Neurology India Medknow Publications on behalf of the Neurological Society of India ISSN: 0028-3886 EISSN: 1998-4022 Vol. 58, Num. 6, 2010, pp. 933-938

Neurology India, Vol. 58, No. 6, November-December, 2010, pp. 933-938

Brief Report

Sleep in Wilson's disease: A polysomnography-based study

Archana B Netto¹, Sanjib Sinha¹, Arun B Taly¹, Samhita Panda¹, Shivaji Rao²

¹ Department of Neurology, National Institute of Mental Health & Neurosciences, Bangalore, India
² Department of Biostatistics, National Institute of Mental Health & Neurosciences, Bangalore, India
Correspondence Address: Sanjib Sinha, National Institute of Mental Health & Neurosciences (NIMHANS), Hosur Road, Bangalore - 560 029, India, sanjib_sinha2004@yahoo.co.in

Date of Acceptance: 27-Aug-2010

Code Number: ni10260

PMID: 21150062
DOI: 10.4103/0028-3886.73752

Abstract

Keywords: Polysomnography, sleep, Wilson's disease

Introduction

Movement disorders such as Parkinson's disease, Huntington's disease and progressive supranuclear palsy frequently cause sleep disturbances as a result of sleep fragmentation leading to decreased sleep efficiency. ^[1],[2],[3] Periodic limb movements in sleep and restless legs syndrome frequently occur in movement disorders. Parkinson's disease is reported to have sleep disturbances in 75% of patients in the form of increased number of awakenings, decreased delta and REM sleep and a scarcity of sleep spindles probably due to degeneration of the sleep-regulating mechanisms. ^[4] Wilson's disease (WD) is an inherited movement disorder resulting from mutations in the ATP7B gene; a membrane-bound copper-transporting ATPase, deficiency of which results in positive copper balance, tissue copper accumulation and copper-induced oxidative damage of liver, brain, etc. ^[5],[6] Patients with WD have neuro-anatomical, pathophysiological and neurochemical basis for sleep disturbances, ^[7] which has been documented in a report by Firneisz et al. ^[8] and a questionnaire study of sleep disturbances by Portala et al. ^[9] The aim of this study was to evaluate the sleep profile and frequency and nature of sleep abnormalities in patients with Wilson's disease using polysomnography, and to correlate these with magnetic resonance imaging (MRI) observations.

Patients and Methods

This prospective study was carried out from January 2007 to January 2009 in the Department of Neurology at the university hospital of a tertiary care center for neurosciences, where a large number of patients of WD are being followed for the last four decades. The study was approved by institutional ethics committee. Patients were recruited from the weekly outpatient Wilson's disease clinic and the inpatient services. All the patients were above the age of 12 years and had confirmed diagnosis of WD. Patients suffering from coexisting medical or surgical condition that can cause sleep disorder or on medications (except antiepileptic drugs) that influence sleep were excluded.

Apart from 25 subjects with WD (M/F ratio, 18:7; age at evaluation, 24.4 ± 9.25 years), 25 normal controls (all males; mean age, 33.1 ± 9.7 years) were also recruited. They were either from among the staff of the institute who were not on shift duties or healthy relatives of inpatients admitted for acquired neurological disorders. Participants were explained about the nature of the study, and an informed consent was obtained. The study consisted of two parts.

Part 1: Phenotypic assessment

a) Demographic, clinical and therapeutic details

A patient was considered as drug naïve if he had not yet received de-coppering agents (penicillamine or zinc sulfate) or discontinued medications for more than 6 months. Details of other medications given for symptomatic treatment of tremor, chorea, dystonia, etc., were also obtained.

b) Clinical evaluation

General examination was carried out focusing on pallor, icterus, Kayser-Fleischer rings (KF) ring, musculoskeletal anomalies, organomegaly and skin changes. Neurological examination involved mini mental status examination; speech assessment; cranial nerve abnormalities, especially those of eye movement; and motor system examination for the evidence of pyramidal, extrapyramidal and cerebellar systems involvement. Severity was assessed using Chu staging. ^[10]

c) Investigations

Apart from routine tests, patients underwent magnetic resonance imaging (MRI) obtained on a Siemens-Magnetom scanner with a super-conducting magnet of 1.5-T field strength in 22 patients and Philips 3-T system in 3 patients.

Part 2: Polysomnography

Polysomnography (PSG) was carried out in the Bio-logic sleep-scan system as per standard procedure. ^[11] Instructions were given to wash the hair thoroughly (without leaving any trace of oil) and avoid afternoon nap on the day of sleep study. The co-prescriptions, along with the penicillamine and zinc, included trihexyphenydyl (n=19), propranolol (n=2), clonazepam (n=1), phenytoin (n=6), phenobarbitone (n=3) and carbamazepine (n=1). Trihexyphenydyl and propranolol were stopped on the previous day, while the other drugs were continued. Subjects were asked to have dinner and report to the sleep lab between 7:30 pm and 8 pm. Sleep laboratory technician (available all through the recording) explained the PSG procedure and clarified doubts if any. Once the subjects were made comfortable, various leads were attached and the monitor was scanned for any artifacts. Once the connections were ready for recording, the lights were switched off and this was recorded as "lights off" time. The recording was stopped temporarily whenever patient required to go to the toilet. The following parameters were recorded: EEG (electroencephalogram), EOG (electro-oculogram), EMG (electromyogram) over mentalis and tibilias anterior muscles; ECG (electrocardiogram); nasal and oral air flow (using pressure transducers); pulse oximeter reading; body position; and chest-wall and abdominal movements.

The data were recorded overnight until the subject woke up naturally from his sleep in the morning or till 7 am, which was the "lights on" time. The data stored in the system were retrieved later. Even though the machine does an automatic scoring, it was recognized that this scoring was incorrect and hence page-by-page corrections of the various stages of sleep, sleep-related movements correlated with video, sleep-related breathing disorders, and heart rate and oxygenation parameter were carried out. The cutoffs for bradycardia and tachycardia were 60 and 100 beats/min, respectively. An Apnea-Hypopnea Index (Respiratory Disturbance Index, RDI) score of more than 5 was considered abnormal. Any disagreement amongst the observers was sorted out by group discussion.

Statistics

Unpaired Student t test was used to compare quantitative variables; and correlation coefficients, for quantitative variables. The Mann-Whitney nonparametric test was used when appropriate. The Fisher exact test was used to compare patients with normal controls. Multivariate analysis was done using canonical discriminant analysis. All computations were performed with SPSS 11 software.

Results

Demography

Twenty-five patients (M/F ratio, 18:7) with WD were recruited. Their mean age at evaluation was 24.4 ± 9.25 years (range, 14-62 years). The duration of illness, computed from the time of onset of initial neurological symptoms to the time of recruitment into the study, varied from 2 months to 312 months (mean, 121.33 ± 129.33 months).

Clinical manifestations

The neurologic abnormalities were tremor- 22 (88%); dysarthria- 20 (80%); writing difficulty- 16 (64%); Parkinsonism- 11 (44%); dystonia- 12 (48%); ataxia- 8 (32%); pyramidal signs- 7 (28%); chorea- 3 (12%); seizures- 6 (24%); and myoclonus- 1 (4%); among others. Six (24%) patients had psychiatric manifestations as their dominant symptoms, which included affective disorders - mania (n=5) and schizophreniform psychosis (n=1). There was no elevation of liver enzymes or bilirubin in any of the patients.

MRI of brain

All the 25 patients underwent MRI study; and in 24 patients, it was carried out within a month of the PSG study. Brain MRI was abnormal in all patients except one (whose MRI became normal after de-coppering). Cerebral atrophy was diffuse and was best evaluated on T1-weighted multiplanar images. In 6 patients, cerebellar and brainstem atrophy was significant and disproportionate to cerebral atrophy. The MR signal abnormalities were noted in midbrain- 18 (72%); putamen- 17 (68%); thalami and globus pallidum- each in 13 (52%); pons- 10 (40%); white matter- 7 (28.0%); cerebellum- 4 (16%); caudate- 3 (12%); and middle cerebellar peduncle- 2 (8%). The pathognomonic "face of giant panda" sign and "central pontine myelinosis-like" changes were observed in 11 and 8 patients, respectively. Three patients had T1 pallidal hyperintensity. The medulla was not involved in any of the patients. White matter signal changes were diffuse and symmetrical in 7 patients and had a frontal preference. There was no neuro-anatomical correlation between PSG parameters and any of the MRI abnormalities.

Therapeutic details

Twenty patients were on de-coppering treatment, while 5 were drug naïve (none discontinued medications for >6 months). Twelve patients were on penicillamine (250 to 750 mg/d), while 20 patients were on zinc sulfate (150-300 mg of elemental zinc per day). The co-prescriptions included trihexyphenydyl (19), propranolol (2), which were prescribed as twice daily doses timed during the morning and afternoon; clonazepam (1); phenytoin (6); phenobarbitone (3); and carbamazepine (1). Among the 6 patients who had seizures, 3 were on a combination of phenytoin and phenobarbitone; 1, on carbamazepine with phenytoin; and 2, on only phenytoin. The severity of WD as measured by Chu staging was stage 1 in 17 patients; stage 2, 6 patients; and stage 3, 2 patients.

PSG observations in patients with Wilson's disease and controls

Among 25 controls recruited for the PSG study, 1 recording was technically inadequate. Hence at final analysis, PSG data of 25 patients and 24 controls were included. There was significant difference in sleep architecture between patients with Wilson's disease and controls. Patients had significantly reduced total sleep-time, sleep-efficiency and percentage of deep sleep and REM-sleep with increased non-REM-sleep and prolonged sleep-onset latency and latency to stage 2 [Table - 1]. The controls had significantly more isolated limb movements in both REM- and non-REM-sleep [Table - 2]. This might mean that patients with Wilson's disease had less of positional changes and limb movements during sleep. Tachycardia was significantly more in patients with WD compared to the controls [Table - 3]. Even though there was no significant difference between patients and controls in the mean number of respiratory events [Table - 4], the number of subjects with RDI > 5 in the control group was 4; and that in the patient group, none; indicating a trend towards statistical significance (P=.05).

Twelve variables were significantly different between the two groups (age at presentation, total sleep-time, sleep-efficiency, sleep-onset latency, latency to stage 2, sleep stage 3/4 %, non-REM-sleep %, Isolated Limb Movement Index in REM-sleep, Isolated Limb Movement Index in non-REM-sleep, minimum heart rate in awake and sleep states and maximum awake-state heart rate) in the univariate analysis. Because the patients and controls were not age matched, a multivariate analysis using canonical discriminant analysis was done. The age at presentation, sleep-efficiency, Isolated Limb Movement Index in REM-sleep and awake-state minimum heart rate emerged as significant discriminators between the two groups. The discriminant function coefficients of these variables were age at presentation, 0.7; sleep-efficiency, 0.7; Isolated Limb Movement Index in REM, 0.5; and awake-state minimum heart rate, −0.6. The variable 'awake-state minimum heart rate' had negative discriminant coefficient, whereas the other three had positive coefficients, i.e., lower mean values among the patients as compared to controls of those variables with positive coefficients. The discriminant function could classify 87.8% of subjects correctly into their respective groups. Using the leaving-one-out method, 81.6% of the subjects were correctly classified into the respective groups, indicating that the above 4 variables were good discriminators.

Sleep study observations in various subgroups of WD

An intra-group comparison of the PSG observations within the Wilson's disease group was attempted based on gender (male or female), age group (less or more than 20 years), treatment details (on de-coppering therapy vs. drug naïve and with and without antiepileptic drugs) and severity of disease (Chu stage 1 vs. 2/3).

Male patients had significantly more bradycardia compared to the female patients, both during awake state (P=.002) and in sleep (P=.03). Younger patients (<20 years) had less REM-sleep, more frequent tachycardia (P= .01), higher periodic limb movements (PLMs) index (P= .01) and more PLMs (P=.01) in non-REM-sleep than older patients. Patients on de-coppering therapy had a significantly prolonged REM-sleep-onset latency (P=.03) and mixed apnea events (P=.04) compared to the drug-naïve group. The Isolated Limb Movement Index in REM-sleep was significantly less in patients with mild disease, viz., disease at Chu stage 1 (P=.05) and in those patients who were not on antiepileptic drugs (P=.03).

Discussion

There was significant difference between patients with Wilson's disease and controls in that the patients had significantly reduced total sleep-time, sleep-efficiency, percentage of deep sleep (stages 3 and 4), and REM-sleep with prolonged sleep-onset latency, latency to stage 2. Wilson's disease is an extrapyramidal disorder with both hyperkinetic and hypokinetic manifestations, ^[12] and the present study found that sleep abnormalities varied as much as the clinical features and shared the PSG findings with those of various other studies on extrapyramidal disorders published in literature [Table - 5]. The reduced isolated limb movements in patients could mean less of position changes during sleep, probably due to the akinetic rigid state as part of the parkinsonian symptoms, though notably the majority of patients had tremor predominance as clinical presentation. Previous literature does not yield data on isolated limb movements in movement disorders, hence comparison is not possible. Assuming that the index of nonperiodic limb movements as a parameter describing the positional changes could be valid, only in part, it would have been ideal to derive data regarding body position monitoring and classifying it under two separate classes, viz., REM- and NREM-sleep . Even though periodic limb movements were found more often in WD patients than in controls (6.2 vs. 3.2), this difference was not significant. Brotini et al. ^[2] opined that sleep fragmentation was the most common nocturnal complaint among patients with Parkinsonism, especially waking during REM-sleep, and they found this was often due to severity of illness, painful leg cramps, discomfort, poor sleep environment, drugs, medical problems such as nocturia, inability to turn over at night, awakening in the middle of the night, difficulty getting out of bed unaided, dystonia of the limbs or face, re-emergence of tremor and rigidity in sleep, vivid dreams, nightmares, jerks, stiffness and anxiety. ^[2] It is possible that patients with WD might also have multiple underlying factors for increased PLMs. There was no difference in respiratory events between patients and controls.

The present study found baseline tachycardia in patients with WD was significantly more, both during awake and sleep states. However, Holter monitoring in this subgroup was not carried out. Meenakshi-Sundaram et al. ^[16] evaluated the various resting electrocardiographic changes in 50 patients with Wilson's disease and found that 15 patients had at least one abnormality in the ECG. Sinus tachycardia and bradycardia were observed in 8 and 6 patients, respectively, apart from the other nonspecific changes. ^[16] It was proposed that the changes were presumably related to an underlying cardiomyopathy due to deposition of copper in heart.

Male patients had significantly lower heart rate (bradycardia) than female patients, both in awake and sleep states. Also, younger patients had higher heart rate (tachycardia) than older ones in sleep. In the study by Portala et al., ^[9] two variables, viz., palpitations and nightmares during the sleep period, were scored significantly higher by the women (n=11) than the men (n=13). The reason for this difference is unclear. ^[9] Adult patients with WD demonstrated higher percentage of REM-sleep than younger patients. This might not be in agreement with the findings of other studies in literature, which report reduced REM-sleep with increasing age. It is possible that adult patients were on de-coppering agents for longer duration, and this could have normalized their sleep architecture to some extent. However, this can be confirmed only by follow-up PSG studies on drug-naïve patients after they have taken adequate treatment.

Patients who were on de-coppering therapy had a significantly prolonged REM-sleep-onset latency compared to controls. The effect of de-coppering agents on sleep is yet to be studied. Trihexyphenydyl could cause REM-sleep depression. Therefore, it would have been appropriate to stop it 35 hours (5 half-lives) prior rather than 24 hours before the PSG recording, to exclude its effect on sleep architecture. However, it is notable that the percentage of REM-sleep was not different between patients and controls. Anti-epileptic drugs (AEDs) have differential effects on sleep architecture, which can be beneficial or otherwise. ^[17] In this cohort, Isolated Limb Movement Index in REM-sleep was significantly low in patients with mild disease and in those patients who were not on AEDs. There was no other difference between patients who were on and those patients who were not on AEDs.

The current MRI observations are matching with detailed description of MRI observations in 100 patients of Wilson's disease given by Sinha et al., ^[18] except that the proportion of patients showing "face of giant panda" sign and "central pontine myelinolysis-like" changes was more common. ^[18] There was no neuro-anatomical correlation between PSG parameters and any of the MRI abnormalities. This may require a larger cohort of patients with more specific anatomical sites of involvement.

Recruitment of large number of patients, truly age- and gender-matched controls, PSG recording on the second night to remove the problems related to "first night" effect, and including patients with isolated anatomical involvement might improve the understanding of sleep disorders in patients with WD.

The study is the first of its kind in literature and reveals significant sleep disturbances in patients with Wilson's disease. Studies of sleep abnormalities among patients with WD are important, and the effects of treatment on sleep abnormalities in these patients in terms of quality of life (QoL) need to be studied.

Acknowledgment

The authors thank electrophysiology technologist Mr. Nagaraj for the PSG recording carried out by him. They also appreciate the cooperation of study subjects in the course of the study.

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