Approach to the Hyperkinetic Patient



B.  Phenomenologic classification.


1.  Rest tremor. Tremor that occurs in a body part that is not voluntarily activated and is completely supported against gravity. Rest tremor amplitude always diminishes during target-directed movements, which helps to separate rest tremor from postural tremors that continue when the limb is supported. It increases with mental stress (counting backward), or when movements of another body part are performed (especially walking). It is mostly found in Parkinson’s disease (PD), but also in other parkinsonian syndromes, including drug-induced parkinsonism. Its presence indicates dysfunction of the nigrostriatal dopamine pathway or its efferent projections to basal ganglia-thalamo-cortical circuits.


2.  Action tremor. Any tremor that is produced by voluntary contraction of muscle, and it includes postural, simple kinetic, intention tremor, and task-specific kinetic tremor.


a.  Postural tremor. Tremor that is present while voluntarily maintaining a position against gravity. It is usually documented by having the patient outstretch the arms.


b.  Simple kinetic tremor. Tremor that occurs during voluntary action that is not target-directed.


c.  Intention tremor. Action tremor whose amplitude increases substantially during the pursuit of a target or goal. Its presence suggests a disturbance of the cerebellum or its afferent/efferent pathways.


d.  Task-specific kinetic tremor. Tremor that occurs during specific activities such as the primary writing tremor and occupational tremors. These tremors are often associated with dystonia.


C.  Etiologic classification.


1.  Physiologic and enhanced physiologic


2.  Hereditary (familial, fragile X-associated tremor/ataxia syndrome [FXTAS], Wilson’s disease, spinocerebellar ataxias [SCAs], hereditary hemochromatosis, and acute intermittent porphyria)


3.  Nonhereditary primary tremor: essential and orthostatic


4.  Degenerative: PD and other parkinsonisms


5.  Ischemic and posthypoxic


6.  Demyelinating disease


7.  Inflammatory, infectious, or immunologic: AIDS and brain abscesses


8.  Neuropathic


9.  Endocrinologic/metabolic: thyroid and hypoglycemia


10.  Posttraumatic


11.  Drug-induced or toxic: valproate acid, amlodipine, selective serotonin reuptake inhibitors (SSRIs), prednisone, cyclosporine A, and tacrolimus (also see section Tardive Syndromes)


D.  Pathophysiology. Tremor is not associated with any uniform brain lesion or clear histopathologic changes in the brain. However, two regions within the central motor pathways, the inferior olive and the relay nuclei of the thalamus, demonstrate oscillatory behavior, and their pharmacologic manipulation in the harmaline mouse model may produce or improve tremor. These regions are functionally interconnected with the cerebellum. Thus, the inferior olive, relay nuclei of the thalamus, and the cerebellum are the principal candidates for the origin of any pathologic central tremor.


E.  Selected clinical syndromes.


1.  Physiologic tremor is a low-amplitude and high-frequency (8 to 12 Hz) postural tremor that is most prominent in outstretched hands. It can be present in normal subjects but can be enhanced under certain circumstances, including fever, drugs, excited mental states, alcohol withdrawal, and caffeine use.


a.  Differential diagnosis.


(1)  Metabolic or endocrine derangements


(2)  Essential tremor


(3)  Cortical myoclonus


(4)  Drug-induced or withdrawal


(5)  Anxiety


b.  Evaluation.


(1)  Blood tests to rule out metabolic problems: hyperthyroidism, hypercorticism, hyperparathyroidism, hypocalcemia, hepatic encephalopathy, hypoglycemia, and pheochromocytoma


(2)  Review of medications (most common cause): thyroid drugs, corticosteroids, lithium, theophylline, 2-adrenergic receptor agonist, SSRIs, and sodium valproate


(3)  Assessment for anxiety


2.  Essential tremor is the most frequent neurologic disease causing tremor in the general population. It is an action tremor, mainly postural and kinetic. It is bilateral, largely symmetric, but it can be also asymmetric or even unilateral. The frequency is usually 4 to 12 Hz but may decrease with age. Conversely, amplitude increases during the follow-up. Its major clinical feature is postural tremor of the hands, but it can also be present in other body parts (distal legs, voice, and head). About 5% of patients may present with tremor almost exclusively in the head and voice. Improvement of tremor amplitude with alcohol is a characteristic feature of the disease but is not present for most patients.


Although most patients have strong family histories, and different gene loci (ETM1 on 3q13, ETM2 on 2p24.1, a locus on 6p23, Lingo-1 overexpression, and missense mutations in TENM4) have been identified in patients and families with the disorder, the cause of essential tremor is unclear. In recent years, systematic postmortem studies have shown essential tremor to be associated with clearly identifiable structural changes, including Purkinje’s cell loss, development of torpedoes in the cerebellum and, in some patients, deposition of Lewy bodies in the brainstem.


a.  Differential diagnosis.


(1)  Physiologic tremor (see above)


(2)  Metabolic or endocrine derangements


(3)  Wilson’s disease (when age of onset of essential tremor is under 40 years)


(4)  Rhythmic myoclonus and cortical tremor


b.  Evaluation.


(1)  Review medication and blood tests to rule out metabolic problems (see Section E.1 under Tremor).


(2)  Assess history of caffeine use, smoking, or alcohol withdrawal.


(3)  Evaluate serum ceruloplasmin to rule out Wilson’s disease (under 40 years).


3.  PD is the most frequent cause of rest tremor. It is typically defined by bradykinesia, rigidity, and impairment of postural reflexes. The neural correlates of rest tremor in PD are unknown, and the participation of other neurotransmitter systems apart from the dopaminergic dysfunction is likely. Parkinsonian tremor occurs at 3 to 7 Hz. It may be unilateral in the early stages of the disease, but it soon spreads to the contralateral side. Characteristically, it remains asymmetric through the course of the disease. Mental stress or movements of another body part (contralateral hand and gait) typically trigger the rest tremor or increase tremor amplitude. Parkinsonian tremor can be also present while maintaining a posture. Postural tremor in PD has been designated as a reemergent tremor, with a latency for the tremor to appear about 9 seconds, which is significantly longer than the latency observed in patients with essential tremor (1 to 2 seconds).


a.  Differential diagnosis.


(1)  Other parkinsonian syndromes: multisystem atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), dementia with Lewy bodies (DLB), Alzheimer’s disease (AD) with extrapyramidal features, and frontotemporal dementia with parkinsonism


(2)  SCA (SCA2, SCA3, SCA8, and SCA12)


(3)  Vascular parkinsonism


(4)  Drug-induced parkinsonism


(5)  Structural lesions involving the substantia nigra pars compacta


b.  Evaluation.


(1)  Review of drugs: dopamine receptor–blocking drugs (haloperidol, risperidone, olanzapine, and metoclopramide), calcium-channel blockers, and trimetazidine


(2)  Computed tomography (CT) scan or brain magnetic resonance imaging (MRI) to rule structural lesions involving the substantia nigra, basal ganglia, or diffuse cerebral white matter disease


(3)  Transcranial ultrasonography can show distinctive patterns in PD versus MSA, PSP, or CBD.


(4)  Dopamine transporter SPECT, a marker of the integrity of the presynaptic nigrostriatal pathway, is increasingly used to separate PD from vascular parkinsonism, essential tremor, or psychogenic parkinsonism


4.  Cerebellar tremor is clinically defined by pure or dominant intention tremor. It may be uni- or bilateral. Postural tremor may be present, but no rest tremor. Typically, tremor frequency is below 5 Hz. Cerebellar tremor is often associated with dysmetria (finger-to-nose and heel-to-shin testing maneuvers) and hypotonia. This kind of tremor can be considered a symptomatic tremor produced by any disease that affects the functionality of the cerebellum or its afferent/efferent pathways.


a.  Differential diagnosis.


(1)  Alcohol or drug abuse


(2)  Drug-induced


(3)  Multiple sclerosis


(4)  SCA, autosomal-recessive hereditary ataxias, and FXTAS


(5)  Space-occupying mass, or an ischemic, toxic, or infectious disorder in the brainstem, the cerebellum, or the frontal lobes (due to diaschisis)


b.  Evaluation.


(1)  Brain MRI to rule out structural lesions in the posterior fossa or the frontal lobes


(2)  Review of drugs: phenytoin, carbamazepine, and phenobarbital


5.  Holmes’ tremor is clinically defined by rest and intention tremor, with postural tremor present in many patients. It is mostly unilateral. Postural tremor tends to be more severe than tremor at rest, and intention tremor more severe than the postural tremor. Tremor frequency is usually <4.5 Hz. This is also a symptomatic tremor that occurs after a brainstem, midbrain, or thalamic lesion, when two systems, the dopaminergic nigrostriatal system and the cerebellothalamic system, are lesioned. A variable delay (4 weeks to 2 years) between the lesion and the appearance of the tremor is typical.


a.  Differential diagnosis and evaluation (see Section E.4 under Tremor).


b.  Treatment. Holmes’ tremor and thalamic tremor do not usually respond to pharmacologic treatments. Although the effects of thalamic deep brain stimulation in the ventral intermediate nucleus are incomplete, functional surgery in complex tremor syndromes appears as the only available therapeutic option and provides significant and lasting functional improvement.


6.  FXTAS. Over the past decade, it has been shown that premutation carriers (especially males) of the FMR1 mutation (55 to 200 CGG repeats) are at risk of developing the FXTAS. Core clinical features of FXTAS are progressive cerebellar gait ataxia, mild parkinsonism, autonomic dysfunction, peripheral neuropathy, and intention tremor. Postural and rest tremor may be also present. FXTAS is often misdiagnosed as essential tremor and PD. As the diagnosis of FXTAS has substantial implications regarding genetic counseling, it is important to consider FXTAS as a cause of tremor when ataxic symptoms are also present image(Videos 28.1 and 28.2).


a.  Differential diagnosis.


(1)  Essential tremor


(2)  PD


(3)  Atypical parkinsonian disorders (MSA, PSP, and CBD)


(4)  SCAs and other hereditary ataxic syndromes


(5)  DLB


b.  Evaluation.


(1)  The presence of combined essential-like tremor, along with gait ataxia or parkinsonism in an adult (usually male) with a grandchild with intellectual disability, should prompt genetic testing for FXTAS.


DYSTONIA


A.  Definition. Dystonia is a syndrome characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Dystonic contractions are mainly characterized by the following:


1.  Consistent directionality. The movements are patterned and repeatedly involve the same muscle groups.


2.  Aggravation by voluntary movement (action exacerbation). Dystonia may be also triggered by particular actions such as writing or playing a musical instrument (task-specific dystonia).


3.  Presence of a “sensory trick,” the use of a tactile or proprioceptive stimulus, generally in some particular spot in the same area where the dystonic movements are present, which can improve the muscle contractions.


B.  Phenomenologic classification.


1.  Focal. The abnormal movements affect single body region such as cervical dystonia, blepharospasm, spasmodic dysphonia, oromandibular dystonia, or brachial dystonia.


2.  Segmental. The abnormal movements affect two or more contiguous body parts, as in Meige’s syndrome (blepharospasm plus oromandibular dystonia), craniocervical dystonia, or bibrachial dystonia.


3.  Multifocal. Two or more noncontiguous body areas are involved.


4.  Hemidystonia. The abnormal movements affect one side of the body.


5.  Generalized. Abnormal movements are present in the legs (or in one leg and the trunk) plus at least one other area of the body.


C.  Classification by age of onset.


1.  Early-onset. ≤26 years.


2.  Late-onset. >26 years.


D.  Etiologic classification.


1.  Primary, or idiopathic, dystonia.


a.  Primary torsion dystonia (PTD). DYT1 (Oppenheim’s dystonia), DYT2, DYT4, DYT6, DYT7, and DYT13


2.  Secondary dystonia.


a.  Dystonia-plus syndromes. Dystonic syndromes with other neurologic features in addition to dystonia, in which clinical and laboratory findings suggest neurochemical disorders, with no evidence of neurodegeneration.


(1)  Dopa-responsive dystonias (DRDs)


(a)  Segawa’s disease (DYT5) = GTP cyclohydrolase 1 deficiency


(b)  Tyrosine hydroxylase deficiency, other biopterin deficiencies, and dopamine-agonist-responsive dystonia due to deficiency of aromatic l-amino acid decarboxylase


(2)  Myoclonus-dystonia (DYT11)


(3)  Rapid-onset dystonia-parkinsonism (DYT12)


b.  Associated with heredodegenerative. Neurodegenerative diseases in which dystonia is sometimes a prominent feature


(1)  Huntington’s disease (HD), pantothenate kinase-associated neurodegeneration (PKAN—formerly known as Hallervorden–Spatz disease), neuroacanthocytosis, SCA, dentatorubropallidoluysian atrophy, and mitochondrial diseases associated with parkinsonian disorders (PD, CBD, PSP, and MSA)


c.  Acquired dystonia. When dystonic movements are symptomatic of an exogenous or environmental cause


(1)  Main causes. Cerebrovascular diseases, central nervous system (CNS) tumor, central trauma, infectious or postinfectious encephalopathies, toxins (CO and manganese), metabolic diseases (Wilson’s disease and GM1 gangliosidosis), paraneoplastic syndromes, perinatal anoxia, kernicterus, and peripheral trauma


E.  Pathophysiology. Dystonia is attributed to basal ganglia abnormalities and to a dysfunction of the cortico-striatothalamo-cortical circuits. Idiopathic dystonia is not associated with any particular structural brain lesion. However, neurophysiologic and neuroimaging techniques have shown a correlation between the cocontraction and overflow of electromyogram (EMG) activity of inappropriate muscles, with reduced pallidal inhibition of the thalamus due to lower firing rates, large sensory receptive fields, and irregular discharges in bursts or groups of bursts in neurons of the medial globus pallidus. Supporting the theory of basal ganglia dysfunction, secondary dystonia is mostly observed in patients with lesions of the putamen and connections with the thalamus and cortex.


F.  Selected clinical syndromes.


1.  PTD. It refers to those syndromes in which dystonia is the only phenotypic manifestation (except for tremor). In cases of PTD, there is no history of brain injury, no laboratory findings exclusive of genetic tests to suggest a cause for dystonia, no consistent associated brain pathology, and no improvement with a trial of low-dose levodopa. Some of these cases can be attributed to a genetic cause. Early-onset PTD (Oppenheim’s dystonia) is inherited as an autosomal-dominant trait with reduced penetrance (30% to 40%). The genetic mutation for the most frequent and severe form of early-onset PTD, named DYT1, was mapped to chromosome 9q34, which encodes the protein TORSIN, whose function remains unknown. The disorder develops before 26 years of age in nearly all cases. It normally begins in one arm or a leg, and spreads to other limbs and trunk, leading to the most severe generalized form of the disease in most cases. Selective or pronounced craniocervical or orofacial involvement is unusual. Conversely, late-onset PTD (>26 years—DYT4, DYT6) normally involves the upper part of the body (cranial–cervical region) and usually remains focal or segmental. In spite of this archetypical pattern, dystonia may remain localized as writer’s cramp in some patients with early-onset PTD.


a.  Differential diagnosis.


(1)  Perinatal hypoxia


(2)  Head trauma


(3)  DRD


(4)  Wilson’s disease


(5)  PKAN and neuroferritinopathy


(6)  Other metabolic disorders. Glutaric acidemia type 1, GM1 and GM2 gangliosidosis, metachromatic leukodystrophy, sialidosis, Krabbe’s disease, Niemann–Pick type C (NPC), vanishing white matter disease, and biotinidase deficiency


(7)  HD (Westphal’s variant)


(8)  Ataxia telangiectasia


(9)  Leigh’s syndrome


b.  Evaluation.


(1)  Brain MRI


(a)  Primary dystonia usually has normal MRI.


(b)  “Eye of the tiger” sign (globus pallidus central hyperintensity with surrounding hypointensity on T2-weighted images) is due to iron deposition in the globus pallidus and very suggestive of PKAN.


(c)  Wilson’s disease has also distinctive neuroimaging findings, with T2-weighted globus pallidal hypointensity, T2-weighted “face of giant panda” sign (hyperintensity of the midbrain, hypointensity of the aqueduct, and relative sparing of red nucleus, superior colliculus, and substantia nigra pars reticulata), and T1-weighted striatal hyperintensity (bilateral thalamus and lenticular nucleus).


(2)  Patients with onset before 26 years of age should be always considered for trial of low-dose levodopa, to exclude DRD.


(3)  Wilson’s disease. To exclude this disorder, slit-lamp eye examination for Kayser–Fleischer rings and determination of serum ceruloplasmin level should be performed in dystonia patients younger than 50 years.


(4)  Screening of metabolic inherited diseases, when atypical features of DYT1 are present (bulbar and orofacial symptoms, cognitive impairment, behavioral disturbances, and polyneuropathy)


(5)  Patients with onset before 26 years of age should be considered for genetic testing for the DYT1 gene. A detailed family history should be obtained.


2.  Focal dystonia.


a.  Blepharospasm is a disorder that consists of uncontrollable involuntary spasms of the eyelids causing spontaneous closure. It often interferes with vision, resulting in functional blindness. It may be worsened by bright light or stress.


b.  Oromandibular dystonia consists of grimacing of the lower part of the face, usually involving the mouth, jaw, and platysma muscle. Depending on the nature of the oromandibular movements, jawclosing, jaw opening, and jaw deviation oromandibular dystonias are differentiated.


c.  Cervical dystonia or spasmodic torticollis consists of intermittent uncontrollable spasms of the neck muscles. The neck may involuntarily turn, tilt, or rotate forward, sideways, or backward.


d.  Spasmodic dysphonia involves only the vocal cords. There are two types of spasmodic dysphonia. With adductor-type spasmodic dysphonia, hyperadduction of the cords produces an intermittent strain and strangle quality to the voice. Often patients also report tightness in the throat during the spasms. With the rarer abductor type of spasmodic dysphonia, there is a whispering quality to the voice.


e.  Task-specific dystonia. The dystonic movements are brought out by performing a specific task such as writing, typing, or playing a musical instrument. Writer’s cramp is the most common and most underdiagnosed form of limb dystonia. Examples of task-specific dystonia include a secretary who has dystonic hand cramps only while typing, and a violinist who has finger spasms only while playing.


(1)  Differential diagnosis of focal dystonia.


(a)  Drug-induced (most common cause of secondary focal dystonia)


(b)  Pseudodystonias


(1)  Sandiffer’s syndrome. Torticollis and paroxysmal dystonic postures induced by gastroesophageal reflux


(2)  Posterior fossa tumors


(3)  Chiari’s malformation


(4)  Atlantoaxial subluxation


(c)  Structural lesions involving the basal ganglia, thalamus, brainstem, or the cervical spinal cord (ischemic, demyelinating, inflammatory, infectious, immunologic lesion, and space-occupying mass)


(2)  Evaluation.


(a)  Review of medication record for dopamine receptor–blocking drugs (metoclopramide, clebopride, haloperidol, risperidone, and tiapride), flupenthixol, melitracene, antidizziness drugs (tietilperazine, sulpiride, and veralipride).


(b)  MRI of the brain including the posterior fossa and the cervical spinal cord. To rule out structural lesions, or images suggestive of metabolic inherited disorders, or of neurodegeneration with brain iron accumulation (PKAN and neuroferritinopathy).


3.  Acquired dystonia. These disorders relate usually to lesions in the CNS, mostly in the basal ganglia, although peripheral trauma in the neck or limbs can result in dystonic posturing of that body part. Stroke, CNS tumor or demyelinating disease, perinatal anoxia, and trauma are the most frequent causes of acquired dystonia. Acquired dystonia typically involves one side of the body (hemidystonia) or only one extremity and may be accompanied by impairment of different neural systems: weakness, sensory disturbances, or pyramidal signs. Peripherally induced dystonia may show atypical dystonic features, such as fixed postures and maintenance of dystonia during sleep, and a worse response to botulinum toxin than seen with other acquired forms.


a.  Evaluation. MRI of the brain including the posterior fossa and the cervical spinal cord to rule out structural lesions


4.  Wilson’s disease. It is the most common known metabolic defect causing secondary dystonia. It is an inherited deficit in copper metabolism.


a.  Differential diagnosis and evaluation (see Section F.1 under Dystonia).


(1)  Neurologic symptoms affecting the basal ganglia, including bradykinesia, dysarthria, dystonia, tremor, ataxia, and abnormal gait, occur in 40% to 60% of patients. Spasmodic dysphonia is a common feature.


(2)  Wing-beating tremor is classically described in patients with Wilson’s disease (55%). This tremor is absent at rest and develops after the arms are extended. Rest tremor may also be present in 5% of the patients.


(3)  Psychiatric symptoms (65%) (psychosis, depression, irritability, agitation, and disinhibition), mild cognitive impairment (70%), and dementia (5%) can be associated with the motor manifestations.


Early treatment can reverse the liver involvement in Wilson’s disease and stop the neurologic impairment.


5.  DYT6. Mutations in the THAP1 gene have been identified as a cause of autosomal-dominant primary dystonia. Families described over the past years have shown the clinical picture of DYT6 patients to be heterogeneous, but some features can help to distinguish them from DYT1 mutation carriers. The combination of cervical, upper limb, or generalized progressive dystonia with spasmodic laryngeal dystonia or oromandibular involvement may guide the clinician to the diagnosis.


6.  Dopa-responsive dystonia—DYT5. This childhood-onset disease usually begins with leg dystonia that gradually progresses to other parts of the body. Typical features are a diurnal fluctuation of the symptoms, so that they worsen as the day progresses or after intense exercise, and they improve after sleep. Patients may also show extensor plantar responses with hyperreflexia in the lower limbs, tremor, and parkinsonism. The most characteristic feature of DRD is a dramatic and sustained response to low-dose levodopa, without the typical complications of motor fluctuations and dyskinesias.


7.  Myoclonus-dystonia (DYT11). This disorder is characterized by involuntary jerks and dystonic movements and postures, both of which may be dramatically alleviated with alcohol. It normally begins in the first or second decade of life (5 to 18 years), with myoclonic jerks and dystonic movements most frequently involving the arms, neck, and face. Although spread to axial muscles and the legs is typical, the condition is compatible with an active life of normal span. Obsessive-compulsive disorder, anxiety/panic/phobic disorders, and alcohol dependence are frequently associated with the motor manifestations.


8.  Rapid-onset dystonia-parkinsonism (DYT12). This very rare condition involves dystonic spasms, bradykinesia, postural instability, severe dysarthria, and dysphagia that develop abruptly over a period ranging from several hours to weeks. Some patients report specific triggers consisting of either physical or psychological stress. There is little response to dopaminergic drugs, and the neurologic sequelae remain stable over time.


9.  Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis. Encephalitis due to NMDA receptor antibodies has been recently associated with the development of jaw opening and other orofacial dystonias. Distonic movements have been reported in combination with opisthotonic posturing, seizures, psychosis, and other behavioral changes. Anti-NMDA receptor antibodies have been even found to cause isolated hemidystonia. As NMDA receptors are present in the neuronal membrane, discovery and treatment of neoplasias producing anti-NMDA receptor antibodies (ovarian and mediastinic teratoma, breast cancer, and pancreatic cancer), and immunotherapy can improve and even resolve the neurologic condition.


10.  NPC. Some neurometabolic disorders may be treatable. In these cases, early diagnosis may slow the degenerative process or even halt the process. Patients with the adult form of NPC, which usually start between the third and fifth decades of life, have specific clinical features very useful in the differential diagnosis of secondary dystonias. The combination of bibrachial dystonia with facial dystonia (‘facial grimacing’), ataxia, and supranuclear vertical gaze palsy usually precede the development of more severe features of the disease like schizophrenia-like symptoms and dementia. NPC can be diagnosed by genetic testing or the Filipin test (analysis of cholesterol perinuclear vesicles in skin fibroblasts culture).


CHOREA


A.  Definition. Chorea is characterized by arrhythmic involuntary movements resulting from a continuous flow of random muscle contractions. When choreic movements are more severe, assuming a large amplitude and sometimes violent character, they are called ballism. Although typical choreic movements are predominantly distal, ballistic movements are more proximal. Athetosis is a related writhing and twisting movement that manifests predominantly in distal arms. Regardless of its cause, chorea has very distinctive clinical features. The differential diagnosis of choreic syndromes relies on differences in the presence of other accompanying findings.


B.  Etiologic classification.


1.  Genetic choreas.


a.  HD


b.  Huntington’s disease–like 2 (HDL2) and other HD-like symptoms


c.  Neuroacanthocytosis (chorea-acanthocytosis, X-linked McLeod syndrome)


d.  PKAN


e.  Neuroferritinopathy


f.  Ataxia telangiectasia


g.  SCA, types 2, 3, or 17


h.  Dentatorubropallidolyusian atrophy


i.  Benign hereditary chorea


j.  Paroxysmal kinesigenic choreoathetosis


k.  C9orf72 hexanucleotide expansion: recent studies have indicated that this is the most common genetic cause of HD phenocopies


2.  Structural basal ganglia lesions.


a.  Vascular chorea in stroke


b.  Hemodynamic ischemia secondary to carotid stenosis


c.  Mass lesions (lymphoma and metastatic brain tumors)


d.  Multiple sclerosis plaques


e.  Extrapontine myelinolysis


f.  Polycythemia vera (generally not related to focal vascular lesions in the basal ganglia)


g.  Moyamoya disease


h.  Postpump chorea (generalized chorea immediately after extracorporeal circulation. Benign prognosis with spontaneous remission in most cases.)


3.  Parainfectious and autoimmune disorders.


a.  Sydenham’s chorea


b.  Systemic lupus erithematosus (SLE)


c.  Chorea gravidarum (chorea during pregnancy)


d.  Antiphospholipid antibody syndrome


e.  Behçet’s disease


f.  Postinfectious or postvaccinal encephalitis


g.  AntiGAD65, antiLGi1 antibodies


h.  Paraneoplastic choreas (anti-CV2/CRMP5, antiCASPR2, or anti-Hu antibodies, associated with small-cell lung cancer, Hodgkin’s lymphoma, or thymoma)


4.  Infectious chorea. HIV primoinfection, toxoplasmosis, cysticercosis, diphtheria, infective endocarditis, neurosyphilis, viral encephalopathies (mumps, measles, and varicella), herpes simplex, and parvovirus B19


5.  Metabolic or toxic encephalopathies.


a.  Hyperglycemic-induced hemichorea–hemiballismus


b.  Acute intermittent porphyria


c.  Hyponatremia/hypernatremia


d.  Hyperthyroidism


e.  Hypoparathyroidism


f.  Hepatic/renal failure


g.  CO, manganese, mercury, and organophophorate intoxication


h.  Hyperhomocysteinemia ± vitamin B12 deficiency


6.  Drug-induced chorea.


a.  Antiparkinsonian drugs. l-Dopa and dopamine agonists


b.  Dopamine receptor–blocking agents (chronic exposure)


c.  Antiepileptic drugs. Phenytoin, carbamazepine, valproic acid, and gabapentin


d.  Psychostimulants and other drugs. Amphetamines, cocaine, heroin, and methylphenidate


e.  Methadone


f.  Calcium-channel blockers. Cinnarizine, flunarizine, and verapamil


g.  Oral contraceptives (likely to induce chorea in patients with previous choreic episodes—such as SLE or Sydenham’s chorea)


h.  Steroids


i.  Antihistamine drugs


j.  Others. Lithium, baclofen, digoxin, tryciclic antidepressants, cyclosporine, theophylline, ribavirine, and α -interferon


C.  Pathophysiology. Chorea results from facilitation of the striato-pallido-thalamic output pathway, leading to thalamo-cortical disinhibition of previously learned and patterned movements. This failure of control comes from dysfunction of neural networks in the basal ganglia that are interconnected with the motor cortical areas. Neurophysiologic and lesional studies and cases of chorea in patients with focal lesions in the basal ganglia have shown that failure of inhibition of movements relates mainly to dysfunction of the caudate nucleus and the subthalamic nucleus.


D.  Selected clinical syndromes.


1.  HD is an autosomal-dominant progressive neurodegenerative disease characterized by chorea, dystonia, loss of balance, cognitive decline, and behavioral changes. Neurodegeneration primarily affects the head of the caudate nucleus and the frontal cortex. The genetic disorder is caused by a trinucleotide (CAG) repeat expansion in the gene encoding huntingtin on chromosome 4p16.3. Polyglutamine expansions are the main component of Huntington that lead to neuronal degeneration, a pattern also seen in several SCA. Healthy individuals have fewer than 35 CAG repeats, and repeats of 40 or above cause HD with 100% penetrance. Individuals with 36 to 39 repeats can develop the disease, but penetrance is incomplete image(Videos 28.3, 28.4, 28.5, and 28.6).


The mean age at onset is 40 years. Although chorea is the main feature of the disease, the full spectrum of motor impairment includes eye-movement abnormalities, parkinsonism, dystonia, myoclonus, tics, cerebellar ataxia, spasticity with hyperreflexia, dysarthria, and dysphagia. Features of chorea are very variable, but choreic orofacial movements and mild slow, sinusoidal, and flowing distal movements in the four extremities are very common in the early stages of the disease. With progressing illness, dystonia and parkinsonism may become the main motor features. Behavioral and cognitive impairment affect almost all patients, with depression, anxiety, apathy, irritability, agitation, obsessive-compulsive symptoms, and social disinhibition accounting for the most frequent disorders. Young-onset disease (<20 years, so-called Westphal’s variant) is associated with >55 CAG repeats and is characterized by predominant dystonic symptoms, myoclonus, parkinsonism, and seizures.


2.  Sydenham’s chorea. It is the most common cause of acute chorea in children worldwide. It has a female preponderance, and the typical age of onset is 8 to 9 years. Sydenham’s chorea represents the prototype of chorea resulting from immune mechanisms, related to rheumatic fever. Up to 25% of patients with rheumatic fever develop generalized chorea 4 to 8 weeks after an episode of b -hemolytic streptococcal pharyngitis, although it can be manifested as hemichorea in 20% of patients. Molecular similarities between streptococcal and basal ganglia antigens seem to be the main pathogenetic mechanism leading to chorea.


Chorea is frequently accompanied by hypotonia, tics, motor impersistence, and behavioral abnormalities (attention-deficit hyperactivity disorder [ADHD] and obsessive-compulsive symptoms). Mitral valvulopathy is also present in up to 60% to 80%. Sydenham’s chorea has a good prognosis. Spontaneous remission often occurs after 8 to 9 months, although in 50% of patients some chorea may persist after 2 years, and recurrences may appear. A medical history of Sydenham’s chorea seems to be a risk factor of development of chorea gravidarum or chorea related to use of oral contraceptives or antiepileptic drugs.


3.  Chorea-acanthocytosis (ChAc), also known as neuro-acanthocytosis. This autosomal-recessive disease is characterized by generalized chorea and severe orofacial dystonia with tongue and lip biting that produce orofacial self-mutilations. Neuropathy, subclinical or mild myopathy, and seizures, along with hepatic disease, are common associated features. X-linked inherited McLeod’s syndrome has indistinguishable clinical findings, with otherwise less frequent orofacial dystonia, and more frequent seizures and severe hepatic failure.


4.  PKAN. This disorder has onset during childhood, with the hallmarks of chorea and generalized dystonia that typically affect bulbar and orofacial muscles, with speech difficulties as a prominent clinical feature. Chorea and dystonia are associated with cognitive impairment and behavioral disorders, parkinsonian, and pyramidal tract features.


5.  Hyperglycemic-induced hemichorea–hemiballismus. This condition occurs mostly in women, ranging from 50 to 80 years of age, and chorea develops in association with nonketotic hyperglycemia in type 2 diabetes mellitus. Patients usually have no previous history of diabetes mellitus but develop choreic or ballistic movements on one side of the body, in the setting of elevated serum glucose levels (range of 400 to 1,000 mg/dL). CT scans may reveal a hyperdense lesion involving the right caudate and lentiform nucleus, but sparing the internal capsule, without mass effect. MRI scans reveal hyperintensity and hypointensity in the same structures in T1- and T2-weighted images, respectively. In most patients, lowering serum glucose levels to the normal range completely reverses the movements within 24 to 48 hours. In some cases, however, chorea persists after correction of the metabolic abnormality.


E.  Differential diagnosis and evaluation. Although classification of chorea is based on etiology, differential diagnosis and evaluation of choreic patients are based primarily on age of onset.


1.  Adult-onset chorea.


a.  Positive family history.


(1)  Genetic testing for HD. Up to 25% of newly diagnosed HD patients have a negative family history because of nonpaternity or ancestral death before disease manifestation.


SCA2, SCA3, and SCA17, neuroferritinopathy, and C9orf72 hexanucleotide expansions must be considered when genetic testing for HD is negative.


(2)  Wilson’s disease. See Section F.1.b under Dystonia.


b.  No family history.


(1)  MRI scan should be done in all cases to exclude vascular, neoplastic, infectious, or inflammatory pathology in the basal ganglia or adjacent structures.


(2)  Rule out other causes of chorea.


(a)  Pregnancy testing


(b)  Review of medication record and drug abuse (see classification)


(c)  Metabolic and autoimmune disorders. Blood testing considering SLE, antiphospholipid antibody syndrome, thyrotoxicosis, or other metabolic disorders (see classification)


(d)  Polycythemia must be considered, especially in the elderly. Chorea associated with polycythemia seems to be related to blood hyperviscosity throughout the brain. Chorea may be the presenting symptom of polycythemia or a sign of hematologic deterioration of the disease. Therapy with repeated phlebotomies may be an effective treatment of chorea in this condition.


(e)  Diagnosis of ChAc must be suspected in young-adult patients with suggestive symptoms, even in the absence of family history. Analysis of acanthocytes in fresh blood samples has very low sensitivity, and repeated measurements must be done. Recently, determination of chorein in peripheral blood samples offers a markedly higher sensitivity and specificity for the diagnosis of ChAc. Western blot detection of chorein strongly supports the clinical diagnosis of ChAc when chorein is low or absent in the erythrocyte membrane.


2.  Childhood-onset chorea.


a.  Positive family history.


(1)  Wilson’s disease. See Section F.1.b under Dystonia.


(2)  Genetic testing for HD


(3)  Genetic testing for benign hereditary chorea, usually associated with slowly progressive ataxia, should be investigated.


(4)  When there is a history of progressive cerebellar ataxia and choreoathetosis, with and without ocular motor apraxia, ataxia telangiectasia should be ruled out by measuring fetoprotein in serum, even if telangiectasias are not observed in the conjunctiva, oral mucosa, or the skin.


(5)  Acanthocytes in blood testing. As acanthocytes are not specific of neuroacanthocytosis (also present in 10% of HDL2 and PKAN patients), they will not be ordered if neuroacanthocytosis is not clinically suspected.


b.  No family history.


(1)  MRI scan


(2)  Sydenham’s chorea. Antistreptolysin-O may be increased, but due to the long latency between streptococcus infection and the onset of chorea, most laboratory tests indicative of preceding streptococcal infection are not useful. Anti-DNase-B titers may be increased up to 1 year after the infection. Echocardiography may be very useful in supporting the diagnosis, when mitral valvulopathy is detected.


(3)  Rule out other autoimmune disorders like SLE and infectious chorea associated with viral (mumps, measles, and varicella) or postvaccination encephalitis.


MYOCLONUS


A.  Definition. Myoclonus is a clinical sign defined as sudden, brief, lightening-like, involuntary movements caused by muscular contractions or inhibitions. Muscular contractions produce so-called positive myoclonus, whereas muscular inhibitions produce negative myoclonus or asterixis.


B.  Etiologic classification. In clinical practice, treatment of myoclonus is mainly based on the treatment of the underlying disorder. However, it can also be classified according to examination findings or neurophysiologic testing.


1.  Physiologic myoclonus. Sleep jerks, anxiety induced, exercise induced, hiccups (singultus), and benign infantile myoclonus with feeding


2.  Palatal myoclonus. Idiopathic or symptomatic


3.  Epileptic myoclonus. Seizures dominate the disease.


a.  Epilepsia partialis continua


b.  Idiopathic stimulus-sensitive myoclonus


c.  Myoclonic absences in petit mal epilepsy


d.  Childhood myoclonic epilepsy. Lennox–Gastaut syndrome, Aicardi’s syndrome, and juvenile myoclonic epilepsy (awakening myoclonus epilepsy of Janz)


4.  Progressive myoclonus encephalopathies.


a.  Baltic myoclonus (Unverricht–Lundborg disease)


b.  Neuronal ceroid lipofuscinoses (Kufs disease)


c.  Sialidosis. cherry-red spot myoclonus


d.  Lafora body disease


e.  PRICKLE-2-related progressive myoclonus epilepsy with ataxia


5.  Symptomatic or secondary myoclonus.


a.  Metabolic. Hyperthyroidism, hepatic failure, renal failure, dialysis syndrome, ion alterations (Na+, K+, Ca+2, and Mg+2), hypoglycemia, nonketotic hyperglycemia, metabolic acidosis, or alkalosis


b.  Myoclonus in the setting of renal failure. Uremic encephalopathy, dialysis encephalopathy, drug-induced (acyclovir, ciprofloxacin, dobutamine, cephalosporins, amantadine, gabapentin), May–White syndrome, Galloway–Mowat syndrome, action myoclonus-renal failure syndrome due to SCARB2 mutations.


c.  Infectious or postinfectious. HIV, subacute sclerosing panencephalitis, progressive multifocal leukoencephalopathy, herpes simplex encephalitis, postinfectious encephalitis, malaria, syphilis, Cryptococcus, and Lyme’s disease


d.  Hashimoto’s encephalopathy


e.  Malabsorption. Celiac disease and Whipple’s disease


f.  Other encephalopathies. Posthypoxia (Lance–Adams syndrome), posttraumatic, and electric shock


g.  Drug-induced myoclonus. Tricyclic antidepressants, selective serotonin uptake inhibitors, monoamine oxidase inhibitors, lithium, antipsychotics, narcotics, anticonvulsants, anesthetics, contrast media, calcium-channel blockers, antiarrhythmics, and drug withdrawal


h.  Basal ganglia degenerations. Wilson’s disease, PKAN, HD, MSA, CBD, PSP, and dentatorubropallidoluysian atrophy


i.  Dementias. Creutzfeldt–Jakob disease, AD, DLB, frontotemporal dementia, and Rett’s syndrome


j.  Focal central or peripheral nervous system damage. This category includes propriospinal or segmental spinal myoclonus.


k.  Spinocerebellar degenerations. Ramsay–Hunt syndrome, Friedreich’s ataxia, and ataxia telangiectasia


l.  Storage disease. Lafora’s body disease, GM2 gangliosidosis, Tay–Sachs disease, Gaucher’s disease, Krabbe’s leukodystrophy, ceroid-lipofuscinosis, and sialidosis


m.  Opsoclonus-myoclonus syndrome. Idiopathic, paraneoplastic (neural crest tumors)


C.  Pathophysiology. Cortical myoclonus is produced by an imbalance between inhibitory and excitatory systems in the sensorimotor cortex rapidly conducting to the pyramidal tracts. Cortical myoclonic activity spreads relatively rapidly from an initial focus in one sensorimotor cortex to other ipsilateral sensorimotor cortical areas through corticocortical pathways and to the opposite sensorimotor cortex through the corpus callosum. Propriospinal myoclonus is explained by changes in spinal cord excitability, probably due to dorsal horn interneuron hyperactivity. In brainstem myoclonus, muscle jerks arise from activity in neuronal centers within the lower brainstem, probably involving the same circuitry as the normal startle reflex.


D.  Selected clinical syndromes.


1.  Cortical myoclonus is multifocal, but predominantly affects body parts with the largest cortical representations such as the hands and face. Patients with cortical myoclonus may have purely focal or multifocal jerks, but they may have additional bilateral or generalized jerks, suggesting the spread of excitatory myoclonic activity between the cerebral hemispheres and across the sensorimotor cortex. As the motor cortex is most involved in voluntary action, the jerks are usually most marked during action. Metabolic encephalopathies cause generalized and spontaneous myoclonus that, like other forms of myoclonus, is triggered or enhanced by sensitive stimuli (light touch or stretch lead to reflex jerks of the stimulated area). Epilepsia partialis continua is a myoclonic epilepsy caused by focal cortical lesions, and myoclonic rhythmic jerks usually occur in the hands or face. Rhythmic forms of the myoclonic jerks can be misinterpreted as tremor.


a.  Differential diagnosis.


(1)  Clonic tics


(2)  Myokymia


(3)  Startle syndromes (hyperekplexia)


(4)  Parkinsonian disorders. Mainly CBD


(5)  Dementing conditions. Creutzfeldt–Jakob disease, DLB, CBD, and AD


b.  Evaluation.


(1)  MRI of the brain including the posterior fossa and the cervical spinal cord, to rule out structural lesions


(2)  Blood tests, to rule out metabolic disturbances. Antithyroid antibodies, to rule out Hashimoto’s encephalopathy


(3)  Review of medication records


(4)  EEG, to rule out epileptogenic discharges


(5)  Lumbar puncture (LP), to rule out encephalitis, Creutzfeldt–Jakob disease, or postinfectious encephalopathies (HIV and subacute sclerosing panence-phalitis)


2.  Brainstem myoclonus. Brainstem motor systems are particularly involved in axial and bilateral movements. Jerks in brainstem myoclonus are generalized, especially axial, with long-lasting electromyographic bursts (>100 ms) and may be provoked by many different types of sensory stimuli, although cutaneous taps around the nose and face are particularly effective. The hallmark is auditory reflex jerks, known as hyperekplexia.


a.  Differential diagnosis.


(1)  Brainstem structural lesions


(2)  Startle syndromes


(3)  Creutzfeldt–Jakob disease


b.  Evaluation.


(1)  MRI of the brain including, to rule out structural lesions


(2)  Family history of startle syndrome


(3)  LP


3.  Propriospinal myoclonus. Spinal segmental systems may become hyperexcitable, often by viral irritation or the isolation of anterior horn cells from inhibitory influences by disorders such as syringomyelia, glioma, or spinal ischemia. The result is myoclonus involving one or two contiguous spinal myotomes. Propriospinal myoclonus leads to predominantly axial flexion and extension jerks that, unlike brainstem myoclonus, spare the face and are not provoked by sound. This form of myoclonus is usually caused by damage to the spinal cord through cervical trauma, inflammation, or a tumor.


a.  Evaluation.


(1)  MRI of the cervical, thoracic, and lumbar spine to rule out structural lesions


(2)  Evaluation for multiple sclerosis


(3)  Personal history of cervical trauma


4.  Palatal myoclonus. This nomenclature is historically respected but phenomenologically inaccurate, and more properly it should be designated as palatal tremor. Palatal movements are fast and rhythmic and can spread to the throat, face, and diaphragm. Patient may hear an “ear click” due to contraction of the tensor veli palatini muscle. Palatal myoclonus/tremor may be idiopathic or symptomatic. Although the presence of the ear click had been classically associated with the idiopathic cases, it can be also present in secondary cases, in patients with structural brainstem lesions. Idiopathic cases have been related to hypertrophy of the inferior olive, and symptomatic cases to lesions (ischemic, neoplastic, and inflammatory) in the triangle of Guillain–Mollaret, which includes the red nucleus, the inferior olive, and the dentate nucleus.


a.  Evaluation. MRI of the brain including the posterior fossa to rule out structural lesions involving the triangle of Guillain–Mollaret.


5.  Posthypoxic action (intention) myoclonus, or Lance–Adams syndrome. This form of cortical myoclonus occurs in survivors of anoxic brain injuries. The jerks are triggered by voluntary movement, and specially, when movements are directed to a particular goal or target. Action-intention myoclonus is the most disabling form of myoclonus associated with provocative factors, with jerks that prevent or disrupt the movement. The myoclonic movements range from simple, localized focal jerks to generalized, disabling jerks.


TICS


A.  Definition. Tics are brief, intermittent, and repetitive, involuntary or semivoluntary movements and sounds. They are preceded by an urge or sensation in the affected muscle group and a sense of temporary relief once the movement is performed. Although tics may resemble other types of hyperkinetic movements (e.g., myoclonus and dystonia), the urge is considered a key characteristic that suggests that the movement is a tic. The patient’s ability to transiently suppress the movements by conscious effort and an increased frequency of tics after efforts to suppress have ceased are additional supportive features of the diagnosis. Onset of tic disorders usually occurs during childhood (before age 18).


B.  Phenomenologic classification.


1.  Anatomic distribution.


a.  Simple motor tics. Focal movements involving one group of muscles (eye blinking, mouth movements, and shoulder elevation)


b.  Complex motor tics. Coordinated or sequential patterns of movement involving various groups of movements. They may resemble usual motor tasks or gestures (jumping and throwing) and include echopraxia (imitating others’ gestures) and copropraxia.


c.  Simple phonic tics are elementary, meaningless noises or sounds (sniffing, grunting, clearing the throat, coughing, and belching).


d.  Complex phonic tics are meaningful syllables, words, or phrases (“okay” and “shut up”) and include pallilalia, echolalia, and coprolalia.


e.  Sensory tics are uncomfortable sensations (pressure, cold, warmth, or paresthesias) localized to certain body parts that are relieved by the performance of an intentional act in the affected area.


2.  Speed of movement.


a.  Clonic tics are brief, sudden, and jerk-like.


b.  Dystonic tics involve sustained twisting, or posturing is present.


c.  Tonic tics involve tensing contraction of muscles (abdominal or limb muscles).


3.  Natural history.


a.  Transient tic disorder. Multiple motor and/or phonic tics with duration of at least 4 weeks, but <12 months. These tics occur in 20% of children during the first decade of life.


b.  Chronic tic disorder. Single motor and/or phonic tics, but not both, which are present for >1 year.


c.  Tourette’s syndrome. Both motor and phonic tics are present for >1 year.


C.  Etiologic classification.


1.  Primary.


a.  Tourette’s syndrome, transient tic disorder, and chronic tic disorder


2.  Secondary.


a.  Hereditary disorders with tics as one manifestation of another primary neurologic condition. HD, neuroacanthocytosis, PKAN, Wilson’s disease, and tuberous sclerosis complex


b.  Infections. Encephalitis, neurosyphilis, and Sydenham’s chorea


c.  Drugs. Methylphenidate, antiepileptic drugs, dopamine receptor–blocking drugs (see section Tardive Syndrome), psychostimulant drugs (amphetamines, pemoline and cocaine), and levodopa


d.  Head trauma


e.  Toxins. Carbon monoxide


f.  Developmental. Autistic spectrum disorders (Rett’s syndrome and Asperger’s syndrome), intellectual disability syndromes, chromosomal disorders (Down’s syndrome, Klinefelter’s syndrome, fragile X syndrome, and triple X)


g.  Focal brain lesions. Stroke and multiple sclerosis


D.  Pathophysiology. Dopaminergic imbalance in the ventral part of the cortico–striatal–thalamocortical pathways (medial prefrontal cortex connecting to the ventral striatum—ventral part of the globus pallidus, and the dorsomedial thalamus) is involved in the expression of tics. However, some data suggest an associated cortical dysfunction in Tourette’s syndrome. In volumetric and functional MRI studies, children with Tourette’s syndrome have shown larger dorsolateral prefrontal regions, increased cortical white matter in the right frontal lobe, and activation of the prefrontal cortex related to tic suppression. Likewise, transcranial-magnetic-stimulation studies suggest that tics originate from impaired inhibition in the motor cortex.


E.  Selected clinical syndromes.


1.  Tourette’s syndrome. Tourette’s syndrome is characterized by multiple motor tics plus one or more phonic tics that wax and wane over time. Diagnosis is made according to the DSM-IV clinical criteria.


a.  Multiple motor and one or more phonic tics (not necessarily concurrently)


b.  Onset before age 21 years


c.  Variations in anatomic location, number, frequency, complexity, and severity of the tics occur over time.


d.  Tics occur many times a day, nearly every day or intermittently for more than a year, with symptom-free intervals not exceeding 3 months.


e.  Tics are not related to intoxication with psychoactive substances or CNS disease (e.g., encephalitis).


f.  Tics cause distress to the patient.


The average age at the onset of tics is 5 years, become more severe at 10 years of age, but half of patients are free of tics by 18 years. Although tics may persist into adulthood, their severity is gradually diminished.


Tourette’s syndrome is commonly associated with behavioral comorbidities such as ADHD (15% to 50%), obsessive-compulsive disorder (35% to 45%), addictive and aggressive behaviors (related to poor impulse control), anxiety, depression, and decreased self-esteem. Obsessive-compulsive symptoms in Tourette’s syndrome are characterized by ritualistic behaviors, and need for completion, symmetry, and perfection. In severe cases, self-injurious behaviors may be also present.


g.  Differential diagnosis.


(1)  Myoclonus (see above)


(2)  HD, neuroacanthocytosis, and PKAN


h.  Evaluation.


(1)  MRI of the brain to rule out structural brain lesions or to disclose images suggesting a metabolic disorder, if neurologic examination demonstrates other findings besides tics


(2)  Review of medication record for drug exposure


(3)  History of drug exposure (psychostimulant drugs)


(4)  Genetic testing for HD if other neurologic symptoms are present (cognitive impairment and ataxia)


(5)  Review of family background for other examples of tics, attention deficits, or OCD


TARDIVE SYNDROMES


A.  Definition. Tardive syndromes refer to a group of disorders characterized by persistent abnormal involuntary movements caused by chronic exposure to a dopamine receptor–blocking drug within 6 months of the onset of symptoms and persisting for at least 1 month after stopping the offending drug.


Tardive syndromes cover the gamut of hyperkinetic movement disorders, often with multiple types. Choreic and stereotypic bucco-linguo-masticatory dyskinesias are characterized by repetitive and predictable or unpredictable movements involving the oral, buccal, and lingual areas (tongue twisting and protusion, lip smacking or elevation, and chewing). Dystonic facial grimacing, and neck and trunk arching movements are also common and can mix with choreic movements. Myoclonus, tics, and restless purposeful movements (akathisia) have also been related to chronic exposure to dopamine receptor–blocking agents. Tardive tremor has been described but is controversial, and parkinsonism in a patient on neuroleptic medication is usually due to an increased dose of neuroleptic (drug-induced parkinsonism), and therefore not considered a tardive syndrome. Tardive syndromes may occur on steady doses of dopamine receptor–blocking agents or also induced by withdrawal.


B.  Drugs reported to cause tardive syndromes.


1.  Neuroleptic drugs. Haloperidol, risperidone, olanzapine, chlorpromazine, pimozide, levomepromazine, thioridazine, tiapride, fluphenazine, perphenazine, among others


2.  Anxyolitics. Flupenthixol and melitracene


3.  Calcium-channel blocker. Cinnarizine and flunarizine


4.  Dihydropiridines. Amlodipine, nifedipine, and nimodipine


5.  Antiemetic drugs. Metoclopramide, clebopride, and cinitapride


6.  Antidizziness drugs. Tietilperazine, sulpiride, amisulpride, and veralipride


7.  Trimetazidine


C.  Risk factors for tardive dyskinesia.


1.  Age older than 65 years


2.  Female sex


3.  Concomitant extrapyramidal symptoms


4.  Basal ganglia lesions on neuroimaging


D.  Selected clinical syndromes.


1.  Typical orofacial buccolingual dyskinesia


2.  Tardive dystonia. This syndrome may be indistinguishable from idiopathic dystonia and can be focal, segmental, or generalized. The movement can improve with sensory tricks. However, contrary to idiopathic dystonia, tardive dystonia often improves with voluntary actions such as walking. When involving the neck, predominates retrocollis, and when the trunk is affected, predominates tonic lateral flexion of the trunk (Pisa syndrome or pleurothotonus), or bench arching (opisthotonus).


3.  Tardive akathisia. Akathisia is characterized by a feeling of inner restlessness. Subjectively, the most common complaint is the inability to keep the legs still and feeling fidgety, but patients can also describe a vague inner tension or anxiety. Objectively, patients are seen rocking from foot to foot, walking in place while sitting, and, occasionally, grunting, or trunk rocking. Characteristically, akathisia may improve with low doses of propranolol.



Key Points


•  PD is the most frequent cause of rest tremor, but other diagnoses must be considered because of their different associated signs and prognoses: MSA, PSP, DLB, frontotemporal dementia with parkinsonism, SCAs, vascular parkinsonism, and drug-induced parkinsonism.


•  FXTAS, characterized by ataxia and intentional tremor, is important to include within the considerations of adult ataxias. According to epidemiologic studies, FXTAS is more frequent than SCAs and has important genetic counseling implications.


•  DYT6 patients can be identified clinically by the combination of cervical, upper limb, or generalized progressive dystonia with spasmodic laryngeal dystonia and/or oromandibular involvement.


•  The combination of bibrachial dystonia with facial dystonia (‘facial grimacing’), ataxia, and supranuclear vertical gaze palsy may guide the clinician to the diagnosis of NPC, a treatable cause of ataxia and dystonia.


•  Chorea may dominate the neurologic picture of multiple, treatable disorders, and these conditions must be carefully considered in patients with an absence of a family history of chorea or with negative tests for HD.


•  ChAc is characterized by generalized chorea and severe orofacial dystonia with tongue and lip biting and feeding dystonia, and can be easily diagnosed by determination of chorein in peripheral blood samples.


•  C9orf72 hexanucleotide expansions appear as the most frequent cause of HD phenocopies.

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Mar 12, 2017 | Posted by in NEUROLOGY | Comments Off on Approach to the Hyperkinetic Patient

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