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Parkinson's disease

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Parkinson's disease
SpecialtyNeurology Edit this on Wikidata
Frequency0.2% (Canada)

Parkinson's disease (PD; paralysis agitans; also known as Parkinson disease in the U.S.) is a neurodegenerative disease of the substantia nigra, an area in the basal ganglia of the brain. The disease was first recognised and its symptoms documented in 1817 in An Essay on the Shaking Palsy by the British physician Dr James Parkinson; the associated biochemical changes in the brain of patients were identified in the 1960s. Some gene defects associated with the disease were identified only recently; others remain unknown.

The disease involves a progressive disorder of the extrapyramidal system, which controls and adjusts communication between neurons in the brain and muscles in the human body. It also commonly involves depression and disturbances of sensory systems.

Parkinson's disease is widespread, with a prevalence estimated between 100 and 250 cases per 100,000 in North America; globally prevalence estimates range from a low of 15 per 100,000 in China to a high of 657 per 100,000 in Argentina. Because prevalence rates can be affected by socio-economically driven differences in survival, incidence is a more sensitive indicator: rates have ranged from 1.5 per 100,000 in China to a high of 14.8 per 100,000 in Finland. [BC Medical Journal Volume 43, Number 3, April 2001, 133-137 Epidemiology of Parkinson’s disease Benjamin C.L. Lai, MD, MSc, and Joseph K.C. Tsui, MD, FRCP(UK), FRCPC]

About 2% of the population develops the disease some time during life, though the mean age at onset is 58-60. Symptoms usually begin in the upper extremities, and are usually unilateral (one-sided) or asymmetrical at onset.

Debate over Causes: A Complex Etiology is Probable

The cause of Parkinson's disease is not known (idiopathic). There are, however, many theories.

Genetic

Geneticists have, since 1997, found nine different specific genetic defects, each of which causes the disease in one or a few families with extraordinarily high incidences of the disease, but such families are rare.

While a strong inheritance pattern occurs in only a very small percentage of cases, an affected individual is three to four times more likely than an unaffected individual to have a close relative with Parkinson's. Having a parent with Parkinson's raises one's lifetime risk of developing the disorder threefold, from the general population's figure of 2% to about 6%. Genes that have been identified include SNCA (protein alpha-synuclein), UCHL1 (protein ubiquitin carboxy-terminal hydrolase L1), PARK2 (protein parkin), "PARK6" (protein PINK1), PARK7 (protein DJ-1), and PARK7 (protein Dardarin or LRRK2). Indeed, recent linkage studies excluded most of the above gene defects from consideration in the causation of sporadic (i.e. non-familial) Parkinson's disease, which constitutes more than 95% of cases. Most recently, a new gene was identified, ND5, mutation in which is thought to account for a vast majority of sporadic PD cases (see below).

Toxins

One theory holds that the disease may result in many or even most cases from the combination of a genetically determined vulnerability to environmental toxins along with exposure to those toxins[1]. This is argued to be consistent with the fact that Parkinson's disease is not distributed homogenously throughout the population: rather, its incidence varies geographically. The toxins most strongly suspected at present are certain pesticides and industrial metals. MPTP is used as a model for Parkinson's as it can rapidly induce parkinsonian symptoms in human beings and other animals, of any age. Other toxin-based models employ paraquat[2] (a herbicide) in combination with maneb, a fungicide [3] rotenone [4] (an insecticide), and specific organochlorine pesticides including dieldrin [5] and lindane [6]. Studies have found an increase in PD in persons exposed to these agricultural chemicals; the risk apparently rises with exposure.

Almost all of the PD-causing toxins act on the mitochondrial complex I of the electron transfer chain, and sporadic PD cases have been found to have a partial loss of activity of this enzyme complex. Studies in cybrids have found that mitochondrial DNA, rather than nuclear DNA, is responsible for the dysfunction. Most recently, microheteroplasmic mutations in one of the mitochondrial complex I genes, ND5, were found to be sufficient to diagnose sporadic PD correctly in 27 out of 28 cases. While additional studies are needed, mitochondrial microheteroplasmic mutations may be the cause of the majority of PD cases.

However, the ubiquity of agricultural chemical exposures makes it difficult to gauge the true extent of the problem. In the current state of knowledge about the origins of the disease, it appears that family history of the disease and (especially) multiple episodes of head-trauma-induced unconsciousness increase individual risk more than does pesticide exposure, but research is continuing.

Head trauma

Past episodes of head trauma are reported more frequently by sufferers than by others in the population [7]http://archneur.ama-assn.org/cgi/content/abstract/48/9/903][8]. A methodologically strong recent study [Bower 2003] found that those who have experienced a head injury are four times more likely to develop Parkinson’s disease than those who have never suffered a head injury. The risk of developing Parkinson’s increases eightfold for patients who have had head trauma requiring hospitalization, and it increases 11-fold for patients who have experienced severe head injury[9]. While emotional or psychological trauma can precipitate the initial symptoms or aggravate existing symptoms, this is probably not the actual cause of the disorder. However, psychological trauma during periods of developmental susceptibility cannot be definitely excluded as triggers.

Other Associations

Loss of dopamine-secreting cells

The symptoms of Parkinson's disease result from the loss of dopamine-secreting (dopaminergic) cells and subsequent loss of melanin, secreted by the same cells, in the pars compacta region of the substantia nigra (literally "black substance"). These neurons project to the striatum and their loss leads to alterations in the activity of the neural circuits within the basal ganglia that regulate movement, in essence an inhibition of the direct pathway and excitation of the indirect pathway.

The direct pathway facilitates movement and the indirect pathway inhibits movement, thus the loss of these cells leads to a hypokinetic movement disorder. The lack of dopamine results in increased inhibition of the ventral lateral nucleus of the thalamus, which sends excitatory projections to the motor cortex, thus leading to hypokinesia.

There are four major dopamine pathways in the brain; the nigrostiatal pathway, referred to above, mediates movement and is the most conspicuously affected in early Parkinson's disease. The other pathways are the mesocortical, the mesolimbic, and the tuberoinfundibular. These pathways are associated with, respectively: volition and emotional responsiveness; desire, initiative, and reward; and sensory processes and maternal behavior. Disruption of dopamine along the non-striatal pathways is the likely explantion for much of the neuropsychiatric pathology associated with Parkinson's disease.

Brain cells producing other brain chemicals such as GABA, norepinephrine, serotonin and acetylcholine exhibit damage in Parkinson's disease, accounting for some of the wide array of symptoms.It is not known whether this damage is a primary disease process, or secondary to loss of normal dopaminergic stimulation.

The mechanism by which the brain cells in Parkinson's are lost appears to center on an abnormal accumulation of the protein alpha-synuclein in the damaged cells. This protein forms proteinaceous cytoplasmic inclusions called Lewy bodies. Excessive accumulations of iron, which are toxic to nerve cells, are also typically observed in conjunction with the protein inclusions.

The precise mechanism whereby aggregates of alpha-synuclein damage the cells is not known. The aggregates may be merely a normal reaction by the cells as part of their effort to correct a different, as-yet unknown, insult. It does appear that alpha-synuclein aggregation is enhanced by the presence of dopamine and the byproducts of dopamine production. Based on this mechanistic hypothesis, a transgenic mouse model of Parkinson's has been generated by introduction of human wild-type α-synuclein into the mouse genome under control of the platelet-derived-growth factor-β promoter.[11]

Symptoms

Cardinal symptoms

Symptoms may vary among patients, and additionally may vary greatly over time in a single patient. However, the cardinal symptoms are:

  • tremor (while this is the best known symptom, it is not displayed by an estimated 30% of patients with little perceptible tremor; these are classified as rigid-akinetic. The classical Parkinsonian tremor is 4-7Hz, often unilateral, decreased by supination and pronation, and responsive to dopaminergics and anticholinergics. In addition, tremors of the chin and lips tend to be Parkinsonian where tremors of the whole head suggest essential tremor.),
  • rigidity (increased tone or stiffness in the muscles),
  • bradykinesia (slowness of movement) and akinesia (lack of spontaneous movement),
  • postural instability (failing balance, walking problems)

(The mnemonic TRAP (Tremor; Rigidity; Akinesia/bradykinesia; Postural instability) can be used to remember these symptoms.)

Additional psychological and cognitive symptoms

These additional signs and symptoms are also commonly associated with Parkinson's Disease:

  • depression: (occurs in 40-70% of cases), (20% of depression cases are major depressive disorder); severity and persistance of depression is positively associated with executive dysfunction and dementia;
  • anxiety or panic attacks
    Note: 70% of individuals with parkinson's disease diagnosed with pre-existing depression go on to develop anxiety; 90% of parkinson's disease patients with pre-existing anxiety subsequently develop depression);
  • executive dysfunction, characterized by difficulties in: differential allocation of attention, impulse control, set shifting, prioritizing, evaluating the salience of ambient data, interpeting social cues, and subjective time awareness. This complex is present to some degree in most parkinson's patients; it may progress to:
  • dementia: a later development in approximately 20-40% of all patients, typically starting with slowing of thought and progressing to difficulties with abstract thought, memory, and behavioral regulation.
  • memory loss; procedural memory is more impaired than declarative memory. Prompting elicits improved recall.
  • apathy or abulia: abulia translates from Greek as the absence or negative of will; apathy is an absence of feeling or desire
  • altered sexual function: characterized by profound impairment of sexual arousal, behavior, orgasm, and drive is found in mid and late parkinson disease. Current data addresses sexual function in men almost exclusively.
  • sleep disturbances: including daytime somnolence; initial, intermediate, and terminal insomnia; disturbances in REM sleep, disturbingly vivid dreams, and REM Sleep Disorder, characterized by acting out of dream content;
  • slowed reaction time; both voluntary and involuntary motor responses are significantly slowed.

Additional sensory symptoms

Additional physical symptoms

Other notes

Symptoms usually only begin to appear after about 80% of the dopamine in the brain has been lost. More recent data based on PET scans suggests that symptoms may occur when 50-60% of dopaminergic neurons are lost. The level of dopamine will continue to fall slowly over time, with an attendant worsening of symptoms.

It is an incapacitating disease, disturbing important human functions and ultimately substantially reducing quality of life. As in many neurologic diseases, psychological complications are often extremely serious and require the patient's family members and relatives to pay keen attention to the emotional fragility that usually follows the emergence of the disease; indeed, the depression which often results is seen by many as one of the worst aspects of the disease.

Fairly effective medication for the movement difficulties of Parkinson disease have been available for some time, but the neuropsychiatric aspects of the disease, especially depression and anxiety, are more recently characterized, less well understood, and often less adequately treated. As patients become more disabled, they become more dependent on care from others to perform all manner of tasks, from eating and bathing to monitoring and taking medication. Helping individuals with chronic disability and psychiatric comorbidity to maintain purposeful engagement with life takes a physical and emotional toll on caregivers, who may consequently experience illness and depression themselves.

Cases of PD are reported at all ages, though it is quite rare in people younger than 30 and the average age at which symptoms begin is 58-60; the risk of developing it substantially increases with age. It occurs in all parts of the world, but appears to be more common in people of European ancestry than in those of African ancestry. Those of East Asian ancestry have an intermediate risk. It is more common in rural than urban areas and men are affected slightly more often than women.

Diagnosis

Differential diagnosis

The differential diagnosis for a patient presenting with Parkinsonian symptoms is:

Parkinson's tremors differ from essential tremors in that the latter are posture or action tremors, have bilateral tremors involving the hands, head and voice, and are alcohol responsive. In contrast, Parkinson's tremors are rest tremors, and usually start unilaterally.

Imaging

SPECT with ([123I]FP-CIT) or PET with 18F-fluorodopa are the two imaging modalities used to assess dopamine transporter density and the integrity of nigrostriatal pathways in the central nervous system. Currently (2005) FP-CIT is widely used in Europe for the diagnostic workup of Clinically Uncertain Parkinsonian Syndromes; although it is not available in the United States.

Treatment

The treatment of Parkinson's disease mainly relies on replacing dopamine with levodopa (L-DOPA) or mimicking its action with dopamine agonists such as pramipexole, ropinirole, pergolide or bromocriptine. Discovered as a Parkinson's treatment by Arvid Carlsson, levodopa is a dopamine precursor that is transfomed into dopamine by dopa-decarboxylase, present in the basal ganglia in the brain as well as other tissues, e.g., the retina. Levodopa is almost always supplemented with carbidopa or benserazide, dopa-decarboxylase inhibitors which prevent levodopa from being prematurely converted into dopamine in the adrenal glands or other peripheral tissues. This leaves more levodopa to reach the brain and allows a reduced dosage to produce the same effect on the central nervous system, thus reducing the peripheral side effects, which included protracted nausea, before the formulation l-dopa with carbidopa.

The most frequent side effects of these dopaminergic drugs are nausea, sleepiness, dizziness, involuntary writhing movements and visual hallucinations. Despite these side effects, treatment of a Parkinson's patient with these two drugs can result a striking "return to life" in the eyes of the patient's family and doctors, to the point that the patient's illness is imperceptibe to most observes.

However, progression is inexorable, and the drugs are not effective forever. A point is reached where the drugs only work for periods of a few hours ("on" periods) which are sandwiched between longer interval during which the drugs are partially or completely ineffective ("off periods").

With protracted use of dopamine replacement, the intervals of partial effectiveness are characterized by writhing, choreiform movements --dyskinesia-- that are involuntary, can be very disruptive of normal movement and communication, and can physically exhaust patients. "On", "off", and "dyskinesia" are motor fluctuations: Almost all patients who use dopamine replacement therapy develop motor fluctuations within ten years, younger patients more quickly than older. Despite their somewhat bizarre appearance, a majority of patients prefer a state of dyskinetic "on" to immobilized "off", possibly because the off state is so subjectively paralyzing, and often accompanied by panic.

Therapy for Parkinson disease typically requires an evolving regimen of multiple medications, each calibrated to individual physiology and symptoms. Medicating to control the side effects of other medications contributes to polypharmacy: Amantadine hydrochloride, anticholinergics and COMT inhibitors tolcapone or entacapone are sometimes prescribed to reduce the motor fluctuations that are a consequence of dopaminergic therapy. Tolcapone should be used with extreme caution because of the possibility of liver failure; Entacapone has not been shown to cause significant alterations of liver function.

Foods rich in proteins can reduce the uptake of levodopa, because some amino acids compete with levodopa for cellular receptor sites. This can usually be dealt with by offsetting medication and meal times: consuming the majority of required proteins towards the evening allows patients to use dopamine medication more effectively during the morning and mid-day when mobility is more critical.

While these therapies are a good attempt at treating the symptoms, they are not a cure--they do not attack the underlying cause of the disease which is a loss of dopamine producing neurons. Only a therapy that addresses the underlying causes of dopamine cell pathology and permits their replacemt is likely to constute a cure.

Regular physical exercise and/or therapy are beneficial to the patient and essential for maintaining and improving mobility, flexibility, balance and a range of motion, and for a better resistance against many of the secondary symptoms and side effects. There is increasing evidence that exercise is both neuroprotective against the development of Parkinson's disease, and also ameliorative of both severity of symptoms, and also possibly of progression. "Alternative" exercise modalities such as yoga, tai chi, and dance may also hold promise as rehabilitation therapies, due to their integration of movement, thought, feeling, and sensory experience. Exercise has also been shown to effectively improve mild-moderate/ depression,

Surgical interventions are an active area of current research, and deep brain stimulation is presently the most popular and effective such treatment. In the future, implantation of cells genetically engineered to produce dopamine or stem cells that transform into dopamine-producing cells may become available.

Even these, however, will not constitute cures because they do not address the widespread loss of several different types of cells in the brain and even for the dopamine-producing cells, do not re-establish all of the original connections with neighboring brain cells. A true cure will have to detect the earliest signs of the disorder before they cause important symptoms and will intervene in the process that damages the brain cells in the first place.

Dopamine deficiency is central, but deficits of serotonin, norepinephrine, and acetylcholine are also typical. The depression and anxiety states that predominate when serotonin and norepinephrine are deficient are often treated with selective serotonine reuptake inhibitors (SSRIs) like Paxil, Zoloft, or Celexa; there is emerging evidence that the SSNRI (selective serotonin and norepinephrine reuptake inhibitor) Effexor may be particularly effective in Parkinson's disease because it augments two deficient neurotransmitters. Amphetimine-like drugs (Ritalin, Concerta) are being prescribed with increasing frequency to treat the Attention Deficit Disorder (ADD)-like attention problems that are almost universal in Parkinson's disease. Finally, there is emerging evidence to suggest that drugs that inhibit the reuptake of acetylcholine, developed as treatments for Alzheimer's dementia, may also improve memory and executive function in Parkinson's disease.

The patient and physicians are confronted with the behavioral and cognitive consequences of disruptions in at least five neurotransmitters; in addition to the four above, GABA is also disrupted. The inevitable cost, risk, and sheer unpleasantness of such complex medication regimens drives both doctors and patients to advocate for better and more comprehensive therapies.

The best evidence is that analytic and synthetic reasoning are relatively spared, even in advancing Parkinson's disease. However, the evidence that executive function impairment begins early and is progressive is growing rapidly. Coupled with the observation that more than 70 percent of Parkinson disease patients meet the criteria for at least one psychiatric diagnosis (most commonly anxiety or depression, with apathy also significant), the picture that emerges is one of considerable neuropsychological disability in individuals with preserved reasoning and awareness.

Because reasoning and awareness are operative, most patients can and should participate in their own care. This is correct from a legal and moral perspective of respect for the dignity and autonomy of individual patients, but it is also good medical practice. The formation of a "therapeutic alliance" between the patient and the physician ensures the optimal exchange of information, and amplifies the effectiveness of medical interventions.

The liberty to exercise preferences, even in regard to seemingly trivial details, has been shown to preserve the intellectual and emotional integrity of very physically compromised individuals. Patients have both a legal and a moral right to participate in their own care to the fullest extent possible.

Ultimately, more than a third of Parkinson patients develop dementia (substantially disabling defects in memory and reasoning). With this fact in mind, patients, families, caregivers and medical personnel should work together to outline clear and pragmatically possible ways to preserve the dignity and choices of patients even when they cannot speak clearly for themselves.

Parkinson-Plus diseases

There are other disorders that are called Parkinson-Plus diseases. These include:

Some people include Dementia with Lewy Bodies (DLB) as one of the 'Parkinson-Plus' syndromes.

Patients often begin with typical Parkinson's disease symptoms and these Parkinson-Plus diseases can only be diagnosed when other symptoms become apparent after some years. These Parkinson-Plus diseases usually progress more quickly than the typical main illness, and the usual anti-Parkinson's medications do not work as well at controlling symptoms.

Secondary parkinsonism

Secondary parkinsonism (or briefly parkinsonism) is a term used for a symptom constellation that is similar to that of Parkinson's disease but is caused by other disorders or medications. Major reasons for secondary parkinsonism are stroke, encephalitis, narcotics, toxins such as manganese or carbon monoxide poisoning, traumatic brain injury, and normal pressure hydrocephalus.

There are other idiopathic (of unknown cause) conditions as Parkinson's disease that may cause parkinsonism. In these conditions the problem is not the deficient production of dopamine but the inefficient binding of dopamine to its receptors located on globus pallidus.

Parkinson's and death

Parkinson's does not by itself cause death, but since the disease may affect the respiratory system, sufferers may eventually contract pneumonia and die. Swallowing difficulties may lead to aspiration of food, causing aspiration pneumonia (a specific form of pneumonia caused by gastric acid, food and digestive tract bacteria) . Immobility may increase susceptibility to infection. Onset of dementia doubles the odds of death; depression more than doubles the odds ratio. [13] However, people may live for 20 to 30 years with the condition.

Notable Parkinson's sufferers

One famous sufferer of young-onset Parkinson's is Michael J. Fox, who has written a book about his experience of the disease. The film Awakenings (starring Robin Williams and Robert de Niro and based on genuine cases reported by Oliver Sacks) deals sensitively and largely accurately with a similar disease, postencephalitic parkinsonism; the state of the art in treatment remains roughly the same as it was at the time of the events depicted, the 1960s, although patients with postencephalitic parkinsonism lose benefit from their medication far faster than do patients with Parkinson's disease. Another famous sufferer was Pope John Paul II.

See also

References

  1. ^ Template:Journal reference issue PMID 10678833
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