PD is named after James Parkinson, an English physician, in 1817. He observed patients with this disease and called it ‘shaking palsy’. Later it was discovered that this is not exactly palsy but the stiffness is due to the rigidly increased muscle tone which manifests throughout the disease. Bulgaria has also contributed to the world history with the work of Ivan Raev who discovered treatment for parkinsonism, particularly for von Economo encephalitis. He isolated atropine from the herb belladonna called ‘cura bulgara’. Thus he managed to cure the Queen of Italy Elena di Savoia as a result of which he was honored with the title of ‘doctor’. As of today, as a token of appreciation, an Italian hospital is named after Ivan Raev.
PD is a chronic, progressive, degenerative disorder with a morbidity rate of more than 1% of the world population at the age of over 60 years. It is caused by the loss of dopaminergic neurons in substantia nigra, gliosis, and accumulation of Lewy bodies. The balance between the suppressive neuromediator, dopamine, and the excitatory mediators, glutamate and acetylcholine, is destroyed which leads to imbalance between the direct and indirect path and occurrence of Parkinson’s disease symptoms. As the first symptoms occur, about 50-80% of dopaminergic neurons are already lost. PD is a multifactor disorder in the genesis of which are involved environmental agents, free radicals with toxic effects, genetic and age factors. Genetic studies have discovered PARK 1 to 16 genetic loci associated with the disease. As far as the environmental toxic factors are concerned, a large number of chemical compounds have been discovered with a structure similar to the substance MPTP (metil-phenil-tetrahydro-piridin) which is considered to be involved in the destruction of dopaniergic neurons. The incidence of PD increases with the age as a result of the action of external and internal factors. It is believed that the use of nicotine and caffeine lowers the risk of development of PD. The pathogenesis of the disease is due to the interaction among oxidative stress resulting from released free radicals, excitotoxicity and inflammatory changes.
PD can be classified as follows:
A) By onset of the disease:
1) Juvenile onset: Below the age of 20
2) Early onset: Between the age of 21 and 40 years
3) Adult onset: Above the age of 40 years
B) By symptoms:
1) Tremor dominant form
2) Akinetic rigid form
3) Mixed form
C) By clinical progression:
1) Slowly progressive
2) Rapidly progressive
D) By heredity:
1) Sporadic
2) Hereditary
E) By stage of progression:
1) Early
2) Late (terminal)
The onset of the disease is undistinguishable and the symptoms are nonspecific, such as tiredness, loss of the sense of smell, pain in the joints. The patients complain of loss of dexterity, difficulty in writing, and tightness of limbs. With PD there are motor, autonomous and mental symptoms. It is characterized by three general symptoms: resting tremor, rigidly increased muscle tone, bradykinesia (slowness of movements). Early onset PD, the so called ‘honeymoon’, is the period from the moment of the first symptoms to the occurrence of motor fluctuations. The first 3-4 years following the first complaints are characterized by comparatively good compensatory possibilities in terms of treatment and management of symptoms. Initially the symptoms occur in one limb, usually the arm, then the leg on the same side is affected, and later the other two limbs. The progression of the disease is individual but, in general, in case of early onset the progression is slower, and in case of adult onset the progression is more rapid. Practically, it is believed that 10 years after onset of the Parkinson’s disease the patient enters into the late phase of the disease characterized by marked motor fluctuations, such as dyskinesias, dystonias, ‘on-off’ phenomena, quick reduction of the effect of a single dose of levodopa (‘wearing off’ phenomenon), freezing phenomenon, narrowing the therapeutic window, need of higher doses if medicines, non-motor symptoms, etc. Dyskinesias and dystonias are involuntary movements in the body and limbs which occur throughout the disease or as a result of the levodopa treatment. These disorders often are disabling and interfere with the patients’ daily activities. The off-period is characterized by the occurrence of unpredictable numbness or slowness of movements. Wearing-off effect means that the effect of a single dose of the medicine has reduced. With the progression of the disease, the period in which the patient feels well after intake of the medicine gets shorter, i.e. if it used to be 4 hours it may be reduced to 1.5 - 2 hours. The freezing phenomenon is characterized by a sudden impossibility of the patient to lift their feet while walking, i.e. they remain stuck to the floor; this effect may last from several seconds to several minutes. The autonomic disorders include urinary problems (frequent urination, nocturia), or sexual problems (decreased or increased libido, erection problems), cardiovascular symptoms, gastrointestinal disorders (most common of which is constipation), etc. The sleep disorders with insomnia (sleeplessness) and night-time akinesia are very common. The neuropsychiatric disorders include cognitive impairment, dementia, depression, psychoses, hallucinations, delirium, as the latter are often due to side effects of the treatment.
The PD diagnostics is based on anamnestic data, neurological assessment and tests (electromyography), pharmacological diagnostic samples, neuroimaging methods (CT, MRT, SPECT). The differential diagnosis is hard to make and includes a wide range of diseases, such as different types of tremor, Parkinson-plus syndromes, Wilson’s disease, Alzheimer’s disease, neuroleptic-induced parkinsonism, vascular parkinsonism, etc.
The PD treatment is symptomatic and aimed at the dopamine metabolism; the aim is to restore dopamine, slow down its decomposition and re-uptake. Contemporary treatment requires a levodopa-sparing therapy, i.e. treatment with other agents is started and levodopa is added at a later stage. The early-onset PD is treated with neuroprotective agents slowing down the progression of the disease. MAO-B inhibitors (rarasagiline, selegiline) and dopamine agonists (mirapexin, pramipexol, ropinirole) are used and when their effect is reduced levodopa is added. An antidepressant drug often has to be included. When patients enter a late PD stage the response to treatment becomes considerably difficult to be maintained and, therefore, the doses of medications have to be increased and the intervals between intakes have to be reduced. Thus, some of them may manifest their side effects, patients experience dyskinesias and dystonias. The severity of complications is greater and their onset is earlier when the patient is treated with high doses of levodopa. The pulsed release of levodopa and dopamine into the brain causes the occurrence of dyskinesias and motor fluctuations. Usually, after 5 years of levodopa treatment, 50% of the patients develop complications of Parkinson’s disease and within 10 years after the start of treatment, such complications were developed in 80% of the patients. Besides motor fluctuations, the levodopa treatment causes oxidative stress and speeds up the degeneration of neurons in the substantia nigra due to the generation of free radicals. Usually, the monothearpy is not effective enough at a late PD stage. The combined therapy allows reduction of the doses of levodopa. Besides levodopa, dopamine agonists, COMT-inhibitors and glutamate antagonists are also administered. When the effect of oral drugs is reduced, there are three methods of treatment of patients with terminal PD: DBS (deep brain stimulation), subcutaneous apomorphine, and treatment with Duodopa intestinal gel. DBS is implantation of electrodes in the subthalamic nuclei and ensures continuous dopaminergic stimulation in basal ganglia. It is used in patients with severe tremor or levodopa-induced motor complications. Apomorphine is a dopamine agonist for subcutaneous administration. Duodopa is an entheral gel suspension of levodopa/carbidopa delivered via a portable pump through a permanent probe using a percutaneous endoscopic gastrostomy tube. The medication is infused directly to the duodenum avoiding problems with the gastric passage and competition with the aminoacids. The pulsed delivery of levodopa, which is continuously infused by a computer, is also avoided. It is administered when all other options are used and the motor complications are threatening the patients’ lives. In Bulgaria, patients are successfully treated with Duodopa, and recently the DBS was also adopted as a method for PD treatment.