Postural reflexes in patients on long-term neuroleptic medication

Dennis J. Beckley*, Bastiaan R. Bloem* * * * , Jaswinder Singh*, Michael P. RemleT*, Nancy S. Wolfe* *, and Raymund A.C. ROOS” * *

Introduction

In standing subjects, sudden toe-up tilts in pitch of a supporting platform induce a backward di- rected postural instability. The resultant passive dorsiflexion of the ankle joint elicits a short (SL) and medium latency (ML) response in the stretched gastro~nemius muscle and a long la- tency (LL) response in the shortened tibialis anterior muscle’. In this experimental para- digm, SL and ML responses in the calf muscula-

ture further accentuate the posterior body sway.

In contrast, LL responses in the tibialis anterior

muscle are helpful in restoring vertical body position.

The amplitude of ML responses is enhanced in patients with Parkinson’s disease2-‘, sugges- ting that the size of the ML response is at least in part controlled by the nigrostriatal dopaminer- gic pathway. However, neuropathologicaP and neurochemical’ studies have documented addi- tional non-dopaminergic abnormalities in Par- kinson’s disease. Therefore, a potential mod- ulatory influence on the amplitude of ML re- sponses by other neurotransmittors cannot be excluded.

In patients treated with neuroleptic drugs, the dopamine deficiency due to postsynaptic striatal receptor blockade is more selective and is pre- sumably more pronounced in patients with clin-

Summary

It is not conclusively known whether the ampli- tude of medium latency postural reflexes is controlled by dopamine. To further assess the influence of supraspinal dopaminergic path- ways on postural reflexes, we studied short (SL), medium (ML) and long latency (LL) reflexes in the lowerextremity of 10 patients on long term (> 6 months) neuroleptic medica- tion, 5 with and 5 without mild drug induced parkinsonism. A control group consisted of 10 age and sex matched healthy volunteers. In both patient groups, latencies and amplitudes of all 3 responses were identical to normal controls. These findings suggest that a moder- ate postsynaptic inhibition of central dopami- nergic pathways is insufficient to cause en- hanced amplitudes of ML responses.

Key words: EMG, neuroleptics, drug induced parkinsonism, medium latency reflexes, long loop.

ical manifestations of drug induced parkinso- nism (DIP)‘~‘* than in clinically asymptomati~ individuals. A comparison of ML response am- plitude in patients with DIP to the well-docu- mented enhancement of ML responses in Par- kinson’s disease2-7 thus permits evaluation of the relative contribution of dopaminergi~ influence on the size of this postural reflex. Therefore, we

* Departments of Neurology and * * Psychiatry, School of Medicine, University of California, DavLs, USA and * * * Depart- ment of Neurology, Academic Hospital of Leiden, The Netherlnnds

Address for correspondence and reprint requests: Dennis 1. Beckfey, M.D. University of California, Davis, Veteru~ Adminis- tration Medical Center - 127, 150 Muir Road, Martinez, California 94553, USA

Accepted 12.9.90

Clin Neural Neurosurg 1991. Vol. 93-2

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studied postural reflexes in psychiatric patients on long-term neuroleptic medication with and without DIP.

Patients

Ten male psychiatric patients (9 schizophrenic, 1 bipolar disorder; mean age 49 years, range 35-72) on long term (> 6 months) neuroleptic medication were recruited from the Martinez VAMC Psychiatry Outpatient Clinic. The con- trol group consisted of 10 male normal volun- teers (mean age 50 years, range 37-68).

Six patients were also taking anticholinergic drugs (4 of the patients with DIP; prophylactic in 2 of the non-parkinsonian patients). Neur- ologic examination revealed mild parkinsonism (Hoehn and Yahr stage IF3) consisting of mini- mal resting tremor, bilateral rigidity in both up- per and lower extremities, bradykinesia and di- minished facial expression in 5 patients. None of the patients had postural instability as assessed by a sudden sternum push. Excluded were pa- tients with other neurological and general dis- orders, as well as those with a history of chronic alcohol abuse or a history of familial Parkinson’s disease. Written informed consent approved by the Institutional Review Board of the Veteran’s Administration Hospital was obtained from all participants.

Methods

Postural reflexes were assessed as previously described’*6. Briefly, each subject stood quietly on a movable forceplate platform (NeuroCom) and was told to look straight ahead and not to lean either forwards or backwards. No special instructions regarding the timing or magnitude of the perturbations were given prior to testing. Stimuli consisted of 4” toe-up ramp rotational perturbations, co-linear with the ankle axis, at 50” per second (total duration 80 msec). In- terstimulus intervals varied between 15 and 30 seconds. EMG activity was recorded with stan- dard disc surface electrodes (2.5 cm apart) from the tibialis anterior and medial gastrocnemius muscles in the right leg. The EMG sweep was triggered by an electrical pulse from the force- plate computer simultaneous with the onset of platform movement. Total post-stimulus sam-

ple period was 500 msec (Bin width I msec). Each subject completed 6 trials that met our acceptance criteria of clear SL and ML rit- sponses in the medial gastrocnemius muscle and LL responses in the tibialis anterior muscle. These acceptance criteria were delimited by post-trigger windows (30-60 msec for the SL; 70-120 msec for the ML; 100-200 msec for the LL response) and voltage threshold levels set at twice the pre-stimulus noise level. The percent- age of rejected trials was similar between at1 groups.

EMG signals were pre-amplified, bandpass filtered (IOHz-lOKHz), full-wave rectified, low- pass filtered (80Hz) and stored to disk for off- line analysis.

Onset latencies for all responses and the dura- tion of the SL response were accordingly deter- mined by visual inspection. In contrast to the SL response, the offset of the ML response was often not visible due to blending with subse- quent muscle activity. The duration of the ML response was therefore defined as the first 75 msec of activity following onset14. Mean ampli- tudes (uV) for the SL and ML responses were tabulated within these measured durations. To allow for comparison of the size of the ML re- sponse between subjects, ML mean amplitude was normalized independently by two different methods: A. a ratio of the mean amplitude of the ML response to the mean amplitude of the SL response (ML&L), which is a variation of the method used by Scholz er uZ.~ and B. a ratio of the mean amplitude of the ML response to the mean amplitude of 75 ms of maximum voluntary contraction for the medial gastrocnemius mus- cle (ML/MGMVC) l’.

Means and standard deviations for all mea- sured responses were calculated for each sub- ject. Group means, standard deviations and standard error of the means were determined for the 2 patient groups and the normal control group. Nonparametric methods (Kruskal-Wai- lis) were used for statistical analysis.

Typical traces of SL and ML responses in the medial gastrocnemius and LL responses in the tibialis anterior are shown for a normal subject and a patient on long-term neuroleptic medica-

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676 626 380’

NORMAL CONTROL PHENOTHIAZINE PHENOTHIAZINE

-ASYMPTOMATIC -MILD PARKINSONISM

Figure 1. Electromyographic responses from a representative normal subject, an asymptomatic patient on chronic neuroleptic medication and a patient with mild drug induced parkinsonism. Short latency (SL) and medium latency (ML) responses are seen in the right medial gastrocnemius muscle (R. Medg.). The long latency (LL) response is seen in the right tibialis anterior muscle (R. Tib. Ant.). Onset latencies are measured relative to the onset of forceplate movement and are indicated by arrows.

tion with and without DIP (Figure 1). No statistical differences in SL, ML or LL

latencies were found between the normal sub- jects and the 10 psychiatric patients. The ampli- tude of the ML response was the same for DIP patients, asymptomatic patients on long-term neuroleptic medication and normal controls, as measured by either the MWSL (P=O.6039) or the ML/MGMVC ratio (P=O.9540).

Discussion

Enhanced ML responses in patients with Par- kinson’s disease*-’ and parkinsonian monkeys on long-term neuroleptic medication16 are sug- gestive of a dopaminergic control of the size of ML responses. While the neuronal pathway em- ployed by ML responses in the lower extremity remains unknown to date”, the nigrostriatal pathway conceivably exerts its modulatory in- fluence on ML response amplitude by setting the gain in spinal interneuronal circuits18. Loss or reduction of the normal inhibitory output of the nigrostriatal pathway, resulting in enhanced supraspinal excitatory influence, would then ei- ther cause an accentuation of normal reflex be- haviour’” or lead to superimposition of a path- ological reflex on normal muscle responses16. The normal amplitude of ML responses in our patients with DIP was therefore unexpected, since these patients probably have a substantial

impairment of the nigrostriatal pathway’@‘2. The normal amplitude of ML responses can

be explained in several ways. In the first place, chronic administration of neuroleptics may re- sult in dopamine receptor hypersensitivity, re- sulting in normal or enhanced nigrostriatal transmissionzO,*‘. Although this may explain the normal postural reflexes in our patients without DIP, it is unlikely to be responsible for the nor- mal ML responses in the DIP group.

Secondly, the simultaneous treatment with an anticholinergic may have suppressed the size of the ML response in 6 patients by correcting the dopaminergic-cholinergic imbalance, thus res- toring the net basal ganglia output. However, suppression of ML response amplitude by anti- cholinergic agents has never been documented. Moreover, it is unlikely that than an actual in- crease in amplitude was masked by anticholi- nergics since we have observed enhanced ML responses in Parkinson’s patients’ treated with the far more potent antiparkinsonian agent le- vodopa in dosages as high as 1000 mg/day.

In the third place, the defect in nigrostriatal transmission may have been insufficient to pro- duce abnormal ML reflexes. All patients were taking only a moderate dosage of neuroleptic medication. In contrast, enlarged ML responses have been observed in monkeys chronically ad- ministered truly toxic doses of a phenothia- zine16, indicating that a more pronounced post-

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synaptic striatal dopamine receptor blockade may yet result in abnormal ML responses.

It has been postulated that enhanced ML re- sponses may be a cause of postural instability in Parkinson’s disease . l8 The normally sized ML responses in our clinically stable patients with DIP are in agreement with this hypothesis.

Interestingly, we have recently observed en- hanced ML responses in patients with parkinso- nism induced by the selective nigrostriatal neu- rotoxin 1-methyl-4-phenyl-1, 2, 3, 6 -tetrahy- drophyridine (MPTP), including a single patient with very mild (Hoehn and Yahr stage I) symp- tomsz2. It therefore appears that a mild dopa- mine deficiency resulting from a presynaptically localized lesion in the substantia nigra is suffi- cient to cause an enhancement of ML re- sponses . ** This suggests that the site of impair- ment in the nigrostriatal pathway may also be an important factor in defective modulation of ML response amplitude.

It is concluded that a mild to moderate block- ade of the nigrostriatal pathway by chronically administered neuroleptic drugs is insufficient to cause enhanced amplitudes of ML responses. However, our observations do not entirely ex- clude a dopaminergic control of the size of the ML response.

Acknowledgements

We express our thanks to Robert Knight and Lourdes Ilog for their assistance in the preparation of this manuscript. This work was supported by a Veteran’s Administration Research Grant. Bastiaan R. Bloem was supported by grants of Sandoz Nederland and De Stichting Bekker-La Bastide Fonds.

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