sections include: symptoms of parkinsonism, causes of parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration
A number of other diseases can cause the symptoms we most often see in Parkinson’s disease: slowness, clumsiness, and increasing fatigue in performing various voluntary activities (referred to as akinesia or bradykinesia) and stiffness or increased muscle tone (rigidity). We therefore use the terms parkinsonism and akinetic-rigid syndrome to describe this group of symptoms.
Sometimes, especially early in the course of a disease, doctors have no way to determine which disorder is causing these symptoms. As a person’s condition progresses, important differentiating features usually (but not always) develop. The term parkinsonism plus indicates these additional abnormalities. Even though most physicians are aware of the potential for diagnostic error, up to 25 percent of people classified as having Parkinson’s disease are found after death to have had one of these other conditions. This highlights the need for more effective methods of diagnosing parkinsonian disorders.
Symptoms of Parkinsonism
A number of complaints are common to all causes of parkinsonism. People with parkinsonism typically experience a general slowing of their movements. They note increasing clumsiness and less dexterity in their hands, which often interferes with such activities as brushing their teeth, doing up buttons, getting arms into sleeves, and writing. Walking commonly slows, and they feel less stable on their feet. Eventually, poor balance may make them need help with walking, and even a wheelchair. Although this problem generally occurs later in the course of the illness, poor stability on the feet and even spontaneous falls can sometimes develop early. Speech frequently becomes softer and hard to understand, and an individual may develop other unusual speech and language difficulties. Chewing and swallowing may become difficult, particularly later in the course of these disorders, and can impair a person’s ability to take in adequate nutrition and also result in such complications as pneumonia.
In contrast to Parkinson’s disease, tremors evident when the limbs are at rest (for example, arms in one’s lap or by one’s sides while walking) are relatively uncommon in other parkinsonian disorders. If a person has any tremor, it most often occurs only during activity, as in bringing a cup to the mouth or writing.
Another important feature distinguishing Parkinson’s from other neurodegenerative causes of parkinsonism is evident in the disorder’s response to the drug levodopa and other dopamine replacement treatment. Parkinson’s disease, which is a disorder primarily of the cells that manufacture and release dopamine, typically responds very well to these treatments. Most other neurodegenerative causes of parkinsonism damage both this region of the brain and others. The additional brain dysfunction generally means dopamine-replacement therapy is inadequate. Although some individuals obtain modest benefit from these treatments early on, the response is usually incomplete and is largely lost over the course of the illness.
Causes of Parkinsonism
There is a long list of causes of parkinsonism. Some of these are exceedingly rare or occur only in certain age groups; causes of the infrequent instances of parkinsonism in children and young adults are very different from those late in life.
In rare cases, strokes cause parkinsonism (ischemic, hemorrhagic). This problem can usually be recognized because the onset of symptoms is abrupt, and people rarely get worse unless they have further strokes or other complications.
Early in the twentieth century parkinsonism was often the result of what we presume was a viral infection of the brain known as encephalitis lethargica. This form of parkinsonism is extremely rare nowadays.
Most of the major Parkinson’s symptoms (rigidity, slowness, tremor) result from the deficiency of the critical neurotransmitter dopamine. Therefore, neuroleptics or other drugs that block the effects of dopamine in the brain may produce parkinsonism. Doctors generally assume that anyone who displays the syndrome while taking one of these agents has drug-induced parkinsonism.
For most people who develop parkinsonism in middle or late life, however, the cause of the symptoms is neurodegenerative, meaning a gradual loss of some functioning in the brain. This section will focus on the most common of this type of disorder. Neurodegenerations typically appear insidiously, with a slow, progressive increase in neurological disability over months or years. Parkinson’s disease is the most common neurodegenerative cause of parkinsonism, accounting for about 80 percent of the cases. Among these disorders, it is also one of the slower to develop.
Because of the symptoms’ faster progression and the poorer response to dopamine-replacement therapy, the prognosis for other neurodegenerative causes of parkinsonism is generally worse than for typical Parkinson’s disease. This serious state of affairs has encouraged considerable research into these disorders, directed both at the possible underlying causes and at new treatments that might alter their natural history. In addition, speech, occupational, and physical therapy may provide people with some useful benefits even when drug therapy fails.
The more common neurodegenerative causes of parkinsonism include progressive supranuclear palsy (PSP), multiple system atrophy, and corticobasal degeneration. Although we say these are the “more common” causes, they are still relatively rare disorders, especially in comparison to Parkinson’s disease. Together they account for perhaps 10 percent of all people with parkinsonian symptoms. Other common neurodegenerative causes of parkinsonism, discussed elsewhere in this book, include Alzheimer’s disease and Lewy body dementia. A number of other neurodegenerative causes of dementia often show some parkinsonian features, especially later in their course.
Progressive Supranuclear Palsy
The name of this disorder highlights one of its most prominent clinical features and most important clues for physicians. “Supranuclear palsy” refers to a disturbance of eye movement that removes a person’s ability to look down. Slowing of up-and-down eye motion precedes this complete loss of downward gaze. These eye movement disturbances may cause people to look wide-eyed and vacant. Some people with early PSP have few or no visual complaints, while others notice that they have trouble seeing the food on their plate or other practical problems. While many people have the walking and balance difficulties that appear in other forms of parkinsonism, people with PSP may have spontaneous falls early in the course of the disease, or they may trip or fall simply because of the difficulty of looking down, which means they cannot see where they are walking. As the disease progresses, they may also notice disturbances of their hand and arm function, such as clumsiness and impaired fine coordination of the hand in writing, as well as the major symptoms of parkinsonism.
As with other neurodegenerative forms of parkinsonism, we do not know the cause of PSP. The degenerative process is relatively widespread in the brain but especially affects the midbrain (which accounts for the eye-movement abnormalities) and other regions of the brain stem, and the basal ganglia (accounting for the parkinsonism). In recent years the involvement of the cerebral cortex has been more widely recognized. The combination of problems in the basal ganglia and cerebral cortex can result in cognitive and behavioral disturbances. Doctors have used the term subcortical dementia to refer to the slowness of mental processes, apathy, and other so-called frontal lobe disturbances they often see in people with these types of problems in PSP.
We estimate that PSP occurs in approximately 6 in 100,000 individuals in the general population. To date, we know of no risk factors for it. PSP generally begins in middle to late life, affects both sexes equally, and is not linked to specific ethnic groups. Rare examples of “familial PSP” have been reported, suggesting that there might be a genetic factor. A number of recent reports have confirmed a type of genetic predisposition involving the gene for the protein tau. But many normal individuals have the same variant gene, so other factors are obviously critical to the development of the disorder. Indeed, recent reports of PSP-like features in residents of the Caribbean islands of Guadeloupe who ate or drank certain fruits or herbal teas suggest that an environmental toxin might be a factor.
As with most other neurodegenerations, there are no specific tests that allow an accurate or early diagnosis of PSP. Magnetic resonance imaging (MRI) scanning may be helpful in showing shrinkage (atrophy) in the regions most affected, especially in the midbrain. MRI will also exclude disorders that can mimic PSP, including multiple strokes and rare examples of brainhydrocephalus.
As with most other parkinsonism-plus disorders, treatment of PSP is relatively ineffective. Although doctors regularly use the standard anti- Parkinson drugs, good responses are uncommon and most people can eventually stop taking these drugs without obvious deterioration. None of the surgical techniques currently available for Parkinson’s disease have shown any benefit in PSP.
Unfortunately, the prognosis for PSP is poor. People die (usually of pneumonia or infections) generally within five to ten years after diagnosis, and current treatments have little or no impact on this course. The most promising paths of research relate to the mechanisms of cell death. We expect that advances in understanding the biology of the tau protein will boost the treatment of PSP as well as a number of other conditions that also involve abnormalities of this critical component of brain cells.
Multiple System Atrophy
Multiple system atrophy (MSA) is another important cause of parkinsonism plus. It is marked by a combination of symptoms—affecting movement, blood pressure, and other body functions—that were originally thought to be several different disorders: Shy-Drager syndrome, striatonigral degeneration, and some forms of olivopontocerebellar atrophy. In Shy-Drager syndrome, the most prominent symptoms involve the autonomic nervous system. Striatonigral degeneration causes parkinsonian symptoms, while olivopontocerebellar atrophy principally affects balance, coordination, and speech. It is now recognized that these conditions are different manifestations of a single disorder.
Most people with MSA have typical parkinsonian symptoms. A smaller proportion will first experience a predominant cerebellar syndrome, usually gait imbalance (ataxia). Eventually, most people with MSA show some features of both.
Parkinsonian MSA is probably the most difficult neurodegenerative cause of parkinsonism to distinguish from Parkinson’s disease. Important clues include a lack of the typical resting tremor of Parkinson’s disease, poor response to levodopa and other dopaminergic drugs, a relative lack of common motor complications of levodopa seen in Parkinson’s disease (the motor fluctuations and dyskinesias described here), and more rapid progression of the condition. Other clues relate to the more widespread distribution of the pathological changes in the brain and spinal cord. However, these features may be lacking, and the patient may demonstrate a picture completely indistinguishable from Parkinson’s disease.
For a clinical diagnosis of MSA, physicians must see signs of degeneration in the autonomic nervous system, which controls, among other things, blood pressure and sexual and bladder and bowel function. People with MSA commonly experience a fall in blood pressure when they move to a more upright position (for example, from sitting to standing, or from lying to sitting), with consequent light-headedness, “dizziness,” and even fainting. This symptom may be aggravated by the drugs used to treat the parkinsonism (and may first appear when these drugs are started). In men, sexual dysfunction may be the first symptom of the disorder, and difficulty in gaining an erection and eventual impotence may predate the development of other neurological complaints by months or even years. Bladder disturbances include increased frequency of urination during the day and night, and particularly, difficulty controlling the urge to urinate, which sometimes results in loss of bladder control (incontinence). Constipation is very common, but this is also a frequent complaint in other parkinsonian disorders.
MSA involves a variety of brain areas: the basal ganglia, several locations in the brain stem, and the cerebellum. It also affects the spinal cord, particularly those regions that serve the autonomic nervous system. Dysfunction of these regions accounts for the disorder’s broad range of symptoms. The cerebral cortex is relatively spared, so significant cognitive decline and behavioral changes are uncommon, in contrast to many other neurodegenerative causes of parkinsonism. This is probably why psychiatric side effects, such as hallucinations, from anti-Parkinson drugs are less common in MSA than in Parkinson’s disease.
It has been recently estimated that MSA occurs in 4 of 100,000 people in the general population. It affects a wide age range, usually from middle to late life and typically not before the age of 40. Men and women are affected equally. The cause of MSA is completely unknown, and there are no recognized risk factors that increase the likelihood of developing this disorder. Examples of more than one individual in a single family having MSA are extremely rare, so it is not believed to be genetic.
As with other neurodegenerative causes of parkinsonism, the diagnosis of MSA is largely clinical. MRI brain scans show abnormalities characteristic of the disease (typically involving the basal ganglia, brain stem, and cerebellum) in some people, making a definitive diagnosis possible. However, other people with typical clinical features may not exhibit these changes in their brains.
More than most other forms of parkinsonism, MSA may respond to some degree to levodopa and other dopaminergic drugs. Occasionally people receive a quite pronounced benefit. Usually the response diminishes gradually with time, although many individuals continue to feel some effect. Some people will experience motor complications, with fluctuations and dyskinesias similar to those seen in Parkinson’s disease, but these are generally less obvious. Other drug therapies are generally ineffective, as are currently available neurosurgical interventions.
MSA is an inexorably progressive disease, with pronounced disability developing within two to three years, and death from pneumonia or infection generally within five to ten years. Neurotransplantation is a treatment approach that is currently being explored in animals, with the hope that we will be able to use it one day in humans.
Corticobasal degeneration (CBD) is an even rarer cause of parkinsonism than PSP and MSA. This is another condition involving abnormalities of the tau protein. Some people with pathological changes of CBD in the brain develop a syndrome dominated by features of parkinsonism, while others primarily experience predominant behavioral and cognitive disturbances (that is, dementia) with little or no parkinsonism until very late in the illness. Doctors once believed that the parkinsonian form predominated, but they have increasingly recognized that the dementia may in fact be the more common of the two forms. Given this complex state of affairs, it is impossible to know how common this disorder really is.
In addition to possible parkinsonism and mental changes, other features of CBD include:
- abnormal postures of the limbs (most often the hand and arm), termed dystonia
- jerky movements of the limbs, particularly when trying to move or in response to a light touch or other stimulation, called stimulussensitive myoclonus
- abnormalities of complex movements we have learned to use in everyday life, as if the person has forgotten how to perform tasks (apraxia)
- “pins and needles” or numbness in the hand
- disturbances of language functions (aphasia), most often causing difficulties with finding words
- peculiar wandering, or seemingly purposeful but involuntary, movements of a limb (called alien limb phenomenon)
The nature of the disability varies greatly from one individual to the next, and the prominence of each of these symptoms varies over the course of the disease.
CBD seems to affect both sexes equally, beginning generally in later adult life. Although most people with the disease lack a family history of it, genetic factors are increasingly recognized as important. Both pathological and genetic overlap exist between CBD and PSP, and investigators are discussing potential links between the two disorders.
Once again, the diagnosis of this form of neurodegenerative parkinsonism is largely clinical. MRI, single-photon-emission computed tomography (SPECT), or positron-emission tomography (PET) scanning of the brain may reveal characteristic changes. For example, it is relatively common for people with CBD to have one side of the body much more affected than the other, and in these situations brain imaging may show that one side of the brain is more shrunken or atrophied. However, no abnormalities are completely specific for the diagnosis.
As is the case in many other types of parkinsonism, people’s response to anti-Parkinson medication is generally very poor. Occasionally some symptoms will show modest improvement after drug therapy (for example, myoclonic jerking may respond to clonazepam, and painful dystonia may be lessened by injections of botulinum toxin into the most affected muscles). However, no treatments have an impact on the course of the disease, which is progressive over a period of five to ten years.
As with other neurodegenerative parkinsonism-plus diseases, patients become bedridden and typically die of infections. Once again, we hope that better understanding of the cause(s) of cell death and the possible genetic predisposition to CBD will alter this dismal prognosis over the next few years.
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