Nonmotor fluctuations in patients with Parkinson's disease

The majority of patients with Parkinson's disease (PD) begin to experience a fluctuating response to levodopa (LD) within 5 years of initiating treatment. ^[1] The most common fluctuations consist of changes in motor function presumably associated with alterations in the concentration and efficacy of striatal dopamine. ^[2] High concentration effects usually consist of dyskinesias (peak dose chorea or dystonia, high-dopa dyskinesias). ^[3] Low concentration, or reduced efficacy, of striatal dopamine is associated with the reemergence of parkinsonian motor symptoms (end-of-dose wearing off), chorea (diphasic, ^[4] low-dopa chorea), dystonia (early morning dystonia, low-dopa dystonia), ^[5] and unpredictable on-off phenomena. Other relatively frequent and disabling decreased LD efficacy symptoms, however, are nonmotor in nature (autonomic, sensory, cognitive/psychiatric). ^[6] The clinical spectrum and frequency of these nonmotor low-dopa phenomena among patients with fluctuating PD symptoms is not known. We therefore studied the nature and occurrence of nonmotor "off" phenomena in 130 consecutive patients with fluctuating PD symptoms and describe a number of previously unrecognized, or little appreciated, nonmotor symptoms associated with the "off" state.

Methods.

During a 6-month period (March 1, 1995 through August 31, 1995), we screened 130 consecutive patients with PD and motor fluctuations during routine outpatient visits. In a nondirected fashion, we asked every patient to tell us about any symptoms they associated with the "off" state. We took an extended history of all patients who had nonmotor "off"-phenomena and correlated these symptoms with documented "off"-state signs such as tremor, rigidity, or akinesia.

Patients and results.

Twenty-two of 130 patients (17%) had 16 different symptoms of nonmotor "off"-phenomena as listed in Table 1. Nonmotor fluctuations were divided into three categories: sensory, autonomic, and cognitive/psychiatric. ^[6] Autonomic complaints were the most frequent, with 10 different symptoms (44% of the total complaints) seen in 15 patients. Three different cognitive/psychiatric symptoms were responsible for 11 complaints (32%). Eight sensory complaints (24%) resulted from three different symptoms. In 12 patients, either an agonist was added or the LD regimen rearranged to reduce the "off" time. Nonmotor fluctuations improved in nine of these patients (75%).

Discussion.

The categorization of nonmotor fluctuations into three major subgroups (autonomic, cognitive/psychiatric, and sensory) ^[6] was generally useful in classifying our patients. Autonomic complaints were the most common (44%), followed by cognitive/psychiatric (32%), and sensory symptoms (24%). The one major difficulty was where to place sensory dyspnea. A number of these episodes in several patients were witnessed by one of us (J.I.S.). These patients were in distress in the sense that they told the examiner that it "felt as if they could not take another breath." The breathing patterns and rates, however, were normal throughout each episode, suggesting that this complaint was not caused by rigidity of the respiratory musculature. Spouses corroborated that this was also the case for episodes that occurred at home. Despite the discomfort, patients stated that they were not anxious. There was no evidence of autonomic or motor dysfunction during each episode other than the usual "off" phenomena characteristic of that patient. In particular, there was no stridor ^[7] or other evidence of upper-airway obstruction, and there was no dystonia or chorea. ^[8] It appeared, therefore, to be a sensation of dyspnea rather than actual respiratory difficulty and, for this reason, we elected to classify these symptoms as sensory in nature.

Another unusual sensory phenomenon was pain in the proximal arm and pectoral area. This particular distribution of "off"-period pain, noted previously by Quinn et al., ^[9] is not common. Most pains and paresthesias mimic radicular or neuropathic patterns, suggesting a spinal cord, peripheral nerve, or autonomic nervous system origin to "off"-period pain. ^[9-13] The proximal limb location in one of the patients, and the symptoms mimicking trigeminal neuralgia, may suggest an origin for these pains above the level of the spinal cord in the basal ganglia or substantia nigra. ^[14-18] A number of sensory stimuli produce electrophysiologic responses in the basal ganglia cells. ^[19] This striatal activity is thought to be mainly inhibitory to sensory pathways. Sensory phenomena during hypodopaminergic states may thus be interpreted as direct effect from release from basal ganglia inhibition. Other nuclei, such as the locus ceruleus, are also inhibitory and have connections that include projection areas such as the spinal trigeminal nucleus. ^[20] Hypodopaminergic states, therefore, also may produce proximal limb or trigeminal neuralgia-like pain indirectly by influencing nondopaminergic nuclei and pathways. ^[21]

Symptoms of autonomic dysfunction ^[22,23] are the most common nonmotor "off" phenomena. Previously reported findings include anal sphincter contraction, abdominal bloating, belching, blood-pressure changes, urinary frequency, pupillary dilation, tachycardia, pallor, temperature changes, and profuse sweating. ^[6,24-26] New "off" phenomena that we describe in this paper include nausea, cough, hunger, limb edema, and facial flushing. Abdominal bloating and belching probably have the same underlying mechanism, bowel hypomotility. Abdominal pain is probably related to gastrointestinal hypomotility with increased gas and bowel distension. Limb edema is commonly due to poor mobility in PD and is often present in the legs as an early sign, sometimes predating a firm diagnosis. Edema in our cases occurred rapidly, was present in the hand in one patient, and disappeared within an hour or less. Poor mobility of the limb during an "off" period is, therefore, an improbable explanation for this phenomenon. Lewy body pathology causing dysfunction in multiple sites of the autonomic nervous system with subsequent vasomotor instability is a more likely explanation.

Cognitive/psychiatric complaints made up a third of all "off" period nonmotor symptoms. Although episodic depression, anxiety, and moaning/screaming are serious complications of PD, ^[27,28] panic attacks are the most debilitating. Panic begins abruptly with many patients describing an uncontrolled feeling that death is imminent. This frightening sensation disappears just as suddenly with the onset of the next "on" state, or if the patient remains "off" by not taking another dose of LD for several hours. Previous reports have suggested that panic attacks in PD patients usually occur in the setting of more generalized anxiety. ^[27,28] This is not always true since some of our patients with panic attacks were only anxious during a low-dopa state (end-of-dose wearing off). Although we listed anxiety and panic in separate categories of nonmotor fluctuations, this distinction is perhaps arbitrary. More likely, there is a continuum from mild "off" period anxiety to severe panic. Depression is present in at least half the patients who had panic attacks or anxiety. The high frequency of cognitive/psychiatric dysfunction may indicate that these patients are beginning to have Lewy body pathology outside the confines of the substantia nigra and other usual brainstem nuclei (diffuse Lewy body disease). ^[29]

Treatment of nonmotor "off" phenomena is not always possible but should be aimed at diminishing the amount of "off" time. Adding a dopamine agonist, using controlled-release preparations of LD, or increasing the frequency of dopaminergic medication may be helpful to some of these patients. Recognition of these symptoms as "off" phenomena will prevent unnecessary diagnostic tests and useless treatments.