Involuntary Movement Disorders

Depression

For the first several years after onset of PD, patients may develop depression secondary to 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 PD patients vary widely due to variability in definitions and criteria among studies. Testing patients at different stages of the illness, including or excluding psychiatric comorbidities, and 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 reported prevalence of depression. By any measure, however, the prevalence of depression is substantial. Studies typically report that at least 30% of all PD patients manifest depression. The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) diagnosis of Depressive Disorder Due to Another Medical Condition would be appropriate in these cases. Standard instruments used for detecting depression are valid for use in patients with PD.

The most powerful risk factors for depression include a history of depression, cognitive impairment, and akinesia, but not tremor. In addition, younger age at onset and longer duration of illness constitute powerful risk factors.

When it occurs, depression accelerates cognitive decline, interferes with sleep, and accentuates physical disabilities. Of the non-motor PD symptoms, depression correlates most closely with a poor quality of life. Anxiety or apathy may complicate depression, but either or both can be present without concomitant depression. Suicide is uncommon, but may be more likely in patients who are younger, have fewer comorbidities, better cognition, and poorer motor function.

Physicians should 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, caregivers shoulder an ever-increasing burden that may overwhelm them. Caregivers are especially susceptible to depression if the patient is depressed or has had a lengthy illness.

Treatment of Comorbid Depression

Psychological support, social services, and rehabilitation often help during the first several years of PD. However, as the disease progresses, optimal treatment almost always requires antidepressants. Neurologists should optimize the patient's antiparkinson medication regimen before anyone prescribes antidepressants because PD medicines can improve mood as well as motor symptoms.

However it is accomplished, treatment of depression improves PD patients' quality of life and reduces their disability. Antidepressants may be just as effective in treating depression comorbid with PD as they are in treating depression unassociated with PD.

Several considerations should guide the choice of an antidepressant. Antidepressants and other psychotropics should be anxiolytic. Earlier studies found tricyclic antidepressants (TCAs) to be more effective than selective serotonin reuptake inhibitors (SSRIs). However, Parkinson disease patients, who are generally elderly, are susceptible to the anticholinergic side effects of TCAs, and more recent research has demonstrated the efficacy of SSRIs in this population.

Although SSRIs carry fewer side effects than TCAs, they may cause a unique problem in PD patients. Prescribing an SSRI in conjunction with a monoamine oxidase (MAO) inhibitor (such as selegiline or rasagiline) can theoretically cause the serotonin syndrome because SSRIs prevent serotonin reuptake while MAO inhibitors prevent its breakdown (see Chapter 6 ). The actual incidence of serotonin syndrome is minuscule because, at the doses used for treating PD, the selegiline 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 selectively 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 or serotonin syndrome.

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

Dementia

During the first 5 years after the onset of PD, patients often continue to work, manage a household, participate in leisure activities, and remain free of cognitive impairment. Even when physically incapacitated, patients may retain cognitive capacity sufficient for routine intellectual activities.

However, as PD progresses and patients age, dementia commonly complicates the illness. In these cases, the DSM-5 would apply the diagnosis of Major Neurocognitive Disorder Due to Parkinson disease. Dementia affects 24% to 50% of patients with PD. Its prevalence increases in proportion to the patient's age, duration of the illness, physical impairments, and carrying apolipoprotein E (ApoE) 4 alleles (see Chapter 7 ). Dementia is more frequent when akinesia and rigidity rather than tremor predominate. When dementia and depression both complicate Parkinson disease, dementia is usually more severe than when it occurs without depression.

PD dementia, which differs clinically from Alzheimer disease dementia, is distinguished by inattention, poor memory, difficulty shifting mental sets, and bradyphrenia (slowed thinking, the cognitive counterpart of bradykinesia). With its almost invariable gait impairment and preserved language function, the dementia of PD serves as a prime example of “subcortical dementia” (see Chapter 7 ). The Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) are both valid screening tests for cognitive impairment in Parkinson disease; however, the MoCA is more sensitive. PD patients typically lose 2.3 points annually on the MMSE.

Of the potential causes of dementia in PD, 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. PET studies have shown a cholinergic deficit in the cerebral cortex of PD 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 (see Chapter 7 ). This illness shares important features with PD including rigidity and bradykinesia, delusions and hallucinations, sleep disturbances, and cognitive impairment. One major clinical distinction is dementia constitutes an early manifestation of dementia with Lewy bodies, but when dementia occurs in PD, it is a relatively late development. On a histologic level, dementia with Lewy bodies features Lewy bodies throughout the cerebral cortex, not just in the substantia nigra.

As with comorbid depression, treatments that reduce PD motor symptoms do not ameliorate comorbid dementia. For example, dopaminergic medicines alleviate tremor and rigidity, but they fail to improve cognitive function. Likewise, deep brain stimulation (DBS), which greatly reduces Parkinson disease motor symptoms (see later), does not reverse dementia. On the other hand, cholinesterase inhibitors, such as rivastigamine (Exelon), may slow cognitive decline and reduce visual hallucinations.

Psychosis

PD patients commonly experience visual hallucinations, such as complex visions of people and animals that fluctuate throughout the daytime and worsen at night. During hallucinations, PD patients initially maintain a clear sensorium and retain some insight. As the disease progresses, most patients develop vivid hallucinations, disordered thinking, and often paranoid ideation that may center on physicians and family members.

Psychosis in PD correlates most closely with dementia and the duration and severity of the illness. It also correlates with the number and dosage of dopaminergic medications and signs of excessive medication, particularly dyskinesias. Notably, although PD medications often precipitate psychosis, they cause neither comorbid depression nor dementia. Other risk factors for psychosis include advanced age, sleep disturbances, and visual impairment. Finally, intercurrent illnesses, such as pneumonia or a urinary tract infection, readily precipitate psychosis or delirium; such reversible causes should always be sought, especially when symptoms begin abruptly in the absence of another identifiable trigger (such as an increase in medication). Thus, depending on the circumstances and clinical features of a particular situation, appropriate DSM-5 diagnoses may be Delirium, Substance/Medication-Induced Psychotic Disorder, or Psychotic Disorder Due to Another Medical Condition.

In any case, once psychosis develops, it predisposes patients to dementia (which may have already developed), nursing home placement, and death within 2 years. Compared to the physical disabilities and cognitive impairment, psychosis imposes the greatest stress on caregivers.

Treatment

If possible, neurologists eliminate benzodiazepines, opioids, and other medicines that cause adverse psychological reactions. However, in view of the likelihood that the antiparkinson medications are the culprit, neurologists first adjust the schedule and then, if necessary, taper or discontinue them.

Because administration of antiparkinson medications before bedtime tends to cause nightmares and hallucinations, and because ease of movement is usually less important when patients are asleep, neurologists advise patients to take the last daily dose in the early evening rather than at bedtime. Also, neurologists avoid suddenly stopping these medicines because abrupt withdrawal may lead to irreversible motor deterioration, complications of immobility, or even the neuroleptic malignant syndrome (NMS) (see Chapter 6 ).

Neurologists then generally reduce antiparkinson medicines in order of the likelihood of their causing psychosis or other mental aberrations: first anticholinergics, then dopamine agonists, and lastly levodopa. Of course, patients can tolerate medication withdrawal only up to a point before disabling motor impairments return. In general, patients, physicians, and caregivers prefer mild rigidity and some immobility to psychosis.

Despite the “black box” warnings and other caveats, doctors may have no choice but to prescribe an antipsychotic if Parkinson-related psychosis becomes persistent, disruptive, or dangerous. However, they should avoid prescribing typical dopamine receptor-blocking agents because they exacerbate parkinsonism and may increase mortality of elderly patients with psychosis from dementia unrelated to Parkinson disease. For Parkinson disease-related psychosis, physicians might prescribe pimavanserin (Nuplazid) because it suppresses visual hallucinations and possibly other symptoms of psychosis. In addition, it does not exacerbate parkinsonism probably because it is an inverse agonist and basically an antagonist of serotonin rather than dopamine (see Chapter 21 ). Clozapine (Clozaril), which also targets serotonin receptors, may be helpful.

Other Psychiatric Conditions

In contrast to the frequency of comorbid depression, bipolar disorder and schizophrenia rarely complicate PD. In fact, the apparent coexistence of schizophrenia and PD contradicts the “dopamine hypothesis” of schizophrenia, which would predict these two conditions, one due to decreased dopamine activity and the other from increased dopamine activity, would be mutually exclusive. (Physicians should consider the diagnoses of dementia with Lewy bodies and drug-induced parkinsonism when PD and schizophrenia appear to co-occur.)

Impulse control disorders , a group of dramatic psychiatric complications of PD, afflicts about 14% of Parkinson disease patients by causing compulsive or pathological gambling, sexual behavior, shopping, or eating—alone or in combination. Sometimes only collateral history from a patient’s partner may disclose potentially embarrassing behavior. Impulse control disorders generally do not develop until at least 4 years of the onset of the disease. Treatment with a dopamine agonist is the most powerful risk factor as it is associated with a fivefold increased incidence of impulse control disorders. Other risk factors include being unmarried, cigarette smoking, and a personal or family history of gambling. Reducing dopamine agonists or, when appropriate, performing DBS usually reduces or even eliminates impulse control disorders. Cognitive-behavioral therapy may reduce their severity.

Another medication-induced behavioral complication of Parkinson disease consists of mindless, repetitive, purposeless behavior— punding . Common examples include incessantly arranging peas on one’s plate into small piles, building and then dismantling small constructions, 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 also displaces normal daily activities and prohibits caregivers from assisting the patient. Punding does not seem to yield any pleasure or excitement. Similar behavior occurs in children with autism and adults with amphetamine intoxication. Other impulse control behaviors that beset PD patients include “hobbyism” (repetitive activities but at a higher level than punding) and hoarding. Reducing dopaminergic medicines or adding an antipsychotic medicine should decrease these behaviors but at the risk of exacerbating parkinsonism.

In a related disorder, dopamine dysregulation syndrome (formerly known as hedonistic homeostatic dysregulation ), some PD patients curiously tend to overmedicate themselves. They express much greater desire for their medication (usually levodopa) than their symptoms warrant and describe their medication requirements in terms associated with an obsession or addiction. At the other extreme, rapidly tapering or abruptly stopping dopaminergic medicines may send PD patients into a state of withdrawal—with cravings, anxiety, and drug-seeking behavior—akin to when amphetamine abusers are deprived of their stimulants.

Fatigue may be severe and may not readily respond to standard treatments. Apathy and anxiety are also common in PD and may have significant impact on patients' quality of life.

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 share a chemical structure with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine ( MPTP , see later), at least doubles the risk of Parkinson disease. Exposure to solvents is also a risk factor. High levels of manganese (manganism), possibly from mining or welding, lead to parkinsonism (see below).

The most infamous PD-producing toxin is MPTP. This substance, a by-product of the illicit manufacture of meperidine (Demerol) and other narcotics, caused fulminant and often fatal PD in dozens of drug abusers who unknowingly administered it to themselves. Researchers have shown MPTP selectively poisons nigrostriatal tract neurons and now use it in the laboratory to produce the standard animal model of PD.

In the opposite situation, some otherwise toxic substances fail to produce Parkinson disease. For example, contrary to initial reports, 3, 4-methylenedioxy-methamphetamine (MDMA) , commonly known as ecstasy , which depletes serotonin, probably does not cause PD. 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 below). Moreover, the small number of cases compared to the large number of probable ecstasy users indicates that ecstasy does not cause PD.

Cigarette smoking varies inversely with the incidence of PD: based on statistics, cigarette smokers develop PD at lower rates. Coffee drinkers, those with elevated uric acid levels, and those who take ibuprofen regularly also have a reduced incidence of Parkinson disease. These associations do not necessarily denote a protective effect of these behaviors, though such an effect has been hypothesized.

In addition to the potential for dopamine receptor-blocking agents to cause reversible parkinsonism (see below), recent publications have raised the possibility that exposure to neuroleptics may increase the risk of eventually developing PD. More research is needed for confirmation of such a relationship and elucidation of the possible mechanisms behind it.

Oxidative Stress

Research stemming from the neurotoxicity of MPTP led to the oxidative stress theory , which proposes that defective mitochondria in Parkinson disease patients cannot detoxify potentially lethal endogenous or environmental oxidants, particularly free radicals , such as superoxides and nitric oxide. Free radicals are atoms or molecules that are unstable because they contain a single, unpaired electron. To complete their electron pairs, free radicals snatch electrons from neighboring atoms or molecules. Loss of electrons oxidizes cells and causes fatal injury.

When endogenous MAO oxidizes MPTP, the product, methylphenylpyridinium (MPP ⁺ ), generates intracellular free radicals that inhibit complex I of the mitochondrial respiratory chain. In laboratory animals, pretreatment with MAO inhibitors blocks this reaction. It thereby prevents MPP ⁺ formation, subsequent tissue oxidation, and development of parkinsonism.

Based upon this theory, neurologists have blamed oxidative stress and free radicals for numerous neurologic illnesses. However, the theory remains unproven. Moreover, antioxidants do not prevent or alter any of the illnesses.

Head Trauma

Even head trauma severe enough to cause loss of consciousness and posttraumatic amnesia only slightly increases the subsequent risk of a patient's developing PD. However, if the patient who sustains comparable head trauma carries one or more alpha-synuclein gene mutations, the subsequent risk of PD rises approximately 3 to 11 times.

Repeated head injuries may cause a Parkinson-like syndrome, dementia pugilistica or, in current parlance, chronic traumatic encephalopathy (see Chapter 22 ). This condition consists of the insidious development of intellectual deterioration, dysarthria, stiffness, clumsiness, spasticity, and striking bradykinesia. Boxers who have been lightweight, alcoholic, and lost many matches have been most susceptible. The impairments, which often end their careers, typically progress after retirement.

CT and MRI show white matter changes, focal contusions, and cerebral atrophy in proportion to the number of boxing matches. Autopsy studies reveal hydrocephalus and atrophy of the corpus callosum and cerebrum. Histologic examination shows Alzheimer-like neurofibrillary tangles and, with special stains, amyloid plaques, but no Lewy bodies.

Genetic Factors

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

When mutations cause the illness, they characteristically lead to early-onset illness, and follow either an autosomal dominant or recessive pattern. Symptoms of hereditary forms of PD appear on 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 parkin , 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 patients with PD who have a family history of the illness carry a LRRK2 mutation. Curiously, cases of genetically determined Parkinson disease lack Lewy bodies in the basal ganglia

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

Prion and Other Infections

Prion diseases result from misfolding of proteins that deposit in the brain and disrupt normal neuronal structure and activity (see Chapter 7 ). Recently, investigators have begun to consider the idea that α - synuclein might act as a prion-like protein. This hypothesis is based on the finding that mutations in the gene coding for α - synuclein, which are known to cause familial PD, cause a conformational change in this protein that promotes aggregation in the brain. Using an animal model, researchers have even succeeded in documenting the spread of Lewy bodies following inoculation of misfolded α - synuclein, as would be expected of an infectious agent.

In a plausible component of this theory, several studies have proposed that α-synuclein from the appendix and other sites in the gastrointestinal tract travels up the vagus nerve to the medulla. Once entrenched there, α-synuclein acts like a prion to cause an ascending, domino-like spread of intraneuronal α-synuclein accumulations in upper areas of the brainstem and cerebrum. This theory stemmed from the observation that individuals who had undergone an appendectomy or truncal vagotomy had a reduced incidence of Parkinson disease, attributed to the inability of α-synuclein to reach the CNS due to the appendectomy or interruption of the vagus nerve.

In addition to the salient respiratory involvement, patients with COVID-19 also manifest a wide variety of neurologic symptoms involving the central and peripheral nervous systems. Loss of smell and taste is perhaps the most common, but stroke, encephalopathy, seizure, and Guillain-Barré syndrome have also been frequent manifestations. However, COVID-19 has not seemed to induce significantly high rates of parkinsonism or other movement disorders.

By way of a historical contrast, the 1918 Spanish influenza pandemic caused encephalitis lethargica . Patients with “Spanish flu,” while acutely ill, often developed acute movement disorders, including dystonia, tremor, chorea, and myoclonus. Years later, survivors frequently developed post-encephalitic parkinsonism. Whether COVID-19 survivors will develop parkinsonism or other movement disorders after a delay of years remains to be seen. Researchers have set up large-scale registries to follow these patients over time.

Antipsychotic Medication-Induced Parkinsonism

When medicines, as opposed to illicit drugs, induce parkinsonism, rigidity is the most prominent feature. In fact, all three cardinal features of parkinsonism occur in only about one-third of cases. As with PD, individuals older than 60 years are vulnerable to medication-induced parkinsonism. Typical and most atypical antipsychotic agents—because to a greater or lesser degree they all block D2 receptors—routinely cause parkinsonism. Likewise, nonpsychiatric medicines that block D2 receptors—such as metoclopramide (Reglan), prochlorperazine (Compazine), and promethazine (Phenergan)—produce the same problem. Tetrabenazine (Xenazine) and related medicines also induce parkinsonism because they deplete dopamine from presynaptic neurons (see later, Figs. 18.3 and 18.11 , and Chapter 21 ). 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 PD that clinical examination cannot reliably distinguish them. As one clue, medication-induced parkinsonism usually causes symmetric, bilateral signs from the onset, but PD 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.

Once physicians discontinue the offending drug, medication-induced parkinsonism usually resolves in a few weeks, but sometimes it lasts for 3 months and occasionally for 1 year. However, physicians must be careful with patients who show persistent parkinsonism because up to 25% harbor PD or a Parkinson-plus syndrome that the medication may have unmasked. 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 or psychosis. Administering anticholinergics to counterbalance the lack of dopamine activity may help, but their side effects may outweigh their benefits. Administering amantadine (Symmetrel, Osmolex), which mildly enhances dopamine activity, may also help (see later). If these medicines reduce the parkinsonism, physicians should taper them after 3 months to determine if they remain necessary.

A DaTscan is valuable in distinguishing true PD from antipsychotic medication-induced parkinsonism (see before). In the true PD, a DaTscan will show decreased, usually asymmetric activity in the basal ganglia, but in antipsychotic medication-induced parkinsonism and essential tremor, a DaTscan will show normal and symmetric activity in the basal ganglia (see Fig. 20.30 ).

Parkinson-Plus Diseases

A group of related neurodegenerative illnesses—loosely termed Parkinson-plus diseases or atypical parkinsonian syndromes —shares many physical signs with PD and its predominantly subcortical dementia. However, other features set them apart from PD and differentiate one from another. Overall, compared to PD, Parkinson-plus diseases follow a more rapid course and respond less to dopaminergic medications.

Multisystem atrophy ( MSA ), a family of Parkinson-plus diseases, includes a cerebellar subtype (formerly olivopontocerebellar degeneration ) that is notable for ataxia and a subtype with pronounced autonomic dysfunction (formerly Shy–Drager syndrome ). MSA, like PD, is a synucleinopathy; however, levodopa is much less beneficial in MSA than in PD.

Progressive Supranuclear Palsy

Patients with PSP usually present with parkinsonism, except that they rarely have a tremor. Eventually they develop dementia, which the DSM-5 would label as Major Neurocognitive Disorder Due to Another Medical Condition.

PSP patients have predominantly axial rigidity that forces their head, neck, and entire spine to remain overly upright and unnaturally straight. Their posture contrasts with the flexed head and neck and kyphosis of the spine typical of a patient with PD (see Fig. 18.9A ). In addition, their postural instability occurs at the onset of PSP and accounts for their falling, which is sometimes incapacitating or even fatal. PSP patients show a slight male predominance and typically begin showing signs of their illness between 60 and 70 years. They inexorably deteriorate over approximately 7 years.

The pathognomonic feature of PSP, which may not appear until 3 years after the onset of parkinsonism, consists of loss of ability to look voluntarily in vertical directions. As the disease progresses, they eventually lose lateral eye movements, and finally their eyes stay fixed in a straight-ahead position. To circumvent the lack of supranuclear (cortical) input, neurologists can recruit the labyrinthine system and brainstem systems by flexing and extending the patient's neck to elicit “doll's eyes” or oculocephalic vertical reflex movements. In PSP, despite the absence of supranuclear control, this maneuver directly stimulates the brainstem nuclei and causes the eyes to move up and down ( Fig. 18.12 ). This constellation of eye movement abnormalities constitutes the best clinical diagnostic test for PSP.

PSP, like frontotemporal dementia, is considered a tauopathy (see Chapter 7 ) because tau-containing neurofibrillary tangles accumulate in neurons. As with frontotemporal dementia patients, PSP patients generally show apathy, aberrant behavior, disinhibition, executive disability, reduced verbal output, and pseudobulbar palsy. Both groups of patients also share cognitive decline to the point of dementia. Many patients with PSP have a variety of pathologic changes in the brain at autopsy, including evidence of concomitant Alzheimer disease, PD, dementia with Lewy bodies, and other abnormalities.

In PSP, the frontal cortex, basal ganglia, and upper brainstem undergo degeneration. MRI can be helpful by demonstrating the hummingbird sign: on sagittal views, due to atrophy of the rostral midbrain, the brainstem looks like a hummingbird. PET shows predominant frontal lobe hypometabolism, but not as distinctively as in frontotemporal dementia. Unfortunately, levodopa replacement does not significantly correct the parkinsonism of PSP, and cholinesterase inhibitors have little or no impact on the dementia.

Parkinsonism in Children and Young Adults

Although PD occasionally arises in individuals younger than 21, such early onset is rare and usually the expression of a gene mutation. Among patients in this age group, parkinsonism more commonly arises from other conditions:

• Dopa-responsive dystonia

• Early-onset generalized (DYT1) dystonia

• Juvenile Huntington disease

• Side effects of medications or illicit drugs

• Wilson disease

In some of these disorders, dementia and psychiatric abnormalities—psychosis, depression, personality disorders—regularly accompanies the parkinsonism. Moreover, other abnormal movements also may be present.

Levodopa (L-DOPA)

Treatments for Parkinson disease alleviate motor symptoms for many years, but do not reverse—or even retard—the neurodegeneration. Medicines maintain normal dopamine activity by enhancing dopamine synthesis, inhibiting its metabolism, or acting as agonists at dopamine receptors. The most effective treatment consists of substituting orally administered levodopa to replace the deficiency of endogenous L-DOPA in the synthetic pathway for dopamine (see Fig. 18.3 ). As a first step in treating Parkinson disease, neurologists most often prescribe the well-known levodopa-carbidopa combination, Sinemet (see later).

Bypassing the tyrosine hydroxylase deficiency, the levodopa penetrates the blood–brain barrier and substitutes for endogenous L-DOPA. It undergoes decarboxylation to form dopamine. (Oral administration of dopamine itself is not effective because it does not cross the blood–brain barrier.) Levodopa 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 express the dopamine receptors, remain intact in PD. They not only respond to dopamine but also to synthetic dopamine agonists; however, dopamine itself remains the most effective stimulus.

Prescribing levodopa as a “precursor replacement strategy” 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 levodopa-derived dopamine. This strategy provides the most powerful, easiest to use, and least complicated symptomatic treatment. Neurologists typically prescribe levodopa as a therapeutic trial and then continue treatment until deterioration requires supplementation with another agent. If the levodopa medicine does not reverse the symptoms, neurologists reconsider the diagnosis of Parkinson disease.

Dopa- and Dopamine-Preserving Medications

Several medications increase nigrostriatal L-DOPA by inhibiting one or both enzymes— dopa decarboxylase and catechol-O-methyltransferase (COMT) —that metabolize it in the systemic circulation ( Fig. 18.13 ). One enzyme-inhibiting medication, carbidopa , inactivates peripheral dopa decarboxylase, resulting in increased penetration of levodopa through the blood–brain barrier and higher concentrations in the brain. In turn, this strategy permits the dose of levodopa to be kept low to avoid systemic dopaminergic side effects—particularly nausea, vomiting, cardiac arrhythmias, and hypotension. The nausea and vomiting, which can be troublesome and result in regurgitating the medicines, stems from high doses of dopamine stimulating the emesis (vomiting) center in the medulla, one of the few areas of the brain not protected by the blood–brain barrier. Pharmaceutical firms have marketed several fixed combinations of carbidopa and levodopa as Sinemet (Latin sine , without + emesis , vomiting) in recognition of the dramatic reduction of vomiting by adding carbidopa. Neurologists can also reduce this side effect by prescribing levodopa by an inhaler (Inbrija).

They sometimes prescribe COMT inhibitors—entacapone (Comtan) or opicapone (Ongentys)—in conjunction with levodopa. Similarly, a combination pill, Stalevo, includes entacapone along with levodopa and carbidopa.

A complementary therapeutic strategy aimed at preserving dopamine activity consists of blocking MAO-B, one of the main enzymes responsible for metabolizing and thus deactivating nigrostriatal dopamine. The MAO-B inhibitors selegiline (Eldepryl) and rasagiline (Azilect) 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 small amounts of methamphetamine and amphetamine that 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, MAO-B inhibitors carry a risk. At high doses, they inhibit MAO-A as well as MAO-B. Because MAO-A metabolizes both serotonin and catecholamine, high doses of MAO-B inhibitors leave patients vulnerable to the serotonin syndrome or a hypertensive crisis (see previous and Chapter 6, Chapter 9, Chapter 21 ).

Dopamine Agonists

As an initial medication or when dopamine production eventually falls to insufficient levels, dopamine agonists stimulate postsynaptic dopamine receptors (see Fig. 18.3 ). Sidestepping dysfunctional presynaptic neurons, dopamine agonists act directly on D2 and to a lesser extent on other postsynaptic dopamine receptors.

Two oral dopamine agonists are currently on the market, pramipexole (Mirapex) and ropinirole (Requip). Another, rotigotine (Neupro), is available as a transdermal patch. The dopamine agonist, apomorphine—available as a subcutaneous injection (Apokyn) and as a sublingual film (Kynmobi)—rescues Parkinson disease patients from a sudden loss of dopamine activity but has a short duration of action. Apomorphine also rapidly reverses dopamine activity deficiency in NMS.

Problems With Dopaminergic Medicines

Even though dopamine precursors and agonists reverse the rigidity and bradykinesia of PD, at least in its early stages, they often fail to alleviate these symptoms in its later stages. Even from the outset, they have little effect on some motor and most neuropsychiatric symptoms. These dopaminergic medicines do not alleviate dysarthria, dysphagia, gait freezing, tendency to fall, dementia, hallucinations, depression, or other neuropsychiatric comorbidities—symptoms that often reduce patients' quality of life.

In addition to failing to help certain symptoms, the dopaminergic agents may cause significant adverse effects, such as dyskinesias, sleep disturbances, visual hallucinations, thought disorders, and other mental status changes. The dyskinesias consist of oral-buccal-lingual movements, chorea, akathisia, dystonic postures, and rocking. Many of the dyskinesias are mild and intermittent and do not inhibit patients' function; however, sometimes they cause gait impairment or resemble tardive dyskinesia (see later). Nevertheless, patients tend to prefer overactivity, which allows them to walk and care for themselves despite having dyskinesias, to under stimulation with the attendant rigidity and immobility.

Other Medications

Alpha tocopherol (vitamin E), a popular 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. Coenzyme Q10 is another antioxidant. In a preliminary study, it appeared to slow progression in PD, but more rigorous research did not support a protective role.

Anticholinergic agents, such as trihexyphenidyl (Artane) and benztropine (Cogentin), reduce tremor in PD and other forms of parkinsonism. By reducing cholinergic activity, these medicines seem to act by maintaining the balance with the diminished dopamine activity (see Fig. 18.11 ). 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. It also has anticholinergic properties. In early mild PD, amantadine provides a temporary, modest improvement in tremor, rigidity, and bradykinesia. An extended-release form of amantadine (Gocovri) may reduce levodopa-induced dyskinesias.

In a newly introduced, different strategy, an adenosine receptor antagonist, istradefylline (Nourianz), reportedly reduces parkinsonian symptoms and signs when added to levodopa. Its mechanism of action is through its inhibiting A _2A adenosine receptors in the striatum, decreasing activation in the indirect output pathway from the striatum, and thereby facilitating movement.

Invasive Procedures

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 improved the quality of life of patients with Parkinson disease, dystonia, and essential tremor. It also has 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.

In DBS surgery for PD patients, neurosurgeons insert tiny electrodes into the subthalamic nucleus or GPi. They then connect the electrodes to a pacemaker-like device inserted into the subcutaneous tissues of the chest. Potential surgical complications include cerebral hemorrhage, infection, and electrode fracture. Unlike the earliest devices, current ones allow patients to undergo MRI.

DBS often allows PD patients to reduce their medication regimen and maintain their mobility with a considerable reduction in dyskinesias. It also helps reduce on–off episodes. However, DBS does not ameliorate gait impairment, postural instability, cognitive impairment, or depression. In one study, depending on the target and various postoperative factors, some PD patients developed or had worsening depression; approximately 0.5% to 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.

Alternatively, a less invasive procedure is external application of a sharply focused ultrasound beam aimed at certain basal or thalamic ganglia. The energy of the sound waves obliterates the chosen structure. This technique improves tremor in tremor-predominant PD and in essential tremor (see later). Unlike the electrode placement in DBS, the lesions produced by ultrasound are fixed. Complications of the procedure, which is too new to have been evaluated in long-term studies, have included dysarthria, gait impairment, and dyskinesias.