Tardive dyskinesia

Tardive dyskinesia (TD) is a disorder characterized by abnormal involuntary movements and associated with neuroleptic therapy. To determine whether the respiratory muscles are involved in this condition, we compared the breathing pattern of ten patients with TD with ten patients with chronic schizophrenia receiving neuroleptic therapy without evidence of TD, and ten age-matched normal control subjects during resting tidal breathing, forearm pronation-supination (a maneuver designed to elicit the abnormal movements of TD), and breathing to a set frequency. Breathing patterns were also assessed in seven patients with TD during a progressive incremental exercise test and an overnight polysomnogram. Patients with TD had an irregular tidal breathing pattern, with a greater variability in both tidal volume and time of the total respiratory cycle (TTOT). Both groups of patients receiving neuroleptic therapy had a rapid shallow breathing pattern when performing forearm pronation-supination compared with control subjects. There were no differences between any of the subject groups when breathing to a set frequency. The patients with TD had a normal response to progressive exercise and inspiratory time and TTOT values were less variable during non-rapid eye movement sleep compared with wakefulness. We conclude that patients with TD have irregular rapid shallow breathing which is less variable during sleep and does not limit their exercise performance.

Tardive dyskinesia (TD) is a disorder characterized by abnormal involuntary movements.[1-3] It has been estimated to occur in 30 to 40 percent of patients receiving long-term neuroleptic therapy.[4-6] Orofacial and cervical muscle groups are most commonly affected, which results in involuntary mouthing, sucking, chewing, and tongue displacement. Choreoathetoid movements of the limbs and axial hyperkinesia also have been recognized as being part of this syndrome.[4]

Respiratory dysrhythmias (RDs) have been reported in association with TD.[7] Irregular respiratory rate and rhythm in association with involuntary grunts and gasping sounds have been described.[8-13] We have compared breathing patterns between patients with and without TD and control subjects to characterize the RD associated with TD. We also have assessed the effect of exercise and sleep on these RDs.

METHODS

Subjects

Ten patients with chronic schizophrenia and TD secondary to neuroleptic therapy, ten age-matched patients with chronic schizophrenia and no evidence of TD, and ten age-matched normal control subjects were recruited. Both groups of patients with chronic schizophrenia had received neuroleptic therapy for at least 2 months prior to the study. Patients were excluded if they had significant cardiopulmonary disease or a previous or family history of a movement disorder other than TD. Neuroleptic dosage was quantitated by using both the average daily dose over the preceding year and the total cumulative dose and expressed as chlorpromazine equivalents. Tardive dyskinesia was determined prior to the assessment of breathing patterns from scores from two standardized multi-item rating scales, the Abnormal Involuntary Movement Score (AIMS) and the Extrapyramidal Symptom Rating Scale (ESRS). These scores were assessed precisely according to the guidelines established for AIMS and ESRS[14] by an experienced physician. Patients receiving neuroleptic therapy without TD were required to have scores of less than or equal to 2 on the AIMS rating scale. Respiratory dysrhythmias including involuntary grunting, gasping, sighing, and irregular breathing were subjectively scored using a scale derived from the ESRS.

All subjects had spirometry and monitoring of breathing patterns. Seven patients with TD who provided consent also had monitoring of breathing patterns during sleep and a progressive exercise test.

Breathing Pattern

Respiratory inductance plethysmography (RIP) (Respitrace Ambulatory Monitoring Equipment, Ardsley, NY) was used to monitor breathing patterns noninvasively. The theory and validation of this technique have been previously described in detail.[15] Calibration was carried out with the subject in both the supine and sitting positions using the least squares method.[16] Validation against known volumes was performed with subjects in the supine position using a Collins wet spirometer before and after assessment of breathing pattern. In one subject, a change of more than 10 percent occurred in the volume calibration, and these results were excluded from further analysis.

Subjects were studied in the supine position in a quiet room. They were discreetly observed to ensure there was no speech or unnecessary movements and that they did not fall asleep. Movements consistent with TD and any subjective impression of RDs were noted. After 10 min to allow for adaptation to the surroundings, breathing patterns were assessed during (1) tidal breathing (10 min); (2) repeated forearm pronation and supination during arm elevation to elicit the involuntary movements of TD (5 min); (3) breathing to a frequency of 12 breaths per minute (3 min). Tidal volume (VT), inspiratory time (TI) and the time of the total respiratory cycle (TTOT) were measured by tracing the RIP sum trace on a calibrated digitizer (GTCO Corp., Rockville, Md) interfaced to a microcomputer.

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Polysomnogram

An overnight polysomnogram was performed in seven patients with TD. Sleep stages were scored using standard electroencephalographic, electro-oculographic, and electromyographic criteria.[17] Arterial oxygen saturation was monitored continuously with a pulse oximeter (model N-100, Nellcor, Inc, Hayward, Cal) attached to the index finger. Airflow was detected by an infrared [CO.sub.2] analyzer (model LB-2; Beckman Instruments, Inc, Schiller Park, Ill). Breathing patterns were assessed using RIP as previously described. Because a constant band position could not be ensured during sleep, calibration of RIP for volume was not performed. The TI and TTOT values were determined from three randomly selected 5-min periods of wakefulness and stage 2 non-rapid eye movement (REM) sleep.

[TABULAR DATA OMITTED]

Exercise Test

A cycle ergometer exercise test was performed to the patient's symptom-limited maximal work load.[18] Breathing frequency, minute ventilation, oxygen uptake ([VO.sub.2]), and carbon dioxide production were determined on a breath-by-breath basis (Sensormedics MMC Horizon System, Anaheim, Cal). Heart rate was recorded from a single ECG lead (modified [V.sub.2]). Arterial oxygen saturation was monitored continuously with a pulse oximeter (model 3700, Ohmeda, Boulder, Colo). Results were compared with data derived from normal control subjects.[19]

Statistical Analysis

A Wilcoxon rank test was used to compare AIMS and ESRS scores and neuroleptic dose between subject groups.[20] A univariate one-way analysis of variance was used to compare VT, TI, and TTOT between subject groups. A Kolmogorov-Smirnov test was used to determine whether the distributions about the mean for VT, TI, and TTOT differed between subject groups. The TI and TTOT values were compared between wakefulness and non-REM sleep with a two-tailed paired Student's t test.

RESULTS

Test Data

Details of the anthropometric data, spirometry data, neuroleptic therapy dose and duration, and clinical scoring for TD and RD are presented in Table 1 for control subjects (group 1) and patients without (group 2) and with (group 3) clinical evidence of TD. Age, sex, and spirometry results were not different between the groups. The average and cumulative doses of neuroleptic therapy were not different between patient groups, but the duration of neuroleptic therapy was longer in patients with TD compared with those without (p [less than] 0.05). As would be expected by the selection criteria, both AIMS and ESRS scores were higher in the patients with TD (p [less than] 0.05). Respiratory dysrhythmias were observed clinically in five patients (mean RD score, 4.1) with TD, but were not observed in any of the control subjects or patients without TD (p [less than] 0.05).

Breathing Patterns

Breathing pattern data are presented in Table 2 during tidal breathing, forearm pronation-supination, and breathing to a set frequency. During tidal breathing there was a progressive, nonsignificant trend to a lower mean VT and TTOT from group 1 to group 3 (Fig 1, top). The TI was less in group 3 when compared with data from both groups 1 and 2 (p [less than] 0.05). Frequency distributions of VT during tidal breathing are shown in Figure 2 for each subject group. Patients with TD had a greater dispersion around the mean (p [less than] 0.05) compared with both control subjects and patients without TD. Similar findings were present with TTOT (p [less than] 0.05) and TI (p = 0.10). There were no differences in breathing pattern frequency distribution between control subjects and patients without TD. Patients with and without TD had rapid, shallow breathing when compared with the control subjects during forearm pronation-supination (Fig 1, center [p [less than] 0.05]). The VT, TI, or TTOT were not significantly different between patients with and without TD during this maneuver. Tardive dyskinesia was noted to be worse in eight of the ten patients with TD during forearm pronation-supination, whereas no TD occurred in the other two subject groups. There were no differences in VT, TI, or TTOT between any of the subject groups while breathing to a set frequency despite the fact that no attempt was made to control tidal volume during this maneuver (Fig 1, bottom). The TI and TTOT were similar between wakefulness (1.2 [+ or -] 0.4 s, 3.7 [+ or -] 1.4 s) (mean [+ or -] SD) and non-REM sleep (1.7 [+ or -] 0.3 s, 3.7 [+ or -] 0.6 s) in patients with TD. However, TI and TTOT were both more variable during wakefulness compared with non-REM sleep (p [less than] 0.05).

All seven patients with TD stopped the exercise test because of leg discomfort and none claimed limitation from dyspnea. All patients failed to reach their predicted maximal [VO.sub.2] (range, 45 to 86 percent predicted). Four patients reached [greater than or equal to] 80 percent of the maximal predicted heart rate and the heart rate/[VO.sub.2] relationship increased along predicted values for all patients. Six patients had an increase in ventilation within the predicted normal values. One patient had a slight increase in ventilation at all levels of [VO.sub.2]; however, the slope of this relationship was parallel to the normal predicted curve. Only one patient reached [greater than or equal to] 80 percent of maximal predicted minute ventilation. All patients demonstrated the typical curvilinear increase in both VT and breathing frequency during exercise. Four patients had a slight tachypnea with a small VT at rest; however, the breathing pattern response became normal with progressive exercise. No patients demonstrated [greater than] 5 percent arterial oxygen desaturation during exercise.

DISCUSSION

This study demonstrates that RDs can be identified in unselected patients with TD, that these dysrhythmias diminish with sleep, and that they do not limit exercise performance. Furthermore, some patients receiving neuroleptic therapy without obvious TD also have an abnormal breathing pattern during certain circumstances.

Weiner and associates[7] described an association between RDs and TD. Three patients receiving long-term neuroleptic therapy had frequent involuntary grunts and gasps with associated RDs. These patients presented with dyspnea and chest pain that could not be explained on the basis of any underlying cardiopulmonary disease. Specific pharmacologic intervention aimed at modifying TD relieved both symptoms and RDs in each patient. Several case reports have documented similar clinical presentations since this initial description.[8-13] A wide variety of neuroleptic drugs have been implicated in causing RDs with the duration of treatment ranging from several months up to 24 years. In two patients, RDs preceded the onset of other manifestations of TD.[10] However, in the majority of patients, orofacial-cervical and limb dysrhythmias coexist with RDs. Although RDs are not usually life-threatening, Casey and Rabins[12] described a patient with RD who presented with acute dyspnea and hypoxemia secondary to severe RDs. When neuroleptic therapy was modified, symptoms were controlled and both RDs and TD resolved.

Despite the clinical recognition of RDs in patients with TD, there has been limited experimental work to characterize this disorder. We have used noninvasive monitoring techniques to demonstrate several patterns of RDs in unselected patients with TD. Some patients have an irregular breathing pattern with a variable rate and VT. This pattern may be analogous to the involuntary movements of the other involved muscle groups. Patients with TD also may have a rapid, shallow and regular breathing pattern which is more marked when the other TD movements are increased. This latter pattern is consistent with the observations of Weiner and coworkers[7] and supports a common pathogenesis for both RDs and TD.

Jackson and coworkers[11] used a simple strain gauge device to compare breathing periodicity among eight institutionalized patients with TD and eight control subjects matched for age, sex, and neuroleptic dose. Patients with TD had more irregular breathing than the control subjects. In our study, patients receiving neuroleptic therapy without obvious TD had a rapid shallow breathing pattern in comparison with control subjects when performing stereotyped upper limb movements. Respiratory dysrhythmias in patients without overt TD may represent an early manifestation of TD. Tardive dyskinesia may have been present but missed on our initial clinical evaluation. The abnormal movements of TD are known to fluctuate throughout the day[21] and may have been minimal at the time of evaluation. It is also possible that RDs may have been identified by the more sensitive quantitation of breathing pattern compared with the subjective scoring used to identify TD. We also demonstrated that RDs could be overcome during a short period of an imposed breathing pattern. Such control may allow a variety of behavioral functions of the respiratory muscles including speech and postural control to proceed in a relatively normal manner. However, some patients with very advanced RDs, have been reported to be unable to voluntarily suppress abnormal breathing patterns.[7]

The abnormal movements of TD decrease or completely resolve during sleep.[22] Our finding that breathing patterns were more regular in non-REM sleep than while patients were awake suggests that this is also true for RDs. Subjective evaluation in several case reports also has suggested a decrease in RDs during sleep.[7,12] Kuna and Awan[9] studied a patient with TD and RDs during sleep and found less variability in respiratory rate during non-REM sleep compared with wakefulness. In contrast to our study, they also noted a marked decrease in the respiratory rate during sleep. This difference may have occurred because of the more marked RDs in their patient.

Exertional dyspnea is a common presenting symptom of patients with RDs. Our results suggest that RDs are not the cause of premature termination of exercise in patients with TD. Maximal predicted ventilation was only approached by one of the seven patients studied, indicating some degree of ventilatory reserve in the majority of patients. Tidal volume and breathing frequency both increased in a normal curvilinear pattern and no patient demonstrated significant arterial oxygen desaturation during exercise.

The pathogenesis of RDs, like that of the other manifestations of TD, has not been clearly established. An important factor appears to be the competitive blockade of dopamine by neuroleptic drugs in the striatum. Tardive dyskinesia has been proposed to occur because of a postsynaptic dopamine supersensitivity following long-term receptor blockade.[23] The response of RDs to central dopaminergic modulation[7] is consistent with a common pathogenesis with the other movement disorders associated with TD. Control of breathing is a complex process resulting from an interaction of the brainstem respiratory centers with higher cortical centers. Proposed sites of abnormal dopaminergic neuronal modulation include extra-pyramidal pathways to the cortex or the medullary and pontine respiratory centers.[7] The mechanisms of the decrease in RDs during sleep are also speculative. Kovacevic and Radulovacki[24] demonstrated a decrease in striatal dopamine content during non-REM sleep which could be responsible for a sleep-related decrease in the facilatory effects of this neurotransmitter.

We have demonstrated that RDs frequently coexist with other manifestations of TD. Currently, RDs are underrecognized in patients with TD because only one of the four commonly used rating scales for TD (ESRS) includes respiratory scoring items. Close clinical observation in conjunction with noninvasive monitoring of breathing pattern will detect RDs in the majority of patients. Although RDs did not result in major functional limitation in our patients with TD, this may occur in patients in whom the TD is more severe.

REFERENCES

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