pii: jc- 00306-15http://dx.doi.org/10.5664/jcsm.5950
CAS E R EPOR T S
Depression as the Primary Cause of Insomnia and Excessive Daytime Sleepiness in a Family with Multiple Cases of Spinocerebellar Ataxia Chun-Hsien Hsu, MD1; Yen-Lin Chen, MD2; Dee Pei, MD3; Shu-Man Yu, MD, MPH1; I-Chao Liu, MD, DSc 4,5 Department of Family Medicine, Cardinal Tien Hospital, School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 2Department of Pathology, Cardinal Tien Hospital, School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 3Department of Internal Medicine, Cardinal Tien Hospital, School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 4Department of Psychiatry, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; 5Department of Psychiatry, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 1
Spinocerebellar ataxia (SCA) is a hereditary disease characterized by central nervous system-related motor dysfunctions. Sleep disorders and frequent non-motor manifestations are commonly comorbid with SCA. To elucidate this relationship, we present three cases in a family that included multiple SCA type 2 patients with various sleep disorders. Complete physical examination, and genetic and imaging studies were performed. Anti-parkinsonism medications were prescribed after neurological examination. Clonazepam and/or quetiapine were administered for sleep disorders but failed to resolve insomnia and excessive daytime sleepiness (EDS). Based on DSM-5 criteria, all cases were diagnosed with depression. After treatment with serotonin-norepinephrine reuptake inhibitors and noradrenergic and specific serotonergic antidepressants, symptoms of insomnia and EDS, which are strongly associated with depression in SCA type 2 patients, improved significantly. It is crucial to recognize insomnia and EDS in neurodegenerative diseases, not only for earlier diagnosis, but also to improve quality of life. Keywords: spinocerebellar ataxia, insomnia, excessive daytime sleepiness, sleep disorders, depression Citation: Hsu CH, Chen YL, Pei D, Yu SM, Liu IC. Depression as the primary cause of insomnia and excessive daytime sleepiness in a family with multiple cases of spinocerebellar ataxia. J Clin Sleep Med 2016;12(7):1059–1061.
I N T RO D U C T I O N
R E P O R T O F CAS E
Spinocerebellar ataxia (SCA) is a hereditary degenerative disease characterized by central nervous system-related motor dysfunctions. SCA is rare, with prevalence estimates of 1.0 to 4.0 per 100,000 in general adult populations worldwide.1 There are several types of SCA, with almost 30 different gene loci; the most common forms are SCA type 1, 2, 3, and 6.1 SCA type 2, which accounts for approximately 15% of SCA cases, is diagnosed using molecular genetic testing and characterized by an abnormal CAG trinucleotide repeat expansion in ATXN2.2 Ataxin-2, the protein encoded by the ATXN2 gene, contains a polyglutamine tract near the N-terminal region, long expansions (greater than 33 repeats) of which result in SCA type 2.2 Motor dysfunction in SCA is characterized by a progressive incoordination of gait, hand, speech, and eye movements. Frequent non-motor manifestations have been observed, including cognitive impairment, psychosis, depression, and sleep disorders in SCA type 2.1 We present multiple cases of SCA type 2 comorbid with various sleep disorders, mainly insomnia and excessive daytime sleepiness (EDS), in members of a single family. After careful examination and both nonpharmacologic and pharmacologic treatments, depression was found to be the primary cause of insomnia and EDS.
We report findings in a family originally from Chia-Yi, Taiwan, with a history of SCA type 2. To date, 14 patients have been recognized in the 4-generation family pedigree, and 5 of them lived in the same nursing home (Figure 1). Two of these patients died due to aspiration pneumonia prior to this case study. The other 3 probands are described here and henceforth referred to as Case 1, Case 2, and Case 3. Their clinical and genetic characteristics are described in Table 1. Case 1 and 3 also had a history of multiple instances of hospitalization due to pneumonia, and both had received nasogastric tube feeding. Case 2 had no other systemic diseases. Complete physical examination and imaging studies were performed. Neurological examination was carried out by a neurologist, who implemented the Scale for the Assessment and Rating of Ataxia, Inventory of Non-Ataxia Signs, and Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale. All cases presented with parkinsonism, and levodopa + benserazide (Madopar) with/without ropinirole (Requip) was prescribed. Brain magnetic resonance imaging revealed bilateral cerebellar atrophy. Brain perfusion single-photon emission computed tomography showed hypoperfusion in the vermis and bilateral frontal and parietal lobes, which is suggestive of cerebellar and
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Journal of Clinical Sleep Medicine, Vol. 12, No. 7, 2016
CH Hsu, YL Chen, D Pei et al. Depression Causing Insomnia and EDS in SCA
Figure 1—Genogram.
Men are represented by squares and women by circles. A total of 14 cases of spinocerebellar ataxia were recognized in the four-generation family pedigree. The probands with sleep disorders are indicated by arrowheads. They were labeled as Case 1, Case 2, and Case 3, respectively. All three experienced insomnia and excessive daytime sleepiness, and depression was found to be the primary cause.
Table 1—Clinical and genetic characteristics of the study subjects. Case 1
Case 2
Case 3
60 45 male
33 29 female
46 38 male
Genetic data CAG repeat number
35
38
36
Neurological examination SARA INAS count MDS-UPDRS
16 6 18
8 3 12
13 5 16
Psychological examination Depression Cognitive impairment Psychosis
Y Y Y
Y N N
Y Y Y
Y Y (14) N N Y N
Y Y (10) N N Y N
Y Y (13) Y Y Y N
Clinical data Age Age of onset Sex
Sleep disorders Insomnia EDS (ESS score)* RLS/WED RBD Snoring Sleep apnea
Accordingly, clonazepam (Rivotril) 0.5–2 mg and/or quetiapine (Seroquel) 25–100 mg at bedtime were administered, but failed to address insomnia; EDS also remained. A psychiatrist was consulted, and all cases were diagnosed with depression based on DSM-5 criteria. After treatment with duloxetine (Cymbalta) 30 mg or venlafaxine (Effexor) 75 mg twice daily with/without mirtazapine (Remeron) 30 mg at bedtime, insomnia and EDS improved significantly. D I SCUS S I O N
*Excessive daytime sleepiness was determined by the Epworth Sleepiness Scale, using a cutoff value of 10, and the scores are shown in parentheses. SARA, Scale for the Assessment and Rating of Ataxia; INAS, Inventory of Non-Ataxia Signs; MDS-UPDRS, Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale; EDS, Excessive Daytime Sleepiness; ESS, Epworth Sleepiness Scale; RLS/WED, Restless legs syndrome/Willis-Ekbom disease; RBD, Rapid Eye Movement Sleep Behavior Disorder; Y, present; N, not present.
frontal-parietal cortical degeneration. Electrophysiology revealed no evidence of polyneuropathy. Sleep disorders were present in all cases. Insomnia symptoms were determined by clinical interview. EDS was evaluated by the Epworth Sleepiness Scale, using a cutoff value of 10.3 Polysomnography revealed snoring without sleep apnea in all cases. Restless legs syndrome/Willis-Ekbom disease (RLS/ WED) and rapid eye movement sleep behavior disorder (RBD) were detected in Case 3. Symptoms of psychosis, such as nocturnal hallucinations, were experienced by Cases 1 and 3. Journal of Clinical Sleep Medicine, Vol. 12, No. 7, 2016
We report three cases of SCA type 2 from the same family. Depression was found to be the primary cause of insomnia and EDS. The scarcity of sleep data from SCA patients has limited the evaluation of the prevalence and causes of sleep disorders. The European integrated project on SCA (EUROSCA) natural history study, a multicenter longitudinal cohort study of 526 patients with SCA type 1, 2, 3, or 6, found that degenerative cerebellar diseases tend to be associated with depressive symptoms. Estimated prevalence of depression was 17.1% according to the Patient Health Questionnaire algorithm and 15.4% when assessed clinically.4 We diagnosed depression using DSM-5 criteria and by measuring the effectiveness of antidepressants. There are strong interrelationships between insomnia, EDS, and depression. Insomnia could be a precursor, symptom, residual symptom, or side effect of depression or its treatment.5 In the current report, symptoms of insomnia and EDS improved after pharmacological treatment of depression. Therefore, we suggest that insomnia and EDS were symptoms of depression. It is worth noting that the onset of SCA in this family occurred at an earlier age in later generations. An earlier age of onset and more severe disease manifestations in offspring is called anticipation. The tendency of the ATXN2 CAG repeat to expand as it is transmitted provides a biological explanation for this phenomenon.2 The presence of early symptoms in patients with SCA stresses the need for careful screening. In particular, insomnia and EDS may represent major diagnostic clues for the presence of SCA. Psychological features and sleep disorders differed among the three cases. For instance, Case 1 and 3 had cognitive impairment and psychosis, probably because they had longer disease durations than Case 2. The frequency of cognitive
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CH Hsu, YL Chen, D Pei et al. Depression Causing Insomnia and EDS in SCA
impairment was approximately 25.9% in patients with SCA type 2 in the EUROSCA study.1 Case 3 had RLS/WED and RBD, the mechanism of which may be secondary to the intrinsic cerebellar dysfunction. RLS/WED has been reported in 18% to 27% of patients with SCA type 2, compared with 2% to 5% in the general population.6 In conclusion, insomnia and EDS in SCA type 2 are highly associated with depression. It is crucial to recognize these symptoms in neurodegenerative diseases, not only to make an earlier diagnosis, but also to improve quality of life.
2. Pulst SM. Spinocerebellar Ataxia Type 2. 1998 Oct 23 [Updated 2015 Nov 12]. In: Pagon RA AM, Ardinger HH, et al., eds. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2015. Available from: http:// www.ncbi.nlm.nih.gov/books/NBK1275/. 3. Johns MW A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14:540–5. 4. Schmitz-Hubsch T, Coudert M, Tezenas du Montcel S, et al. Depression comorbidity in spinocerebellar ataxia. Mov Disord 2011;26:870–6. 5. Fava M. Daytime sleepiness and insomnia as correlates of depression. J Clin Psychiatry 2004;65 Suppl 16:27–32. 6. Pedroso JL, Braga-Neto P, Felicio AC, et al. Sleep disorders in cerebellar ataxias. Arq Neuropsiquiatr 2011;69:253–7.
SUBM I SSI O N & CO R R ESPO NDENCE I NFO R M ATI O N
A B B R E V I AT I O N S
Submitted for publication July, 2015 Submitted in final revised form March, 2016 Accepted for publication March, 2016 Address correspondence to: I-Chao Liu, Department of Psychiatry, Shuang Ho Hospital, No. 291, Zhongzheng Rd., Zhonghe District, New Taipei City 23561, Taiwan (R.O.C.); Tel: +886 2 22490088; Fax: +886 2 22480900; Email: [email protected]
EDS, excessive daytime sleepiness EUROSCA, European integrated project on spinocerebellar ataxia RBD, rapid eye movement sleep behavior disorder RLS/WED, restless legs syndrome/Willis-Ekbom disease SCA, spinocerebellar ataxia
D I SCLO S U R E S TAT E M E N T This was not an industry supported study. The authors have indicated no financial conflicts of interest.
R E FE R E N CES 1. Schmitz-Hubsch T, Coudert M, Bauer P, et al. Spinocerebellar ataxia types 1, 2, 3, and 6: disease severity and nonataxia symptoms. Neurology 2008;71:982–9.
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CAS E R EPOR T S
Depression as the Primary Cause of Insomnia and Excessive Daytime Sleepiness in a Family with Multiple Cases of Spinocerebellar Ataxia Chun-Hsien Hsu, MD1; Yen-Lin Chen, MD2; Dee Pei, MD3; Shu-Man Yu, MD, MPH1; I-Chao Liu, MD, DSc 4,5 Department of Family Medicine, Cardinal Tien Hospital, School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 2Department of Pathology, Cardinal Tien Hospital, School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 3Department of Internal Medicine, Cardinal Tien Hospital, School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 4Department of Psychiatry, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; 5Department of Psychiatry, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 1
Spinocerebellar ataxia (SCA) is a hereditary disease characterized by central nervous system-related motor dysfunctions. Sleep disorders and frequent non-motor manifestations are commonly comorbid with SCA. To elucidate this relationship, we present three cases in a family that included multiple SCA type 2 patients with various sleep disorders. Complete physical examination, and genetic and imaging studies were performed. Anti-parkinsonism medications were prescribed after neurological examination. Clonazepam and/or quetiapine were administered for sleep disorders but failed to resolve insomnia and excessive daytime sleepiness (EDS). Based on DSM-5 criteria, all cases were diagnosed with depression. After treatment with serotonin-norepinephrine reuptake inhibitors and noradrenergic and specific serotonergic antidepressants, symptoms of insomnia and EDS, which are strongly associated with depression in SCA type 2 patients, improved significantly. It is crucial to recognize insomnia and EDS in neurodegenerative diseases, not only for earlier diagnosis, but also to improve quality of life. Keywords: spinocerebellar ataxia, insomnia, excessive daytime sleepiness, sleep disorders, depression Citation: Hsu CH, Chen YL, Pei D, Yu SM, Liu IC. Depression as the primary cause of insomnia and excessive daytime sleepiness in a family with multiple cases of spinocerebellar ataxia. J Clin Sleep Med 2016;12(7):1059–1061.
I N T RO D U C T I O N
R E P O R T O F CAS E
Spinocerebellar ataxia (SCA) is a hereditary degenerative disease characterized by central nervous system-related motor dysfunctions. SCA is rare, with prevalence estimates of 1.0 to 4.0 per 100,000 in general adult populations worldwide.1 There are several types of SCA, with almost 30 different gene loci; the most common forms are SCA type 1, 2, 3, and 6.1 SCA type 2, which accounts for approximately 15% of SCA cases, is diagnosed using molecular genetic testing and characterized by an abnormal CAG trinucleotide repeat expansion in ATXN2.2 Ataxin-2, the protein encoded by the ATXN2 gene, contains a polyglutamine tract near the N-terminal region, long expansions (greater than 33 repeats) of which result in SCA type 2.2 Motor dysfunction in SCA is characterized by a progressive incoordination of gait, hand, speech, and eye movements. Frequent non-motor manifestations have been observed, including cognitive impairment, psychosis, depression, and sleep disorders in SCA type 2.1 We present multiple cases of SCA type 2 comorbid with various sleep disorders, mainly insomnia and excessive daytime sleepiness (EDS), in members of a single family. After careful examination and both nonpharmacologic and pharmacologic treatments, depression was found to be the primary cause of insomnia and EDS.
We report findings in a family originally from Chia-Yi, Taiwan, with a history of SCA type 2. To date, 14 patients have been recognized in the 4-generation family pedigree, and 5 of them lived in the same nursing home (Figure 1). Two of these patients died due to aspiration pneumonia prior to this case study. The other 3 probands are described here and henceforth referred to as Case 1, Case 2, and Case 3. Their clinical and genetic characteristics are described in Table 1. Case 1 and 3 also had a history of multiple instances of hospitalization due to pneumonia, and both had received nasogastric tube feeding. Case 2 had no other systemic diseases. Complete physical examination and imaging studies were performed. Neurological examination was carried out by a neurologist, who implemented the Scale for the Assessment and Rating of Ataxia, Inventory of Non-Ataxia Signs, and Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale. All cases presented with parkinsonism, and levodopa + benserazide (Madopar) with/without ropinirole (Requip) was prescribed. Brain magnetic resonance imaging revealed bilateral cerebellar atrophy. Brain perfusion single-photon emission computed tomography showed hypoperfusion in the vermis and bilateral frontal and parietal lobes, which is suggestive of cerebellar and
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Journal of Clinical Sleep Medicine, Vol. 12, No. 7, 2016
CH Hsu, YL Chen, D Pei et al. Depression Causing Insomnia and EDS in SCA
Figure 1—Genogram.
Men are represented by squares and women by circles. A total of 14 cases of spinocerebellar ataxia were recognized in the four-generation family pedigree. The probands with sleep disorders are indicated by arrowheads. They were labeled as Case 1, Case 2, and Case 3, respectively. All three experienced insomnia and excessive daytime sleepiness, and depression was found to be the primary cause.
Table 1—Clinical and genetic characteristics of the study subjects. Case 1
Case 2
Case 3
60 45 male
33 29 female
46 38 male
Genetic data CAG repeat number
35
38
36
Neurological examination SARA INAS count MDS-UPDRS
16 6 18
8 3 12
13 5 16
Psychological examination Depression Cognitive impairment Psychosis
Y Y Y
Y N N
Y Y Y
Y Y (14) N N Y N
Y Y (10) N N Y N
Y Y (13) Y Y Y N
Clinical data Age Age of onset Sex
Sleep disorders Insomnia EDS (ESS score)* RLS/WED RBD Snoring Sleep apnea
Accordingly, clonazepam (Rivotril) 0.5–2 mg and/or quetiapine (Seroquel) 25–100 mg at bedtime were administered, but failed to address insomnia; EDS also remained. A psychiatrist was consulted, and all cases were diagnosed with depression based on DSM-5 criteria. After treatment with duloxetine (Cymbalta) 30 mg or venlafaxine (Effexor) 75 mg twice daily with/without mirtazapine (Remeron) 30 mg at bedtime, insomnia and EDS improved significantly. D I SCUS S I O N
*Excessive daytime sleepiness was determined by the Epworth Sleepiness Scale, using a cutoff value of 10, and the scores are shown in parentheses. SARA, Scale for the Assessment and Rating of Ataxia; INAS, Inventory of Non-Ataxia Signs; MDS-UPDRS, Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale; EDS, Excessive Daytime Sleepiness; ESS, Epworth Sleepiness Scale; RLS/WED, Restless legs syndrome/Willis-Ekbom disease; RBD, Rapid Eye Movement Sleep Behavior Disorder; Y, present; N, not present.
frontal-parietal cortical degeneration. Electrophysiology revealed no evidence of polyneuropathy. Sleep disorders were present in all cases. Insomnia symptoms were determined by clinical interview. EDS was evaluated by the Epworth Sleepiness Scale, using a cutoff value of 10.3 Polysomnography revealed snoring without sleep apnea in all cases. Restless legs syndrome/Willis-Ekbom disease (RLS/ WED) and rapid eye movement sleep behavior disorder (RBD) were detected in Case 3. Symptoms of psychosis, such as nocturnal hallucinations, were experienced by Cases 1 and 3. Journal of Clinical Sleep Medicine, Vol. 12, No. 7, 2016
We report three cases of SCA type 2 from the same family. Depression was found to be the primary cause of insomnia and EDS. The scarcity of sleep data from SCA patients has limited the evaluation of the prevalence and causes of sleep disorders. The European integrated project on SCA (EUROSCA) natural history study, a multicenter longitudinal cohort study of 526 patients with SCA type 1, 2, 3, or 6, found that degenerative cerebellar diseases tend to be associated with depressive symptoms. Estimated prevalence of depression was 17.1% according to the Patient Health Questionnaire algorithm and 15.4% when assessed clinically.4 We diagnosed depression using DSM-5 criteria and by measuring the effectiveness of antidepressants. There are strong interrelationships between insomnia, EDS, and depression. Insomnia could be a precursor, symptom, residual symptom, or side effect of depression or its treatment.5 In the current report, symptoms of insomnia and EDS improved after pharmacological treatment of depression. Therefore, we suggest that insomnia and EDS were symptoms of depression. It is worth noting that the onset of SCA in this family occurred at an earlier age in later generations. An earlier age of onset and more severe disease manifestations in offspring is called anticipation. The tendency of the ATXN2 CAG repeat to expand as it is transmitted provides a biological explanation for this phenomenon.2 The presence of early symptoms in patients with SCA stresses the need for careful screening. In particular, insomnia and EDS may represent major diagnostic clues for the presence of SCA. Psychological features and sleep disorders differed among the three cases. For instance, Case 1 and 3 had cognitive impairment and psychosis, probably because they had longer disease durations than Case 2. The frequency of cognitive
1060
CH Hsu, YL Chen, D Pei et al. Depression Causing Insomnia and EDS in SCA
impairment was approximately 25.9% in patients with SCA type 2 in the EUROSCA study.1 Case 3 had RLS/WED and RBD, the mechanism of which may be secondary to the intrinsic cerebellar dysfunction. RLS/WED has been reported in 18% to 27% of patients with SCA type 2, compared with 2% to 5% in the general population.6 In conclusion, insomnia and EDS in SCA type 2 are highly associated with depression. It is crucial to recognize these symptoms in neurodegenerative diseases, not only to make an earlier diagnosis, but also to improve quality of life.
2. Pulst SM. Spinocerebellar Ataxia Type 2. 1998 Oct 23 [Updated 2015 Nov 12]. In: Pagon RA AM, Ardinger HH, et al., eds. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2015. Available from: http:// www.ncbi.nlm.nih.gov/books/NBK1275/. 3. Johns MW A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14:540–5. 4. Schmitz-Hubsch T, Coudert M, Tezenas du Montcel S, et al. Depression comorbidity in spinocerebellar ataxia. Mov Disord 2011;26:870–6. 5. Fava M. Daytime sleepiness and insomnia as correlates of depression. J Clin Psychiatry 2004;65 Suppl 16:27–32. 6. Pedroso JL, Braga-Neto P, Felicio AC, et al. Sleep disorders in cerebellar ataxias. Arq Neuropsiquiatr 2011;69:253–7.
SUBM I SSI O N & CO R R ESPO NDENCE I NFO R M ATI O N
A B B R E V I AT I O N S
Submitted for publication July, 2015 Submitted in final revised form March, 2016 Accepted for publication March, 2016 Address correspondence to: I-Chao Liu, Department of Psychiatry, Shuang Ho Hospital, No. 291, Zhongzheng Rd., Zhonghe District, New Taipei City 23561, Taiwan (R.O.C.); Tel: +886 2 22490088; Fax: +886 2 22480900; Email: [email protected]
EDS, excessive daytime sleepiness EUROSCA, European integrated project on spinocerebellar ataxia RBD, rapid eye movement sleep behavior disorder RLS/WED, restless legs syndrome/Willis-Ekbom disease SCA, spinocerebellar ataxia
D I SCLO S U R E S TAT E M E N T This was not an industry supported study. The authors have indicated no financial conflicts of interest.
R E FE R E N CES 1. Schmitz-Hubsch T, Coudert M, Bauer P, et al. Spinocerebellar ataxia types 1, 2, 3, and 6: disease severity and nonataxia symptoms. Neurology 2008;71:982–9.
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