ADVERTISEMENT

Off spells and dyskinesias: Pharmacologic management of motor complications

July 1, 2012|Cleveland Clinic Journal of Medicine
Tarannum S. Khan, MD
Author and Disclosure Information

Tarannum S. Khan, MD
Neurologist, Movement Disorders Program, Cleveland Clinic Florida, Weston, FL

Correspondence: Tarannum S. Khan, MD, Dept. of Neurology, Cleveland Clinic Florida, 2950 Cleveland Clinic Blvd., Weston, FL 33331; khant@ccf.org

Dr. Khan reported that she has no financial interests or relationships that pose a potential conflict of interest with this article.

This article is based on Dr. Khan’s presentation at "The Annual Therapy Symposium on Movement Disorders for the Modern Clinician" held in Fort Lauderdale, Florida, on January 29, 2011. The article was drafted by Cleveland Clinic Journal of Medicine and was then reviewed, revised, and approved by Dr. Khan.

ABSTRACTThere are two major causes of disability in patients with Parkinson disease: motor fluctuations that occur when a dose of levodopa becomes ineffective, leading to a “wearing off,” and hyperkinetic movements (dyskinesias) caused by excessive levels of dopamine. The utility of continuous levodopa treatment is therefore limited by motor complications. Pharmacologic options to treat wearing off include adding (or increasing the dosage of) levodopa, adding (or increasing the dosage of) a dopamine agonist, or adjunctive treatment with a monoamine oxidase inhibitor or catechol-O-methyltransferase inhibitor. Dyskinesias will respond to a reduction in levodopa dosage at the expense of worsening parkinsonism and an increase in the number of “off” episodes. Continuous dopamine stimulation may overcome the pulsatile stimulation of postsynaptic dopamine receptors produced by standard oral formulations of levodopa that lead to motor complications.

Dopaminergic treatment is extremely beneficial in inducing symptom improvement in early Parkinson disease (PD). Patients typically experience a smooth and even response to the early stages of levodopa treatment. With disease progression, however, the effect of levodopa begins to weaken approximately 4 hours after each dose, leaving patients anticipating the need for their next dose and vulnerable to motor fluctuations and dyskinesias.

Motor fluctuations refer to the unanticipated loss of effect of a given dose of levodopa; instead of a smooth, predictable symptomatic benefit, the patient may lose benefit earlier than usual (termed “wearing off”) or may suddenly switch from “on” (symptoms controlled) to “off” (symptoms return). Dyskinesias, or involuntary movements, occur when dopamine levels are too high.

Motor complications are a major cause of disability in PD. They affect 60% to 90% of PD patients after 5 to 10 years of treatment. Moreover, in one study of 143 PD patients, motor complications diminished quality of life; the most strongly affected dimensions were mobility, activities of daily living, communication, and stigma.1

PATHOGENESIS OF MOTOR COMPLICATIONS

Under physiologic conditions, dopamine stimulation of the striatal dopamine receptors occurs in a sustained fashion. In early PD, the pool of remaining neurons of the substantia nigra is believed to be sufficiently active to smooth out changes in levodopa levels, providing a relatively constant amount of dopamine. Many PD patients therefore have several years of trouble-free treatment following diagnosis. In the advanced disease states, however, the number of presynaptic dopaminergic neurons progressively decreases. With fewer dopaminergic neurons, a constant dopaminergic concentration cannot be sustained. As PD advances, the progressive loss of dopaminergic neurons leads to impaired dopamine storage. Thus, the buffering capacity of dopaminergic neurons decreases and synaptic dopamine levels begin to reflect systemic or exogenous levodopa levels.

Figure. Pathogenesis of motor complications related to the Parkinson disease (PD) process and levodopa therapy. As PD advances (left), the progressive loss of dopaminergic neurons associated with nigrostriatal damage leads to impaired dopamine storage and clearance. This reduces the buffering capacity of dopaminergic neurons, causing early wearing off. During chronic levodopa treatment (right), pulsatile dopaminergic stimulation causes changes in postsynaptic receptors, referred to as “priming,” that increase the responsiveness of the receptors. The increased response results in severe levodopa-induced dyskinesias and on-off fluctuations. These postsynaptic changes are mediated through postsynaptic dopamine D1 receptors and N-methyl-d-aspartate glutamate receptors.
With disease progression, the “honeymoon” phase diminishes, and most PD patients begin to develop motor complications after 5 or more years. At this stage, medications frequently need to be adjusted, which can be a complex task for the physician and patient. The schema for the pathogenesis of motor complications related to the disease process and chronic levodopa treatment are depicted in the Figure.

According to current views, the total motor response to levodopa results from the combination of endogenous dopamine production along with the short-duration response (SDR) and the long-duration response (LDR) to exogenous levodopa.2 The SDR represents an improvement in parkinsonian symptoms and signs, lasting minutes to hours, that is closely related to the rise and fall of plasma levodopa concentrations. The SDR parallels the fluctuations in motor response and has received the most attention in the literature. The LDR is an improvement in parkinsonism that builds up over days and likewise decays over days. The LDR decays more rapidly in severely affected patients. Negative response, or “super off,” is a transient worsening of motor function to below the baseline level that may occur as the effects of the SDR dissipate.

The proportions of the SDR and LDR can vary according to disease progression. The LDR is more prominent in early stages, accounting for the stable response seen in the honeymoon period of treatment.

Peripheral factors

Additional peripheral factors such as changes in gastric motility and absorption contribute to motor complications. Levodopa is transported by a saturable active transporter system, the large neutral amino acid system, in the gut, and across the blood-brain barrier. Levodopa absorption is thus affected by food intake, especially protein. Levodopa and dietary amino acids compete with each other for absorption at the intestinal and blood-brain levels. Levodopa and other dopaminergic therapies further chronically reduce gastric emptying.

Pulsatile dopamine stimulation

The latency from the time of levodopa administration to the onset of motor improvement is typically 30 to 90 minutes. Latency is longer in late stages when the striatal buffer is weakened and the plasma concentration of levodopa fluctuates.

TYPES OF MOTOR FLUCTUATIONS

Fluctuating motor response in levodopa-treated patients refers to clinically apparent oscillations in motor function. Management of the fluctuating response may require frequent daily dosing of levodopa.

Motor fluctuations in PD take four forms: wearing off, off, delayed on/no on, and dyskinesias.

Wearing off

Wearing off refers to the premature loss of benefit from a given dose of levodopa, causing a predictable return of parkinsonian symptoms (bradykinesia, tremors, rigidity, and gait problems) in advance of the next scheduled dose. Observed in early and moderate PD, wearing off is the most common type of motor fluctuation. Its pathophysiology relates to disease progression and pharmacokinetics of levodopa. It can be sudden or gradual, predictable or unpredictable.

Off state

The off state is the unpredictable reappearance of parkinsonian symptoms at a time when central levels of antiparkinsonian drugs are expected to be within the target therapeutic range. Such symptoms include pain, stiffness, paresthesia, cognitive symptoms (depression, anxiety, difficulty with concentration, and mental slowing), inner restlessness, and inner tremulousness. The off state can be sudden or gradual, predictable or unpredictable.

Delayed on/no on

Delayed on is a prolongation of the time required for the central antiparkinsonian drug effect to appear. As the disease progresses, wearing off becomes more complicated and more unpredictable. The dosing responses vary, and patients sometimes report delayed on. The causes of delayed on or no on can be an insufficient dose, dosing with high-protein meals, or delayed gastric emptying. Metoclopramide or domperidone can help with gastric emptying. Metoclopramide can cross the blood-brain barrier and thus may cause adverse effects related to dopaminergic blockade; domperidone does not cross the blood-brain barrier.

Dyskinesias

Dyskinesias are hyperkinetic movements related to dopaminergic effects that are greater or less than the therapeutic threshold. They are common with long-term levodopa therapy and have three patterns:

Off dystonia occurs when levodopa concentrations are low and the SDR has dissipated. Dystonic states may be a manifestation of too little or too much levodopa; differentiating the two is important. Off dystonia occurs mostly in the early mornings, when plasma levodopa levels are low, and mostly involves the more affected side first.

Peak-dose dyskinesia, which occurs during the SDR, is the most common type of dykinesia and is related to peak plasma levodopa levels. It is characterized by stereotypic, choreic abnormal movements involving the head, neck, trunk, and limbs, and possibly hemidyskinesia in young-onset PD. Peak-dose dyskinesias are sometimes severe enough to be disabling.

Diphasic dyskinesias are stereotyped, dystonic, or choreic movements that occur at the beginning of the SDR and again as the SDR dissipates. They predominantly affect the legs and spare the trunk, neck, and arms.

ADVERTISEMENT
ADVERTISEMENT
ADVERTISEMENT