Administration of zonisamide in three cases of dementia with Lewy bodies

Authors

  • Toshinari Odawara MD, PhD,

    Corresponding author
    1. Psychiatric Center, Yokohama City University Medical Center and
    2. Department of Psychiatry, Yokohama City University School of Medicine, Kanagawa, Japan
      Toshinari Odawara, MD, PhD, Psychiatric Center, Yokohama City University Medical Center, 4-57, Urafune-cho, Minami-ku, Yokohama, Kanagawa-ken 232-0024, Japan. Email: odawara@yokohama-cu.ac.jp
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  • Kazumasa Shiozaki MD, PhD,

    1. Department of Psychiatry, Yokohama City University School of Medicine, Kanagawa, Japan
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  • Takashi Togo MD, PhD,

    1. Department of Psychiatry, Yokohama City University School of Medicine, Kanagawa, Japan
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  • Yoshio Hirayasu MD, PhD

    1. Department of Psychiatry, Yokohama City University School of Medicine, Kanagawa, Japan
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Toshinari Odawara, MD, PhD, Psychiatric Center, Yokohama City University Medical Center, 4-57, Urafune-cho, Minami-ku, Yokohama, Kanagawa-ken 232-0024, Japan. Email: odawara@yokohama-cu.ac.jp

Abstract

Zonisamide (ZNS) add-on administration was used to treat parkinsonian symptoms in three cases of dementia with Lewy bodies (DLB). ZNS was added after doses of the anti-Parkinson's disease drugs were fixed for at least 4 weeks. A total of 25 mg of ZNS produced mild–moderate improvement of parkinsonian symptoms in two cases, but it did not affect the cognitive functions and behavioral or psychological symptoms. Caregiver burdens were decreased in two cases. Although dizziness and drowsiness were detected, these were improved by decreasing the dose. ZNS may be useful for the treatment of motor symptoms in DLB patients.

DEMENTIA WITH LEWY BODIES (DLB) is a progressive neurodegenerative disorder in which Lewy bodies appear extensively throughout the central nervous system, and which is clinically characterized by fluctuating cognitive function, visual hallucination, and parkinsonism.1 The concept of Lewy body disease, which includes Parkinson's disease (PD), Parkinson's disease with dementia and DLB, is often useful in understanding the underlying disease mechanism and treatment.2 Levodopa is now widely used to treat parkinsonism in PD and DLB,3 but no systematic control trial has ever been performed in DLB patients. Levodopa may be less effective clinically in parkinsonism with DLB compared with idiopathic PD.

Murata et al. reported that administration of zonisamide (ZNS), which was synthesized in Japan and used as an anti-epileptic agent, with anti-PD drugs, was beneficial for treating parkinsonism in nine PD patients.4 A follow-up double-blind controlled study, consisting of PD patients in Japan, was performed using a low dose of ZNS in combination with levodopa. The results indicated that ZNS was effective in improving all the cardinal symptoms of PD.5

This is the first reported study wherein ZNS was found to be effective in improving the motor function of DLB patients.

METHODS

The clinical features of all the subjects are presented in Tables 1,2. All patients had mild–severe progressive cognitive impairment and had more than two core features of DLB: cognitive fluctuation, visual hallucination and parkinsonism during illness. Brain magnetic resonance imaging showed mild–moderate cortical atrophy without prominent cerebrovascular disease. The onset of cognitive impairment preceded the appearance of parkinsonism or occurred within 1 year after onset of parkinsonism. Therefore, all cases met the diagnostic criteria of probable DLB.1 In addition to core features, several supportive features were detected. Patient 2 had depression and patient 3 had depressive tendency and systemized delusions that a stranger broke into her house nightly. All patients had low uptake on MIBG myocardial scintigraphy. The severity of parkinsonism for each patient is presented in Table 1. Motor fluctuation was not detected in any patients.

Table 1.  Patient data
Patient no.Age (years), sexDuration of CI (years)Duration of PS (years)Core featuresPrior therapy (mg)Response to LD
  1. APZ, aripiprazole; CI, cognitive impairment; CF, cognitive fluctuation; CNP, clonazepam; DPZ, donepezil; LD, levodopa; MS, mianserin; NZP, nitrazepam; PMP, pramipexole; PS, parkinsonism; QTP, quetiapine; VH, visual hallucination.

172, F23CF, VH, PSLD 200, QTP 50, NZP 5Good
260, F22VH, PSDPZ 5, LD 250, QTP 25
MS 30
Good
378, F54CF, VH, PSDPZ 5, LD 300, PMP 3
APZ 1.5, CNP 0.5
Poor
Table 2.  Assessment of cognitive function
 Patient
123
04 weeks12 weeks04 weeks12 weeks04 weeks12 weeks
  1. CDR, Clinical Dementia Rating; CGI-I, Clinical Global Impression–Improvement scale; GDS, Geriatric Depression Scale; iADL, instrumental Activities of Daily Living scale; MMSE, Mini-Mental State Examination; NPI, Neuropsychiatric Inventory; UPDRS, Unified Parkinson's Disease Rating Scale; Zarit, Zarit Caregiver Burden Interview; ZNSS, zonisamide.

ZNS (mg)5025255025255010050
MMSE26 2525 249 12
CDR0.5 0.51 12 2
UPDRS II20 1213 1025 25
 III21 1619 1524 28
Barthel index   90 9555 55
iADL4 4      
GDS4 410 68 9
NPI1 19 428 21
Zarit35 2126 1931 30
CGI-IModerately improvedMinimally improvedNo change
Adverse effectsDizziness → improvedDizziness → improvedNone → drowsiness → improved

Anti-PD drugs of levodopa and dopamine agonist had already been administered and no further increases in doses of the drugs were needed to prevent deterioration of the behavioral and psychological symptoms of dementia (BPSD). The doses of the anti-PD drugs were fixed for at least 4 weeks before the start of this trial. In all cases, donepezil and/or neurotropics were also administered to treat BPSD. A starting dose of 50 mg administered twice per day of ZNS was added to the administration of anti-PD drugs with reference to a prior trial in PD patients.4 After 12 weeks of ZNS administration, subjects were assessed for cognitive functions on Mini-Mental State Examination, for motor functions using the Unified Parkinson's Disease Rating Scale, for activities of daily living using Barthel index or instrumental Activities of Daily Living scale (iADL), for BPSD using the Geriatric Depression Scale and Neuropsychiatric Inventory, and for caregiver burdens using the Zarit Caregiver Burden Interview.

This study was approved by the ethics committee of Yokohama City University Medical Center and written informed consent was obtained from all subjects and their caregivers.

RESULTS

The results summarized in the Table 2 showed that two patients had mild–moderate improvement in parkinsonian symptoms following ZNS treatment. For patient 1, akinesia and postural instability were moderately improved after administration of ZNS, whereas for patient 2, tremor and akinesia showed mild improvement. Cognitive functions and BPSD, including depression, did not deteriorate in any subjects after 12 weeks of ZNS administration. Patient 3 continued to be delusional but did not worsen. Caregiver burdens were decreased for patients 1 and 2. The adverse effects for both patient 1 and 2 were dizziness, after the administration of 50 mg of ZNS, and drowsiness for patient 3 after the increase of ZNS from 50 mg to 100 mg. Decreasing the dose of ZNS ameliorated the adverse effects.

DISCUSSION

DLB patients often display both motor and psychiatric symptoms. These patients are sensitive to psychotropic drugs and levodopa can sometimes evoke or deteriorate psychiatric symptoms, such as visual hallucination, delusion, and anxiety. Therefore, simultaneous treatments of motor and psychiatric symptoms are difficult in DLB patients in comparison to PD patients.

Recently, low doses of ZNS were reported to have beneficial effects on the cardinal symptoms of PD patients.4 In a double-blind controlled study of ZNS in PD patients, the appearance of prominent psychotic symptoms was not observed.5 Therefore, in the present study we tested the effect of ZNS on the treatment of motor symptoms in DLB patients. Because ZNS had not been approved for PD patients when we performed this trial, we selected 50 mg ZNS/day as the starting dose according to a prior study.4

The present results showed that 25 mg ZNS was beneficial in two patients who had responded to levodopa in a study prior to this trial. These results also showed that 50 mg ZNS was ineffective in one patient who had not responded favorably to a PD drug. For the two patients who showed an improvement in motor symptoms, their caregiver burden was reduced.

Adverse effects, such as somnolence, reduced appetite, and apathy, were frequently reported in ZNS-treated PD patients.5 Dizziness was experienced by two of the present patients after the administration of 50 mg ZNS. That disappeared, however, after decreasing the dose to 25 mg/day. In one case, increasing the dose to 100 mg evoked drowsiness, but a return to the initial dose diminished the extent of this adverse effect. No deterioration of cognitive function and BPSD was detected in any patients.

ZNS has been reported to have a biphasic effect on the dopamine system in that therapeutic doses of ZNS increase the intracellular and extracellular dopamine levels in the rat striatum, but the supratherapeutic dose reduces the intracellular dopamine levels.6,7 The pharmacologically successful mechanisms of ZNS in PD patients remain unclear. It is thought, however, that ZNS activates dopamine synthesis by increasing the messenger RNA and protein levels of tyrosine hydroxylase.6

Because DLB patients often show sensitivity to psychotropics, the present results suggest that lower doses of ZNS may be beneficial for these patients. The results therefore suggest that ZNS can be useful in the treatment of motor symptoms in DLB patients without causing a deterioration of BPSD.

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