Neurodegenerative disorders, including movement disorders, are complex multisystem disorders characterized by abnormal protein aggregates that accumulate in select regions in the central, peripheral, and autonomic nervous systems. Movement disorders are neurologic syndromes characterized by either an excess of movement or a paucity of voluntary and automatic movements, unrelated to weakness or spasticity. Clinically, movement disorders are manifestations of the loss of modulatory influence by the extrapyramidal system and may be classified as hyperkinetic or hypokinetic disorders. Under hyperkinetic disorders, we will discuss restless leg syndrome (RLS) and abnormal movements, including tremor, dystonia, myoclonus, chorea, and tics. Under hypokinetic disorders, we will discuss Parkinson disease (PD) and Parkinson plus syndromes, including progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal ganglionic degeneration (CBGD).
Hyperkinetic Disorders
Hyperkinetic disorders are characterized by excessive movement. To categorize these disorders, one must be able to recognize the type and pattern of the involuntary movements (e.g., tremor, chorea, myoclonus, etc.). When a combination of different movements occurs in the same individual, it can be very difficult to ascertain the right one. It is advisable to do repeated examinations and, if needed, video recording over time can be extremely helpful. It may be difficult to classify a particular abnormal movement even with repeated examinations and video.
Restless Leg Syndrome
Restless leg syndrome (RLS) is characterized by a deep, ill-defined discomfort or dysesthesia in the legs that arises during prolonged rest or when the patient is drowsy and trying to fall asleep, especially at night. Patients experience sensory disturbances in the legs that are characteristically relieved by movement. RLS may be a primary condition or occur in association with other conditions, such as diabetes mellitus, uremia, carcinoma, pregnancy, malabsorption, or chronic obstructive airway disease.
The estimated prevalence of RLS is 2% to 15%. It is slightly more common in women and in individuals of Northern European descent. Although it is considered a condition that primarily affects middle-aged to older individuals, one third of patients experience symptom onset younger than 20 years of age.
Regarding the diagnosis of RLS, there are five essential diagnostic criteria, which are outlined in the following paragraph. First-line treatment for RLS involves long-acting dopaminergic compounds and iron supplements, particularly in patients with low serum ferritin (less than 50 to 80 mg/L). Second-line treatment includes anticonvulsants, such as gabapentin, pregabalin, or carbamazepine. Benzodiazepines and opioids, such as methadone or oxycodone, are also used.
As defined by the International Restless Legs Syndrome Study Group, the following are the essential diagnostic criteria:
- 1.
An urge to move the legs usually but not always accompanied by or felt to be caused by uncomfortable and unpleasant sensations in the legs.
- 2.
The urge to move the legs and any accompanying unpleasant sensations begin or worsen during periods of rest or inactivity, such as lying down or sitting.
- 3.
The urge to move the legs and any accompanying unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues.
- 4.
The urge to move the legs and any accompanying unpleasant sensations during rest or inactivity only occur or are worse in the evening or night than during the day.
- 5.
The occurrence of the features listed in points 1 to 4 is not solely accounted for as symptoms primary to another medical or a behavioral condition (e.g., myalgia, venous stasis, leg edema, arthritis, leg cramps, positional discomfort, habitual foot tapping).
Abnormal Movements
Tremor
Tremor is defined as a rhythmic, oscillatory movement produced by alternating or synchronous contracting of antagonist muscle pairs. Tremors may be described as fast or slow, coarse or fine, uniplanar or biplanar. Resting tremor is usually observed when the body part is at complete rest, as is seen in Parkinson tremor. Postural tremor appears while maintaining a body posture; when the tremor is produced during a movement, it is termed an action tremor. Tremors may involve the limbs, neck, tongue, and voice. Resting tremor has notable characteristics, such as the following:
- •
Appears within the body part completely at rest.
- •
Subsides with action.
- •
Subsides with assuming a posture.
Another type of tremor is termed physiologic tremor. This tremor occurs resulting from the muscle fibers whose motor units are being recruited at subtetanic rates. Physiologic tremor can be exacerbated by anxiety, fatigue, hypoglycemia, thyrotoxicosis, alcohol withdrawal, lithium use, sympathomimetic drugs, methylxanthines such as caffeine, and sodium valproate. These causes should be excluded before coming to a diagnosis of other types of tremors. Some tremors can be seen both at rest and with action, such as rubral tremors. These are caused by lesions of the cerebellar outflow pathways in the midbrain.
The most common movement disorder is essential tremor (ET) ( and ). Typically, it is a postural tremor but may be accentuated by goal-directed activities. Upper limbs are usually involved frequently, and the tremor can be asymmetrical. ET is typically uniplanar with flexion-extension movement of the hand. It may also be present in the head, voice, tongue, lips, and trunk. These tremors may be solitary or in combination. In some severe cases, it can interfere with hydration and nutrition. Anxiety, stress, and central nervous system stimulants can worsen the tremor. Consumption of small quantities of alcohol improves ET in most cases, and alcohol ingestion is an often-used clinical challenge to aid diagnosis. Although other forms of tremor may respond to alcohol, this is one of the characteristics of ET. However, care should be taken by the clinician to not imply to the patient that alcohol use is a recommended treatment. ET can begin at any age. More than 50% of patients inherit this disease. Neurologic examination may be normal in most patients, but mild abnormalities of muscle tone, posture, and balance may be seen.
Dystonia
Dystonia is defined as an abnormal movement characterized by sustained muscle contractions, frequently causing twisting and repetitive movements, which may progress to prolonged abnormal postures. Although its clinical presentation closely resembles myoclonus, electromyographic (EMG) studies show prolonged bursts typical of dystonia rather than characteristic short-duration bursts seen in myoclonus. Dystonia is autosomal dominant in inheritance.
Dystonia can be classified according to the site of involvement:
- •
Focal dystonia: One part of the body is involved, such as blepharospasm, oromandibular dystonia, and cervical dystonia.
- •
Segmental dystonia: Two or more contiguous parts involved, such as Meige syndrome.
- •
Multifocal dystonia: Two or more noncontiguous parts are involved.
- •
Hemidystonia: One side of the body is affected.
- •
Generalized dystonia.
Dystonia may occur at rest or when a body part has a voluntary action. Rest dystonia may worsen on action. Dystonia may be task-specific, such as writer’s cramp or musician’s cramp. Parkinsonism may also be associated with dystonia and may respond to levodopa. Patients with dystonia may report that the condition is aggravated by anxiety, stress, and fatigue. Frequently, it is relieved by rest or sleep. One of the peculiar features is that some patients have the ability to relieve the dystonic movement by sensory tricks, usually tactile stimuli. For example, sometimes blepharospasm can be relieved by touching the area around the eye. This is a unique phenomenon to dystonia. Diurnal variations may be seen in dopa-responsive dystonia. Dystonia may be classified according to the causes as primary (idiopathic) and secondary (symptomatic). Thirty percent of dystonia is secondary dystonia.
Myoclonus
Myoclonus is defined as sudden, shocklike movements that are usually random and range in severity from mild to severe enough to move the whole body. On occasions it may be rhythmic or oscillatory. Myoclonic movements may be caused by active muscle contractions, as seen in positive myoclonus, or they may also be caused by sudden, brief lapses of muscle contraction in active postural muscles, as seen in negative myoclonus. Myoclonic movements are irregular in time, as seen in choreic movements, but unlike chorea, the movement is more abrupt. The origin of myoclonus may be cortical or subcortical (brainstem or spinal cord). It can be physiologic and can be seen after exercise, excessive fatigue, or sometimes when the individual is falling asleep, such as hypnagogic jerks.
It can occur spontaneously or it can occur by touch, light, noise, etc. Similar to other movement disorders, myoclonus may be essential myoclonus (idiopathic). Its onset can be at any age with a positive family history. Cortical or epileptic myoclonus is almost always associated with other forms of seizures and is more common in younger populations.
Specific Types of Myoclonus
Spinal Myoclonus.
Usually repetitive in nature in one limb. Lesions in the spinal cord such as trauma, tumor, or inflammation can be responsible for this type of myoclonus.
Palatal Myoclonus.
Characterized by rhythmic jerking of the soft palate sometimes in conjunction with the laryngeal, pharyngeal, and extra ocular muscles and diaphragm.
Asterixis.
Also known as negative myoclonus. Brief lapses of tone in a limb held in a posture against gravity. Asterixis is commonly seen in metabolic encephalopathies, as a reaction to general anesthetics, and during anticonvulsant therapy. EMG reveals irregular periods of silence during these lapses.
Chorea
The word chorea is derived from the Greek word khoreia , which means dance.
The term was introduced in the sixteenth century by Paracelsus and described bizarre motor and mental manifestations similar to the deliriant trance, dancing mania of medieval pilgrims.
Chorea is defined by the irregular, unpredictable, brief jerky movements that are usually of low amplitude. The movements are usually distal and range in severity. Chorea results from pathologic changes in the basal ganglia. Mild chorea may resemble fidgetiness in children, whereas severe chorea may interfere with speech, swallowing, ability to maintain posture, or ability to ambulate. Choreic movements are irregularly timed, as are myoclonic movements, but the movement in chorea is more abrupt in character. These movements may be seen in some genetic disorders or may be secondary to infectious, autoimmune, iatrogenic, or metabolic causes. These movements may vary in severity from restlessness to mild, intermittent exaggeration of gestures and expression, fidgeting movements of the hands, unstable dancelike postures to a continuous flow of disabling violent movements. Usually the condition fluctuates according to stress as well as physical and mental activities. Initially, it dominates in the face and on the acral parts (peripheral parts) of the extremities. Grimacing is a typical finding in chorea. A protruding tongue or blepharospasm may also be seen with this disorder. There are no valid data regarding the incidence of chorea; however, there are a number of diseases that might be accompanied by chorea such as Huntington disease, benign hereditary chorea, and Wilson disease. Socially, afflicted individuals may suffer embarrassment and may be mischaracterized by others because they are often assumed to be intoxicated. This may lead to loss of employment and community stature, among other consequences.
Tics
Tics are defined as abnormal movements (motor tics) or abnormal sounds (phonic tics) that are brief, involuntary, rapid, and nonrhythmic. There is often an irresistible urge to move before the tic, resulting in a tension that builds and is subsequently relieved by execution of the tic. If both motor tics and phonic tics are present, then the designation of Tourette syndrome is commonly applied.
Tics can be classified as simple and or complex tics.
Simple Motor Tic.
Abrupt, brief, isolated movement as an eye blink, facial grimace, shoulder shrug, or head jerk. The movements may be slower and sustained. Simple vocal tics usually consist of throat clearing, grunting, coughing, snorting, or animal sounds such as barking, hissing, and crowing.
Complex Motor Tic.
These include stereotyped facial expressions or patterned coordinated movements such as touching, grooming, scratching, kicking, hand shaking, or obscene gesturing. It is sometimes difficult to distinguish complex motor tics from obsessive-compulsive behavior. Complex vocal tics include words, phrases, obscene utterances, or religious profanities.
Stress, anxiety, and fatigue may worsen tics. Tics can be relieved by concentrating on a task or absorbing activities such as playing a musical instrument or reading. Tics vary in frequency, amplitude, duration, and location.
Hypokinetic Disorders
Hypokinetic disorders are characterized by a paucity of movement, or hypokinesis. This section includes PD as well as Parkinson plus syndromes. Parkinson plus syndromes are a group of neurodegenerative conditions that are characterized by the classical “TRAP” features of PD (tremor, rigidity, akinesia/bradykinesia, and postural instability) in addition to other features that distinguish them from PD. These conditions include PSP, MSA, and CBGD.
Parkinson Disease
Epidemiology
Parkinson disease (PD) affects approximately 10 to 20 in every 100,000 individuals in the worldwide population and 1 in 100 Americans ages 60 years older. PD is currently the second most common age-related neurodegenerative disease after Alzheimer disease. More than 1 million people in the United States have PD, more than multiple sclerosis, amyotrophic lateral sclerosis, muscular dystrophy, and myasthenia gravis combined. The prevalence of PD increases with age and is expected to increase as the Baby Boomer generation ages. The Parkinson’s Disease Foundation has estimated that the combined annual direct and indirect cost of PD in the United States is $25 billion.
The prevalence of PD varies with both ethnicity and geographic distribution. A population-based study of Medicare beneficiaries found that the prevalence of PD in African Americans and Asian Americans is 50% less than that in white Americans. The study also found substantially higher rates of PD in the Midwest/Great Lakes region and along the northeastern U.S. seaboard, which was potentially attributed to industrial and agricultural exposures that are higher in these regions. There is considerable interest in pesticides and herbicides as risk factors for PD, though research is ongoing.
Genetics
In addition to suspected environmental exposure risk factors, there is a genetic contribution to PD. The majority of PD cases are sporadic because familial forms only account for approximately 10% of all PD cases. Monogenic causes of PD include both autosomal dominant and autosomal recessive inherited mutations. In addition to monogenic forms of PD, there are a number of genes and loci associated with increased risk for PD.
Autosomal Dominant Forms of Parkinson Disease: LRRK2 , SNCA , VPS35 , and EIF4G1 .
The most common cause of autosomal dominant inherited PD involves mutations in the LRRK2 gene, which accounts for up to 10% of all familial forms. Clinically, patients with LRRK2 mutations display characteristics of classical PD, but the age of onset is broad. The second most common cause of autosomal dominant inherited PD is SNCA gene mutations. Patients with SNCA -related PD may vary in clinical presentation because there is a direct relationship between SNCA gene dosage and disease severity. Patients with SNCA duplications often display a classical PD phenotype, whereas patients with triplications display more severe phenotypes with atypical features including myoclonus, severe dysautonomia, and dementia in addition to parkinsonism. Patients with SNCA -related PD may also exhibit progressive loss of levodopa responsiveness.
The SNCA gene encodes the protein alpha-synuclein. Lewy bodies, the histologic finding seen in classic PD, are formed by aggregates of alpha-synuclein. Both LRRK2 and SNCA mutations are thought to affect a common cellular pathway leading to alpha-synuclein aggregation, although the exact role of LRRK2 in this pathway remains unclear.
Autosomal Recessive Forms of Parkinson Disease: PARK2 , PINK1 , and DJ-1.
The age of onset seen in autosomal recessive forms of PD is earlier compared with autosomal dominant forms of PD. Autosomal recessive inherited mutations include PARK2 , PINK1 , and DJ-1 . PARK2 mutations are the most common, accounting for almost 50% of early-onset familial recessive PD cases. Mutations in PARK2 are also found in approximately 15% of sporadic PD cases with onset before 45 years. PARK2 -related PD does not generally show Lewy bodies, as is seen in autosomal dominant forms. PARK2 -related PD is characterized by early or juvenile onset (generally before 45 years), excellent and sustained response to levodopa, and a benign course. However, motor fluctuations often become prominent during the disease course. Mutations in PINK1 and DJ-1 are also seen as forms of autosomal recessive PD, but these mutations are much less prevalent than PARK2 mutations. PINK1 mutations are seen in 1% to 8% of early-onset cases and DJ-1 mutations are seen in 1% to 2% of early-onset cases.
Genetic Risk Factors for Parkinson Disease.
In addition to monogenic forms of PD, there are a number of genes and loci associated with increased risk for PD. For example, dominantly inherited, heterozygous mutations in the glucocerebrosidase ( GBA ) gene are a frequent and strong risk factor for PD. Carriers of only one mutated allele have a fivefold increased risk to develop PD compared with noncarriers, making GBA one of the strongest genetic risk factors reported to date. Patients with GBA mutations demonstrate classical PD with a possible slightly earlier age of disease onset. Recent studies have shown a more rapid motor and cognitive decline in GBA mutation carrier patients with PD compared with noncarriers. Further research is needed to determine whether GBA carrier status in patients with PD could represent a prognostic factor for rate of disease progression.
Pathophysiology
PD is thought to be caused by the progressive loss of dopaminergic neurons from the substantia nigra par compacta of the midbrain in association with alpha-synuclein intracellular inclusions, termed Lewy bodies. More recent thinking has further posited that degeneration starts in the dorsal motor nucleus of the glossopharyngeal and vagal nerves and anterior olfactory nucleus and then proceeds to the locus coeruleus and raphe nucleus before disrupting basal ganglion functioning. While the disease advances, frontal brain areas are frequently affected. It appears that before the involvement of the basal ganglion the individual may only manifest subtle subclinical manifestations, but once the basal ganglion is significantly involved classical idiopathic Parkinson disease symptoms are exhibited.
Clinical Presentation
It is helpful to conceptualize PD as an intersection of three major areas: motor, nonmotor, and autonomic nervous system (ANS) symptoms ( Box 45-1 ).
- 1.
Named after Dr. James Parkinson (1755-1824) by the French neurologist Jean-Martin Charcot (also known as the father of neurology).
- 2.
1 in 100 Americans older than 60 years of age is affected by this disease.
- 3.
1 in 20 people diagnosed with Parkinson disease are younger than 40 years of age.
- 4.
Risk increases if older than 50 years of age.
- 5.
Parkinson disease is caused by the loss of dopaminergic cells in the substantia nigra. Symptoms appear when 60% to 70% of cells have died.
- 6.
Presently, there are no clearly identifiable causes why cells die.
- 7.
No cure is available, but treatments can help control symptoms and maintain quality of life.
- 8.
Parkinson disease can be managed with a combination of drug therapies and rehabilitation.
- 9.
The main symptoms of Parkinson disease are tremors, bradykinesia, and rigidity.
- 10.
Diagnosis is clinical; as of today no laboratory testing or imaging is definitive.
Motor Symptoms.
The cardinal motor signs of PD include resting tremor, bradykinesia, rigidity, shuffling gait, and postural instability. A helpful mnemonic for remembering PD cardinal motor symptoms is “TRAP”: tremor ( ), rigidity, akinesia/bradykinesia, and postural instability. The presence of these symptoms should raise concern for PD. However, if postural instability is prominent at onset, this should suggest an atypical form of parkinsonism such as PSP. Because the onset of these signs is insidious, patients and family often attribute them to the normal aging process. Although PD is progressive, there is great variability in the rates of motor progression.
Nonmotor Symptoms.
Nonmotor symptoms of PD include neuropsychiatric symptoms, cognitive symptoms, and sleep disturbances.
Neuropsychiatric Symptoms.
Although motor issues are often the most visible problems afflicting those with movement disorders, nonmotor factors are now recognized as important considerations in the treatment and management of the patient with PD. The prime psychological issues observed in patients with movement disorders are depression, anxiety, and hallucinations. It is not entirely certain whether psychiatric conditions are the result of, or prodromal to, the development of PD. Psychiatric symptoms may be underdiagnosed resulting from the clinical focus on motoric symptoms, limited examination time, and overlap of psychiatric symptoms to PD manifestations (e.g., masked expression, apathy, fatigue, low libido, sleep disruption, bradykinesia). The prevalence of co-occurring PD and depression is estimated to vary from 20% to 40%, while anxiety is thought to occur in 30% to 50% of patients with PD during the course of the disease, although some suggest that the true prevalence is closer to 67%. Anxiety and depression frequently co-occur. Hallucinations, primarily visual, are seen in 25% of those with PD, and are thought to be side effects of treatment medications. The use of dopamine agonists in treating PD has been associated with a higher incidence of impulse control disorders, notably gambling and increased sexual behaviors.
Depressed or saddened mood is often experienced at the time of initial diagnosis and upon learning that the disorders are progressive in course until death. Those with PD often become more adjusted after learning that the disease does not inevitably have a rapid progression and that good medical treatment and rehabilitation can allow for a quality of life spanning years in many cases. Often, it is the functional limitations (pace and fluidity of conversation, public dining, ease of entrancing and exiting social venues such as religious services, theater, etc.) caused by tremors, dysarthria, gait disturbance, and other motor problems that worsen dysphoria and frustration. Depression may contribute to cognitive dysfunction and adds significant disability beyond that attributed to motor dysfunction alone.
Although some argue that anxiety is prodromal, the levels experienced by the patient after a PD diagnosis can be exacerbated by any number of factors, such as fears of eventual disability and dependency, concern over finances, uncertainty regarding the ability to maintain a home, and the welfare of other family members. In older patients, this overlays the expected developmental anxieties of dependency upon others and general mortality concerns. Risk factors for anxiety in patients with PD include female gender, younger age, presence of motor fluctuations, fear of being sustained in the “off phase,” and a history of anxiety disorders.
Both anxiety and depressed mood can be treated supportively by the attending physician (or psychotherapist if indicated), with pharmacotherapy, and by patient/family education and regular support groups.
Cognitive Symptoms.
Cognitive impairment is frequently seen in PD and has important clinical management implications. Executive functions are the first and most severely affected cognitive domains. Executive functions include ability in “set-switching,” problem-solving strategies, concept formation, attention capacities, decision-making, and effective use of working memory. Deficits in executive functions may be expressed clinically as difficulties with everyday activities such as organizing medications or paying bills.
Impairment in visuospatial function is also present early in the course of PD. However, it may not be detected initially, because it often requires specific neuropsychological testing for diagnosis. The clock-drawing test is frequently used to assess both executive and visuospatial functions. The Mini-Mental State Examination may be used as a screen for global cognitive function in PD, with a score of less than 24 indicating more significant cognitive impairment. Memory deficits are typically seen later in the disease course, as PD progresses. Clinically, patients often exhibit retrieval deficits rather than immediate recall deficits, suggesting that encoding processes are intact. As the disease progresses, thought processes become more rigid and perseverative.
The relative risk of dementia is five times that of matched controls, although the likelihood of mild cognitive impairment has been reported after PD onset as approximately 25%. Various subtypes of dementia have been identified including PD dementia and Lewy body dementia. Both are associated with abnormal alpha-synuclein deposits. The clinical differentiation of the two types is somewhat arbitrary and based on time of onset. The current convention is to term a dementia as Lewy body dementia that is manifested before or within a year of Parkinson disease symptoms, whereas PD dementia is used to describe the condition in those who develop dementia after at least a year of exhibiting Parkinson disease symptoms. Both share a course of progressive cognitive decline, impaired memory, and poor executive functioning (functions include ability in “set-switching,” problem-solving strategies, concept formation, attention capacities, decision making, and effective use of working memory), with Lewy body dementia also manifesting with hallucinations and delusions at times. Cholinesterase inhibitors and memantine are often used to treat cognitive decline, but effectiveness has not been clearly demonstrated.
Sleep Disturbances.
Sleep disturbances are also common in PD, although their cause is unclear and likely to be multifactorial. Factors that may contribute to sleep disturbances in PD include stimulant effects of PD medications, anxiety, RLS, sleep cycle dysregulation caused by poor sleep hygiene, and reduced bed mobility. Reduced activity levels and exercise, frequent nocturia, and nocturnal disorientation caused by cognitive impairment or vivid dreams can also contribute to sleep disturbance. Specific symptoms include insomnia, nightmares, and excessive daytime sleepiness.
Autonomic Nervous System Symptoms
ANS symptoms include orthostatic hypotension, constipation, urinary frequency and urgency, erectile dysfunction and vaginal tightness, and sweating. Orthostatic hypotension is defined as a decrease of 20 mm Hg in systolic or 10 mm Hg in diastolic blood pressure within 3 minutes in an upright position with or without postural symptoms. Orthostatic hypotension most commonly occurs in the advanced stages of PD. Symptoms of orthostatic hypotension include dizziness, blurred vision, postural instability, light-headedness, and syncope. Approximately 30% of all patients with PD will become symptomatic in their lifetime. Care should be taken in the clinic to measure blood pressure in both the seated and standing positions to detect orthostasis.
Diagnosis
Understanding the clinical presentation of PD is especially important because the diagnosis of PD is clinical ( Box 45-2 ). The most widely used comprehensive instrument used by movement disorder specialists to assess PD is the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (UPDRS). This scale was originally developed in the 1980s and was revised in 2008. The UPDRS is a clinical scale consisting of four parts: Part I: nonmotor experiences of daily living; Part II: motor experiences of daily living; Part III: motor examination; and Part IV: motor complications. Several questions from Part I and all questions from Part II were designed to lend themselves to a questionnaire format that may be filled out by the patients and their caregivers. The remainder of Part I and Part IV must be conducted by a movement disorder specialist. Part III covers objective measures of parkinsonism, as assessed by the clinician.
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