National Centre for Human Retrovirology

LONDON, UNITED KINGDOM

What is HAM/TSP?

HAM/TSP (HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis) is an inflammation of the spinal cord seen in some people infected with the Human T-Lymphotropic Virus Type 1.

The condition TSP had been recognised in the Caribbean for many decades but the cause was unknown until 1985 when evidence of HTLV-1 infection was found in the blood of the majority of tested patients with TSP in Martinique. During the same period, and quite separately, neurologists in Japan found that patients with a particular pattern of neurological symptoms were infected with HTLV-1. They called this condition HTLV-1-associated myelopathy (HAM). TSP and HAM are in fact the same disease and the names have now been combined. Although a few patients with a disease resembling TSP are not infected with HTLV-1, the information presented here is only about HAM/TSP and not about HTLV-1 negative TSP.

 

Who is likely to be affected?

In the UK we have calculated that approximately 3 out of every 100 people infected with HTLV-1 will develop HAM/TSP at some stage in their life. Similar rates of disease (1.7-7%) have been reported from Africa, the Caribbean, South America and the USA. The disease seems less common in Japanese carriers of HTLV-1 in whom a 0.25% life-time risk is reported. There are additional factors that make the development of HAM/TSP more or less likely:

• Gender - women infected with HTLV-1 are more likely to develop HAM/TSP than men (3 women to every 2 men).

• Time or route of infection - initial infection with HTLV-1 in adult life is a risk factor.

• The amount of virus in the blood (this is known as viral load) - the risk increases if more than 1 lymphocyte per 100 in the blood is infected with HTLV-1.

• Immune system genetics - certain HLA types (these are also called Tissue types and are like blood types on white blood cells rather than on red blood cells) seem to increase protection against HAM/TSP whereas others may increase susceptibility.

 

How does HAM/TSP start?

Most people who develop HAM/TSP will have been infected with HTLV-1 for months, years or even decades. Current evidence suggests that the levels of HTLV-1 infection in the blood are set within a few months of infection. Thus patients who develop HAM/TSP may have had high HTLV-1 viral load for many years before the onset of symptoms. So whilst high viral load is a requirement for the development of HAM/TSP it is of itself insufficient to cause the disease. Most persons infected with HTLV-1 with high proviral load do not develop HAM and we do not know what triggers the inflammation to start in high viral load carriers.

 

What are the symptoms of HAM/TSP?

The symptoms of HAM/TSP most often present for the first time between the ages of thirty and fifty years, but may occur at any time after childhood. Disease in childhood although reported is very rare.

 

The earliest symptoms of HAM/TSP are often mild and could be caused by a number of other more common diseases, or are simply attributed to getting older. This often results in a delay in the correct diagnosis being made. Damage to nerves in the spinal cord causes a variety of symptoms such as, muscle stiffness or weakness of the legs resulting in walking and balance difficulties, partial loss of bladder or bowel control, impotence and lower back pain. Bladder symptoms or backache are often the first symptoms to appear.

 

The most common bladder problems are:

• Increased frequency - this refers to the number of visits to the toilet to pass urine (every 3-4 hours is normal).

• Urgency - needing to pass urine with very little "warning", often the volume of urine passed is only small.

• Nocturia - having to get up at night to pass urine more than once.

• Incontinence - not being able to get to the toilet in time / having unexpected accidents

 

These symptoms are usually due to an "overactive bladder" and occur when the bladder wants to empty before it is properly full. In some patients with HAM/TSP the bladder is "underactive" or partially paralysed, in which case the sensation (urge) to empty the bladder is very weak or absent despite the bladder being full. Urine retained in the bladder may become infected causing cystitis, often referred to as a UTI (urinary tract infection). Untreated UTIs can lead to generalised illness with fever and sometimes to infection of the kidneys. An overfull bladder should be emptied by a catheter to protect the kidneys from back pressure. In some patients with HAM/TSP the bladder contracts actively but the urethra (the tube through which urine is expelled) does not relax (open). This leads to patients experiencing an urge to pass urine, but being unable to empty the bladder completely, because of poor and interrupted urine flow. In this disorder a considerable amount of urine could be retained in the bladder. Any bladder symptoms should be fully investigated as they may be caused by other health problems and not HAM/TSP.

 

Bowel function can slow down resulting in troublesome constipation in some patients. Many treatments for pain also cause constipation which can make the problem worse.

 

Inflammation of the nerves can result in pain. This is most common in the lumbar spine (low back) but can also be felt in the buttocks and back of the legs.

 

HAM/TSP may not be diagnosed until the nerves that carry instructions from the brain to the leg muscles are affected. This will manifest as a change in walking. The first complaint may be that the legs feel stiff, a tendency to trip or worsening balance, difficulty on the stairs or difficulty getting out of a low chair. The weakness in the legs is usually most marked at the hips and then the knees rather than around the ankles.

 

Men with HAM/TSP may complain of impotence or erectile dysfunction. This is likely to be due to the inflammation affecting the nerves responsible for the maintenance of sexual function.

 

The nerves responsible for feeling/sensation in the legs are, however, not usually affected at the start.

 

Although the arms can be affected this is not usually the case and even when the legs are very weak or stiff the strength in the arms remains normal. Changes in the feelings in the arms should not be routinely attributed to HAM/TSP and investigations for other causes should be initiated.

 

How is HAM/TSP diagnosed?

The diagnosis of HAM/TSP is made by:

• Recognising the pattern of symptoms.

• Diagnosing HTLV-1 or HTLV-2 infection by detecting HTLV-1 or HTLV-2 antibodies in the blood.

• Ruling out other conditions, particularly pressure on the spinal cord.

 

It is also helpful to confirm the diagnosis by:

• Detecting HTLV-1 or HTLV-2 antibodies in the cerebrospinal fluid (CSF), fluid which bathes the brain and spinal cord.

• Measuring HTLV-1 or HTLV-2 viral load in the blood and CSF. HAM/TSP is unusual if less than 1 peripheral blood mononuclear cell per 100 in the peripheral blood is infected. Furthermore, the viral burden per cell is almost always higher in the CSF than in the blood.

 

Can HAM/TSP be treated?

Although there is no cure for HAM/TSP a number of treatments are available. There are two approaches to treatment: treatment for the symptoms (e.g. pain or stiffness) and treatment of the cause (i.e. the inflammation in the spinal cord). Ideally there should be a treatment of the underlying infection but this is not yet available.

 

What is the normal course of HAM/TSP?

The natural course of HAM/TSP is very variable. It has been reported that most change occurs during the first couple of years after the first symptoms with the condition more stable or worsening only very slowly thereafter. However several studies which have followed up patients with HAM/TSP for years have identified that the condition progresses slowly in the majority of patients. The final level of disability varies greatly from person to person. Some patients have very mild disability that hardly interferes with their lives. However, up to half of all patients with HAM/TSP eventually need to use a wheelchair. It can take twenty years before this becomes necessary. Needing to use a walking aid such as a stick or frame is common. A small subset of patients with HAM/TSP progress rapidly and start needing to use walking aids within a few weeks of first symptoms. They frequently progress to needing a wheelchair within a year of first symptoms.

 

Can HAM/TSP be treated?

Although there is no cure for HAM/TSP a number of treatments are available. There are two approaches to treatment: treatment for the symptoms (e.g. pain or stiffness) and treatment of the cause (i.e. the inflammation in the spinal cord). Ideally there should be a treatment of the underlying infection but this is not yet available.

 

Treating the symptoms (symptomatic treatments):

i.e. relieves symptoms like bladder frequency and urgency, constipation, impotence, back pain, stiffness of the legs.

 

The medications mentioned in this section are not an exclusive list – but examples. All medications should be discussed with your doctor before starting, stopping or changing dose.

 

Frequency, urgency and nocturia due to an overactive bladder can be improved with a drug called Oxybutynin or related medications such as Solifenacin that reduce bladder muscle activity. Similar symptoms of urgency and frequency (usually also with pain on passing urine and or fever or generally feeling unwell) may indicate the presence of a bladder infection that will require antibiotic treatment.

 

A "floppy bladder" may be best managed by intermittent self-catheterisation using an "in-and-out" urinary catheter (tube) to empty the bladder.

 

Constipated bowels are treated with changing the diet to increase the amount of roughage. If laxatives are required these can be adjusted according to response. Suppositories or enemas can be prescribed if diet and laxatives have insufficient effect.

 

Treatments such as Sildenafil are available to help maintain sexual function in men.

 

Pain is managed by analgesics (painkillers) such as Paracetamol or Codeine, by anti-inflammatory treatments, by specialised drugs for nerve pain such as Gabapentin or Pregabalin, by injection of local anaesthetics or steroids and by a variety of physical methods such physiotherapy.

Painful spasms and stiffness of the legs are treated with Tizanidine or Baclofen. Botulinum toxin (Botox) injections can be used in some circumstances.

 

A specialist physiotherapist can play an important role in assessing and managing patients with walking problems, balance deficits, muscle weakness, and pain caused by HAM/TSP.  Walking difficulties can be helped by reducing stiffness or pain in the low back and legs as well as using appropriate walking aids.  Restoring muscle strength through exercise after any illness is important to maintain mobility and overall quality of life.

 

A home assessment, gym visit, or work visit by a physiotherapist can be beneficial for patients living with HAM/TSP to maintain or improve muscle strength, flexibility, cardiovascular endurance, walking ability, and basic functional mobility such as transfers, standing, and activities of daily living.

 

Treating the symptoms (symptomatic treatments):

 

STEROIDS

Corticosteroids - that have been used in many other inflammatory conditions, like asthma and arthritis, are commonly used to reduce the inflammation in the spinal cord in HAM/TSP. How best to use this type of treatment, which can have important side-effects if used for a long time, needs to be determined by properly conducted research with patients. To avoid chronic steroid treatment a common approach is ‘PULSED’ therapy. In this, a high dose of a corticosteroid called methylprednisolone is given, directly into a vein over 1 hour, on 3 consecutive days. Several studies have reported early benefit, lasting several weeks, particularly for pain. Responses vary between patients and may be determined by the duration of symptoms prior to treatment. Repeated courses appear to be less beneficial but individual responses vary. To maintain the benefits of such steroid therapy and yet avoid the long-term problems with steroids has led to the use of steroid sparing anti-inflammatory therapies.

 

STEROID SPARING (ANTI-INFLAMMATORY)

Ciclosporin – In 2012 we published the results of a proof of concept study of Ciclosporin in patients with HAM/TSP. Ciclosporin is most commonly used in transplant recipients to reduce the risk of organ rejection. The objective of the study was to determine whether ciclosporin, by reducing the activation of T-lymphocytes, could improve pain, mobility and bladder function in patients with HAM/TSP. Seven patients were enrolled and treated for up to 48 weeks and then followed up for a further 24 weeks. Two stopped treatment early due to side-effects. Five patients completed 48 weeks treatment with improvement in mobility, pain and bladder function. During the follow-up, off-treatment phase of the study, the condition of two of these five patients deteriorated early and at their request they recommenced treatment with ciclosporin. We concluded that there was sufficient evidence from this observational study to justify further studies of ciclosporin for the treatment of HAM/TSP.

 

As described above, not all patients tolerate Ciclosporin the use of which is made more difficult by the need to measure ciclosporin concentrations. For those who could not tolerate ciclosporin we switched to Methotrexate, an immunosuppressive therapy widely used in the long-term treatment of diseases such as Rheumatoid arthritis. Methotrexate is given once per week with folic acid supplementation the next day. Monitoring is still required for side-effects. The commonest in our patient population being a reversible increase in the blood levels of liver enzymes. We have found treatment with methotrexate to reduce pain and improve mobility in patients with HAM/TSP and this is currently our first choice therapy.

 

If neither ciclosporin nor methotrexate can be taken other anti-inflammatory options are mycophenylate mofetil, hydroxychloroquine and sulphasalazine. However randomised controlled trials of all these therapies including corticosteroids are urgently required to prove their effectiveness in patients with HAM/TSP.

 

Interferon-alpha (IFN-a) is a protein made in the body in a response to infections. A synthetic copy of this protein is often given to boost the immune response. It has been tried in patients with HAM/TSP but the benefits were mostly found to be short-term.

 

Anti-viral drugs

Anti-viral drugs are designed to reduce the amount of the virus in the blood of an infected person. Unfortunately the anti-viral treatments tried so far have not been able to reduce HTLV-1 viral load and consequently had no impact on the inflammation.

 

If you are interested in taking part in a treatment study (clinical trial) please ask your doctor or contact the National Centre for Human Retrovirology for more information.

 

What tests and investigations are usual?

A number of tests are needed to diagnose HAM/TSP and to exclude other diseases which may present with similar symptoms. These include blood tests, CT and MRI scans, nerve studies, ultrasound and a lumbar puncture.

 

BLOOD TESTS

Evidence of HTLV-1/HTLV-2 infection-antibodies is essential, but not sufficient to a make a diagnosis of HAM/TSP.

Quantifying the amount of virus is helpful.

Other blood tests are needed to exclude other possible causes.

 

SCANS

CT and MRI are imaging techniques to visualise the spinal cord and the brain, to look for signs of inflammation and to exclude other diseases especially any cause of pressure on the spinal cord, such as a prolapsed disc.

 

CT Scans - CT is a computer-enhanced x-ray technique. CT can detect a wide range of brain and spinal cord disorders.

 

MRI

magnetic resonance imaging - uses a magnetic field and very high frequency radio waves to produce high quality pictures that show more details than CT.

 

ULTRASOUND IMAGING

Is a method of obtaining images from inside the body through the use of high frequency sound waves. The reflected sound waves echoes are recorded and displayed as a real time visual image. No radiation (x-ray) is involved. Ultrasound is a useful way of examining many organs, including the heart, liver, gallbladder, spleen, kidneys and bladder. In HAM/TSP ultrasound is used to evaluate the bladder, especially its capacity and the ability to empty completely.

 

LUMBAR PUNCTURE (spinal tap)

Involves passing a fine needle carefully into the spinal canal below the end of the spinal cord. This allows a sample of the fluid, (CSF, cerebrospinal fluid), that surrounds the brain and spinal cord to be safely withdrawn for laboratory examination. Examination of the cerebrospinal fluid can detect evidence of infections, injury, tumours, and bleeding in the brain and spinal cord.

 

In patients with HAM/TSP examination of the CSF fluid gives information about the degree of inflammation in the spinal cord and is useful to exclude other infections or causes of inflammation. Detecting antibodies to HTLV-1 and quantifying the HTLV-1 viral load in the CSF can be important in making the right diagnosis in some cases.

 

ELECTROMYOGRAPHY (EMG)

Measures electrical impulses of muscles at rest and during contraction. EMG helps diagnose diseases that damage muscle tissue, nerves or the junctions between nerve and muscle.

 

NERVE CONDUCTION STUDIES

Measure the speed at which motor or sensory impulses travel through the nerve to the brain and back. Nerve conduction studies are used to determine whether symptoms are caused by disease of muscles or nerves.

 

Other inflammatory conditions associated with HAM/TSP

Persons with HAM/TSP may also develop other inflammatory conditions such as:

 

• "Uveitis " (inflammation of the eye)

• "Arthritis" (inflammation of one or more joints)

• "Alveolitis" (inflammation of lung tissue)

• "Polymyositis" (inflammation of muscle)

• "Keratoconjuctivitis" (inflammation of the cornea and conjunctiva)

• "Infectious dermatitis" (inflammation of the skin)

• “Thyroiditis” (inflammation of the thyroid gland)

 

Summary

HAM/TSP is a chronic inflammation of the spinal cord caused by a virus called HTLV-1. Early diagnosis of HAM/TSP is important to enable early use of treatments that may halt, slow or partially reverse the disease.

 

The diagnosis of HAM/TSP is made by recognising the pattern of symptoms and signs, diagnosing HTLV-1 infection by an antibody test, demonstrating that the HTLV-1 viral burden in the blood is high, confirming the presence of HTLV-1 antibodies or HTLV virus in the CSF and by the exclusion of other diseases that may cause similar presentations.

 

Although there is currently no cure for HAM/TSP many treatments are available to relieve symptoms whilst anti-inflammatory treatments can reduce the severity of the disease. New treatments are under investigation.

 

Patients with HAM/TSP are usually cared for by a multidisciplinary team including a neurologist, infection specialist, physiotherapist and a nurse-specialist with access to other specialists especially for bladder and pain management.

The National Centre for Human Retrovirology Clinic  Imperial College Healthcare NHS Trust, Ground Floor, Winston Churchill Wing, St Mary's Hospital, Praed Street, London W2 1NY

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