© Borgis - Postępy Nauk Medycznych 11/2009, s. 878-882
*Urszula Fiszer
Pathogenesis and treatment of Parkinson´s disease – evolution of views
Patogeneza i leczenie choroby Parkinsona – ewolucja poglądów
Department of Neurology and Epileptology of the Postgraduate Medical Education Centre
Department Director: prof. dr hab. med. Urszula Fiszer
Streszczenie
Since a long time Parkinson´s disease (PD) focuses interest of numerous researchers. Views regarding this disease gradually evolved in the course of analysis of the research results. A proper evaluation and classification of clinical symptoms still has a fundamental importance for diagnostics, whereas additional examinations – only play a supporting role. A marker typical for this disease has not yet been determined. Views that PD must be related to the Lewy´s bodies have been proved to be wrong. Pathological changes may begin in brain stem, and subsequently involve substantia nigra and cortex. The occurrence of early autonomic disturbances may be a prodromal symptom of PD, and clinical picture, as well as the course of PD in men and women, are different.
Neuroprotective treatment or treatment modifying the course of the PD are not known, only a symptom-reactive treatment is applied. Recently published papers suggest that there are no fundamental differences in the course of the disease in the levodopa treatment vs dopamine agonists. It has been also established that in PD the variations of the synaptic dopamine level preceed the occurrence of motoric fluctuations.
The desire to permanent dopaminergic stimulation is important in the dopaminergic treatment. Reseach regarding the influence of genetic factors are being performed. It has been noticed that disability of PD patients is mainly related to symptoms not reacting to levodopa treatment. A particular attention must be paid to the treatment of PD patients with autonomous and neuropsychiatric disturbances and pain symptoms.
Currently new treatment strategies, influencing the natural course of this disease, are under preparation.
Summary
Choroba Parkinsona (chP) od dawna cieszy się zainteresowaniem wielu badaczy. Poglądy na to schorzenie stopniowo ewoluowały w wyniku analizy uzyskiwanych rezultatów przeprowadzonych badań. Właściwa ocena i klasyfikacja objawów klinicznych ma nadal podstawowe znaczenie dla diagnostyki, a badania dodatkowe – tylko znaczenie pomocnicze. Nie określono jeszcze markera charakterystycznego dla tego schorzenia. Poglądy, że chP musi być powiązana z ciałami Lewy´go okazały się niesłuszne. Zmiany patologiczne mogą rozpoczynać się w pniu mózgu i opuszce węchowej, a następnie obejmować istotę czarną i korę mózgową. Występowanie wczesnych zaburzeń autonomicznych może być objawem prodromalnym chP, a obraz kliniczny i przebieg chP u kobiet i mężczyzn są różne.
Nie są znane możliwości leczenia neuroprotekcyjnego/modyfikującego przebieg chP, stosowane jest jedynie leczenie objawowe. Ostatnio opublikowane prace sugerują, że nie ma zasadniczych różnic w przebiegu choroby przy leczeniu lewodopą vs agoniści dopaminy. Stwierdzono także, że w chP wahania synaptycznego poziomu dopaminy poprzedzają wystąpienie fluktuacji motorycznych.
W leczeniu dopaminergicznym istotne jest dążenie do ciągłej stymulacji dopaminergicznej. Prowadzone są badania dotyczące wpływu czynników genetycznych na przebieg leczenia. Zaobserwowano, że niesprawność osób z chP jest głównie związana z objawami niereagującymi na leczenie lewodopą. Szczególną uwagę należy zwracać na leczenie osób z chP z zaburzeniami autonomicznymi, zaburzeniami neuropsychiatrycznymi oraz objawami bólowymi.
Obecnie są w opracowaniu nowe strategie leczenia poprzez wpływ na naturalny przebieg tej choroby.
Parkinson´s disease (PD) is a progressive condition characterized by motor and non-motor symptoms (smell disorder, neuropsychiatric disorder and autonomic nervous system disorder). The number of people with PD will grow together with the general ageing of society, in turn causing increased social costs of providing care (1, 2).
PD has attracted the attention of researchers for a long time. As a result of analysis of the results of studies carried out, gradual changes are taking place in views on PD concerning certain issues (3, 4).
Disease definition
The classical definition of the disease as a progressive disorder, starting in an adult person with symptoms of increasing parkinsonian syndrome, responding to levodopa treatment and often connected with motor disorders during treatment, is currently commonly accepted by clinicians (5). PD can occur in three clinical forms: akinetic-hypertonic, tremulous and mixed. Particularly in patients with akinetic-hypertonic form there are often problems with the correct diagnosis in the initial stage of the disease. New assessments of diagnostic criteria of PD have been made (6). The correct assessment and classification of clinical symptoms is of key significance for their diagnosis, and additional examinations (e.g. neuroimaging) are only of auxiliary significance (7). A marker characteristic for this disease has not been identified yet.
Aetiopathogenesis
Genetic and environmental factors undoubtedly have an influence on natural development of PD. The discovery of genetic mutations has contributed to the new view on the pathogenesis of the disease. However, papers within pathology have brought the most unexpected results. The view that PD must be connected with Lewy bodies (8) turned out to be erroneous. Pathological changes may start in the brainstem and olfactory bulb, and then involve the substantia nigra and cerebral cortex (9, 10). This concept has not been commonly accepted yet, and some researchers associate PD only with damage of the substantia nigra.
Autonomic disorders
Criteria used so far for diagnosing PD do not include a requirement to detect the occurrence of autonomic disorders in the person under diagnosis. However, according to recent views the occurrence of early autonomic disorders may be a prodromal symptom of PD (11). The main autonomic disorders in PD comprise: disorders of the cardiovascular system, digestive system, genitourinary system, feeding, excessive secretion of sebum and thermoregulation. Autonomic symptoms in PD are connected with dysfunction of the parasympathetic and sympathetic nervous system (12, 13, 14).
Differences in the course of the disease in women and men
It has been known for a long time that the clinical picture and the course of PD are different in women and men; this is also confirmed by the new observations (15, 16, 17).
Experimental studies on the influence of gender on genetic expression in the substantia nigra showed the increased expression of genes connected with signal transduction and neurons maturing in women and pathogenesis of PD (alpha-synuclein and PINK) in men, which permits the conclusion that the predisposition to the development of PD as well as the nature of the disease and the response to treatment is dependent on gender (18).
Therapeutic approaches
1) Treatment modifying the course of the disease
Current methods of pharmacological treatment of PD concern the treatment of symptoms only. The possibilities for neuroprotective treatment modifying the course of the disease are unknown. None of the drugs researched so far have clearly shown an effect modifying the course of the disease (19, 20, 21). Methods have been worked out to perform studies permitting one to distinguish actions modifying the course of the disease from the symptomatic effect (22).
It is currently thought that distinguishing endogenous compensatory mechanisms in the initial stage of the disease is also important (23).
In the studies on animal models most drugs have a protective effect against the toxic effects of MPTP and other toxins. However, these models turned out to be useless in predicting the clinical neuroprotective effect. So it is essential to develop animal models better imitating PD in people (4).
2) Drugs applied in symptomatic treatment
The following drugs can be given for PD:
levodopa (with dopa decarboxylase inhibitor (decreasing peripheral breakdown of levodopa): levodopa + carbidopa or levodopa + benserazide),
catechol-o-methyl transferase inhibitors (entacapone, tolcapone), dopamine agonists (bromocriptine, pergolide, cabergoline, pramipexole, ropinirole, piribedil, apomorphine, rotigotine),
anticholinergic drugs (trihexyphenidyl, biperiden),
monoamine oxidase inhibitors (selegiline, rasagiline)
and amantadine (amantadine sulphate) (1, 24).
Levodopa, supplementing dopamine deficiency, is undoubtedly the basic drug in PD. However, drug-induced movement disorders can occur (motor fluctuations or dyskinesias – in approximately 50% of patients after 3-5 years of levodopa use). Movement disorders are a fundamental problem in PD; they may be an expression of the disease, and also an adverse symptom/side effect of levodopa treatment. Movement disorders are accompanied by fluctuation of non-motor symptoms – sensory, autonomic and neuropsychiatric (25).
3) Initiation of treatment
There has been an ongoing discussion for years about which way of treatment is more beneficial for the patient – initiation of therapy with levodopa or a dopamine agonist (24, 26, 27).
It seems beneficial for patients to take dopaminergic drugs in the case of minor clinical symptoms (levodopa>60 years old, dopamine agonists <60 years old, with the possibility for quick replacement with levodopa if there is no improvement or adverse symptoms/side effects occur).
Recently published papers suggest that there are not fundamental differences in the course of the disease when treating with levodopa vs dopamine agonists (28, 29, 30).
4) Levodopa-induced motor fluctuations
Persons with PD can be divided into two groups of patients: a stable group (patients without a tendency for motor disorders after levodopa) and a group of so-called fluctuators (patients with a tendency for motor disorders after levodopa). It was also found that in PD fluctuations of synaptic dopamine level precede the occurrence of motor fluctuations. Using positron emission tomography (PET) levodopa-induced changes in the synaptic dopamine level were studied and two groups of patients were distinguished, i.e. the stable group and the group of so-called fluctuators, where increased dopamine turnover was recorded (31).
The development of levodopa-induced motor disorders is connected with central and peripheral mechanisms (32, 33, 34, 35, 36). The central mechanisms comprise progression of multiple system atrophy, changes in dopaminergic receptors and effects of levodopa. The peripheral mechanisms are connected with absorption and metabolism of levodopa.
The risk factors of independent occurrence of levodopa-induced dyskinesias were found to be: female gender, early initiation of the disease, longer therapy and higher dose of levodopa (37).
5) Aspiration for permanent dopaminergic stimulation
A new way of treating PD was developed, consisting in giving gel containing levodopa (Duodopa) directly into the duodenum with the help of a gastric tube or gastroscopy (38). Also a transdermal system with a dopamine agonist – rotigotine – ensuring a stable level of the drug for twenty-four hours was introduced to the treatment (39).
6) Influence of genetic factors on the course of treatment
Currently under study is the role of genetic factors in the response to the applied treatment (40). In PD the influence of genetic factors on disorders during the levodopa treatment has been studied. A relationship between dopamine transporter gene polymorphism and adverse symptoms (dyskinesia, psychosis) (41) was found, as well as polymorphism of angiotensin-converting enzyme (psychosis) (42). However, determination of these parameters does not yet have clinical significance.
7) Recommendations developed for PD treatment
The analysis of scientific research concerning the ways of treatment has already been carried out several times and levels of recommendations based on evidence (19, 26, 43, 44, 45) have been determined.
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