Abnormal Movements (Case 55)
Case: A 68-year-old man has been noticing a tremor in his right hand for the past year. The tremor began in his thumb, but it has spread to the entire hand and now his arm. It generally appears while he is watching television, walking, or is otherwise occupied, and lately it has been occurring more frequently. The shaking has been accompanied by a loss of dexterity of the same hand. He is finding it hard to button his left sleeve cuff and to tie his shoes. In addition, his wife has noticed a change in his gait. He seems to drag the right foot slightly when he takes a step, and he appears not to be able to walk as fast he used to. During the interview the patient’s wife also comments that her sleep has been interrupted because the patient has had several outbursts of yelling and flailing of his arms and legs during his sleep. He adds that he has been having some wild dreams. Upon direct questioning, he also admits that he has not been able to smell his wife’s cooking as well for the past 10 years.
Parkinson disease (PD)
Multiple system atrophy (MSA)
Progressive supranuclear palsy (PSP)
Essential tremor (ET)
PD is the most common movement disorder. Despite its being a progressive, degenerative disease, a variety of treatments can help patients with PD to live a normal life span, with a greatly improved quality of life. In evaluating someone with possible PD, establish that he or she presents with the key clinical criteria. Specifically, look for tremor at rest, stiffness (rigidity), slowness of movement (bradykinesia), abnormalities of gait or balance (postural instability), and an overall development of these symptoms in a unilateral or at least asymmetric pattern. The patients may not be aware of some of the issues in which you are interested, but a spouse or family member may have noticed other problems. In addition, there are nonmotor symptoms of which lay people are unaware that are connected with PD but that become relevant and more disabling with disease progression. These include depression, anxiety, and cognitive dysfunction with slowed processing, but most functions are still generally intact, except for planning and judgment (frontal lobe symptoms), autonomic dysfunction including neurogenic bladder, erectile dysfunction, orthostatic hypotension, rapid eye movement (REM) behavior disorder (the seeming acting out of dreams), and loss of sense of smell. In more advanced cases a discussion with the caregiver assumes greater significance as specific issues that make it difficult to care for the patient but do not seem to be specifically part of the disease may come to light.
• Be aware of subtle symptoms or findings that may have been ignored by the patient or family but may be relevant to the diagnosis. For example, the patient may hold one arm slightly stiff while walking or may seem not to blink quite as frequently as one would expect in a healthy person.
• Stretching exercises may lower the risk of contractures, and exercising will keep the muscles active, minimizing the development of rigidity. Patient mobility is, of course, a significant issue for the patient as well as for the caregivers.
• When the patient is walking, is one leg being dragged, or are there episodes of freezing (no obvious weakness, but seeming inability to move the legs, often occurring in doorways and approaching a chair or a crowd)?
• Utilize the Unified Parkinson’s Disease Rating Scale (UPDRS), which is routinely performed on all new PD patients. This scale includes cognitive concerns, ADLs, motor complaints, medication complications, a detailed movement-disorders exam, as well as several other details. Applying this scale at each visit enables the physician to compare each symptom, finding, and complaint across visits. Following the total UPDRS score over time is one way to monitor the degree and rapidity of disease progression.
• Be sure to ask about use of neuroleptic medications, as antipsychotics are dopamine antagonists and may induce a parkinsonian condition. Typically, drug-induced parkinsonism has a symmetrical onset, while idiopathic PD begins unilaterally, although this is not always the case.
• To help distinguish between the tremor of PD and that of essential tremor, the tremor of ET is generally more symmetrical and manifests during action, while that of PD is an asymmetric resting tremor. Also, ET may improve after the ingestion of alcohol, while PD will be unaffected or worsen.
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The central component of PD is the loss of the dopamine-secreting cells originating in the substantia nigra pars compacta. This causes a chain reaction throughout the basal ganglia that results in higher levels of inhibitory signals sent to the thalamus and motor cortex, thus slowing voluntary movement. There are also many nonmotor symptoms of PD, which are probably due to widespread neurodegeneration, suggesting involvement of neurotransmitters other than dopamine. They may include mood disorders, cognitive decline, orthostatic hypotension, speech difficulty, and dysphagia. Pathologically, the cells of the substantia nigra demonstrate Lewy bodies, which are intracellular collections of abnormal proteins, including α-synuclein (a membrane protein) and ubiquitin.
PD usually presents unilaterally, with abnormal movements in one arm or hand or occasionally one leg. Frequently, tremor is the initial symptom, but not always. In non–tremor-predominant variants (i.e., akinetic-rigid syndromes), patients may notice rigidity and loss of dexterity in their hands before any tremor. Patients may recall a permanent loss of sense of smell, often beginning several years before the onset of motor symptoms. There may also be a history that sounds similar to REM behavior disorder (which involves acting out of dreams or even just talking in one’s sleep) and constipation.
Rule out secondary (drug-induced) parkinsonism by determining neuroleptic use. There are genetic tests available if the patient is uncommonly young or has an extensive PD family history. If there are atypical symptoms or an atypical pattern of symptom development (e.g., stepwise progression, gait and balance being affected first, cognitive decline appearing unusually early), an MRI can be performed to rule out vascular parkinsonism or perhaps some of the “parkinson plus” conditions (e.g., multiple system atrophy, progressive supranuclear palsy, and dementia with Lewy bodies). PET scans can be used to delineate decreased activity in the basal ganglia, but they are expensive and not completely reliable. Clinical assessment via thorough history and examination, possibly including a standardized rating scale, is the usual method of diagnosis and subsequent monitoring.
The mainstay of PD treatment is the exogenous replenishment of dopamine in the form of levodopa or dopamine agonists, although these medications affect primarily motor symptoms. Nonmotor symptoms generally require symptomatic treatment (blood pressure support for orthostatic hypotension or antidepressants for depression). Long-term care for a PD patient may become complicated, as patients may become less responsive to medication and develop fluctuations of their response to the medications. In addition, they may develop side effects, such as dyskinesias, which are coarse, choreic (writhing) involuntary movements. In the past decade, implantation of an electrical stimulator in the basal ganglia (known as deep brain stimulation [DBS]) has demonstrated excellent results in controlling the symptoms of moderate-to-severe PD. Other nonmedical modalities can be helpful, such as physical therapy, speech therapy, and behavioral therapy for gait difficulties, dysarthria, and psychiatric problems. See Cecil Essentials 122.
Multiple System Atrophy
MSA is characterized by the development of α-synuclein inclusions in glial cells of various regions of the brain, including substantia nigra pars compacta, locus ceruleus, putamen, inferior olive, pontine nuclei, cerebellar Purkinje cells, and intermediolateral columns. The degeneration may occur in different proportions, resulting in a spectrum of syndromes that vary based on the affected area. MSA-parkinsonism (MSA-P) involves mostly the degeneration of the striatonigral pathways. While it was originally thought that MSA affects presynaptic and postsynaptic dopaminergic neurons, patients with MSA-P may be responsive, at least in part, to levodopa therapy. MSA-cerebellar (MSA-C) mostly affects the olivocerebellar connections, with disproportionate involvement of the middle cerebellar peduncles. MSA-autonomic (MSA-A, also known as Shy-Drager syndrome) is characterized by the degeneration of the locus ceruleus, the dorsal motor nucleus of cranial nerve X, and the catecholamine-producing neurons of the ventrolateral medulla.
Although there are three variants of MSA, a typical patient may have components of all of them. MSA-C shows disproportionate ataxia, MSA-P includes parkinsonism, and MSA-A is primarily characterized by autonomic dysfunction, which may include orthostatic hypotension and bladder dysfunction. The presence of symptoms from two of these categories suggests a diagnosis of MSA.
There is no definitive test for MSA, much as seen for PD. The diagnosis is clinical, and the probability of having MSA rises with an increased number of symptoms from an increased number of categories (autonomic dysfunction, parkinsonism, and cerebellar dysfunction).
There is no disease-modifying treatment for MSA; treatment is symptomatic. Often parkinsonian patients have a limited response to levodopa and other dopaminergic agents. Autonomic dysfunction can be managed by giving vasoconstrictors and mineralocorticoids to increase blood pressure and using antispasmodics or catheters in the setting of urinary incontinence. Physical and speech therapies may also be useful. See Cecil Essentials 122.
Progressive Supranuclear Palsy
PSP is characterized by inclusion bodies similar to the neurofibrillary tangles of Alzheimer disease and composed of tau protein. Both neurons and glial cells are affected. Tufted astrocytes and globose tangles can be seen in the brainstem, particularly in the midbrain; the basal ganglia, particularly the subthalamic nucleus, substantia nigra, and globus pallidus; and in the cerebral cortex of the frontal lobes.
PSP usually manifests with early gait impairment or balance problems associated with falls. Eye movement abnormalities (slow saccades, vertical gaze palsy) are typical but may present late in the course. In addition, dysarthria and dysphagia commonly occur in PSP, as well as some degree of cognitive impairment. The dementia of PSP (as with all parkinsonian disorders) tends to be a subcortical dementia with loss of frontal functions, which include judgment and executive decision making. Thus, there tends to be a “dysexecutive syndrome” with mild behavioral abnormality. This is unlike Alzheimer disease, which tends to affect primarily memory or visuospatial recognition. Some PSP patients may exhibit typical parkinsonism, though with a poor response to levodopa.
Similar to PD and MSA, there are no specific diagnostic tests for PSP, and the diagnosis is based on an accurate history and neurologic examination. Two primary variants of PSP have been distinguished. Richardson syndrome is the name given to “classic” PSP, which presents with postural instability, eye movement abnormalities, and dysphagia or cognitive dysfunction. PSP-parkinsonism presents with more typical PD symptoms (including tremor and limb rigidity), may be more responsive to levodopa therapy, and has a better prognosis overall. A specific rating scale has recently been created to support the diagnosis and clinical monitoring of PSP.
Brain MRI may show atrophy of midbrain, superior colliculi, superior cerebellar peduncle, and the region around the third ventricle. This results in enlargement of the third ventricle and the interpeduncular cistern. One may see the “penguin” or “hummingbird” sign on a midline sagittal cut, due to the abnormal thinning of the midbrain tegmentum. Detailed neuropsychological testing can help in establishing the severity of the cognitive dysfunction.
There is no treatment for PSP. Levodopa can relieve parkinsonian symptoms in some cases. There have been reports of benefit with amitriptyline, amantadine, or zolpidem, but there is very little consensus on the usefulness of these drugs. Supportive measures, including walking aids or wheelchairs, and gastrostomy tubes for dysphagia, may become more relevant with disease progression. See Cecil Essentials 122.
The pathophysiology of ET is poorly understood, but it seems to be related to the involvement of cerebello-thalamo-cortical circuitry. Since ET runs in families, there seems to be a genetic predisposition, although no gene has as yet been identified. A number of environmental factors, including toxins, are also under investigation. Recent studies have suggested that ET might have a neurodegenerative component. ET might be a family of degenerative diseases rather than a single disease.
Symptoms may be unilateral or bilateral, and usually manifest as a postural or an action tremor. That is, the shaking becomes more apparent when trying to perform an action, such as pouring a drink, bringing a cup to the mouth, or writing. There is little stiffness or postural instability, although severe tremor can affect walking and balance. There may be tremor in the head or in the voice.
The diagnosis is made on clinical grounds. About 50% of ET cases are familial, so having an affected family member aids in the diagnosis. Various tasks are performed to assess tremor severity. There are blood tests that can help to rule out other conditions that may present with tremor, such as hyperthyroidism. In addition, tremor improvement with alcohol intake strongly suggests a diagnosis of ET.
First-line medications are primidone and propranolol, either alone or in combination. Other new-generation antiepileptic medications have been tried, with varying success. DBS of the thalamus has also demonstrated benefit in most severe and medication-resistant cases. Often patients learn to consume an alcoholic drink during social occasions to relieve the embarrassment caused by tremor (care should be taken that ET patients do not develop tolerance or dependence on alcohol). See Cecil Essentials 122.
Ischemic lesions of the basal ganglia may cause parkinsonian symptoms without pathologic degeneration of the dopaminergic cells. Significant atherosclerotic disease can lead to microvascular changes in the basal ganglia and in the corticospinal tracts. The attribution of the parkinsonism disorder to vascular lesions identified at imaging is often quite tricky, but a few anatomic and clinical observations have confirmed that vascular parkinsonism does exist.
Most frequently, vascular parkinsonism presents as an “atypical” parkinsonian syndrome, with predominant gait disorder, little or no resting tremor, presence of associated neurologic signs, and lower sensitivity to levodopa. There may also be a more postural tremor.
Clinically, these patients are older, have more vascular risk factors (e.g., hypertension, diabetes, hyperlipidemia, and smoking), and present with early gait abnormality. Brain MRI shows subcortical white-matter disease that can be extensive.
Patients with vascular parkinsonism are less responsive to levodopa than are those with PD. As with most ischemic lesions, the mainstay of treatment is often physical therapy. Similarly to that for stroke patients, treatment is also geared toward minimizing future ischemic events by improving risk factors (lowering blood pressure, and controlling blood sugar and cholesterol). See Cecil Essentials 122.
There are numerous therapeutic agents that can block dopamine synapses. For example, antipsychotics such as haloperidol are powerful blockers of dopamine D2 receptors. An understandable side effect of these medicines is the development of parkinsonian symptoms, including tremor, rigidity, and slowness of movement.
Neuroleptic-induced syndromes can develop acutely within hours or a few days, subacutely over several weeks, or after prolonged exposure to the dopamine blocker. When parkinsonism develops ≥6 months after exposure, the term “tardive” is used, implying a delayed onset. Drug-induced parkinsonism resembles idiopathic PD, with tremor, rigidity, and akinesia. Symptoms are usually (though not necessarily) bilateral and possibly reversible.
Diagnosis is suspected through the history. Patients with tardive parkinsonism normally have a psychiatric history and a known history of neuroleptics intake. It is important to consider that patients, particularly when hospitalized, are administered drugs, the purpose of which they may be unaware. For example, an elderly person developing parkinsonian symptoms after being discharged from the hospital may have received haloperidol for agitation. Some antiemetic medications also have antidopaminergic activity (e.g., metoclopramide). Symmetrical symptom progression is often an element of drug-induced parkinsonism.
Discontinuing the offending agent is the first step. On some occasions the patient has a significant psychiatric disease necessitating continuation of the antidopaminergic agent. The prescribing physician should be consulted to discuss other options, including use of atypical neuroleptics (e.g., clozapine, quetiapine). In some cases, even after the agent is removed the symptoms persist. In these cases patients should be treated the same as patients with regular PD. See Cecil Essentials 122.
a. Dementia with Lewy bodies: Pathologically, this syndrome resembles PD in that affected cells have the same cytoplasmic inclusion bodies, known as Lewy bodies. In this case, however, the affected area may include the cerebral cortex, causing early cognitive impairment out of proportion to the accompanying motor symptoms, which usually include rigidity and bradykinesia more than tremor. There may be early development of visual hallucinations as well. Diagnostic workup should exclude Alzheimer disease and other dementias, but treatment includes therapy for dementia (including cholinesterase inhibitors) and for the parkinsonian symptoms.
b. Spinocerebellar ataxias (SCAs): This is a heterogeneous group of progressive ataxias caused by trinucleotide repeats. Patients present with various constellations of symptoms, including ataxia of gait and stance, limb movement ataxia, eye movement abnormalities, pyramidal tract signs, muscle atrophy, basal ganglia symptoms, bladder dysfunction, dysphagia, and dementia. While most of the SCAs do not typically present with parkinsonian findings, patients with SCA type 2 may have prominent parkinsonism in the absence of cerebellar signs. Age of presentation varies but is often within the first few decades of life.
c. Wilson disease, also known as hepatolenticular degeneration, is an autosomal-recessive disorder affecting copper binding, resulting in excessive copper buildup in the liver and brain. This results in basal ganglia dysfunction as well as behavioral and mental changes. Patients may present at an early age with tremor (more prominent in “wing-beating” position), rigidity, postural instability, dystonia, dysarthria, athetosis, and psychiatric problems such as depression, mania, or loss of impulse control. The hallmark finding is the Kayser-Fleischer ring, a brownish golden haze seen at the corneal rim, most visible on slit-lamp exam. MRI may show T2 hypodensities in the superior colliculi and hyperdensities in the medial substantia nigra and tegmentum (resulting in a pattern resembling a panda’s face). Treatment is with D-penicillamine, a copper-chelating agent, in early stages of the disease.
d. Huntington disease typically presents with chorea, slow saccades, and behavioral or cognitive changes, but in its juvenile form, parkinsonian symptoms may predominate. Rigidity, bradykinesia, resting tremor, dystonia, and ataxia may be present, as may seizures and myoclonus. HD is a trinucleotide-repeat disorder that is at this point untreatable. Chorea can be managed with dopamine-blocking or dopamine-depleting agents, but these may exacerbate the parkinsonian symptoms.