Awakenings – a review for healthcare staff

(See also what the International Movie Database says about Awakenings)

Please note: This article may spoil your spontaneous enjoyment of the film. A number of significant events are revealed, so if you want to watch the film without preconceptions, we advise you to read the article after watching the film.

Awakenings

Oliver Sachs, the author of "Awakenings” was born in London in 1933. He is professor of clinical neurology at Albert Einstein College of Medicine in New York. Oliver Sachs grew up in a large Jewish family of Russian origin, where both parents were doctors who owned a large house in central London. His father was moderately orthodox, but regularly took his son to the synagogue to hear services lasting up to three hours, where it was the choir and the music that Oliver appreciated more than anything else. His mother, also a doctor was raised in a large family with 18 children, half boys and half girls. She was an anatomist and a surgeon, but the routine medical discussions in the home frightened Oliver, who became increasingly hypochondriac.

By Jan-Edvin Olsson, Professor of Neurology, University of Linköping

In an attempt to counteract this development, his mother would take him along to cadaver dissections when he was only 14 years old; this frightened him so much that he swore never to become a doctor.

Even though a doctor today, his hypochondria persists, and is best depicted in his autobiographical book "A Leg To Stand On", in which Oliver Sachs, during a trip to Norway in 1974, climbs a mountain, is chased by a goat, and then falls and injures his left leg. He is completely convinced that the leg is broken, and finds himself unable to leave the site of the accident; he is instead transported with great difficulty from the mountainside to the hospital in Odda, where he does not want to be treated, instead travelling home to London via Bergen.

It then becomes clear that the leg is not broken, and that the injury is purely minor in physical terms. Oliver Sachs then describes, which is not uncommon among doctors, the role of being a patient and misunderstood.

For many years he has corresponded by letter with the Russian neurologist Luria, known for his neuroanatomical descriptions of soldier's gunshot wounds to the head during the Second World War and their linguistic impairments. Oliver Sachs' period of illness is described in the book as a wonderful inner voyage that allows him deeper insight into the psychological change that illness entails. Luria asks him if he thinks there would be any difference if he instead had injured his right leg, since left-side injuries correspond to the influence of the right, non-dominant hemisphere of the brain, which is known to produce the neglect phenomenon.

Growing up in World War II London left deep marks on Oliver Sachs. As a 10 year-old he was evacuated to the English countryside and then placed in a school for the poor, where the rector was a sadist and would often hit the boys. Upon returning to London after the end of the war, he would eventually become interested in chemistry, especially the periodical table. He set up a laboratory at home with the help of his uncle Dave, who makes incandescent bulbs with thin filaments of tungsten.

This would later lead to the book "Uncle Tungsten", reviewed in depth by professor Lars Erik Böttiger in 2001 in the newspaper Svenska Dagbladet. The mineral tungsten was discovered in 1751 by Cronstedt, a Swede, and it was von Scheele who was later able to show that it contained tungstic acid (given the chemical name "wolfram" in Swedish, even though "tungsten" is still used in English). Uncle Tungsten is subtitled "Memories of a Chemical Boyhood" and as such is also an autobiographical work.

Despite his childhood experiences, Oliver Sachs studied to become a doctor, and moved to the USA, where he worked for 24 years as a neurologist in a mental hospital in Bronx, New York. He then left a career as a researcher to begin writing full-time. Several of his books focus on medical case descriptions, however, and his best-known book is "The Man who Mistook his Wife for a Hat", which appeared in 1985. The story that gives the book its title describes a renowned singer with a strange case of brain damage, possibly vascular agnosia, which causes him to take his wife's head for a hat. Several of these depictions give no certain diagnosis, largely revealing the diagnostic difficulties that marked neurology before the advent of digital tomography.

"Awakenings" describes how patients in Oliver Sachs' hospital lived in a daze for a long time, at least 40 years, having sunk into "sleeping sickness"– encephalitis lethargica, a remarkable neurodegenerative illness that spread across the world at the end of the 1920s after the Spanish influenza.

"Sleeping sickness – encephalitis lethargica, a remarkable neurodegenerative illness that spread across the world at the end of the 1920s after the Spanish influenza."

Patients experienced a reduced level of awareness, possibly caused by swine influenza or some type of herpes-like virus, and when they awoke, about half would have severe Parkinson's-like symptoms including rigidity, bradykinesia, slight tremors, and curious eye movements, so-called oculogyric crises - an uncommon symptom in idiopathic Parkinson's disease.

In deceased patients, it was possible to observe severe levels of destruction in the black substance (substantia nigra) of the brain stem in a much more defined way than in normal Parkinson's, more closely resembling toxic MPTP damage. Levodopa had then started to be used in usual Parkinson's with relatively good results, despite peripheral side-effects because of the high doses used.

Oliver Sachs convinced hospital management to obtain money and authorisation to try levodopa on his post-encephalitic patients as well.
Initial results were strikingly positive, especially in the patient who would later become the main character played by Robert de Niro in the Oscar-winning film version of the book. Unfortunately, it had not yet become common practice at the time to titrate levodopa dosage slowly, which is especially important in post-encephalitic patients; as a result, patients entered a psychotic state that was difficult to manage, and the treatment study was discontinued in a very crushing way for the young Doctor Sachs.

There is also a certain connection in this book and film - and even a theatre piece by Harold Pinter – on Oliver Sachs' own childhood. Sachs' parents were very interested in the dramas of Henrik Ibsen, and one of his lesser-known plays from 1899, "When we dead awaken", depicts patients awakening from stupor. Romantic elements are uncommon in Sachs' books, but in an almost platonic love story, a young nurse tries to console him, but without much success, and the book, like the film, concludes with a number of unanswered questions.

Aside from these his most well-known books, Oliver Sachs has also written a book on migraines (from which he also suffers), including detailed descriptions on aural phenomena and hallucinatory experiences. "An Anthropologist on Mars" describes seven clinical cases, such as that of a surgeon who is plagued by uncontrollable tics whenever he is not operating, or that of an artist who loses his colour vision after a car accident only to then find a new motif and  creativity in black and white, or that of an autistic professor who is an expert on human intuitive understanding of animal behaviour, but who cannot manage the most basic social relationships with other people.

Sachs' mother was also highly interested in plants, especially fruit trees and ferns, and from his childhood Oliver Sachs recalls the palms and fern trees of her greenhouse. As an adult he would undertake his own botanical travels, such as his trip to Mexico, which is described in his book "Oaxaca Journal". Most widely known, however, is "The Island of the Colour-blind", where on the small Pacific island of Pingelap, Sachs encounters the problems of the colour blind, and then opens a small clinic in the island's primitive pharmacy. He also visits the island of Guam, known through Nobel Laureate Prusiner's description of the illness Kuru, which is spread through cannibalism but with great similarities to "mad cow disease" or Creutzfeldt-Jakob syndrome. 

I have personally met with Oliver Sachs on two occasions. The first time was during a 1994 Parkinson's conference in Rome, when he was showing a film on the striking effect of levodopa in Parkinson's patients. He made the biggest impression, however, in the hotel's swimming pool, where he swam and snorted like a large seal. He has said himself how important it is to swim, at least three times a day. The next time was in 1996, when he was visiting Stockholm and the Karolinska Institut as part of the launch of "The Island of the Colour-blind", which also includes descriptions of the world of the deaf. He made an almost timid impression and described his own stage fright before his lecture.

It has now been a while since Oliver Sachs has released a new book, and it may be some time until his next one. I can wholeheartedly recommend his celebrated film "Awakenings" not only to doctors and medical personnel, but also to patients and the general public.

“By opening a man’s eyes to the world, he opened his own.”

By Bo Johnels, Senior lecturer, Sahlgrenska Hospital, Gothenburg

The research front
- an overview

Cause

The cause for the development of Parkinson's disease is still shrouded in mystery. Genetic defects in a number of chromosomes have been shown capable of producing Parkinson's-like illnesses, often with early onset. As a whole, heredity can only account for about 5 percent of all occurrences of Parkinson's disease. One of these genetic defects concerns an intracellular protein known as alpha-synuclein.

A hypothesis launched by the German neurologist Heikki Braak suggests that Parkinson's disease occurs when genetic defects result in a successively increasing level of alpha-synuclein in the brain stem, and once this level reaches a certain point, the protein is released to characteristic inclusion bodies (Lewy bodies) in the cells. The high level of alpha-synuclein results in cell poisoning and a drop in dopamine neurons.

Dopamine shortage then causes the characteristic symptoms of Parkinson's disease, mainly hypokinesia, rigidity and tremors. Brain stem nuclei can also be afflicted, resulting in conditions such as orthostatic hypotension. If the presence of Lewy bodies spreads to cells in the cortex, then a typical form of dementia will develop, often with elements of Parkinson's symptoms (Diffuse Lewy-Body Dementia).

American researchers have pointed out the similarity between the intraneuronal processes in Alzheimer's disease and Amyotrophic Lateral Sclerosis (ALS). If these hypotheses can be validated, this will open up the possibility of curative medication (inhibitors) in Parkinson's disease through measures to prevent the occurrence of excessive alpha-synuclein in the nervous system. There is also the possibility that external agents, "environmental toxins" such as pesticides or heavy metals, may influence the development of the disease or accelerate the loss of nerve cells. A number of reports from the USA suggest that the risk of Parkinson's disease increases with exposure to environmental toxins.

Medication

Medication in Parkinson's disease is based on four groups of drugs: levodopa substances, drugs that inhibit the breakdown of dopamine (MAO and COMT inhibitors), dopamine agonists, substances with dopamine-like (receptor-stimulative) properties ("imitators of dopamine") and a group including drugs with effects on neural pathways with other signal substances (anticholinergic substances and Amantadine).

Since its introduction in 1967, levodopa has been considered the gold standard, the most effective drug against Parkinson's disease. Early administration of levodopa has been shown to extend lifespan even if levodopa only has symptom-alleviating and non-healing qualities. The drug has two drawbacks, first that its half-life in tissue is short and the duration of the drug's effect is dependent on the number of remaining dopamine-storing cells in the brain, and secondly that levodopa has a greater tendency to cause overdose effects such as involuntary movements and cramps ("dyskinesia").

Animal experiments suggest that these drawbacks can be reduced through a combination of levodopa with substances containing the so-called dopamine breakdown inhibitors (MAO or COMT inhibitors). Clinical studies are underway to verify these effects in humans.

Dopamine agonists are substances that pass from the blood into the nervous system, where they mimic the stimulating effect of dopamine. Repeat clinical studies have shown that these are less effective than levodopa, but that they have a more long-lasting effect, and dopamine agonists are thought to be less likely to cause dyskinesia. At higher doses they also have several side-effects, such as nausea, fatigue and psychological impact.

Clinical experience suggests that a combination of levodopa and dopamine agonists is often advantageous, because when taken together they result in a greater reduction of troublesome symptoms, such as severe tremors or muscle cramping ("dystonia").

"Clinical experience suggests that a combination of levodopa and dopamine agonists is often advantageous, because when taken together they result in a greater reduction of troublesome symptoms."

Symton Fluctuations

In more advanced stages of illness, peroral medication often results in uneven effects of the ingested medication throughout the day, as the time for passage from stomach to intestines can vary greatly. The symptom fluctuations that then occur may result in so-called off-syndrome (during times of dopamine shortage), with significant movement impairment, muscle cramping, speech difficulties, etc.

There may also be periods of overdose symptoms such as dyskinesia or sensory hallucinations parallel with good mobility (in the "on-phase"). These problems may be alleviated by using a portable pump system to administer the dopamine agonist apomorphine subcutaneously or levodopa to the intestinal tract through a percutaneous gastroduodenal sound.

Use of these medications has been shown to be capable of reducing symptom fluctuation and the "on-off" phenomenon throughout the day. Clinical studies are also underway with transdermal administration of the medication through patches. Various substances have been previously tested, but only one (rotigotine) has been approved for clinical use (not yet subsidised in Sweden, as of November 2007). Another advantage is that it is possible to attain even administration of dopamine-stimulating substances; the disadvantage is that the clinical effect is thought to be somewhat weaker in comparison with peroral medication, and that skin problems may also result.

Surgery

Electrostimulation in the brain with neurosurgically implanted electrodes and a pulse transmitter placed subcutaneously under the clavicle, so-called "Deep Brain Stimulation (DBS)" is a treatment that has shown itself effectively capable of counteracting severe fluctuations ("on-off" condition) or in cases where the patient cannot tolerate such a high dose of medication, so that mobility is restored without significant dyskinesia.

After nearly 10 years of experience and repeated studies, the method has been demonstrated to be safe. Serious surgical complications are uncommon, occurring in less than one percent of those who undergo such operations. In Parkinson's disease, electrodes are usually placed bilaterally in the nucleus subthalamicus. The effect of the stimulation here is usually very good in terms of increased tonification and hypokinesia, while it is somewhat less effective against tremors. Stimulation in the nucleus subthalamicus has been reported to increase the risk for depression, possibly through simultaneous reduction of previous dopaminergic stimulation.

Electrostimulation in the thalamus nucleus ventrointermedius ("VIM") effectively reduces tremors of various geneses. The effect is thought to be best in Essential Tremor. Stimulation in the inner palladium nucleus has shown itself capable of reducing muscle cramping in dystonia conditions, most effectively in generalised dystonia ("DYT 1, dystonia musculorum deformans"). Trials are also being conducted with electrostimulation against conditions such as epilepsy, depression, Tourette's, and eating disorders.

Neurotrophics and Gene transfer

Animal experiments suggest that the brain produces proteins with a growth-stimulating effect, so-called neurotrophics, which can counteract cell death in experimental Parkinsonism. Clinical trials have therefore been conducted with infusion into the brain's ventricle system, but with uncertain effect. Since the path from spinal fluid compartments to the nerve cells is long, so-called gene transfer has been attempted in animal studies, in which new DNA material is introduced directly into the cells so that these can increase production of neurotrophics through administration of a modified virus. The latter technique is not, however, ready to be clinically tested on humans.

Stem Cells

There are great expectations associated with the implantation of stem cells in the brain to increase dopamine secretion. During the 1990s a number of Parkinson's patients underwent surgery in Lund for neurological implantation of dopaminergic cells via dissection of nerve tissue obtained from clinical abortions. The trial demonstrated that the transplanted cells can survive and also form network-like contacts with other cells in the recipient's brain.

Clinical effect varied but seemed positive in a few cases. As abortion technique has changed over to use of "abortion pills", such tissue is no longer accessible; high hopes are now placed on the culturing of stem cells obtained from fertilised human egg cells. Trials in animal models of Parkinson's disease have shown a certain symptom-alleviating effect, but significant work remains to be done before daring to try this technique on humans, as the risks include the possibility that it would not be possible to control the implant, thus leading to formation of tumours or overdose effects.

By Olle Lindvall, Professor, Neurology Clinic, University Hospital of Lund

Can Parkinson’s be treated with stem cells?

The most common symptoms in Parkinson's disease are caused when the dopamine-producing nerve cells in the substantia nigra in the mesencephalon die. These cells normally send their nerve fibres to the striatum; the disease causes a significant drop in dopamine levels in this region. Nerve cell transplantation in Parkinson's disease builds on the idea that the patient might be able to regain mobility if the dead cells could be replaced with new, fresh dopamine cells.

In support of this idea, animal studies have shown that Parkinson's-like symptoms in rats and apes can be alleviated if dopamine cells taken from the mesencephalon of animal foetuses are transplanted to the striatum. The improvement is brought about when the surviving dopamine cells send out their nerve fibres to the striatum, which then gets enough dopamine to return to normal function.

In the transplants that have been performed up to now on nearly 350 Parkinson's patients worldwide, almost fully developed dopamine cells from the mesencephala of six to nine week old aborted foetuses were used. These cells are not stem cells, but have stopped dividing. During the operation, a cell solution was injected into several places in the striatum using stereotactic neurosurgery.

Most patients were then treated with drugs to avoid rejection reactions. The results demonstrate that the transplanted dopamine cells were able to survive for more than ten years in the brains of these patients, despite the fact that the disease continued to attack their own dopamine cells. The new cells sent out their nerve fibres into the striatum and restored normal dopamine signalling. Certain patients improved dramatically and were able to live without L-dopa treatment for several years. Other patients showed only moderate improvement or none at all.

Even if the results of these clinical studies have given a proof of principle for the cell transplant method as a new treatment strategy in Parkinson’s disease, it is unlikely that use of foetal dopamine cells near full development will become a routine method. In order to achieve a significant alleviation of symptoms, tissue from at least six foetuses per patient was necessary, and therefore only a few patients could be addressed. The quality of the tissue material that was transplanted also varied greatly, which partly explains differences in clinical effect between patients. Finally, 15% of the transplanted patients developed severe involuntary movements, so-called dyskinesia.

Many laboratories world-wide are currently working to try to culture functioning dopamine cells from stem cells, which could be able to solve the problem of tissue shortage and make cell preparation become more standardised. This entails clarifying how stem cells are to be instructed so that they form dopamine cells but not other nerve cells in large masses. This is no easy task, since it is not enough for the new cells just to produce dopamine; they must also presumably be able to function just like the type of cells that have died, i.e. substantia nigra cells, in order to produce good clinical effect.

There are four different types of stem cells that might be able to produce dopamine cells: embryonic stem cells from the fertilized egg, and stem cells from the brain of a foetus, adult brain, or other organ, such as bone marrow. In order for the dopamine cells to be able to be used clinically, the stem cells must be taken from a human. So far, it has been possible to develop dopamine cells from embryonic stem cells and from stem cells in the brain of the foetus, and probably also in adult bone marrow.

The most promising results have been observed with embryonic stem cells that have formed dopamine cells in large numbers when stimulated with the right combination of growth factors and signal molecules. Unfortunately, these dopamine cells, when produced from human embryonic stem cells, had poor rates of survival after transplantation in animal models. There is also a risk for tumour formation from embryonic stem cells that has to be able to be eliminated before any clinical application.

It will most likely still be several years before stem cells can be used for transplantation in patients with Parkinson's disease. Meanwhile, it will not be enough for dopamine cells to be able to be produced in practically unlimited numbers for us to be able to attain a competitive transplantation treatment in Parkinson's disease. We also have to clarify at what point in the progression of the disease transplantation has the best effect, and which patients are best-suited for this treatment.

We also have to avoid development of dyskinesia and control immune reactions. It is especially important before the operation to use modern imaging technology such as MRI and PET scans to chart the areas of the patient's brain that have lost their dopamine nerves. This will determine where the transplant is made, thereby making it possible to custom-tailor treatment for each individual patient.

Lastly, one might wonder if it is worth going to such lengths to develop cell transplantation when there are already many treatment alternatives for patients with Parkinson’s disease. The unique thing about cell transplants is the possibility of replacing just the very cells that have died and thereby achieving alleviation of symptoms. We already know that if this succeeds, it may lead to dramatic improvements and the patient will be able to get along without L-dopa medication for many years.

1. Isolation of neural stem cell

2. Expansion

3. Differentiation

4. Dopamine cells

5. Transplantation

What might future stem cell treatment for Parkinson's disease look like? The schematic drawing shows that it is possible to begin with embryonic stem cells, neural stem cells in the brain of the foetus or adult, or from stem cells in other tissues, such as bone marrow. The stem cells are isolated, increased (expanded), and led to mature (differentiated) into functioning dopamine cells, which are then transplanted with stereotactic technology into the patient's brain.

References

Lindvall O.and Björklund A. Cell therapy in Parkinson’s disease. NeuroRx 1: 382-393, 2004.
Lindvall O. and Kokaia Z. Stem cells for the treatment of neurological disorders. Nature 441: 1094-1096, 2006.

By Ann-Kathrine Granérus, Professor Emeritus, Dept. of Geriatrics, University of Linköping

Parkinson's in the elderly

Parkinson's disease (PD) is the most common neurological disease in the elderly, marked by both increasing incidence and prevalence with increasing age. PD is probably caused by a complicated connection between genetic disposition, exposure to neurotoxic substances, and aging factors. The number of dopaminergic neurons is reduced with increasing age, which results in increased risk for clinical symptoms upon exposure to PD triggers.

"The reduced functioning and other simultaneous illnesses of the elderly are significant factors when it comes to how well anti-Parkinson's treatment can be carried out."

The fact that prevalence increases does not depend only on increasing incidence with increasing age and demographical changes in more and more elderly people, but also on the fact that much better therapeutic possibilities have led to increasing survival rates. Well-treated PD patients currently live almost as long as individuals without PD. In Sweden, it is calculated that in the order of one half of the approximately 15,000 -20,000 individuals with PD are over 65-70 years of age.

Diagnostics in PD are the same regardless of age: Characteristic symptoms that slowly progress, over the course of months at least and often up to a half-year to a year, are the basis for a correct diagnosis. Other symptoms mean that differential diagnoses need to be considered, but especially when it comes to the elderly there are not only motoric but also non-motoric symptoms, which is significant in both diagnosis and treatment.

Motoric Symptoms

Symptoms caused by hypokinesia are the most handicapping, especially in older PD patients, and these are what most limit independent living ability. If hypokinesia in an elderly patient inhibits function, then dopa treatment is indicated as a first line of treatment, because dopa is by far the best at reducing symptoms related to hypokinesia, and because side-effects are no more pronounced than for other medications.

However, it is critical for treatment to be carried out in the right manner, i.e. with relatively low induction to avoid setbacks with side-effects, but not too slow, since in such a case treatment may be difficult to evaluate. A dosage increase of 50 mg dopa combined with dopa decarboxylase inhibitors a few times a week, up to a maintenance dose not exceeding 500 mg of dopa per day is often recommended. With well-executed treatment, most PD patients, even those at advanced ages, can improve, and over the course of a few years, they can reach a clearly improved quality of life.

Other anti-Parkinson's treatments can be considered, especially if dopa treatment fails to produce sufficient results. Older PD patients who are otherwise healthy also have the greatest likelihood of tolerating other anti-Parkinson's medications, such as dopamine agonists and MAO-inhibitors. COMT-inhibitors essentially entail a reinforcement of dopa, and do not have their own intrinsic effect. Anti-cholinergics should meanwhile be avoided in the elderly because of the great risk for psychological side-effects, especially disorientation, and risk for a certain degree of cognitive degradation.

Even if the right treatment means that many elderly maintain good vitality into their later years, the number of elderly patients with complicated PD symptoms and with other simultaneous treatment-dependent illnesses is likely to increase. The reduced functioning and other simultaneous illnesses of the elderly are significant factors when it comes to how well anti-Parkinson's treatment can be carried out.

Side-effects may complicate or hinder execution of the treatment plan. Psychological symptoms constitute the greatest risk for side-effects of a serious nature, usually as disorientation with or without hallucinations, something which has definitely been seen with the many-times higher doses given by Oliver Sachs in the early days of dopa treatment – no one was prepared for such dramatic effects.

In older, vulnerable individuals, the risk for psychological side-effects is manifest in all medications for PD, but careful dosage increase allows time to discover these, and the treatment can be reduced before the symptoms become dramatic. The greatest risk for disorientation is seen in patients with reduced cognitive functions, where treatment must be carried out with particular caution. Patients with dementia are sometimes unable to tolerate any form of anti-Parkinson's treatment for these reasons, even if motor function is improved.

Dementia

Dementia is over-represented in PD, and has been judged to be 5-10 times more frequent in comparison with older patients of an equal age without PD. However, this does not mean that all patients with PD will develop dementia, but it does apply to perhaps half of all patients if they live long enough. Treatment of these patients also places extensive demands on both medical skill and adequate care, especially as these patients often have very extensive motor difficulties.

Treatment trials with addition of cholinesterase inhibitors and memantine are currently underway. A certain degree of improvement of cognitive functions has been seen in some studies with cholinesterase inhibitors, but sometimes with certain setbacks, especially with respect to tremors.

Depression

Depression is also over-represented in PD, and occurs in 30-40% of all patients, where the minority of these have severe depression. One diagnostic problem is the overlapping of symptoms in these two conditions - for example, do motoric inhibition, sleep disorder and anxiety have a physical and/or psychiatric background?

Treatment of depression in PD is in principle the same as in depressed patients without PD, where, however, SSRI are preferable in older patients, since all tricyclic anti-depressants have an anticholinergic effect with a risk for disorientation. In the case of severe and life-threatening depression, ECT may become a viable option, which, in addition to its antidepressant effect, may also have a positive outcome on motor-related symptoms.

Autonomic Dysfunction

Older patients with PD are especially prone to have problems with blood pressure regulation upon standing, constipation, and incontinence, symptoms that may exist both as a part of neurodegenerative conditions in themselves and which can also be accentuated by
anti-Parkinson's drugs. Treatment is often problematic when it comes to balancing possible and undesirable effects against one another.

To prevent orthostatism, rapid changes of position should be avoided (which are often prevented by the disease in- and of itself), and fluorocortisone, which results in fluid retention, can be tried (but attention must be paid to bone oedema or dyspoenea), dietary supplementing with fibre and motor activity (a problem in itself) are significant to counteract constipation, and urinary incontinence can be treated pharmacologically, but these substances also have an anticholinergic effect with a risk for disorientation.

Long-term Problems

At least half of all PD patients undergoing long-term treatment develop a fluctuating symptom profile, which is described in the section by Jan-Edvin Olsson. For the treatment of the elderly with fluctuating PD symptoms, the above-mentioned cautionary measures with regard to
treatment should be observed. Results during long-term treatment of PD vary widely from one patient to another. Certain patients probably have slow progression of neurodegeneration and thereby better chances of maintaining good treatment results for many years. For other patients a more rapid degenerative progress takes place, which, once it reaches a certain extent, complicates the clinical profile.

In advanced illnesses, a number of patients may appear no longer to obtain any effect from anti-Parkinson's treatment, but are rather severely hypokinetic, possibly with a certain fluctuation in symptomology and with psychological symptoms such as anxiety and disorientation. For this group of patients, there may be despite everything a certain room for dopa to reduce symptoms, if the other anti-Parkinson's medication - which may contribute to psychological symptoms - are reduced in dosage or discontinued.

It is especially important when dealing with this group of patients to note that other simultaneous illnesses, not uncommonly an infection, can accentuate PD symptoms. A severely ill PD patient may have limited opportunity to influence their own condition, and is therefore nearly entirely dependent on the care and the adaptive stimulation provided by the environment.

Forms of Care

The majority of patients can be taken into care in an open healthcare facility, and if possible a speciality, who is usually a neurologist or specialist in geriatric medicine, or at least in consultation with these. Professional skill sets other than those of the doctors are significant, especially for older patients. In many instances Parkinson's teams are formed, comprised of doctors, nurses, and paramedical personnel for a global evaluation of the patient and to facilitate the patient's connection with adequate healthcare systems. In very advanced stages of disease, permanent, closed-facility care may be required, which also requires access to the proper medical competence and paramedical personnel.

It is essential for those who undertake treatment of PD patients to have the proper awareness in both theoretical terms and from experience with a reasonably large number of patients with different forms and degrees of severity in their illness. PD is a relatively common disease, but not so common that there are ever more than a few PD patients at most in the admissions area of a healthcare centre.

Meanwhile, PD patients are often of an age when they have other medical conditions that result in contact with general practitioners, and it is therefore essential for general practitioners to be familiar with the symptoms and treatment of PD. Regardless of the degree of severity of the disease, the best treatment strategy consists of cooperation between general and specialised care, with a mutual exchange of experience.

Summary

The treatment strategy for older patients, who might be entirely healthy except for PD, may be the same as for younger PD patients. Older PD patients, with different reductions in function and other simultaneous illnesses, are a delicate group that requires special consideration with respect to treatment and care.

By Jan-Edvin Olsson, Professor of Neurology, University of Linköping

Treatment of Parkinson's Disease

Parkinson's disease was already described in the ancient Indian Vedic scriptures, but became most known after James Parkinson's description of five patients with "Shaking Palsy" in 1817. Prior to the discovery of dopamine shortages in the brain about 50 years ago, there was no effective treatment other than anticholinergic drugs that resulted in a certain reduction in tremors and bradykinesia, though with significant side-effects.

Since DA does not pass through the blood-brain barrier, it took a few years before introduction of the L-dopa precursor came into general use as a standard treatment of PD. L-dopa is still considered the gold standard and has resulted in significant alleviation of symptoms and improved lifetime for PD patients. However, after 5-10 years of L-dopa treatment, many Parkinson's patients, develop motoric fluctuations, "on-off", which often begin within 5 years after the introduction of L-dopa treatment as a "loosening of dose" or "wearing off", where the dose interval reduces, which in the beginning is relatively easy to handle by increasing and fractioning the L-dopa supply.

After several years of treatment with L-dopa, however, the side-effects may increase with random swings in motor condition, dys/hypokinesia, significantly invalidating the patient with walking- and balance difficulties as a result. This means that younger Parkinson's patients in particular will try to offset the introduction of L-dopa treatment with either enzyme inhibitors or dopamine agonists.

L-dopa is one of three treatment models for Parkinson's, and accounts for pre-synaptic replenishment and increase of pre-synaptic dopamine stores. 30 years ago, L-dopa was given in gramme-doses, which resulted in psychological side-effects, sometimes psychoses and severe pain, most often in the legs, as well as peripheral side-effects in the form of nausea, vomiting, stomach upset, and orthostatism.

By combining L-dopa with the enzyme inhibitor dopa-decarboxylase, the total dose given of L-dopa could be reduced, and the peripheral side-effects were reduced with the combination drug Madopark® (L-dopa + benserazid) and Sinemet® (L-dopa + carbidopa). Over the last few years, the triple combination Stalevo® has also become available, consisting of L-dopa + carbidopa + entacapone, which is an inhibitor of the enzyme cathechol-O-methylansferase (COMT), which is active in the breakdown of dopamine both peripherally and centrally around the blood-brain barrier.

The other main group of medications in Parkinson's disease includes dopamine agonists, which work post-synaptically on dopamine receptors and "mimic" the effect of the natural transmitter dopamine. There are several dopamine agonists on the market, and the most effective one, aside from dopamine, is apomorphine, which is usually given as a subcutaneous injection to rapidly curtail an "off" condition, or with a pump to stabilize motoric fluctuations.

There are four oral dopamine agonists registered in Sweden, the ergot-based drugs bromocriptine (Pravidel®) and cabergoline (Cabaser®) as well as ropinirole (Requip®) and pramipexol (Sifrol®). All of these work in slightly different way on the five dopamine receptors, which are split into two main groups, D1 and D2. Half-life also varies among the dopamine agonists: Pravidel® 3-5 hours, Requip® and Sifrol® 6-8 hours, while Cabaser® is effective for at least 24 hours and can therefore be given as a single daily dose.

The dopamine agonists can generally (and especially in younger patients with only tremors) replace L-dopa for several years, but in the long run they have a weaker effects on bradykinesia and rigidity. Dopamine agonists also have a side-effect on the autonomic nervous system, with orthostatic hypotension and increase the risk for psychological side-effects, especially visual hallucinations.

The third group of Parkinson's medications are the enzyme inhibitors, which prevent breakdown of L-dopa and dopamine. The enzyme cathechol-O-methyltransferase (COMT) is active in the breakdown of L-dopa peripherally and dopamine centrally around the blood-brain barrier. COMT inhibitors have no intrinsic effect of their own.

There are two medications on the market, including entacapone (Comtess ®), which works peripherally around the blood-brain barrier and reduces peripheral breakdown of L-dopa and thereby supplies the brain with more dopamine. Over the last few years, the triple combination Stalevo® has also become available, consisting of L-dopa + carbidopa + entacapone. The other COMT-inhibitor is tolcapone (Tasmar ®), which works both peripherally and centrally.

Tolcapone contributed to a few fatal cases of liver failure and therefore became a licensed substance, but has returned to the Swedish market, though with requirements for frequent liver tests and as a second-line medication after having first tried Comtess®. Aside from the decarboxylase inhibitors included in Madopark® and Sinemet®, there are also two inhibitors of the enzyme monoamineoxidase (MAO) type B, which breaks down DA in the brain: selegiline (Eldepryl ®) and rasagiline (Azilect®).

Eldepryl® has been available for many years, and has a slight symptomatic effect, but a number of side-effects, including a blood-pressure lowering effect and a central stimulative effect which can result in unrest, anxiety, and sleeping disturbance because of conversion into amphetamine metabolites. Azilect®, which has recently been registered in Sweden, does not have these side-effects, and is metabolised to an inactive substance without amphetamine-like properties.

Together with Selegiline, Rasagiline is included in the group of Parkinson's medications that inhibit the MAO-B enzyme and thereby reduce breakdown of dopamine in the brain. In many countries, including Norway, MAO-B inhibitors are used initially, both as a light symptomatic drug and for a neuro-protective effect. As the disease progresses and the motor symptoms become handicapping, treatment with L-dopa is initiated, which is the most potent Parkinson's medication.

In younger patients, especially those with tremor-dominated difficulties, a dopamine agonist can be given instead for several years if there is a desire to put off L-dopa medication in order to delay the occurrence of motor fluctuations of the "on-off" type and dyskinesia. L-dopa works pre-synaptically, while dopamine agonists work post-synaptically on dopamine receptors and in advanced conditions there may sometimes be grounds for combining L-dopa with a dopamine agonist.

In early motor fluctuations of the "wearing-off" type, the L-dopa effect may be amplified by the COMT-inhibitor entacapone, or should the effect prove insufficient, try tolcapone under strict observation of liver status. Rasagiline today also serves as a treatment alternative in early loosening of dose as an addition to L-dopa.