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Wed 16 Aug 2006 04:00 AM

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After the Diagnosis: Managing Parkinson’s Disease

Healthcare Middle East reveals the new treatments that are helping to ease the symptoms of PD.

Healthcare Middle East reveals the new treatments that are helping to ease the symptoms of PD.

“Rivastigmine tartrate is the first drug to be approved by the FDA for the treatment of mild to moderate dementia in PD.”

Parkinson’s disease (PD) is a progressive disorder caused by a loss of dopamine-producing cells. This loss prompts changes in the connections between the substantia nigra and the corpus striatum, predominately affecting movement.

PD is one of the most common neurodegenerative movement disorders and, while there is no cure, advances in treatment have made it easier for sufferers to remain active for longer.

Researchers are increasingly recognising that dopamine-producing nerve cells can be disturbed in brain areas other than those involved in motor control, and even outside the brain, which helps explain the host of symptoms that can accompany the disorder.

Normally, smooth and controlled movements are regulated in the mid-brain area of the substantia nigra. Classic PD symptoms, such as tremor, slow movement, rigidity or stiffness, and poor balance and posture, occur when 80% of the dopamine-producing cells in this area are lost. It is not clear what causes this loss.

In some cases, PD is simply inherited; several of the mutations involved have been identified. Heredity alone accounts for only a handful of cases, but studying these may suggest what goes wrong in all PD. For example, some mutations interfere with the functioning of mitochondria. Toxins that interfere with mitochondrial function, such as the chemical MPTP, can also cause PD.

Other PD genes disrupt the processes that clear away alpha synuclein. Excess amounts of it appear to play a role in the death of cells in the substantia nigra.

Some theories link PD to chronic inflammation, premature aging, or an overabundance of free radicals. Discovering the combination of factors that causes PD will point the way to better strategies for preventing and treating it.

"Supplements may help delay the progression of PD symptoms. Some physicians already recommend coenzyme Q10 on the basis of encouraging preliminary findings."

While movement problems are the most noticeable PD symptom, many patients will tell you that they’re not the most distressing. In one survey, 88% of patients reported troubling nonmotor symptoms, and these tend to become more prominent as the disease progresses. The following symptoms, if they’re not recognised as part of PD and treated accordingly, can severely impair a person’s quality of life:

• Depression
Depression affects more than half of people with PD and is increasingly recognised as a symptom of the disease itself (sometimes even appearing before tremor), rather than a secondary reaction to chronic illness. Depression and PD share certain symptoms, such as decreased energy and weight loss, so it may be difficult to diagnose depression unless you ask a patient specifically about feelings of sadness, anxiety, and hopelessness, or thoughts of death or suicide.

According to the American Academy of Neurology, the most effective drug treatment for depression in PD is the tricyclic antidepressant amitryptiline — although it’s not necessarily a first choice because of side effects that include drowsiness, a drop in blood pressure, and dry mouth. Deep brain stimulation may be effective for depression and other symptoms, such as tremor and rigidity.

• Cognitive problems
Dementia occurs in an estimated 40% of people with PD, a rate six times that in the general population. The dementia associated with PD is characterised by dysexecutive syndrome, affecting mainly executive and visuospatial functions, while memory is relatively preserved.
If a patient has trouble staying alert, solving problems, or switching thoughts from topic to topic, it may be a sign of PD-associated dementia. To find out, ask questions that test memory, problem-solving ability, attention span, and language skills. Two medications, rivastigmine and donepezil, are sometimes used to treat PD-associated dementia, but the benefits seem to be small.
Earlier, this year, Rivastigmine tartrate (Excelon) became the first drug to be approved by the FDA for the treatment of mild to moderate dementia in PD. However, it is associated with significant gastrointestinal adverse reactions and may worsen tremors.

• Hallucinations and delusions
At least 20% of people with PD develop hallucinations or delusions. They are commonly viewed as a side effect of antiparkinsonian treatment, but other factors may be involved. Some studies have suggested that cognitive impairment and sleep disturbances, amongst others, may be cofactors in the origin of hallucinations. A common delusion is the belief that a spouse is having an affair. The neurologist must rely on the patient or caregiver to report these symptoms, which can be treated by eliminating any underlying causes, adjusting medications or adding an antipsychotic drug, such as clozapine or quetiapine. These medications can effectively control hallucinations at low doses without worsening PD symptoms.

• Sexual problems
Women with PD sometimes report decreased libido, vaginal tightness, and loss of the ability to achieve orgasm. Treatment with dopamine-boosting agents may overcorrect this deficiency, leading to hypersexual behaviours. This can ranging from intrusive sexual thoughts, urges or remarks, to overt, inappropriate sexual behaviours that can seriously damage relationships, especially if it is not recognised as a side effect of the treatment. Changing medications can help.

Erectile dysfunction is also a significant problem in PD sufferers, and is thought to affect 50-75% of patients. Medications, such as Viagra, have been shown to be of benefit.

• Compulsive behaviors
In a survey of people with Parkinson’s disease presented at the April 2006 meeting of the American Academy of Neurology, researchers from NINDS found that 10 patients developed problem gambling after they started treatment, losing an average of $150,000 each. Seven others developed hypersexuality, and two began compulsive shopping. Almost all were being treated with both levodopa and a dopamine-boosting drug. Such impulse-control disorders are thought to be related to abnormalities in the brain’s ‘reward circuit’, which is also a dopamine-mediated neural system and sensitive to dopaminergic medications. If a patient exhibits uncharacteristic behaviour, it may be necessary to change their medication.

• Anosmia
Anosmia has been documented as one of the early clinical signs of PD, often appearing long before motor symptoms emerge. A study, published by researchers at the University of Pennsylvania School of Medicine, suggested that the loss of smell in PD sufferers is linked to the increased presence of key disease proteins, such as tau and alpha-synuclein, found in brain regions associated with smelling.

Smell can’t be revived, but foods with strong flavours and a pleasing appearance can help spur the appetite.

• Constipation
This is a common symptom of Parkinson’s disease. Autopsies have shown that Lewy bodies, a characteristic of Parkinson-affected cells, can develop in nerves controlling the colon. Standard treatments, such as increased fiber, fluid, and exercise, with added laxatives if necessary, can help.

• Orthostatic hypotension
PD interferes with the nervous system’s control of heart function, making it difficult for the body to adjust blood pressure, for example when moving from lying down to standing. This can cause orthostatic hypotension, which may result in fainting or a fall. Orthostatic hypotension can be caused by the PD medication. It may help to change meds, increase fluids and salt in the diet, or add a drug that counters sudden drops in blood pressure.

No lab test or scan will conclusively diagnose PD, but tests can be used to rule out other explanations, such as another neurological disease with similar symptoms. If a patient’s symptoms improve with a single dose of a PD medication, it’s likely that he has the disorder. But all PD medications have side effects, so you may want to postpone drug treatment.

“It’s okay to have some of the symptoms as long as they’re not interfering with your professional or other important activities,” Dr Anne B. Young, head of the neurology department at Boston’s Massachusetts General Hospital tells patients. “When you’re not able to work, be active socially, or travel, it’s time for treatment.”

Several nondrug approaches, including exercise and physical therapy to improve strength, balance, stamina, and flexibility, can help maximise a patient’s ability to function. Other types of therapy can help ease dysphagia and speech difficulties and teach new ways to carry out movements and tasks made difficult by PD. Supplements that may help delay the progression of PD symptoms are under investigation. The National Institute of Neurological Disorders and Stroke (NINDS) is evaluating coenzyme Q10. Some physicians already recommend it on the basis of safety and encouraging preliminary findings. On the other hand, vitamin E does not delay the development of Parkinson’s symptoms and is not recommended.

Once symptoms warrant treatment, patients may receive a dopamine-boosting agent or other drugs such as selegiline and amantadine. Sinemet, an older but effective medication, is also commonly used. Sinemet contains levodopa, combined with carbidopa. More than 90% of patients respond to Sinemet, with motor symptoms and the ability to carry out normal activities improving by about 50%. Possible side effects include nausea and dyskinesias.

Unfortunately, levodopa and other medications often provide reliable relief only for a brief ‘honeymoon’ period. After that, medications may become less effective or totally ineffective — or effective only on and off (called the on-off phenomenon). A patient may require higher doses that can cause troubling side effects, including dyskinesias.

In April 2006, the American Academy of Neurology announced new guidelines for the management of on-off phenomenon and dyskinesia. After evaluating research results on a number of medications, they found evidence that two drugs can reduce the amount of ‘off’ time. Entacapone is an enzyme inhibitor that increases the amount of levodopa that reaches the brain. A medication called Stalevo combines entacapone with levodopa and carbidopa. Rasagiline — available in many countries since 2005 but still awaiting final FDA approval — slows dopamine breakdown. Other drugs have less evidence behind them but may help with particular symptoms.

The Academy also reported that deep brain stimulation (DBS) can reduce motor symptoms and the need for medication. This procedure involves the insertion of an electric probe into the subthalamus region of the brain, attaching it to a pacemaker-like device that regulates brain activity with bursts of electricity. DBS doesn’t help with speech or balance, but it can reduce tremor and dyskinesias in the 10%–20% of patients for whom levodopa loses its effectiveness. Because it’s reversible and adjustable, DBS is generally preferred over surgical techniques that destroy portions of brain tissue. About 30,000 patients now have a DBS device implanted, and use of the technique is becoming more widespread.

Medications and surgery may ease symptoms, but they don’t stop or reverse the underlying disease process. Whatever a patient’s condition, physical, occupational, and speech therapy can help them to function better. Therapeutic exercise can help prevent falls and improve the ability to breathe, speak, and swallow.

The search continues for ways to slow or halt the progression of PD and make the disease more manageable.
In February 2006, at the first World Parkinson Congress in Washington, D.C., NINDS announced that two compounds — the antibiotic minocycline and the amino acid creatine — showed enough promise to warrant large clinical trials of their ability to protect healthy neurons and delay the need for drug treatment in early PD.

Investigators are also considering new ways to deliver standard dopamine-influencing drugs, such as keeping dopamine levels steady by the use of a skin patch or direct infusion into the intestine. A product called Neupro patch has recently been licensed for use in the UK. The patch delivers a continuous dose of rotigotine, a dopamine agonist, over 24 hours, so patients only have to change the patch once a day. Other treatments under investigation include medications that act on other neurotransmitters involved in movement control, and a protein that promotes the growth of brain cells.

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