The Parkinson's fix

            24 July 2004

            Anil Ananthaswamy


THE woman slumped to one side and started crying. "I'm falling down in my head," she said. "I no longer wish to live." The doctor asked if she was in pain. "No," she replied, "I'm fed up with life." The 65-year-old patient seemed in the depths of depression. Yet moments earlier she had shown no such distress. She had long-standing Parkinson's disease, the progressive neurological condition that causes tremor, stiffness and movement problems, but had no history of depression. What had changed?

It was the mere flick of a switch. The woman had just undergone surgery to receive a futuristic new treatment for Parkinson's disease. The procedure involves implanting electrodes that send a current into the brain. When switched on, they somehow stop a region of the brain only a few millimetres in size from functioning. Known as deep brain stimulation (DBS), the technique gives neurosurgeons the almost magical ability to reach into the brain and turn off troublesome areas at will.

In the case of Parkinson's disease, the brain areas targeted are those whose hyperactivity cause the condition's distressing symptoms. DBS can produce dramatic improvements and over the past two years it has been used for growing numbers of people with Parkinson's disease, as well as other tremor and movement disorders and chronic pain. The number treated in the US now runs into thousands.

But cases like the woman who suddenly became depressed illustrate what a mysterious technology DBS still is. As the number of people treated grows, so do reports of side effects. They range from complications caused by surgery and failure of the device itself to more disturbing reports of depression, perhaps even leading to suicide in a few cases. Could doctors be letting their enthusiasm for an exciting new therapy get the better of their judgement? The technique's developer, Alim-Louis Benabid, head of neurosurgery at Grenoble University Hospital in France, says: "When one designs a new method and it's powerful, there is a risk of overuse and mispractice. I'm aware of that - and quite frightened."

Parkinson's disease is caused by the degeneration of groups of neurons on either side of the brain that normally release a chemical called dopamine into brain areas that control movement. The lack of dopamine causes these control centres to go haywire and become hyperactive. The main treatment for Parkinson's is a medicine called levodopa, which the brain converts into dopamine. But the drug causes other movement problems such as twitches and jerks, and over time its effectiveness wanes. Other medicines can help to some extent, but people with long-standing Parkinson's can be severely disabled. A few centres have even tried putting dopamine-producing neurons from aborted fetuses into patients' brains but some suffered bad side effects from too much dopamine.

The approach of turning off the hyperactive movement-control centres has a long history. After a chance finding in the 1950s, surgeons began trying to help badly affected patients by destroying small areas of brain tissue - about the size of a Tic Tac - in the movement-control centres. Such surgery produces an impressive reduction of symptoms for some people, but it carries serious risks. The procedure can cause bleeding in the brain, which may lead to a possibly fatal stroke, and if the surgical lesion is only slightly off target, patients can end up with slurred speech or muscular weakness. To help identify the right area of the brain in which to make a lesion, surgeons would sometimes use electrodes to deliver an excitatory current of between 10 and 30 hertz.

It was in 1987 while performing this kind of surgery for Parkinson's and other tremor disorders, that Benabid's breakthrough came. At frequencies of around 100-130 hertz, the current inhibited the neurons rather than excited them, he found. When he applied the electrodes to certain areas of the movement control centers patients' tremors vanished. Eventually, when facing a patient for whom lesion surgery would have been especially risky, he decided to try implanting the electrodes permanently. "The effects replicated those of lesions, but reversibly," says Benabid. "I felt I had reached the end of a quest."

People severely affected by Parkinson's disease may have fluctuating responses to their medication, and between doses they can be frozen to the spot, incapable of movement. Benabid, and other surgeons, use terms like "miraculous" and "spectacular" to describe the effects of DBS on the condition. "You turn on the stimulation, and within seconds the patient will melt down," says Benabid. "I have videos of people waltzing in front of me."

Miraculous though the results can be, implanting the DBS device is a complex procedure that requires neurosurgical skills of the highest order. Dauntingly for patients, they must be awake during the operation so that the surgeon can monitor their responses to stimulation from the electrodes. Only a local anesthetic can be given. The patient's head is immobilized by a computer-guided frame, which indicates the approximate target area, based on brain scans. Then a recording microelectrode the width of human hair is threaded deep into the brain. When it signals that the desired area of the brain is reached, the surgeon removes it and inserts the permanent stimulatory electrode.

Once the electrodes are in place, the wire is run down the neck and connected to a device called a neurostimulator, which is implanted under the collarbone and generates the electric current (see Graphic). A few days later, once the patient has recovered from surgery, the device is tested and fine-tuned to deliver the correct pattern of electrical stimulation. It may take a few months to programme the neurostimulator to optimal settings. The equipment is made by the US firm, Medtronic.

Through the 1990s growing numbers of neurosurgeons started offering DBS for Parkinson's disease and other tremor or movement disorders. Numerous small studies confirmed the benefits of the technique, and the device was approved to treat tremor in the US in 1997 and Parkinson's disease in 2002. It was approved in Europe and Australia in 1998.

But some doctors are concerned about the rapid uptake of this technology. For a start, the lack of large randomized trials of DBS means it is hard to work out just how common adverse effects are. Surgery on the brain is never something to be undertaken lightly. As with lesion surgery, implanting the electrodes can occasionally cause bleeding and strokes as well as visual, speech and cognitive problems. And if there are complications like slipped electrodes or broken wires, patients must undergo a second round of surgery.

Perhaps surprisingly for a procedure that is becoming increasingly common, there is no consensus about whether it needs to be performed on both sides of the brain or just one. Parkinson's is an asymmetric disease in which symptoms start on one side of the body and progress to the other, and this asymmetry is preserved even in advanced stages. Some people have a device implanted just on their worse side, and this reduces symptoms on the other side too. But many surgeons are starting to routinely put in two implants, which could be unnecessarily exposing someone to double the risk. "There is a sub-population of patients that may not even need a second side," says neurologist Ali Samii of the University of Washington in Seattle. "We just don't know who they are."

The best site for the implant is also debatable. Surgeons generally target one of two different regions of the brain that control movement: the subthalamic nucleus (STN) or the globus pallidus interna (GPi). Medium-sized trials have suggested implantation in the STN has the edge, but there have been no large-scale, randomized head-to-head trials. Samii is carrying out a study of 250 patients, but this is unlikely to be complete before 2007.

Perhaps the most serious concern over DBS, however, is its potential for causing dramatic mood disturbances. Though it seems rare, there have been reports of patients experiencing depression, mania, aggression, anxiety and even thoughts of suicide. Most have occurred while the electrodes were first being tested - as in the case described at the start of this article (The New England Journal of Medicine, vol 340, p 1476) and they can be tackled by fine-tuning the stimulation. Others have only emerged months later.

Most alarming of all have been reports that a small number of people with the implants have made suicide attempts, a few of which have succeeded. A study by Benabid, for example, which was published last month, showed that out of 77 consecutive patients who had received DBS, within three years one had committed suicide and four had made suicide attempts (Journal of Neurology, Neurosurgery and Psychiatry, vol 75, p 834).

Of course, severe Parkinson's disease is enough to make anyone depressed, points out T.R.K. Varma, a neurosurgeon at the Walton Centre for Neurology and Neurosurgery in Liverpool, UK. "You have a group of very disabled patients with a progressive disorder," he says. Another possibility is that DBS is causing these effects indirectly - perhaps the surgery's success leads to medication being reduced or lifestyle changes, which could conceivably affect mood. That would not, however, explain the sudden mood changes that have occasionally been seen when the electrodes are first switched on.

If the effect were a direct one, what could be causing it? One possibility is that the current from the electrodes is spreading to areas adjacent to the STN and GPi that are involved in regulating mood. Alternatively, the STN and GPi are both known to have neurons that carry signals to the outer cortex of the brain, to regions involved in mood and thought.

Last year researchers at the University of Florida in Gainesville carried out a small study that suggests that one cause could be a slight mispositioning of the electrodes (Journal of Neurology, Neurosurgery and Psychiatry, vol 74, p 1584). Nine people with Parkinson's disease were stimulated in either the STN or GPi and, during the procedure, were assessed using a questionnaire that measured various aspects of mood. When the electrodes were moved slightly from the site where they produced the optimal improvement in Parkinson's symptoms, some patients experienced small but noticeable mood changes. Most were for the worse, although some were improvements. These findings suggest accurate placement of the electrodes is crucial. "It's a huge concern," says Michael Okun, who carried out the research.

The findings also seemed to bear out hints that mood changes may be more common with STN targeting than with GPi, although the study was so small this result was nowhere near statistically significant. Okun, who plans to do further, larger studies, points out that the STN is a smaller target than the GPi - with a volume of about 160 cubic millimeters, compared with 480 - with less room for error.

The STN is targeted more commonly, due to the studies suggesting that it is more effective. But is this at the expense of increased risks? If so, perhaps surgeons should rethink their choice of target, says Okun, particularly for patients who seem most at risk of depression or cognitive problems.

Wouldn't a small risk of mood changes be an acceptable price for a reduction in Parkinson's symptoms? Perhaps - but only if that is the choice made by fully informed patients. At the moment not all doctors are aware of this potential risk, says Okun, never mind patients. And if doctors are unaware they cannot be extra-vigilant for the problem.

Last year the UK's influential National Institute for Clinical Excellence (NICE) produced guidelines on DBS for Parkinson's disease. While the full version acknowledged that a few cases of depression have been reported, the summary version - a separate document that is the one most likely to be seen by patients - did not. And the possibility that some patients could experience mood changes severe enough to cause suicide got no mention. This is defended by Varma, who advised the NICE authors. "It is a very small number worldwide that has been reported," he insists. And Medtronic says: "There is no evidence to suggest that DBS, applied by skilled clinicians in appropriately selected patients can cause depression, let alone suicide. It is much more likely that in these rare cases, the underlying features of Parkinson's disease are responsible for the patients' actions." But Benabid says: "In the population of stimulated patients around the world, the reported cases of suicides are not negligible. And they might be due to [electrode] misplacement."

The concerns make all the more worrying the rapid growth in the number of hospitals now performing DBS, particularly in the US since its approval for Parkinson's disease two years ago. Okun claims that at some smaller centres, neurosurgeons have started to carry out the procedure without the full multidisciplinary team needed. They may lack a psychiatrist or neuropsychologist to ensure the patient has no depression, or a trained physiologist to monitor the recording microelectrode during surgery. When things go wrong, patients have to be referred to larger hospitals such as Okun's. "It's tremendously worrisome," he says. "We are seeing increasing numbers of complications."

There are also fears that some surgeons may be too keen to recommend the procedure. DBS is only supposed to be given to people who have advanced Parkinson's disease, for whom all drug therapies have been tried without success, and who do not have any mental illness. Estimates for the proportion of people with Parkinson's meeting these criteria range from 5 to 20 per cent. Benabid is worried that surgeons may be carrying out the procedure too often: "I know that some teams have done as many cases in one year as I have done in 10," he says. Benabid and other surgeons in Europe are now drawing up a set of standards that they believe all surgical teams should have to meet.

Doctors in other medical specialties are also starting to experiment with DBS. Severe epilepsy has long been treated by lesioning the brain region that seems to trigger the seizures, so DBS is being tried for this condition, with some success. Some groups are even carrying out small pilot studies using the technique to treat obsessive-compulsive disorder, and have had positive initial results. The limits to the future applications of this technology are anyone's guess.

But some doctors believe there is a need for more caution, not less. No one is arguing that surgeons should stop using DBS for Parkinson's disease. The dramatic benefits it brings for most patients are incontrovertible. But people need to be fully informed about all the potential risks from this procedure, and surgeons need to exercise more caution, says Okun. "We need to warn our patients, and treat complications aggressively, and if possible try to prevent them," he says. "We have to recognise mood and cognitive complications as a reality that we don't yet fully understand."

From issue 2457 of New Scientist magazine, 24 July 2004, page 40