is diagnosed based on the presence of the typical neurological presentation and confirmed by looking for HTLV antibodies in blood and CSF as well as viral RNA by PCR. Although many laboratories can do HTLV antibody tests on blood they cannot test CSF and don’t do the PCR. The antibody blood test only shows past infection. In order to prove active infection specialist reference laboratories are required to test for antibodies and virus in the CSF as well as the blood as this proves ongoing virus replication.
How is HTLV infection treated?
As of yet there are no really effective treatment regimens for ATL. Treatment is under Haematologists using various chemotherapeutic regimens, however average survival after chemotherapy is still only 8 months.
The treatment of HAM/TSP is mainly supportive. Steroids have been used and in some patients may slow the onset of symptoms. A new monoclonal antibody called Mogamulizumab has been used in 21 patients so far and has been shown to give some improvement in symptoms but further work is needed to see if this is an effective treatment.
So our patient underwent a lumbar puncture which confirmed the presence of HTLV in her CSF and the diagnosis was confirmed. There was then a very difficult conversation about treatment options as current treatment makes very little difference and progressive paralysis will occur over the next 20 years. The Microbiologist may have made a “very clever” diagnosis but he couldn’t help thinking that there was no satisfaction in making such a dreadful diagnosis…