Movement Disorders (1)

Question 1

Movement disorders are among the most fascinating disorders within the realm of neurology. They do not involve paralysis of movement but rather distortions or perversions of movements and span a spectrum from disorders that produce excessive movement to disorders that result in a paucity of movement.

Question 2

Movement disorders are the result of dysfunction or damage to the portions of the brain that are collectively referred to as ____ _______

Answer 2

the basal ganglia.

Question 3

What are the basal ganglia nuclei?

Answer 3

The nuclei that are generally considered to comprise the basal ganglia are the caudate, putamen, globus pallidus, subthalamic nucleus, and the substantia nigra.

Question 4

What is the main function of the basal ganglia?

Answer 4

The basic function of the basal ganglia is not to produce or initiate movement – that is the function of the pyramidal system – but to modulate movement. In so doing, the basal ganglia work to facilitate intended movements while suppressing unwanted movements.

Question 5

Disease processes that damage the basal ganglia, then, will produce a clinical picture of either too little movement or excessive, unwanted movement. Disorders that result in too little movement are labeled what?

Answer 5

hypokinetic movement disorders, while disorders that produce excessive, or unwanted or distorted movement are referred to as hyperkinetic movement disorders.

Question 6

Some movement disorders damage the basal ganglia in such a way that elements of both too little and distorted movement may be present. These are called what?

Answer 6

mixed movement disorders.

Question 7

Three of the most frequently encountered hypokinetic movement disorders are:

Answer 7

Parkinson’s disease,

progressive supranuclear palsy, and

multiple system atrophy.

Question 8

How common is PD?

Answer 8

Parkinson’s disease (PD) is a relatively common neurologic disease. It is the second-most common neurodegenerative disorder, after Alzheimer’s disease.

If one looks at the entire population, PD may not seem so common, with a prevalence of only 100 per 100,000 (1 per thousand). However, it is an age-related disorder, so that if one looks at individuals age 60 and above, a very different picture emerges. In this elderly population, the prevalence of PD is approximately 2000 per 100,000 - or 2% of this age group, and some figures place this prevalence even higher.

Question 9

What causes PD?

Answer 9

The etiology of PD is not known and, indeed, there may not be a single uniform etiology for everyone with the disorder. For a relatively small proportion of individuals with PD, specific genetic mutations have been identified and it is probable that more will be identified in the future.

In individuals with young-onset PD, where PD symptoms appear before age 50, genetic factors are more likely to be operative than in persons who develop PD later in life. In these individuals, who actually make up the majority for PD patients, other factors appear to be important. A number of environmental factors have been suggested to be involved in the genesis of PD, but none have been unequivocally proven.

Question 10

The typical age of onset of PD motor symptoms is when?

Answer 10

between the ages of 55-65. Approximately 10% of individuals develop their first symptoms before age 40. With current PD treatment, the life expectancy of someone with PD is almost, though not quite, normal.

Question 11

How does PD present initially?

Answer 11

The motor features of PD typically first involve one side of the body, but eventually become bilateral. The initial asymmetry of dysfunction, however, is often maintained.

Question 12

PD is characterized by four primary, or cardinal, motor features. Namely:

Answer 12

Tremor, typically appearing with the limb at rest and disappearing with movement, is the most frequent initial motor feature of PD.

Rigidity: characterized by increased muscle tone that is persistently present throughout passive movement (unlike the “clasp-knife” pattern of increased tone evident with spasticity).

The term bradykinesia literally means slow movement, but the concept of bradykinesia actually involves much more – it includes difficulty both initiating and terminating movement, slowness in carrying out movement, difficulty performing repetitive movements, and difficulty carrying out simultaneous movements.

Postural instability

Question 13

Postural instability, or balance impairment, is a cardinal feature of PD but is different from the other cardinal features. How?

Answer 13

In that it does not appear early in the course of PD, but makes its appearance later in the course of the disease.

In fact, if an individual with parkinsonism develops balance impairment and falling within the first year of the appearance of motor dysfunction, he or she almost certainly does not have idiopathic PD but rather one of the other parkinsonian syndromes, such as progressive supranuclear palsy or multiple system atrophy.

Question 14

There are a number of additional motor features of PD that are very characteristic of the disorder, but are not referred to as cardinal features. Namely:

Answer 14

Reduced facial expression, or facial masking, is often present and magnified by reduced frequency of blinking.

The posture of the person with PD gradually becomes more stooped.

Gait changes also develop in which the PD patient walks with smaller steps, although still on a narrow base, and doesn’t pick up one or both feet normally, which results in a shuffling character to the gait.

Reduced arm swinging when walking is also characteristic.

Speech becomes softer and often somewhat slurred – the term hypokinetic dysarthria is applied to this characteristic PD speech pattern.

Handwriting may become progressively smaller in size – sometimes a pattern will be evident in which the handwriting starts out virtually normal in size, but becomes progressively smaller the longer the individual writes (aka micrographia)

Question 15

This slide gives a sense of the facial masking characteristic of PD

Answer 15

This slide demonstrates the stooped posture characteristic of PD

Question 16

PD is also characterized by a number of features that have nothing to do with motor function. These are called what?

Answer 16

non-motor features.

Question 17

Behavioral changes are probably the most widely recognized non-motor features of PD. What are some common ones?

Answer 17

Depression occurs in 40-50% of PD patients at some point during the course of their illness, and may actually precede the development of motor features.

Anxiety may develop in up to 40% of individuals also.

Progressive cognitive impairment may become evident as PD progresses. However, if it develops early in the course of an individual with parkinsonism, the diagnosis is probably not idiopathic PD but rather one of the other “parkinsonism-plus” syndromes such as dementia with Lewy bodies.

Cognitive impairment

Question 18

Describe the cognitive impairment seen in PD

Answer 18

Characterized by executive dysfunction, in which individuals experience difficulty making decisions and carrying out plans, rather than the more pure memory impairment characteristic of Alzheimer’s disease.

Question 19

Autonomic dysfunction is another non-motor facet of PD. Virtually all aspects of autonomic function may be affected. Describe some.

Answer 19

Gastrointestinal dysfunction in the form of constipation is most widely recognized, but dysphagia and impaired gastric emptying may also be present.

Bladder dysfunction most often takes the form of bladder over-activity with frequency and urgency, but underactive bladder function, with impaired bladder emptying, may be present in some patients.

Erectile dysfunction is common in men with PD and diminished libido in both men and women.

Impaired blood pressure regulation, with orthostatic hypotension is often attributed to PD medications, but can occur as part of PD itself.

Cardiac sympathetic denervation is also evident in many patients with PD, but doesn’t produce clear-cut symptoms.

Individuals with PD may display thermoregulatory dysfunction in the form of episodic profuse sweating, which is embarrassing and aggravating but not dangerous.

Question 20

Non-motor dysfunction in PD may also entail a variety of other features. What are some?

Answer 20

Impairment of olfaction may become evident years before the classic motor features of PD make their appearance.

Blurred vision, particularly for near tasks, is frequently described by PD patients. Pain is also common in the setting of PD. In fact, shoulder discomfort, often misdiagnosed as bursitis, may be the presenting symptom of PD.

Question 21

Individuals with PD may also display a number of sleep-related problems. Like what?

Answer 21

Sleep fragmentation, with frequent awakenings, is very common.

The most characteristic sleep-related problem of PD, however, is the development of REM sleep behavior disorder, in which individuals retain the ability to move during dreaming and, thus, may “act out” their dreams with hitting, kicking, hollering, and even jumping out of bed.

Fatigue is yet another very frequent non-motor feature of PD that is poorly understood.

Question 22

Although the pathologic process that constitutes PD is clearly more complicated and widespread, the primary basis of the motor dysfunction of PD – and the classic pathologic abnormality of PD – is what?

Answer 22

degeneration of pigmented neurons that have their cell body in the substantia nigra pars compacta in the midbrain. Neurons in other brainstem nuclei, such as the locus ceruleus and the dorsal motor nucleus of the vagus, are also affected.

Below: This slide demonstrates the loss of pigmentation in the substantia nigra in PD.

Question 23

Microscopically, the pathological hallmark of PD is the presence of what?

Answer 23

cytoplasmic inclusion bodies, called Lewy bodies, within surviving pigmented neurons within the substantia nigra and elsewhere. Lewy bodies are also present within the enteric nervous system, although here they are not within pigmented neurons.

Below: The fried egg-appearing inclusion within the cytoplasm of this pigmented neuron is a Lewy body.

Question 24

A primary component of Lewy bodies is a protein called ________

Answer 24

alpha-synuclein. Thus, disease processes in which alpha-synuclein aggregates are labelled synucleinopathies.

Question 25

The neurochemical hallmark of PD is ______ deficiency, classically within the substantia nigra in the midbrain and the striatum within the cerebrum.

Answer 25

dopamine. This is the result of the degeneration and death of the pigmented neurons with their cell bodies in the substantia nigra and their axons terminating within the striatum, which utilize dopamine as their neurotransmitter. **Dopamine neuronal loss, however, is not confined to the substantia nigra and involves dopaminergic neurons in other locations as well.**

Question 26

It has also become clear that the neurochemical disturbances in PD do not involve dopaminergic neurons exclusively. In fact, multiple other neurotransmitter systems are also involved. What are some?

Answer 26

Nor, Serotonin, glutamate, others

Question 27

What is Progressive supranuclear palsy (PSP)?

Answer 27

Characterized by features of parkinsonism, but also by additional features not seen in PD. Therefore it is classified as a “parkinsonism-plus” syndrome.

Question 28

How common is PSP? Prognosis?

Answer 28

PSP is much less common than PD. Reports of prevalence range from approximately 1.0-6.5 per 100,000. No genetic basis for PSP has been uncovered. Its usual age of onset is somewhat younger than that of PD, typically between the ages of 50-60. In contrast to PD, there is no effective treatment for the symptoms of PSP and **it follows a relentlessly progressive course with a life expectancy of only approximately 10 years.**

Question 29

What are the neruologic features of PSP?

Answer 29

The parkinsonian features of PSP consist primarily of rigidity and bradykinesia. Unlike PD, the features of PSP are often quite symmetric. Axial musculature is especially likely to be involved and this may sometimes result in **neck extension** (in contrast to the neck flexion of PD), **although neck extension is not present in the majority of individuals with PSP.** Individuals with PSP may display facial masking in the form of a peculiar “astonished” facial expression that differs from that seen in PD. **Dysarthria** is often an early development in PSP and may be severe.

Question 30

What are some other neurologic features of PSP?

Answer 30

Gait and balance disturbances are also early developments in persons with PSP and **unexplained falling may even be the presenting feature of the disease.** This is in marked contrast to PD. Another prominent difference between the two disorders is that **tremor is typically not present in PSP.** Behavioral dysfunction in the form of emotional lability and dementia are frequent in PSP and may develop early in the course of the disease process.

Question 31

What is the defining clinical feature of PSP – the feature that most clearly separates it from PD and ultimately permits diagnosis?

Answer 31

**The development of a characteristic eye movement abnormality, called a supranuclear gaze palsy**.

Question 32

The initial clinical manifestation of the supranucleur gaze palsy is what?

Answer 32

impairment of volitional downgaze (aka may present as messy eater, dirty tie sign, or difficulty descending stairs). This is diametrically different from PD, where difficulty with upgaze is often present. With progression of the oculomotor dysfunction, upgaze is then affected and eventually horizontal gaze also becomes impaired.

Question 33

What causes the impairment of eye movement in PSP?

Answer 33

Not due to paralysis of the extraocular muscles, but rather due to dysfunction at a level above the brainstem nuclei involved with eye movements, prompting the term “supranuclear” gaze palsy for the abnormality. That the eyes are actually still capable of moving can be demonstrated by the oculocephalic maneuver, in which the patient is asked to fix his or her gaze on a point while the head is then passively rotated in a vertical or horizontal plane and full excursion of the eyes elicited. Individuals with PSP may also display difficulty with opening closed eyes when asked to do so, despite being able to do so spontaneously. This is termed apraxia of eyelid opening.

Question 34

Other features of PSP?

Answer 34

Persons with PSP may also develop signs of pyramidal tract involvement, such as positive Babinski signs, and may also display a variety of sleep disturbances.

Question 35

From a gross anatomic standpoint, PSP is characterized by what?

Answer 35

**midbrain and cerebral cortical atrophy.** Microscopically, _neuronal loss and gliosis_ are present in multiple areas, including the substantia nigra and other areas of the rostral midbrain, including the pedunculopontine nucleus. The globus pallidus is also prominently affected.

Question 36

\_\_\_\_\_\_\_\_\_\_\_\_, composed of unpaired straight filaments that contain abnormally phosphorylated tau protein are a pathological hallmark of PSP. Thus PSP is called a **tauopathy.**

Answer 36

Neurofibrillary tangles

Question 37

\_\_\_\_\_\_\_ is the most prominent neurochemical abnormality of PSP.

Answer 37

Nigrostriatal dopaminergic deficiency. However, other neurotransmitter systems are also affected, including **cholinergic (ACh), GABAergic and noradrenergic (Nor).**

Question 38

What is MSA?

Answer 38

Multiple system atrophy (MSA) is another parkinsonism-plus syndrome, characterized by parkinsonian features plus additional distinctive clinical and pathological abnormalities.

Question 39

What is now known as MSA was initially described as three different disease processes – the Shy-Drager syndrome, olivopontocerebellar atrophy, and striatonigral degeneration - until it was ultimately realized that the pathologic changes in all three were identical, although the initial clinical presentations differed.

Question 40

How common is MSA?

Answer 40

Like PSP, MSA is also much more rare than PD. Although prevalence figures are somewhat tenuous, available reports place the prevalence in the range of 2.3-5.7 cases per 100,000. **MSA is generally considered to be a sporadic disease process without any genetic component.** The typical age of onset of symptoms is noticeably younger than that of PD, typically between the ages of 50-55. Although figures vary, most place life expectancy after symptom onset within the range of 5-10 years.

Question 41

What are the neruological features of MSA?

Answer 41

Harkening back to its initial description as three different disease processes, **MSA may present in one of several clinical patterns.** Some individuals present with a clinical picture of parkinsonism, some with progressive autonomic failure, and some with a cerebellar syndrome. Eventually, however, the clinical picture progresses to also involve the other features, although all individuals do not necessarily develop the entire triad.

Question 42

Neurological features of MSA

Answer 42

Extrapyramidal dysfunction in the form of parkinsonism eventually develops in almost 90% of patients with MSA. It is typically characterized by rigidity and bradykinesia. As with PSP, postural instability with balance impairment and frequent falling often develops early in the course of the disease, frequently within the first year following symptom onset. **Tremor is unusual**, but may occur and in some individuals is transiently responsive to levodopa, making diagnostic separation from PD more difficult.

Question 43

What are the autonomic features of MSA?

Answer 43

**Progressive autonomic failure** is often considered to be the clinical hallmark of MSA, _but it does not necessarily develop in all patients_. Multiple aspects of autonomic function are affected, although cardiovascular dysfunction with orthostatic hypotension is perhaps the most widely recognized. Urogenital dysfunction is also very common. Compared with PD, autonomic dysfunction in MSA typically begins earlier and is more severe

Question 44

Cerebellar dysfunction is less universally recognized in patients with MSA and its presence may be evident in only 55% of patients. A broad spectrum of cerebellar symptoms and signs may appear, including:

Answer 44

ataxia, dysarthria, and oculomotor abnormalities.

Question 45

Evidence of pyramidal tract involvement is also relatively common in MSA. Signs may include:

Answer 45

hyperreflexia, + Babinski responses, spasticity, and pseudobulbar palsy may be evident in 61% of individuals.

Question 46

Behavioral changes may appear in a minority of patients with MSA. What are they commonly?

Answer 46

Personality changes may become evident and depression is quite common. Cognitive dysfunction in the form of executive dysfunction may develop in patients with MSA but unlike dementia typically does not occur. **In fact, some investigators list dementia as an exclusionary feature for the diagnosis of MSA.**

Question 47

What are some other features of MSA?

Answer 47

Several other interesting features are known to occur in the setting of MSA, although the percentage of individuals who develop some of these features is not known. Respiratory (laryngeal) stridor, probably produced in most instances by vocal cord abductor weakness, may develop in approximately one-third of patients with MSA and confers an increased risk of sudden nocturnal death. Involuntary sighing, Raynaud’s phenomenon, and postural myoclonus of the hands are additional distinctive features that are displayed by some, but certainly not all, patients with MSA.

Question 48

MSA is characterized pathologically by what?

Answer 48

cell loss and gliosis in multiple regions of the brain and brainstem. The substantia nigra and posterior putamen are most prominently involved; the cortex is relatively spared.

Question 49

The microscopic hallmark of MSA is the presence of:

Answer 49

glial cytoplasmic inclusion bodies that, like PD, stain for alpha synuclein.

Question 50

Note that the neurochemical features of MSA are not well-characterized.

Question 51

Three of the more common hyperkinetic movement disorders include:

Answer 51

Huntington’s disease, Tourette’s syndrome, and primary (idiopathic) dystonia.

Question 52

What causes HD?

Answer 52

HD is a genetic disorder. It is **autosomal dominant** in its inheritance pattern. The genetic mutation responsible for HD was found to reside on the short arm (p) of **chromosome 4**. The Huntingtin gene (HTT) contains a trinucleotide CAG repeat sequence and produces a protein called huntingtin (HTT). The causative mutation in HD is an expanded trinucleotide repeat segment that results in an altered or mutant form of huntingtin protein and consequent neuronal damage.

Question 53

When does HD present?

Answer 53

Although the genetic mutation is present in individuals destined to develop HD from birth, **the symptoms of HD generally do not appear until the ages of 35-45.**_The age of symptom onset is at least partially determined by the number of CAG repeats in the mutation – individuals with larger numbers of repeats develop the onset of symptoms at an earlier age and usually display a more rapid disease progression._ The average life expectancy of an individual with HD is approximately 15-20 years following symptom onset.

Question 54

What are the main neurological features of HD?

Answer 54

The neurological hallmark of HD is the development of chorea. Chorea consists of relatively rapid, random, jerky movements that seem to flow from one movement into another and impart a restless, “wiggly”, or dancing appearance to the affected patient. **As the disease progresses, chorea gradually lessens and is replaced by dystonia and eventually rigid/akinetic parkinsonism**. Dysarthria is common and is the result choreiform movements of the tongue and lips interfering with speech. **When the number of CAG repeats is very long, the symptoms of HD may appear as early as the teenage years**. This is referred to as juvenile HD and is often characterized by the development of parkinsonism, rather than chorea, right from the onset.

Question 55

What behavioral changes are seen in HD?

Answer 55

Behavioral changes are the other dominant clinical feature of HD and may represent the initial disease symptom in 35-73% of individuals. A variety of behavioral changes may occur. Personality change, characterized by impulsiveness, irritability, obsessive behavior, and sometimes even aggression, frequently emerges. **Depression is also very common in individuals with HD** and an increased suicide rate has been documented for individuals with HD. Progressive cognitive impairment with eventual dementia develops in most individuals with HD. The dementia is subcortical in nature and characterized by executive dysfunction, with impairment of planning, organizing, reasoning, abstraction, and judgment.

Question 56

Other features of HD?

Answer 56

A variety of abnormalities of oculomotor function also are frequently evident in HD patients. Examples include difficulty initiating saccades, slowed saccades, and difficulty maintaining gaze with resultant gaze impersistence. Progressive weight loss and cachexia often become evident in the advanced stages of HD

Question 57

Neuronal loss and gliosis, with consequent atrophy are characteristic of HD. This is especially evident in what areas?

Answer 57

the caudate and putamen.

Question 58

How common in Tourette's Syndrome (TS)?

Answer 58

Tourette’s syndrome (TS) has been considered a rare disease but is probably much more common than generally realized. Prevalence estimates vary rather widely, but most fall within the range of 100-1000 per 100,000. **TS is almost certainly an inherited disorder and mutations have been identified in a small number of patients**, but for the vast majority of patients neither the genetic mutation nor even the exact mode of inheritance has been identified. **There is a distinct male predominance. The onset of TS symptoms is during childhood, typically between the ages of 2-15**. Symptoms often diminish in adulthood and may completely disappear. _TS does not affect life expectancy._

Question 59

How does TS present?

Answer 59

TS is characterized by the development of tics, which are defined as sudden, stereotyped, non-rhythmic movements or vocalizations. Motor tics may be simple or complex in character and are preceded by a premonition or urge that is satiated by making the movement. Vocal, or phonic, tics are vocalizations that may consist of simple sounds or more complex vocalizations. Sensory tics are unusual, stereotyped, transient somatic sensations that are close to the skin – an itch, tickle or sense of tightness might be examples – that trigger intentional movement. These may also occur in TS.

Question 60

T or F. A hallmark of TS is that, over time, the complement of tics changes.

Answer 60

T. Some tics disappear, to be replaced by new tics. The frequency and severity of tics also waxes and wanes over time

Question 61

The formal diagnostic criteria for TS, taken from the DSM-IV-TR, are:

Answer 61

* Multiple motor tics and at least one vocal (phonic) tic must be present at some point during the course, though not necessarily concurrently * Tics must occur many times per day, almost every day, or intermittently over the course of more than a year, with no tic-free period of greater than 3 consecutive months * Onset must be before age 18 * The disorder must not be explainable by any other condition

Question 62

Examples of simple motor tics seen in TS. The potential list of such tics is much longer.

Answer 62

–Muscle jerks –Head shaking –Shoulder shrugging –Eye blinking –Lip pouting

Question 63

This slide lists examples of complex motor tics in TS. **Echopraxia is the involuntary repetition or imitation of another person’s movement**. _Copropraxia is the involuntary performance of obscene or forbidden gestures._

Answer 63

–Jumping –Throwing –Clapping –Touching –Echopraxia –Copropraxia

Question 64

Examples of simple vocal, or phonic, tics are listed on this slide. The potential list of such tics is much longer.

Answer 64

–Sniffing –Grunting –Barking –Hissing –Clearing throat

Question 65

This slide lists examples of complex vocal tics.

Answer 65

–Words, phrases, sentences –Echolalia (the involuntary repetition of vocalizations made by another person) –Palilalia (the rapid repetition or echoing of one’s own words.) –Coprolalia (consists of involuntary swearing or utterance of obscene, socially inappropriate, or derogatory words. ) **Coprolalia is actually quite rare in TS, with only approximately 10% of individuals with TS displaying this phenomenon.**

Question 66

Behavioral features are also characteristic of TS. Explain

Answer 66

**Attention deficit hyperactivity disorder (ADHD) is the most frequently occurring behavioral disorder in persons with TS.** Some investigators would place its presence as high as 90%, although most reports indicate a somewhat lower prevalence in the range of 50%. **Obsessive-compulsive disorder is evident in 30-50% of individuals with TS.**_The obsessions in TS often have to do with thoughts about symmetry, counting, sex and violence._ The compulsions often involve counting, touching, checking, and making sure things are “just right.”

Question 67

No definite pathologic changes have ever been identified in TS. The presumption has been that the pathology is located within the basal ganglia. However, recent investigation utilizing Magnetic Transfer Imaging has suggested that the **pathology may lie in the prefrontal cortex rather than the basal ganglia.**

Answer 67

Similarly, no definitive neurochemical abnormality has been identified in TS. The response of motor tics to drugs that block dopaminergic function suggests involvement of dopaminergic systems, but no clear-cut dopaminergic alteration has been identified. Involvement of other neurotransmitter systems (nor, 5-HT, opiod, adenosine) has also been hypothesized, but not proven.

Question 68

What is dystonia?

Answer 68

Dystonia is characterized by sustained muscle contraction that produces sustained, and sometimes repetitive, twisting movements that result in abnormal postures.

Question 69

A variety of classification systems have been utilized for categorizing dystonia. What are some?

Answer 69

It can be classified by etiology into two categories: 1) Primary Dystonia, where the etiology may be unknown or due to a specific genetic mutation or 2) Secondary Dystonia, where an underlying disease process is responsible for the development of dystonia. Alternatively, dystonia can be classified by its topographic distribution into two categories: 1) Generalized Dystonia, in which there is involvement of muscles throughout the body or 2) Focal Dystonia, in which the dystonia is limited to a single muscle or group of contiguous muscles. These classification systems can also be combined.

Question 70

How common is primary generalized dystonia?

Answer 70

Primary generalized dystonia is a rare condition, with a prevalence of approximately 3 per 100,000. Its onset is during childhood, most often between 7-10 years of age.

Question 71

Most, but not all, primary generalized dystonia is due to what?

Answer 71

a mutation of the DYT1 gene on chromosome 9, which is characterized by a GAG deletion and consequent altered function of the protein, Torsin A. **The mechanism by which the altered protein produces dystonia is unknown.** This mutation is especially prevalent in families of Ashkenazi Jewish ethnic origin. Although the mutation is autosomal dominant in character, penetrance is only in the range of 30-40%, which means that most individuals with the mutation may not actually ever develop dystonia. More recently, a number of additional mutations capable of producing generalized dystonia have also been identified

Question 72

The initial appearance of dystonia in PGD affected children is:

Answer 72

focal, typically first appearing as an action dystonia (that is, dystonia induced by movement) involving the foot or toes. As such, it might consist of ankle inversion or plantar flexion of the toes. Over time, the dystonia spreads proximally and eventually involves axial musculature in addition to the limbs.

Question 73

How does PGD progress?

Answer 73

Over time, abnormalities of gait and posture develop and eventually become fixed. Flexion at the hips and extension at the neck may produce a “dromedary” quality to the gait, which may also be accompanied by exaggerated hip abduction and knee hyperextension. Cognition, strength and sensation remain normal, although some individuals may display tremor as part of the clinical picture.

Question 74

No consistent pathologic changes have been identified to date that would explain primary generalized dystonia. **It is presumed that the dysfunction originates within the central nervous system.** Both the basal ganglia and the cerebellum have been proposed as the site of pathologic origin.

Answer 74

No consistent neurochemical abnormality has been identified either, although some studies have suggested involvement of **dopaminergic, noradrenergic, or GABAergic systems.**

Question 75

Describe primary focal dystonia

Answer 75

In contrast to generalized dystonia, focal dystonia typically appears during adulthood and typically does not appear to have a genetic basis, although recently genetic mutations have been identified in some patients. It is also more common than primary generalized dystonia, with a prevalence of 30 per 100,000.

Question 76

How does PFD present?

Answer 76

Various muscle groups may be affected by focal dystonia, but most often the involved muscles are above the waist, involving the arm, neck, or face. The dystonia typically progresses over a period of several years and then becomes static. Some focal dystonias are task-specific in that the dystonia only becomes evident when the affected individual is attempting to perform certain motor actions or tasks, such as writing or playing a musical instrument.

Question 77

Another peculiar characteristic of focal dystonias is what?

Answer 77

that the dystonia can sometimes be alleviated by the patient performing certain specific actions, or “sensory tricks”. An example of this would be a person who can alleviate the neck twisting of cervical dystonia by simply touching the cheek on the side of the face opposite to which the neck is turning.

Question 78

Focal dystonia is often given different names, depending on the specific muscles involved. Focal dystonia involving the muscles around the eyes, resulting in involuntary eye closure, is called \_\_\_\_\_\_\_

Answer 78

blepharospasm. When severe, it can produce functional blindness because of the sustained eye closure.

Question 79

Focal dystonia is labeled _________ if it involves the muscles that move the jaw and mouth.

Answer 79

oromandibular. The dystonia can result in either forced mouth closure or forced mouth opening.

Question 80

The larynx can also be the target of focal dystonia. If the dystonia forces the vocal cords closed, words may be cut off and speech may have a strained or “strangled” quality to it. If the dystonia forces the vocal cords open, speech becomes breathy and takes on a whispering quality. Dystonia involving the neck muscles is called \_\_\_\_\_\_\_\_\_

Answer 80

cervical dystonia or spasmodic torticollis. ## Footnote •Limb dystonia –Writer’s cramp –Musician’s dystonias

Question 81

No consistent pathologic abnormality has been uncovered to explain focal dystonia.

Answer 81

Similarly, No consistent neurochemical abnormality has been identified to explain focal dystonia.

Question 82

Some movement disorders typically demonstrate a mixture of both hypokinetic and hyperkinetic features. What are some?

Answer 82

Wilson's Disease

Question 83

How common is WD?

Answer 83

As with many of the movement disorders we have been discussing, WD also is a rare disorder, with most studies placing its prevalence in the range of 3 per 100,000. Carrier frequency in the general population is approximately 1 in 90.

Question 84

What is MOI of WD?

Answer 84

WD is an autosomal recessive disorder.

Question 85

What causes WD?

Answer 85

The site of mutation in WD is in the ATP7B gene on the long arm of chromosome 13. The gene product, which is a protein that is also called ATP7B, is a copper-transporting ATPase that under normal conditions transports copper within the liver to apo-ceruloplasmin, thus forming ceruloplasmin. However, under conditions of elevated copper within the liver, ATP7B assumes an additional function and assists with the biliary excretion of copper. Mutated ATP7B is not able to perform these functions, with consequent accumulation of copper within the liver. Over time, the capacity of the liver to store copper is ultimately exceeded and copper then escapes from the liver and is deposited in other tissues, including the brain. More than 300 different mutations in the ATP7B gene have been identified thus far, making routine genetic testing for WD impractical at the present time.

Question 86

When does WD present?

Answer 86

The symptoms of WD typically first appear during the teenage years but symptom onset has been reported as early as age 3 and as late as in the 70’s. As might be expected, hepatic symptoms or signs of hepatic dysfunction are the most frequent mode of clinical presentation of WD, representing the initial feature in approximately 40–50 percent of cases. Neurologic symptoms are the presenting clinical feature in approximately 40% and psychiatric symptoms in roughly 20%. The average age of symptom onset for individuals who present with hepatic symptoms is approximately 11-15 years of age; persons who present with neurologic symptoms have a somewhat later average age of symptom onset, typically around age 19-20.

Question 87

The hepatic manifestations of WD can take any one of several forms, including:

Answer 87

* Acute transient hepatitis * Acute fulminant hepatitis * Chronic active hepatitis * Progressive cirrhosis Acute fulminant hepatitis with fulminant hepatic failure has a very grave prognosis without emergent liver transplantation.

Question 88

A broad array of extrapyramidal features due to basal ganglia dysfunction may appear in the setting of WD (parkinsonism, chorea dystonia, incoordination). Both hypokinetic and hyperkinetic features may be present. **Tremor is the most frequent neurological presenting feature**. The most classic type of tremor is:

Answer 88

a kinetic, or intention, tremor but postural and rest tremor may also be present. Dysarthria eventually develops in most patients with WD and may be extrapyramidal or cerebellar in character.

Question 89

Most individuals with WD will display some psychiatric dysfunction at some point during the course of their illness. Not surprisingly, psychiatric symptoms typically develop in persons who also display neurological dysfunction. A variety of psychiatric symptoms have been described in the setting of WD, including:

Answer 89

Personality change, depression, mania, psychosis, dementia Perhaps surprisingly, frank dementia is actually quite rare in WD. although a range of more modest cognitive difficulties are not infrequent.

Question 90

Several very characteristic ophthalmologic abnormalities are associated with WD, including:

Answer 90

Kayser-Fleischer ring and sunflower cataract formation.

Question 91

What is Kayser-Fleisher ring?

Answer 91

The formation of brown pigment around the outer rim of the cornea. The brown discoloration is produced by copper deposition in Descemet’s membrane within the cornea. They may be very difficult or even impossible to see on routine eye examination in individuals with brown eyes, requiring slit lamp examination by an experienced ophthalmologist or neuroophthalmologist. **Kayser-Fleischer rings are virtually always present in individuals with WD who have developed neurological or psychiatric dysfunction, but may not be present in persons with only hepatic symptoms or in presymptomatic individuals.**

Question 92

What is this?

Answer 92

This slide demonstrates a sunflower cataract in WD. These typically can only be seen on slit-lamp exam and are due to copper deposition in the lens.

Question 93

WD is characterized by copper deposition and copper-induced damage in various tissues. Copper deposition in the liver eventually produces hepatic fibrosis and cirrhosis; In the brain, what happens?

Answer 93

neuronal loss and gliosis are especially prominent in the **putamen, thalamus and cortex.**

Question 94

A microscopic hallmark of WD is what?

Answer 94

the Opalski cell, which is an altered glial cell that can be found in the basal ganglia of individuals with WD.

Question 95

Certain laboratory studies can be helpful in identifying patients with WD, although there is no single pathognomonic test. Describe these.

Answer 95

Serum ceruloplasmin is characteristically, although not invariably, decreased in WD. Total serum copper is typically reduced as a consequence of the reduced ceruloplasmin. Thus, obtaining total serum copper levels is not particularly useful in the evaluation of suspected WD patients. Serum free (or unbound) copper is characteristically elevated in WD, but the test is not usually available and the serum free copper level must be calculated. 24-hour urinary copper levels are generally markedly elevated in individuals with WD who have developed neurological or psychiatric dysfunction. However, urinary copper levels may still be normal in presymptomatic individuals in whom copper accumulation within the liver has not been saturated.

Question 96

\_\_\_\_\_\_\_\_ __ \_\_\_\_\_ _______ \_\_\_\_ is the single most sensitive and accurate test for WD (except for genetic testing, which is not currently routinely available).

Answer 96

Elevation of hepatic copper levels. However, it requires liver biopsy and is not without risk.