238 COMMUNICATIONS

Segment 2 Surface recording with additional electrode attached to the ear lobe shows a frequency of -l/s for auricular movements.

Segment 3: Movements are unchanged minutes after intravenous administration of normal saline.

Segment 4: The movements are markedly reduced after administration of diazepam, 5 mg intravenously.

Segment 5: Movements continue during stage 1 sleep (less intense).

Segment 6 Movements stop during deeper sleep. Segment 7: Auricular movements are resumed upon

Bahman Jabbari Jonathan Braiman

Neurology Service of Walter Reed Army Medical Center

Washington, D.C. U.S.A. and

Uniformed Services University of the Health Sciences Bethesda, Maryland, U.S.A.

awakening.

References

1 . Kirk A, Heilman KM. Auricular myoclonus. Can J Neurol Sci 1991;18:503-504.

2. Grant JCB. Grant’s atlas of anatomy. Baltimore: Williams and Wilkins, 1962.

3. Dreifuss F. Classification of epileptic seizures. In: Dam M, Gram E, eds. Comprehensive epileptology. New York: Raven Press, 1991:7746.

4. Niedermeyer E. Epileptic seizure disorder. In: Niedermeyer E, Lopez da Silva F, eds. Electroencephalography. Balti- more: Urban and Scwharzenberg, 1987:482.

5. Brodal A. Neurological anatomy. Oxford: Oxford Univer- sity Press, 1981:495-508.

6. Leeds JL, Tolosa E. Tics. In: Jankovic J, Tolosa E, eds. Parkinson’s disease and movement disorders. Baltimore: Williams and Wilkins, 1993:32%335.

7. Guillain G. The syndrome of synchronous and rhythmic palato-phalyngo-oculo-diaphragmatic myoclonus. Proc Roy Soc Med 1938;31:1030-1038.

FIG. 1. Magnetic resonance study after administration of gad- olinium. TR:500, TE:30. Trans- verse (A) and axial (B) images show an area of intense enhance- ment in the right anterior parietal region. The tumor was a ganglio- glioma.

8. Babinski J. Hemispasme facial peripherique. Rev Neurol (Paris) 1905 ; 1 3 : 15 1-1 58.

Zotepine Reversibly Induces Akinesia and Rigidity in Parkinson’s Disease Patients with Resting

Tremor or Drug-Induced Psychosis

To the Editor: In -20% of Parkinson’s disease patients (l), treatment

with dopamimetic drugs like L-DOPA, bromocriptine, or lisuride and other dopamine agonists induces psychosis with delusions or visual hallucinations. Reduction of do- paminergic drugs usually leads to deterioration of Park- insonian symptoms. Medical treatment of these psy- chotic symptoms is difficult because common neuroleptic drugs such as chlorpromazine and haloperidol induce se- vere akinesia due to their dopamine antagonistic proper- ties.

The atypical neuroleptic drugs are characterized by high affinity to the dopamine D, receptor and very low affinity to the dopamine D, receptor (2). Clozapine has been used since 1985 (3) in the therapy of drug-induced psychosis because this drug does not aggravate Parkin- sonian symptoms (43). In single cases, however, severe agranulocytosis has been reported. For this reason, we searched for an alternative therapy. The novel drug zotepine has been classified as an atypical neuroleptic, based on its pharmacologic properties; zotepine has a me- dium D, pK, value and a high 5-HT, pK, value (6). To our knowledge, zotepine has not been reported to depress white blood cells. Verbal communication with the manu- facturer about the use of zotepine in patients with Par- kinson’s disease (PD) and drug-induced psychosis re- vealed no reports of akinesia. We report here on four patients with PD according to United Kingdom Parkin- son’s Disease Society Brain Bank criteria, a fluctuating response to oral L-DOPA therapy and resting tremor re- sistant to standard antiparkinsonian medication (n = 2) or L-DOPA induced psychosis (n = 2).

Movement Disorders, Vol. 9 , No. 2, 1994

COMM UNKCA TKONS 239

Zotepine (Nipolept, Klinge Pharma, Munich, Ger- many) was given in a starting dose of 12.5 mg (= I/t tablet) in the afternoon. A weekly dosage increment was planned, until a beneficial effect could be observed or adverse events were reported. Since aU patients reported akinesia while on treatment, we discontinued the trial af- ter the fourth patient.

Patient 1

A 78-year-old woman with a 23-year history of PD had been treated effectively with clozapine for 9 weeks 4 years previously because of severe drug-induced halluci- nations; she had stopped clozapine therapy because of sedation. Dopaminergic therapy with 450 mg L-DOPA (+ 112.5 mg carbidopa), 17.5 mg bromocriptine, and 2.5 mg deprenyl per day had induced persistent visual hallucina- tions. During ON periods she was able to walk unaided with peak dose hyperkinesia. During this time, the Hoehn and Yahr stage was 3. After 2 days of therapy with zotepine (12.5 mg daily), she developed progressive aki- nesia and rigidity, but the hallucinations stopped. Five days after initiation of zotepine, the patient was not only unable to walk, but was bedridden; therapy with L-DOPA was ineffective during this period; the Hoehn and Yahr stage was 5. Five days after discontinuation of zotepine, therapy with L-DOPA, bromocriptine, and deprenyl was as effective as before, although hallucinations developed once again.

Patient 2

A 78-year-old woman with a 19-year history of PD was first seen in 1988. L-DOPA had to be increased up to 350 mg (+ 87.5 rng benserazide) and 10 mg bromocriptine daily during the following 4 years. With this medication the patient had visual hallucinations and paranoid reac- tions. Zotepine was introduced and rapidly increased up to 150 mg daily. With this high dosage, the patient showed a marked improvement with regard to her psychotic signs; an akinetic state, however, was noted. The Hoehn and Yahr stage deteriorated from 3 to 5 . Zotepine was stopped after 2 months. The akinesia was fully reversible, but psychotic symptoms returned.

Patient 3

A 69-year-old woman with a 9-year history of PD had a severe resting tremor of both arms and the right leg un- responsive to 450 mg L-DOPA (+ 112.5 carbidopa in a retard formulation), 5 0 mg L-DOPA (+ 12.5 mg benser- a ide in a standard formulation), and 2.5 mg deprenyl. The Hoehn and Yahr state in ON periods was 2.5. Resting tremor had reached rank 4 on the Unified Parkinson’s Disease Rating Scale for tremor. Zotepine at a dosage of 25 mg daily led to improvement of resting tremor, al- though mild akinesia developed; the drug was increased to 50 mg per day. During the following week, the patient complained of difficulty in walking and stiffness; the Hoehn and Yahr stage was 4. Zotepine was discontinued and the symptoms reverted over the next week, whereas tremor again reached rank 4 on the tremor scale of the Unified Parkinson’s Disease Rating Scale. The patient

improved markedly with a new dopaminergic drug under investigation,

Patient 4

A 68-year-old man with a 7-year history of PD had a marked resting tremor and slight rigidity and bradykinesia of the right arm despite therapy including 300 mg L-DOPA (+ 75 mg benserazide) and 0.1 mg lisuride. In ON phases, the Hoehn and Yahr staging was 2. Increased dopamimetic therapy led to disabling and painful peak dose dystonia. Zotepine (12.5 mg daily) resulted in severe rigidity and akinesia; the Hoehn and Yahr stage was 4 and L-DOPA therapy was ineffective. The symptoms re- verted after discontinuation of zotepine. A second trial with zotepine again resulted in rigidity and akinesia. Therapy with clozapine was started and increased up to 25 rng; tremor improved markedly without deterio- ration in bradykinesia or rigidity. Depression of white blood cell count was not observed during 30 weeks of follow-up.

Conclusion

This patient showed a definite adverse reaction to zotepine according to the criteria of Karch and Lasagna (7): his symptoms reappeared during a second trial with zotepine therapy. In first reports on zotepine therapy, Parkinsonian symptoms and tardive dyskinesia in schizo- phrenic patients seemed to be rare (8,9). Zotepine has only been available for a short time in certain countries (in Japan and Germany; registration procedure is in prog- ress in Switzerland and Austria and planned in the United Kingdom, Canada, and the United States). However, in a recent study, the frequency of Parkinsonian adverse re- actions and tardive dyskinesias has been reported to be higher than in previous investigations (10) (half compared with haloperidol). In agreement with this, all four patients with PD reported here experienced akinesia and rigidity on zotepine therapy as would be expected on a typical neuroleptic drug. For ethical reasons, we discontinued the open study with zotepine in PD patients. Due to the observed adverse-although reversible-reactions the classification of zotepine as an atypical neuroleptic drug is not justified.

We conclude that zotepine is no alternative to cloza- pine in the treatment of resting tremor and drug-induced psychosis in PD.

G. Arnold C. Trenkwalder

J. Schwarz W. H. Oertel

Department of Neurology Klinikum Grosshadern

University of Munich Munich, Germany

References 1. Lesser RP, Fahn S, Snider SR, Cote LJ, Isgreen WP, Barrett

RE. Analysis of the clinical problems in parkinsonism and the complications of long-term levodopa therapy. Neurology 1979;291253-1260.

Movement Disorders, Vol. 9, No, 2. 1994

240 COMMUNICATIONS

2.

3.

4.

5 .

6.

7.

8.

9.

10.

Seeger TF, Thal L, Gardner EL. Behavioural and biochem- ical aspects of neuroleptic-induced dopaminergic supersen- sitivity: studies with chronic clozapine and haloperidol. Psy- chopharmacology 1982;76: 182-187. Scholz E, Dichgans J . Treatment of drug-induced exogenous psychosis in parkinsonism with clozapine and fluperlapine. Eur Arch Psychiatr Neurol Sci 1985:235:6W. Wolters EC, Hurwitz TA, Perppard RF, Calne DB. Cloza- pine: an antipsychotic agent in Parkinson’s disease? Clin Neuropharmacol 1989;12:83-90. Friedman JH, Lannon MC. Clozapine in the treatment of psychosis in Parkinson’s disease. Neurology 1989;39: 1219- 1221. Meltzer HY, Matsubara S , Lee J. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonine, pKi values. J Pharmacol Exp Ther 1989;25 1 :238-246. Dieterle DM, Ackenheil M, Miiller-Spahn F, Kapfhammer HP. Zotepine, a neuroleptic drug with bipolar therapeutic profile. Pharmacopsychiatry 1987;20:52-57. Karch FE, Lasagna L. Adverse drug reactions. JAMA 1975; 234: 12361241. von Bardleben U, Benkert 0, Holsboer F. Clinical and neu- roendocrine effects of zotepine-a new neuroleptic drug. Pharmacopsychiatry 1987;20:28-34. Barnas C, Stuppack CH, Miller C, Haring C, Sperner- Unterweger B, Fleischhacker WW. Zotepine in the treat- ment of schizophrenic patients with prevailingly negative symptoms. A double blind trial vs. haloperidol. Int Clin Psy- chop harmacol 1 992;7: 23-27.

Delayed Onset of “Rubral Tremor” 23 Years After Brainstem Trauma

To the Editor: Some rare tremors are still a matter of debate as far as

their classification as separate entities is concerned. “Ru- bral tremor” is one of them. This tremor was first de- scribed by Holmes (1) and later termed midbrain tremor (2) or myorhythmia (3,4). We consider a tremor to be a “rubral tremor” if (a) the tremor is present at rest, with posture, and during goal-directed movements, (b) the fre- quency is between 2 and 4 Hz (rarely up to 5.5 Hz), and (c) a delay occurs between the underlying lesion and the occurrence of the rest tremor (whenever the date of lesion can be defined) (5).

This tremor has been described in multiple sclerosis, multisystem degeneration, Parkinson’s disease with addi- tional brainstem lesions, tumors or angiomas of the mid- brain, severe trauma to the brain, infarcts, and Wilson’s disease (5). Whereas it is common for posttraumatic “ru- bral tremor” to develop within several months after the traumatic event (2), our patient developed a “rubral tremor” after more than 20 years of stable posttraumatic ataxia.

Case Report

A 26-year-old man suffered a head trauma at work in 1968. That same day, on admission to the neurosurgical department (University of Giessen), the patient was co- matose and was noted to have Cheyne-Stokes breathing, The right pupil was larger than the left and both pupils

showed only weak reaction to light. There were extensor responses of both arms and legs and a bilateral Babinski’s sign. The echoencephalogram showed a 4-5-mm devia- tion of the third ventricle to the left. After a right temporal trepanation, 60 ml of a subdural hematoma were evacu- ated. Postoperatively the comatose patient showed flexor responses of arms and legs. He remained comatose for 3% weeks. After 2 months, the patient was fully oriented. Pupils were normal. A limitation of downward gaze was noted on the right and of upward gaze on the left. He had a spastic tetraparesis predominantly on the left with bi- lateral Babinski’s sign and with a left-sided hemihypaes- thesia. There was a severe right sided ataxia and the pa- tient was unable to stand or walk unassisted.

Twenty-three years later, in 1991, the patient presented at the neurology department (University of Giessen), complaining of a coarse slowly progressive right-sided tremor evolving during the last 6 months. The tremor was severely disabling and his right arm was functionally use- less. He had difficulties in falling asleep, as the tremor persisted when lying down. He had neither present nor past history of centrally acting medication. On examina- tion, he had a right IVth nerve palsy and a hypalgesia and a thermohypaesthesia of the left face. He was hypo- mimic. Speech was slurred. He had a coarse resting tremor of his right arm, which persisted on adopting a posture, and a severe intention tremor of the right arm. There was also an intention tremor of the right leg and gait was ataxic. He had a dissociated hemihypaesthesia on the left. Computed tomography (CT) scan showed a large right-sided trepanation defect and a right parietal concussion defect. Magnetic resonance imaging (MRI) additionally showed a lesion along the right-sided upper cerebellar peduncle extending into the midbrain. The re- gions of the right locus coeruleus and the lower dorsolat- eral part of the right substantia nigra showed a lesion, whereas the nucleus ruber seemed to be unaffected (Fig. 1). Tremor analysis showed the presence of a 2.8-Hz rest- ing and postural tremor in the accelerometer and electro- myogram (EMG) signals.

Treatment with clonazepam 1.5 mg led to subjective improvement mainly due to better sleep, but no objective improvement of the tremor could be found. After initiat- ing anticholinergic treatment with increasing doses of tri- hexyphenidyl up to 6 mg, the patient noted a dramatic improvement of the tremor within 8 days. On examina- tion no more resting tremor was found. The patient still had a very mild proximal postural tremor of his right arm and an intention tremor of his right arm and leg. The other clinical signs of brainstem and cerebellar dysfunction re- mained unaffected. The beneficial response has now been stable for 18 months on low-dose anticholinergic medica- tion.

Discussion

More than 20 years after a severe head trauma, a dying back theory can hardly explain the delayed appearance of a resting tremor in our patient. Thus we assume that in addition to the existing cerebellar disturbance, a second dysfunction of the nigrostriatal system is responsible for the resting tremor component. In our patient, one could

Movement Disorders, Vol. 9, No . 2 , 1994