movement disorders (cohen)

Question 1

PARKINSON’S DISEASE

Answer 1

Probably occurred for centuries, but first described in 1817 by James Parkinson
Increased incidence due to industrialization, large-scale agriculture?
Parkinson called it “the shaking palsy”
Tremulousness, weakness, bent or stooped posture, festinating gait, but “senses…not injured”
But we now know there is no palsy (weakness) in Parkinson’s Disease, and many patients do have dementia eventually

Question 2

Parkinson’s Disease:Four cardinal features

Answer 2

1. Resting tremor, usually beginning in one hand
2. Bradykinesia, a slowness of movement, in initiating and executing movements, even in spontaneous facial expressions (stare)
3. Dysequilibrium, or instability of gait and posture, leading to a higher risk of falls
4. Rigidity, especially later in the course of the illness

Occasionally the diagnosis is made of PD with “only” resting tremor, but ideally patients should have at least three of these four signs

Question 3

Definitions of Tremor

Answer 3

Tremor is a fairly regular, oscillatory, to-and-fro movement carried out by irregularly synchronous contractions of antagonistic muscles
It is rhythmic and biphasic, and limited in pattern over time, if not amplitude
Other movement disorders can vary minute-by-minute-, such as chorea, myoclonus, athetosis, and dystonic movements
Physiologic tremor is a normal tremor that occurs, especially with complex movements, mostly of the hands and fingers, but minimal disability to people
1. Exacerbated by fatigue , stress, drugs, and age
2. Faster frequency than pathological tremors

Question 4

Tremor as a disease

Answer 4

Pathologic tremor disturbs normal functioning
Noticed by patients especially when it first appears, or worsens
Often regarded by patients and their families as a sign of nervousness or related to diet, especially caffeine or alcohol
Embarrassing to most patients, who often try to mask its appearance, or avoid friends or some public events
Occasionally hysterical: no regular rhythm, often just one arm or one leg, or will move if one limb is held

Question 5

Resting Tremor in Parkinson’s

Answer 5

Perhaps the most common presentation of Parkinson’s, but about half of patients notice other symptoms first
Nearly always an ASYMMETRIC tremor of the hands, less commonly the legs
Considered a “resting tremor,” and may disappear for a moment with change in position of the hand
Usually 4-7 hertz in frequency
May spread less often to the lips and jaws but not the entire head
Occasionally the only feature of Parkinson’s
Present in 75 – 80% of patients eventually

Question 6

Bradykinesia in Parkinson’s

Answer 6

Slowness of movement, almost becoming no movement
Patients may look like statues, especially when sitting; no fidgeting or easy adjustment of position; staring, almost a “reptilian” or “masked” look
Decreased rate of blinking; 5 – 10 instead of 15 – 20 /minute
Hard to swallow, so patients drool
Occasionally under duress, patients may walk or speak briefly with greater speed: kinesis paradoxica

Question 7

Dysequilibrium in Parkinson’s

Answer 7

Hard to become steady on their feet
Often fall backwards, retropulsion, when starting to walk
Try to catch-up with themselves, so they walk faster and faster, or festination of gait
Can’t correct themselves while walking, so increased falls
Balance worsened by lack of arm swinging
One of the most dangerous signs, and least responsive to medication and surgery

Question 8

Rigidity in Parkinson’s

Answer 8

Usually a later sign, but very debilitating
Perhaps the source of pain in many patients, along with cramps, especially in the shoulders
Seen by the physician in the form of cogwheeling, or ratcheting with passive movements of the patient’s arms or even legs
Especially problematic when a medication wears-off, or patients suddenly freeze in one position

Question 9

Other early symptoms and signs of parkinson’s

Answer 9

Sleep disorders, such as insomnia or REM Behavior Disorder
Loss of sense of smell
Autonomic problems, such as impotence, incontinence, hypotension
Cramps, pains especially in the back and shoulders
Depression, loss of usually activities, sometimes an early dementia
Smaller, incomprehensible handwriting
Loss of power of voice, with monotonous and hurried speech

Question 10

Pathology of Parkinson’s

Answer 10

Loss of cells (> 70%) in the substantia nigra, or “black body” in the midbrain, which projects dopamine releasing axons to the striatum of the cerebral hemispheres
Easily seen with an autopsy, but not quite yet with MRIs
In the striatum (caudate and putamen) there is a significant loss of dopaminergic transmission
Loss of other cells in brainstem, thalamus, cerebral hemispheres and autonomic ganglia

Question 11

Lewy bodies

Answer 11

Eosinophilic structures in the cytoplasm of neurons, especially in the substantia nigra, but in multiple other locations in the brains of Parkinson’s patients
May be seen in the absence of Parkinson’s disease, including Lewy Body Disorder, or apparent Alzheimer’s Disease
Contain increased amounts of alpha-synuclein, as is true of neurons in patient with Lewy Body Disorder
Synuclein is a protein which helps facilitate the movement of synaptic vesicles to the end of the axon; why does the amount of synuclein increase so much in Parkinson’s Disease?

Question 12

Genetics of Parkinson’s

Answer 12

Perhaps hereditary in less than 15 % of patients
Rare in monozygotic or dizygotic twins
Some “PARK” genes are associated with Parkinson’s, in some families
PARK1 – PARK 11
A parkin protein has been discovered, of unknown function
Familial cases tend to be younger than sporadic ones

Question 13

Epidemiology of parkinson’s

Answer 13

Peak age of incidence 55 – 59 years, especially in the range of 40 – 70
The older the age of onset, in general, the more rapid the deterioration
Possible associations with Not smoking, Not consuming caffeine, somehow; but how can smoking and excessive use of caffeine prevent any disease?
More common in rural areas, perhaps from pesticides or other contaminants in well water?
A slight majority of Parkinson’s patients are men

Question 14

Parkinson’s Best Treatment:

Answer 14

L-Dopa

Immunofluoresence studies in the 1950s and 1960s showed a deficiency of dopamine in the caudate and putamen, presumably due to loss of cellular input from the substantia nigra
Injection or oral intake of dopamine not helpful: dopamine DOES NOT cross the blood brain barrier
Levodopa DOES cross the BBB, and then it is converted to dopamine
Levodopa with carbidopa (a dopa-decarboxylase inhibitor) was introduced in the 1960s was very effective
Now sold as Sinemet, in ratios of 100mg/25mg, 100mg/10mg, and 250mg/25mg of levodopa/carbidopa

Question 15

rate limiting step of dopamine and NE synthesis

Answer 15

tyrosine hydroxylase converting tyrosine to dopa

Question 16

levodopa/carbidopa: Sinemet

Answer 16

Most commonly prescribed drug for Parkinson’s Disease
Partly replaces what’s lost in the substantia nigra
Can cause nausea, hypotension and nightmares if advanced too quickly
After 5 – 10 years may seem to cause wearing-off, or on-off effect, but still helpful
Dyskinesias, or extra uncomfortable movements may ultimately in most patients who need high doses
Probably not toxic to neurons
Psychosis may occur, and aggressive behavior may be unleashed

Question 17

Other Parkinson’s drugs

Answer 17

Agonists which bind to dopamine receptors in the striatum, especially D2
Two newest, and best tolerated:
1. Mirapex (pramipaxole)
2. Requip (ropinirole)
Can be used as first-line, instead of Sinemet, especially in younger patients, with less wearing-off effect and dyskinesias are less common
However, not as effective as Sinemet, and achieving the best dose may take months
Also cause hypotension, behavioral changes (punding, or obsessions with certain activities)
Psychosis, and visual hallucinations may occur even more frequently than with levodopa/carbidopa

Question 18

Parkinson’s Treatments

Answer 18

AMANTADINE: may increase dopamine release
1. also anticholinergic, possibly antagonizes glutamate receptors
ANTICHOLINERGICS such as trihexyphenidyl
1. Originally used to counter loss of dopamine, less often used now due to anticholinergic effects, including delirium and constipation

Inhibitors of monoamine oxidase and catechol-O-methyltransferase

  1. May prolong the benefits of levodopa by limiting its degradation
  2. Originally hoped to be “neuroprotective” for Pakinson’s patients but they probably do not do much more than alleviate symptoms a little bit

Question 19

Psychiatric problems in PD

Answer 19

DEMENTIA certainly does occur in PD, and is often a sign that patients are in their last years of life
A. Drugs for Alzheimer’s Disease can be helpful, including rivastigmine, an inhibitor of acetylcholine esterase in the brain

DEPRESSION is very common, right from the start, but is treatable

PSYCHOSIS is troubling, including violent/aggressive behavior
A. The old antipsychotics were antidopaminergic so they can’t be used, but the “atypicals” are helpful
B. Pimavanserin is in Phase III trials, helps via serotonin 5HT- 2A inverse agonism, which reduces activity even more than antagonists

Question 20

Other resources for Parkinson’s

Answer 20

Physical therapy, especially for those with dysequilibrium and rigidity
Walking, swimming, even weight lifting and singing, as much as tolerable
Support groups for patients and spouses, and family
Precautions for potential falls, and choking/aspiration pneumonia
Approximately 50% of Parkinson’s Disease patient will die within @ 15 years

Question 21

Surgery for PD

Answer 21

Long known that some small strokes in the lower basal ganglia, especially the thalamus or subthalamic nucleus, can either cause or relieve the symptoms of PD
Surgical cuts or strong stimulation has been done in the globus pallidus (pallidotomy) with limited benefit
Now DEEP BRAIN STIMULATION of one or both subthalamic nuclei is very effective, probably by stimulation the nuclei so quickly that it effectively loses all function, and no “misinformation” goes to the cerebral cortex

Question 22

Deep brain stimulation

Answer 22

After the electrodes are under the skull, patients come out of anesthesia, and stereotactic guidance is used to place a titanium electrode in the subthalamic nucleus, which can later be checked by an MRI scan

Question 23

Progressive Supranuclear Palsy

Answer 23

Often misdiagnosed as Parkinson’s disease, because of bradykinesia, rigidity, dysequilibrium, and difficulty walking with falls,
The disease eventually causes LIMITED VERTICAL AND HORIZONTAL EYE MOVEMENTS (basis for its name)
However, unlike PD, there is little or NO tremor
Slowly developing dementia, usually not as severe as Alzheimer’s Disease, or there is almost no dementia; patients have limited speech and dysarthria so it is hard to know how demented they truly are
Patients become unable to swallow within a few years, and can die from choking or aspiration pneumonia
Pathology appears to be degeneration of the entire brain stem, especially of the midbrain, due to a tauopathy

Question 24

The look of PSP

Answer 24

Patients develop a worried, puzzled look on their faces, with raised eyebrows and wrinkled foreheads. They often seen to have a dystonic extension of the neck, also, and tend to keep their mouths open much of the time. Limited blinking, like PD, with prominent eyes that eventually do not move.

Question 25

PSP Treatments:

Answer 25

No completely effective treatment exists for this degenerative disease
However, at least a quarter of the patients do respond to the drugs for Parkinson’s Disease, such as carbidopa/levodopa, and dopaminergic drugs
A. In fact, most of the patients were originally misdiagnosed as having Parkinson’s Disease and have not done very well on the usual drugs for Parkinson’s
Important to make the diagnosis, even if it is difficult in the first few years, and counsel patients about the two most common causes of death: choking, falls

Question 26

Essential tremor

Answer 26

Perhaps the most common movement disorder seen in clinical practice
Patients complain about tremors WHEN THEY ARE DOING THINGS, SUCH AS EATING, WRITING, USING COMPUTERS
Symmetric in most cases, involving the hands and forearms, sometimes the head, voice, but much less common in the legs
Also called action tremor or familial tremor; most cases are inherited, possibly autosomal dominant
Politically incorrect to call it senile tremor or benign tremor today, and neither was true
May be evident in childhood, and especially by the twenties, with some progression in most cases
More rapidly disabling when it first appears at an elderly age
Probably due to disease in the thalamus

Question 27

diagnosing Essential tremor

Answer 27

Diagnosed by history and lack of other evidence of basal ganglia or cerebellar disease
Family history is important for at least 80 % of patients
Physical examination also very helpful; look at outstretched hands, or patient’s ability to flex arms and not quite touch the opposing fingers or the nose
May be evident in the voice, and with a head tremor, which are also very embarrassing to patients
Rule-out hyperthyroidism, a medication side effect, cerebellar disease, and any possible parkinsonian features

Question 28

Essential Tremor Treatment

Answer 28

Mild cases may be helped by reassurance about the diagnosis, and told they don’t have Parkinson’s
Putting weights on the wrists may “dampen” the tremor
Patients should use heavier utensils: mugs, glasses, wooden forks and spoons; drinking alcohol may work for an hour or two to suppress essential tremor

Two medications work well for more severe cases:
A. PROPANOLOL is commonly used, and helps most of the patients: not for asthmatics or patients with heart block
B. PRIMIDONE is also very helpful, but the first dose can cause severe confusion and disorientation
For severe cases: surgery is helpful via deep brain stimulation

Essential “Premor” (PRopanolol PRimidone)

Question 29

Tics

Answer 29

Rapid movements (motor tics) or sounds (vocal tics)
Usually simple, as with sniffing, grunting, blinking, clearing the throat, protruding the chin, wrinkling the face, shrugging the shoulders
But sometimes more complicated movements of the limbs
Usually the patient is aware of tics, and can suppress them for a short time
Often develop in children, and may fade with time
Never a serious pathology, although parents may be worried; CNS imaging not indicated unless other findings

Question 30

Tourette’s Syndrome

Answer 30

A more worrisome tic disorder, defined as the combination of BOTH motor tics and vocal tics, starting before age 21, and usually in the first decade
Mostly tics of the head and shoulders
Grunting, sniffing sounds, echolalia, and rarely obscenities
Usually does not fade away with adolescence
Much more traumatic to the patient and family, disruptive at school
Many patients also have obsessive-compulsive disorder , and less often, depression

Question 31

Tourette’s pathology/treatment

Answer 31

Pathology still not known for Tourette Syndrome
Possible derangement of dopamine at synapses, or other transmitters
Occasionally reports of other physiological findings or MRI abnormalities
Probably associated with OCD, obsessive-compulsive disorder, and less so with ADHD and depression
May be brought-out or worsened by use of stimulants in children with ADHD, but drugs are not a contraindication or likely danger
Treated with HALOPERIDOL or other D2 blockers, newer antipsychotics, occasionally clonidine is effective

Question 32

Chorea: A “Dance-like” Disorder

Answer 32

A completely IRREGULAR AND VARIABLE movement disorder, which can be rather smooth, and is continuous
No clear pattern or rhythm to it at all, unlike tremors
Movements are usually slower than with any other movement disorder
Less commonly seen now
1. Sydenham chorea: (St Vitus’ Dance) from untreated Group A streptococcal infections
2. Rarely seen any more during pregnancy or from high dose oral contraceptives
3. Can be hereditary in some infants, who are otherwise healthy

Question 33

Huntington Disease (Chorea)

Answer 33

AN INHERITED DISEASE, in virtually all cases, due to chromosome 4, which is AUTOSOMAL DOMINANT
Can begin expressing itself at almost any age, but most typically begins in the 40s and 50s, when patients who don’t know they have the disease may have had children already; a juvenile form also exists in children
Progressive neurological and psychiatric disorder of the basal ganglia causing an incapacitating and fatal triad:
1. Movement disorder: including chorea, but also tremors, jerks. Clumsiness, “fidgetiness”
2. Cognitive loss: dementia
3. Psychiatric: agitation, depression, psychosis

Question 34

HD: Diagnosis

Answer 34

In most cases, there is a known family history, and patients have these typical symptoms developing slowly in middle age
Occasionally there is no family history, and one may suspect the genetic carrier had a very mild form of the disease, or die at a young age of another disease, or there may have been a spontaneous mutation
Genetic testing is available in university medical centers, and is very accurate, in measuring the huntingtin gene product, which in HD patients has large numbers of a repeating triniculeotide (CAG)
The testing should be done only after counseling the patient of the chance of having a fatal diagnosis

Question 35

Restless legs syndrome

Answer 35

This is a common disorder in which patients cannot stop moving or “kicking” their legs, rarely their arms, also
It is diagnosed in at least 5% of middle aged and elderly people, less commonly in children or young adults
The patients have a painful, disturbing, “creepy, crawly” sensations deep inside both legs which can be partly relieved by continuous movement of the legs
The patients cannot stop moving their legs to get this temporary relief, especially when they get into bed
There are reports of patients literally “kicking” their bed partners to the floor
Most patients have the onset as they approach bedtime, and it always interferes with the onset of sleep
Other patients have this feeling continuously, or starting in the afternoon

Question 36

The pathology of Restless legs syndrome

Answer 36

Nothing definitive has been found on MRIs, but autopsies do show reductions of total iron in the brain, especially the substantia nigra
Patients do have reduced dopaminergic activity in the brainstem and basal ganglia, and may have reduced activity of tyrosine hydroxylase, which requires iron as a cofactor
These patients seem more likely to have polyneuropathy than people without RLS, but this is still a minority
There appears to be some genetic predisposition, with at least autosomal recessive inheritance

Question 37

Treatment of RLS

Answer 37

Dopaminergic drugs which were developed originally for Parkinson’s Disease are the most effective treatments. They often are effective in a few days.
A. Pramipexole seems more effective than Ropinirole
B. Levodopa/carbidopa may help but the benefit wears off quickly

Giving oral supplements of iron can also be very helpful, especially in patients whose laboratory tests show low serum iron or serum ferritin

Benzodiazepines, especially the long acting clonazepam, can help
Some studies suggest gabapentin may help RLS
Opioids can also be used, as a last resort

All of these medications should be taken at least a half hour before the expected onset of sleep, or around the clock in patients with continuous restless legs syndrome