Involuntary Movement Disorders

Chapter 18 Involuntary Movement Disorders


Involuntary movement disorders occur frequently and cause serious physical disabilities. In some disorders, dementia and depression routinely precede or overshadow the movements, but, despite causing profound physical disability, others show neither psychiatric nor cognitive impairment. Also, these illnesses can provide instructive clinical-anatomic correlations.


Abnormalities of the basal ganglia underlie the classic movement disorders: Parkinson disease, athetosis, chorea, hemiballismus, Wilson disease, and generalized dystonia. In contrast, no specific basal ganglia abnormality underlies several other disorders, including focal dystonias, essential tremor, tics and Tourette disorder, and myoclonus. Certain movements, particularly those that mimic tremor or dystonia, occasionally stem from psychiatric disorders or malingering.


Laboratory tests may confirm the clinical diagnosis of many movement disorders; however, for all of them, the initial diagnosis rests on clinical grounds. As they do with neurocutaneous disorders and many other illnesses, neurologists relish “diagnosis by inspection.”



The Basal Ganglia


Five subcortical gray-matter macroscopic nuclei (Figs 18-1 and 18-2) constitute the basal ganglia:



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FIGURE 18-1 A, This axial view, the one used in computed tomography and magnetic resonance imaging studies, shows the basal ganglia in relation to other brain structures. The heads of the caudate nuclei (C) indent the lateral undersurface of the anterior horns of the lateral ventricles. The caudate and putamen (P) constitute the striatum. The globus pallidus (G), which has internal and external segments, and the putamen form the lenticular nucleus, named for its resemblance to an old-fashioned lens (see Fig. 18-1, C). The posterior limb of the internal capsule (IC) separates the lenticular nucleus from the thalamus (T), which is not a member of the basal ganglia family. B, In this coronal view of the diencephalon, the substantia nigra (SN), as well as the subthalamic nuclei (STN), sits below the thalamus. The substantia nigra, because of its characteristic shape and pigmentation, serves as a landmark. The lateral ventricles are bounded laterally by the heads of the caudate nuclei (C) and superiorly by the corpus callosum (CC). This myelin stain has blackened the heavily myelinated fibers of the internal capsule (IC) and corpus callosum (CC). C, A coronal view shows extrapyramidal circuits. The putamen sends a direct and an indirect dopamine tract to the internal segment of the globus pallidus (GPi). Dopaminergic neurons in the substantia nigra project to the putamen, where neurons with D1 receptors project directly to the GPi. Putaminal neurons with D2 receptors project through the globus pallidus external segment (GPe) and subthalamic nucleus and thence to GPi. The GPi innervates the ventrolateral nucleus of the thalamus, which projects to the motor cortex. The cortex, completing a circuit, innervates the putamen.


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FIGURE 18-2 This computer-generated rendition of the midbrain should be compared to a photograph (see Fig. 2-9), functional drawings (see Figs 4-5 and 4-9), and an idealized sketch (see Fig. 21-1). The lower third of the midbrain, which lies just caudal to the diencephalon, contains the pair of horizontal but gently curved, elongated, pigmented nuclei – the substantia nigra. In Parkinson disease, the substantia nigra and other pigmented nuclei lose their pigment and, compared to normal, thus appear blanched. The midbrain also houses the prominent aqueduct of Sylvius, which is the dorsal heart-shaped hole surrounded by the periaqueductal gray matter. Cerebrospinal fluid passes from the third ventricle, through the aqueduct, to the fourth ventricle.


Neuroanatomical tracts, of spaghetti-like complexity, link the basal ganglia to each other and to the thalamus, conjugate oculomotor circuits, and the frontal lobe. Projections from the basal ganglia constitute the extrapyramidal tract, which complements the pyramidal (corticospinal) tract. The extrapyramidal tract modulates the corticospinal tract. It promotes, inhibits, and sequences movement. In addition, it maintains appropriate muscle tone and adjusts posture.


Although the extrapyramidal tract seems to play merely a supportive role – indirectly influencing the corticospinal tract by acting on thalamocortical connections and projecting only within the brain – it comprises several clinically important tracts. The most important one, from a clinical viewpoint, is the nigrostriatal tract, which, as its name suggests, extends from the substantia nigra to the striatum (Fig. 18-3). This tract provides dopamine innervation directly and indirectly, via the subthalamic nucleus, to the globus pallidus’ internal segment (GPi).



The globus pallidus is essentially an inhibitory, gamma-aminobutyric acid (GABA)-based nucleus. In contrast, the subthalamic nucleus is essentially an excitatory, glutamate-based nucleus.


One of the main differences between dopamine receptors is that, in the striatum, dopamine binding to dopamine 1 (D1) receptors stimulates adenyl cyclase activity, but dopamine binding to dopamine 2 (D2) receptors inhibits adenyl cyclase activity (see Table 21-1).


Physical or biochemical injuries of the basal ganglia typically produce hypokinesia (too little movement) and, when patients move, bradykinesia or akinesia (slow or absent movement), rigidity, and impaired postural reflexes. Alternatively, such injuries may produce a hyperkinesia (excessive movement), which takes the form of tremor, athetosis, chorea, hemiballismus, or dystonia. Neurologists often refer to each of these movements as a dyskinesia. Sometimes the injuries even produce combinations of too little and too much movement. For example, Parkinson disease creates akinesia and tremor.


As with other injuries of the brain – except for those in the cerebellum – unilateral injuries of the basal ganglia induce clinical abnormalities in the contralateral side of the body. When illnesses affect only the extrapyramidal tracts, patients have no signs of pyramidal (corticospinal) tract damage, such as paresis, spasticity, hyperactive reflexes, and Babinski signs. Similarly, they have no signs of cerebral cortex damage, such as dementia and seizures.



General Considerations


The involuntary movement disorders share several clinical features. Anxiety, exertion, fatigue, and stimulants (including caffeine) increase the movements, but willful concentration and sometimes biofeedback may suppress them, at least transiently. Most movements disappear during sleep. The exceptions – hemifacial spasm, myoclonus, palatal tremor, tics, and specific sleep-related disorders, such as restless legs syndrome (RLS) and periodic movements – persist without regard to sleep stage (see Chapter 17).


Neurologists typically measure four parameters of involuntary movements:



The diagnosis of patients with involuntary movement disorders is fraught with at least two potential errors. Although possibly debilitated by uncontrollable movements and inarticulate speech, patients may remain fully alert, intelligent, and, possibly by resorting to unconventional techniques, able to communicate. Unless physicians are astute, they may misdiagnose these individuals as having Intellectual Developmental Disorder, the diagnosis from the preliminary Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) that replaces mental retardation, or dementia.


Another error may occur when patients, at first glance, appear to have a psychogenic movement disorder (see later and Chapter 3). In many situations, the lack of a definitive confirmatory laboratory test forces neurologists to rely exclusively on their clinical judgment.



Parkinson Disease


Essential tremor and RLS are more frequently occurring, but Parkinson disease remains the quintessential movement disorder. Parkinson disease has three cardinal features:



The initial and ultimately most disabling physical feature of Parkinson disease is usually bradykinesia or, in the extreme, akinesia. Slow or absent movement produces the classic masked face (Fig. 18-4), paucity of trunk and limb movement (Figs 18-5 and 18-6), and impairment of activities of daily living. Parkinson patients sometimes liken their slow movements to slogging through hip-deep mud, wearing lead clothing, or driving a car with an engaged emergency brake.





Rigidity typically accompanies bradykinesia (Fig. 18-7). Although rigidity is one of the cardinal features of Parkinson disease, it often appears as a manifestation of other extrapyramidal disorders. No matter the context, physicians should not confuse rigidity with spasticity, which signals corticospinal tract disease (see Chapter 2).



Tremor is often the most conspicuous feature of Parkinson disease; however, it is the least specific sign, least debilitating symptom, and least associated with dementia and depression. In Parkinson disease, the affected body part usually oscillates in a single plane with a regular rate, although with a variable amplitude. It primarily involves the hands. Even more characteristically, the tremor appears when patients rest quietly with their arms supported. Neurologists call it a resting tremor (Fig. 18-8) and can show that it differs from cerebellar and essential tremors. When patients have tremor as their primary symptom, neurologists refer to them as having “tremor-predominant” Parkinson disease.



These cardinal features, in contrast to signs of most other movement disorders, typically first develop in an asymmetric or unilateral pattern. Even as Parkinson disease progresses to involve both sides of the body, its manifestations continue to predominate on the side initially involved.


Another important feature of Parkinson disease consists of the cardinal features’ response to levodopa (L-dopa) treatment in almost 80% of cases. In the absence of a definitive laboratory test for the illness, a positive response to L-dopa confirms the diagnosis for most neurologists. Likewise, failure to respond prompts them to consider alternative diagnoses, such as medication-induced parkinsonism, progressive supranuclear palsy, and Wilson disease (see later).


Additional symptoms and signs may emerge as Parkinson disease advances. Patients lose their postural reflexes, which are neurologic compensatory mechanisms that adjust muscle tone in response to change in position. Loss of these reflexes, in combination with akinesia and rigidity, results in a characteristic gait impairment, marche à petit pas or festinating gait, which consists of a tendency to lean forward and accelerate the pace (Fig. 18-9, A). In a test of postural reflexes, the pull test, the examiner pulls the patient from the shoulders (Fig. 18-9, B). Normal individuals merely sway. Patients who have mild impairment of their postural reflexes take a few steps back, i.e., have retropulsion. More severely affected ones rock stiffly backwards without flexion or other compensatory movement and topple, en bloc, into the examiner’s arms.



Parkinson disease patients’ gait abnormality and impaired postural reflexes prevent them from walking safely. Many fall and fracture a hip. These disabilities eventually confine them to bed and prove fatal.


Even at the onset of the illness, patients’ handwriting deteriorates to a small and tremulous script, micrographia (Fig. 18-10). In a parallel fashion, their voice loses both volume and normal fluctuations in pitch and cadence, i.e., their speech becomes hypophonic and monotonous. Also, because of their illness or the medications used to treat it, Parkinson disease patients develop sleep disturbances, characteristically rapid eye movement sleep behavior disorder (see Chapter 17).



After several years of disease, inadequate buffering, storage, release, and reuptake of dopamine – from both endogenous and exogenous sources – may cause fluctuating symptoms, termed “on-off.” During “on periods,” patients remain well treated and asymptomatic, but during “off periods,” which last 30 minutes to 2 hours, they are impaired by rigidity and bradykinesia. Even if patients reach a state of complete rigidity resembling catatonia in their off periods, they have no change in their level of consciousness or electroencephalogram (EEG).


Nonmotor physical problems also emerge. For example, Parkinson patients characteristically lose their sense of smell. The anosmia, which also occurs in Alzheimer disease, reflects the neurodegenerative nature of these illnesses (see Chapters 4 and 7). They also routinely develop problems with their autonomic nervous system, including dysphagia, constipation, urinary incontinence, and abnormal sweating.




Psychiatric Conditions Comorbid with Parkinson Disease



Depression


For the first several years of Parkinson disease, patients’ mood may reflect their failing health, isolation from coworkers and friends, reduced income, and loss of independence. A second phase of depression emerges after several years as the disease, despite optimal treatment, begins to incapacitate patients. Reports of prevalence of depression in Parkinson disease patients vary widely because studies used different criteria. Testing patients at different stages of the illness, including or excluding psychiatric comorbidities, failing to weigh manifestations of the illness that may reflect either mood disorder or motor impairment, such as hypophonia, facial immobility, and sleep disturbances, all affect the prevalence of depression. By any measure, however, prevalence of depression is substantial. Typical studies report that approximately 30% of all Parkinson disease patients manifest depression.


The most powerful risk factors for depression include a history of depression, cognitive impairment, and akinesia, but not tremor. In addition, the illness developing at a young age and having a long duration constitute powerful risk factors.


When it occurs, depression accelerates cognitive decline, interferes with sleep, and accentuates physical disabilities. Of nonmotor Parkinson disease symptoms, it correlates most closely with a poor quality of life. The depression provokes anxiety, which may also occur separately as another comorbidity. Parkinson disease with or without comorbid depression generally does not increase the suicide rate.


Physicians might also keep in mind the well-being of the patient’s caregivers. Studies show that affective disorders and reduced quality of life are commonplace among caregivers and anxiety scores are high among women caregivers. As the illness progresses, they shoulder an ever-increasing burden that may consume them. If the patient is depressed or has had a lengthy illness, caregivers are even more susceptible to depression.



Treatment of Comorbid Depression


Psychological support, social services, and rehabilitation often help during the first several years of Parkinson disease. However, during that period and certainly when the disease progresses, optimum treatment almost always requires antidepressants. Neurologists should optimize the antiparkinson medication regimen before any physician prescribes antidepressants.


Treatment of depression improves Parkinson patients’ quality of life and reduces their disability. Not surprisingly, antidepressants are less effective in treating depression comorbid with Parkinson disease than depression without comorbid Parkinson disease. Several considerations should guide the choice of an antidepressant.


Antidepressants and other psychotropics should be anxiolytic. Studies found that tricyclic antidepressants (TCAs) are preferable to selective serotonin reuptake inhibitors (SSRIs). TCAs and trazodone tend to improve patients’ mood and restore restful sleep. However, Parkinson disease patients, who are generally elderly, are especially susceptible to these medicines’ anticholinergic side effects.


Although SSRIs carry fewer side effects than TCAs in the population of depressed Parkinson disease patients, they may cause a unique problem. Prescribing SSRIs in conjunction with selegiline (deprenyl [Eldepryl]) can theoretically cause the serotonin syndrome because SSRIs prevent serotonin reuptake while selegiline, a monoamine oxidase (MAO) inhibitor, prevents its breakdown (see Chapter 6). The actual incidence of serotonin syndrome is very low because selegiline, in the doses used for Parkinson disease treatment, selectively inhibits only MAO-B, which metabolizes dopamine; whereas the serotonin syndrome is mostly a complication of inhibition of MAO-A, which metabolizes serotonin. Similarly, when physicians prescribe the selegiline patch (Emsam) for depression, as long as the dose remains below 12 mg/day, which is standard, it inhibits MAO-B; however, selegiline patch doses greater than 12 mg/day inhibit MAO-A as well as MAO-B, and leave patients at risk of tyramine-induced hypertension.


Electroconvulsive therapy (ECT) is effective and safe for depression in Parkinson disease. In addition, it temporarily improves the rigidity and bradykinesia.


Notably, although L-dopa and dopamine agonists – dopaminergic medications – readily treat most of the illness’ physical features, they do not reverse depression. In other words, although a dopamine deficiency lies at the heart of Parkinson disease, it probably does not explain one of its chief comorbidities, depression.



Dementia


Throughout the first 5 years of Parkinson disease, patients typically continue to work (even as physicians), manage a household, participate in leisure activities, and remain free of cognitive impairment. Even when physically incapacitated, patients may retain sufficient cognitive capacity for routine intellectual activities.


However, as the illness progresses and patients age, dementia routinely complicates the illness. Dementia affects about 20% of all Parkinson disease patients, 40% of those older than 70 years, and more than 80% who have had the illness for 20 years. Its prevalence increases in proportion to the patient’s age, duration of the illness, and physical impairments. Dementia is more frequent when akinesia and rigidity rather than tremor predominate in Parkinson disease. Unlike the dementia in Alzheimer disease, the dementia in Parkinson disease is not associated with apolipoprotein E4 alleles (see Chapter 7).


Parkinson disease dementia, which differs clinically from that of Alzheimer disease dementia, is distinguished by inattention, poor memory, difficulty shifting mental sets, and bradyphrenia (slowed thinking, the cognitive counterpart of bradykinesia), as well as hallucinations. With its almost invariable gait impairment and preserved language function, Parkinson disease dementia serves as a prime example of “subcortical dementia” (see Chapter 7). The Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) are each valid screening tests for cognitive impairment in Parkinson disease; however, the MoCA is more sensitive.


When dementia and depression both complicate Parkinson disease, dementia is usually more pronounced but not qualitatively different than when it occurs without depression. Patients typically lose 2.3 points annually on the MMSE.


Of the potential causes of dementia in Parkinson disease, studies have not implicated dopamine deficiency. The simplest evidence is that dopaminergic medicines do not prevent or alleviate the dementia. One possible cause or contributor is an acetylcholine (ACh) deficiency. Positron emission tomography (PET) studies have shown a cerebral cortex cholinergic deficit in Parkinson disease patients with dementia that is more pronounced than in Alzheimer disease.


A special diagnostic hazard when evaluating a patient with parkinsonism and dementia is failing to recognize dementia with Lewy bodies disease. This illness and Parkinson disease share rigidity and bradykinesia, delusions and hallucinations, and sleep disturbances as well as cognitive impairment. One major clinical difference is that in dementia with Lewy bodies disease, dementia constitutes an initial, not a late-developing, manifestation (see Chapter 7), but it is at least a relatively late development in Parkinson’s disease. On a histologic level, dementia with Lewy bodies disease features Lewy bodies in the cerebral cortex, not just confined to the basal ganglia.






Other Psychiatric Conditions


In contrast to the frequent occurrence of comorbid depression, bipolar disorder and schizophrenia rarely complicate Parkinson disease. In fact, the rare coexistence of schizophrenia and Parkinson disease contradicts the “dopamine hypothesis” of schizophrenia, which would predict that these two conditions, one from decreased dopamine activity and the other from increased dopamine activity, would be mutually exclusive.


A dramatic comorbid psychiatric disorder that affects about 14% of Parkinson disease patients is the dopamine dysregulation syndrome (DDS), which consists of one or more of the following aberrant behaviors: compulsive self-gratifying behavior, particularly pathologic gambling, compulsive sexual behavior, compulsive buying, or binge-eating disorder. Treatment with a dopamine agonist is the most powerful risk factor. Others include being unmarried, cigarette smoking, and a family history of gambling. Reducing dopamine agonists or treating appropriate patients with DBS usually eliminates it.


Another medication-induced behavioral complication of Parkinson disease, which may be a variant of the compulsive behavior in DDS, consists of mindless, repetitive, purposeless behavior – punding. Common examples include patients’ incessantly arranging peas on their plate into small piles, dismantling small constructions and then rebuilding them, opening and shutting a door, and folding and unfolding a newspaper without reading it. Not only does punding capture the patient’s entire attention, it displaces normal daily activities and prohibits caregivers from assisting the patient. Unlike the behavior in DDS, punding does not seem to yield any pleasure or excitement. Similar behavior occurs in children with autism and adults with amphetamine intoxication. In Parkinson disease, reducing dopaminergic medicines or adding an antipsychotic medicine will reduce punding but at the risk of exacerbating parkinsonism.


In a different disorder, some Parkinson disease patients curiously tend to overmedicate themselves. They seem to express disproportionately much greater concern for their medications than their symptoms warrant, and describe their medication requirements in terms associated with an obsession or addiction. Their behavior correlates with a history of mood disorder and dopamine agonist treatment. At the other extreme, rapidly tapering or abruptly stopping their dopaminergic medicines may cast Parkinson disease patients into a state of withdrawal – with cravings, anxiety, and drug-seeking behavior – akin to when amphetamine abusers are deprived of their stimulants.



Pathology of Parkinson Disease


A well-established synthetic pathway in presynaptic nigrostriatal tract neurons normally converts phenylalanine to dopamine:



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In Parkinson disease, the nigrostriatal neurons slowly degenerate and lose their tyrosine hydroxylase. Degeneration of neurons in Parkinson disease has given rise to the term “neurodegenerative diseases.” Amyotrophic lateral sclerosis (ALS), Alzheimer disease, Huntington disease, and several other chronic, progressive illnesses also fall into this category.


The loss of tyrosine hydroxylase represents the critical failure in Parkinson disease because this enzyme is the rate-limiting enzyme in dopamine synthesis (see Fig. 18-3). With the tyrosine hydroxylase deficit, the ever-shrinking pool of remaining nigrostriatal tract neurons cannot sustain the essential synthetic pathway. Once approximately 30% of these neurons degenerate, the nigrostriatal tract cannot synthesize adequate dopamine and Parkinson disease symptoms appear.


The illness also impairs synthesis of other neurotransmitters. In particular, it leads to reduced concentrations of serotonin in the brain and cerebrospinal fluid (CSF).


The characteristic neuropathologic finding of Parkinson disease, which is immediately evident on gross examination of the brain, consists of loss of normal pigment (depigmentation) in certain brainstem nuclei: the substantia nigra (black), locus ceruleus (copper sulfate-like or blue), and vagus (Latin, wandering) motor nuclei (black).


On a microscopic level, neurons in these locations characteristically accumulate Lewy bodies, which contain a core of α-synuclein (see Chapter 7). In contrast, Lewy bodies located in the cerebral cortex, as well as the basal ganglia, constitute the histologic hallmark of dementia with Lewy bodies disease. With their abundance of Lewy bodies, both Parkinson disease and dementia with Lewy bodies disease fall under the rubric of synucleinopathies.


PET studies using fluorodopa usually show decreased dopamine activity in the basal ganglia in presymptomatic individuals as well as in those with overt Parkinson disease. Imaging presynaptic dopamine transporters may distinguish Parkinson disease from non-Parkinson conditions, including drug-induced parkinsonism (see later). Other tests, such as magnetic resonance imaging (MRI), computed tomography (CT), transcranial ultrasound examination of the substantia nigra, and routine serum and CSF analyses, fail to reveal consistent, readily identifiable abnormalities. Given the lack of specificity or sensitivity and expense of these tests, the diagnosis of Parkinson disease remains based on the patient’s clinical features and response to L-dopa treatment.



Possible Causes of Parkinson Disease


Parkinson disease ranks second to Alzheimer disease as the most commonly occurring neurodegenerative illness. In contrast to the absence of responsible toxins in Alzheimer disease, studies have implicated various environmental and industrial toxins as causes of, or even potential protectors against, Parkinson disease. As with Alzheimer disease, genetic studies have discovered several mutations as risk factors and causes of Parkinson disease in a minority of patients.



Toxins


Parkinson disease has an increased incidence in people who drink well water, particularly farmers and other workers exposed to herbicides, insecticides, and pesticides. For example, exposure to the commercial insecticides rotenone and paraquat, which shares a chemical structure with MPTP (see later), at least doubles the risk of Parkinson disease. Miners and welders who probably inhale manganese and individuals who have used illicit drugs, such as ephedrine (methcathinone), which contains potassium permanganate (KMnO4), have a markedly increased incidence of the illness. Another finding that implicates manganese among other metals in the environment is that the incidence of Parkinson disease is greatest in the Midwest and Northeast, which host most metal-emitting facilities. Solvents, particularly trichloroethylene, are more than risk factors. They also seem, in some way, to cause Parkinson disease.


The most infamous Parkinson-producing toxin is methyl-phenyl-tetrahydro-pyridine (MPTP). This substance, a byproduct of the illicit manufacture of meperidine (Demerol) or other narcotic, caused fulminant and often fatal Parkinson disease in dozens of drug abusers who unknowingly administered it to themselves. Researchers have shown that MPTP selectively poisons nigrostriatal tract neurons and use it to produce the standard laboratory animal model of Parkinson disease.


In the opposite situation, some otherwise toxic substances fail to produce Parkinson disease. For example, contrary to initial reports, 3,4-methylenedioxmethamphetamine (MDMA), commonly known as ecstasy, which depletes serotonin, probably does not cause Parkinson disease. Although several young adults developed parkinsonism after using ecstasy, they may have used MPTP or other illicit drugs or possibly carried a genetic mutation (see later). Moreover, the small number of cases, compared to the large number of probable ecstasy users, suggests that ecstasy is benign in this particular regard.


In the reverse situation, cigarette smoking varies inversely with the incidence of Parkinson disease, i.e., based on statistics, cigarette smoking seems to provide a protective effect. Coffee drinkers, those with elevated uric acid levels, and those who take anti-inflammatory drugs also have a reduced incidence of Parkinson disease.





Genetic Factors


Genetic factors play a significant role when the onset of symptoms occurs before 50 years of age and, obviously, when multiple family members have the illness. Overall, only 10–15% of Parkinson disease patients have a first-degree relative with the same illness and only about 5% of all patients have a genetic cause. Even of Parkinson disease patients younger than 50 years, only about 17% carry a mutation and many of those mutations show low penetrability.


When they cause the illness, mutations characteristically lead to early-onset illness, but follow either an autosomal dominant or recessive pattern. Genetic-induced symptoms appear on the average as young as 45 years, and occasionally in adolescence or childhood. Genetically determined varieties also differ from the sporadically occurring illness in that their histology usually lacks Lewy bodies.


Several different mutations, including ones in the PARK (the most common), leucine-rich repeat kinase-2 (LRRK2), and α-synuclein genes, either cause or allow Parkinson disease in some families. In fact, 30% or more of North African Arab and Ashkenazi (Eastern European) Jewish Parkinson disease patients who have a family history of the illness carry an LRRK2 mutation.


Recent studies have also linked a mutation in a gene encoding glucocerebrosidase (GBA) to Parkinson disease. Deficiency in this enzyme, which ordinarily leads to Gaucher disease, occurs in approximately 15% of Ashkenazi and 3% of non-Jewish Parkinson disease patients. Although the association is undoubtedly close and perhaps the most frequently occurring mutation among Parkinson disease patients, GBA deficiency may confer susceptibility rather than act as a cause.



Parkinsonism


The clinical features of Parkinson disease – in the absence of the illness – constitute the clinical condition parkinsonism. For example, when dopamine-blocking neuroleptics produce tremor, rigidity, and bradykinesia, the patient has parkinsonism, not Parkinson disease. Notably, in many illnesses characterized by parkinsonism – dementia pugilistica, Parkinson-plus diseases, and dementia with Lewy bodies disease (see later) – dementia may appear as the first or most prominent symptom.



Medication-Induced Parkinsonism


When medicines, as opposed to illicit drugs, induce parkinsonism, rigidity is the most prominent feature, all three cardinal features occur in only about one-third of cases, and individuals older than 60 years and women are particularly susceptible. Typical and most atypical antipsychotic agents – because to a greater or lesser degree they block D2 receptors – routinely cause parkinsonism. Tetrabenazine (Xenazine) induces parkinsonism because it depletes dopamine (see later and Figs 18-3 and 18-12). Similarly, nonpsychiatric medicines that block D2 receptors, such as metoclopramide (Reglan), trimethobenzamide (Tigan), prochlorperazine (Compazine), and promethazine (Phenergan), produce the same problem. Case reports have also implicated valproate (Depakote), lithium, amiodarone, and calcium channel blockers – medicines with no direct connection to D2 receptors.


Medication-induced parkinsonism so closely resembles Parkinson disease that a clinical examination cannot easily distinguish them. As one clue, medication-induced parkinsonism usually causes symmetric, bilateral signs from the onset, but Parkinson disease tends to cause asymmetric signs at its onset and remain asymmetric throughout its course. Also, antipsychotic agents often induce akathisia and dyskinesias along with the parkinsonism.


Medication-induced parkinsonism, once physicians discontinue the offending drug, should fully resolve in a few weeks. Nevertheless, signs often persist for 3 months and occasionally for 1 year. However, physicians must be careful with persistent parkinsonism patients because approximately 10% harbor Parkinson disease and some probably have dementia with Lewy bodies disease (see Chapter 7). In children and young adults, persistent parkinsonism following antipsychotic treatment suggests several neurologic illnesses (see later).


If reducing or withdrawing the suspected medicine fails to reverse medication-induced parkinsonism, physicians may institute treatment while they reconsider the diagnosis. They should, however, resist the temptation to override an antipsychotic’s block of the D2 receptors by administering dopaminergic medicines. That plan will not work and it may precipitate delirium. Administering anticholinergics to counterbalance the lack of dopamine activity may help, but their side effects may outweigh their benefits. Administering amantadine, which mildly enhances dopamine activity, may also help (see later). If these medicines reduce the parkinsonism, physicians should withdraw them after 3 months to determine if they remain necessary.





Therapy of Parkinson Disease



Medications



L-Dopa.


Treatments for Parkinson disease alleviate motor symptoms for many years, but do not reverse the neurodegeneration. Medicines maintain normal dopamine activity by enhancing dopamine synthesis, retarding its metabolism, or acting as agonists at dopamine receptors. Enhancing dopamine synthesis, usually the initial treatment, consists of substituting orally administered L-dopa for endogenous but deficient DOPA in the synthetic pathway (Fig. 18-3).



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To bypass the tyrosine hydroxylase deficiency, L-dopa penetrates the blood–brain barrier and inserts itself into the synthetic chain where it substitutes for DOPA. Acting as endogenous DOPA, L-dopa undergoes decarboxylation to form dopamine:



L-dopa remains effective until almost all the nigrostriatal tract neurons degenerate and the remaining ones can no longer synthesize, store, and appropriately release dopamine.


In contrast to the degenerating presynaptic neurons, the postsynaptic nigrostriatal neurons, which are coated with the dopamine receptors, remain intact. These receptors respond to dopamine agonists as well as to naturally synthesized and L-dopa-derived dopamine.


Prescribing L-dopa, in the “precursor replacement strategy,” is highly effective and maintains most patients’ functional status for approximately the first 5 years of the illness. During that time, enough nigrostriatal neurons remain intact to synthesize, store, and release the L-dopa-derived-dopamine. This strategy provides the most powerful, easiest to use, and least complicated symptomatic treatment. Neurologists typically prescribe L-dopa as a therapeutic trial and then for treatment until deterioration requires supplement with a dopamine agonist.



Dopa- and Dopamine-Preserving Medications


Several medications increase nigrostriatal dopa by inhibiting two enzymes – dopa decarboxylase and catechol-O-methyltransferase (COMT) – that metabolize it in the systemic circulation (Fig. 18-11). With a relative increase in nigrostriatal dopa, nigrostriatal dopamine concentration increases.



These enzyme-inhibiting medications cannot, in any significant concentration, cross the blood–brain barrier. Because the blood–brain barrier essentially excludes them from the nigrostriatal tract, they do not interfere with the normal nigrostriatal metabolism of L-dopa to dopamine. They act outside the brain to prevent the metabolism of L-dopa to dopamine or other metabolite within the systemic circulation.


One enzyme-inhibiting medication, carbidopa, inactivates dopa decarboxylase. Pharmaceutical firms have marketed fixed combinations of carbidopa and L-dopa as Sinemet. Another enzyme-inhibiting medication, entacapone (Comtan), inhibits COMT. A commercial preparation, Stalevo, combines both enzyme inhibitors – carbidopa and entacapone – with L-dopa.


These dopa-preserving medications maintain cerebral dopamine concentrations while allowing a reduced L-dopa dosage. They allow patients to avoid systemic side effects, particularly nausea, vomiting, cardiac arrhythmias, and hypotension. Some of the most troublesome side effects, nausea and vomiting, result from high doses of dopamine stimulating the emesis (vomiting) center in the medulla, which is one of the few areas of the brain not protected by the blood–brain barrier. The L-dopa and carbidopa commercial combination, Sinemet (Latin, sine without, em vomiting), almost completely eliminates that problem.


A complementary therapeutic strategy consists of blocking MAO-B, one of the main enzymes responsible for metabolizing and thus deactivating nigrostriatal dopamine. Selegiline and rasagiline (Azilect) – MAO-B inhibitors – preserve dopamine activity because they impair the oxidation of both endogenous and medically derived dopamine. As an added benefit of selegiline, its own metabolism produces minute amounts of methamphetamine and amphetamine, which provide a small but definite antidepressant effect. At least on a theoretical level, MAO-B inhibitors may also confer some neuroprotection by providing an antioxidant effect and reducing free radical formation.


On the other hand, although they ameliorate some symptoms and provide a modicum of antidepressant effect, antiparkinson MAO-B inhibitors carry a caveat. At high doses, they inhibit MAO-A as well as MAO-B. Because MAO-A is important in both serotonin and catecholamine metabolism, MAO-B inhibitors place patients in a position where they are vulnerable to the serotonin syndrome or a hypertensive crisis (see previously and Chapters 6, 9, and 21).





Other Medications


Coenzyme Q10 plays a vital role in the mitochondrial respiratory chain. Presumably because of its antioxidant effect, pretreatment with coenzyme Q10 greatly reduces the Parkinson-producing potential of MPTP. Preliminary studies suggest that it may slow the progression of Parkinson disease.


Alpha tocopherol (vitamin E), another antioxidant and free radical scavenger, should protect dopamine from destruction by free radicals and other toxins. Despite that solid rationale, a major study in Parkinson disease showed that tocopherol, either alone or in combination with selegiline, failed to slow progression of the illness.


Anticholinergics reduce tremor in Parkinson disease and other forms of parkinsonism. By reducing cholinergic activity, these medicines seem to act by maintaining the balance with the diminished dopamine activity (Fig. 18-12). On the other hand, anticholinergics routinely produce mental and physical side effects, especially in the elderly.



Amantadine enhances dopamine activity by acting on presynaptic neurons to facilitate dopamine release and inhibit its reuptake. Amantadine provides a temporary, modest improvement in rigidity and bradykinesia. It may also ameliorate L-dopa-induced dyskinesias. Unless the patient has underlying dementia, amantadine rarely produces confusion or hallucinations.



Deep Brain Stimulation


Studies have not yet established the ideal location for the electrodes, the parameters of stimulation, or even its mechanism of action, but DBS has unequivocally raised the quality of life of patients with Parkinson disease, dystonia, and essential tremor. It also has clearly helped in many cases of Tourette disorder, spasmodic torticollis, tardive dyskinesias, chronic pain, and certain psychiatric conditions, including treatment-resistant depression and obsessive-compulsive disorder (OCD: see later).


To implant DBS in Parkinson disease patients, neurosurgeons insert tiny electrodes in the subthalamic nucleus or GPi. They then connect the electrodes to a pacemaker-like device inserted into the subcutaneous tissues of the chest. For a procedure that involves a neurosurgeon’s inserting a probe deeply into each side of the brain, DBS is relatively safe.


DBS allows Parkinson disease patients to reduce their medication regimen and maintain their mobility with a great reduction in dyskinesias. It also helps patients beset by constant on-off episodes. However, DBS does not ameliorate gait impairment, postural instability, cognitive impairment, or depression. In fact, depending on the target, postoperative dopaminergic medication regimen, and other postoperative factors, several percent of Parkinson patients have developed or have had worsening of depression, approximately 0.5–1.0% had suicide ideation or attempts, and a larger proportion showed apathy. Of course, in many of these cases the symptoms were mild, transient, or amenable to treatment. Moreover, DBS does not hasten cognitive deterioration.



Athetosis


Athetosis consists of involuntary slow, continually changing, twisting movements predominantly affecting the face, neck, and distal limbs (Fig. 18-13). It sits at the beginning of a sequence – athetosis, choreoathetosis, chorea, and hemiballismus – of progressively larger and more irregular involuntary movements. In a potentially confusing aspect, additional involuntary movements may coexist with athetosis. For example, rapid jerks of chorea may punctuate slow movements of athetosis, and powerful twists of dystonia may interrupt and override athetosis’ slow fluctuations.



Usually encountered as a variety of cerebral palsy (see Chapter 13), athetosis is usually not apparent until early childhood. Most often athetosis results from combinations of perinatal hyperbilirubinemia (kernicterus), hypoxia, and prematurity. Genetic factors are unimportant.


Because athetosis originates in brain injuries that occur during the first 30 days after birth as well as in utero, which neurologists consider congenital brain injuries, seizures and mental retardation frequently accompany this movement disorder. However, with damage confined to the basal ganglia, as in many cases of athetosis, patients have normal intelligence despite disabling movements and garbled speech. Physicians, schoolteachers, family members, and friends should recognize that these patients retain cognitive and emotional capacities despite devastating physical neurologic disabilities.*


Dopamine antagonists may suppress athetosis, but their long-term use may lead to complications. Paradoxically, neurologists often offer an empiric trial of L-dopa to children with athetosis for the possibility that the movements do not represent cerebral palsy but a different illness, dopa-responsive dystonia (see later). According to preliminary reports, DBS may also reduce athetosis. Injections of one of the varieties of botulinum toxin, onabotulinumtoxinA (Botox), abobotulinumtoxinA (Dysport), rimabotulinumtoxinB (Myobloc) or incobotulinumtoxin (Xeomin), may offer several months of reduced particularly troublesome movement or coexistent spasticity. (This book refers to all these medicines as “botulinum” or “botulinum toxin.”) When neurologists inject botulinum for spasticity, dystonia, or other reason (see below), it may induce temporary weakness. Moreover, because the affected neurons reconstitute themselves, neurologists must repeat the injections – usually every 3 months.



Chorea



Huntington Disease


Of the many causes of chorea (Box 18-1), Huntington disease, previously called “Huntington’s chorea,” remains pre-eminent. Chorea, dementia, and behavioral abnormalities characterize this autosomal dominantly inherited disorder. Symptoms first emerge when patients are, on the average, approximately 37 years. However, approximately 10% of patients develop symptoms in childhood or adolescence and 25% when they are older than 50 years. Adults with the illness usually succumb to aspiration and inanition one to two decades after the diagnosis.


Jun 4, 2016 | Posted by in NEUROLOGY | Comments Off on Involuntary Movement Disorders

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