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.

Treatment of Comorbid Dementia

As with comorbid depression, treatments that reduce Parkinson disease motor symptoms do not ameliorate comorbid dementia. For example, dopaminergic medicines alleviate tremor and rigidity, but they fail to improve cognitive function. Cholinesterase inhibitors may slow cognitive decline and reduce visual hallucinations. Even deep brain stimulation (DBS), which greatly reduces Parkinson disease motor symptoms (see later), does not reverse dementia.

Psychosis

Parkinson disease patients commonly experience visual hallucinations that usually fluctuate throughout daytime and worsen at night. They usually constitute complex visions of people and animals. Patients typically initially maintain a clear sensorium and retain some insight. As the disease progresses, the majority of patients develop disordered thinking and often paranoid ideation that may center on treating physicians and family members, as well as more vivid hallucinations.

Psychosis in Parkinson disease correlates most closely with dementia and the illness’ duration and severity. It also correlates with the number and strength of dopaminergic medications and signs of excessive medication, particularly dyskinesias. Notably, although Parkinson disease medications often precipitate psychosis, they cause neither the comorbid depression nor dementia. Other risk factors for psychosis include advanced age, sleep disturbances, and visual impairment. Finally, intercurrent illnesses, such as pneumonia, readily precipitate psychosis or delirium.

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 and cognitive disabilities, psychosis imposes the greatest stress on caregivers.

Treatment of Comorbid Psychosis

Because of antiparkinson medications’ role in causing or exacerbating psychosis, neurologists usually taper or adjust their schedule before adding antipsychotics. They generally reduce medicines by the likelihood of their causing mental aberrations: anticholinergics, dopamine agonists, and lastly, L-dopa. Of course, patients can tolerate medication withdrawal only up to a point. Afterwards disabling motor impairments return. In general, patients, physicians, and caregivers prefer mild rigidity and some immobility to psychosis.

Because administration of antiparkinson medication before bedtime tends to cause nightmares and hallucinations, neurologists advance the last daily dose to the early evening. Also, they avoid suddenly stopping these medicines because their abrupt withdrawal may lead to irreversible motor deterioration, complications of immobility, or even the neuroleptic-malignant syndrome (NMS) (see Chapter 6).

Despite the “black box” warnings and other caveats, physicians eventually prescribe an antipsychotic in the majority of cases because the psychosis typically overwhelms the situation. Clozapine is more likely to suppress psychosis and less likely to exacerbate parkinsonism than risperidone, olanzapine, quetiapine, and aripiprazole. Anticholinesterases, such as rivastigmine, may reduce visual hallucinations and improve cognitive impairments.

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.

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.

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.

Accepting the 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 at least to cause loss of consciousness and posttraumatic amnesia only slightly increases the subsequent risk of the patient’s developing Parkinson disease. However, if the patient who sustains comparable head trauma carries one or more alpha-synuclein genes, the subsequent risk of Parkinson disease rises approximately 3–11 times.

Repeated head injuries may cause a Parkinson-like syndrome, dementia pugilistica, which the public recognizes as the “punch-drunk syndrome.” Dementia pugilistica consists of insidiously developing intellectual deterioration, dysarthria, stiffness, clumsiness, spasticity, and striking bradykinesia. Boxers who have been lightweight, alcoholic, and lost many matches have been most susceptible to this disorder. The impairments, which often herald the end of their career, often 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. As in Parkinson disease, the substantia nigra lose their pigmentation. Histologic examination shows Alzheimer-like neurofibrillary tangles and, with special stains, amyloid plaques. However, despite its similarity to Parkinson disease, dementia pugilistica’s histology does not include Lewy bodies and its clinical features do not respond to L-dopa.

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.

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.

Parkinson-Plus Diseases

A group of related neurodegenerative illnesses – loosely termed Parkinson-plus diseases – share many of Parkinson disease physical signs and its predominantly subcortical dementia. However, other features set them apart from Parkinson disease and separate one from another. Overall, compared to Parkinson disease, Parkinson-plus diseases follow a more rapid course and respond less well to dopaminergic medications.

Limited oculomotor movements and axial rigidity characterize the most commonly occurring Parkinson-plus disease, progressive supranuclear palsy. Multisystem atrophy (MSA), a family of Parkinson-plus diseases, includes olivopontocerebellar degeneration, which is notable for ataxia, and Shy–Drager syndrome, notable for pronounced autonomic dysfunction. MSA, like Parkinson disease, is a synucleinopathy; however, in contrast to Parkinson disease, MSA causes loss of postsynaptic D₂ receptors and does not respond to L-dopa treatment.

Parkinsonism in Children and Young Adults

Although Parkinson disease occasionally arises in individuals younger than 21 years, such an early onset is rare and usually the expression of a gene mutation. Among patients in this age group, other conditions more commonly cause parkinsonism. In some of them, dementia, psychosis, depression, a personality disorder, or other psychiatric symptom regularly accompanies the parkinsonism:

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).

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.

FIGURE 18-11 Medicines that inhibit catechol-O-methyltransferase (COMT), such as entacapone, and those that inhibit decarboxylase, such as carbidopa, slow the metabolism of L-dopa. Because of the blood–brain barrier, they do not affect dopamine synthesis in the nigrostriatal tract. These enzymes, combined with L-dopa, permit smaller L-dopa doses, which minimizes systemic side effects.

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).

Dopamine Agonists

As an initial medication or when dopamine production eventually falls to inadequate levels, dopamine agonists – pramipexole and ropinirole – provide stimulation of postsynaptic dopamine receptors (see Fig. 18-3). Bypassing degenerated presynaptic neurons, dopamine agonists act directly on D₂ and, to a lesser extent, on other postsynaptic dopamine receptors.

One dopamine agonist – injectable apomorphine – rescues Parkinson disease patients from a sudden loss of dopamine activity. More important, it also rapidly reverses dopamine activity deficiency in NMS.

Problems with These Dopaminergic Medicines

Even though dopamine precursors and agonists miraculously reverse the rigidity and bradykinesia in at least the early stages of Parkinson disease, they often fail to alleviate these symptoms in its latter stages and cannot, at any time, alleviate others. In particular, these dopaminergic medicines do not alleviate dysarthria, dysphagia, gait freezing, tendency to fall, dementia, hallucinations, depression, or other psychiatric comorbidities – symptoms that often most reduce the quality of life.

In addition to failing to help certain symptoms, the dopaminergics may cause 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. Most of the dyskinesias are transient and do not inhibit patients’ function; however, sometimes they cause gait impairment or resemble tardive dyskinesia (see later). Despite most patients’ problems with dyskinesias, they prefer overactivity, which allows them to walk and care for themselves, to understimulation, with its rigidity and immobility.

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.

FIGURE 18-12 In a classic but limited model, dopamine and acetylcholine (cholinergic) activity normally balance each other. When Parkinson disease reduces dopamine activity, the left side of the scale rises. Dopamine precursors, dopamine agonists, and anticholinergics – Parkinson disease treatments – restore the balance. Conditions characterized by excessive dopamine activity, such as chorea, push the left side downward. Substances that either antagonize or deplete dopamine, or enhance cholinergic activity, restore the balance.

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.

Clinical Features

In contrast to the slow, writhing, continuous movements of athetosis, chorea consists of random, discrete, rapid movements that jerk the pelvis, trunk, and limbs (Fig. 18-14). Chorea also includes involuntary facial movements that produce brief, meaningless expressions (Fig. 18-15). When walking, the chorea characteristically interrupts patients’ cadence and stability (Fig. 18-16). In fact, the abnormal gait gave rise to the term chorea, (Greek, chorea, dance).

FIGURE 18-14 As in this woman with Huntington disease, chorea consists of intermittent, random involuntary movements, such as brisk pelvic, trunk, and limb jerks. It also encompasses a mere flick of a finger or wrist, forward jutting of the leg, or shrugging of the shoulder.

FIGURE 18-15 Huntington disease patients characteristically make unexpected, inappropriate, and incomplete facial expressions. Without provocation, they frown, raise eyebrows, and smirk. Because their tongue frequently protrudes, this chorea occasionally mimics tardive dyskinesia.

FIGURE 18-16 The signature of Huntington disease is a jerky gait that results from intermittent, unexpected trunk and pelvic motions, spontaneous knee flexion and extension, lateral swaying, variable cadence, and unequal stride length.

Movements in chorea occur with random timing and distribution. In other words, chorea consists of nonstereotyped movements. Also, chorea, as well as other classic movement disorders, comes with no psychic investment in the movements. In contrast, akathisia, RLS, and tics follow a premonitory urge to move, entail a compulsion to move, and bestow relief if patients move. In addition, if patients resist moving, these disorders cause psychologic discomfort (see later).

Chorea in its earliest stage merely resembles nonspecific “fidgety” movements seen with anxiety, restlessness, discomfort, or clumsiness. It may then consist of only excessive face or hand gestures, weight shifting, leg crossing, or finger twitching (Fig. 18-17). Chorea also impairs the ability to sustain a voluntary muscle contraction, which causes motor impersistence. Because of it, patients cannot either hold a firm grasp or extend their hands or tongue for more than 10 seconds. For example, when asked by the examiner to squeeze two fingers, patients exert irregular, variable pressure that neurologists call the “milkmaid’s sign.” Patients also show motor impersistence by intermittently, involuntarily withdrawing the tongue when neurologists ask them to protrude it for 30 seconds. Neurologists refer to that finding as a “Jack-in-the-box tongue.” The motor impersistence also prevents patients from sustaining postures. For example, when “standing at attention,” patients’ fingers twitch outward and their torso bends.

FIGURE 18-17 With their arms and hands extended, Huntington disease patients fidget with their fingers and wrists, in movements that neurologists label “piano playing.”

Huntington disease also characteristically interferes with normal eye movements (see Fig. 12-13). In particular, Huntington disease impairs saccades, which are the rapid, almost reflexive, conjugate eye movements that people normally use to glance from one object to another. In Huntington disease, patients cannot make a rapid, smooth, and accurate shift of their gaze toward an object that suddenly enters their visual field. They routinely first blink or jerk their head to initiate the saccade. Although characteristic, impaired saccades are not peculiar to Huntington disease. Patients with schizophrenia, for example, also have abnormal saccades.

In addition, this disease impairs ocular pursuit movements, which are the normal, relatively slow conjugate eye movements that follow (track) moving objects, such as a baseball thrown into the air or ducks flying across the horizon. Huntington disease patients typically show irregular, inaccurate, and slow pursuit movements. As with abnormal saccades, abnormal pursuit movements are not peculiar to Huntington disease.

Even before dementia appears, which is inevitable, patients often display inattentiveness, erratic behavior, apathy, personality changes, and impaired judgment. Dementia typically begins within 1 year of the chorea. Poor memory, impaired planning ability, and faulty judgment, especially in financial matters, characterize their dementia. In Huntington disease, as in Parkinson disease, the MoCA is more sensitive than the MMSE in detecting subtle cognitive impairment.

As almost an integral part of the disease, about 50% of patients have comorbid depressive symptoms that generally strike earlier rather than later in the illness. Most patients have agitation, anxiety, apathy, dysphoria, and irritability, and about 10% develop psychotic thinking. Sometimes these symptoms precede both the dementia and chorea.

At a higher rate than in other neurodegenerative illnesses, up to 10% of individuals who are carriers or have overt signs of Huntington disease commit suicide. They tend to have had depression or anxiety, aggression, impaired judgment, or impetuous behavior – alone or in combination. They commit suicide most often before learning the results of their genetic testing and later when beginning to lose their independence. Notably, the suicide rate immediately before undergoing a diagnostic test exceeds that after receiving a result that indicates the presence of the disease.

The caregiver stress involved with Huntington disease exceeds that with Alzheimer disease because Huntington patients almost always have behavioral as well as cognitive impairments. Moreover, if the spouse of the Huntington patient has the role of caregiver, that person is also often the parent of one or more children with overt or presymptomatic disease.

Neurologists can base a preliminary diagnosis of Huntington disease on a patient’s having chorea, dementia, and a relative with a similar disorder. Readily available DNA testing for patients and potential carriers, including a fetus, can confirm or exclude the diagnosis.

Neurologists reduce chorea by prescribing either dopamine-blocking antipsychotic agents or tetrabenazine, which depletes dopamine. However, these medicines neither improve other motor functions nor reverse dementia. Moreover, because tetrabenazine depletes stores of norepinephrine and serotonin as well as dopamine, it sometimes also leads to sedation, depression, and suicide ideation. In mild cases of anxiety, benzodiazepines may suffice. Both TCAs and SSRIs may improve the depression.

Juvenile Huntington Disease

Sometimes symptoms appear in children and adolescents – individuals younger than 21 years of age. This variant, juvenile Huntington disease, comprises 10% of all cases and produces some different manifestations than the common, adult form. Their schoolwork declines and behavioral disturbances develop as the first signs. Also, rather than causing chorea as its initial physical symptom, juvenile Huntington disease presents with rigidity, dystonia, and akinesia (Fig. 18-18). Many affected children and adolescents look as though they have Parkinson disease. Another difference is that, unlike the adult variety, juvenile Huntington disease causes seizures. More importantly, juvenile Huntington disease progresses much more quickly and leads to death twice as rapidly as the adult form.

FIGURE 18-18 Having had deteriorating grades and progressively greater isolation from his family and friends, this 18-year-old high-school student came for evaluation. During the interview, he sat motionlessly, had few facial or limb gestures, and moved slowly; however, he had no tremor. He was apathetic and lacked insight. He did not fully cooperate with routine mental status testing, but it seemed to show deficits. When the neurologist flexed and extended his right arm, she detected rigidity. After a routine evaluation, she ordered tests for conditions that cause parkinsonism accompanied by mental deterioration in teenagers – Wilson disease, drug abuse, and the juvenile variety of Huntington disease. After the neurologist received the report that the genetic testing showed 85 CAG trinucleotide repeats, she asked to evaluate the father. He displayed subtle but definite chorea and cognitive impairment. His genetic testing also revealed 50 CAG repeats.

Because the genetic abnormality (excessive trinucleotide repeats [see later]) is more likely to increase if the father rather than mother transmits the gene, the child’s father transmits the juvenile variety in almost all cases of juvenile Huntington disease. In other words, an affected father is more likely than an affected mother to have a child with juvenile Huntington disease. The reverse is also true: a child with Huntington disease is more likely to have a father than mother with Huntington disease. Nevertheless, despite important clinical differences, the underlying genetic abnormality of the juvenile variety differs quantitatively – not qualitatively – from the adult variety.

Genetics

The abnormality underlying juvenile and adult varieties of Huntington disease – as with myotonic dystrophy, several spinocerebellar ataxias, and fragile X syndrome – is a genetic mutation consisting of excessive trinucleotide repeats (see Chapter 6 and Appendix 3D). This gene, located on the short arm of chromosome 4, normally consists of 11–35 repeats of the trinucleotide base cytosine-adenine-guanine (CAG). Individuals with 36–39 trinucleotide repeats, whom neurologists classify as “indeterminate,” have no clinical signs or merely a forme fruste of the disease; however, because of the gene’s tendency to enlarge (see later), indeterminate individuals’ children may have unequivocal disease. Individuals with 40 or more trinucleotide repeats invariably develop all manifestations of the illness and the age of appearance of their symptoms correlates inversely with the number of their repeats.

In general, with more numerous trinucleotide repeats, the disease shows itself at a younger age and pursues a more rapid course. When the mutation consists of 60 or more trinucleotide repeats, the juvenile variant develops.

As with other genes containing expanded trinucleotide sequences, the huntingtin gene is unstable and tends to increase further in length in successive generations. The progressive expansion or “escalating tendency” of the gene (amplification) explains why carriers of the mutation show signs at progressively younger ages in successive generations (anticipation). In addition, the gene’s trinucleotide sequences enlarge further in sperm than in eggs. Thus, paternal inheritance confers a greater likelihood of an earlier onset and greater severity of the disease, and the preponderance of affected fathers among children with the disease.

Pathology

In Huntington disease, the mutation causes excessive polyglutamine synthesis, which leads to production of huntingtin, a cytoplasmic protein, by neurons vulnerable to neurodegeneration. Thus, neurologists designate Huntington disease and other illnesses transmitted by excessive CAG repeats as polyglutamine diseases. In another aspect of the pathology, glutamate and other excitatory amino acids overstimulate N-methyl-D-aspartate (NMDA) receptors. This pathologic interaction, excitotoxicity, allows a fatal influx of calcium into neurons (see Chapter 21).

Apoptosis, the cell death that occurs in Huntington disease, ALS, and several other neurodegenerative illnesses, differs from necrosis, the more common cell death that occurs in strokes, trauma, and tumors. Apoptosis is programmed, sequential, and energy-requiring. It often occurs as a normal, vital process. For example, apoptosis characterizes the cell death that allows for closure of the patent ductus arteriosus and involution of the thymus. On a histologic level, apoptosis does not provoke inflammation. For example, macrophages and other mononuclear cells do not infiltrate the area of cells dying of apoptosis. Neurologists refer to apoptosis as an expectable, clean, orderly, and dignified cell death, but necrosis as an unpredictable, bloody, and messy cell death.

Pathologists note that Huntington disease causes degeneration through apoptosis of the striatal neurons that produce GABA. The caudate, which is part of the striatum, shows pronounced atrophy, and its GABA concentrations fall to less than 50% of normal.

Atrophy of the caudate nuclei, almost a pathognomonic macroscopic finding, correlates roughly with the severity of dementia. The atrophy of the caudate nuclei permits the lateral ventricles to balloon outward, i.e., develop a convex outline. They expand so much that neurologists call them “bat wing ventricles.” CT and MRI readily show the caudate atrophy and enlarged, convex ventricles (see Fig. 20-5). As Huntington disease progresses, the cerebral cortex also undergoes atrophy. PET studies demonstrate caudate hypometabolism even early in the illness.

By way of contrast, while normal aging and Alzheimer disease also cause cerebral atrophy, their atrophy does not preferentially affect the caudate nuclei. In these non-Huntington conditions, the caudate nuclei still bulge into the lateral ventricles. The ventricles enlarge, but they maintain a concave contour (see Figs 20-2, 20-3, and 20-18).

Sydenham Chorea

Sydenham chorea, originally known as St. Vitus dance, is one of the major diagnostic criteria for and complications of rheumatic fever. In fact, rheumatic fever accounts for almost all cases of acute chorea in childhood. Sydenham chorea predominantly affects children between the ages of 5 and 15 years and, of children older than 10 years, girls twice as frequently as boys.

In the most plausible explanation, group A β-hemolytic streptococcal infections, which cause rheumatic fever, inadvertently trigger an antibody-mediated attack on the basal ganglia. Thus, the chorea usually coincides with rheumatic fever, but it may begin as long as 2–6 months afterwards, when children have apparently recovered their health. It lasts for an average of 2 months, but often reappears during recurrences of rheumatic fever. With the decreasing incidence of rheumatic fever, Sydenham chorea seems restricted to small outbreaks – “miniepidemics” – occurring mostly in neighborhoods with cramped living space and limited access to health care. Often siblings and “best friends” develop the disorder simultaneously or in quick succession.

The chorea begins insidiously with grimaces and limb movements (Fig. 18-19). Sometimes the movements take on an urgency that makes the child seem willfully hyperactive. Sydenham chorea is one of the commonest neurologic causes of hyperactivity in children. A list of those causes would also include attention deficit hyperactivity disorder (ADHD), side effects from medications or illicit drugs, tics and Tourette disorder, and withdrawal-emergent syndrome (WES).

FIGURE 18-19 Children with Sydenham chorea may appear to have coy smiles and brief grimaces, and walk with a playful sashay. However, the pathologic nature of their movements – chorea – can be made obvious if the children attempt to maintain a fixed position, such as standing at attention, standing on the ball of one foot, or protruding their tongue. The involuntary movements cause dysarthria that is occasionally so severe that children refuse to speak. Surprisingly, the chorea may be asymmetric or unilateral in at least 20% of cases. It usually lasts between several weeks and 2 months.

The chorea’s significance lies not only in its warning of an underlying life-threatening condition, but also because of its neuropsychiatric comorbidity. Obsessive-compulsive behavior, OCD, and ADHD occur several-fold more frequently in children with Sydenham chorea compared to healthy controls. In addition, psychiatrists sometimes hold up Sydenham chorea along with Tourette disorder as prime examples of PANDAS (see later), but neurologists remain dubious about this concept.

Some children reportedly also have learning disabilities following Sydenham chorea; however, in many cases their lower socioeconomic status may have already compromised their educational status. In any case, despite the serious nature of the illness, Sydenham chorea does not lead to frank cognitive impairment.

The chorea usually spontaneously resolves, but if it causes discomfort, functional impairment, sleeplessness, or exhaustion, neurologists prescribe a short course of either valproate or a dopamine-blocking agent. In some cases, neurologists have interrupted the inflammatory process and reduced the symptoms by administering steroids or immunoglobulins.

Estrogen-Related Chorea

Oral contraceptive-induced chorea occasionally complicates the use of oral estrogen-containing contraceptives. This variety of chorea, which is not associated with mental abnormalities other than anxiety, develops in young women several months after starting these contraceptives and resolves after stopping it.

Chorea gravidarum, a related disorder, develops almost exclusively in young primigravidas in the first two trimesters of their pregnancy. Emotional lability, delirium, and rarely psychotic thinking are comorbid with the chorea. The chorea sometimes causes so much exhaustion that a woman spontaneously aborts. To relieve severe chorea, women must undergo a therapeutic abortion. Once the pregnancy is terminated, symptoms resolve.

Many women affected by oral contraceptive-induced chorea or chorea gravidarum have had previous episodes of either condition or Sydenham chorea. Also, their close relatives often have had one of these conditions. Nevertheless, if chorea develops in a woman who is pregnant or taking oral contraceptives, physicians must consider conditions in addition to the estrogen-related choreas, including Sydenham chorea, systemic lupus erythematosus, antiphospholipid syndrome (see Chapter 11), hyperthyroidism, and even Huntington disease.

Early-Onset Primary Dystonia

Early-onset primary dystonia or idiopathic torsion dystonia develops predominantly among Ashkenazi Jews. The illness typically appears in 9–11-year-old children, but almost always by the age of 26 years. The dystonia usually begins with torsion of one hand or foot (Fig. 18-23) and subsequently the other limbs, pelvis (tortipelvis), trunk, and neck (torticollis). Untreated, it eventually incapacitates its victims (Fig. 18-24).

FIGURE 18-23 When the girl with early-onset primary dystonia walks, the foot twists slowly inward and on to its side. Even though incomplete, the twisting causes her to limp. Using one of her “sensory tricks,” she can correct her limp by skipping, dancing, or walking backward.

FIGURE 18-24 As early-onset primary dystonia encompasses the remaining limb and axial musculature, patients develop generalized dystonic postures. Because muscles continually contract, they hypertrophy. Patients lose their subcutaneous fat from the incessant exertion. Patients with Wilson disease or tardive dystonia may resemble those with early-onset primary dystonia because all these illnesses may cause generalized dystonia.

A mutation in the DYT1 gene, located on chromosome 9, carries the illness in an autosomal dominant pattern, but its penetrance is only 30%. DNA testing for the DYT1 gene nevertheless can establish the diagnosis. In contrast to genes characterized by excessive trinucleotide repeats, the DYT1 gene consists of deletion of the trinucleotide GAG. Several other DYT genes also carry dystonia, but they vary as to whether they express the illness in a dominant or recessive pattern, which ethnic groups carry them, and their physical manifestations.

With various tests – blood chemistry, MRI or CT, PET, and brain tissue analysis – revealing no consistent abnormality, the mechanism through which the mutations produce the movements remains unknown. One clue is that, unlike in other movement disorders, studies of CSF and autopsy material found abnormalities in norepinephrine metabolism. On the other hand, several observations implicate a dopamine disturbance: Dopamine alleviates dopamine response dystonia and prolonged dopamine receptor blockade causes dystonia (see below).

As for treatment, anticholinergics, baclofen (Lioresal) and carbamazepine (Tegretol) provide only modest and generally inconsistent benefit. However, DBS directed at the GPi greatly relieves dystonia, restores mobility, improves the quality of life, and lifts mild to moderate depression. The improvement is often dramatic and lasts at least a decade. DBS also eliminates any need for the oral medicines, which often induce changes in mental status. Also, dystonia patients, unlike Parkinson patients who undergo DBS, do not exhibit postoperative cognitive changes. Children as well as adults are candidates.

Dopa-responsive dystonia

In an illness first described by Segawa and his Japanese colleagues and often named after him, dopa-responsive dystonia (DRD) gives rise to dystonia that appears in children and follows a distinctive diurnal pattern. The predominant symptom, dystonia, becomes evident in children, on the average, when they are 8 years old. The dystonia is typically absent in the morning but pronounced by the late afternoon and evening (Fig. 18-25). As with early-onset dystonia, DRD first affects children’s legs, interfering with walking, and then progresses to become generalized. In a related sign, DRD sometimes superimposes parkinsonism on the dystonia. Neurologists include DRD in the DYT family as DYT5.

FIGURE 18-25 During the previous year, this 8-year-old boy began to have leg and trunk movements that forced him to walk on his toes after returning from school in the afternoon. In the evening, his arms and hands showed dystonic posturing and his legs assumed straightened positions until he went to sleep. When he awoke in the morning, he walked and ran normally. His parents initially thought that he had developed cerebral palsy (see Fig. 13-3) and a psychologic disturbance. Pediatric neurologists detected dystonia, more so in his legs than his arms, and elicited a positive response to the pull test (see Fig. 18-9, B). Cognitive testing showed no abnormality. For many reasons, including that cerebral palsy does not develop after age 5 years or show a diurnal fluctuation, pediatric neurologists administered a therapeutic trial of a daily small dose of L-dopa. The boy immediately reverted to normal. Genetic tests later confirmed the diagnosis of dopa-responsive dystonia.

The title, DRD, describes not only the diagnostic test for the illness, but also its treatment. Small L-dopa doses, typically 10% of those used to treat Parkinson disease, dramatically ameliorate DRD. Because of the success of L-dopa in DRD, neurologists routinely give it as a therapeutic trial to children who have developed dystonia or almost any movement disorder resembling dystonia. If children improve, neurologists order genetic testing to confirm the diagnosis.

DRD exists in all ethnic groups. In affected families, cases usually appear in an autosomal dominant pattern with incomplete penetrance. Several different mutations of a gene carried on chromosome 14 may impair the synthesis of tetrahydrobiopterin, which is a cofactor for both phenylalanine hydroxylase and tyrosine hydroxylase. The tetrahydrobiopterin deficiency, in turn, eventually leads to serotonin and dopamine deficiencies that are more pronounced as daily activities deplete their stores.

Secondary Generalized Dystonia

Several other neurologic illnesses – Wilson disease, juvenile Huntington disease, and tardive dyskinesia – occasionally express themselves as generalized dystonia rather than as their characteristic movement disorder. When these illnesses produce dystonia, neurologists designate it secondary or symptomatic dystonia.

One of these dystonia-producing illnesses, Lesch–Nyhan syndrome, an X-linked recessive genetic disorder, produces one of neurology’s most bizarre symptoms: 2–13-year-old boys and, extraordinarily rarely, girls develop ferocious self-mutilation (Fig. 18-26). This symptom, the quintessential neuropsychiatric abnormal behavior, consists of children biting their own lips and fingers. This self-injurious behavior begins abruptly and furiously. In addition to the self-mutilation, they have mental retardation, spasticity, and seizures, as well as dystonia. By way of contrast, in mental retardation and autism, self-injurious behavior usually consists of head banging and hitting that begin insidiously and remain relatively mild.

FIGURE 18-26 This mentally retarded boy shows the self-mutilation, as well as dystonia, that characterizes Lesch–Nyhan syndrome. A, His right lower lip has the scars of where he gnawed through it, even after his parents and physicians had his front teeth removed to prevent him from continuously biting himself. B, His limbs writhe and his thumb curls into his palm. C, In an apparent compulsion, he uncontrollably chews his fingers and already has amputated the tip of the smallest one. D, Prying away his left thumb exposes deep excoriations on his palm.

The basic abnormality in Lesch–Nyhan syndrome consists of a deficiency of a purine metabolism enzyme attributable to a mutation in the hypoxanthine phosphoribosyl transferase (HPRT1) gene. By late childhood, the mutation leads to an accumulation of uric acid in the blood (hyperuricemia) and renal insufficiency or failure. Although allopurinol corrects the hyperuricemia, its does not prevent the neurologic damage.

Cranial Dystonias

Blepharospasm, an easily recognizable and frequently occurring focal dystonia, consists of bilateral, simultaneous contractions of the orbicularis oculi (eyelid) and sometimes the frontalis (forehead) muscles (Fig. 18-28). The muscle spasms force the eyelids closed and tend to render patients functionally blind, as well as causing disfiguring facial expressions. Although neurologists cannot establish the cause in most cases, various eye diseases, including “dry eye,” represent powerful risk factors.

FIGURE 18-28 This man with blepharospasm has unprovoked, bilateral, and prolonged (average duration, 5 seconds) contractions (spasms) of his orbicularis oculi (eyelid) muscles. Because the spasms block his vision, he often resorts to prying open his eyelids. In contrast to eyelid closure as a tic, the closures in blepharospasm are longer, more forceful, and not provoked by a “need” to close the eyes.

To overcome the involuntary contractions, patients unconsciously learn tricks that temporarily suppress the contractions (Fig. 18-29). As with other focal dystonias, botulinum injections reduce or abolish blepharospasm, at least on a temporary basis, with each set of injections. If excessive botulinum causes ptosis from weakness of the upper eyelid levator muscles, apraclonidine, a weak alpha-adrenergic stimulant, will retract the eyelid. (Like any other sympathomimetic agent, apraclonidine will also dilate the pupil.)

FIGURE 18-29 A, During periods of blepharospasm, this man cannot open his eyelids. He attempts, perhaps unconsciously, to open them by elevating his forehead muscles. B, He has instinctively learned that the sensory trick of pressing one eyebrow (a geste antagoniste) alleviates the spasms for several minutes.

Oromandibular dystonia consists of prominent contractions of the lower facial muscles and jaw muscles. Although oromandibular dystonia, like the oral-buccal-lingual movements of tardive dyskinesia, involves oral-buccal movements, it is distinguishable by the symmetric involvement and absence of tongue protrusions.

When the contractions involve the entire face, as though blepharospasm joined oromandibular dystonia, neurologists call the condition Meige syndrome (Fig. 18-30). This disorder mimics tardive dyskinesia except that, like oromandibular dystonia, it lacks tongue involvement. Preliminary studies have shown that DBS of the GPi suppresses the movements of Meige syndrome.

FIGURE 18-30 This patient with Meige syndrome (cranial dystonia) has contractions of her entire facial musculature.

Hemifacial spasm, a completely different cranial dystonia, consists of spasms of the muscles on only one side of the face – all those innervated by the ipsilateral facial nerve (the seventh cranial nerve) (Fig. 18-31). In this disorder, spasms occur irregularly at 1–10-per-minute, often in flurries, disfigure the face, and close the eyelids. Unlike dystonia and almost all other movement disorders, hemifacial spasm routinely persists during sleep.

FIGURE 18-31 Beset by hemifacial spasm for several years, this 53-year-old woman has bursts of left-sided facial muscle contractions. The contractions repetitively squeeze shut her left eyelids and pull her mouth to her left side, but the upper and lower face muscles do not contract synchronously. As a compensatory mechanism to uncover her left eye, she elevates her left eyebrow.

Also unlike other cranial dystonias, hemifacial spasm often has an identifiable and correctable cause. In most cases, an aberrant vessel compresses and presumably irritates the facial nerve as it exits from the pons at the cerebellopontine angle. Sometimes, misdirected regrowth of the facial nerve after an injury, including Bell’s palsy, leads to the disorder.

Neurosurgeons can alleviate hemifacial spasm resulting from an aberrant blood vessel by performing a microvascular decompression. This procedure consists of their inserting a cushion between the vessel and the facial nerve, which is similar to microvascular decompression of the trigeminal nerve (the fifth cranial nerve) for trigeminal neuralgia.

Cervical Dystonias

In spasmodic torticollis (Latin, tortus twisted + collum, neck), the most frequently occurring focal dystonia, the sternocleidomastoid and adjacent neck muscles involuntarily contract to rotate and tilt the head and neck (Figs 18-32 and 18-33). The movements initially persist for several seconds to several minutes. As the disease progresses, the abnormal postures become continuous and a superimposed tremor often complicates the picture. Unlike facial dystonias, spasmodic torticollis causes pain because the muscle contractions forcefully compress and rotate the cervical vertebra on each other and irritate the cervical nerve roots that emerge between them.

FIGURE 18-32 Spasmodic torticollis consists of contraction of neck muscles that causes rotation, tilting, flexion (anterocollis), or extension (retrocollis) – usually in a combination – of the head and neck. Shoulder elevation, as though the head and shoulder pull toward each other, accompany the other movements. Continuous contractions result in muscle hypertrophy and pain.

FIGURE 18-33 As with blepharospasm and other focal dystonias, patients instinctively learn sensory tricks, such as applying slight counter-rotational pressure against the chin, which is a classic geste antagoniste. In spasmodic torticollis, these maneuvers not only temporarily stop the movement, but they also camouflage it by allowing the patient to strike a studious pose.

Although it usually occurs as a separate entity, spasmodic torticollis occasionally serves as a component of primary dystonia. About 10% of cases occur within families. Head and neck injuries, especially “whiplash” from motor vehicle accidents, have allegedly produced isolated cases of spasmodic torticollis and other varieties of focal dystonia. Also, long-term use of dopamine-blocking agents leads to a variation of torticollis – retrocollis (backward bending of the neck) – as a component of tardive dystonia (see later). Whatever the cause, intramuscular botulinum injections alleviate the movements. Moreover, that treatment also greatly reduces the secondary pain. Preliminary studies have shown that severe cases respond to DBS.

Spasmodic dysphonia, previously called “spastic dysphonia,” consists of a distinctive speech abnormality caused by a sudden, involuntary contraction of the laryngeal muscles when patients speak. The voice takes on an intermittently and abruptly strained tone – as if trying to speak while being strangled. Nevertheless, patients can shout, sing, and whisper because these varieties of speech bypass the larynx and rely on the lips, mouth, and tongue. Likewise, patients can use the appropriate neighboring muscles normally to swallow and breathe.

Other cranial and cervical dystonias and head tremors often accompany spasmodic dysphonia. Clinical evaluation can distinguish it from related conditions, such as anxiety-induced vocal tremor, vocal cord tumors, and pseudobulbar palsy (see Chapter 4). Electromyography-guided botulinum injections through the anterior of the throat directly into the laryngeal muscles reduce or eliminate patients’ involuntary contractions and restore their voice.

Citing several similarities, some investigators have suggested that stuttering (disfluency) represents a variety of vocal dystonia. However valid the comparison, treatment with botulinum produces only a hoarse or hypophonic voice without alleviating the dysfluency.

Limb Dystonias

Limb dystonias usually involve arms more than legs. When hand muscles contract shortly after individuals engage in a repetitive action that forms the basis of their livelihood, neurologists term the disorder occupational dystonia or task-specific dystonia. The disorder prevents workers from continuing their job. Paradoxically, they remain able to perform other functions with their affected hand.

In writer’s cramp, a clear example of an occupational dystonia, shortly after authors begin to write, spasmodic contractions seize their finger and hand muscles. The contractions distort their hand and prevent it from properly grasping a pen or pencil (Fig. 18-34). However, writer’s cramp does not prevent eating, buttoning clothing, or manipulating small objects – movements that require dexterity equal to handwriting.

FIGURE 18-34 This patient is an author with writer’s cramp. She develops finger and hand muscle spasms several minutes after starting to write. The spasms force her hand into a fist and flex her wrist, which prevents her from holding a pen. They also cause moderate pain. However, when she uses the same hand to type, eat, or button clothing, she does not develop the cramps.

Because affected individuals can still dictate or type material that they cannot write, writer’s cramp differs from the psychologic phenomenon of writer’s block. Fatigue-induced cramps also differ from writer’s cramp in that they occur only after hours of performing the same task, cause considerable pain, and prohibit using the hand for any purpose.

Other examples include pianist’s, guitarist’s, and violinist’s cramps, in which repetitive, rapid, and intricate movements of these musicians’ hands and fingers precipitate cramplike movements. Similarly, brass and woodwind players are vulnerable to embouchure dystonia, in which playing their instrument triggers debilitating lip, jaw, and tongue muscle contractions. Focal occupational dystonias strike professional musicians as frequently as 1/200, which is greater than in any other professional group, and signal the end of high-level performances. Although occupational dystonias that affect these individuals readily attract neurologists’ attention, they also affect workers in less cerebral occupations, such as bricklaying and sewing.

Comorbid Psychiatric Conditions

Psychiatric disturbances complicate the basic clinical picture in about 80% of cases. Those few patients who are unencumbered by psychiatric comorbidity enjoy relatively few behavioral disabilities and a better overall outcome. For the vast majority, one or more psychiatric comorbidities threaten to dominate the clinical picture. ADHD, the most frequently occurring comorbidity, affects about 60% of boys and one-half of girls with Tourette disorder. It precedes the development of tics by 1–2 years.

A dilemma regarding hyperactive children with Tourette disorder has centered on the concern that prescribing stimulants to control hyperactivity would worsen the tics. Studies have shown that, although stimulants, such as methylphenidate, may cause a transient flare-up in tics, the stimulants’ benefits outweigh their risks.

Another common comorbidity of Tourette disorder consists of obsessive-compulsive symptoms, either alone or as part of OCD. This comorbidity occurs in about 30% of both males and females, and also emerges several years after the onset of tics. Obsessions and compulsions in Tourette disorder differ somewhat from those that are manifestations of OCD without comorbid Tourette disorder, i.e., pure OCD. For example, obsessions in Tourette disorder relate to sex, violence, and aggression, but those in pure OCD relate to dirt, germs, and illness. Similarly, compulsions in Tourette disorders typically consist of checking and ordering, but those in pure OCD consist of more elaborate activities, such as handwashing or housecleaning.

Anxieties, phobias, and related disturbances also complicate Tourette disorder in about 20% of patients of both genders. These disturbances’ frequency and severity vary directly with the severity of the tics.

Children with Tourette disorder have normal intelligence and no propensity toward psychosis. Although many of them have learning disabilities, this problem may be an indirect aspect of the disorder. For example, ADHD and social factors that interfere with children’s early education contribute to learning disabilities.

Other Associations

Many patients have soft neurologic signs and minor, nonspecific EEG abnormalities. Their CT, MRI, and PET do not reveal consistent, specific abnormalities. However, some studies have found increased D₂ receptor activity in the caudate nucleus.

Etiology

Studies have suggested that a single autosomal dominant gene makes children vulnerable to Tourette disorder. For example, penetrance reaches almost 90% in monozygotic twins, and, depending on the criteria, 10–15% of an affected individual’s first-degree relatives will have the disorder.

The theory of pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) proposes, for at least a subpopulation, that group A β-hemolytic streptococcus infections cause or trigger tics, Tourette disorder, and Sydenham chorea and, more importantly, induce obsessive-compulsive symptoms – all through antibody cross-reactivity or “molecular mimicry.” Despite its popularity, neurologists do not give credence to the theory since several clinical and basic science studies have challenged it.

Several observations indicate that dopamine hypersensitivity leads to the tics. For example, agents that reduce dopamine activity suppress tics and dopamine-enhancing substances, such as cocaine, exacerbate them. Moreover, as if a feedback loop senses excessive dopamine stimulation, the spinal fluid contains reduced concentrations of the dopamine metabolic product homovanillic acid.

Treatment

Behavior therapy, including “habit reversal training,” may reduce tics or at least postpone them until after potentially embarrassing times. When tics require treatment, neurologists may try several approaches.

Clonidine and guanfacine, α-adrenergic agonists, suppress tics through unknown mechanisms of action. In addition, guanfacine may help ADHD. A more potent treatment consists of reducing dopaminergic activity. For example, dopamine receptor antagonists, such as haloperidol, fluphenazine, and pimozide, suppress both vocal and most motor tics in about 80% of patients. Likewise, the dopamine depleter tetrabenazine lessens tics; however, the Food and Drug Administration (FDA) has not yet approved its use in Tourette disorder. Putting aside withdrawal dyskinesias and other transient complications, dopamine receptor antagonist treatment of Tourette disorder rarely causes tardive dyskinesia. In fact, one paper reporting an extremely low complication rate quipped, “Does Tourette syndrome prevent tardive dyskinesia?” Botulinum injections may temporarily eliminate single, particularly bothersome, motor tics.

Preliminary studies have shown that DBS suppresses motor and vocal tics; however, they have not established if the best target for electrode placement is the GPi or thalamus. Also, the studies have not answered various technical questions. Even so, DBS directed at tic control will probably not improve the comorbid OCD because, experience so far indicates, its control requires completely different targets, such as the anterior cingulate gyrus or anterior limb of the internal capsule.

Related Conditions

A stereotypy consists of a repetitive, patterned, rhythmic, and often complex involuntary movement. Stereotypies may be manifestations of autism, Rett syndrome, and Sydenham chorea, as well as Tourette disorder. Examples include slapping, flapping of the hands; twisting and wringing of fingers; repetitive forceful closure of the jaw with grinding of the teeth (bruxism); and rocking, twirling, and weight shifting of the body.

Despite their association with serious illnesses, stereotypies may also reflect relatively benign disabilities. For example, continual rocking – a stereotypy – seems to compensate for sensory deprivation in blind or mentally retarded individuals. Stereotypies also appear during complex partial seizures – sometimes as their only outward manifestation. Cocaine use can cause 2–6 days of various stereotypies as well as tics, akathisia-like leg movements (“crack dancing”), and punding (see before). Many of the movements in tardive dyskinesia may also fall under the rubric of stereotypies (see later).

Oculogyric Crisis and Other Acute Dystonias

Acute dystonic reactions consist of the abrupt development of limb or trunk dystonic postures, repetitive jaw and face muscle contractions, tongue protrusion, torticollis, or, in a special case, oculogyric crisis (Fig. 18-38). These dyskinesias may occur alone or in combinations, but typically cervical and jaw dystonia accompany oculogyric crisis. Physicians must keep in mind that several serious neurologic disorders – seizures, tetanus, drugs of abuse, and strychnine poisoning – can cause similar movements. For example, in large, urban hospitals, patients who present with oculogyric crisis or other acute dystonia and do not respond to anticholinergics and antihistaminics are often experiencing phencyclidine (PCP) intoxication.

FIGURE 18-38 During an oculogyric crisis, the eyes forcefully roll upward but sometimes sideways. Whichever direction, the eyes move conjugately. Simultaneously, in a mandibular and cervical dystonia component, the jaw opens or closes and the neck bends backwards (extends). Parenteral anticholinergics almost always abort this frightening dyskinesia.

The pathophysiology of acute dystonic reactions remains unknown. Of course, their temporal relationship to dopamine blockade suggests that lack of dopamine activity causes them. In the opposite scenario, because of the drug-induced dopamine blockade, a feedback loop may provoke an increased secretion of dopamine or a dopamine-like neurotransmitter that causes the movement. Another theory suggests that the movements’ favorable response to anticholinergics shows that they result from excessive cholinergic activity.

Akathisia

In akathisia, almost regular limb and trunk movements continually plague the patient (Fig. 18-39). Although akathisia can involve the trunk and arms, it predominantly affects the legs. Most importantly, it forces patients to move about and prohibits their sitting still or lying quietly in bed. When standing, patients tend to shuffle, march in place, or rock on their heels and toes. When sitting, which they find difficult, patients squirm, sway back and forth, or rub their feet on the floor; hence, the origin of the term “akathisia” (Greek, a + kathisis, without sitting).

FIGURE 18-39 Beset by akathisia, this woman, who just began a regimen of antipsychotic medicines, continually shuffles her legs in regular to-and-fro sliding movements. Although it can lead to repetitive semi-purposeful arm movements, such as scratching, hair smoothing, and rubbing, akathisia predominantly affects the legs. In another characteristic of akathisia, she feels driven to move her legs.

A subjective component of akathisia frequently disturbs the patient as much as the movements. As with tics, a psychic urge drives akathisia; however, moving does not relieve the urge. For example, patients with akathisia may experience intense restlessness, a need or compulsion to move, or even an irresistible desire to walk. This component of the problem sometimes forces patients to abandon their medical regimen.

In subtle cases, akathisia often remains undetected because the movements are mostly an exaggeration of normal ones. In a more problematic situation, physicians may reasonably confuse akathisia with insufficiently treated anxiety, psychosis, or agitated depression. Thus, psychiatrists must often decide either to increase or reduce an antipsychotic medicine for a restless psychotic patient.

Akathisia also resembles movements induced by fluoxetine, cocaine (“crack dancing”), or excessive L-dopa. In addition, although RLS looks like akathisia and RLS patients share the urge to move their legs, akathisia patients do not experience the paresthesias that characterize RLS and their movements are not specifically related to sleep. To emphasize that akathisia, tics, and RLS stem in part from uncomfortable sensations, one neurologist quipped that patients with these disorders move because they are distressed, but patients with most other movement disorders are distressed because they move.

Propranolol (a β-blocker), clonidine (an α₂-agonist), and mirtazapine may suppress the movements, but anticholinergics will not help. When the physician cannot distinguish between akathisia and restlessness from undertreated psychosis, prescribing a benzodiazepine until the diagnosis emerges is a credible strategy.

Oral-Buccal-Lingual Variety

Neurologists refer to the common antipsychotic-induced oral-buccal-lingual (also called choreic or orofacial) dyskinesia as one of several varieties of tardive dyskinesia (see Box 18-2). In a potential nomenclature conflict, many psychiatrists apply the term “tardive dyskinesia” to all varieties of the disorder.

Oral-buccal-lingual dyskinesia consists of stereotyped tongue, jaw, and face movements (Fig. 18-40); however, tardive dyskinesia often involves movements of the extremities and trunk. Unlike tics and RLS, urges do not provoke any of these movements.

FIGURE 18-40 The oral-buccal-lingual variety of tardive dyskinesia consists of repetitive tongue movements accompanied by continual jaw and facial muscle contractions. These movements typically include tongue darting, lip smacking, kissing, lip puckering, chewing, and sometimes blepharospasm. Unlike the tongue movements in chorea and cranial dystonias, tongue movements in oral-buccal-lingual tardive dyskinesia are not only prominent, but they may lead to tongue enlargement (macroglossia).

The Abnormal Involuntary Movement Scale (AIMS) allows recording of the presence, locations, and severity of abnormal movements (Fig. 18-41). It provides a global rating scale that allows physicians to assess pretreatment status and subsequent changes. However, even assuming interrater reliability, the AIMS has several drawbacks. It quantifies dyskinesias that vary in intensity during the day. The measurements are gross. The AIMS does not recognize akinesia (lack of movement), which should carry as much diagnostic weight as hyperkinesia. It does not distinguish between chorea, dystonia, tics, and stereotypies. Finally, it omits several important movements, such as tremor, dysarthria, and respiratory tics.

FIGURE 18-41 The Abnormal Involuntary Movement Scale (AIMS) guides the examiner through inspection for dyskinesias of the face, jaw, tongue, trunk, and limbs. The examiner records observations when the patient is at rest, extending the tongue or limbs, or performing certain activities, such as finger tapping, standing, or walking. In addition, the examiner checks for rigidity. This revision of the original (Guy, 1976) requests that patients remove their shoes and socks, and it does not rate as less severe those movements that are activated by voluntary movements.

Most, but not all, studies have concluded that the overall incidence of tardive dyskinesia is higher with first- than second-generation antipsychotics. Explanations for that finding include the facts that dopamine-blocking antipsychotic agents with a high affinity for D₂ receptors, which are mostly first-generation, remain the strongest risk factor for tardive dyskinesia; second-generation antipsychotics act primarily on 5HT2A receptors and produce a high 5HT2A/D₂ blockade ratio; second-generation antipsychotics adhere either weakly or transiently to the D₂ receptor; and some, such as aripiprazole, partially agonize as well as block the D₂ receptor. Other powerful risk factors include the duration of treatment and total medication dosage, age greater than 60 years, and female gender (especially for patients older than 65 years). Interesting but less powerful risk factors include medication-induced extrapyramidal side effects, dementia or other sign of brain damage, underlying affective rather than psychotic illness, and certain genes.

Some studies found that the yearly incidence of tardive dyskinesia remained constant throughout medication exposure and concluded that patients have the same chance of developing this complication during the first year as during the fifth year of treatment. Others found a slight annual increased incidence.

Etiology

Despite its limitations, the classic dopamine receptor hypersensitivity theory remains consistent with several of the condition’s major clinical features (Fig. 18-42). Tardive dyskinesia begins only after 6 months from the start of dopamine-blocking medicines. The dyskinesias resemble movements produced by excessive L-dopa. Maneuvers that expose the postsynaptic neuron to increased dopamine activity – reducing the dosage of the dopamine receptor blocker, stopping it, or adding L-dopa – intensify the movements. Likewise, increasing the medication dosage, which reduces dopamine receptor activity, suppresses the movements.

FIGURE 18-42 The denervation hypersensitivity theory proposes that when antipsychotic agents, such as haloperidol (H), bind to postsynaptic dopamine receptors, the remaining receptors become particularly sensitive and new ones develop. Then, minute quantities of dopamine (DA) – either released from the presynaptic neuron or present in the ambient fluid – evade the blockade and trigger these hypersensitive receptors.

An alternate theory attributes the disorder to deficient or abnormal GABA activity in the striatum. Another one posits that the glutamate system triggers excitotoxicity through the NMDA receptors. Still another suggests that catecholamine metabolism creates neurotoxic free radicals.

Treatment

Physicians should, of course, avoid prescribing antipsychotic and other medications associated with tardive dyskinesias, but when their use is indicated, physicians should prescribe minimal doses. Once tardive dyskinesia appears, physicians should resist a natural temptation to stop the medicine abruptly. They should slowly taper it – over weeks or months – because abruptly stopping it may unmask WES (see later). Even without intervention, approximately 33% of oral-buccal-lingual cases undergo remission.

Alternatively, switching from a first- to a second-generation antipsychotic or from one second-generation antipsychotic to another sometimes helps. Although the benefit may take months to materialize, switching to clozapine in cases of refractory, disabling tardive dyskinesia in patients who require antipsychotic treatment is a standard strategy.

Studies have found that tetrabenazine reduces tardive dyskinesias, undoubtedly by reducing dopamine activity. However, depression and suicide ideation may complicate its use. Moreover, it has not yet received an FDA indication for use in tardive dyskinesia (see before). Also to reduce dopamine activity, but as a last resort, physicians have reinforced the dopamine receptor blockade by increasing the dosage of a typical dopamine-blocking medication, substituting a more potent one, or restarting it. This strategy risks creating a vicious cycle where recurrence of the dyskinesia again requires additional medication.

A different approach counterbalances enhanced dopamine activity by increasing ACh activity. Despite the credibility of the theory, physostigmine, which prolongs ACh activity, and ACh precursors, such as deanol (Deaner), lecithin, or choline, help for only brief periods. The opposite approach, giving anticholinergics, also does not help.

Medications that affect other neurotransmitters also fail to help. For example, GABA agonists, such as valproate and baclofen, a calcium channel blocker diltiazem (Cardizem), lithium, opiates, and clonazepam provide no consistent relief.

Neurologists have hesitated to use botulinum injections for tongue dyskinesias. Injecting the tongue’s main muscles (the genioglossus and geniohyoid) would require a needle to pass through their rich vascular supply and risk an uncontrollable hemorrhage. Moreover, botulinum might weaken tongue or throat muscles enough to occlude the airway.

Most importantly, preliminary studies have found that DBS directed at the GPi ameliorates oral-buccal-lingual and other varieties of tardive dyskinesia. Moreover, patients may discontinue the medicines that physicians prescribed to reduce the movements and enjoy an improved quality of life. DBS causes no cognitive impairment or exacerbation of depression.

Tardive Dystonia

Another tardive dyskinesia, tardive dystonia, consists of sustained, powerful, twisting, predominantly extensor movements of the neck, upper arms, and trunk – the axial musculature (Fig. 18-43). Unlike the rotation (torsion) and tilting that characterize common, idiopathic spasmodic torticollis, the increased tone of the extensor neck muscles in tardive dystonia produces its characteristic feature, retrocollis. Related movements, including oral-buccal-lingual dyskinesia, blepharospasm, and akathisia, often accompany tardive dystonia. Otherwise, tardive dystonia resembles other secondary dystonias, as would be observable in Wilson, juvenile Huntington, and DYT1 diseases.

FIGURE 18-43 After receiving neuroleptic treatment for 6 years, this 25-year-old man began to develop prolonged, forceful twisting (torsion) and extension of his arms, extension of his head and neck (retrocollis), and exaggerated arching of his back. Subsequently, subtle oral-buccal-lingual choreiform movements, blepharospasm, or other varieties of tardive dyskinesia arose. After excluding Wilson disease and DYT1 and other varieties of dystonia, his physicians diagnosed his condition as tardive dystonia.

A relatively short exposure to dopamine-blocking agents, sometimes as brief as 3 months, can cause tardive dystonia. Thereafter, it complicates exposure at a low but constant yearly rate. Spontaneous remissions occur in only about 12% of cases.

Several entirely different medicines, which have systemic effects, may suppress tardive dystonia. In contrast to their lack of benefit in oral-buccal-lingual dyskinesia, anticholinergics sometimes reduce tardive dystonia. Clozapine and tetrabenazine, which each reduce dopamine activity thorough different mechanisms, often help. Botulinum injections may alleviate dystonia in problematic muscle groups, such as the neck extensors. Even if the neck movements represent spasmodic torticollis, DYT1 dystonia, or tardive dystonia, botulinum injections will stop them and produce no systemic side effects.

Although some technical details remain unresolved, DBS alleviates tardive dystonia just as it does with DYT1 dystonia. It provides the same benefits and safety margin as when used for oral-buccal-lingual dyskinesia.

Other Tardive Dyskinesias

Tardive akathisia, which resembles the acutely developing disorder, persists by definition for longer than 6 months after the medication is begun. In addition, it may appear only after the patient has stopped the offending medication. As with tardive dystonia, other tardive dyskinesias often accompany tardive akathisia.

Opioids, benzodiazepines, and propranolol can sometimes alleviate tardive akathisia. Reported benefits from reserpine, tetrabenazine, amantadine, anticholinergics, and other medications remain unconfirmed.

As other varieties of tardive dyskinesia, patients may have tardive verbal tics, which involve persistent simple vocalizations, such as grunts, and respiratory tics, in which patients make sudden, loud, irregular gasps. They can also have tardive oculogyric crises, tardive tremors, and various persistent movements usually associated with acute dyskinesias or other movement disorders. As with tardive dystonia and akathisia, oral movements often accompany each of these varieties.