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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 2  |  Issue : 1  |  Page : 9-14

Sleep disturbances in patients with Huntington’s disease: A questionnaire-based study


1 Department of Neurology, All India Institute of Medical Sciences (AIIMS), Bhubaneshwar, Orissa
2 Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka, India
3 Department of Clinical Neurosciences, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka, India
4 Department of Molecular Biology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka, India
5 Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka, India

Date of Web Publication17-Apr-2019

Correspondence Address:
Dr. Pramod Kumar Pal
Address for correspondence: Dr. Pramod Kumar Pal, Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru 560029, Karnataka, India.
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AOMD.AOMD_1_19

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  Abstract 

OBJECTIVES: To compare the sleep profiles of genetically proven cases of Huntington’s disease (HD) with healthy controls and to correlate the results of various sleep-related parameters with disease severity, duration, and length of cytosine–adenine–guanosine repeats.METHODS: This prospective study was conducted at the National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, India, which included 31 genetically confirmed patients with HD and 50 controls. All the subjects were evaluated for sleep disturbances using standardized sleep questionnaires (Pittsburgh Sleep Quality Index [PSQI] and Epworth Sleepiness Scale [ESS]).RESULTS: The mean age of the patients during the first consultation was 46.0±12.7 years (range: 28–80). The mean age at onset of symptoms was 40.5±13.8 years. Nineteen patients (61.2%) gave history of sleep disturbances. Symptom suggestive of rapid eye movement sleep behavior disorder was present in 8 patients (25.8%). Difficulty in falling asleep was the most common sleep-related disturbance reported by 16 patients (51.6%). The mean ESS score of the patients was 6.22±2.89 and that of the control population was 3.00±2.8 (P value < 0.001). The mean PSQI score of the patients was 8.90±3.50 and that of the control population was 3.3±2.9 (P value < 0.001).CONCLUSIONS: This study demonstrates sleep disturbances in patients with HD compared to healthy controls and the sleep disturbances correlated significantly with the disease duration, severity, and coexistent anxiety and depression.

Keywords: Epworth Sleepiness Scale, Hamilton anxiety rating scale, Hamilton depression rating scale, Huntington’s disease, Pittsburgh Sleep Quality Index, sleep questionnaires


How to cite this article:
Jha M, Kamble N, Lenka A, Yadav R, Purushottam M, Jain S, Pal PK. Sleep disturbances in patients with Huntington’s disease: A questionnaire-based study. Ann Mov Disord 2019;2:9-14

How to cite this URL:
Jha M, Kamble N, Lenka A, Yadav R, Purushottam M, Jain S, Pal PK. Sleep disturbances in patients with Huntington’s disease: A questionnaire-based study. Ann Mov Disord [serial online] 2019 [cited 2019 May 21];2:9-14. Available from: http://www.aomd.in/text.asp?2019/2/1/9/256490




  Introduction Top


Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder due to abnormal expansion of cytosine–adenine–guanosine (CAG) trinucleotide in the gene encoding the protein huntingtin (HTT) located on chromosome 4p16.3.[1],[2] In addition to the core clinical features such as motor impairment, cognitive decline, and behavioral problems, patients with HD may have multiple problems related to sleep, which may substantially hamper the quality of life of patients as well as their caregivers.[3],[4] Identification of factors associated with disturbed sleep in patients with HD is not only essential for rational management but also in understanding the pathogenesis behind sleep disturbances in these patients. Literature on sleep disturbances in patients with HD is sparse and currently there is no published literature from India on the same topic. Hence we undertook this prospective case control study, which aims to compare the sleep profiles of genetically proven cases of HD with healthy controls and to correlate the results of various sleep-related questionnaires with disease severity, duration, and length of CAG repeats.


  Methodology Top


This study was conducted at the National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, India. Institute Ethics Committee of NIMHANS had approved this study and all the subjects were recruited from the neurology outpatient clinics and movement disorders clinic after obtaining written informed consent. A single movement disorder neurologist (PKP) and a single psychiatrist (SJ) had evaluated all the patients. The clinical criteria proposed by Folstein et al.[5] were used to screen patients before subjecting the patients for genetic testing. The criteria are (i) chorea or impaired voluntary motor function that was not present at birth, which was insidious in onset and progressive in nature, with or without dementia or behavior abnormalities, (ii) family history of at least one other member with the typical symptoms of HD, and (iii) typical clinical features of HD even in the absence of a family history.

CAG repeat length (from 5′ region of HTT gene) was determined after polymerase chain reaction amplification of genomic DNA obtained from the peripheral blood. Patients with repeat length >35 were considered to be genetically confirmed cases of HD. Consecutive patients with HD were included in the study after obtaining written informed consent from them and patients who were not willing to participate in the study were excluded. Thirty-one patients confirmed to have HD after genetic testing were recruited along with 50 age-, education-, and gender-matched healthy controls. None of the healthy controls had positive family history of HD or have any motor, behavior, or cognitive abnormalities.

Demographic and clinical details and treatment history were documented from all participants. Folstein Mini-Mental State Examination was used to screen for cognitive impairment.[6] Severity of the motor symptoms of HD was assessed using Unified Huntington’s Disease Rating Scale (UHDRS) motor score.[7] Quality of sleep, daytime somnolence, and associated risk factors were assessed using the Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS).[8],[9] The PSQI primarily evaluates nighttime sleep, consisting of 19 self-rated questions and 5 questions rated by the bed partner or roommate. Scores are grouped in seven domains, which assess subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleep medication, and daytime dysfunction. The component scores are summed to produce a global score (range: 0–21). A PSQI global score of more than 5 is suggestive of significant sleep disturbance. The ESS evaluates daytime sleepiness and this scale requires the subjects to rate their chance of dozing off in eight different situations. The maximum score is 24 and a score more than 10 suggests presence of excessive sleepiness. In addition to the aforementioned scales, Hamilton Anxiety Rating Scale (HAM-A) and Hamilton Depression Rating Scale (HAM-D) was used to determine the presence and severity of anxiety and depression.[10],[11] In HAM-A, the score ranges from 0 to 56. A score of <17 indicates mild severity, 18–24 indicates mild-to-moderate severity, and 25–30 indicates moderate-to-severe anxiety. Similarly in HAM-D, a score of 0–7 is considered as normal, a score of 8–13 is mild depression, 14–18 is moderate depression, 19–22 is severe depression, and ≥23 indicates very severe depression.

Statistical analysis

Statistical analysis was performed using SPSS version 16. Data were expressed using descriptive statistics such as for continuous variables, mean, and standard deviation and for categorical variables, frequency, and percentage. Comparison between continuous variables was performed using independent student t test and chi-square test for categorical variables. Correlation between continuous variable was conducted using Pearson’s correlation coefficient. P value <0.05 was considered statistically significant.


  Results Top


The mean age of the patients during the first consultation was 46.0±12.7 years (range: 28–80). Men (61%) outnumbered women (39%), and a positive family history of HD was present in 30 patients (97%). The mean age at onset (AAO) of symptoms was 40.5±13.8 years. There was one patient with juvenile onset HD (AAO < 20 years). The mean duration of symptoms of HD was 5.5±4.9 years (range: 1–25 years) [Table 1]. The most common presenting motor symptom was chorea, which was observed in all patients.
Table 1: Demographic and clinical profile of patients with HD

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The mean CAG repeat length of the normal allele was 18.0±2.4 (range: 14–22), whereas the mean length of CAG repeat in the expanded allele was 43.87±3.3 (range: 39–58) [Table 1].

The mean UHDRS motor score was 29.35±11.3. The mean HAM-D score in the HD cohort was 14.77±6.33 (range 5–25). On the basis of HAM-D scores, 3 had severe depression (HAM-D score: 19–22), 8 had mild depression (HAM-D score: 8–13), and 18 had moderate depression (HAM-D score: 14–18). The mean HAM-A score of patients with HD was 16.19±6.09 (range: 7–26). On the basis of HAM-A scores, four patients had severe anxiety (HAM-A score: 19–22) and nine patients had moderate anxiety (HAM-A score: 14–18). Rest of the 18 patients had HAM-A score less than 17 suggestive of no evidence of anxiety.

All the patients were on medications at the time of recruitment. Carbamazepine was the most commonly used drug (80.6%). The other drugs were tetrabenazine (64.5%), clonazepam (51.6%), antidepressants (35.4%), antipsychotics (29%), haloperidol (6.5%), trihexyphenidyl (6.5%), and sodium valproate (3.2%).

Sleep disturbances and scores

Nineteen patients (61.2%) gave history of sleep disturbances [Tables 2] and [3]. Of these patients, sleep-related complaints were present since the onset of symptoms in 5 patients whereas in the rest of the 14 patients sleep disturbances developed after the onset of HD symptoms. Among these patients with sleep disturbances, symptom suggestive of rapid eye movement (REM) sleep behavior disorder (RBD) was present in 8 patients (25.8%). Sleep disturbances did not precede the symptoms in any of the patients.
Table 2: Sleep disturbances reported by patients with HD

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,
Table 3: Comparison of sleep questionnaire scores between patients with HD and controls

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Difficulty in falling asleep was the most common sleep-related disturbance reported by 16 patients (51.6%); 9 patients (29%) reported frequent awakening, 7 patients (22.5%) experienced nightmares, and another 8 patients (25.8%) reported involuntary limb movement during sleep. In five patients (16%), the sleep disturbance was severe enough to disturb the sleep continuity. Eleven patients (35.4%) had excessive daytime somnolence.

The mean ESS score of the patients was 6.22±2.89 and that of the control population was 3.00±2.8 (P value < 0.001). An abnormal score of ≥10 was seen in 4 patients (13%) suggestive of excessive daytime somnolence.

The mean PSQI score of the patients was 8.90±3.50 and that of the control population was 3.3±2.9 (P value < 0.001) [Figure 1]. An abnormal score of >5 was seen in 20 patients (64.5%).
Figure 1: Comparison of ESS and PSQI scores between HD and controls. ESS = epworth sleepiness score, HD = huntington’s disease, PSQI = pittsburgh sleep quality index

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A significant correlation was seen between the sleep scores of ESS and PSQI with the duration and severity (UHDRS) of the disease and HAM-A and HAM-D scores (P value <0.001) [Table 4]. On multiple logistic regression analysis, very weak association was observed between ESS/PSQI and the other clinical scores (duration, UHDRS, HAM-A, HAM-D). However, no significant correlation was observed between the scores of ESS and PQSI with CAG repeat length.
Table 4: Correlation between the sleep and clinical scores

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  Discussion Top


A high prevalence of sleep disorders has been reported in many neurodegenerative diseases; however, literatures on sleep quality in the HD population are sparse. To the best of our knowledge, this is the first study from India on patients with HD in which subjective sleep quality and daytime somnolence have been systematically assessed in relation with CAG repeat length size and clinical symptoms and signs. Our study shows that patients with HD have significant sleep disturbances. History of sleep disturbances was reported by 19 of the 31 patients (61.2%), which is lower than community survey conducted by Taylor and Bramble who reported prevalence of sleep problems in HD to be as high as 87.8% and the sleep problems were rated by 61.7% of patients as either “very” or “moderately” important contributing factors to the overall morbidity.[4] Among the patients who reported sleep disturbances, difficulty in falling asleep was the most common symptom (51.6%), followed by frequent awakenings after sleep onset (29%), which is in agreement with previous findings of increased sleep onset latency and difficulty in maintaining sleep in HD.[12],[13] RBD has been commonly reported in synucleiopathies but is under-recognized in HD.[14] There is limited data on REM sleep in HD with controversial findings as some authors have reported reduced REM sleep[12],[15] whereas others did not find any significant differences in REM sleep parameters in patients with HD from healthy controls.[16] In a study of 25 patients with HD by Arnuf et al.,[15] 3 patients (12%) were found to have RBD, whereas Videnovic et al.[17] reported symptoms suggestive of RBD in seven out of 30 patients in their study (23%). In our study, dream enactment behaviors suggestive of RBD was seen in 8 patients (25.8%), which is similar to that seen by Videnovic et al.[17] This difference could be due to lack of objective measures and differences in patient characteristics such as severity of disease, coexisting anxiety, and depression in the two studies, whereas in the study by Arnuf et al.,[15] patients underwent nighttime video and sleep monitoring in addition. The clinical outcome of these behaviors is the risk of injury either to the patient or to the bed partners.

Data on excessive daytime sleep (EDS) in HD are sparse. In our study, the mean ESS score in patients with HD was 6.2±2.0 as compared to 3.0±2.8 in controls. Though a history of EDS was present in 11 patients (35.4%), an abnormal score of ≥10 was present in only 4 patients (13%) as compared to 6% seen in healthy controls, which is in agreement with the study done by Aziz et al.,[18] in which 12.7% of patients with HD had an ESS score of 10 or higher as compared to 7.9% of controls. Arnuf et al.[15] did not find more frequent daytime somnolence in patients with HD relative to controls in their study as well.[15] In contrast, a higher prevalence of EDS (50%) was seen by Videnovic et al.,[17] which was associated with coexistent depression, which supports the association between depression and sleep disturbances in extrapyramidal diseases.[17]

Nighttime sleep impairment as tested by PSQI score showed a higher percentage of patients with HD having a score of 5 or higher compared with controls (64.5% vs. 14%), which is consistent with previous studies.[17],[18] Poor nocturnal sleep correlated with longer disease duration, anxiety, depression, UHDRS score, and ESS in our study, which is in partial agreement with the study conducted by Videnovic et al.[17] and Aziz et al.[18] in which PSQI score correlated with longer disease duration and depression, whereas no correlation between ESS and UHDRS score was seen.[17],[18] There was no correlation between CAG repeat length and sleep disturbances seen in our study, which is consistent with the previous studies.[15],[18]

Circadian rhythm alterations are well-established cause’s of sleep disturbances. Recently it has been suggested that patients with HD have a disrupted circadian rhythm.[13] Circadian changes are associated with reduced expression of circadian clock genes, and treatments aimed at restoring circadian rhythms slow cognitive decline in animal HD models.[13],[19] Although we did not assess indicators of circadian homeostasis in our cohort, this may be an important future direction of sleep-related research in HD.

A questionnaire-based study that contained 45 questions focusing on different sleep-related issues, such as duration and quality of sleep, abnormal nocturnal behavior, and quality of life in patients with HD, showed that a significantly greater proportion of patients with HD reported difficulty in falling asleep and took longer to get to sleep than control subjects. Many patients also reported experiencing repeated jerking or twitching of the arms or legs during sleep, as well as fidgeting a lot in bed, and wandering about at night.[20]

Studies have shown poor sleep that affects up to 90% of patients with HD with symptoms including difficulty in sleep initiation and maintenance, reduced sleep efficiency, and total sleep time.[20],[21] Circadian rhythms also become progressively more disrupted as the disease process advances, resulting in further sleep–wake disruption.[13]

Non-motor symptoms and signs such as psychiatric disturbances, sleep disturbances, and metabolic dysfunction in HD are part of the disease manifestation. These features may be due to the changes in the hypothalamus that is involved in the regulation of emotion, sleep, and metabolism. Studies using voxel-based morphometry analyses of magnetic resonance imaging scans have indicated that there is a reduction in signal intensity in voxels in the hypothalamic region in early symptomatic stages of the disease.[22],[23]

Hence, there is some evidence of degeneration of the hypothalamus in HD individuals and also there is evidence of lowered melatonin levels.[24],[25],[26] Recent studies have also disclosed accelerated thalamic degeneration and poorer neuropsychiatric outcomes in patients with HD with sleep disturbances. However, the mechanism underlying circadian rhythmicity disruption and sleep disturbance in these patients are still unclear and need to be investigated further in order to develop effective treatments.[27]

A study of sleep and daytime somnolence in neurodegenerative disorders in general is very challenging. These patients commonly have impaired cognition, anxiety, depression, and are treated with numerous drugs with central effects.[28] All these are significant contributors to poor overnight seep and/or daytime somnolence. Therefore, it is difficult to precisely characterize a sleep phenotype in neurodegenerative disorders without significant confounders.

There are several limitations in our study and the major limitation was a lack of objective measures of sleep as we could not do the whole-night polysomnography in our study populations, which could have provided relatively accurate measure of the sleep architecture. Another limitation of our study is the modest sample size as a larger sample size would have been helpful for several subgroup analyses. Majority of the patients in our study were on carbamazepine, trihexyphenidyl, clonazepam, and antidepressants, which may alter the sleep pattern and act as confounding factor. As it was a cross-sectional study, patients who did not have sleep disturbance during the interview might have developed later in the course of the illness.


  Conclusions Top


To conclude, this study demonstrates sleep disturbances in patients with HD compared to healthy controls and the sleep disturbances correlated with the disease duration, severity, and coexistent anxiety and depression. We did not find any significant correlation between CAG repeat lengths and sleep disturbances. Focused management of disturbed sleep and EDS in HD, with special emphasis on coexistent anxiety and depression, may improve quality of life of patients and their caregivers. As sleep disturbances might contribute to cognitive dysfunction in HD, managing the sleep disturbances may be crucial to prevent the rate of cognitive decline. Longitudinal studies in future involving large number of patients and involving combination of subjective as well as objective measures of sleep quality are warranted to provide better insight and better understanding of the sleep problems in HD.


  Financial support and sponsorship Top


Nil.


  Conflicts of interest Top


There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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