Browse the corpus

Movement Disorders inherited genetic mutation. CJD is a prion-related disorder follow-up evaluation and dose decreases. These drugs are that often presents with rapidly progressive dementia. Prion associated with an increased risk of sudden death (likely diseases have no known therapy. Time from disease onset to cardiac), especially in the first 3 to 6 months of taking the death is approximately 12 months in as many as 80% of patients medication; this risk should be clearly discussed with fami- with CJD. The rapid cognitive decline seen with this disorder lies before initiating the therapy and only after all other is associated with myoclonus, gait problems, visual compro- treatments have been tried. It is also advisable to obtain an mise, and interruption of the circadian rhythm. MRI is one of ECG before the first dose to ensure that the patient’s QT the most sensitive diagnostic tools for CJD, typically showing a interval is normal; if the corrected QT interval is prolonged pattern of increased intensity in the diffusion-weighted (>450 ms for men and >470 ms for women), antipsychotic sequence in the basal ganglia and various cortical regions. agents should not be used. Periodic sharp wave complexes are often seen on electroen- cephalography and are helpful but not necessary in making the diagnosis. CSF testing may establish the presence of 14-3-3 Movement Disorders protein and an elevation in total tau protein levels, but these findings lack sufficient sensitivity and specificity. The real- Overview of Movement Disorders time quaking-induced conversion assay has higher sensitivity Movement disorders are characterized by hypokinetic and and specificity for detecting prion proteins than CSF analysis. hyperkinetic patterns of motor output. The most typical hypokinetic pattern, parkinsonism, is characterized by pau- city and slowness of movements. Hyperkinetic disorders are e Prion disease should be part of the differential diagnosis categorized on the basis of the type of involuntary excessive in a patient of any age with otherwise unexplained rap- movements displayed (Table 31). idly progressive dementia and ataxia. Neurologic examination of movement disorders should e MRI is one of the most sensitive diagnostic tools for include detailed assessment of motor function and gait. The CreutzfeldtJJakob disease and typically showsa pattern of key features in the classification of movement disorders are an increased intensity in the diffusion-weighted sequence the speed, amplitude, and fatigability of voluntary move- in the basal ganglia and various cortical regions. ments and the rhythmicity, suppressibility, randomness, and directionality of hyperkinetic movements. Muscle tone should be assessed for rigidity, which is an increase in resist- Treatment Approach to Neurobehavioral ance to passive movements that is independent of the veloc- Symptoms of Dementia ity and direction of those movements. Gait examination Behavioral and psychiatric symptoms of dementia are a com- should consider the base of standing, pace of ambulation, mon problem in patients with dementia disorders and are stride length, foot clearance off the ground, postural stability, among the most common reasons for admission to long-term and arm swing. care facilities. Multidisciplinary care, massage and touch ther- apy, and music combined with massage and touch therapy were clinically more efficacious than usual care, including e The key features in the classification of movement

inherited genetic mutation. CJD is a prion-related disorder follow-up evaluation and dose decreases. These drugs are that often presents with rapidly progressive dementia. Prion associated with an increased risk of sudden death (likely diseases have no known therapy. Time from disease onset to cardiac), especially in the first 3 to 6 months of taking the death is approximately 12 months in as many as 80% of patients medication; this risk should be clearly discussed with fami- with CJD. The rapid cognitive decline seen with this disorder lies before initiating the therapy and only after all other is associated with myoclonus, gait problems, visual compro- treatments have been tried. It is also advisable to obtain an mise, and interruption of the circadian rhythm. MRI is one of ECG before the first dose to ensure that the patient’s QT the most sensitive diagnostic tools for CJD, typically showing a interval is normal; if the corrected QT interval is prolonged pattern of increased intensity in the diffusion-weighted (>450 ms for men and >470 ms for women), antipsychotic sequence in the basal ganglia and various cortical regions. agents should not be used. Periodic sharp wave complexes are often seen on electroen- cephalography and are helpful but not necessary in making the diagnosis. CSF testing may establish the presence of 14-3-3 Movement Disorders protein and an elevation in total tau protein levels, but these findings lack sufficient sensitivity and specificity. The real- Overview of Movement Disorders time quaking-induced conversion assay has higher sensitivity Movement disorders are characterized by hypokinetic and and specificity for detecting prion proteins than CSF analysis. hyperkinetic patterns of motor output. The most typical hypokinetic pattern, parkinsonism, is characterized by pau- city and slowness of movements. Hyperkinetic disorders are e Prion disease should be part of the differential diagnosis categorized on the basis of the type of involuntary excessive in a patient of any age with otherwise unexplained rap- movements displayed (Table 31). idly progressive dementia and ataxia. Neurologic examination of movement disorders should e MRI is one of the most sensitive diagnostic tools for include detailed assessment of motor function and gait. The CreutzfeldtJJakob disease and typically showsa pattern of key features in the classification of movement disorders are an increased intensity in the diffusion-weighted sequence the speed, amplitude, and fatigability of voluntary move- in the basal ganglia and various cortical regions. ments and the rhythmicity, suppressibility, randomness, and directionality of hyperkinetic movements. Muscle tone should be assessed for rigidity, which is an increase in resist- Treatment Approach to Neurobehavioral ance to passive movements that is independent of the veloc- Symptoms of Dementia ity and direction of those movements. Gait examination Behavioral and psychiatric symptoms of dementia are a com- should consider the base of standing, pace of ambulation, mon problem in patients with dementia disorders and are stride length, foot clearance off the ground, postural stability, among the most common reasons for admission to long-term and arm swing. care facilities. Multidisciplinary care, massage and touch ther- apy, and music combined with massage and touch therapy were clinically more efficacious than usual care, including e The key features in the classification of movement pharmacologic care, in treating aggressive and agitated behav- disorders are the speed, amplitude, and fatigability of

inherited genetic mutation. CJD is a prion-related disorder follow-up evaluation and dose decreases. These drugs are that often presents with rapidly progressive dementia. Prion associated with an increased risk of sudden death (likely diseases have no known therapy. Time from disease onset to cardiac), especially in the first 3 to 6 months of taking the death is approximately 12 months in as many as 80% of patients medication; this risk should be clearly discussed with fami- with CJD. The rapid cognitive decline seen with this disorder lies before initiating the therapy and only after all other is associated with myoclonus, gait problems, visual compro- treatments have been tried. It is also advisable to obtain an mise, and interruption of the circadian rhythm. MRI is one of ECG before the first dose to ensure that the patient’s QT the most sensitive diagnostic tools for CJD, typically showing a interval is normal; if the corrected QT interval is prolonged pattern of increased intensity in the diffusion-weighted (>450 ms for men and >470 ms for women), antipsychotic sequence in the basal ganglia and various cortical regions. agents should not be used. Periodic sharp wave complexes are often seen on electroen- cephalography and are helpful but not necessary in making the diagnosis. CSF testing may establish the presence of 14-3-3 Movement Disorders protein and an elevation in total tau protein levels, but these findings lack sufficient sensitivity and specificity. The real- Overview of Movement Disorders time quaking-induced conversion assay has higher sensitivity Movement disorders are characterized by hypokinetic and and specificity for detecting prion proteins than CSF analysis. hyperkinetic patterns of motor output. The most typical hypokinetic pattern, parkinsonism, is characterized by pau- city and slowness of movements. Hyperkinetic disorders are e Prion disease should be part of the differential diagnosis categorized on the basis of the type of involuntary excessive in a patient of any age with otherwise unexplained rap- movements displayed (Table 31). idly progressive dementia and ataxia. Neurologic examination of movement disorders should e MRI is one of the most sensitive diagnostic tools for include detailed assessment of motor function and gait. The CreutzfeldtJJakob disease and typically showsa pattern of key features in the classification of movement disorders are an increased intensity in the diffusion-weighted sequence the speed, amplitude, and fatigability of voluntary move- in the basal ganglia and various cortical regions. ments and the rhythmicity, suppressibility, randomness, and directionality of hyperkinetic movements. Muscle tone should be assessed for rigidity, which is an increase in resist- Treatment Approach to Neurobehavioral ance to passive movements that is independent of the veloc- Symptoms of Dementia ity and direction of those movements. Gait examination Behavioral and psychiatric symptoms of dementia are a com- should consider the base of standing, pace of ambulation, mon problem in patients with dementia disorders and are stride length, foot clearance off the ground, postural stability, among the most common reasons for admission to long-term and arm swing. care facilities. Multidisciplinary care, massage and touch ther- apy, and music combined with massage and touch therapy were clinically more efficacious than usual care, including e The key features in the classification of movement pharmacologic care, in treating aggressive and agitated behav- disorders are the speed, amplitude, and fatigability of iors in patients with dementia, according to a recent system- voluntary movements and the rhythmicity, suppressi-

inherited genetic mutation. CJD is a prion-related disorder follow-up evaluation and dose decreases. These drugs are that often presents with rapidly progressive dementia. Prion associated with an increased risk of sudden death (likely diseases have no known therapy. Time from disease onset to cardiac), especially in the first 3 to 6 months of taking the death is approximately 12 months in as many as 80% of patients medication; this risk should be clearly discussed with fami- with CJD. The rapid cognitive decline seen with this disorder lies before initiating the therapy and only after all other is associated with myoclonus, gait problems, visual compro- treatments have been tried. It is also advisable to obtain an mise, and interruption of the circadian rhythm. MRI is one of ECG before the first dose to ensure that the patient’s QT the most sensitive diagnostic tools for CJD, typically showing a interval is normal; if the corrected QT interval is prolonged pattern of increased intensity in the diffusion-weighted (>450 ms for men and >470 ms for women), antipsychotic sequence in the basal ganglia and various cortical regions. agents should not be used. Periodic sharp wave complexes are often seen on electroen- cephalography and are helpful but not necessary in making the diagnosis. CSF testing may establish the presence of 14-3-3 Movement Disorders protein and an elevation in total tau protein levels, but these findings lack sufficient sensitivity and specificity. The real- Overview of Movement Disorders time quaking-induced conversion assay has higher sensitivity Movement disorders are characterized by hypokinetic and and specificity for detecting prion proteins than CSF analysis. hyperkinetic patterns of motor output. The most typical hypokinetic pattern, parkinsonism, is characterized by pau- city and slowness of movements. Hyperkinetic disorders are e Prion disease should be part of the differential diagnosis categorized on the basis of the type of involuntary excessive in a patient of any age with otherwise unexplained rap- movements displayed (Table 31). idly progressive dementia and ataxia. Neurologic examination of movement disorders should e MRI is one of the most sensitive diagnostic tools for include detailed assessment of motor function and gait. The CreutzfeldtJJakob disease and typically showsa pattern of key features in the classification of movement disorders are an increased intensity in the diffusion-weighted sequence the speed, amplitude, and fatigability of voluntary move- in the basal ganglia and various cortical regions. ments and the rhythmicity, suppressibility, randomness, and directionality of hyperkinetic movements. Muscle tone should be assessed for rigidity, which is an increase in resist- Treatment Approach to Neurobehavioral ance to passive movements that is independent of the veloc- Symptoms of Dementia ity and direction of those movements. Gait examination Behavioral and psychiatric symptoms of dementia are a com- should consider the base of standing, pace of ambulation, mon problem in patients with dementia disorders and are stride length, foot clearance off the ground, postural stability, among the most common reasons for admission to long-term and arm swing. care facilities. Multidisciplinary care, massage and touch ther- apy, and music combined with massage and touch therapy were clinically more efficacious than usual care, including e The key features in the classification of movement pharmacologic care, in treating aggressive and agitated behav- disorders are the speed, amplitude, and fatigability of iors in patients with dementia, according to a recent system- voluntary movements and the rhythmicity, suppressi- atic review. Nonpharmacologic environmental and behavioral bility, randomness, and directionality of hyperkinetic

pharmacologic care, in treating aggressive and agitated behav- disorders are the speed, amplitude, and fatigability of iors in patients with dementia, according to a recent system- voluntary movements and the rhythmicity, suppressi- atic review. Nonpharmacologic environmental and behavioral bility, randomness, and directionality of hyperkinetic treatments should be emphasized for these patients, although movements. some pharmacologic therapies may improve function and patient safety. Antidepressant agents should be considered first-line therapy for symptoms related to mood and anxiety. If Hypokinetic Movement Disorders appropriate, acetylcholinesterase inhibitors also may be tried The most common type of hypokinetic movement disorder is early in the disease course. Benzodiazepines should be parkinsonism. Parkinson disease is the most common form of avoided, except in cases of extreme anxiety. parkinsonism; Parkinson-plus syndromes combine features The use of antipsychotic agents to treat behavioral and of parkinsonism with other features found in the patient’s psychiatric symptoms of dementia should be considered on history or physical examination. Vascular parkinsonism an individual basis. Strong evidence links use of antipsy- results from microvascular disease or large strokes and is chotic agents with increased mortality in older persons with characterized by predominant gait impairment with relative dementia. At the same time, there is evidence of benefit for sparing of upper extremities. Parkinsonism also may arise as certain antipsychotic agents (such as risperidone, aripipra- an adverse effect of medication. Some patients with normal zole, and olanzapine). If antipsychotic agents are needed, pressure hydrocephalus exhibit parkinsonism with gait insta- newer-generation medications should be started at low bility, dementia, and urinary incontinence (see Cognitive doses with a regimented titration and a plan for regular Impairment). 50

Movement Disorders TABLE 31. Classification of Movement Disorders Movement Type Clinical Features Examples | | Hypokinetic Parkinsonism Cardinal features: bradykinesia/hypokinesia, rigidity, Parkinson disease, Parkinson-plus syndromes, rest tremor, postural instability dementia with Lewy bodies, vascular parkinsonism, hydrocephalus, medication-induced parkinsonism, Additional features: freezing gait, stooped posture, Wilson disease, young-onset Huntington disease masked face, hypophonia, micrographia | Hyperkinetic Tremor Rhythmic oscillations of a body part, can occur at rest Rest tremor: parkinsonism | eovmasrongnalie i ie pa uiae ion (i i a r kineti Postural and kinetic tremor: essential tremor, enhanced || ee 5

Tremor Rhythmic oscillations of a body part, can occur at rest Rest tremor: parkinsonism | eovmasrongnalie i ie pa uiae ion (i i a r kineti Postural and kinetic tremor: essential tremor, enhanced || ee 5 Intention tremor is characterized by marked increase in physiologic tremor t li near ta : ee wget Intention tremor: cerebellar Dystonia Sustained or intermittent, stereotyped, and directional Primary: primary generalized dystonia (DYT1), dopa- twisting and posturing movements of various body responsive dystonia, torticollis, blepharospasm, writer's parts; can be associated with sensory trick (“geste cramp antagoniste” or movement ortouch that interrupts . | fad ee dystonia) Secondary: basal ganglia lesion, anoxic injury, ¥ postencephalitic, cerebral palsy, medications | | Chorea Random, nonrepetitive, quick, unsustained, Huntington disease, neuroacanthocytosis, purposeless movements with a flowing dance-like poststreptococcal (Sydenham chorea), chorea pattern gravidarum, autoimmune, metabolic, vascular, medications

Intention tremor is characterized by marked increase in physiologic tremor t li near ta : ee wget Intention tremor: cerebellar Dystonia Sustained or intermittent, stereotyped, and directional Primary: primary generalized dystonia (DYT1), dopa- twisting and posturing movements of various body responsive dystonia, torticollis, blepharospasm, writer's parts; can be associated with sensory trick (“geste cramp antagoniste” or movement ortouch that interrupts . | fad ee dystonia) Secondary: basal ganglia lesion, anoxic injury, ¥ postencephalitic, cerebral palsy, medications | | Chorea Random, nonrepetitive, quick, unsustained, Huntington disease, neuroacanthocytosis, purposeless movements with a flowing dance-like poststreptococcal (Sydenham chorea), chorea pattern gravidarum, autoimmune, metabolic, vascular, medications Hemiballismus Unilateral high-amplitude proximal flailing, ballistic, Lesions of contralateral subthalamic or adjacent parts choreiform movements of limbs of basal ganglia (often stroke) Athetosis Slow convoluted writhing movements of digits and Early-life damage to basal ganglia (hypoxia, kernicterus, toes vascular event) Pseudoathetosis similar but elicited by eye closure Pseudoathetosis caused by lesions of proprioceptive pathway

Athetosis Slow convoluted writhing movements of digits and Early-life damage to basal ganglia (hypoxia, kernicterus, toes vascular event) Pseudoathetosis similar but elicited by eye closure Pseudoathetosis caused by lesions of proprioceptive pathway Tic Stereotyped, brief, purposeless, rapid movements that Tourette syndrome, autism, developmental delay break the flow of normal movements; can be simple or syndromes, Huntington disease, medications complex, motor or vocal; premonitory sensory urges, Stereotypy can be normal in young children or suggestibility, and suppressibility associated with developmental delay and Stereotypy is a coordinated ritualistic and highly neurometabolic syndromes repetitive movement Myoclonus Rapid, shock-like, jerky movement of isolated body Metabolic, medications, infections, autoimmune, parts or whole body myoclonic epilepsies, benign essential myoclonus, corticobasal degeneration, Alzheimer disease, prion disease, sleep-related (hypnic jerks) Akathisia Inner restlessness associated with repetitive Drug-induced, restless legs syndrome movements Psychogenic Highly variable, inconsistent, distractible, acute onset, Conversion disorder, malingering episodic, with variable frequency of tremor, with fixed dystonia, with acrobatic uneconomic gait (astasia- abasia)

Psychogenic Highly variable, inconsistent, distractible, acute onset, Conversion disorder, malingering episodic, with variable frequency of tremor, with fixed dystonia, with acrobatic uneconomic gait (astasia- abasia) Parkinson Disease Clinical Features of Parkinson Disease Parkinson disease is a slowly progressive neurodegenerative Parkinson disease has four cardinal signs: tremor at rest, brad- disorder involving the gradual loss of dopamine-producing ykinesia, rigidity, and gait/balance impairment. Resting tremor neurons in the substantia nigra. Pathologic findings include is characteristically unilateral at onset and remains asymmet- Lewy bodies, which are intracytoplasmic eosinophilic inclu- ric; it most commonly is noticed in the upper extremities and sions composed of a-synuclein and ubiquitin. Both genetic jaw. If a resting tremor is absent, a tremor typically emerges influences and exposure to certain environmental factors, after few seconds of outstretched posturing of the arms and including pesticides, can increase the risk for Parkinson dis- during ambulation. Bradykinesia is characterized by progres- ease. Aging is a major risk factor, and a sharp rise in global sive decrements in speed and amplitude of repetitive move- incidence is expected over the next 20 years. Patients with the ments. This feature often is associated with reductions in facial onset of movement disorders before age 40 years should be expression and arm swing. Small handwriting (micrographia) screened for Wilson disease. is common, and patients may report difficulty with both fine 51

Movement Disorders and gross movements. Speech becomes slower with a low- Cognitive impairment in Parkinson disease is not uncom- volume voice. Rigidity, manifesting as increased resistance to mon and initially involves mild subcortical deficits, especially movement, is often asymmetric, may occur on the same side as in processing speed, short-term memory, and attention tremor, and may be “cogwheel” with intermittent release of the domains. Cortical functions, such as language and declarative rigidity with passive movement, which results in a jerking or memory (memory of facts and events), are relatively spared. As ratcheting quality of movement. As many as 30% of patients many as a third of patients may develop dementia in the later with Parkinson disease have a tremor-free akinetic rigid syn- stages of Parkinson disease, but early cognitive impairment is drome at presentation. Gait disturbance manifests as a slow, a red flag pointing to other diagnoses, such as dementia with narrow-based, and shuffling gait with associated reduced arm Lewy bodies (see Cognitive Impairment). swings, stooped posture, and imbalance when turning. As the disease progresses, severe freezing of gait and postural instabil- Diagnosis of Parkinson Disease ity are noted. In contrast, cerebellar ataxic gait is characterized The diagnosis of Parkinson disease requires the presence of

and gross movements. Speech becomes slower with a low- Cognitive impairment in Parkinson disease is not uncom- volume voice. Rigidity, manifesting as increased resistance to mon and initially involves mild subcortical deficits, especially movement, is often asymmetric, may occur on the same side as in processing speed, short-term memory, and attention tremor, and may be “cogwheel” with intermittent release of the domains. Cortical functions, such as language and declarative rigidity with passive movement, which results in a jerking or memory (memory of facts and events), are relatively spared. As ratcheting quality of movement. As many as 30% of patients many as a third of patients may develop dementia in the later with Parkinson disease have a tremor-free akinetic rigid syn- stages of Parkinson disease, but early cognitive impairment is drome at presentation. Gait disturbance manifests as a slow, a red flag pointing to other diagnoses, such as dementia with narrow-based, and shuffling gait with associated reduced arm Lewy bodies (see Cognitive Impairment). swings, stooped posture, and imbalance when turning. As the disease progresses, severe freezing of gait and postural instabil- Diagnosis of Parkinson Disease ity are noted. In contrast, cerebellar ataxic gait is characterized The diagnosis of Parkinson disease requires the presence of by a wide base, frequent truncal swaying and veering, and bradykinesia and at least one other cardinal feature and the impaired tandem walking in a straight line. Early prominent absence of red flags for atypical forms of parkinsonism postural instability with frequent falls is not typical in Parkinson (Table 33). A therapeutic trial of levodopa also can help when disease and suggests a Parkinson-plus condition. the diagnosis is in question; patients with Parkinson disease Parkinson disease also is associated with various nonmo- usually respond well, but other disorders rarely improve with tor symptoms, ranging from autonomic dysfunction to prob- levodopa. Brain imaging is recommended to rule out vascular lems with sleep, mood, and cognition (Table 32). Premotor disease and hydrocephalus. A dopamine transporter scan, symptoms, including hyposmia (diminished sense of smell), such as a single-photon emission CT scan of the brain using constipation, and rapid eye movement (REM) sleep behavior ioflupane-123 ligand, can be used as a confirmatory test. Its disorder (RBD) (see Restless Legs Syndrome and Sleep-Related use, however, should be limited to select patients in whom the Movement Disorders), may precede onset of motor symptoms differentiation between Parkinson disease and essential by years. tremor or drug-induced parkinsonism is not possible on clinical grounds. The test cannot distinguish between

by a wide base, frequent truncal swaying and veering, and bradykinesia and at least one other cardinal feature and the impaired tandem walking in a straight line. Early prominent absence of red flags for atypical forms of parkinsonism postural instability with frequent falls is not typical in Parkinson (Table 33). A therapeutic trial of levodopa also can help when disease and suggests a Parkinson-plus condition. the diagnosis is in question; patients with Parkinson disease Parkinson disease also is associated with various nonmo- usually respond well, but other disorders rarely improve with tor symptoms, ranging from autonomic dysfunction to prob- levodopa. Brain imaging is recommended to rule out vascular lems with sleep, mood, and cognition (Table 32). Premotor disease and hydrocephalus. A dopamine transporter scan, symptoms, including hyposmia (diminished sense of smell), such as a single-photon emission CT scan of the brain using constipation, and rapid eye movement (REM) sleep behavior ioflupane-123 ligand, can be used as a confirmatory test. Its disorder (RBD) (see Restless Legs Syndrome and Sleep-Related use, however, should be limited to select patients in whom the Movement Disorders), may precede onset of motor symptoms differentiation between Parkinson disease and essential by years. tremor or drug-induced parkinsonism is not possible on clinical grounds. The test cannot distinguish between TABLE 32. Nonmotor Symptoms of Parkinson Disease Parkinson disease and Parkinson-plus conditions. Recent efforts to develop specific biomarkers for Parkinson disease | Category Nonmotor Symptoms are underway and include assays to measure a-synuclein in | Cognitive Bradyphrenia (slow processing), mild cerebral spinal fluid and other biofluids, functional fluorode- | subcortical cognitive impairment (slow processing speed, impaired short-term oxyglucose PET imaging, and transcranial ultrasonography of memory, and attention deficits with the substantia nigra. The clinical utility of these methods relative sparing of cortical functions, such remains unclear. | as language and declarative memory), | dementia possible at advanced stages Depression and Fall Screening i]

TABLE 32. Nonmotor Symptoms of Parkinson Disease Parkinson disease and Parkinson-plus conditions. Recent efforts to develop specific biomarkers for Parkinson disease | Category Nonmotor Symptoms are underway and include assays to measure a-synuclein in | Cognitive Bradyphrenia (slow processing), mild cerebral spinal fluid and other biofluids, functional fluorode- | subcortical cognitive impairment (slow processing speed, impaired short-term oxyglucose PET imaging, and transcranial ultrasonography of memory, and attention deficits with the substantia nigra. The clinical utility of these methods relative sparing of cortical functions, such remains unclear. | as language and declarative memory), | dementia possible at advanced stages Depression and Fall Screening i] | Affective and Primary: depression, anxiety, apathy, | behavioral pseudobulbar affect (emotional All patients with Parkinson disease should be screened for incontinence) depression and be assessed for fall risk. Depression and anxi- Medication-induced: psychosis, impulse ety are common nonmotor symptoms of Parkinson disease control disorder, punding (purposeless and can be detected by using common clinical mood and anxi- stereotyped behavior), dopamine dysregulation syndrome (craving for ety scales. Treatments include psychotherapy, antidepressants dopaminergic medications) (excluding antipsychotic agents), and dopaminergic medica-

| Affective and Primary: depression, anxiety, apathy, | behavioral pseudobulbar affect (emotional All patients with Parkinson disease should be screened for incontinence) depression and be assessed for fall risk. Depression and anxi- Medication-induced: psychosis, impulse ety are common nonmotor symptoms of Parkinson disease control disorder, punding (purposeless and can be detected by using common clinical mood and anxi- stereotyped behavior), dopamine dysregulation syndrome (craving for ety scales. Treatments include psychotherapy, antidepressants dopaminergic medications) (excluding antipsychotic agents), and dopaminergic medica- | Sleep related Sleep fragmentation, sleep-wake reversal, tions (when mood symptoms correlate with motor symp- rapid eye movement sleep behavior toms). Depression should be distinguished from apathy, a state disorder, restless legs syndrome, of reduced motivation and goal-directed behavior that is not medication-related sedation and sleep attacks, fatigue associated with sad mood and emotional distress. Falls in Parkinson disease may be related to postural Autonomic Constipation, postural hypotension, bladder and sexual dysfunction, imbalance, impaired stepping, freezing of gait, or orthostatic sialorrhea, seborrhea, excessive sweating, hypotension. Detection of risk factors for falling and imple- hyposmia or anosmia (impaired sense of mentation of a multidisciplinary management approach— smell) including medications, therapy, supportive devices, and | Musculoskeletal Truncal and cervical stooped posturing, education—can reduce morbidity and costs related to falls. camptocormia (truncal flexion during standing and walking), frozen shoulder, Postural stability can be best assessed by the pull test, in which dystonic joint deformities in hands and an examiner throws the patient off balance by pulling back- toes, and fall-related injuries ward on the shoulders. A positive test, characterized by top- | Pain related Painful dystonia, painful rigidity, pling into examiner’s arms or taking more than two corrective steps, is the most reliable predictor of a risk of backward falls.

| Sleep related Sleep fragmentation, sleep-wake reversal, tions (when mood symptoms correlate with motor symp- rapid eye movement sleep behavior toms). Depression should be distinguished from apathy, a state disorder, restless legs syndrome, of reduced motivation and goal-directed behavior that is not medication-related sedation and sleep attacks, fatigue associated with sad mood and emotional distress. Falls in Parkinson disease may be related to postural Autonomic Constipation, postural hypotension, bladder and sexual dysfunction, imbalance, impaired stepping, freezing of gait, or orthostatic sialorrhea, seborrhea, excessive sweating, hypotension. Detection of risk factors for falling and imple- hyposmia or anosmia (impaired sense of mentation of a multidisciplinary management approach— smell) including medications, therapy, supportive devices, and | Musculoskeletal Truncal and cervical stooped posturing, education—can reduce morbidity and costs related to falls. camptocormia (truncal flexion during standing and walking), frozen shoulder, Postural stability can be best assessed by the pull test, in which dystonic joint deformities in hands and an examiner throws the patient off balance by pulling back- toes, and fall-related injuries ward on the shoulders. A positive test, characterized by top- | Pain related Painful dystonia, painful rigidity, pling into examiner’s arms or taking more than two corrective steps, is the most reliable predictor of a risk of backward falls. 52

Movement Disorders TABLE 33. Red Flags for Atypical Forms of Parkinsonism Red Flags Features Likely Alternative Diagnosis | | | Dysautonomia Prominent orthostatic hypotension, urinary incontinence, Multiple system atrophy impotence, inappropriate sweating (mild autonomic deficits can be seen in early Parkinson disease) Abnormal eye movements Supranuclear vertical gaze palsy, slowness of vertical Progressive supranuclear saccades palsy Prominent early cognitive impairment Dementia within first year of onset (mild cognitive Dementia with Lewy bodies impairment common in Parkinson disease; dementia but sometimes progressive may develop in a notable subgroup of patients in supranuclear palsy or advanced stages) vascular parkinsonism Visual hallucinations Early and not provoked by medications (levodopa- Dementia with Lewy bodies induced hallucinations can be seen in Parkinson disease, especially in later stages) Early prominent postural instability and Within first year of onset Multiple system atrophy, falls progressive supranuclear palsy

Early prominent postural instability and Within first year of onset Multiple system atrophy, falls progressive supranuclear palsy Prominent gait ataxia Wide-based gait with variable stepping, with or without Multiple system atrophy additional cerebellar deficits (dysmetria, nystagmus) Symmetric or markedly asymmetric In Parkinson disease, characteristically asymmetric at involvement onset and throughout its course Lack of asymmetry indicative of atypical parkinsonism Multiple system atrophy, progressive supranuclear palsy Very severe asymmetric involvement, possibly suggestive Corticobasal degeneration of corticobasal degeneration, and usually associated with severe fixed dystonic posturing, myoclonus, apraxia, and sensory cortical deficits Rapid onset and step-wise deterioration More suggestive of vascular parkinsonism (Parkinson Vascular parkinsonism disease is associated with slow onset and gradual course)

Rapid onset and step-wise deterioration More suggestive of vascular parkinsonism (Parkinson Vascular parkinsonism disease is associated with slow onset and gradual course) Lack of response to levodopa? Most important red flag of atypical parkinsonism Multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, vascular parkinsonism *Must not be secondary to adverse effects or insufficient dosing of medication.

Lack of response to levodopa? Most important red flag of atypical parkinsonism Multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, vascular parkinsonism *Must not be secondary to adverse effects or insufficient dosing of medication. Treatment of Parkinson Disease and to delay the onset of levodopa-related motor complica- Currently, no medication with established efficacy is available tions. Patients taking dopamine agonists should be warned to slow the progression of Parkinson disease. Rigorous daily about impulse control disorder, which manifests as a tendency exercise can improve the quality of gait and balance and also to engage in out-of-character impulsive behaviors, such as may provide disease-modifying benefits. excessive gambling, overspending, and hypersexuality. Other Symptomatic treatments include medications (Table 34), adverse effects include sleep attacks, dependent edema, nau- surgical therapy, and supportive measures. Dopaminergic sea, hallucinations, and confusion. medications (various formulations of the dopamine precursor Eventually, all patients with Parkinson disease will require levodopa, pramipexole, ropinirole, and rotigotine) are the levodopa. The drug should be started as initial therapy in older mainstay in the treatment of motor symptoms. Several other patients and as replacement or additional therapy in younger medications can supplement the dopaminergic agents and patients with insufficient response to dopamine agonists. help reduce the medication-induced complications that may Carbidopa, a peripheral decarboxylase inhibitor, blocks the emerge over time as Parkinson disease progresses. adverse effects of levodopa outside the brain and is used in Dopamine agonists, such as pramipexole and ropinirole, combination with levodopa. In patients who experience severe are the preferred initial first-line dopaminergic medications in peripheral adverse effects of levodopa, such as nausea or patients younger than 65 years and may be used with levodopa orthostatic hypotension, higher doses of carbidopa may allevi- as an adjunct treatment at any point in the disease course. ate these symptoms. Many experts encourage the use of dopamine agonists in As many as 50% of patients may develop motor fluctua- younger patients to decrease long-term exposure to levodopa tions after few years of treatment with levodopa. Motor

Treatment of Parkinson Disease and to delay the onset of levodopa-related motor complica- Currently, no medication with established efficacy is available tions. Patients taking dopamine agonists should be warned to slow the progression of Parkinson disease. Rigorous daily about impulse control disorder, which manifests as a tendency exercise can improve the quality of gait and balance and also to engage in out-of-character impulsive behaviors, such as may provide disease-modifying benefits. excessive gambling, overspending, and hypersexuality. Other Symptomatic treatments include medications (Table 34), adverse effects include sleep attacks, dependent edema, nau- surgical therapy, and supportive measures. Dopaminergic sea, hallucinations, and confusion. medications (various formulations of the dopamine precursor Eventually, all patients with Parkinson disease will require levodopa, pramipexole, ropinirole, and rotigotine) are the levodopa. The drug should be started as initial therapy in older mainstay in the treatment of motor symptoms. Several other patients and as replacement or additional therapy in younger medications can supplement the dopaminergic agents and patients with insufficient response to dopamine agonists. help reduce the medication-induced complications that may Carbidopa, a peripheral decarboxylase inhibitor, blocks the emerge over time as Parkinson disease progresses. adverse effects of levodopa outside the brain and is used in Dopamine agonists, such as pramipexole and ropinirole, combination with levodopa. In patients who experience severe are the preferred initial first-line dopaminergic medications in peripheral adverse effects of levodopa, such as nausea or patients younger than 65 years and may be used with levodopa orthostatic hypotension, higher doses of carbidopa may allevi- as an adjunct treatment at any point in the disease course. ate these symptoms. Many experts encourage the use of dopamine agonists in As many as 50% of patients may develop motor fluctua- younger patients to decrease long-term exposure to levodopa tions after few years of treatment with levodopa. Motor 53

TABLE 34. Medications for Parkinson Disease j Cc lass Forms Clinical Indication | f || i Dopamine precursor Levodopa Most effective treatment for motor deficits | Initial therapy in patients older than 65 years or those with | | | severe motor symptoms, freezing, or falls Second-line treatment in younger patients who have failed dopamine agonists Oral Immediate-release levodopa Maintenance therapy during waking hours, peak effect provides good “on"-time benefit Continued-release levodopa Nighttime therapy Extended-release levodopa Maintenance therapy if immediate-release formulation causes motor fluctuations and dyskinesia Orally disintegrating levodopa Rapid relief of sudden “off” state Inhaled Inhaled levodopa Rapid relief of sudden “off” state Enteral gel Enteral levodopa Maintenance therapy in advanced Parkinson disease associated with severe motor complications of immediate- release levodopa, provides sustained levodopa release, can cause a higher rate of gastrointestinal complications Decarboxylase inhibitors Carbidopa, benserazide? Suppression of peripheral adverse effects of levodopa Dopamine agonists

Enteral gel Enteral levodopa Maintenance therapy in advanced Parkinson disease associated with severe motor complications of immediate- release levodopa, provides sustained levodopa release, can cause a higher rate of gastrointestinal complications Decarboxylase inhibitors Carbidopa, benserazide? Suppression of peripheral adverse effects of levodopa Dopamine agonists Oral Pramipexole, ropinirole, First-line treatment in younger patients, adjuvant therapy to cabergoline? limit total dose of levodopa, treatment to counteract wearing-off phenomenon Patch Rotigotine Similar to oral forms Subcutaneous injection Apomorphine Rapid relief of sudden “off"-time Catechol-O-methyltransferase Entacapone (often used), Counteracting of wearing-off phenomenon, prolongation inhibitors tolcapone (hepatic toxicity) of levodopa effect Monoamine oxidase type B Selegiline, rasagiline, safinamide Initial therapy in mild cases, potentiation of levodopa effect, inhibitors tremor Glutamate NMDA antagonist Amantadine, rimantidine Dyskinesia, tremor, fatigue Anticholinergic agents Trihexyphenidyl, benztropine Tremor, mild benefit against parkinsonism, higher adverse effect profile in old age and dementia

Glutamate NMDA antagonist Amantadine, rimantidine Dyskinesia, tremor, fatigue Anticholinergic agents Trihexyphenidyl, benztropine Tremor, mild benefit against parkinsonism, higher adverse effect profile in old age and dementia Antipsychotic agents Pimavanserin, quetiapine Medication-induced psychosis, medication-reduction strategies should be prioritized, increased mortality risk in patients with dementia Norepinephrine precursor Droxidopa Neurogenic orthostatic hypotension, requires coadministration with carbidopa; other measures (including liberal salt intake, fludrocortisone, and midodrine) also are effective NMDA = N-methyl-D-aspartate. Available in Europe but not the United States.

Norepinephrine precursor Droxidopa Neurogenic orthostatic hypotension, requires coadministration with carbidopa; other measures (including liberal salt intake, fludrocortisone, and midodrine) also are effective NMDA = N-methyl-D-aspartate. Available in Europe but not the United States. fluctuations include the “wearing-off” phenomenon (loss of levodopa have a rapid peak dose effect that many patients find the beneficial effect of the medication before the next dose is helpful. The newer extended-release formulations may pro- administered), “sudden off” state (unrelated to timing of the vide a more sustained control of symptoms throughout the medication), and “early morning off” state. Levodopa-induced day, which can prove beneficial by reducing any wearing off dyskinesias may emerge as a result of hypersensitization of between doses. Wearing off also can be lessened by frequent dopamine receptors and manifest as involuntary choreiform dosing of levodopa and by the addition of dopamine agonists, movements during peak doses of levodopa. catechol-O-methyltransferase inhibitors, or monamine oxi- Several formulations of levodopa are commercially avail- dase B inhibitors. Inhaled levodopa can be used as rescue able, including oral immediate-release, extended-release, and therapy in patients who experience sudden “off” symptoms. rapidly disintegrating formulations; an enteral gel infusion Amantadine can be added to the treatment regimen to prevent and an inhaled formulation also have recently become availa- dyskinesia. Anticholinergic medications also can be added to ble (see Table 34). The immediate-release formulations of provide additional benefit in patients with prominent tremor

fluctuations include the “wearing-off” phenomenon (loss of levodopa have a rapid peak dose effect that many patients find the beneficial effect of the medication before the next dose is helpful. The newer extended-release formulations may pro- administered), “sudden off” state (unrelated to timing of the vide a more sustained control of symptoms throughout the medication), and “early morning off” state. Levodopa-induced day, which can prove beneficial by reducing any wearing off dyskinesias may emerge as a result of hypersensitization of between doses. Wearing off also can be lessened by frequent dopamine receptors and manifest as involuntary choreiform dosing of levodopa and by the addition of dopamine agonists, movements during peak doses of levodopa. catechol-O-methyltransferase inhibitors, or monamine oxi- Several formulations of levodopa are commercially avail- dase B inhibitors. Inhaled levodopa can be used as rescue able, including oral immediate-release, extended-release, and therapy in patients who experience sudden “off” symptoms. rapidly disintegrating formulations; an enteral gel infusion Amantadine can be added to the treatment regimen to prevent and an inhaled formulation also have recently become availa- dyskinesia. Anticholinergic medications also can be added to ble (see Table 34). The immediate-release formulations of provide additional benefit in patients with prominent tremor 54

Movement Disorders or dystonia but should be avoided in older patients with inverse agonist, is the only FDA-approved medication for dementia. Parkinson psychosis; quetiapine and clozapine also are often Medication-induced psychosis, especially visual halluci- used as less expensive, albeit off-label, options. nations, also can occur with use of dopaminergic medications. Deep brain stimulation (DBS) is a surgical therapy that Uncontrolled psychosis is a major risk factor for nursing home involves the delivery of electrical stimulation to key brain tar- placement and contributes to increased mortality in Parkinson gets, such as the subthalamic nucleus and the globus pallidus disease. Treatment strategies include addressing any systemic interna. This mode of treatment is indicated for patients who trigger, simplifying the medication regimen (including continue to benefit from levodopa but experience motor fluc- removal of non-levodopa medications and decreasing the lev- tuations or have a refractory tremor. An algorithm for the odopa dosage), and, if needed, using certain antipsychotic treatment of Parkinson disease and the selection of appropri- agents. Pimavanserin, a selective serotonin 5-HT2b receptor ate candidates for DBS surgery is shown in Figure 22. Parkinsonism Red flags Present |< for atypical > Absent parkinsonism

or dystonia but should be avoided in older patients with inverse agonist, is the only FDA-approved medication for dementia. Parkinson psychosis; quetiapine and clozapine also are often Medication-induced psychosis, especially visual halluci- used as less expensive, albeit off-label, options. nations, also can occur with use of dopaminergic medications. Deep brain stimulation (DBS) is a surgical therapy that Uncontrolled psychosis is a major risk factor for nursing home involves the delivery of electrical stimulation to key brain tar- placement and contributes to increased mortality in Parkinson gets, such as the subthalamic nucleus and the globus pallidus disease. Treatment strategies include addressing any systemic interna. This mode of treatment is indicated for patients who trigger, simplifying the medication regimen (including continue to benefit from levodopa but experience motor fluc- removal of non-levodopa medications and decreasing the lev- tuations or have a refractory tremor. An algorithm for the odopa dosage), and, if needed, using certain antipsychotic treatment of Parkinson disease and the selection of appropri- agents. Pimavanserin, a selective serotonin 5-HT2b receptor ate candidates for DBS surgery is shown in Figure 22. Parkinsonism Red flags Present |< for atypical > Absent parkinsonism Y Y 5 : Moderate severity or Lack of clear benefit Atypical parkinsonism: Parkinson disease bothersome symptoms: . with medications Supportive management, diagnosis dopamine agonists, "| despite sufficient dosing DBS not indicated levodopa and schedule

Y Y 5 : Moderate severity or Lack of clear benefit Atypical parkinsonism: Parkinson disease bothersome symptoms: . with medications Supportive management, diagnosis dopamine agonists, "| despite sufficient dosing DBS not indicated levodopa and schedule Vv Vv Mild symptoms: Atypical parkinsonism: No treatment, or treatment with Supportive management, selegiline, rasagiline, or amantadine DBS not indicated Vv Good motor benefit Good motor benefit from from dopaminergic drugs dopaminergic drugs with complications without major adverse effects (motor fluctuations, dyskinesia, i hallucinations, excessive sedation, etc.) Continue y medications Adjust dose and schedule of medications, add adjunct medications v

Continue y medications Adjust dose and schedule of medications, add adjunct medications v ¢ If complications are refractory despite medical management, or ¢ if presence of adverse effects prohibits optimal dosing of medications, or e if tremor is severe and refractory: refer to movement disorder neurologist iz Assessment of response to levodopa during off- and on-medication states : If levodopa causes notable motor benefit (at least 30% improvement in UPDRS motor score) and provided major cognitive or mood disorder is absent: refer for DBS surgery FIGURE 22. Algorithm for evaluation of candidacy for deep brain stimulation in Parkinson disease. DBS = deep brain stimulation; UPDRS = Unified Parkinson Disease Rating Scale. 55

Movement Disorders TABLE 35. Medications Causing Drug-Induced Parkinsonism e The diagnosis of Parkinson disease requires the pres- ence of bradykinesia and at least one of the other cardi- Medication Class Examples nal features of the disorder (tremor at rest, cogwheel Common rigidity, and gait or balance impairment) and the Dopamine receptor Typical antipsychotics: haloperidol, absence of red flags for atypical forms of parkinsonism. blockers chlorpromazine HVC e In Parkinson disease, a dopamine transporter single- Atypical antipsychotics: risperidone, olanzapine, photon emission CT scan of the brain is unnecessary ziprasidone, aripiprazole except to differentiate between Parkinson disease and Antiemetics: metoclopramide, essential tremor or drug-induced parkinsonism if the prochlorperazine distinction cannot be made on clinical grounds. Dopamine depleters — Tetrabenazine, reserpine HVC e Detection of risk factors for falling and implementation i] Uncommon | of a multidisciplinary management approach-—including | | Mood stabilizers, Lithium, valproic acid |

HVC e In Parkinson disease, a dopamine transporter single- Atypical antipsychotics: risperidone, olanzapine, photon emission CT scan of the brain is unnecessary ziprasidone, aripiprazole except to differentiate between Parkinson disease and Antiemetics: metoclopramide, essential tremor or drug-induced parkinsonism if the prochlorperazine distinction cannot be made on clinical grounds. Dopamine depleters — Tetrabenazine, reserpine HVC e Detection of risk factors for falling and implementation i] Uncommon | of a multidisciplinary management approach-—including | | Mood stabilizers, Lithium, valproic acid | medications, therapy, supportive devices, and educa- | antiepileptic agents | tion—can reduce morbidity and costs related to falls; a } Other Amiodarone, flunarizine (rarely), | positive pull test is the most reliable predictor of a risk selective serotonin reuptake | of backward falls in Parkinson disease. inhibitors |

Other Amiodarone, flunarizine (rarely), | positive pull test is the most reliable predictor of a risk selective serotonin reuptake | of backward falls in Parkinson disease. inhibitors | e¢ Dopamine agonists are the preferred initial first-line medication in patients younger than 65 years and levo- Drug-Induced Parkinsonism dopa is the preferred initial therapy in older patients. A number of drugs, especially dopamine receptor-blocking e Deep brain stimulation is indicated for patients who antipsychotic agents, can cause parkinsonism (Table 35). continue to benefit from levodopa but experience severe Drug-induced parkinsonism is symmetric, lacks nonmotor motor fluctuations or have a refractory tremor. features, and is reversible after removal of the causative agent. In 10% of patients, parkinsonism persists more than Parkinson-Plus Syndromes 6 months after removal of the offending agent, which rep- Parkinson-plus syndromes typically present with a combina- resents the unmasking of a preclinical neurodegenerative tion of parkinsonism and additional features that are atypical disease. Several other extrapyramidal complications of for idiopathic Parkinson disease. These conditions often are dopamine-receptor blockers have also been described more rapidly progressive than Parkinson disease and are (Table 36). refractory to standard therapies, particularly levodopa. The primary syndromes include progressive supranuclear palsy,

e¢ Dopamine agonists are the preferred initial first-line medication in patients younger than 65 years and levo- Drug-Induced Parkinsonism dopa is the preferred initial therapy in older patients. A number of drugs, especially dopamine receptor-blocking e Deep brain stimulation is indicated for patients who antipsychotic agents, can cause parkinsonism (Table 35). continue to benefit from levodopa but experience severe Drug-induced parkinsonism is symmetric, lacks nonmotor motor fluctuations or have a refractory tremor. features, and is reversible after removal of the causative agent. In 10% of patients, parkinsonism persists more than Parkinson-Plus Syndromes 6 months after removal of the offending agent, which rep- Parkinson-plus syndromes typically present with a combina- resents the unmasking of a preclinical neurodegenerative tion of parkinsonism and additional features that are atypical disease. Several other extrapyramidal complications of for idiopathic Parkinson disease. These conditions often are dopamine-receptor blockers have also been described more rapidly progressive than Parkinson disease and are (Table 36). refractory to standard therapies, particularly levodopa. The primary syndromes include progressive supranuclear palsy, multiple system atrophy (formerly Shy-Drager syndrome), and Hyperkinetic Movement Disorders corticobasal degeneration. Patients with progressive supranu- Essential Tremor clear palsy have parkinsonism, axial rigidity, prominent pos- Tremor is an oscillatory movement of a body part that is tural instability with early falls, impairment in both ocular classified by its presence at rest or with action (Table 37). range of movement and saccades (very fast jumps from one eye Essential tremor is the most common movement disorder. It position to another, particularly in the vertical direction), is defined as an isolated tremor syndrome of at least 3 years’ facial dystonia, dysphagia, dysarthria, and subcortical demen- duration characterized by action tremor in the upper tia. Multiple system atrophy presents with a combination of extremities. This type of tremor also can involve the voice, parkinsonism, ataxia, and severe dysautonomia (orthostatic head, or legs. Common features include a positive family hypotension and urinary dysfunction) and is also associated history (50% of patients), slow progression, and onset in with early falls. Corticobasal degeneration often presents with either adolescence or middle age. The tremor may be allevi- markedly asymmetric parkinsonism and frequently is associ- ated by alcohol and may be aggravated by stress, illness, ated with dystonia, myoclonus, cortical sensory deficits, fatigue, or the use of stimulants. A minority of affected cognitive deficits, aphasia, and apraxia (impaired motor patients experience substantial progression, leading to planning). marked disability. If essential tremor presents with mild additional neurologic signs, such as mild ataxia or isolated tremor at rest without bradykinesia, it would be classified e Parkinson-plus syndromes often are more rapidly pro- as “essential tremor plus.” The differential diagnosis gressive than Parkinson disease, have additional fea- includes enhanced physiologic tremor, which is a low- tures that are atypical for idiopathic Parkinson disease, amplitude tremor that is unnoticeable in most people but and are less responsive to standard antiparkinsonian may become prominent because of physical and psycho- therapies, particularly levodopa. logical stressors, medications, caffeine, or thyrotoxicosis.

multiple system atrophy (formerly Shy-Drager syndrome), and Hyperkinetic Movement Disorders corticobasal degeneration. Patients with progressive supranu- Essential Tremor clear palsy have parkinsonism, axial rigidity, prominent pos- Tremor is an oscillatory movement of a body part that is tural instability with early falls, impairment in both ocular classified by its presence at rest or with action (Table 37). range of movement and saccades (very fast jumps from one eye Essential tremor is the most common movement disorder. It position to another, particularly in the vertical direction), is defined as an isolated tremor syndrome of at least 3 years’ facial dystonia, dysphagia, dysarthria, and subcortical demen- duration characterized by action tremor in the upper tia. Multiple system atrophy presents with a combination of extremities. This type of tremor also can involve the voice, parkinsonism, ataxia, and severe dysautonomia (orthostatic head, or legs. Common features include a positive family hypotension and urinary dysfunction) and is also associated history (50% of patients), slow progression, and onset in with early falls. Corticobasal degeneration often presents with either adolescence or middle age. The tremor may be allevi- markedly asymmetric parkinsonism and frequently is associ- ated by alcohol and may be aggravated by stress, illness, ated with dystonia, myoclonus, cortical sensory deficits, fatigue, or the use of stimulants. A minority of affected cognitive deficits, aphasia, and apraxia (impaired motor patients experience substantial progression, leading to planning). marked disability. If essential tremor presents with mild additional neurologic signs, such as mild ataxia or isolated tremor at rest without bradykinesia, it would be classified e Parkinson-plus syndromes often are more rapidly pro- as “essential tremor plus.” The differential diagnosis gressive than Parkinson disease, have additional fea- includes enhanced physiologic tremor, which is a low- tures that are atypical for idiopathic Parkinson disease, amplitude tremor that is unnoticeable in most people but and are less responsive to standard antiparkinsonian may become prominent because of physical and psycho- therapies, particularly levodopa. logical stressors, medications, caffeine, or thyrotoxicosis. 56

Movement Disorders TABLE 36. Extrapyramidal Complications of Dopamine Receptor Blockers Type of Movement Disorder Symptoms | | Acute reactions (reversible) | Acute dystonia Immediate dystonic spasms; often involves neck, face, larynx, and eyes (oculogyric crisis); | | rapid reversal with intravenous diphenhydramine | | Acute akathisia Immediate sensation of restlessness with urge to constantly move and pace | Subacute or chronic syndromes | (reversible) Parkinsonism Similar to Parkinson disease, dose dependent, resolves within months after removal of the offending agent; symmetry and absence of nonmotor features favor a drug-induced over an idiopathic cause Tardive syndromes (late onset, may be irreversible) Tardive dyskinesia Repetitive stereotyped choreiform movements, oral-buccal-lingual predominance (tongue protrusion, lip smacking, puckering and chewing movements), also can affect the extremities (piano playing movements, foot tapping) and trunk (including respiratory muscles) Tardive dystonia Sustained dystonic posturing commonly affecting the face, neck, trunk, and arms; extensor cervical and axial dystonia Tardive akathisia Chronic sensation of inner restlessness with urge to constantly move and pace, leg crossing, body rocking Tardive tics Clinical presentation similar to Tourette syndrome but triggered after exposure to | dopamine blockers Other disorders

Tardive akathisia Chronic sensation of inner restlessness with urge to constantly move and pace, leg crossing, body rocking Tardive tics Clinical presentation similar to Tourette syndrome but triggered after exposure to | dopamine blockers Other disorders Withdrawal emergent syndrome Choreiform dyskinesia starting after sudden withdrawal from a neuroleptic agent and (reversible) stopping with reinstitution of the causative agent (or another agent from same class) and a subsequent slow taper within a few months; differential diagnosis of tardive dyskinesia that may be masked by antipsychotic agents and only unmasked after their removal (and may become persistent) Neuroleptic malignant syndrome Idiosyncratic; rapid onset and progressive; rigidity, dystonia, hyperthermia, (treatable emergency) rhabdomyolysis, and altered mental status

Withdrawal emergent syndrome Choreiform dyskinesia starting after sudden withdrawal from a neuroleptic agent and (reversible) stopping with reinstitution of the causative agent (or another agent from same class) and a subsequent slow taper within a few months; differential diagnosis of tardive dyskinesia that may be masked by antipsychotic agents and only unmasked after their removal (and may become persistent) Neuroleptic malignant syndrome Idiosyncratic; rapid onset and progressive; rigidity, dystonia, hyperthermia, (treatable emergency) rhabdomyolysis, and altered mental status Assessment of any form of action tremor should include The treatment of essential tremor is symptomatic. thyroid and renal function studies, liver chemistries, meas- Weighted utensils and wrist weights can help reduce tremor urement of serum electrolytes, and a review of medications amplitude during feeding. The most effective pharmacologic (Table 38). Patients younger than 40 years should undergo treatments for essential tremor are propranolol, primidone, screening for Wilson disease with serum ceruloplasmin and and topiramate. Additional second-line options include aten- 24-hour urine copper measurements. Slit-lamp ophthalmo- olol, sotalol, clonazepam, gabapentin, and nimodipine. logic examination for Kayser-Fleischer rings (Figure 23) also Botulinum toxin injection can help with some tremors, espe- should be considered. Other rare causes of action tremor cially those involving the neck and voice, but its benefit include dystonic tremor, rubral tremor, and orthostatic for limb tremor is limited by local weakness. Medication- tremor (see Table 37). refractory tremor can be effectively treated by targeting the ventral intermediate nucleus of the thalamus with DBS (uni- laterally or bilaterally) or focused ultrasound thalamotomy (unilaterally).

Assessment of any form of action tremor should include The treatment of essential tremor is symptomatic. thyroid and renal function studies, liver chemistries, meas- Weighted utensils and wrist weights can help reduce tremor urement of serum electrolytes, and a review of medications amplitude during feeding. The most effective pharmacologic (Table 38). Patients younger than 40 years should undergo treatments for essential tremor are propranolol, primidone, screening for Wilson disease with serum ceruloplasmin and and topiramate. Additional second-line options include aten- 24-hour urine copper measurements. Slit-lamp ophthalmo- olol, sotalol, clonazepam, gabapentin, and nimodipine. logic examination for Kayser-Fleischer rings (Figure 23) also Botulinum toxin injection can help with some tremors, espe- should be considered. Other rare causes of action tremor cially those involving the neck and voice, but its benefit include dystonic tremor, rubral tremor, and orthostatic for limb tremor is limited by local weakness. Medication- tremor (see Table 37). refractory tremor can be effectively treated by targeting the ventral intermediate nucleus of the thalamus with DBS (uni- laterally or bilaterally) or focused ultrasound thalamotomy (unilaterally). e Essential tremor is the most common movement disor- der and often presents with an isolated bilateral upper extremity action tremor; common features include a positive family history, alleviation by alcohol, slow pro- gression, and onset in either adolescence or middle age.

e Essential tremor is the most common movement disor- der and often presents with an isolated bilateral upper extremity action tremor; common features include a positive family history, alleviation by alcohol, slow pro- gression, and onset in either adolescence or middle age. e The treatment of essential tremor is symptomatic; the FIGURE 23. Kaiser-Fleischer rings seen in a patient with Wilson disease. Note most effective pharmacologic agents are propranolol, the circumferential discoloration that occurs at the sclera-iris border owing to copper primidone, and topiramate. deposition in Descemet's membrane. 57

Movement Disorders TABLE 37. Classification of Tremors Tremor Type Disease Association Features Resting tremor® Parkinsonian resting Parkinson disease Asymmetric; may emerge during ambulation; associated with other parkinsonian tremor signs (rigidity, bradykinesia, gait impairment) Atypical, drug-induced, Similarto Parkinson disease; tremor sometimes symmetric; red flags for atypical and vascular parkinsonism sometimes present parkinsonism Dystonic tremor Dystonia Associated with dystonic posturing; seen both at rest and with action; task specificity seen with action; position dependent, with a null point at which tremor stops Action tremor Postural and kinetic Essential tremor Present in the outstretched arm position and with various actions; commonly (but tremor? not universally) associated with a positive family history and improvement with alcohol; possible presence of head and voice tremor; possible emergence (after a delay of several seconds) of a postural tremor of the outstretched arms Enhanced physiologic Noticeable form of physiologic low-amplitude, high-frequency tremor seen in tremor association with triggers, such as stress, caffeine, drugs, and thyroid disease; similar to essential tremor but resolves with resolution of underlying trigger

Enhanced physiologic Noticeable form of physiologic low-amplitude, high-frequency tremor seen in tremor association with triggers, such as stress, caffeine, drugs, and thyroid disease; similar to essential tremor but resolves with resolution of underlying trigger Intention tremor’ Cerebellar disease Tremor during movements that increases in amplitude as hand approaches target (also known as terminal tremor); possible association with other cerebellar symptoms, including dysmetria Severe essential tremor Terminal tremor can be seen but often without prominent cerebellar dysmetria Fragile X-associated Neurodegenerative disease seen in older men who are carriers of a premutation tremor/ataxia syndrome in the fragile X intellectual disability 1 gene; typically, there is a family history of intellectual disability in young males and premature ovarian failure in females; symptoms of (intention) tremor, ataxia, parkinsonism, neuropathy and dementia Rubral tremor Cerebellar outflow Coarse proximal tremor present at rest, worse with posturing (especially large- disorders (multiple amplitude and proximal tremors in the wing-beating position with elbows flexed), sclerosis, stroke, and most severe during movements traumatic brain injury) Task-specific tremor Primary writing tremor Only present with specific task Orthostatic tremor Orthostatic tremor High-frequency tremor emerging in the legs only during standing (orthostatic position) and resolving with sitting or walking

Task-specific tremor Primary writing tremor Only present with specific task Orthostatic tremor Orthostatic tremor High-frequency tremor emerging in the legs only during standing (orthostatic position) and resolving with sitting or walking Neuropathic tremor Demyelinating Action tremor, associated with weakness, areflexia, and sensory loss neuropathies “Tremor present with the affected extremity resting unsupported. »Postural tremor is present with the arm in an outstretched position, and kinetic tremor is present during reaching, writing, and other movements. | ‘Intention tremor is a specific subtype of kinetic tremor that becomes very prominent near target, exhibiting a crescendo of increased severity at the terminal section i} of the i movement path. | L TABLE 38. Medications Causing Drug-Induced Action Tremor Medication Class Examples B-Adrenergic agonists Albuterol, terbutaline, theophylline Stimulants Amphetamines, methylphenidate, nicotine, caffeine Mood stabilizers/antiepileptic drugs Lithium, valproic acid, carbamazepine, lamotrigine Neuroleptic agents Haloperidol, olanzapine (postural and at rest) Tricyclic antidepressants Amitriptyline Selective serotonin reuptake inhibitors Fluoxetine Immunosuppressant agents Cyclosporine, tacrolimus Other agents Amiodarone, procainamide, mexiletine, levothyroxine, verapamil, atorvastatin, glucocorticoids, antihistamines 58

Movement Disorders TABLE 39. Classification of Dystonia limited to one side of the body. Generalized dystonias often start at a young age (<25 years) and have inherited, metabolic, Clinical Feature Subtype or vascular causes. The most common type of generalized Age of onset Infancy, childhood (<13 years), dystonia involves mutation in the dystonia 1 gene (DYT1). adolescence (13-18 years), young adulthood (18-40 years), late Patients with primary generalized dystonia should be chal- adulthood (>40 years) lenged by a short trial of levodopa to screen for dopa-respon- Temporal pattern Persistent, paroxysmal, action induced sive dystonia, a rare but treatable cause of generalized dysto-

TABLE 39. Classification of Dystonia limited to one side of the body. Generalized dystonias often start at a young age (<25 years) and have inherited, metabolic, Clinical Feature Subtype or vascular causes. The most common type of generalized Age of onset Infancy, childhood (<13 years), dystonia involves mutation in the dystonia 1 gene (DYT1). adolescence (13-18 years), young adulthood (18-40 years), late Patients with primary generalized dystonia should be chal- adulthood (>40 years) lenged by a short trial of levodopa to screen for dopa-respon- Temporal pattern Persistent, paroxysmal, action induced sive dystonia, a rare but treatable cause of generalized dysto- Associated Isolated dystonia (no other deficits), nia. Young adults with progressive dystonia should be screened neurologic features dystonia plus (with parkinsonism or for Wilson disease, especially in the presence of other associ- myoclonus) ated findings (such as tremor and parkinsonism). Anatomic Focal, segmental (contiguous regions), Focal adult-onset dystonias are often sporadic and distribution multifocal (noncontiguous regions), include cervical dystonia (spasmodic torticollis), eyelid dys- hemidystonia (affecting half of the body), generalized (trunk plus two tonia (blepharospasm), vocal cord spasmodic dysphonia, other regions) and task-specific hand dystonia (writer’s cramp). Cervical Paroxysmal Primary genetic paroxysmal dyskinesia dystonia often involves involuntary deviation of the head (kinesigenic, nonkinesigenic, exercise from the midline, an irregular head tremor that lessens induced, hypnogenic), secondary with positional changes (null point), and transient improve- paroxysmal dyskinesia (stroke, demyelination) ment of movements by specific sensory tricks (such as gen-

Associated Isolated dystonia (no other deficits), nia. Young adults with progressive dystonia should be screened neurologic features dystonia plus (with parkinsonism or for Wilson disease, especially in the presence of other associ- myoclonus) ated findings (such as tremor and parkinsonism). Anatomic Focal, segmental (contiguous regions), Focal adult-onset dystonias are often sporadic and distribution multifocal (noncontiguous regions), include cervical dystonia (spasmodic torticollis), eyelid dys- hemidystonia (affecting half of the body), generalized (trunk plus two tonia (blepharospasm), vocal cord spasmodic dysphonia, other regions) and task-specific hand dystonia (writer’s cramp). Cervical Paroxysmal Primary genetic paroxysmal dyskinesia dystonia often involves involuntary deviation of the head (kinesigenic, nonkinesigenic, exercise from the midline, an irregular head tremor that lessens induced, hypnogenic), secondary with positional changes (null point), and transient improve- paroxysmal dyskinesia (stroke, demyelination) ment of movements by specific sensory tricks (such as gen- Diurnal variation Dopa-responsive dystonia tly touching the face with the hand). Treatment includes i

Associated Isolated dystonia (no other deficits), nia. Young adults with progressive dystonia should be screened neurologic features dystonia plus (with parkinsonism or for Wilson disease, especially in the presence of other associ- myoclonus) ated findings (such as tremor and parkinsonism). Anatomic Focal, segmental (contiguous regions), Focal adult-onset dystonias are often sporadic and distribution multifocal (noncontiguous regions), include cervical dystonia (spasmodic torticollis), eyelid dys- hemidystonia (affecting half of the body), generalized (trunk plus two tonia (blepharospasm), vocal cord spasmodic dysphonia, other regions) and task-specific hand dystonia (writer’s cramp). Cervical Paroxysmal Primary genetic paroxysmal dyskinesia dystonia often involves involuntary deviation of the head (kinesigenic, nonkinesigenic, exercise from the midline, an irregular head tremor that lessens induced, hypnogenic), secondary with positional changes (null point), and transient improve- paroxysmal dyskinesia (stroke, demyelination) ment of movements by specific sensory tricks (such as gen- Diurnal variation Dopa-responsive dystonia tly touching the face with the hand). Treatment includes i } (better in morning) anticholinergic agents, benzodiazepines, baclofen, levo- dopa, injection with botulinum toxin, and, in refractory | Cause Example cases, DBS therapy. Genetic Autosomal dominant (DYT1, DYT6, ATP1A3), autosomal recessive (Wilson disease), X-linked (Lesch-Nyhan syndrome), mitochondrial (Leigh e Dystonia involves sustained or intermittent muscle con- syndrome) tractions leading to stereotyped and directional twisting Structural lesion Hemidystonia secondary to stroke, vascular malformation, or lesion in and posturing movements of various body parts. contralateral basal ganglia; e Treatment of cervical dystonia includes anticholinergic postencephalitis, posttraumatic, postanoxic agents, benzodiazepines, baclofen, levodopa, and injec- tion with botulinum toxin. Neurodegeneration Parkinson disease, Parkinson-plus syndromes, Huntington disease

} (better in morning) anticholinergic agents, benzodiazepines, baclofen, levo- dopa, injection with botulinum toxin, and, in refractory | Cause Example cases, DBS therapy. Genetic Autosomal dominant (DYT1, DYT6, ATP1A3), autosomal recessive (Wilson disease), X-linked (Lesch-Nyhan syndrome), mitochondrial (Leigh e Dystonia involves sustained or intermittent muscle con- syndrome) tractions leading to stereotyped and directional twisting Structural lesion Hemidystonia secondary to stroke, vascular malformation, or lesion in and posturing movements of various body parts. contralateral basal ganglia; e Treatment of cervical dystonia includes anticholinergic postencephalitis, posttraumatic, postanoxic agents, benzodiazepines, baclofen, levodopa, and injec- tion with botulinum toxin. Neurodegeneration Parkinson disease, Parkinson-plus syndromes, Huntington disease Perinatal brain Dystonia associated with cerebral Choreiform Disorders and Huntington Disease | injury palsy, delayed-onset dystonia Chorea manifests as random, nonrepetitive, flowing dance-like | Sporadic Adult-onset focal dystonia (torticollis, movements and can be caused by medications, endocrine blepharospasm, writer's cramp, derangement, streptococcal infection (as in Sydenham chorea musician's cramp, spasmodic dysphonia), Meige syndrome (facial in rheumatic fever), autoimmune disease, pregnancy and neu- and oromandibular segmental rodegenerative disorders involving the basal ganglia (Table 40). | dystonia) Patients with acute and subacute onset of chorea should be | Psychological Psychogenic dystonia assessed for reversible acquired causes, whereas a more insidi- Medications Neuroleptic-induced tardive dystonia, ous onset is typical of neurodegenerative disorders. The most antiemetic-induced acute dystonic common neurodegenerative cause of generalized chorea is reaction Huntington disease, an autosomal dominant condition marked by symptoms of progressive parkinsonism, gait Dystonia impairment, impulsiveness, psychiatric disease, dementia, Dystonia involves sustained or intermittent muscle contrac- and premature death. Symptomatic treatments of chorea tions leading to repetitive twisting and posturing movements of include the dopamine depleters valbenazine, deutetrabena- various body parts. Dystonias are classified according to age of zine, and tetrabenazine; antipsychotic agents; clonazepam;

Perinatal brain Dystonia associated with cerebral Choreiform Disorders and Huntington Disease | injury palsy, delayed-onset dystonia Chorea manifests as random, nonrepetitive, flowing dance-like | Sporadic Adult-onset focal dystonia (torticollis, movements and can be caused by medications, endocrine blepharospasm, writer's cramp, derangement, streptococcal infection (as in Sydenham chorea musician's cramp, spasmodic dysphonia), Meige syndrome (facial in rheumatic fever), autoimmune disease, pregnancy and neu- and oromandibular segmental rodegenerative disorders involving the basal ganglia (Table 40). | dystonia) Patients with acute and subacute onset of chorea should be | Psychological Psychogenic dystonia assessed for reversible acquired causes, whereas a more insidi- Medications Neuroleptic-induced tardive dystonia, ous onset is typical of neurodegenerative disorders. The most antiemetic-induced acute dystonic common neurodegenerative cause of generalized chorea is reaction Huntington disease, an autosomal dominant condition marked by symptoms of progressive parkinsonism, gait Dystonia impairment, impulsiveness, psychiatric disease, dementia, Dystonia involves sustained or intermittent muscle contrac- and premature death. Symptomatic treatments of chorea tions leading to repetitive twisting and posturing movements of include the dopamine depleters valbenazine, deutetrabena- various body parts. Dystonias are classified according to age of zine, and tetrabenazine; antipsychotic agents; clonazepam; onset, body distribution, temporal pattern, associated features, and antiepileptic drugs. and cause (Table 39). Dystonia is distinguished from chorea by the nonrandom and directional nature of its movements and e Huntington disease is an autosomal dominant condi- from myoclonus by its slower speed. Generalized dystonias tion marked by symptoms of progressive parkinsonism, involve multiple body parts, including the trunk, whereas focal gait impairment, impulsiveness, psychiatric disease, and segmental dystonias have a more restricted distribution and dementia. and usually spare the lower extremities. Hemidystonia is

onset, body distribution, temporal pattern, associated features, and antiepileptic drugs. and cause (Table 39). Dystonia is distinguished from chorea by the nonrandom and directional nature of its movements and e Huntington disease is an autosomal dominant condi- from myoclonus by its slower speed. Generalized dystonias tion marked by symptoms of progressive parkinsonism, involve multiple body parts, including the trunk, whereas focal gait impairment, impulsiveness, psychiatric disease, and segmental dystonias have a more restricted distribution and dementia. and usually spare the lower extremities. Hemidystonia is 59

Movement Disorders TABLE 40. Causes of Chorea Myoclonus | Cause Example Myoclonus is a brief, shock-like, jerky movement that can be physiologic (hiccups, hypnic jerks at sleep onset) or pathologic Medications Antipsychotic agents, estrogen- containing drugs, levodopa, (caused by medications, toxins, or systemic or central disease) amphetamines, methylphenidate, (Table 41). Myoclonus can originate from various parts of the lithium, phenytoin, opioids nervous system, including the cortex, subcortical structures, | Pregnancy Chorea gravidarum the spine, or peripheral nerves. Cortical myoclonus is often Endocrine Hyperglycemia (especially acute), | epileptic. Negative myoclonus is caused by sudden loss of mus- thyrotoxicosis | cle tone, as seen in asterixis and in the legs after hypoxia Infection Streptococcal (Sydenham chorea), | (Lance-Adams syndrome). Management of myoclonus prion disease, herpes encephalitis, HIV includes addressing the underlying systemic or toxic causes Autoimmune Systemic lupus erythematosus, and administering antimyoclonic agents, such as clonazepam antiphospholipid syndrome, anti-GAD | or valproic acid. antibody, celiac disease

| Cause Example Myoclonus is a brief, shock-like, jerky movement that can be physiologic (hiccups, hypnic jerks at sleep onset) or pathologic Medications Antipsychotic agents, estrogen- containing drugs, levodopa, (caused by medications, toxins, or systemic or central disease) amphetamines, methylphenidate, (Table 41). Myoclonus can originate from various parts of the lithium, phenytoin, opioids nervous system, including the cortex, subcortical structures, | Pregnancy Chorea gravidarum the spine, or peripheral nerves. Cortical myoclonus is often Endocrine Hyperglycemia (especially acute), | epileptic. Negative myoclonus is caused by sudden loss of mus- thyrotoxicosis | cle tone, as seen in asterixis and in the legs after hypoxia Infection Streptococcal (Sydenham chorea), | (Lance-Adams syndrome). Management of myoclonus prion disease, herpes encephalitis, HIV includes addressing the underlying systemic or toxic causes Autoimmune Systemic lupus erythematosus, and administering antimyoclonic agents, such as clonazepam antiphospholipid syndrome, anti-GAD | or valproic acid. antibody, celiac disease Paraneoplastic Anti-CRMP5 antibody, anti- NMDA antibody (orofacial and limb e Treatment of myoclonus includes addressing the under- dyskinesias), LGI1 antibody, CASPR2 antibody, IgLON5 antibody lying systemic or toxic causes and administering anti- myoclonic agents, such as clonazepam or valproic acid. Genetic Benign hereditary chorea, neuroferritinopathy

Paraneoplastic Anti-CRMP5 antibody, anti- NMDA antibody (orofacial and limb e Treatment of myoclonus includes addressing the under- dyskinesias), LGI1 antibody, CASPR2 antibody, IgLON5 antibody lying systemic or toxic causes and administering anti- myoclonic agents, such as clonazepam or valproic acid. Genetic Benign hereditary chorea, neuroferritinopathy Neurodegenerative — Huntington disease, Huntington-like Tic Disorders and Tourette Syndrome disease 2, spinocerebellar ataxia 17 Tics are stereotyped, rapid movements interrupting the flow of and 8, C9orf72 expansion syndrome, Friedreich ataxia, chorea- normal movements. Tics may provide transient relief in acanthocytosis, neurodegeneration response to premonitory unconformable sensations and are at with brain iron accumulation least partially suppressible. Tics usually start during childhood CASPR2 = contactin-associated protein 2; CRMPS5 = collapsin response mediator and subside during adulthood, but they may persist in a protein 5; GAD = glutamic acid decarboxylase; |IgLON5 = IgLON family member 5; LGI1 = leucine-rich, glioma inactivated 1; NUDA = N-methyl-D-aspartate. | minority of those affected. Waxing and waning of tics over time is common.

Neurodegenerative — Huntington disease, Huntington-like Tic Disorders and Tourette Syndrome disease 2, spinocerebellar ataxia 17 Tics are stereotyped, rapid movements interrupting the flow of and 8, C9orf72 expansion syndrome, Friedreich ataxia, chorea- normal movements. Tics may provide transient relief in acanthocytosis, neurodegeneration response to premonitory unconformable sensations and are at with brain iron accumulation least partially suppressible. Tics usually start during childhood CASPR2 = contactin-associated protein 2; CRMPS5 = collapsin response mediator and subside during adulthood, but they may persist in a protein 5; GAD = glutamic acid decarboxylase; |IgLON5 = IgLON family member 5; LGI1 = leucine-rich, glioma inactivated 1; NUDA = N-methyl-D-aspartate. | minority of those affected. Waxing and waning of tics over time is common. TABLE 41. Causes of Acquired Myoclonus Cause Example Features Metabolic Kidney, hepatic, or respiratory failure; sleep apnea; Both positive and negative myoclonus (asterixis) hyponatremia; hypocalcemia; hyperglycemia Endocrine Hyperthyroidism With tremor and ophthalmopathy Toxic Opioids, gabapentin, amiodarone, SSRIs, quinolone — Prominent in serotonin syndrome antibiotics, lamotrigine, phenytoin, lithium

Endocrine Hyperthyroidism With tremor and ophthalmopathy Toxic Opioids, gabapentin, amiodarone, SSRIs, quinolone — Prominent in serotonin syndrome antibiotics, lamotrigine, phenytoin, lithium Infectious Lyme disease, Whipple disease, viral encephalitis Oculomasticatory myorhythmia (rhythmic (especially herpes), prion disease movements of eye convergence with chewing) in Whipple Paraneoplastic Opsoclonus-myoclonus syndrome Anti-Ri antibody Autoimmune Celiac disease, associated with thyroid antibodies, With other symptoms, such as ataxia or DPPX antibody encephalitis encephalopathy Cortical pathology Epileptic myoclonus (primary and secondary Epileptic activity on EEG, giant somatosensory myoclonic epilepsies), posthypoxic myoclonus evoked potentials (Lance-Adams syndrome), corticobasal degeneration, advanced Alzheimer disease | Basal ganglia pathology Myoclonus dystonia Genetic, associated with dystonia, alcohol-sensitive | Brainstem pathology Brainstem reticular myoclonus Stimulus-sensitive (noise or action) myoclonus, coordinated flexion of trunk and limbs

| Basal ganglia pathology Myoclonus dystonia Genetic, associated with dystonia, alcohol-sensitive | Brainstem pathology Brainstem reticular myoclonus Stimulus-sensitive (noise or action) myoclonus, coordinated flexion of trunk and limbs | Cord pathology Segmental spinal myoclonus, propriospinal Jerks in limited myotomes (segmental) or spreading myoclonus, multiple sclerosis, cord tumor or trauma distally and proximally (propriospinal), associated with myelopathy signs | Peripheral nerve Hemifacial spasm Focal compression or irritation of the facial nerve pathology (cranial nerve VII) DPPX = dipeptidyl! peptidase-like protein 6; EEG = electroencephalography; SSRI = selective serotonin reuptake inhibitor. 60

Movement Disorders Tourette syndrome is characterized by childhood-onset restricted to patients with severe symptoms recalcitrant to motor and phonic tics with a duration of at least 1 year. other therapies. Physicians prescribing opioids for RLS should Phonic tics include vocalizations and, less commonly, echo- be adherent to the Centers for Disease Control and Prevention lalia (repetition of others’ words) and coprolalia (utterance of guideline for prescribing opioids (see MKSAP 19 General obscenities). Tic severity may range from minimal to very Internal Medicine 1). disruptive. Common comorbidities include attention-deficit Periodic limb movements of sleep are brief triple flexion hyperactivity disorder, obsessive compulsive disorder, and (ankle, knee, hip) movements of the legs that repeat in mood disorders. Diagnosis is clinical. Treatment options 20-second cycles during sleep. This disorder is very common include reassurance (in mild disease), cognitive behavioral and can occur independently of or be associated with RLS, therapy, and addressing psychiatric comorbidities. Anti-tic sleep-disordered breathing, or narcolepsy. The diagnosis is medications are indicated when tics interfere with daily made by using polysomnography. Treatment of this disorder functioning, education, or work. First-line treatments is only required if it causes marked sleep fragmentation. include clonidine, guanfacine, topiramate, levetiracetam, RBD is caused by loss of normal paralysis during the and tetrabenazine. In refractory disease, antipsychotic REM phase of sleep, leading to dream-enactment behavior. agents, injections with botulinum toxin, and DBS therapy Patients with this condition tend to shout, kick, punch, and may be considered. jump while dreaming. History is often obtained from a bed partner because patients do not recall their dream- enactment behavior. Diagnosis can be confirmed by poly- e Tics are stereotyped, rapid, partially suppressible move- somnography. Differential diagnosis includes nocturnal epi- ments interrupting the flow of normal movements and lepsy, and non-REM parasomnias. Isolated RBD has a high may provide transient relief in response to premonitory predictive value as a specific and early marker of future unconformable sensations. development of synuclein-related neurodegeneration, such e Tourette syndrome is characterized by childhood-onset as Parkinson disease, multiple system atrophy, or dementia motor and phonic tics with a duration of at least 1 year. with Lewy bodies. Patients with RBD are an appropriate target for potential disease-modifying interventions aimed at prevention of these disorders. RBD responds well to mela- Restless Legs Syndrome and Sleep-Related tonin and clonazepam. Movement Disorders Restless legs syndrome (RLS) is a common movement disor- der characterized by an urge to move the legs. Patients report e Patients with restless legs syndrome should be screened

Tourette syndrome is characterized by childhood-onset restricted to patients with severe symptoms recalcitrant to motor and phonic tics with a duration of at least 1 year. other therapies. Physicians prescribing opioids for RLS should Phonic tics include vocalizations and, less commonly, echo- be adherent to the Centers for Disease Control and Prevention lalia (repetition of others’ words) and coprolalia (utterance of guideline for prescribing opioids (see MKSAP 19 General obscenities). Tic severity may range from minimal to very Internal Medicine 1). disruptive. Common comorbidities include attention-deficit Periodic limb movements of sleep are brief triple flexion hyperactivity disorder, obsessive compulsive disorder, and (ankle, knee, hip) movements of the legs that repeat in mood disorders. Diagnosis is clinical. Treatment options 20-second cycles during sleep. This disorder is very common include reassurance (in mild disease), cognitive behavioral and can occur independently of or be associated with RLS, therapy, and addressing psychiatric comorbidities. Anti-tic sleep-disordered breathing, or narcolepsy. The diagnosis is medications are indicated when tics interfere with daily made by using polysomnography. Treatment of this disorder functioning, education, or work. First-line treatments is only required if it causes marked sleep fragmentation. include clonidine, guanfacine, topiramate, levetiracetam, RBD is caused by loss of normal paralysis during the and tetrabenazine. In refractory disease, antipsychotic REM phase of sleep, leading to dream-enactment behavior. agents, injections with botulinum toxin, and DBS therapy Patients with this condition tend to shout, kick, punch, and may be considered. jump while dreaming. History is often obtained from a bed partner because patients do not recall their dream- enactment behavior. Diagnosis can be confirmed by poly- e Tics are stereotyped, rapid, partially suppressible move- somnography. Differential diagnosis includes nocturnal epi- ments interrupting the flow of normal movements and lepsy, and non-REM parasomnias. Isolated RBD has a high may provide transient relief in response to premonitory predictive value as a specific and early marker of future unconformable sensations. development of synuclein-related neurodegeneration, such e Tourette syndrome is characterized by childhood-onset as Parkinson disease, multiple system atrophy, or dementia motor and phonic tics with a duration of at least 1 year. with Lewy bodies. Patients with RBD are an appropriate target for potential disease-modifying interventions aimed at prevention of these disorders. RBD responds well to mela- Restless Legs Syndrome and Sleep-Related tonin and clonazepam. Movement Disorders Restless legs syndrome (RLS) is a common movement disor- der characterized by an urge to move the legs. Patients report e Patients with restless legs syndrome should be screened an uncomfortable sensation that is worse at rest and at night for iron deficiency because iron supplementation in the

Tourette syndrome is characterized by childhood-onset restricted to patients with severe symptoms recalcitrant to motor and phonic tics with a duration of at least 1 year. other therapies. Physicians prescribing opioids for RLS should Phonic tics include vocalizations and, less commonly, echo- be adherent to the Centers for Disease Control and Prevention lalia (repetition of others’ words) and coprolalia (utterance of guideline for prescribing opioids (see MKSAP 19 General obscenities). Tic severity may range from minimal to very Internal Medicine 1). disruptive. Common comorbidities include attention-deficit Periodic limb movements of sleep are brief triple flexion hyperactivity disorder, obsessive compulsive disorder, and (ankle, knee, hip) movements of the legs that repeat in mood disorders. Diagnosis is clinical. Treatment options 20-second cycles during sleep. This disorder is very common include reassurance (in mild disease), cognitive behavioral and can occur independently of or be associated with RLS, therapy, and addressing psychiatric comorbidities. Anti-tic sleep-disordered breathing, or narcolepsy. The diagnosis is medications are indicated when tics interfere with daily made by using polysomnography. Treatment of this disorder functioning, education, or work. First-line treatments is only required if it causes marked sleep fragmentation. include clonidine, guanfacine, topiramate, levetiracetam, RBD is caused by loss of normal paralysis during the and tetrabenazine. In refractory disease, antipsychotic REM phase of sleep, leading to dream-enactment behavior. agents, injections with botulinum toxin, and DBS therapy Patients with this condition tend to shout, kick, punch, and may be considered. jump while dreaming. History is often obtained from a bed partner because patients do not recall their dream- enactment behavior. Diagnosis can be confirmed by poly- e Tics are stereotyped, rapid, partially suppressible move- somnography. Differential diagnosis includes nocturnal epi- ments interrupting the flow of normal movements and lepsy, and non-REM parasomnias. Isolated RBD has a high may provide transient relief in response to premonitory predictive value as a specific and early marker of future unconformable sensations. development of synuclein-related neurodegeneration, such e Tourette syndrome is characterized by childhood-onset as Parkinson disease, multiple system atrophy, or dementia motor and phonic tics with a duration of at least 1 year. with Lewy bodies. Patients with RBD are an appropriate target for potential disease-modifying interventions aimed at prevention of these disorders. RBD responds well to mela- Restless Legs Syndrome and Sleep-Related tonin and clonazepam. Movement Disorders Restless legs syndrome (RLS) is a common movement disor- der characterized by an urge to move the legs. Patients report e Patients with restless legs syndrome should be screened an uncomfortable sensation that is worse at rest and at night for iron deficiency because iron supplementation in the and is transiently relieved by movement. RLS can interfere presence of low-normal ferritin levels may resolve the

Tourette syndrome is characterized by childhood-onset restricted to patients with severe symptoms recalcitrant to motor and phonic tics with a duration of at least 1 year. other therapies. Physicians prescribing opioids for RLS should Phonic tics include vocalizations and, less commonly, echo- be adherent to the Centers for Disease Control and Prevention lalia (repetition of others’ words) and coprolalia (utterance of guideline for prescribing opioids (see MKSAP 19 General obscenities). Tic severity may range from minimal to very Internal Medicine 1). disruptive. Common comorbidities include attention-deficit Periodic limb movements of sleep are brief triple flexion hyperactivity disorder, obsessive compulsive disorder, and (ankle, knee, hip) movements of the legs that repeat in mood disorders. Diagnosis is clinical. Treatment options 20-second cycles during sleep. This disorder is very common include reassurance (in mild disease), cognitive behavioral and can occur independently of or be associated with RLS, therapy, and addressing psychiatric comorbidities. Anti-tic sleep-disordered breathing, or narcolepsy. The diagnosis is medications are indicated when tics interfere with daily made by using polysomnography. Treatment of this disorder functioning, education, or work. First-line treatments is only required if it causes marked sleep fragmentation. include clonidine, guanfacine, topiramate, levetiracetam, RBD is caused by loss of normal paralysis during the and tetrabenazine. In refractory disease, antipsychotic REM phase of sleep, leading to dream-enactment behavior. agents, injections with botulinum toxin, and DBS therapy Patients with this condition tend to shout, kick, punch, and may be considered. jump while dreaming. History is often obtained from a bed partner because patients do not recall their dream- enactment behavior. Diagnosis can be confirmed by poly- e Tics are stereotyped, rapid, partially suppressible move- somnography. Differential diagnosis includes nocturnal epi- ments interrupting the flow of normal movements and lepsy, and non-REM parasomnias. Isolated RBD has a high may provide transient relief in response to premonitory predictive value as a specific and early marker of future unconformable sensations. development of synuclein-related neurodegeneration, such e Tourette syndrome is characterized by childhood-onset as Parkinson disease, multiple system atrophy, or dementia motor and phonic tics with a duration of at least 1 year. with Lewy bodies. Patients with RBD are an appropriate target for potential disease-modifying interventions aimed at prevention of these disorders. RBD responds well to mela- Restless Legs Syndrome and Sleep-Related tonin and clonazepam. Movement Disorders Restless legs syndrome (RLS) is a common movement disor- der characterized by an urge to move the legs. Patients report e Patients with restless legs syndrome should be screened an uncomfortable sensation that is worse at rest and at night for iron deficiency because iron supplementation in the and is transiently relieved by movement. RLS can interfere presence of low-normal ferritin levels may resolve the with falling or staying asleep. Patients with RLS should be symptoms.

an uncomfortable sensation that is worse at rest and at night for iron deficiency because iron supplementation in the and is transiently relieved by movement. RLS can interfere presence of low-normal ferritin levels may resolve the with falling or staying asleep. Patients with RLS should be symptoms. screened for iron deficiency because iron supplementation ¢ The diagnosis of periodic limb movements of sleep is made in the presence of low-normal ferritin levels (15-75 ng/mL by using polysomnography; treatment is only required if {15-75 wg/L]) may resolve the symptoms. Supplementation the disorder causes marked sleep fragmentation. with intravenous ferric carboxymaltose is likely efficacious in idiopathic RLS, whereas efficacy of oral iron supplementa- tion remains unproven. Other risk factors for RLS include Other Drug-Induced Movements uremia, sleep apnea, pregnancy, and certain medications Tardive Dyskinesia (including selective serotonin reuptake inhibitors, antipsy- Tardive dyskinesia is an extrapyramidal complication of dopa- chotic agents, and stimulant drugs). Nonpharmacologic mine receptor-blocking medications (see Table 36). It is asso- measures include improvement of sleep hygiene, exercise, ciated with characteristic choreiform and dystonic craniofacial and the use of a vibrational device. First-line pharmacologic movements, which often involve other body parts, such as the treatments include the dopamine agonists pramipexole, rop- neck and trunk. Other movements, such as tremor, myo- inirole, and rotigotine. Additional options include levodopa, clonus, and akathisia (restlessness) also can be part of a tardive pergolide, gabapentin, gabapentin enacarbil, pregabalin, and syndrome. Treatment involves removal of the offending medi- opioid agonists (such as prolonged-release oxycodone-nalox- cation. Symptoms of dyskinesia, however, can take months to one and methadone). Chronic use of dopamine agonists, resolve or become permanent. Longer duration and higher however effective, may lead to either augmentation (that is, doses of medication exposure, older age, and female gender symptoms start earlier in the day) or rebound (that is, symp- increase the risk of irreversibility. Risk is highest with typical toms return with greater severity after the medication wears antipsychotic agents, but many atypical antipsychotic and off). Use of long-acting formulations can lessen both compli- antiemetic agents also can cause tardive dyskinesia. All cations. Nondopaminergic medications are another alterna- patients receiving these agents must be warned about the risk tive in patients with augmentation. Opioids are typically of this complication. Treatment includes the monoamine

screened for iron deficiency because iron supplementation ¢ The diagnosis of periodic limb movements of sleep is made in the presence of low-normal ferritin levels (15-75 ng/mL by using polysomnography; treatment is only required if {15-75 wg/L]) may resolve the symptoms. Supplementation the disorder causes marked sleep fragmentation. with intravenous ferric carboxymaltose is likely efficacious in idiopathic RLS, whereas efficacy of oral iron supplementa- tion remains unproven. Other risk factors for RLS include Other Drug-Induced Movements uremia, sleep apnea, pregnancy, and certain medications Tardive Dyskinesia (including selective serotonin reuptake inhibitors, antipsy- Tardive dyskinesia is an extrapyramidal complication of dopa- chotic agents, and stimulant drugs). Nonpharmacologic mine receptor-blocking medications (see Table 36). It is asso- measures include improvement of sleep hygiene, exercise, ciated with characteristic choreiform and dystonic craniofacial and the use of a vibrational device. First-line pharmacologic movements, which often involve other body parts, such as the treatments include the dopamine agonists pramipexole, rop- neck and trunk. Other movements, such as tremor, myo- inirole, and rotigotine. Additional options include levodopa, clonus, and akathisia (restlessness) also can be part of a tardive pergolide, gabapentin, gabapentin enacarbil, pregabalin, and syndrome. Treatment involves removal of the offending medi- opioid agonists (such as prolonged-release oxycodone-nalox- cation. Symptoms of dyskinesia, however, can take months to one and methadone). Chronic use of dopamine agonists, resolve or become permanent. Longer duration and higher however effective, may lead to either augmentation (that is, doses of medication exposure, older age, and female gender symptoms start earlier in the day) or rebound (that is, symp- increase the risk of irreversibility. Risk is highest with typical toms return with greater severity after the medication wears antipsychotic agents, but many atypical antipsychotic and off). Use of long-acting formulations can lessen both compli- antiemetic agents also can cause tardive dyskinesia. All cations. Nondopaminergic medications are another alterna- patients receiving these agents must be warned about the risk tive in patients with augmentation. Opioids are typically of this complication. Treatment includes the monoamine 61