Carlos Singer, MD

Parkinson disease (PD) is a slowly progressive neurodegenerative disorder. Early PD, or stage 1 or 2 on the Unified Parkinson’s Disease Rating Scale (UPDRS), is characterized by mild symptoms, minimal to mild disability, and lack of postural instability or cognitive decline. The goal of therapy in PD is to help patients retain functional independence for as long as possible. Therapeutic choices in early PD are guided by the effect of symptoms on function and quality of life, consideration of complications associated with long-term levodopa, the likelihood of response fluctuations to levodopa, and the potential for a neuroprotective effect.

SYMPTOMATIC THERAPIES IN EARLY PD

Dopaminergic replacement therapy with levodopa is a legitimate choice for the treatment of early PD. Use of carbidopa-levodopa has been shown to slow the progression of PD in a dose-dependent manner as evidenced by a decrease in total score on the UPDRS in patients with early PD who were randomly assigned to receive carbidopa-levodopa compared with those who received a placebo.¹

Alternatives to levodopa

There are several reasons to choose an alternative to levodopa for the treatment of early PD. The first is to postpone the development of levodopa-induced dyskinesias, which are linked to duration of levodopa treatment and total exposure to levodopa. The second is postponement of the “wearing-off” effect; that is, the reemergence of symptoms that occurs in some patients before their next scheduled dose of levodopa. Such reasoning applies to early PD patients with minimal or no disability and—in particular—to young-onset PD patients who tend to develop vigorous dyskinesias and dramatic wearing-off phenomena. Pharmacologic alternatives to levodopa in early PD include monoamine oxidase (MAO)-B inhibitors, amantadine, and dopamine agonists.

Reprinted with permission from The New England Journal of Medicine (Olanow CW, et al. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med 2009; 361:168–178). © 2009 Massachusetts Medical Society.

MAO-B inhibitors. Two MAO-B inhibitors are approved by the US Food and Drug Administration for the treatment of PD: rasagiline and selegiline. These agents have a mildly symptomatic effect. In the Attenuation of Disease Progression with Azilect Given Once-daily (ADAGIO) trial, use of rasagiline at doses of 1 and 2 mg/d slowed the rate of worsening of the UPDRS score compared with placebo in patients with untreated PD (Figure 1).² Patients were randomly assigned to an early-start group (rasagiline, 1 or 2 mg/d, or placebo for 72 weeks) or a late-start group (placebo for 36 weeks followed by rasagiline, 1 or 2 mg/d, or placebo for 36 weeks). The rate of change in the UPDRS score was slowed significantly with early treatment with rasagiline at a dosage of 1 mg/d, but not at 2 mg/d. Because the hierarchical primary end points for the ADAGIO trial were met only for the cohort receiving 1 mg of rasagiline early, it remains inconclusive whether rasagiline has a neuroprotective effect.

In a placebo-controlled study of selegiline in de novo early-phase PD, Pålhagen et al showed that selegiline monotherapy delayed the need for levodopa. When used in combination with levodopa, selegiline was able to slow the progression of PD as measured by the change in UPDRS total score.³

Amantadine. In an early study of 54 patients with PD, functional disability scores improved significantly with administration of amantadine 200 to 300 mg/d compared with placebo.⁴ A small subset of patients, perhaps 20% or less, who are treated with amantadine experience robust symptom improvement. Side effects of amantadine include hallucinations, edema, livedo reticularis, and anticholinergic effects. A more recently discovered potential side effect is corneal edema.

Dopamine agonists. Pramipexole (immediate-release [IR] and extended-release [ER]), and ropinirole IR and ER are dopamine agonists that have demonstrated disease-modifying effects and efficacy in improving PD symptoms.

Pramipexole ER administered once daily in early PD was shown to be superior to placebo on the mean UPDRS total score.⁵ Ropinirole ER produced mean plasma concentrations over 24 hours similar to those achieved with ropinirole IR, and showed noninferiority to ropinirole IR on efficacy measures in patients with de novo PD.⁵

The effective dosage range of pramipexole ER in early PD is 0.375 to 4.5 mg/d. Side effects include hallucinations, edema, excessive diurnal somnolence, and impulse control disorders (ie, pathologic gambling, hypersexuality, excessive craving for sweets). Compared with pramipexole IR, compliance is enhanced with the ER formulation because of ease of administration, but this formulation also is more expensive.

In early PD, the effective dosage range of ropinirole ER is 8 to 12 mg/d.⁶ The side effects are the same as with pramipexole ER with the same compliance advantage and cost disadvantage compared with the IR formulation.

Research indicates that dopamine agonists may have a neuroprotective effect. In two large clinical trials in which patients with PD were followed with an imaging marker of dopamine neuronal degeneration (using single-photon emission computed tomography or positron emission tomography), recipients of pramipexole⁷ or ropinirole⁸ showed slower neuronal deterioration compared with levodopa recipients. A counterargument to the neuroprotective theory is that these differences between the dopamine agonists and levodopa reflect neurotoxicity of levodopa rather than neuroprotection by dopamine agonists. The absence of a placebo comparison in both trials adds to the difficulty in drawing a conclusion, as some critics ascribed the differences between groups to downregulation of tracer binding with levodopa.

Nonergoline dopamine agonist. Transdermal rotigotine is a nonergot D₁/D₂/D₃ agonist. Higher doses produce higher plasma levels of rotigotine, which remain steady over the 24-hour dosing interval.⁹ Transdermal rotigotine has demonstrated effectiveness in early PD in several clinical trials.^10,11 The patch, applied once daily, provides a constant release of medication. Removing the patch immediately interrupts drug administration.

Rotigotine patches must be refrigerated to prevent crystallization, a requirement that has delayed the product’s arrival on the market. The patch is reputed to be difficult to peel from its backing and apply. Skin reactions are a side effect, and nonergot side effects are possible. Despite these drawbacks, transdermal rotigotine represents a convenient option for perioperative management of PD and in patients with dysphagia.

Exercise. Exercise has symptomatic and possibly neuroprotective benefits in PD, supporting its use as an additional medical measure. Evidence supports the value of treadmill walking and high-impact exercise in improving stride length, quality of life, and motor response to levodopa.

 

SYMPTOMATIC THERAPIES: THE FUTURE

Partial dopamine agonists

Pardoprunox is a partial dopamine agonist with full 5-HT_1A–agonist activity. A partial dopamine agonist acts in two ways: (1) It stimulates dopamine production in brain regions with low dopamine tone, and (2) it has dopamine antagonist activity under circumstances of high dopamine sensitivity, theoretically avoiding overstimulation of dopamine receptors. Because it inhibits excessive dopamine effect, pardoprunox may prevent dyskinesia. In addition, because pardoprunox has serotonin agonist activity, it may also act as an antidepressant.

In a phase 2 study, significantly more patients randomized to pardoprunox had a 30% or greater reduction in UPDRS motor score compared with placebo at end-of-dose titration (35.8% for pardoprunox vs 15.7% for placebo; P = .0065) and at end point (50.7% for pardoprunox vs 15.7% for placebo; P < .0001).¹²

Adenosine A_2A-receptor antagonists

Adenosine A_2A receptors are located in the basal ganglia, primarily on gamma aminobutyric acid (GABA)–mediated enkephalin-expressing medium spiny neurons in the striatum. These receptors modulate dopamine transmission by opposing D₂-receptor activity. The D₂ pathway is an indirect pathway that promotes suppression of unnecessary movement.

Two A_2A-receptor antagonists have demonstrated efficacy in clinical trials. Vipadenant has been proven effective as monotherapy in phase 2 clinical trials. Preladenant has been shown to improve “off time” as an adjunct to levodopa without increasing dyskinesia.

Safinamide

Safinamide, currently in phase 3 clinical trials, has three mechanisms of action. It is an inhibitor of dopamine reuptake, a reversible inhibitor of MAO-B, and an inhibitor of excessive glutamate release. The addition of safinamide to a stable dose of a single dopamine agonist in patients with early PD resulted in improvement of motor symptoms and cognitive function.^13,14

NEUROPROTECTIVE STRATEGIES UNDER INVESTIGATION

Four neuroprotective strategies are under study: enhanced mitochondrial function, antiinflammatory mechanisms, calcium channel blockade, and uric acid elevation.

Enhanced mitochondrial function

Creatine has generated interest as a disease-modifying agent in response to preclinical data showing that it could enhance mitochondrial function and prevent mitochondrial loss in the brain in models of PD. Creatine is now the subject of a large phase 3 National Institutes of Health–sponsored clinical trial in patients with early-stage PD.¹⁵

Coenzyme Q10 (CoQ 10) exhibited a trend for neuroprotection at 1,200 mg/d, lowering the total mean UPDRS score compared with placebo in a 16-month study.¹⁶ Current efforts are directed at determining whether 1,200 or 2,400 mg/d of CoQ10 are neuroprotective. A nanoparticulate form of CoQ10, 100 mg three times a day, has been shown to produce plasma levels of CoQ10 equivalent to those produced by 1,200-mg doses of the standard form.¹⁷ CoQ10 is free of symptomatic effects.

Antiinflammatory mechanisms

Parkinson disease may have an important inflammatory component. A meta-analysis of seven studies showed an overall hazard ratio of 0.85 for development of PD in users of nonaspirin nonsteroidal antiinflammatory drugs (NSAIDs), with each of the seven studies demonstrating a hazard ratio less than 1.¹⁸ A similar meta-analysis showed no such association.¹⁹ Further study is warranted.

The antidiabetic agent pioglitazone, shown in mice to prevent dopaminergic nigral cell loss, has been entered into a phase 2 clinical trial to assess its antiinflammatory properties in PD.

Calcium channel blockade

A sustained-release formulation of isradipine, an L-type calcium channel blocker, is being studied in a phase 2 clinical trial for the treatment of early PD; experimental evidence in animals suggests that it may be neuroprotective against PD.

Uric acid elevation

Urate concentration in the cerebrospinal fluid predicts progression of PD, with higher levels associated with slower progression of disease.²⁰ Urate may delay oxidative destruction of dopaminergic neurons that occurs with progression of PD. Pharmacologic elevation of uric acid is being explored as a treatment option in PD.

ELECTRODES, VECTORS, AND STEM CELLS

Deep brain stimulation

Reprinted with permission from Movement Disorders (Espay AJ, et al. Early versus delayed bilateral subthalamic deep brain stimulation for Parkinson’s disease: a decision analysis. Mov Disord 2010; 25:1456–1463). Copyright © 2010 Movement Disorder Society.

Deep brain stimulation (DBS) is currently used as a treatment for advanced PD (patients suffering from levodopainduced motor complications), but it might also slow the progression of cognitive and motor decline in earlier stages of PD. The annual rate of progression of both cognitive and motor decline was slower when DBS was administered earlier in the course of PD (off time on levodopa of about 2 hours) versus in a later stage of PD (off time on levodopa of about 4 hours) (Figure 2).²¹ The strategy is being tested further in clinical trials of early PD.

Stem cell therapy

Stem cells obtained from blastocytes, fibroblasts, bone marrow, or the adult, embryonic, or fetal central nervous system through “molecular alchemy” can form dopaminergic neuroblasts. Given the high cost and potential risks of stem cell therapy, it must be proven superior to DBS to be considered an option for early PD. Several practical problems act as hurdles to successful stem cell therapy. Efficient generation of dopamine-producing neurons and successful grafting are required. Tumor growth is a risk. Involuntary movements have been observed in some patients who received fetal implants. A limitation of stem cell therapy is that it will only affect those aspects of PD that are dependent on dopamine.

Gene therapy

Gene delivery of the growth factor analogue adeno-associated type-2 vector (AAV2)-neurturin has been investigated in patients with advanced PD. When surgically placed inside a neuron, neurturin enhances neuron vitality, enabling it to better fight oxidative stress and other attacks. It fared no better than sham surgery on changes in UPDRS motor score at 12 months in a randomized trial.²² A few patients enrolled in this trial have been followed for longer than 12 months, at which time the mean change in motor scores appears to favor the group assigned to gene delivery of AAV2-neurturin. A phase 1/2 trial is investigating the safety and efficacy of bilateral intraputaminal and intranigral administration of neurturin.

SUMMARY

Levodopa is a legitimate choice for the treatment of early PD. Two MAO-B inhibitors, rasagiline and selegiline, have a symptomatic effect.

Long-acting oral and transdermal dopamine agonists are effective symptomatic therapies, but they also have an interesting array of side effects, making levodopa a reasonable alternative treatment sooner or later despite its dyskinetic effect. Potential neuroprotective effects remain to be identified.

Amantadine is sometimes overlooked as an option for treating early PD, but it has some special side effects including leg edema, livedo reticularis, and corneal edema. Amantadine does not cause orthostatic hypotension and is free of the side effects of excessive diurnal somnolence and impulse control disorders that are prevalent with dopamine agonists.

In the future, partial dopamine agonists and adenosine antagonists may provide us with additional symptomatic therapies. CoQ10, creatine, calcium channel blockers, and inosine, as well as NSAIDs, are being actively studied as potential disease-modifying agents. Further studies are likely to come from the use of NSAIDs.

Early DBS is a new avenue of investigation as a potential disease modifier. Stem cells are still being studied and limitations of sufficient production and potential tumor growth, among others, have delayed the institution of clinical trials. Gene therapy is an interesting additional treatment modality in active research.

Parkinson disease (PD) is a slowly progressive neurodegenerative disorder. Early PD, or stage 1 or 2 on the Unified Parkinson’s Disease Rating Scale (UPDRS), is characterized by mild symptoms, minimal to mild disability, and lack of postural instability or cognitive decline. The goal of therapy in PD is to help patients retain functional independence for as long as possible. Therapeutic choices in early PD are guided by the effect of symptoms on function and quality of life, consideration of complications associated with long-term levodopa, the likelihood of response fluctuations to levodopa, and the potential for a neuroprotective effect.

SYMPTOMATIC THERAPIES IN EARLY PD

Dopaminergic replacement therapy with levodopa is a legitimate choice for the treatment of early PD. Use of carbidopa-levodopa has been shown to slow the progression of PD in a dose-dependent manner as evidenced by a decrease in total score on the UPDRS in patients with early PD who were randomly assigned to receive carbidopa-levodopa compared with those who received a placebo.¹

Alternatives to levodopa

There are several reasons to choose an alternative to levodopa for the treatment of early PD. The first is to postpone the development of levodopa-induced dyskinesias, which are linked to duration of levodopa treatment and total exposure to levodopa. The second is postponement of the “wearing-off” effect; that is, the reemergence of symptoms that occurs in some patients before their next scheduled dose of levodopa. Such reasoning applies to early PD patients with minimal or no disability and—in particular—to young-onset PD patients who tend to develop vigorous dyskinesias and dramatic wearing-off phenomena. Pharmacologic alternatives to levodopa in early PD include monoamine oxidase (MAO)-B inhibitors, amantadine, and dopamine agonists.

Reprinted with permission from The New England Journal of Medicine (Olanow CW, et al. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med 2009; 361:168–178). © 2009 Massachusetts Medical Society.

MAO-B inhibitors. Two MAO-B inhibitors are approved by the US Food and Drug Administration for the treatment of PD: rasagiline and selegiline. These agents have a mildly symptomatic effect. In the Attenuation of Disease Progression with Azilect Given Once-daily (ADAGIO) trial, use of rasagiline at doses of 1 and 2 mg/d slowed the rate of worsening of the UPDRS score compared with placebo in patients with untreated PD (Figure 1).² Patients were randomly assigned to an early-start group (rasagiline, 1 or 2 mg/d, or placebo for 72 weeks) or a late-start group (placebo for 36 weeks followed by rasagiline, 1 or 2 mg/d, or placebo for 36 weeks). The rate of change in the UPDRS score was slowed significantly with early treatment with rasagiline at a dosage of 1 mg/d, but not at 2 mg/d. Because the hierarchical primary end points for the ADAGIO trial were met only for the cohort receiving 1 mg of rasagiline early, it remains inconclusive whether rasagiline has a neuroprotective effect.

In a placebo-controlled study of selegiline in de novo early-phase PD, Pålhagen et al showed that selegiline monotherapy delayed the need for levodopa. When used in combination with levodopa, selegiline was able to slow the progression of PD as measured by the change in UPDRS total score.³

Amantadine. In an early study of 54 patients with PD, functional disability scores improved significantly with administration of amantadine 200 to 300 mg/d compared with placebo.⁴ A small subset of patients, perhaps 20% or less, who are treated with amantadine experience robust symptom improvement. Side effects of amantadine include hallucinations, edema, livedo reticularis, and anticholinergic effects. A more recently discovered potential side effect is corneal edema.

Dopamine agonists. Pramipexole (immediate-release [IR] and extended-release [ER]), and ropinirole IR and ER are dopamine agonists that have demonstrated disease-modifying effects and efficacy in improving PD symptoms.

Pramipexole ER administered once daily in early PD was shown to be superior to placebo on the mean UPDRS total score.⁵ Ropinirole ER produced mean plasma concentrations over 24 hours similar to those achieved with ropinirole IR, and showed noninferiority to ropinirole IR on efficacy measures in patients with de novo PD.⁵

The effective dosage range of pramipexole ER in early PD is 0.375 to 4.5 mg/d. Side effects include hallucinations, edema, excessive diurnal somnolence, and impulse control disorders (ie, pathologic gambling, hypersexuality, excessive craving for sweets). Compared with pramipexole IR, compliance is enhanced with the ER formulation because of ease of administration, but this formulation also is more expensive.

In early PD, the effective dosage range of ropinirole ER is 8 to 12 mg/d.⁶ The side effects are the same as with pramipexole ER with the same compliance advantage and cost disadvantage compared with the IR formulation.

Research indicates that dopamine agonists may have a neuroprotective effect. In two large clinical trials in which patients with PD were followed with an imaging marker of dopamine neuronal degeneration (using single-photon emission computed tomography or positron emission tomography), recipients of pramipexole⁷ or ropinirole⁸ showed slower neuronal deterioration compared with levodopa recipients. A counterargument to the neuroprotective theory is that these differences between the dopamine agonists and levodopa reflect neurotoxicity of levodopa rather than neuroprotection by dopamine agonists. The absence of a placebo comparison in both trials adds to the difficulty in drawing a conclusion, as some critics ascribed the differences between groups to downregulation of tracer binding with levodopa.

Nonergoline dopamine agonist. Transdermal rotigotine is a nonergot D₁/D₂/D₃ agonist. Higher doses produce higher plasma levels of rotigotine, which remain steady over the 24-hour dosing interval.⁹ Transdermal rotigotine has demonstrated effectiveness in early PD in several clinical trials.^10,11 The patch, applied once daily, provides a constant release of medication. Removing the patch immediately interrupts drug administration.

Rotigotine patches must be refrigerated to prevent crystallization, a requirement that has delayed the product’s arrival on the market. The patch is reputed to be difficult to peel from its backing and apply. Skin reactions are a side effect, and nonergot side effects are possible. Despite these drawbacks, transdermal rotigotine represents a convenient option for perioperative management of PD and in patients with dysphagia.

Exercise. Exercise has symptomatic and possibly neuroprotective benefits in PD, supporting its use as an additional medical measure. Evidence supports the value of treadmill walking and high-impact exercise in improving stride length, quality of life, and motor response to levodopa.

 

SYMPTOMATIC THERAPIES: THE FUTURE

Partial dopamine agonists

Pardoprunox is a partial dopamine agonist with full 5-HT_1A–agonist activity. A partial dopamine agonist acts in two ways: (1) It stimulates dopamine production in brain regions with low dopamine tone, and (2) it has dopamine antagonist activity under circumstances of high dopamine sensitivity, theoretically avoiding overstimulation of dopamine receptors. Because it inhibits excessive dopamine effect, pardoprunox may prevent dyskinesia. In addition, because pardoprunox has serotonin agonist activity, it may also act as an antidepressant.

In a phase 2 study, significantly more patients randomized to pardoprunox had a 30% or greater reduction in UPDRS motor score compared with placebo at end-of-dose titration (35.8% for pardoprunox vs 15.7% for placebo; P = .0065) and at end point (50.7% for pardoprunox vs 15.7% for placebo; P < .0001).¹²

Adenosine A_2A-receptor antagonists

Adenosine A_2A receptors are located in the basal ganglia, primarily on gamma aminobutyric acid (GABA)–mediated enkephalin-expressing medium spiny neurons in the striatum. These receptors modulate dopamine transmission by opposing D₂-receptor activity. The D₂ pathway is an indirect pathway that promotes suppression of unnecessary movement.

Two A_2A-receptor antagonists have demonstrated efficacy in clinical trials. Vipadenant has been proven effective as monotherapy in phase 2 clinical trials. Preladenant has been shown to improve “off time” as an adjunct to levodopa without increasing dyskinesia.

Safinamide

Safinamide, currently in phase 3 clinical trials, has three mechanisms of action. It is an inhibitor of dopamine reuptake, a reversible inhibitor of MAO-B, and an inhibitor of excessive glutamate release. The addition of safinamide to a stable dose of a single dopamine agonist in patients with early PD resulted in improvement of motor symptoms and cognitive function.^13,14

NEUROPROTECTIVE STRATEGIES UNDER INVESTIGATION

Four neuroprotective strategies are under study: enhanced mitochondrial function, antiinflammatory mechanisms, calcium channel blockade, and uric acid elevation.

Enhanced mitochondrial function

Creatine has generated interest as a disease-modifying agent in response to preclinical data showing that it could enhance mitochondrial function and prevent mitochondrial loss in the brain in models of PD. Creatine is now the subject of a large phase 3 National Institutes of Health–sponsored clinical trial in patients with early-stage PD.¹⁵

Coenzyme Q10 (CoQ 10) exhibited a trend for neuroprotection at 1,200 mg/d, lowering the total mean UPDRS score compared with placebo in a 16-month study.¹⁶ Current efforts are directed at determining whether 1,200 or 2,400 mg/d of CoQ10 are neuroprotective. A nanoparticulate form of CoQ10, 100 mg three times a day, has been shown to produce plasma levels of CoQ10 equivalent to those produced by 1,200-mg doses of the standard form.¹⁷ CoQ10 is free of symptomatic effects.

Antiinflammatory mechanisms

Parkinson disease may have an important inflammatory component. A meta-analysis of seven studies showed an overall hazard ratio of 0.85 for development of PD in users of nonaspirin nonsteroidal antiinflammatory drugs (NSAIDs), with each of the seven studies demonstrating a hazard ratio less than 1.¹⁸ A similar meta-analysis showed no such association.¹⁹ Further study is warranted.

The antidiabetic agent pioglitazone, shown in mice to prevent dopaminergic nigral cell loss, has been entered into a phase 2 clinical trial to assess its antiinflammatory properties in PD.

Calcium channel blockade

A sustained-release formulation of isradipine, an L-type calcium channel blocker, is being studied in a phase 2 clinical trial for the treatment of early PD; experimental evidence in animals suggests that it may be neuroprotective against PD.

Uric acid elevation

Urate concentration in the cerebrospinal fluid predicts progression of PD, with higher levels associated with slower progression of disease.²⁰ Urate may delay oxidative destruction of dopaminergic neurons that occurs with progression of PD. Pharmacologic elevation of uric acid is being explored as a treatment option in PD.

ELECTRODES, VECTORS, AND STEM CELLS

Deep brain stimulation

Reprinted with permission from Movement Disorders (Espay AJ, et al. Early versus delayed bilateral subthalamic deep brain stimulation for Parkinson’s disease: a decision analysis. Mov Disord 2010; 25:1456–1463). Copyright © 2010 Movement Disorder Society.

Deep brain stimulation (DBS) is currently used as a treatment for advanced PD (patients suffering from levodopainduced motor complications), but it might also slow the progression of cognitive and motor decline in earlier stages of PD. The annual rate of progression of both cognitive and motor decline was slower when DBS was administered earlier in the course of PD (off time on levodopa of about 2 hours) versus in a later stage of PD (off time on levodopa of about 4 hours) (Figure 2).²¹ The strategy is being tested further in clinical trials of early PD.

Stem cell therapy

Stem cells obtained from blastocytes, fibroblasts, bone marrow, or the adult, embryonic, or fetal central nervous system through “molecular alchemy” can form dopaminergic neuroblasts. Given the high cost and potential risks of stem cell therapy, it must be proven superior to DBS to be considered an option for early PD. Several practical problems act as hurdles to successful stem cell therapy. Efficient generation of dopamine-producing neurons and successful grafting are required. Tumor growth is a risk. Involuntary movements have been observed in some patients who received fetal implants. A limitation of stem cell therapy is that it will only affect those aspects of PD that are dependent on dopamine.

Gene therapy

Gene delivery of the growth factor analogue adeno-associated type-2 vector (AAV2)-neurturin has been investigated in patients with advanced PD. When surgically placed inside a neuron, neurturin enhances neuron vitality, enabling it to better fight oxidative stress and other attacks. It fared no better than sham surgery on changes in UPDRS motor score at 12 months in a randomized trial.²² A few patients enrolled in this trial have been followed for longer than 12 months, at which time the mean change in motor scores appears to favor the group assigned to gene delivery of AAV2-neurturin. A phase 1/2 trial is investigating the safety and efficacy of bilateral intraputaminal and intranigral administration of neurturin.

SUMMARY

Levodopa is a legitimate choice for the treatment of early PD. Two MAO-B inhibitors, rasagiline and selegiline, have a symptomatic effect.

Long-acting oral and transdermal dopamine agonists are effective symptomatic therapies, but they also have an interesting array of side effects, making levodopa a reasonable alternative treatment sooner or later despite its dyskinetic effect. Potential neuroprotective effects remain to be identified.

Amantadine is sometimes overlooked as an option for treating early PD, but it has some special side effects including leg edema, livedo reticularis, and corneal edema. Amantadine does not cause orthostatic hypotension and is free of the side effects of excessive diurnal somnolence and impulse control disorders that are prevalent with dopamine agonists.

In the future, partial dopamine agonists and adenosine antagonists may provide us with additional symptomatic therapies. CoQ10, creatine, calcium channel blockers, and inosine, as well as NSAIDs, are being actively studied as potential disease-modifying agents. Further studies are likely to come from the use of NSAIDs.

Early DBS is a new avenue of investigation as a potential disease modifier. Stem cells are still being studied and limitations of sufficient production and potential tumor growth, among others, have delayed the institution of clinical trials. Gene therapy is an interesting additional treatment modality in active research.

Parkinson disease (PD) is a slowly progressive neurodegenerative disorder. Early PD, or stage 1 or 2 on the Unified Parkinson’s Disease Rating Scale (UPDRS), is characterized by mild symptoms, minimal to mild disability, and lack of postural instability or cognitive decline. The goal of therapy in PD is to help patients retain functional independence for as long as possible. Therapeutic choices in early PD are guided by the effect of symptoms on function and quality of life, consideration of complications associated with long-term levodopa, the likelihood of response fluctuations to levodopa, and the potential for a neuroprotective effect.

SYMPTOMATIC THERAPIES IN EARLY PD

Dopaminergic replacement therapy with levodopa is a legitimate choice for the treatment of early PD. Use of carbidopa-levodopa has been shown to slow the progression of PD in a dose-dependent manner as evidenced by a decrease in total score on the UPDRS in patients with early PD who were randomly assigned to receive carbidopa-levodopa compared with those who received a placebo.¹

Alternatives to levodopa

There are several reasons to choose an alternative to levodopa for the treatment of early PD. The first is to postpone the development of levodopa-induced dyskinesias, which are linked to duration of levodopa treatment and total exposure to levodopa. The second is postponement of the “wearing-off” effect; that is, the reemergence of symptoms that occurs in some patients before their next scheduled dose of levodopa. Such reasoning applies to early PD patients with minimal or no disability and—in particular—to young-onset PD patients who tend to develop vigorous dyskinesias and dramatic wearing-off phenomena. Pharmacologic alternatives to levodopa in early PD include monoamine oxidase (MAO)-B inhibitors, amantadine, and dopamine agonists.

Reprinted with permission from The New England Journal of Medicine (Olanow CW, et al. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med 2009; 361:168–178). © 2009 Massachusetts Medical Society.

MAO-B inhibitors. Two MAO-B inhibitors are approved by the US Food and Drug Administration for the treatment of PD: rasagiline and selegiline. These agents have a mildly symptomatic effect. In the Attenuation of Disease Progression with Azilect Given Once-daily (ADAGIO) trial, use of rasagiline at doses of 1 and 2 mg/d slowed the rate of worsening of the UPDRS score compared with placebo in patients with untreated PD (Figure 1).² Patients were randomly assigned to an early-start group (rasagiline, 1 or 2 mg/d, or placebo for 72 weeks) or a late-start group (placebo for 36 weeks followed by rasagiline, 1 or 2 mg/d, or placebo for 36 weeks). The rate of change in the UPDRS score was slowed significantly with early treatment with rasagiline at a dosage of 1 mg/d, but not at 2 mg/d. Because the hierarchical primary end points for the ADAGIO trial were met only for the cohort receiving 1 mg of rasagiline early, it remains inconclusive whether rasagiline has a neuroprotective effect.

In a placebo-controlled study of selegiline in de novo early-phase PD, Pålhagen et al showed that selegiline monotherapy delayed the need for levodopa. When used in combination with levodopa, selegiline was able to slow the progression of PD as measured by the change in UPDRS total score.³

Amantadine. In an early study of 54 patients with PD, functional disability scores improved significantly with administration of amantadine 200 to 300 mg/d compared with placebo.⁴ A small subset of patients, perhaps 20% or less, who are treated with amantadine experience robust symptom improvement. Side effects of amantadine include hallucinations, edema, livedo reticularis, and anticholinergic effects. A more recently discovered potential side effect is corneal edema.

Dopamine agonists. Pramipexole (immediate-release [IR] and extended-release [ER]), and ropinirole IR and ER are dopamine agonists that have demonstrated disease-modifying effects and efficacy in improving PD symptoms.

Pramipexole ER administered once daily in early PD was shown to be superior to placebo on the mean UPDRS total score.⁵ Ropinirole ER produced mean plasma concentrations over 24 hours similar to those achieved with ropinirole IR, and showed noninferiority to ropinirole IR on efficacy measures in patients with de novo PD.⁵

The effective dosage range of pramipexole ER in early PD is 0.375 to 4.5 mg/d. Side effects include hallucinations, edema, excessive diurnal somnolence, and impulse control disorders (ie, pathologic gambling, hypersexuality, excessive craving for sweets). Compared with pramipexole IR, compliance is enhanced with the ER formulation because of ease of administration, but this formulation also is more expensive.

In early PD, the effective dosage range of ropinirole ER is 8 to 12 mg/d.⁶ The side effects are the same as with pramipexole ER with the same compliance advantage and cost disadvantage compared with the IR formulation.

Research indicates that dopamine agonists may have a neuroprotective effect. In two large clinical trials in which patients with PD were followed with an imaging marker of dopamine neuronal degeneration (using single-photon emission computed tomography or positron emission tomography), recipients of pramipexole⁷ or ropinirole⁸ showed slower neuronal deterioration compared with levodopa recipients. A counterargument to the neuroprotective theory is that these differences between the dopamine agonists and levodopa reflect neurotoxicity of levodopa rather than neuroprotection by dopamine agonists. The absence of a placebo comparison in both trials adds to the difficulty in drawing a conclusion, as some critics ascribed the differences between groups to downregulation of tracer binding with levodopa.

Nonergoline dopamine agonist. Transdermal rotigotine is a nonergot D₁/D₂/D₃ agonist. Higher doses produce higher plasma levels of rotigotine, which remain steady over the 24-hour dosing interval.⁹ Transdermal rotigotine has demonstrated effectiveness in early PD in several clinical trials.^10,11 The patch, applied once daily, provides a constant release of medication. Removing the patch immediately interrupts drug administration.

Rotigotine patches must be refrigerated to prevent crystallization, a requirement that has delayed the product’s arrival on the market. The patch is reputed to be difficult to peel from its backing and apply. Skin reactions are a side effect, and nonergot side effects are possible. Despite these drawbacks, transdermal rotigotine represents a convenient option for perioperative management of PD and in patients with dysphagia.

Exercise. Exercise has symptomatic and possibly neuroprotective benefits in PD, supporting its use as an additional medical measure. Evidence supports the value of treadmill walking and high-impact exercise in improving stride length, quality of life, and motor response to levodopa.

 

SYMPTOMATIC THERAPIES: THE FUTURE

Partial dopamine agonists

Pardoprunox is a partial dopamine agonist with full 5-HT_1A–agonist activity. A partial dopamine agonist acts in two ways: (1) It stimulates dopamine production in brain regions with low dopamine tone, and (2) it has dopamine antagonist activity under circumstances of high dopamine sensitivity, theoretically avoiding overstimulation of dopamine receptors. Because it inhibits excessive dopamine effect, pardoprunox may prevent dyskinesia. In addition, because pardoprunox has serotonin agonist activity, it may also act as an antidepressant.

In a phase 2 study, significantly more patients randomized to pardoprunox had a 30% or greater reduction in UPDRS motor score compared with placebo at end-of-dose titration (35.8% for pardoprunox vs 15.7% for placebo; P = .0065) and at end point (50.7% for pardoprunox vs 15.7% for placebo; P < .0001).¹²

Adenosine A_2A-receptor antagonists

Adenosine A_2A receptors are located in the basal ganglia, primarily on gamma aminobutyric acid (GABA)–mediated enkephalin-expressing medium spiny neurons in the striatum. These receptors modulate dopamine transmission by opposing D₂-receptor activity. The D₂ pathway is an indirect pathway that promotes suppression of unnecessary movement.

Two A_2A-receptor antagonists have demonstrated efficacy in clinical trials. Vipadenant has been proven effective as monotherapy in phase 2 clinical trials. Preladenant has been shown to improve “off time” as an adjunct to levodopa without increasing dyskinesia.

Safinamide

Safinamide, currently in phase 3 clinical trials, has three mechanisms of action. It is an inhibitor of dopamine reuptake, a reversible inhibitor of MAO-B, and an inhibitor of excessive glutamate release. The addition of safinamide to a stable dose of a single dopamine agonist in patients with early PD resulted in improvement of motor symptoms and cognitive function.^13,14

NEUROPROTECTIVE STRATEGIES UNDER INVESTIGATION

Four neuroprotective strategies are under study: enhanced mitochondrial function, antiinflammatory mechanisms, calcium channel blockade, and uric acid elevation.

Enhanced mitochondrial function

Creatine has generated interest as a disease-modifying agent in response to preclinical data showing that it could enhance mitochondrial function and prevent mitochondrial loss in the brain in models of PD. Creatine is now the subject of a large phase 3 National Institutes of Health–sponsored clinical trial in patients with early-stage PD.¹⁵

Coenzyme Q10 (CoQ 10) exhibited a trend for neuroprotection at 1,200 mg/d, lowering the total mean UPDRS score compared with placebo in a 16-month study.¹⁶ Current efforts are directed at determining whether 1,200 or 2,400 mg/d of CoQ10 are neuroprotective. A nanoparticulate form of CoQ10, 100 mg three times a day, has been shown to produce plasma levels of CoQ10 equivalent to those produced by 1,200-mg doses of the standard form.¹⁷ CoQ10 is free of symptomatic effects.

Antiinflammatory mechanisms

Parkinson disease may have an important inflammatory component. A meta-analysis of seven studies showed an overall hazard ratio of 0.85 for development of PD in users of nonaspirin nonsteroidal antiinflammatory drugs (NSAIDs), with each of the seven studies demonstrating a hazard ratio less than 1.¹⁸ A similar meta-analysis showed no such association.¹⁹ Further study is warranted.

The antidiabetic agent pioglitazone, shown in mice to prevent dopaminergic nigral cell loss, has been entered into a phase 2 clinical trial to assess its antiinflammatory properties in PD.

Calcium channel blockade

A sustained-release formulation of isradipine, an L-type calcium channel blocker, is being studied in a phase 2 clinical trial for the treatment of early PD; experimental evidence in animals suggests that it may be neuroprotective against PD.

Uric acid elevation

Urate concentration in the cerebrospinal fluid predicts progression of PD, with higher levels associated with slower progression of disease.²⁰ Urate may delay oxidative destruction of dopaminergic neurons that occurs with progression of PD. Pharmacologic elevation of uric acid is being explored as a treatment option in PD.

ELECTRODES, VECTORS, AND STEM CELLS

Deep brain stimulation

Reprinted with permission from Movement Disorders (Espay AJ, et al. Early versus delayed bilateral subthalamic deep brain stimulation for Parkinson’s disease: a decision analysis. Mov Disord 2010; 25:1456–1463). Copyright © 2010 Movement Disorder Society.

Deep brain stimulation (DBS) is currently used as a treatment for advanced PD (patients suffering from levodopainduced motor complications), but it might also slow the progression of cognitive and motor decline in earlier stages of PD. The annual rate of progression of both cognitive and motor decline was slower when DBS was administered earlier in the course of PD (off time on levodopa of about 2 hours) versus in a later stage of PD (off time on levodopa of about 4 hours) (Figure 2).²¹ The strategy is being tested further in clinical trials of early PD.

Stem cell therapy

Stem cells obtained from blastocytes, fibroblasts, bone marrow, or the adult, embryonic, or fetal central nervous system through “molecular alchemy” can form dopaminergic neuroblasts. Given the high cost and potential risks of stem cell therapy, it must be proven superior to DBS to be considered an option for early PD. Several practical problems act as hurdles to successful stem cell therapy. Efficient generation of dopamine-producing neurons and successful grafting are required. Tumor growth is a risk. Involuntary movements have been observed in some patients who received fetal implants. A limitation of stem cell therapy is that it will only affect those aspects of PD that are dependent on dopamine.

Gene therapy

Gene delivery of the growth factor analogue adeno-associated type-2 vector (AAV2)-neurturin has been investigated in patients with advanced PD. When surgically placed inside a neuron, neurturin enhances neuron vitality, enabling it to better fight oxidative stress and other attacks. It fared no better than sham surgery on changes in UPDRS motor score at 12 months in a randomized trial.²² A few patients enrolled in this trial have been followed for longer than 12 months, at which time the mean change in motor scores appears to favor the group assigned to gene delivery of AAV2-neurturin. A phase 1/2 trial is investigating the safety and efficacy of bilateral intraputaminal and intranigral administration of neurturin.

SUMMARY

Levodopa is a legitimate choice for the treatment of early PD. Two MAO-B inhibitors, rasagiline and selegiline, have a symptomatic effect.

Long-acting oral and transdermal dopamine agonists are effective symptomatic therapies, but they also have an interesting array of side effects, making levodopa a reasonable alternative treatment sooner or later despite its dyskinetic effect. Potential neuroprotective effects remain to be identified.

Amantadine is sometimes overlooked as an option for treating early PD, but it has some special side effects including leg edema, livedo reticularis, and corneal edema. Amantadine does not cause orthostatic hypotension and is free of the side effects of excessive diurnal somnolence and impulse control disorders that are prevalent with dopamine agonists.

In the future, partial dopamine agonists and adenosine antagonists may provide us with additional symptomatic therapies. CoQ10, creatine, calcium channel blockers, and inosine, as well as NSAIDs, are being actively studied as potential disease-modifying agents. Further studies are likely to come from the use of NSAIDs.

Early DBS is a new avenue of investigation as a potential disease modifier. Stem cells are still being studied and limitations of sufficient production and potential tumor growth, among others, have delayed the institution of clinical trials. Gene therapy is an interesting additional treatment modality in active research.

Chorea is characterized by continuous, random, brief, involuntary muscle contractions that result from a variety of causes.¹ These involuntary movements are nonstereotyped and irregular. Although choreic disorders are among the most common involuntary movement disorders, their diagnosis and treatment present several important challenges, including identifying and removing the cause if possible, controlling and preventing motor symptoms, and managing neuropsychologic complications.¹ This article provides an overview of the diagnosis and treatment of choreic disorders, using Sydenham chorea to illustrate the management of autoimmune choreas and Huntington disease as the model for the management of heritable choreas.

Management of choreic disorders begins with a first-pass diagnosis and the use of symptomatic therapies. Even if this first pass yields no firm diagnosis, it at least rules out causes that have the most practical significance. A subsequent second-pass evaluation can be undertaken to look for rarer causes. Symptomatic therapies are continued throughout the diagnostic period. More specific therapies can be administered if an etiologic or pathogenic mechanism is determined (eg, postinfectious, autoimmune, metabolic).

CHOREIC DISORDERS: A PRACTICAL DIAGNOSTIC APPROACH

In general, choreic disorders may be subdivided into six categories:

1. Heredodegenerative disorders, such as Huntington disease and other genetically heterogeneous choreas, include Huntington disease–like 2 (HDL2) and benign hereditary chorea.¹ Sporadic cases include those of unknown paternity; X-linked disorders (eg, McLeod syndrome); and autosomal-recessive disorders such as chorea-acanthocytosis, which is characterized by chorea, dystonia with prominent orofacial involvement, self-mutilation, myopathy, and neuropathy.²

2. Drug-induced choreas include neurolepticinduced tardive dyskinesia and nontardive hyperkinetic drug-related choreas, the most common of which is levodopa-induced dyskinesias.³ Tardive drug-induced choreas may occur while using the culprit drug, while tapering the drug, or after it has been discontinued. The culprit drugs are represented by dopamine-receptor blockers and include the first-generation neuroleptics (eg, phenothiazines, haloperidol), antidepressants (lox-apine), and gastrointestinal agents (metoclopramide, prochlorperazine). Drug-induced choreas are possible with a wide range of pharmacologic agents, including antiparkinsonian drugs (eg, levodopa, dopamine agonists, anticholinergics), sympathomimetics (eg, amphetamines, cocaine), anticonvulsants, calcium channel blockers, and oral contraceptives.¹

3. Autoimmune choreas include Sydenham chorea, systemic lupus erythematosus, and antiphospholipid antibody syndromes. The latter encompass lupus anticoagulant and anticardiolipin antibodies.

4. Metabolic choreas are most often associated with hyperthyroidism, although case reports have described choreas in patients with vitamin B₁₂ deficiency. A variety of hereditary metabolic diseases are also included in this category.

5. Vascular choreas include polycythemia vera and cerebrovascular accidents, the latter frequently presenting as hemiballismus. Polycythemia vera is associated with a high incidence of neurologic symptoms, including a reported incidence of chorea of 0.5% to 5%,⁴ and should be considered as a potential cause of chorea.

6. Other choreic disorders include a variety of entities such as rare paraneoplastic disorder/syndrome, and posttraumatic and postanoxic presentations.

The first-pass diagnostic approach includes a family history, drug history, and brain magnetic resonance imaging to identify potential structural causes of chorea. Genetic testing for Huntington disease or other choreic disorders may also be performed, although it is essential to consider the potential implications of a positive test result. Intensive pretest and posttest counseling is important both for the patient and for currently asymptomatic family members who may also be affected.¹

Other testing includes:

• Complete blood count
• Creatine phosphokinase
• Peripheral smear for acanthocytes
• Comprehensive metabolic panel
• Ceruloplasmin level
• Measurement of thyroxine (T₄) and triiodothyronine (T₃)
• B₁₂ tests
• Antinuclear antibody sedimentation rate
• Lupus anticoagulant-anticardiolipin antibodies
• Antistreptolysin O (ASO) titer
• Anti-DNase-B titer.

GENERAL CONSIDERATIONS FOR THE TREATMENT OF CHOREIC DISORDERS

In some cases, choreic disorders have a treatable underlying etiology, such as thyroid disease or vitamin B₁₂ deficiency. Tardive syndromes may require treatment beyond drug discontinuation, including use of dopamine depleters for the classic tardive dyskinetic syndromes and anticholinergics for the tardive dystonic syndromes. Levodopa dyskinesia may be treated using amantadine, clozapine, or deep brain stimulation.^5,6 The treatment of patients with autoimmune choreas is not well defined. It may include anticoagulation in patients with positive anticardiolipin antibodies to prevent venous or arterial thromboembolism,⁷ but the risk of arterial thromboembolism is uncertain, and it is unclear whether chorea is truly a harbinger of vascular events.

A negative ASO titer does not exclude Sydenham chorea, a result of childhood infection with group-A beta-hemolytic streptococcus, and antibiotics should be considered in the appropriate context. Some researchers have argued that immune responses associated with acute infections may result in autoimmune neuropsychiatric symptoms. In pediatric patients, this has been referred to as pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS).⁸

A related phenomenon has been proposed as a potential mechanism of some types of chorea, although the relationship between acute infection and chorea is controversial. Patients with elevated ASO titer or anti-DNase-B titers may be candidates for antibiotics. By 6 weeks after the onset of infection, these titers will fall and a diagnosis of Sydenham chorea can be postulated or based exclusively on clinical judgment.

 

SYDENHAM CHOREA

Unique to Sydenham chorea is the use of penicillin as prophylaxis. Other than that, the management of Sydenham chorea exemplifies the management approach for the larger category of autoimmune choreic disorders. Pathogenic-based treatment options include immune modulation with cortico steroids, intravenous immunoglobulin (IVIG), and plasma exchange; all treatments must be administered in the appropriate clinical context.

One double-blind clinical trial examined the effectiveness of corticosteroid treatment in children with Sydenham chorea randomly assigned to receive either prednisone (n = 22) or placebo (n = 15).⁹ Prednisone was administered at a dose of 2 mg/kg/day for 4 weeks, followed by gradual tapering and discontinuation. The median time to remission of chorea was significantly lower for patients in the prednisone group (54.3 days) compared with those in the placebo group (119.9 days; P < .001). Patients in the prednisone group also exhibited significantly better scores on a chorea intensity rating scale at 8 weeks and 12 weeks (P < .001). Potential limitations of this approach include relapse of chorea symptoms and corticosteroid-related adverse events (eg, Cushing syndrome, hypertension).

A second study compared the effectiveness of three modalities: IVIG at a dose of 1 g/kg/day for 2 days (n = 4), plasma exchange (n = 8), and prednisone (n = 6).¹⁰ Although differences between treatment groups were not statistically significant, the authors noted that the clinical improvement in chorea symptoms tended to be greater for patients who received IVIG or plasma exchange than for those who received prednisone. Mean chorea scores improved from baseline by 72% for the IVIG group, 50% for the plasma exchange group, and 29% for the prednisone group.

After etiology-dependent treatments have been considered, several other options may be effective regardless of the specific etiology. These include symptomatic treatments such as haloperidol, atypical neuroleptics, and amantadine.¹¹ Antiepileptic medications or benzodiazepines may also help to control symptoms, although less information is available about the use of these agents for the treatment of Sydenham chorea. Tetrabenazine may be considered for patients who will require long-term treatment.

HUNTINGTON DISEASE

Pharmacotherapy of Huntington disease may be unnecessary if symptoms are mild or not bothersome. Symptomatic treatment options include tetrabenazine, amantadine, and either first-generation neuroleptics (eg, haloperidol) or second-generation atypical neuroleptics (eg, olanzapine, quetiapine, risperidone, ziprasidone).

Treating choreas with tetrabenazine or amantadine

Considerable recent attention has focused on the efficacy and safety of tetrabenazine for the treatment of Huntington disease and other choreic disorders. Tetrabenazine is a central monoamine depleter that reversibly binds to the type-2 vesicular monoamine transporter.¹² The TETRA-HD study examined the efficacy and safety of tetrabenazine for the short- and long-term control of Huntington disease.¹² An initial study compared tetrabenazine with placebo in 75 patients who were treated for up to 13 weeks. In an extension study, all patients received individualized tetrabenazine doses for up to 80 weeks.

The mean total maximal chorea (TMC) scores from the Unified Huntington Disease Rating Scale (UHDRS) decreased markedly during the first 10 weeks of tetrabenazine treatment, remained lower than baseline throughout 80 weeks, and then returned to baseline levels after tetrabenazine discontinuation (Figure 1). At week 80, the mean TMC score was reduced by 4.6 UHDRS units compared with baseline (P < .001) The long-term extension phase was completed by 45 of 75 patients. Treatment-related adverse events that prompted discontinuation included depression, delusions, and vocal tics. The most commonly reported adverse events included sedation or somnolence (n = 18), depressed mood (n = 17), anxiety (n = 13), insomnia (n = 10), and akathisia (n = 9). Scores of parkinsonism and dysphagia increased significantly from baseline over the 80-week study.

Amantadine is an option for patients who cannot tolerate tetrabenazine. A double-blind, placebo-controlled study performed by researchers at the National Institutes of Health (NIH) examined the efficacy and safety of amantadine in 24 patients with Huntington disease.¹³ Patients were treated with oral amantadine 400 mg/day or placebo for 2 weeks, and were then crossed over to the other treatment. Amantadine was associated with a median reduction in extremity chorea score at rest of 36% from baseline (P = .04), versus 0% improvement with placebo. The mean improvement with amantadine was 56% for the 10 patients with the highest drug plasma levels.

Improvement in chorea scores from baseline for amantadine compared with placebo was rated with four different methods: (1) maximal chorea severity measured from video recordings; (2) maximal chorea severity measured by live raters; (3), chorea severity at rest measured from video recordings; and (4) extremity chorea at rest measured from video recordings. Amantadine was superior to placebo according to all four rating methods. Treatment was generally safe and well tolerated, and no consistent changes in cognitive function were noted with amantadine therapy.

Reprinted with permission from Neurology (Lucetti C, et al. IV amantadine improves chorea in Huntington’s disease: an acute randomized, controlled study. Neurology 2003; 60:1995–1997). Copyright © 2003 by AAN Enterprises, Inc.

A second study examined the effects of amantadine as a 2-hour IV infusion in nine patients with Huntington disease.¹⁴ Amantadine or placebo was administered in a randomized, double-blind manner on the first day of the study, and patients were then crossed over to the other treatment on the second day. All patients then received open-label oral amantadine for an additional 1 year. During the randomized placebo-controlled phase, mean dyskinesia scores, evaluated using the Abnormal Involuntary Movement Scale, were significantly lower for patients randomly assigned to amantadine compared with placebo. During the randomized placebo-controlled phase, the decrease in mean dyskinesia score was significantly greater 90 minutes after treatment with amantadine compared with placebo (Figure 2). In the open-label amantadine continuation phase, oral amantadine was associated with a further gradual improvement in symptoms over 3 to 6 months. No significant changes were observed in neuropsychologic tests or psychiatric rating scales.

 

 

Managing nonmotor complications

In addition to addressing chorea, it is also important to manage nonmotor complications of Huntington disease, including cognition, mood, and thought disorders. Rivastigmine was assessed for the treatment of motor symptoms, functional disability, and cognitive impairment associated with Huntington disease in an open-label study of 18 patients; 11 received rivastigmine 6 mg/day and 7 control patients did not.¹⁵ Motor and cognitive function were assessed for up to 2 years by raters who were blinded to treatment assignment. Ratings on a global motor performance scale were significantly better for patients who received rivastigmine than for control subjects. Rivastigmine treatment was also associated with trends toward improvements in functional disability and cognitive impairment, although these differences were not statistically significant.

A small open-label study examined the effects of donepezil for movement and cognitive symptoms associated with Huntington disease.¹⁶ Donepezil did not significantly improve cognitive symptoms, although the study enrolled only eight patients. All patients tolerated oral donepezil at a dose of 5 mg/day, but four patients withdrew from the study when the dose was increased to 10 mg/day. In two patients, chorea worsened and falls increased, moderate to severe diarrhea developed in three patients, and one patient reported anxiety and irritability.

Depression is another common complication of Huntington disease. The incidence of depression among patients with Huntington disease is approximately 40%, and the risk of suicide is at least eightfold greater than that among the general population.¹⁷ Treatment must be guided by clinical judgment. Selective serotonin reuptake inhibitor antidepressants have been recommended. Other options to manage depression include mirtazapine, monoamine oxidase inhibitors, or electroshock therapy. Mood-stabilizing agents (eg, carbamazepine, lamotrigine, valproate) may also be indicated in helping with impulse control. Haloperidol and second-generation antipsychotics are used for the treatment of a broad range of psychiatric conditions, many of which may overlap with Huntington disease, including schizophrenia and schizophreniform disorder, schizoaffective disorder, bipolar disorder, dementia, and disruptive behavior.¹⁸ The risk of tardive dyskinesia may be as much as fivefold lower with second-generation antipsychotics.¹⁸ Many patients with Huntington disease require treatment for aggression. A variety of approaches are available, including behavior modification, the antidepressant sertraline, buspirone, antipsychotic agents (eg, risperidone, olanzapine), propranolol, and lithium (combined with haloperidol).

Long-term care considerations

As a consequence of the diverse clinical manifestations of choreic disorders in movement, function, mood, and cognition, the treatment of Huntington disease requires a multidisciplinary approach that involves a number of different health care specialties across the long-term course of the disorder. Members of the Huntington disease treatment team may include neurologists, psychiatrists, nurses, social workers, geneticists, physical therapists, occupational therapists, speech therapists, dietitians, and other supporting groups or professional societies. The clinical manifestations of Huntington disease may evolve over time, as symptoms such as bradykinesia, dystonia, rigidity, cognitive decline, and gait instability become more significant.¹⁹ As a result, optimal management strategies for patients with Huntington disease may change significantly across the long-term course of the disease. During the early course of the disease, the typical clinical presentation is largely hyperkinesis, irritability, and distractibility. These patients will require initiation of drug therapy and linkage to sources of support. In the later stages of the disease, the presentation shifts to a more hypokinetic and apathetic profile, and patients are more likely to require drug regimen review and modification, nursing home placement, and palliative care services.¹⁹

Another important concern in Huntington disease treatment is care of the caregiver. Surveys show that the key concerns of caregivers include the expertise of the health care professionals who are treating the patient and the availability of sufficient services in the community.²⁰ Several resources are available for Huntington disease caregivers, including local support groups, the Huntington’s Disease Society of America, Q Foundation, and the Huntington Study Group. The Lundbeck pharmaceutical company operates a patient assistance program (LundbeckShare. com) as well as an information center that can be accessed toll free at (888)457-4273. Approximately 90% of patients who request copayment assistance qualify for aid, regardless of the type of insurance they carry.

SUMMARY AND CONCLUSIONS

The approach to a patient with chorea starts with a search for specifically treatable etiologies. Autoimmune, metabolic, and vascular causes should be sought first and treated. The symptomatic treatment of all choreas is based on the model described here for Huntington disease, and includes attention to cognitive, psychiatric, and social support issues. The recommended approach is multidisciplinary, with a change in the mix of services as the disease progresses. It is also important to recognize the burden of Huntington disease on the caregiver and consider steps to make this burden more manageable.

Chorea is characterized by continuous, random, brief, involuntary muscle contractions that result from a variety of causes.¹ These involuntary movements are nonstereotyped and irregular. Although choreic disorders are among the most common involuntary movement disorders, their diagnosis and treatment present several important challenges, including identifying and removing the cause if possible, controlling and preventing motor symptoms, and managing neuropsychologic complications.¹ This article provides an overview of the diagnosis and treatment of choreic disorders, using Sydenham chorea to illustrate the management of autoimmune choreas and Huntington disease as the model for the management of heritable choreas.

Management of choreic disorders begins with a first-pass diagnosis and the use of symptomatic therapies. Even if this first pass yields no firm diagnosis, it at least rules out causes that have the most practical significance. A subsequent second-pass evaluation can be undertaken to look for rarer causes. Symptomatic therapies are continued throughout the diagnostic period. More specific therapies can be administered if an etiologic or pathogenic mechanism is determined (eg, postinfectious, autoimmune, metabolic).

CHOREIC DISORDERS: A PRACTICAL DIAGNOSTIC APPROACH

In general, choreic disorders may be subdivided into six categories:

1. Heredodegenerative disorders, such as Huntington disease and other genetically heterogeneous choreas, include Huntington disease–like 2 (HDL2) and benign hereditary chorea.¹ Sporadic cases include those of unknown paternity; X-linked disorders (eg, McLeod syndrome); and autosomal-recessive disorders such as chorea-acanthocytosis, which is characterized by chorea, dystonia with prominent orofacial involvement, self-mutilation, myopathy, and neuropathy.²

2. Drug-induced choreas include neurolepticinduced tardive dyskinesia and nontardive hyperkinetic drug-related choreas, the most common of which is levodopa-induced dyskinesias.³ Tardive drug-induced choreas may occur while using the culprit drug, while tapering the drug, or after it has been discontinued. The culprit drugs are represented by dopamine-receptor blockers and include the first-generation neuroleptics (eg, phenothiazines, haloperidol), antidepressants (lox-apine), and gastrointestinal agents (metoclopramide, prochlorperazine). Drug-induced choreas are possible with a wide range of pharmacologic agents, including antiparkinsonian drugs (eg, levodopa, dopamine agonists, anticholinergics), sympathomimetics (eg, amphetamines, cocaine), anticonvulsants, calcium channel blockers, and oral contraceptives.¹

3. Autoimmune choreas include Sydenham chorea, systemic lupus erythematosus, and antiphospholipid antibody syndromes. The latter encompass lupus anticoagulant and anticardiolipin antibodies.

4. Metabolic choreas are most often associated with hyperthyroidism, although case reports have described choreas in patients with vitamin B₁₂ deficiency. A variety of hereditary metabolic diseases are also included in this category.

5. Vascular choreas include polycythemia vera and cerebrovascular accidents, the latter frequently presenting as hemiballismus. Polycythemia vera is associated with a high incidence of neurologic symptoms, including a reported incidence of chorea of 0.5% to 5%,⁴ and should be considered as a potential cause of chorea.

6. Other choreic disorders include a variety of entities such as rare paraneoplastic disorder/syndrome, and posttraumatic and postanoxic presentations.

The first-pass diagnostic approach includes a family history, drug history, and brain magnetic resonance imaging to identify potential structural causes of chorea. Genetic testing for Huntington disease or other choreic disorders may also be performed, although it is essential to consider the potential implications of a positive test result. Intensive pretest and posttest counseling is important both for the patient and for currently asymptomatic family members who may also be affected.¹

Other testing includes:

• Complete blood count
• Creatine phosphokinase
• Peripheral smear for acanthocytes
• Comprehensive metabolic panel
• Ceruloplasmin level
• Measurement of thyroxine (T₄) and triiodothyronine (T₃)
• B₁₂ tests
• Antinuclear antibody sedimentation rate
• Lupus anticoagulant-anticardiolipin antibodies
• Antistreptolysin O (ASO) titer
• Anti-DNase-B titer.

GENERAL CONSIDERATIONS FOR THE TREATMENT OF CHOREIC DISORDERS

In some cases, choreic disorders have a treatable underlying etiology, such as thyroid disease or vitamin B₁₂ deficiency. Tardive syndromes may require treatment beyond drug discontinuation, including use of dopamine depleters for the classic tardive dyskinetic syndromes and anticholinergics for the tardive dystonic syndromes. Levodopa dyskinesia may be treated using amantadine, clozapine, or deep brain stimulation.^5,6 The treatment of patients with autoimmune choreas is not well defined. It may include anticoagulation in patients with positive anticardiolipin antibodies to prevent venous or arterial thromboembolism,⁷ but the risk of arterial thromboembolism is uncertain, and it is unclear whether chorea is truly a harbinger of vascular events.

A negative ASO titer does not exclude Sydenham chorea, a result of childhood infection with group-A beta-hemolytic streptococcus, and antibiotics should be considered in the appropriate context. Some researchers have argued that immune responses associated with acute infections may result in autoimmune neuropsychiatric symptoms. In pediatric patients, this has been referred to as pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS).⁸

A related phenomenon has been proposed as a potential mechanism of some types of chorea, although the relationship between acute infection and chorea is controversial. Patients with elevated ASO titer or anti-DNase-B titers may be candidates for antibiotics. By 6 weeks after the onset of infection, these titers will fall and a diagnosis of Sydenham chorea can be postulated or based exclusively on clinical judgment.

 

SYDENHAM CHOREA

Unique to Sydenham chorea is the use of penicillin as prophylaxis. Other than that, the management of Sydenham chorea exemplifies the management approach for the larger category of autoimmune choreic disorders. Pathogenic-based treatment options include immune modulation with cortico steroids, intravenous immunoglobulin (IVIG), and plasma exchange; all treatments must be administered in the appropriate clinical context.

One double-blind clinical trial examined the effectiveness of corticosteroid treatment in children with Sydenham chorea randomly assigned to receive either prednisone (n = 22) or placebo (n = 15).⁹ Prednisone was administered at a dose of 2 mg/kg/day for 4 weeks, followed by gradual tapering and discontinuation. The median time to remission of chorea was significantly lower for patients in the prednisone group (54.3 days) compared with those in the placebo group (119.9 days; P < .001). Patients in the prednisone group also exhibited significantly better scores on a chorea intensity rating scale at 8 weeks and 12 weeks (P < .001). Potential limitations of this approach include relapse of chorea symptoms and corticosteroid-related adverse events (eg, Cushing syndrome, hypertension).

A second study compared the effectiveness of three modalities: IVIG at a dose of 1 g/kg/day for 2 days (n = 4), plasma exchange (n = 8), and prednisone (n = 6).¹⁰ Although differences between treatment groups were not statistically significant, the authors noted that the clinical improvement in chorea symptoms tended to be greater for patients who received IVIG or plasma exchange than for those who received prednisone. Mean chorea scores improved from baseline by 72% for the IVIG group, 50% for the plasma exchange group, and 29% for the prednisone group.

After etiology-dependent treatments have been considered, several other options may be effective regardless of the specific etiology. These include symptomatic treatments such as haloperidol, atypical neuroleptics, and amantadine.¹¹ Antiepileptic medications or benzodiazepines may also help to control symptoms, although less information is available about the use of these agents for the treatment of Sydenham chorea. Tetrabenazine may be considered for patients who will require long-term treatment.

HUNTINGTON DISEASE

Pharmacotherapy of Huntington disease may be unnecessary if symptoms are mild or not bothersome. Symptomatic treatment options include tetrabenazine, amantadine, and either first-generation neuroleptics (eg, haloperidol) or second-generation atypical neuroleptics (eg, olanzapine, quetiapine, risperidone, ziprasidone).

Treating choreas with tetrabenazine or amantadine

Considerable recent attention has focused on the efficacy and safety of tetrabenazine for the treatment of Huntington disease and other choreic disorders. Tetrabenazine is a central monoamine depleter that reversibly binds to the type-2 vesicular monoamine transporter.¹² The TETRA-HD study examined the efficacy and safety of tetrabenazine for the short- and long-term control of Huntington disease.¹² An initial study compared tetrabenazine with placebo in 75 patients who were treated for up to 13 weeks. In an extension study, all patients received individualized tetrabenazine doses for up to 80 weeks.

The mean total maximal chorea (TMC) scores from the Unified Huntington Disease Rating Scale (UHDRS) decreased markedly during the first 10 weeks of tetrabenazine treatment, remained lower than baseline throughout 80 weeks, and then returned to baseline levels after tetrabenazine discontinuation (Figure 1). At week 80, the mean TMC score was reduced by 4.6 UHDRS units compared with baseline (P < .001) The long-term extension phase was completed by 45 of 75 patients. Treatment-related adverse events that prompted discontinuation included depression, delusions, and vocal tics. The most commonly reported adverse events included sedation or somnolence (n = 18), depressed mood (n = 17), anxiety (n = 13), insomnia (n = 10), and akathisia (n = 9). Scores of parkinsonism and dysphagia increased significantly from baseline over the 80-week study.

Amantadine is an option for patients who cannot tolerate tetrabenazine. A double-blind, placebo-controlled study performed by researchers at the National Institutes of Health (NIH) examined the efficacy and safety of amantadine in 24 patients with Huntington disease.¹³ Patients were treated with oral amantadine 400 mg/day or placebo for 2 weeks, and were then crossed over to the other treatment. Amantadine was associated with a median reduction in extremity chorea score at rest of 36% from baseline (P = .04), versus 0% improvement with placebo. The mean improvement with amantadine was 56% for the 10 patients with the highest drug plasma levels.

Improvement in chorea scores from baseline for amantadine compared with placebo was rated with four different methods: (1) maximal chorea severity measured from video recordings; (2) maximal chorea severity measured by live raters; (3), chorea severity at rest measured from video recordings; and (4) extremity chorea at rest measured from video recordings. Amantadine was superior to placebo according to all four rating methods. Treatment was generally safe and well tolerated, and no consistent changes in cognitive function were noted with amantadine therapy.

Reprinted with permission from Neurology (Lucetti C, et al. IV amantadine improves chorea in Huntington’s disease: an acute randomized, controlled study. Neurology 2003; 60:1995–1997). Copyright © 2003 by AAN Enterprises, Inc.

A second study examined the effects of amantadine as a 2-hour IV infusion in nine patients with Huntington disease.¹⁴ Amantadine or placebo was administered in a randomized, double-blind manner on the first day of the study, and patients were then crossed over to the other treatment on the second day. All patients then received open-label oral amantadine for an additional 1 year. During the randomized placebo-controlled phase, mean dyskinesia scores, evaluated using the Abnormal Involuntary Movement Scale, were significantly lower for patients randomly assigned to amantadine compared with placebo. During the randomized placebo-controlled phase, the decrease in mean dyskinesia score was significantly greater 90 minutes after treatment with amantadine compared with placebo (Figure 2). In the open-label amantadine continuation phase, oral amantadine was associated with a further gradual improvement in symptoms over 3 to 6 months. No significant changes were observed in neuropsychologic tests or psychiatric rating scales.

 

 

Managing nonmotor complications

In addition to addressing chorea, it is also important to manage nonmotor complications of Huntington disease, including cognition, mood, and thought disorders. Rivastigmine was assessed for the treatment of motor symptoms, functional disability, and cognitive impairment associated with Huntington disease in an open-label study of 18 patients; 11 received rivastigmine 6 mg/day and 7 control patients did not.¹⁵ Motor and cognitive function were assessed for up to 2 years by raters who were blinded to treatment assignment. Ratings on a global motor performance scale were significantly better for patients who received rivastigmine than for control subjects. Rivastigmine treatment was also associated with trends toward improvements in functional disability and cognitive impairment, although these differences were not statistically significant.

A small open-label study examined the effects of donepezil for movement and cognitive symptoms associated with Huntington disease.¹⁶ Donepezil did not significantly improve cognitive symptoms, although the study enrolled only eight patients. All patients tolerated oral donepezil at a dose of 5 mg/day, but four patients withdrew from the study when the dose was increased to 10 mg/day. In two patients, chorea worsened and falls increased, moderate to severe diarrhea developed in three patients, and one patient reported anxiety and irritability.

Depression is another common complication of Huntington disease. The incidence of depression among patients with Huntington disease is approximately 40%, and the risk of suicide is at least eightfold greater than that among the general population.¹⁷ Treatment must be guided by clinical judgment. Selective serotonin reuptake inhibitor antidepressants have been recommended. Other options to manage depression include mirtazapine, monoamine oxidase inhibitors, or electroshock therapy. Mood-stabilizing agents (eg, carbamazepine, lamotrigine, valproate) may also be indicated in helping with impulse control. Haloperidol and second-generation antipsychotics are used for the treatment of a broad range of psychiatric conditions, many of which may overlap with Huntington disease, including schizophrenia and schizophreniform disorder, schizoaffective disorder, bipolar disorder, dementia, and disruptive behavior.¹⁸ The risk of tardive dyskinesia may be as much as fivefold lower with second-generation antipsychotics.¹⁸ Many patients with Huntington disease require treatment for aggression. A variety of approaches are available, including behavior modification, the antidepressant sertraline, buspirone, antipsychotic agents (eg, risperidone, olanzapine), propranolol, and lithium (combined with haloperidol).

Long-term care considerations

As a consequence of the diverse clinical manifestations of choreic disorders in movement, function, mood, and cognition, the treatment of Huntington disease requires a multidisciplinary approach that involves a number of different health care specialties across the long-term course of the disorder. Members of the Huntington disease treatment team may include neurologists, psychiatrists, nurses, social workers, geneticists, physical therapists, occupational therapists, speech therapists, dietitians, and other supporting groups or professional societies. The clinical manifestations of Huntington disease may evolve over time, as symptoms such as bradykinesia, dystonia, rigidity, cognitive decline, and gait instability become more significant.¹⁹ As a result, optimal management strategies for patients with Huntington disease may change significantly across the long-term course of the disease. During the early course of the disease, the typical clinical presentation is largely hyperkinesis, irritability, and distractibility. These patients will require initiation of drug therapy and linkage to sources of support. In the later stages of the disease, the presentation shifts to a more hypokinetic and apathetic profile, and patients are more likely to require drug regimen review and modification, nursing home placement, and palliative care services.¹⁹

Another important concern in Huntington disease treatment is care of the caregiver. Surveys show that the key concerns of caregivers include the expertise of the health care professionals who are treating the patient and the availability of sufficient services in the community.²⁰ Several resources are available for Huntington disease caregivers, including local support groups, the Huntington’s Disease Society of America, Q Foundation, and the Huntington Study Group. The Lundbeck pharmaceutical company operates a patient assistance program (LundbeckShare. com) as well as an information center that can be accessed toll free at (888)457-4273. Approximately 90% of patients who request copayment assistance qualify for aid, regardless of the type of insurance they carry.

SUMMARY AND CONCLUSIONS

The approach to a patient with chorea starts with a search for specifically treatable etiologies. Autoimmune, metabolic, and vascular causes should be sought first and treated. The symptomatic treatment of all choreas is based on the model described here for Huntington disease, and includes attention to cognitive, psychiatric, and social support issues. The recommended approach is multidisciplinary, with a change in the mix of services as the disease progresses. It is also important to recognize the burden of Huntington disease on the caregiver and consider steps to make this burden more manageable.

Chorea is characterized by continuous, random, brief, involuntary muscle contractions that result from a variety of causes.¹ These involuntary movements are nonstereotyped and irregular. Although choreic disorders are among the most common involuntary movement disorders, their diagnosis and treatment present several important challenges, including identifying and removing the cause if possible, controlling and preventing motor symptoms, and managing neuropsychologic complications.¹ This article provides an overview of the diagnosis and treatment of choreic disorders, using Sydenham chorea to illustrate the management of autoimmune choreas and Huntington disease as the model for the management of heritable choreas.

Management of choreic disorders begins with a first-pass diagnosis and the use of symptomatic therapies. Even if this first pass yields no firm diagnosis, it at least rules out causes that have the most practical significance. A subsequent second-pass evaluation can be undertaken to look for rarer causes. Symptomatic therapies are continued throughout the diagnostic period. More specific therapies can be administered if an etiologic or pathogenic mechanism is determined (eg, postinfectious, autoimmune, metabolic).

CHOREIC DISORDERS: A PRACTICAL DIAGNOSTIC APPROACH

In general, choreic disorders may be subdivided into six categories:

1. Heredodegenerative disorders, such as Huntington disease and other genetically heterogeneous choreas, include Huntington disease–like 2 (HDL2) and benign hereditary chorea.¹ Sporadic cases include those of unknown paternity; X-linked disorders (eg, McLeod syndrome); and autosomal-recessive disorders such as chorea-acanthocytosis, which is characterized by chorea, dystonia with prominent orofacial involvement, self-mutilation, myopathy, and neuropathy.²

2. Drug-induced choreas include neurolepticinduced tardive dyskinesia and nontardive hyperkinetic drug-related choreas, the most common of which is levodopa-induced dyskinesias.³ Tardive drug-induced choreas may occur while using the culprit drug, while tapering the drug, or after it has been discontinued. The culprit drugs are represented by dopamine-receptor blockers and include the first-generation neuroleptics (eg, phenothiazines, haloperidol), antidepressants (lox-apine), and gastrointestinal agents (metoclopramide, prochlorperazine). Drug-induced choreas are possible with a wide range of pharmacologic agents, including antiparkinsonian drugs (eg, levodopa, dopamine agonists, anticholinergics), sympathomimetics (eg, amphetamines, cocaine), anticonvulsants, calcium channel blockers, and oral contraceptives.¹

3. Autoimmune choreas include Sydenham chorea, systemic lupus erythematosus, and antiphospholipid antibody syndromes. The latter encompass lupus anticoagulant and anticardiolipin antibodies.

4. Metabolic choreas are most often associated with hyperthyroidism, although case reports have described choreas in patients with vitamin B₁₂ deficiency. A variety of hereditary metabolic diseases are also included in this category.

5. Vascular choreas include polycythemia vera and cerebrovascular accidents, the latter frequently presenting as hemiballismus. Polycythemia vera is associated with a high incidence of neurologic symptoms, including a reported incidence of chorea of 0.5% to 5%,⁴ and should be considered as a potential cause of chorea.

6. Other choreic disorders include a variety of entities such as rare paraneoplastic disorder/syndrome, and posttraumatic and postanoxic presentations.

The first-pass diagnostic approach includes a family history, drug history, and brain magnetic resonance imaging to identify potential structural causes of chorea. Genetic testing for Huntington disease or other choreic disorders may also be performed, although it is essential to consider the potential implications of a positive test result. Intensive pretest and posttest counseling is important both for the patient and for currently asymptomatic family members who may also be affected.¹

Other testing includes:

• Complete blood count
• Creatine phosphokinase
• Peripheral smear for acanthocytes
• Comprehensive metabolic panel
• Ceruloplasmin level
• Measurement of thyroxine (T₄) and triiodothyronine (T₃)
• B₁₂ tests
• Antinuclear antibody sedimentation rate
• Lupus anticoagulant-anticardiolipin antibodies
• Antistreptolysin O (ASO) titer
• Anti-DNase-B titer.

GENERAL CONSIDERATIONS FOR THE TREATMENT OF CHOREIC DISORDERS

In some cases, choreic disorders have a treatable underlying etiology, such as thyroid disease or vitamin B₁₂ deficiency. Tardive syndromes may require treatment beyond drug discontinuation, including use of dopamine depleters for the classic tardive dyskinetic syndromes and anticholinergics for the tardive dystonic syndromes. Levodopa dyskinesia may be treated using amantadine, clozapine, or deep brain stimulation.^5,6 The treatment of patients with autoimmune choreas is not well defined. It may include anticoagulation in patients with positive anticardiolipin antibodies to prevent venous or arterial thromboembolism,⁷ but the risk of arterial thromboembolism is uncertain, and it is unclear whether chorea is truly a harbinger of vascular events.

A negative ASO titer does not exclude Sydenham chorea, a result of childhood infection with group-A beta-hemolytic streptococcus, and antibiotics should be considered in the appropriate context. Some researchers have argued that immune responses associated with acute infections may result in autoimmune neuropsychiatric symptoms. In pediatric patients, this has been referred to as pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS).⁸

A related phenomenon has been proposed as a potential mechanism of some types of chorea, although the relationship between acute infection and chorea is controversial. Patients with elevated ASO titer or anti-DNase-B titers may be candidates for antibiotics. By 6 weeks after the onset of infection, these titers will fall and a diagnosis of Sydenham chorea can be postulated or based exclusively on clinical judgment.

 

SYDENHAM CHOREA

Unique to Sydenham chorea is the use of penicillin as prophylaxis. Other than that, the management of Sydenham chorea exemplifies the management approach for the larger category of autoimmune choreic disorders. Pathogenic-based treatment options include immune modulation with cortico steroids, intravenous immunoglobulin (IVIG), and plasma exchange; all treatments must be administered in the appropriate clinical context.

One double-blind clinical trial examined the effectiveness of corticosteroid treatment in children with Sydenham chorea randomly assigned to receive either prednisone (n = 22) or placebo (n = 15).⁹ Prednisone was administered at a dose of 2 mg/kg/day for 4 weeks, followed by gradual tapering and discontinuation. The median time to remission of chorea was significantly lower for patients in the prednisone group (54.3 days) compared with those in the placebo group (119.9 days; P < .001). Patients in the prednisone group also exhibited significantly better scores on a chorea intensity rating scale at 8 weeks and 12 weeks (P < .001). Potential limitations of this approach include relapse of chorea symptoms and corticosteroid-related adverse events (eg, Cushing syndrome, hypertension).

A second study compared the effectiveness of three modalities: IVIG at a dose of 1 g/kg/day for 2 days (n = 4), plasma exchange (n = 8), and prednisone (n = 6).¹⁰ Although differences between treatment groups were not statistically significant, the authors noted that the clinical improvement in chorea symptoms tended to be greater for patients who received IVIG or plasma exchange than for those who received prednisone. Mean chorea scores improved from baseline by 72% for the IVIG group, 50% for the plasma exchange group, and 29% for the prednisone group.

After etiology-dependent treatments have been considered, several other options may be effective regardless of the specific etiology. These include symptomatic treatments such as haloperidol, atypical neuroleptics, and amantadine.¹¹ Antiepileptic medications or benzodiazepines may also help to control symptoms, although less information is available about the use of these agents for the treatment of Sydenham chorea. Tetrabenazine may be considered for patients who will require long-term treatment.

HUNTINGTON DISEASE

Pharmacotherapy of Huntington disease may be unnecessary if symptoms are mild or not bothersome. Symptomatic treatment options include tetrabenazine, amantadine, and either first-generation neuroleptics (eg, haloperidol) or second-generation atypical neuroleptics (eg, olanzapine, quetiapine, risperidone, ziprasidone).

Treating choreas with tetrabenazine or amantadine

Considerable recent attention has focused on the efficacy and safety of tetrabenazine for the treatment of Huntington disease and other choreic disorders. Tetrabenazine is a central monoamine depleter that reversibly binds to the type-2 vesicular monoamine transporter.¹² The TETRA-HD study examined the efficacy and safety of tetrabenazine for the short- and long-term control of Huntington disease.¹² An initial study compared tetrabenazine with placebo in 75 patients who were treated for up to 13 weeks. In an extension study, all patients received individualized tetrabenazine doses for up to 80 weeks.

The mean total maximal chorea (TMC) scores from the Unified Huntington Disease Rating Scale (UHDRS) decreased markedly during the first 10 weeks of tetrabenazine treatment, remained lower than baseline throughout 80 weeks, and then returned to baseline levels after tetrabenazine discontinuation (Figure 1). At week 80, the mean TMC score was reduced by 4.6 UHDRS units compared with baseline (P < .001) The long-term extension phase was completed by 45 of 75 patients. Treatment-related adverse events that prompted discontinuation included depression, delusions, and vocal tics. The most commonly reported adverse events included sedation or somnolence (n = 18), depressed mood (n = 17), anxiety (n = 13), insomnia (n = 10), and akathisia (n = 9). Scores of parkinsonism and dysphagia increased significantly from baseline over the 80-week study.

Amantadine is an option for patients who cannot tolerate tetrabenazine. A double-blind, placebo-controlled study performed by researchers at the National Institutes of Health (NIH) examined the efficacy and safety of amantadine in 24 patients with Huntington disease.¹³ Patients were treated with oral amantadine 400 mg/day or placebo for 2 weeks, and were then crossed over to the other treatment. Amantadine was associated with a median reduction in extremity chorea score at rest of 36% from baseline (P = .04), versus 0% improvement with placebo. The mean improvement with amantadine was 56% for the 10 patients with the highest drug plasma levels.

Improvement in chorea scores from baseline for amantadine compared with placebo was rated with four different methods: (1) maximal chorea severity measured from video recordings; (2) maximal chorea severity measured by live raters; (3), chorea severity at rest measured from video recordings; and (4) extremity chorea at rest measured from video recordings. Amantadine was superior to placebo according to all four rating methods. Treatment was generally safe and well tolerated, and no consistent changes in cognitive function were noted with amantadine therapy.

Reprinted with permission from Neurology (Lucetti C, et al. IV amantadine improves chorea in Huntington’s disease: an acute randomized, controlled study. Neurology 2003; 60:1995–1997). Copyright © 2003 by AAN Enterprises, Inc.

A second study examined the effects of amantadine as a 2-hour IV infusion in nine patients with Huntington disease.¹⁴ Amantadine or placebo was administered in a randomized, double-blind manner on the first day of the study, and patients were then crossed over to the other treatment on the second day. All patients then received open-label oral amantadine for an additional 1 year. During the randomized placebo-controlled phase, mean dyskinesia scores, evaluated using the Abnormal Involuntary Movement Scale, were significantly lower for patients randomly assigned to amantadine compared with placebo. During the randomized placebo-controlled phase, the decrease in mean dyskinesia score was significantly greater 90 minutes after treatment with amantadine compared with placebo (Figure 2). In the open-label amantadine continuation phase, oral amantadine was associated with a further gradual improvement in symptoms over 3 to 6 months. No significant changes were observed in neuropsychologic tests or psychiatric rating scales.

 

 

Managing nonmotor complications

In addition to addressing chorea, it is also important to manage nonmotor complications of Huntington disease, including cognition, mood, and thought disorders. Rivastigmine was assessed for the treatment of motor symptoms, functional disability, and cognitive impairment associated with Huntington disease in an open-label study of 18 patients; 11 received rivastigmine 6 mg/day and 7 control patients did not.¹⁵ Motor and cognitive function were assessed for up to 2 years by raters who were blinded to treatment assignment. Ratings on a global motor performance scale were significantly better for patients who received rivastigmine than for control subjects. Rivastigmine treatment was also associated with trends toward improvements in functional disability and cognitive impairment, although these differences were not statistically significant.

A small open-label study examined the effects of donepezil for movement and cognitive symptoms associated with Huntington disease.¹⁶ Donepezil did not significantly improve cognitive symptoms, although the study enrolled only eight patients. All patients tolerated oral donepezil at a dose of 5 mg/day, but four patients withdrew from the study when the dose was increased to 10 mg/day. In two patients, chorea worsened and falls increased, moderate to severe diarrhea developed in three patients, and one patient reported anxiety and irritability.

Depression is another common complication of Huntington disease. The incidence of depression among patients with Huntington disease is approximately 40%, and the risk of suicide is at least eightfold greater than that among the general population.¹⁷ Treatment must be guided by clinical judgment. Selective serotonin reuptake inhibitor antidepressants have been recommended. Other options to manage depression include mirtazapine, monoamine oxidase inhibitors, or electroshock therapy. Mood-stabilizing agents (eg, carbamazepine, lamotrigine, valproate) may also be indicated in helping with impulse control. Haloperidol and second-generation antipsychotics are used for the treatment of a broad range of psychiatric conditions, many of which may overlap with Huntington disease, including schizophrenia and schizophreniform disorder, schizoaffective disorder, bipolar disorder, dementia, and disruptive behavior.¹⁸ The risk of tardive dyskinesia may be as much as fivefold lower with second-generation antipsychotics.¹⁸ Many patients with Huntington disease require treatment for aggression. A variety of approaches are available, including behavior modification, the antidepressant sertraline, buspirone, antipsychotic agents (eg, risperidone, olanzapine), propranolol, and lithium (combined with haloperidol).

Long-term care considerations

As a consequence of the diverse clinical manifestations of choreic disorders in movement, function, mood, and cognition, the treatment of Huntington disease requires a multidisciplinary approach that involves a number of different health care specialties across the long-term course of the disorder. Members of the Huntington disease treatment team may include neurologists, psychiatrists, nurses, social workers, geneticists, physical therapists, occupational therapists, speech therapists, dietitians, and other supporting groups or professional societies. The clinical manifestations of Huntington disease may evolve over time, as symptoms such as bradykinesia, dystonia, rigidity, cognitive decline, and gait instability become more significant.¹⁹ As a result, optimal management strategies for patients with Huntington disease may change significantly across the long-term course of the disease. During the early course of the disease, the typical clinical presentation is largely hyperkinesis, irritability, and distractibility. These patients will require initiation of drug therapy and linkage to sources of support. In the later stages of the disease, the presentation shifts to a more hypokinetic and apathetic profile, and patients are more likely to require drug regimen review and modification, nursing home placement, and palliative care services.¹⁹

Another important concern in Huntington disease treatment is care of the caregiver. Surveys show that the key concerns of caregivers include the expertise of the health care professionals who are treating the patient and the availability of sufficient services in the community.²⁰ Several resources are available for Huntington disease caregivers, including local support groups, the Huntington’s Disease Society of America, Q Foundation, and the Huntington Study Group. The Lundbeck pharmaceutical company operates a patient assistance program (LundbeckShare. com) as well as an information center that can be accessed toll free at (888)457-4273. Approximately 90% of patients who request copayment assistance qualify for aid, regardless of the type of insurance they carry.

SUMMARY AND CONCLUSIONS

The approach to a patient with chorea starts with a search for specifically treatable etiologies. Autoimmune, metabolic, and vascular causes should be sought first and treated. The symptomatic treatment of all choreas is based on the model described here for Huntington disease, and includes attention to cognitive, psychiatric, and social support issues. The recommended approach is multidisciplinary, with a change in the mix of services as the disease progresses. It is also important to recognize the burden of Huntington disease on the caregiver and consider steps to make this burden more manageable.