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Parkinson's Disease: A silent progression to Paralysis?
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Parkinson's disease (also called Paralysis agitans or shaking palsy) is a progressive neurological disorder that mainly affects the motor system but can cause cognitive disturbance and autonomic nervous system dysfunction as well. It is related to several dopamine neurotransmission systems in the brain and can probably arise from several different causes. Although incurable it is treatable with increasing effectiveness and tolerability by medication, neurosurgical procedures, brain stimulation and regenerative therapy.

INTRODUCTION:

There are many ancient descriptions of Parkinson’s disease, including passages in the Ebers medical papyrus from ancient Egypt, Ayurvedic texts from India, the Bible and the writings of Galen. There were no clear references to parkinsonism in medieval and Renaissance texts, but discussions of parkinsonian symptoms were published by the Dutch anatomist Sylvius and the English surgeon John Hunter during the 17th and 18th centuries.
Quote:The First Described Case and Nomenclature
The first systematic description of paralysis agitans ;was given by the English surgeon, paleontologist and radical politician James Parkinson in an “Essay on the Shaking Palsy” in 1817. 

Parkinson described the characteristic rigidity, tremor, hypokinesia and abnormalities of gait and posture in 3 of his own patients and 3 other individuals he had seen on the street. 

He correctly established the distinction between resting and motion (intention) tremor that is still recognized today.

But, he was with time found not to be correct in his observation of “the senses and intellect being uninjuredand was wrong in attributing the disorder to a lesion of the cervical spinal cord [1].



[Image: james-parkinson.jpg]
Dr. James Parkinson
(source: allaboutparkinsons.com)

Parkinson’s essay prompted communications from a number of British, French and German clinicians, and between 1868 and 1881 Jean-Martin Charcot elucidated the clinical features of several types of paralysis agitans and proposed that the syndrome be named after Parkinson [2].

Time Line of Some Significant Events in the History of Parkinson's Disease

  • The association between parkinsonism and dementia in some patients was recognized by the beginning of the 20th century, and characteristic inclusion bodies were described in affected patients by Lewy.
  • The brain regions responsible for parkinsonian symptoms, chiefly the basal ganglia and particularly the substantia nigra, were identified by Tretiakoff in 1919, and pathological confirmation was provided by Hassler in 1938.
  • The neurochemistry of these centers and the role of dopamine deficiency in parkinsonian symptoms were clarified by Carlsson and Hornykiewicz in the 1950s [3].
  • This led in turn to the treatment of these symptoms with dopamine, which was much more successful than previous therapeutic attempts with acetylcholine antagonists and surgical lesioning of the corticospinal tract or basal ganglia structures [4].
  • Electrical stimulation of deep brain structures was introduced in the 1990s and has been effective in refractory Parkinon’s disease [5], and recent attention has been focused on the potential regenerative effects of stem cell infusion [6].



CLINICAL FEATURES

Parkinson’s disease has primarily motor symptoms, but since Parkinson’s initial description, non-motor manifestations have been increasingly recognized and may in fact precede motor symptoms.
The motor hallmarks of the disorder are:
a) Bradykinesia or hypokinesia (slowness or reduction of movement)
b) Rigidity (increased muscle tone and resistance to movement due to continuous muscle contraction)
c) Tremor (involuntary rhythmic movement of the limbs when at rest)
d) An abnormal and unstable posture

Non-motor symptoms are numerous and include:
a) Dementia and behavioral or emotional disturbances
b) Autonomic nervous system dysfunction
c) Abnormalities of vision and eye movements [7].

[Image: parkpic1335108259020.png]
Source:http://classconnection.s3.amazonaws.com/762/flashcards/918762/png/parkpic1335108259020.png


Digging deep into the Symptoms

MOTOR SYMPTOMS

Effect on Movements
The characteristic posture and slowness of the disorder reflect an increasing number of difficulties in initiating and executing movements with the progression of the disease. Fine movements that are involved in daily activities are commonly affected early, and bradykinesia is the first cause of disability.  Some kinds of movement are more prominently affected than others and this varies from patient to patient, as well as being influenced by level of activity and emotional state. Such difficulties can be assessed on neurological examination by performance of rapid alternating movements with hands and feet, and during examination and in day-to-day activities motor performance is often improved by an external cue such as being touched or supported [8].

Muscle Rigidity in Parkinson's Disease

Rigidity reflects an abnormal increase in muscle tone and may be continuous and cause the limb to feel like a “lead pipe” or to be ratchety like the movement of a “cogwheel”. Cogwheel rigidity is thought to be due to the combination of rigidity and tremor. Rigidity usually begins in the neck and shoulders and is asymmetrical, but becomes symmetrical and more generalized with the progression of the disease. Although pain is not usually part of the parkinsonian syndrome, rigid limbs and stiff joints may be painful to patients. The face is often rigid and mask-like, and stiffness of the vocal cords leads to progressive impairment of speaking and swallowing [9].

Tremors in Parkinson's Disease
Tremor is the most apparent symptom, but may be absent in a third of patie, and is usually predominant distally and has a frequency of 4 to 6 Hz. The tremor is present at rest, decreases with movement and disappears during sleep; the circular motion of the hand and fingers resemble the movements formerly used by pharmacists to form pills, and the movement has been called a “pill-rolling” tremor. The tremor plus rigidity will produce characteristic small and tremulous handwriting (micrographia) [10].

Postural Abnormalities in Parkinson's Disease
Postural abnormality is evident early in the disease, with a stooped posture, forward flexion of the trunk when walking and shuffling steps with a tendency to accelerate when walking (festination). Disabling loss of balance is common, with falling occurring in 40 per cent of patients and 10 per cent having weekly falls with a high rate of injury and fracture [11].

NON-MOTOR SYMPTOMS
  • Nonmotor symptoms of Parkinson’s disease include daytime sleepiness, nocturnal insomnia and decreased rapid eye movement (REM) sleep. 
  • The autonomic nervous system is also involved and this can result in orthostatic hypotension, which aggravates postural instability and the consequences of falling, as well as sweating disturbances, constipation and urinary incontinence and characteristic oily skin (seborrhea). 
  • Impairment of both voluntary and involuntary eye movements can cause blurred or double vision. The major nonmotor problems, however are cognitive and behavioral. Depression, anxiety, apathy and agitation are predominant psychiatric symptoms in that order [12].
  • Impulse control disorders, chiefly pathological gambling and eating, hypersexuality and compulsive shopping, have been associated with treated parkinsonism, and are currently ascribed to the effects of dopamine-altering medications [13].
Dementia is an increasingly recognized complication of parkinsonism. The incidence of dementia is increased sixfold in Parkinson’s disease patients compared to others of the same age, and the quality of life for Parkinson’s patients with dementia, and for their caregivers, is significantly worse than for nondemented patients and those who care for them. Mortality and inability to live independently are also significantly increased in the presence of dementia. Cognitive problems are in fact evident early in the course of Parkinson’s disease and affect most parkinsonian patients and increase in severity with duration of the disease. The cognitive problems are mostly executive functions, like planning, initiating appropriate responses and inhibiting inappropriate ones and speed and flexibility of thinking and abstraction. Memory disturbances are dominated by impaired recall of learned information, and like motor slowness the slowness of recall can be improved by external cues [15].

Monitoring Progression of Parkinson's Disease

  • The progression of Parkinson’s disease has classically been measured by the five-stage Hoehn and Yahr scale, which extends from minimal symptoms in stage I to bedfast immobility in Stage V. 
  • The Unified Parkinson’s Disease rating scale (UPDRS) is a more common recent metric, and suggests loss of the ability to ambulate after 8 years of disease and immobility after 10 years if not successfully treated. 
Quote:The multiplicity of available treatments has prolonged survival, but progression to requirement for caretakers occurs over about 15 years. Fifty per cent of treated patients have disability from various problems with dopamine-augmenting medications during the first 5 years of treatment, whereas disability is predominantly due to nonmotor symptoms like cognitive decline and autonomic dysfunction after 10 years of treatment. Life expectancy is significantly reduced, and mortality rates are also about three times greater in those with parkinsonism [16].


EPIDEMIOLOGY

  • Parkinson’s disease afflicts about 7 million people around the world and around 1 million in the United States, making it the second most common neurodegenerative disorder after Alzheimer’s disease. Its prevalence is around 0.3 per cent in general, 1 per cent at age 60 and 4 per cent in the population over 80 years old, while its incidence is 8 to 18 cases per 100,000.

  • Ninety-five per cent have onset around age 60, the remainder (young-onset Parkinson’s disease) beginning usually between 20 and 50 years old. Most studies suggest a predominance in Caucasians, and some also suggest a greater incidence in men. 

  • Parkinsonism is more common after head injury, and an increase in boxers (dementia pugilistica) is well known and epitomized by longtime heavyweight champion Muhammad Ali.  Higher rates of parkinsonism have also been associated with rural domicile and certain chemical exposures, particularly pesticides and aluminium, and lower rates have been reported in cigarette smokers [17].


GENETICS


About 15 per cent of parkinsonian patients have a first-degree relative with Parkinson’s disease, and heredity because of an identifiable genetic mutation has been shown in 5 per cent.
  • The best-known mutations involve the SNCA gene that codes for alpha-synuclein, the protein contained in the inclusion bodies described a century ago by Lewy in patients with parkinsonism and dementia.
  • Another genetic association involves parkin, a protein involved in the degradation of other proteins that is coded by the PARK2 gene; mutation of this gene produces autosomal recessive Parkinson’s disease of juvenile onset.
  • The LLRK2 gene which codes for leucine-rich repeat kinase 2 or dardarin, a name derived from the Basque word for “trembling”, has been linked with accelerated cell death in cortical neurons and with an increased risk for Parkinson’s and Crohn’s diseases, and is the most common cause of familial parkinsonism.
As with other degenerative disorders, it is not yet clear how closely related these inherited cases are to sporadic Parkinson’s disease [18].


CAUSES

The cause of Parkinson’s disease remains unknown but it is clearly related to dopamine and related neurotransmitters. The chief pathological feature is death of dopamine-containing cells in the substantia nigra in the midbrain, particularly the front or ventral part of the pars compacta, ordinarily a dense collection of cell bodies that is highly pigmented by melanin but in Parkinson’s disease largely depopulated and depigmented, as up to 70 per cent of dopaminergic neurons are gone by the time of death. This brain region has widespread connections through 5 different pathways which involve dopamine neurotransmission, dysfunction of which can produce the characteristic symptoms of Parkinson’s disease: these pathways involve motor cortex, limbic system, orbitofrontal cortex, association cortex and oculomotor projections.
[Image: parkinsons-disease.jpg]
Source: callmyfamilydoctor.com

The motor pathway may exert an inhibitory effect on the other motor centers and neurons, and dopamine may act to reduce that inhibition so that appropriate motor activity can take place; high levels of dopamine would be associated with increased motor activity, as is often seen with overtreatment of parkinsonian symptoms, while low levels would be associated with hypokinesia. Projections to the limbic system connecting the midbrain, frontal and temporal lobes may be responsible for psychosis and other mental symptoms, while projections to the frontal lobes and orbitofrontal cortex may play a role in diminished inhibition of inappropriate behavior and impairment of executive functions. Another dopamine projection is to association areas of the cerebral cortex, which could be involved in memory dysfunction, and the disturbances of eye movement and visuospatial perception characteristic of the disease could reflect impaired dopamine input through the oculomotor pathway that connects to eye movement fields in the frontal lobes [19].

The cause of the massive neuronal cell death is not known, but attention is increasingly focused on the inappropriate accumulation of possibly toxic proteins, by analogy with other neurodegenerative disorders. Recent evidence suggests that one or more of several types of accumulated synuclein may cause the cell death, perhaps by an immune mechanism, and that this may be in some cases triggered by environmental exposures and in other cases due to the permissive effect of genetic factors like LLRK-2 deficiency or malfunction. Misfolded and therefore inactive proteins due to virus-like infectious protein particles (prions) that have been linked to “mad-cow” disease, scrapie in sheep and kuru in humans may also trigger parkinsonian neurodegeneration. This has led to promising trials of immunotherapy with monoclonal antibodies and neuroprotection through infusion of stem cells [20].


DIAGNOSIS


Parkinson’s disease is diagnosed clinically by a history of motor and cognitive symptoms and a neurological examination showing tremor, rigidity, bradykinesia and abnormal gait and posture.



  • Computed tomography (CT) and magnetic resonance imaging (MRI) are generally normal but may help in excluding alternative causes for symptoms.
  • Positron tomography (PET) and single photon emission CT (SPECT) with radioactive iodine or fluorine tracers may show decreased dopamine activity in the basal ganglia [21].
Quote:Clinical diagnostic criteria have been proposed by the Parkinson’s Disease Society Brain Bank in the United Kingdom and the National Institute of Neurological Disorders and Stroke in the United States: these involve excluding other causes for motor symptoms and finding resting tremor, unilateral onset or asymmetric symptoms, progression of symptoms with time, a clinical course of 10 or more years, response to levodopa for at least 5 years or excessive movement (dyskinesia) if given excessive levodopa [22].

TREATMENT


Great advances have been made in the past 50 years in treatment of Parkinson’s disease.


The approaches to treatment may be classified into (a) Medical (b) Surgical

Medical treatment has been aimed at replacement of dopamine, augmentation of its effect at dopamine receptors, impairment of its degradation so as to preserve dopamine effects at the receptors, stabilization of its highly variable effects over time and amelioration of symptoms with drugs that act by different mechanisms.


Surgical lesioning of pathways responsible for the motor symptoms was supplanted by ablation of subcortical areas involved in them, and subsequently by transcortical magnetic stimulation or the implantation of pacemaker devices to stimulate deep brain structures.

Recent studies of immunotherapy and neuroprotection have also attracted attention.


Medical approaches have focused on dopamine replacement or augmentation. L-DOPA (levodopa) is converted to dopamine by the enzyme DOPA decarboxylase in dopaminergic neurons, and has been used since in 1970s to replace depleted dopamine and alleviate motor symptoms. Since only about 5 per cent of  L-DOPA crosses the blood-brain barrier and the remainder causes peripheral symptoms of dopamine excess such as nausea, peripheral DOPA decarboxylase inhibitors such as carbidopa and benserazide have been given along with levodopa or added to combination preparations such as Sinemet, the combination of carbidopa and levodopa which was named from the Latin for “without vomiting”. With increasing duration of treatment, patients may become less responsive to levodopa or have disabling fluctuations between rigidity and hyperkinesis, the “on-off” phenomenon. These were first addressed by “drug holidays”, periods in which levodopa was withdrawn, but opinion has turned against this because dyskinesias may become worse and life-threatening neuroleptic malignant syndrome may occur when the dopamine replacement is restarted.

Adjunctive drugs that inhibit the enzyme catechol-o-methyltransferase (COMT), which breaks down levodopa, may prolong and stabilize the dopaminergic effect. The first such drug, tolcapone, proved to have potentially fatal liver toxicity and has been withdrawn in most countries and is very rarely used in the others. Entacapone does not have the same toxicity, and is used by itself or in a combination preparation with levodopa and carbidopa. Another way to augment the effect of levodopa is to slow the metabolism of the dopamine it is made into by inhibiting monoamine oxidase B (MAO-B). This can be done with the vitamin E derivatives seligiline and rasagaline.

Direct stimulation of the dopamine receptor may be an alternative to levodopa, and have been shown to delay the onset of motor complications like dyskinesias and “on-off”. Bromocriptine, pergolide, pramipexole, ropinirole and cabergoline, along with piribedil outside the United States, can be taken orally, while apomorphine is given by injection and two receptor agonists (lisuride and rotigotine) can be administered through skin patches. These are increasingly used in the attempt to avoid levodopa early in the disease and to lessen motor complications later.

Surgical treatments began with lesions of the corticospinal tract to control tremor. With the introduction of the anticholinergic drugs such procedures declined, and lesions were occasionally made in selected motor areas in refractory patients, chiefly to diminish disabling dyskinesias. Pallidotomy, the cauterization of a small part of the globus pallidus, which is adjacent to the substantia nigra and through which most of its motor nerve output passes, has been the most common lesional operation for the combination or rigidity, tremor and dyskinesia. Lesioning of the thalamus (thalamotomy) with electrical cauterization or the application of a supercooled probe has also been carried out, particular for severe tremor, and has mainly focused on the subthalamic nucleus on the side opposite to the tremor. The operations are usually done under local anesthesia, as the brain itself is insensitive to pain, and the effect of the lesion on motor symptoms can be immediately assessed. The complications are those of craniotomy, chiefly bleeding and infection.


Deep Brain Stimulation grew out of lesioning surgeries, and was approved in the United States for tremor in 1997 and Parkinson’s disease in 2002, as well as for dystonia, obsessive-compulsive disorder, refractory depression and chronic pain. An implantable pulse generator in titanium housing is placed below the clavicle or in the abdomen, and is connected to a polyurethane-insulated coiled wire with four electrodes made of platinum and iridium, that are placed in one or two target nuclei. The electrodes are placed in the globus pallidus or subthalamic nucleus. The implantation is often done under general anesthesia with the device and the target nuclei visualized by intraoperative MRI, after which the effects of stimulation on tremor and dyskinesia can be calibrated when the patient is awake. The potential risks are again infection, estimated at 3 to 5 per cent, and hemorrhage in 1 or 2 per cent. There has also been interest in noninvasive brain stimulation through the skull with the transcortical magnetic device approved for refractory depression and migraine; some improvement in levodopa-related dyskinesia has been reported [23].

[Image: 161px-Parkinson_surgery.jpg]
Electrode insertion during deep brain stimulation (Source: wikimedia)

New developments include promising attempts at treatment derived from the evidence that the accumulation of proteins normally disposed of may be harmful or fatal to the neurons of the substantia nigra by inciting an immune response, by triggering the processes of cell death that are programmed into all tissues or by the lack or loss of trophic factors or substances that protect neurons against this process. After promising studies in which monoclonal antibodies were targeted with beneficial effect against beta-amyloid, the protein whose inappropriate accumulation may be responsible for Alzheimer’s disease, studies are underway of passive and active immunization against the alpha-synuclein which accumulates in neurons in parkinsonism with apparent fatal effect. Active immunization involves injecting a small fraction of synthetic alpha-synuclein to induce the formation of antibodies, while passive immunization involves the preparation of monoclonal antibodies against alpha-synuclein which are then infused. The third approach is similar to recent advances in the treatment of amyotrophic lateral sclerosis, and involves transforming pluripotent adult stem cells into cells capable of secreting nerve growth factors known to be protective against cell death, then reinfusing these stem cells into the patient to offer neuroprotection to the imperiled dopaminergic neurons. These therapeutic options are now approaching or beginning phase 2 trials in hopes of demonstrating efficacy against Parkinson’s disease [20].

REFERENCES

1. Wilkins RH, Brody IA (1997). Neurological Classics. New York, Thieme. Pp. 87-92.
2. Lees AJ (2007). Unresolved issues related to the shaking palsy on the celebration of James Parkinson’s 250th birthday. Movement Disord, 22(suppl 17): S327-334.
3. Fahn S (2008). The history of dopamine and levodopa in the treatment of Parkinson’s disease. Movement Disord, 23(suppl 3): S497-508.
4. Lanska DJ (2010). The history of movement disorders. Handbook Clin Neurol, 95: 501-546.
5. Coffey RJ (2009). Deep brain stimulation devices: a brief technical history and review. Artif Organs, 33(3): 208-220.
6. Pollitis M, Lindvall O (2012). Clinical application of stem cell therapy in Parkinson’s disease. BMC Medicine, 10: 1.
7. Rodriguez-Oroz MC, Jahanshahi M, Krack P, Litvan I, Macias R, Bezard E, Obeso JA (2009). Initial clinical manifestations of Parkinson’s disease: features and pathophysiological mechanisms. Lancet Neurol, 8(12): 1128-1139.
8. Jankovic J (2008). Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiat, 79(4): 368-376.
9. Fung VS, Thompson PD (2007). Rigidity and spasticity. In, Tolosa E, Jankovic J (eds). Parkinson’s Disease and Movement Disorders. Hagerstown MD, Lippincott Williams & Wilkins, pp. 504-513.
10. Cooper G, Eichhorn G, Rodnitzky RL (2008). Parkinson’s disease. In, Conn PM (ed). Neuroscience in Medicine. Totowa NJ, Humana Press, pp. 508-512.
11. Yao SC, Hart AD, Terzella MJ (2013). An evidence-based osteopathic approach to Parkinson’s disease. Osteopath Fam Phys, 5(3): 96-101.
12. Murray ED, Buttner EA, Price BH (2012). Depression and psychosis in neurological practice. In, Bradley WG, Daroff RB, Fenichel GM, Jankovic J (eds). Bradley’s Neurology in Clinical Practice, ed. 6. Philadelphia, Elsevier-Saunders, pp. 102-103.
13. Ceravolo R, Frosini D, Rossi C, Bonuccelli U (2009). Impulse control disorders in Parkinson’s disease: definition, epidemiology, risk factors, neurobiology and management. Parkinson Relat Disord, 15(suppl 4): S111-115.
14. Friedman JH (2010). Parkinson’s Disease psychosis 2010: A review article. Parkinson Relat Disord, 16(9): 553-560.
15. Caballol N, Martí MJ, Tolosa E (2008). Cognitive dysfunction and dementia in Parkinson disease. Movement Disord, 22 (suppl 17): S358-366.
16. Poewe W (2006). The natural history of Parkinson’s Disease. J Neurol, 253(7 suppl): vii2-vii6.
17. Wright-Willis A, Evanoff BA, Lian M (2010). Geographic and ethnic variation in Parkinson disease: a population-based study of U.S. Medicare beneficiaries. Neuroepidemiol, 34: 143-151.
18. Shulman JM, De Jager PL, Feany MB (2011). Parkinson’s Disease: genetics and pathogenesis. Ann Rev Pathol, 6: 193-222.
19. Sontheimer H (2015). Diseases of the Nervous System. Waltham, MA, Elsevier. Pp. 134-166.
20. Stetka BS, Facheris M (2015). Prions, the pipeline and the latest in Parkinson’s disease. Medscape Neurology, May 8, 2015.
21. Brooks DJ (2010). Imaging approaches to Parkinson’s Disease. J Nucl Med, 51(4): 596-609.
22. Lingor P, Liman J, Kallenberg K, Sahlmann C-O, Bähr M (2011). Diagnosis and differential diagnosis of Parkinson’s Disease. In, Rana AQ (ed). Diagnosis and Treatment of Parkinson’s Disease. Rijeka, Croatia, InTech,com, pp. 1-20.
23. Koch G (2010). rTMS effects on levodopa-induced dyskinesias in Parkinson’s disease patients: searching for effective cortical targets. Restor Neurol Neurosci, 28(4): 561-568.
About Author:

Miles E. Drake
Ph.D., M.D


A.B.- Harvard University
M.D.- Duke University School of Medicine

Professor emeritus (1982 to 2007) -Ohio State University College of Medicine and Public Health
Lecturer (2007-2013) - AGU School of Medicine
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