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Scattered pictures – brain impairment and HIV

Gus Cairns, Theo Smart
Published: 01 May 2009

Gus Cairns and Theo Smart investigate HIV-related brain impairment, memory loss and dementia

As people with HIV survive into old age there is increasing focus on conditions associated with ageing. The evidence that HIV increases the chance of getting things like heart disease and some cancers may cause anxiety, but for many the biggest concern may be whether we are more likely to develop memory loss and dementia. So it was not surprising that a group of studies on brain impairment presented at the Conference on Retroviruses and Opportunistic Infections (CROI) this year raised considerable concern amongst the HIV-positive community.

In the 1980s, obvious dementia was fairly common in advanced HIV disease, but became unusual after the introduction of AZT. Mild to moderate neurological disorders continued to be observed in people with late-stage AIDS,1 but there was clear evidence of improvement with the introduction of antiretroviral therapy (ART).2 More subtle neurological symptoms seemed to persist in some people, though, despite the life-saving therapies that were so effectively managing other HIV-related conditions.

So in 2002, the US National Institutes of Health launched a multi-site study called CHARTER (it stands for CNS [central nervous system] HIV Anti-Retroviral Therapy Effects Research). It will look comprehensively at the prevalence in people with HIV of neurological disorders - nerve or brain damage that can be detected by physical tests - and cognitive disorders - disorders in thinking and memory that can be picked up in psychological tests. It will try and find ways of predicting whether people will develop brain impairment and diagnosing it accurately when they do.

To some people, CHARTER’s first results were a shock.3 It found that at study entry, out of the 1555 people with HIV in the United States whose brain function was measured, more than half – 53% - had some form of neuro-cognitive impairment. One in ten had clearly noticeable impairment, and one in fifty moderate HIV-associated dementia, though the prevalence of classic ‘AIDS dementia’ was under 1%.

So does this mean that more than half of us are already on the way to losing our minds? No. The evidence that HIV infection does cause a specific kind of mild impairment in mental function is strong, but it may not resemble or have the same causes as classic dementia, will not necessarily progress, and may not be noticeable in daily life.

Dr Simon Rackstraw is Medical Director of Mildmay UK, a hospital in Shoreditch, east London, which is the UK's only specialist unit for people with HIV-related brain impairment.

“CHARTER’s findings are robust,” he says, “however I’m not sure how important this mild impairment is.”

Rackstraw continues. “Sensitive psychological tests can pick it up, but in real-life terms it’s not interfering with daily life and people won’t be noticing symptoms. You’re talking about the sort of things – lack of concentration, losing things, clumsiness, forgetting names – that most of us experience at some time or other. The effects these tests pick up are the same sort of things that could be produced by a hangover, not enough sleep, or depression.

“The 10% with moderate impairment, however, may notice difficulty with relatively complex tasks like driving. Other people may notice changes better than the person concerned.

Rackstraw explains that HIV-related brain impairment often presents a different picture from classic dementia. “People have difficulties with executive function – the ability to make choices and decisions – and may put things off more. Muscular co-ordination may be lost too. On the other hand verbal fluency is usually retained; people remain mobile and energetic, but get a bit chaotic. One of my patients talks very convincingly about running a share portfolio – though I’m not sure how effectively - but can’t open a can of baked beans. Classic Alzheimer’s is more memory-oriented and people become more apathetic.”

Very importantly, and of some reassurance to those of us who keep losing their keys, mild brain impairment appears to be reversible. In another study presented at CROI, Dr Scott Letendre4 cited the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials (ALLRT), a study of 1160 HIV-positive people who had been on therapy for an average of about 20 weeks.5 At the start, despite most people being on therapy, about 39% demonstrated at least mild impairment. When ALLRT re-tested participants 48 weeks later, it found that over half of people who had impairment at baseline still had it, but in 44% of cases the impairment had apparently reversed – brain function appeared normal again. However, among people who had normal results at their first testing and then were re-tested, just over a fifth (21%) had new impairment.

In other words HIV brain impairment appears to be on average progressive amongst this group, but slowly, at a rate of about 4% more patients with some degree of brain impairment a year. But the average conceals the fact that nearly half of patients who have brain impairment at one test don’t have it next time.

Even then, it isn’t clear that HIV-related neurological impairment will always progress to HIV-associated dementia if left untreated, or even that they’re the same thing: there may be more than one pathological process involved in the development of neurological problems in people with HIV.

In addition, although age is a factor, some recent studies showed that HIV-specific brain impairment is by no means restricted to older people. One study from St Mary’s Hospital in west London,6 for instance, found that – relative to others of their age – HIV-related brain impairment was actually more common in younger people with recent diagnosis. Rackstraw confirms this. “The youngest I have currently on the ward is 22,” he says, “and I’ve treated a number of teenagers.” HIV brain impairment and age may not always be linked.

What causes it?

What are the risk factors for brain impairment, and why might some of it reverse? The CHARTER researchers found that the strongest predictor of brain impairment was the lowest-ever CD4 count (the CD4 nadir) – though having a high current viral load was also important. One more reason to start HIV treatment early.

Simon Rackstraw comments that “I have seen remarkable recoveries just from putting people on antiretrovirals. Over 90% of our referrals are either people diagnosed late or people diagnosed a while ago who dropped out of medical care. If we see brain impairment progressing in people on antiretrovirals, it’s due to a cause other than HIV like alcohol abuse.”

HIV disease is not the only cause of brain impairment. Hepatitis C has neurocognitive effects of its own. Alcohol and substance abuse, stress and poor sleep may all be more damaging than HIV itself. Then there are psychological disorders like depression. “Depression may look like brain impairment,” says Rackstraw. “We find that sometimes if patients are given antidepressants this is sufficient to produce a remarkable recovery.” In other words, there are modifiable factors which, when changed, may improve function.

Being in an HIV risk group may raise your risk of brain impairment in itself. Two pre-ART studies found rates of 17 and 9% of neurocognitive impairment in a control group of HIV-negative gay men where the expected rate in the general population is about 3 to 4%.7,8 It’s not known why.

 

HIV in the brain

What might HIV be doing to the brain? It doesn’t replicate in nerve cells, so the theory was that damage occurred because HIV, brought inside immune-system cells, was setting up an inflammation in the brain. It’s not clear, however, that there’s a strong association between current HIV viral load in the blood and viral load in the cerebro-spinal fluid (CSF, the fluid that bathes the brain and spinal cord), or between CSF viral load and dementia.

Instead the reason brain impairment may get worse despite HIV treatment and with an undetectable viral load  is because early HIV infection may set up brain cells to be permanently more vulnerable to the conventional risk factors for brain impairment (alcohol, depression, drugs and so on). “This means that even if you take the HIV out, it may not stop,” comments Simon Rackstraw. We may need to take care of our brains better than other people.

Because neurocognitive problems have so many different causes, a team from St Thomas’ hospital in south London recently conducted a smaller study9 amongst HIV patients on ART with few other risk factors to try and see if brain impairment was more common even amongst them than the general population.

They selected 40 gay men who had been on stable HIV therapy for over six months with a CD4 count over 200 cells/mm3. They had minimal recent and lifetime use of alcohol, cannabis and other recreational drugs, had no hepatitis B or C, and no current or past significant psychiatric, medical or neurological conditions. Anyone who had previously reported memory problems was excluded. They identified 20 men aged 20 to 40, and 20 men aged 50 to 75, for the study. They put them through a large battery of neuropsychological tests and four different kinds of brain scan. They also put two control groups of 20 HIV-negative gay men with similar characteristics and ages through the same tests.

There was a tendency for the HIV-positive men in both age groups to have more cognitive impairment but this did not reach statistical significance. Fifteen per cent of HIV-positive men had brain impairment compared with 10% of the older HIV-negative men and 9% of the younger ones. Note that even in the HIV-negative men, there was three times as much brain impairment as expected in men of their age.

The brain images revealed a specific and significant loss of grey matter (the nerve cells that actually do the thinking) from a part of the brain called the medial and superior frontal gyrus. This area, located right above the centre of the forehead, deals with decision-making and choice. However, the patients with loss of nerve cells were not the same people as the patients who had cognitive impairment.

HTU talked to HIV consultant Dr Babu Kulasegaram and neuropsychiatrists Dr Mervi Pitkanen and Professor Mike Kopelman about their study.

“I was seeing more and more patients who were coming in and saying ‘I’m not as sharp as I was’,” says Kulasegaram. “So we wanted to see if there was any sign of brain impairment in people on HIV treatment with every other causative factor eliminated, as far as possible.” One possibly controversial decision was only to include white UK gay men. Why exclude other ethnicities? “We very much want to look at the African population too,” says Pitkanen, “but some of the neurocognitive tests are very culturally specific – asking you about current politicians, for instance – and we wanted as homogeneous a group as possible.”

HIV treatment and brain impairment

Are some HIV drugs better than others for brain impairment? In the large US studies, having a detectable CSF viral load and performing less well on tests was associated with using antiretroviral drugs less likely get into the brain.

“We don’t have to put every HIV patient on brain-penetrating regimens,” says Simon Rackstraw, “but I’ve put people with impairment on drugs that get into the brain better and they have improved.”

At St Thomas’, Mervi Pitkanen comments that although people with HIV may be more vulnerable to brain impairment there is no indication that, if their risk factors are controlled, it will inevitably get worse.

“Our brain scan images may be picking up on trouble to come,” she says. “But we know we can say to diabetics: ‘If we keep your diabetes under control, there’s a pretty good chance we can avoid you getting kidney problems 20 years hence.’ We need to be able to offer the same reassurance to people with mild brain impairment – that if we keep it stable, it won’t lead to dementia.”

The best thing to do, then, is to try to eliminate as many of those other risk factors as possible – cut down on alcohol, recreational drugs and smoking, treat high cholesterol and blood pressure, and get help tackling depression. The brain is a very adaptable organ and can, up to a point, compensate for losses of nerve cells and connections. Numerous studies in HIV-negative people have found that the more active you keep your mind as you age, the less likely you are to develop dementia. In one often-cited study10 researchers found that, among other things, reading, doing puzzles, playing board games, playing musical instruments, and dancing were associated with a reduced risk of dementia. Your daily Sudoku really may help to keep your mind sharp.

What if it does progress, however? Even if people with HIV only get as much dementia as everyone else, we may still need HIV-specific support and housing. “There’s a real lack of supportive housing schemes and care homes for people with brain impairment and HIV,” says Simon Rackstraw. “We still get supportive housing schemes saying things like ‘We would take this person but they have HIV’. Conversely, by no means all our cognitively impaired patients are old and a typical nursing home is no place for them. Unfortunately the cognitively impaired don’t write to their MPs.”

Although we should look to the future with optimism, we need to be realistic too. Who knows what it will hold?

Living with brain impairment: Lee’s story

Lee, a 52-year-old gay south Londoner, was diagnosed with HIV at his workplace: he is a former healthcare assistant. He’d run a lot of risks in his 20s, but put off testing for HIV till he came down with bacterial pneumonia in 1997. “I didn’t want to know: HIV felt like a time bomb waiting to go off.”

When a colleague finally persuaded him to get an HIV test he found he was lucky to be alive: his CD4 count in that first year hovered between zero and five.

Distressed at the death of his partner, he took an overdose of his HIV medications in 1998. Lee blames the brain impairment and mental problems he’s suffered from since then on this. Whether it was the cause or a symptom of them, he’s since survived other life-threatening nervous system illnesses, a section under the Mental Health Act, two stays in conventional psychiatric hospitals, and a number of shorter and longer rehabilitation stays at the Mildmay.

“It was really weird after I took the overdose. I was having nightmares when I was awake.”

He was moved to the psychiatric ward at the Royal Free Hospital. “That was a low point. I remember crying and thinking ‘Get me out of here’. I’d heard of the Mildmay and eventually they visited and assessed me for rehabilitation. They did a good job – got my CD4s up to 90. I enjoyed it there: we were allowed to go out, though they send the nurses out to watch you and assess how you’re doing. If you feel ready to leave, they do a big meeting with doctors, nurses, a social worker and an independent doctor. It took me three goes to get out.”

The brain impairment has intermittent, and selective, effects, he explains. He has great difficulty remembering the sequence of events and how long his stays in hospital were. On the other hand he is currently briefing a solicitor in order to reverse the local council’s refusal to extend the tenancy of his flat to his current partner.

How does he assess his own state? “I know I’m getting bad when I start shaking and [feeling] stressed. I feel myself getting aggressive and having suicidal thoughts. These days I’ve got ways of stopping it happening before it goes too far.”

As for getting better, he says, his yardstick is phone numbers. “At the Royal Free, every phone number I’d ever remembered went out of my head. Then one night at the Mildmay my brother’s popped into my head and I rang him. The others all reappeared slowly.”

He’s had a couple of other episodes of neurological illness. One may have been partly self-inflicted. “I came off my HIV pills in 2005. It was an experiment; I wanted to see if it worked.” His CD4 count stayed stable for quite a while, “but eventually my weight dropped down to seven stone.”

He tells a funny and painful story. “I looked in the mirror and thought ‘I look like I’ve got AIDS. I know, I’ll piss off to Sitges!’” [the gay resort town in Spain]. Lee describes a scene where, staggering and hallucinating, he was arrested by three policemen at Gatwick. “I can’t stop my mouth when I’m like that. I told one, ‘I recognise you, I had you in a back room in Brighton’. Well, they didn’t like that! They put me on a mental health section [compulsory admission] for six months in The Lambeth Hospital in Clapham. No one knew where I was.

“Eventually my niece found me. She alerted the Mildmay who got the Mental Health Section reversed. The Mildmay had me in for months, got my CD4 count up to 255, highest it’s ever been’.”

“I owe everything to the Mildmay, they keep getting me out of scrapes. I really wanted to go with my boyfriend when he died, but now, well, I don’t want to get old and decrepit, but if I look like I do now at 60, I might not shoot myself! I want to get better still.”

References

1. Heaton RK et al. The HNRC 500-neuropsychology of HIV infection at different disease stages. HIV Neurobehavioral Research Center. J Int Neuropsychol Soc 1(3):231-51, 1995.

2. Sacktor N et al. HIV-associated cognitive impairment before and after the advent of combination therapy. Journal of Neurovirology 8(2):136-142, 2002.

3. Heaton R et al. HIV-associated Neurocognitive Impairment Remains Prevalent in the Era of Combination ART: The CHARTER Study. 16th Conference on Retroviruses and Opportunistic Infections, Montreal, abstract 154, 2009.

4. Letendre S et al. Neurocognitive complications of HIV and their management. 16th Conference on Retroviruses and Opportunistic Infections, Montreal, abstract 181, 2009.

5. Robertson KR et al. The prevalence and incidence of neurocognitive impairment in the HAART era. AIDS 21(14): 1915-1921, 2007.

6. Garvey LJ et al. High rates of asymptomatic neurocognitive impairment (aNCI) in HIV-1-infected subjects receiving stable combination antiretroviral therapy (CART) with undetectable plasma HIV RNA. Fifteenth BHIVA Conference,

Liverpool, poster P84, 2009.

7. Grant I et al. Evidence for early central nervous system involvement in the acquired immunodeficiency syndrome (AIDS) and other human immunodeficiency virus (HIV) infections. Studies with neuropsychologic testing and magnetic

resonance imaging. Ann Intern Med. 107(6):828-36,1987.

8. Op cit (Heaton, 1995)

9. Towgood K et al. Cognitive function and brain grey matter change in HIV-1 younger and older positive ‘men who have sex with men’ in the post-HAART era. 15th BHIVA Conference, Liverpool, oral presentation 027,2009.

10. Verghese J et al. Leisure Activities and the Risk of Dementia in the Elderly. N Engl J Med 348:2508-16, 2003.

This content was checked for accuracy at the time it was written. It may have been superseded by more recent developments. NAM recommends checking whether this is the most current information when making decisions that may affect your health.