What are fluctuating manifestations in Parkinson’s disease?

Fluctuating Manifestations in Parkinson's Disease

Fluctuating manifestations in Parkinson's disease are treatment-related variations in clinical state that occur primarily in patients on chronic levodopa therapy, encompassing motor fluctuations (wearing-off, on-off phenomena, dyskinesias), nonmotor fluctuations (autonomic, cognitive/psychiatric, sensory symptoms), and short-duration phenomena like freezing episodes. 1, 2

Motor Fluctuations

Medium-Duration Fluctuations (Minutes to Hours)

Wearing-off phenomenon represents the most common motor fluctuation, where parkinsonian symptoms predictably return before the next levodopa dose as the medication effect wanes 2, 3. This includes:

• End-of-dose deterioration with return of bradykinesia, rigidity, and tremor 3
• Morning akinesia occurring after overnight medication absence 3
• Patients experience OFF episodes averaging ≥3 hours per day in advanced disease 4

On-off fluctuations manifest as unpredictable, sudden transitions between mobility ("on" state) and immobility ("off" state) that are not clearly related to medication timing 2, 5.

Dyskinesias

Peak-dose dyskinesias occur when levodopa levels are highest, presenting as painless choreiform or mobile dystonic movements 2.

Biphasic dyskinesias appear at the beginning and/or end of dose effect, characterized by severe, ballistic, stereotypic movements 2.

Off-period dyskinesias are relatively fixed, painful, and dystonic in nature, occurring when medication effect has worn off 2.

Short-Duration Fluctuations (Seconds to Minutes)

Freezing episodes require careful distinction 2:

• Off-period freezing responds to measures that increase "on" time 2
• On-and-off period freezing is present in both states and extremely difficult to treat 2

Paradoxic kinesis represents sudden, brief improvements in mobility lasting seconds to minutes 2.

Nonmotor Fluctuations

Nonmotor fluctuations occur in approximately 17% of PD patients with motor fluctuations and are classified into three major categories 1, 6:

Autonomic Fluctuations

• Gastrointestinal symptoms including nausea occurring as end-of-dose phenomena 6
• Urinary dysfunction varying between on and off states 2
• Cardiovascular changes with blood pressure fluctuations 1, 2
• Thermoregulatory symptoms including drenching sweats, temperature changes, and facial flushing 1, 6
• Respiratory dysfunction with sensory dyspnea 6
• Unilateral limb edema as an off-state phenomenon 6

Cognitive/Psychiatric Fluctuations

• Mood disturbances with panic, anxiety, and depression occurring instantly in off periods with relief upon turning on 1, 2
• Hallucinations fluctuating with medication state 1
• Hypomania during on periods 1
• Confusion and cognitive dysfunction varying with dopaminergic state 1
• Moaning/screaming episodes 1
• Sexual deviations and dopamine dysregulation syndrome 1

Sensory Fluctuations

• Pain syndromes with instant relief as patients turn on, including proximal limb pain and trigeminal neuralgia-like pain 2, 6
• Akathisia (inner restlessness) 1
• Internal tremor 1
• Numbness and paresthesias 1

Pathophysiology and Timing

Postsynaptic pharmacodynamic factors play the major role in determining fluctuations, with two mechanisms proposed 5:

• Chronic intermittent dopaminergic therapy leads to postsynaptic receptor downregulation 5
• Receptor changes occur independently of treatment due to structural adaptation of the postsynaptic dopaminergic system to progressive nigrostriatal pathway decline 5

A critical long-duration pharmacodynamic response to levodopa lasting up to 2 weeks exists, meaning the ultimate effect of treatment alterations may take 2 weeks to equilibrate in the brain 2.

Critical Clinical Distinctions

The "off" state is not equivalent to untreated PD and may represent rebound worsening after levodopa's beneficial effect has worn off 2.

Transient worsening can occur at the onset of a dose effect, not just at wearing-off 2.

Common Pitfalls

Nonmotor fluctuations are usually mild and less disabling than motor fluctuations but can lead to unnecessary diagnostic tests and inappropriate treatments when not recognized 1, 6. Off-state nonmotor symptoms are less frequently diagnosed than on-state phenomena because they are less well known 1.

Optimization of levodopa therapy cannot realistically occur during brief inpatient admissions due to the 2-week equilibration period required, making this primarily a long-term outpatient procedure 2.

Taking levodopa with meals reduces absorption due to competition with dietary large neutral amino acids, worsening fluctuations 7. Levodopa should be taken at least 30 minutes before meals 7.