Journal of Attention Disorders

Journal ofhttp://jad.sagepub.com/ Attention Disorders

A Retrospective Survey of Childhood ADHD Symptomatology Among Adult Narcoleptics Edward J. Modestino and Jeanna Winchester Journal of Attention Disorders 2013 17: 574 originally published online 2 April 2013 DOI: 10.1177/1087054713480033 The online version of this article can be found at: http://jad.sagepub.com/content/17/7/574

Published by: http://www.sagepublications.com

Additional services and information for Journal of Attention Disorders can be found at: Email Alerts: http://jad.sagepub.com/cgi/alerts Subscriptions: http://jad.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav Citations: http://jad.sagepub.com/content/17/7/574.refs.html

>> Version of Record - Sep 10, 2013 OnlineFirst Version of Record - Apr 11, 2013 OnlineFirst Version of Record - Apr 10, 2013 OnlineFirst Version of Record - Apr 2, 2013 What is This?

Downloaded from jad.sagepub.com at US DEPT OF VETERAN AFFAIRS on September 11, 2013

480033

research-article2013

JADXXX10.1177/1087054713480033Journal of Attention DisordersModestino and Winchester

Special Section on Sleep and ADHD

A Retrospective Survey of Childhood ADHD Symptomatology Among Adult Narcoleptics

Journal of Attention Disorders 17(7) 574–582 © 2013 SAGE Publications Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1087054713480033 jad.sagepub.com

Edward J. Modestino1,2,3 and Jeanna Winchester4

Abstract Objective: This study examined the retrospective history of childhood ADHD symptomatology in an adult narcoleptic population (Narcolepsy Group [NG]: n = 161) compared with a control group (CG: n = 117). Method: Both groups completed the Wender Utah Rating Scale (WURS), a retrospective self-report questionnaire indicating the presence of childhood ADHD symptomatology in adults. Results: Childhood ADHD symptoms were significantly greater in NG than CG (p < .001). Joint prevalence calculations of childhood ADHD symptomatology in NG were more than 8 to 15 times greater than expected. Among NG, those individuals with a greater score on the WURS, indicative of childhood ADHD symptomatology, also had shorter sleep onsets on the Multiple Sleep Latency Test, a common objective measure of sleepiness, t(97) = −7.11, p < .05. Conclusion: It appears that self-reported childhood ADHD symptomatology history among adult narcoleptics is common. Future research is warranted with adult narcoleptics to elucidate the true nature of this. (J. of Att. Dis. 2013; 17(7) 574-582) Keywords ADHD, narcolepsy, hypersomnia, comorbidity, WURS

The stereotype of ADHD is a hyperactive child (Gajaria, Yeung, Goodale, & Charach, 2011); whereas narcoleptics are often viewed as sleepy and/or underactive adults (Stores, 2009). However, significant research over the past 20 years has revealed that ADHD is not always outgrown. Many adults with a childhood history of ADHD still suffer from it (Coogan et al., 2012). Furthermore, studies of narcolepsy have shown it often first emerges in childhood or adolescence (Nevsimalova, 2009). The misconception of ADHD as being synonymous with hypervigilance and at the opposite end of the vigilance spectrum from disorders of hypovigilance, such as narcolepsy, appears to be incorrect. ADHD and these disorders of hypovigilance (i.e., narcolepsy and hypersomnia) appear to be closely related to one another (Brumback, 2000). In fact, those with ADHD may be underaroused and hypovigilant; hyperactivity in such people with ADHD may be a coping mechanism or an attempt to arouse a hypovigilant state. Stimulant medications may in fact wake the sleeping brains of those with ADHD and thus, the hyperactivity and inattention subsides (Brown & McMullen, 2001). Finally, there has been recent evidence that adults with a diagnosis of narcolepsy may have a history of ADHD (Nevsimalova, 2009; Walters, Silvestri, Zucconi, Chandrashekariah, & Konofal, 2008). The literature that shows a clinical overlap between ADHD and narcolepsy/hypersomnia is extensive. In some cases, the connection between ADHD and disorders of

hypovigilance (narcolepsy and hypersomnia) is ignored, believed to be pure coincidence and/or due to misdiagnosis (Dahl, Holttum, & Trubnick, 1994; Gau et al., 2007; Kotagal & Swink, 1996; Mohsenin, 2009; Navelet, Anders, & Guilleminault, 1976; Oosterloo, Lammers, Overeem, de Noord, & Kooij, 2006). Another body of literature has suggested that there is an authentic overlap of diagnoses and clinical symptomatology. Perhaps this first clinical connection between these disorders was published by Yoss (1970). One child (age 9) had a diagnosis of hyperkinesis (ADHD) and was treated with methylphenidate. Testing of the child off his medicine revealed that he was hyperactive and inattentive with pupillographic results consistent with narcolepsy. In 1991, Duane wrote of his work with Yoss in the 1970s. He stated that his latest research showed that approximately 50% of people with ADHD had excessive daytime sleepiness and “nonalertness.” Similarly, Palm, Persson, Bjerre, Elmqvist, 1

University of Virginia Health System, Charlottesville, USA Cedar Creek Institute, Charlottesville, VA, USA 3 Atlantic University, Virginia Beach, VA, USA 4 University of California Irvine, USA 2

Corresponding Author: Edward J. Modestino, Atlantic University, 215 67th Street, Virginia Beach, VA 23451, USA. Email: [email protected]


575

Modestino and Winchester and Blennow (1992) reported that a subgroup of their study of children with ADHD had hypersomnia. In addition, Chiang et al. (2010) found that a subtype of ADHD, ADHD-I (predominantly inattentive type), was associated with a comorbid diagnosis of hypersomnia. Furthermore, Drake, Hietter, Bogner, and Andrews (1992) and Allen, Singer, Brown, and Salam (1992) reported about a group of individuals with ADHD and comorbid Tourette’s syndrome. Apparently, these individuals manifest a disorder of hypoarousal or underalertness, which the authors attribute to combined ADHD and Tourette’s syndrome. Finally, some researchers have suggested an entirely new syndrome combining symptoms of both ADHD and narcolepsy/hypersomnia. Warren Weinberg (Weinberg & Brumback, 1990) presented a new disorder, Primary Disorder of Vigilance (PDV) which consists of all three ADHD core symptoms: inattentiveness, impulsivity, and hyperactivity, combined with narcolepsy symptoms, such as daytime sleepiness and sleep attacks. He claimed that most of his patients with PDV do not have narcolepsy or hypersomnia. However, the patients in this case study did not have adequate testing to rule out the diagnosis of narcolepsy or hypersomnia. In 1993, Weinberg and another colleague (Weinberg & Harper, 1993) published a second article about PDV. They recounted that sufferers are hyperactive (constantly in motion) in an attempt to force themselves to stay awake and alert. This article includes a reprint of the very same six case studies from the previous article. Interestingly, in this publication, the authors state that they have seen several children with both PDV (ADHD) and narcolepsy. Similarly, Sultan, Bertrim, Kimoff, and Baltzan (1998) coined Syndrome Z. This syndrome consists of a combination of a Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association [APA], 1994) diagnosis of ADHD, excessive daytime somnolence (EDS), Rapid Eye Movement (REM) behavioral disorder, and other comorbidities. Only one half were given the blood test for human leukocyte antigen (HLA)-DR2. Significantly, one third of the participants had cataplexy. This abstract shows a group of 28 patients within which 86% had a diagnosis of ADHD with EDS. This clearly represents a link between ADHD and the narcolepsy/hypersomnia symptomatology. In this study, it was proposed to discover whether there was a link between patients’ clinical history, perhaps undiagnosed, of ADHD (core symptoms: inattentiveness, impulsivity, and hyperactivity; Diagnostic and Statistical Manual of Mental Disorders [4th ed., text rev.; DSM-IV-TR; APA, 2000]), based on their retrospective self-report on the Wender Utah Rating Scale (WURS), and their subsequent development of narcolepsy (a core symptom of irresistible daytime sleep attacks, but may include cataplexy, sleep paralysis, sleep-onset REM, and hypnopompic and hypnogogic hallucinations [DSM-IV-TR; APA, 2000], and is often associated with genetic markers such as the broad antigen

serotype HLA-DR2 and the allele HLA-DQB1*0602; Mignot, 1998). The cohort was drawn from the National Narcolepsy Registry (NNR), a group of narcoleptics. All registrants were sent an unlabeled (and were thus blind to the true purpose) inventory scale for retrospective childhood history of ADHD. In addition, a control group (CG) of normals, screened to rule out a diagnosis of or history of ADHD, was collected for comparison. We hypothesized that there would be significant childhood ADHD symptomatology in the self-reported history of adult narcoleptics (from the WURS), that this would be significantly greater than in the CG, and that there may be a connection between WURS score, indicative of childhood ADHD, and the various objective measures we had from the NNR (i.e., Multiple Sleep Latency Test [MSLT], HLA-DR2, HLA-DQB1*0602, etc.) for the narcoleptics. If such an association exists between childhood ADHD symptomatology and adult narcolepsy, treatment of individuals with ADHD may change. This could be prompted by the realization that most people do not outgrow ADHD, and that a subgroup of these individuals may be more likely to develop narcolepsy or its atypical variant hypersomnia. This may require lifelong treatment. Furthermore, undiagnosed childhood ADHD may obscure this issue. Thus, early intervention can only occur with proper screening. From the perspective of an abnormal neurological development, a subtype of ADHD may in fact be the early stages in a progressive neurological syndrome that ultimately manifests in disorders of hypovigilance such as hypersomnia or the extreme phenotype narcolepsy.

Method Participants Two groups of adults, narcoleptics plus controls (N = 281), were recruited for this study’s protocols. Recruitment procedures for each group are detailed below. Recruitment and experimental protocols were approved by the Institutional Review Board (IRB) of the University of Pennsylvania and the National Sleep Foundation, for data collection related to the narcoleptic group. The IRB for the University of Utah Health Sciences Center approved data related to collection of the CG. All protocols were in compliance with Health Insurance Portability and Accountability Act (HIPPA), the Helsinki Declaration of 1975, the Belmont Report, and the minimum standards set by 45 Code of Federal Regulations (CFR) 46 of the Department of Health & Human Services and 21 CFR 50/21 CFR 56 of the Food and Drug Administration.

NG A population of adults, ranging in age from 18 to 86, who had been previously diagnosed with narcolepsy (n = 161;


576

Journal of Attention Disorders 17(7)

M age = 49.68 ± 16.64) was sampled for this study’s protocols and comprised the NG. This group included 109 female (M age = 49.52 ± 15.51) and 52 male adults (M age = 54.09 ± 18.12), who were recruited anonymously from the National Sleep Foundation’s NNR (refer to the next section, “Recruitment Procedures for the NNR,” for more details) between the years 1998 and 1999. Gender was not a factor that was specifically controlled in this study. Therefore, the gender distribution of NG represents the natural distribution of male and female respondents to the recruitment materials detailed in the next section.

Recruitment Procedures for the NNR Prior to this study’s initiation, the NNR gathered data related to variables that may describe, diagnose, and/or give insight into the symptoms of those living with narcolepsy. This section is a description of those earlier procedures, which were separate from this study’s methods used by the lead investigator (the first author) that will be elaborated on further in the subsequent “Recruitment Procedures of NG” section. The NNR was a component of the National Sleep Foundation’s “Towards the Cause of Narcolepsy” program, which aimed to increase public awareness of narcolepsy through educational materials and research. Although the recruitment of new data for this registry has ceased, the NNR is currently housed at Stanford University. The NNR made initial contact with the population via telephone screenings. During this initial screening, either the patient or the patient’s caregiver registered the patient with the NNR and gave verbal consent to receive additional written information pertaining to the registry’s data recruitment protocols. On receiving these materials, the registrants provided information pertaining to demographic, medical, and general information (see “Recruitment Procedures of NG” section below for more information about this study’s questionnaire). This packet of information was returned via prepaid standard mail provided by the NNR. Consent to continue participation in the registry was implied on returning the completed packets of medical information to the registry. Registrants and their medical providers provided medical reports including a formal diagnosis of narcolepsy, supplementary information such as full medical history, family medical history, and diagnostic test reports, including an overnight sleep lab polysomnography, the MSLT, and serum blood tests for HLA genetic markers for narcolepsy (HLA-DR2 and HLA-DQB1*0602). This information was available for use in this study.

Recruitment Procedures for the NG The lead investigator worked with the NNR to make materials for the current protocol available to the NNR registrants. To that end, the NNR requested 1,000 copies of the questionnaire to be used in this study, the WURS unlabeled and

a study-specific cover letter which informed the registrants that this study would ask them questions about nonspecific childhood symptoms they may or may not have experienced.1 This cover letter also provided the registrants with information about the lead investigator and IRB approval; specifically, patients were instructed to return the questionnaires to the lead investigator, and that this act implied consent to participate in the study. The lead investigator provided the NNR with 1,000 prestamped envelopes to send to registrants along with prestamped self-addressed return envelopes allowing the registrants to mail the questionnaires directly back to the lead investigator.2 The NNR generated address labels for registrants and collated the questionnaires (adding in registrant numbers to the bottom of the questionnaire allowing for subsequent access to the database medical information, including genetic markers and objective test findings, specific to those who responded), the letters, and return envelopes, before mailing them to registrants. No identifiable patient information was made available to the investigators by the NNR, and the NNR maintained strict confidentiality regarding the names and addresses of the registrants. The questionnaire, the study-specific cover letter, and the NNR cover letter were mailed to the NNR registrants. Inclusion in NG occurred for adults older than 18, who were registrants of the NNR and returned a WURS questionnaire that could be scored.

CG Data for the CG (n = 120; M age = 34.74 ± 8.59) consisted of 60 female (M age = 34.18 ± 8.97) and 60 male adults (M age = 35.30 ± 8.24) between the ages of 22 and 54. This was sampled for the purpose of this study by the University of Utah Health Science Center’s Mood Disorders Clinic staff. (Recruitment procedures for this data set are detailed in the next section.) Gender was not a factor that was specifically controlled in this study and therefore, the gender distribution of CG represents the fact that the data set from which the CG was sampled had an equal number of male and female respondents. The recruitment procedures carried out earlier by the University of Utah, for this study, are detailed in the next section.

Recruitment Procedures for the CG at the University of Utah For this study, the University of Utah Health Science Center’s Mood Disorders Clinic gathered normative data on adult couples who did not have ADHD. This section is a description of those procedures, which were separate from the methods previously described above. One third of the participants were recruited at the University of Utah via posters. Two thirds were recruited via local church groups (n ~ 67% of population) throughout the Lincoln, Nebraska,


577

Modestino and Winchester

Figure 1. Flow diagram summarizing population recruitment procedures. Note: WURS = Wender Utah Rating Scale.

area between 2006 and 2009. Telephone screenings were conducted to determine eligibility before setting up a faceto-face appointment. Inclusion and exclusion criteria are detailed below. After data collection was completed, it was discovered that one patient was diagnosed with Multiple Sclerosis (MS) and was receiving the treatment Adderall (a stimulant commonly prescribed for ADHD). In addition, one female and one male adult had probable ADHD. To be conservative, the patient with a neurological degenerative disorder of MS and the two individuals with probable ADHD were removed, resulting in a final population of CG n = 117. To be included in CG, participants needed to be adults between the ages of 20 and 50. In addition, they needed to be able to read and write at a level sufficient to provide written informed consent, and to be capable of completing the WURS questionnaire. Potential participants were excluded from CG if they had a child currently being treated for ADHD, or if they themselves have had a childhood history of ADHD, Oppositional Defiant Disorder, or Conduct Disorder, using DSM-IV-TR criteria. Additionally, they were excluded if they had had a DSM-IV Axis I disorder within the last three months and/or received treatment for a psychotic or unstable psychiatric condition. One exception was that participants could be on an antidepressant if the depressive symptoms were in remission. Finally, exclusion could occur if the participant had a history of hospitalization or treatment for a psychotic disorder or were currently being

treated for a medical problem that would interfere in participating in the interview. Figure 1 is a flow diagram summarizing the recruitment steps and population.

Questionnaire: WURS The WURS is a previously validated 61-item self-report questionnaire. This questionnaire aims to retrospectively elucidate childhood symptoms of ADHD in adults. Previous validity and reliability assessments have indicated that a 25-item subset of the WURS’s questions was sufficient for accurately identifying childhood history of ADHD in adults, with scores of 36 or greater correctly identifying 96% of adults with ADHD and excluding 96% of normals (Rossini & O’Connor, 1995; Ward, Wender, & Reimherr, 1993). In addition, a cutoff score of 46 points or higher on the WURS has been shown to be 86% accurate in identifying childhood ADHD symptoms in those later diagnosed with ADHD as adults, and to be 81% accurate in excluding patients suffering from clinical depression (Ward et al., 1993). Reliability and validity of this assessment have been demonstrated in both female and male adults (Stein et al., 1995).

Cutoff Scores, Scoring Strategy, and the WURS Scores of above 36 on a subset, 25 of the 61 questions, are suggestive of childhood ADHD symptomatology. Scores of 46 or greater are consistent with childhood ADHD and rules


578


out the possibility of depression causing such symptoms (Ward et al., 1993). However, one narcoleptic registrant, a 63-year-old female, scored 33 and had an official diagnosis of ADHD (refer to Case Study 3 in appendix).3 Following the 36-or-greater cutoff, this person would have been missed. Thus, the analysis was broken up into three ADHD cutoff categories: (a) Scores of 30 or greater were termed childhood ADHD symptomatology, (b) scores of 36 or greater were termed probable childhood ADHD diagnosis, and (c) scores of 46 or higher were termed probable childhood ADHD diagnosis with depression ruled out.

Data Analysis All data materials were collected, collated, and entered into a Microsoft Excel spreadsheet for later analysis. All data were analyzed in SPSS using standard linear statistical methods, which included independent-samples t-tests. Finally, the comorbid prevalence of ADHD and narcolepsy was calculated and reported below. According to the DSMIV-TR (APA, 2000), the prevalence of ADHD is 3% to 7% in school-aged children and adulthood statistics are not known. Because childhood symptoms of ADHD are needed to make a diagnosis even among adults, the lifetime incidence rate of ADHD might be considered to be the same as the prevalence rate. However, some individuals with childhood ADHD remit. In addition, many individuals remain undiagnosed and thus, the true incidence may be even greater. According to the DSM-IV-TR, the prevalence of narcolepsy is 0.02% to 0.16% in the general population (APA, 2000). Similarly, many people are undiagnosed for years and thus, the true prevalence may even be higher. Here we used a simple calculation to look for stochastic dependence or independence of these two syndrome complexes from one another, or the random chance of person having a childhood history of ADHD and adult narcolepsy without there being a direct relationship between the two. This was accomplished by multiplying the prevalence of one disorder by the other. A percentage larger than this among this study’s population would suggest a direct relationship between childhood ADHD symptomatology and the development of adult narcolepsy.

Results All results reported below were independent of age, gender, race, and the presence of clinical depression.

Retrospective ADHD Symptomatology in NG As previously discussed in the section “Cutoff Scores, Scoring Strategy, and the WURS,” using a cutoff score of 30 for the WURS is valid for determining the presence of ADHD in this study. Interestingly, using this cutoff revealed

three female narcoleptics (1.86% out of 161 total NG), ages 46, 53, and 63, who all had comorbid official diagnoses of ADHD. Further information related to these three case studies has been provided in the appendix. Results from each of the three cutoff score categories (scores of 30 or greater, 36 or greater, and 46 or greater) for NG are reported here. Individuals who had a WURS score of 30 or greater, indicating the presence of childhood ADHD symptomatology, made up 37.88% (or 61 out of 161 NG) of the total NG population, with 35.77% (or 39 out of 109 NG) female and 42.3% male adults (or 22 out of 52 NG). Individuals with a WURS score of 36 or greater, indicating the presence of probable childhood ADHD made up 25.46% of the total NG population (or 41 out of 161 NG), with 24.77% (or 27 out of 109 NG) female and 26.92% male adults (or 14 out of 52 NG). Excluding the possibility of depression inflating the WURS by using a cutoff score of 46 or greater, it was noted that 12.42% of the total NG had probable childhood ADHD (or 20 out of 161 NG), with 14.67% of those being female (or 16 out of 109 NG) and 7.69% being male adults (or 4 out of 52 NG).

NG Versus CG: WURS Score As previously discussed in the section “Questionnaire: WURS”, there are 25 questions from the WURS that, when evaluated together in total, most consistently correlate with the presence of ADHD. Therefore, these 25 questions were incorporated into this study’s analyses. Comparison of the NG versus CG WURS scores, using a two-tailed independent-samples t-test with a p < .05 and assuming equal variances, revealed a significant difference, t(276) = -6.739, p < .001, with the NG being significantly greater. Without assuming equal variances, this difference was still significant, t(264.505) = −7.291, p < .001. The mean score for CG (n = 117) was 14.2051; whereas the mean score for NG (n = 161) was 25.6273. The standard error of the mean (SEM) for CG was 0.88255, whereas the SEM for NG was 1.29427. Given a 95% confidence interval determined by calculations ±1.96 × SE, we determined an upper limit of 28.16402 and a lower limit of 23.0905 for ADHD WURS score among the NG. This confidence interval does not include the CG (normal) mean, demonstrating grounds for an association between ADHD symptoms among NG.

Joint Prevalence of ADHD and Narcolepsy Details for calculating the joint prevalence of ADHD among adults with narcolepsy were provided in “Data Analysis” under “Method” Section. Following the procedures provided in that section, it was determined that the joint prevalence or co-occurrence of ADHD and narcolepsy should be far less than 1% in our group; calculation: 7 (highest ADHD prevalence percentage) × 0.16 (highest narcolepsy


579

Modestino and Winchester prevalence percentage) = 0.07 × 0.0016 = 0.000112 or 112 / 1,000,000 or 0.01%. In a random sampling of the population, one would expect the joint prevalence, or comorbidity of narcolepsy and ADHD, to be present in about 11 / 100,000 people or 112 / 1,000,000 people, if there is no relationship or interaction between these two syndromes. Therefore, it appears that these survey statistics (WURS > 30) which suggest comorbidity rates ranging from approximately 36% to 42% of this study’s NG population base are indicative of relationship between childhood ADHD symptomatology and subsequent adult narcolepsy. Using the score of 36 as a cutoff gives us a range of 25% to 27% of adult narcoleptics with probable childhood diagnoses of ADHD. Finally, using the most conservative cutoff, a score of 46 or greater, gives us a range of approximately 8% to 15% of the total narcoleptics with significant childhood ADHD symptomatology, and ruling out depression as a cause for the symptoms. This is more than 8 to 15 times greater than would be expected by chance even when using this most conservative estimate.

Prevalence of ADHD Among NG Relatives There were eight NG registrants (5 female and 3 male adults) who had first-degree relatives with diagnoses of ADHD. This included one female adult with a formal diagnosis of comorbid ADHD (refer to Case Study 2 in appendix). Another female from the NG had a half-brother diagnosed with ADHD. In total, nine out of the 161 NG (or 5.59%) had relatives with official ADHD diagnoses.

ADHD Symptomatology in NG: Not Due to Depression Some evidence suggests that the presence of depression can falsely inflate the scoring of the WURS (this topic will be elaborated on further in the “Results” section); therefore, a history of depression was examined in NG. There was a total of 17 of 161 NG (or 10.55%), who had a history of a depressive disorder. This included those with a history of diagnoses of Dysthymia, Chronic Major Depression, Bipolar Disorder, and Schizoaffective Disorder Bipolar Type. Of these 17 NG with a history of a depressive disorder, 8, or almost half of them (47.05%), or 4.96% of the total NG, had scores below the range suggestive of ADHD. The other half, or only 9 out of 161 (5.59%) of the total NG had a depressive disorder history and scored in the ADHD range (2 between 30 and 35, 3 between 36 and 45, and 4 above 46.). Furthermore, using the general linear model and a univariate analysis, it was shown that a history of depression did not correlate with one’s score on the WURS. Thus, we can assume that depression did not falsely inflate this WURS score in this study. So, scores of 36 and higher can

be taken to be indicative of a childhood diagnosis of ADHD. Furthermore, scores of 30 to 35 can be taken as indicative of significant childhood ADHD symptomatology.

Narcolepsy Genetic Markers in NG Of the 161 registrants in the NG, 70 (43.47%) were tested for HLA-DQB1*0602. This population consisted of 45 (64.28%) carriers and 25 (35.71%) HLA-DQB1*0602 noncarriers. For the HLA-DR2 marker, 32 (19.8%) of the 161 NG were tested, and 9 out of the 32 (28.12%) were carriers, along with 24 (75%) noncarriers. In total, 80 (49.68%) out of 161 were tested for HLA-DQB1*0602 and/or HLA-DR2. Among this group, 23 (14.28% NG out of 161) had data for both genotypes. Within this subgroup of 23, 6 (26.08%) individuals identified as carriers for both genetic markers, 6 (26.08%) as noncarriers for both genetic markers, and 11 (47.82%) as a carrier for only one genetic marker. Out of the total of 80 who were tested, 48 (60%) were positive as carriers for one or both markers, whereas 32 (40%) were noncarriers, who tested negative. In total, 81 out of 161 NNR registrant responders (50.31%) had no genetic testing available in the NNR database.

Narcolepsy Genetic Markers in NG and WURS Score For NG, only those individuals who were carriers for at least one of the genetic markers noted in the section “Narcolepsy Genetic Markers in NG” were included in this analysis. Here, independent-samples t-tests adjusted for unequal sample sizes were conducted, wherein the WURS score for the NG “carriers” group (n = 45) was compared with the WURS score for the NG “noncarriers” group (n = 25). The results reveal no significant difference between the carrier’s and noncarriers’ WURS score.

The MSLT and WURS Score For NG, MSLT data (in minutes) was available in n = 98 patients. For these patients, the WURS score was compared with the MSLT via independent-samples t-tests. Results from this analysis indicate that those individuals with greater WURS score had shorter MSLT, t(97) = −7.11, p < .05; mean WURS = 30.21; mean MSLT = 3.80 min.

Discussion In this study, more than 37% of all NG patients demonstrated a presence of childhood ADHD symptomatology. Comparing NG with CG, the results revealed that NG had significantly greater WURS scores than CG. Joint prevalence rates indicated a comorbid presence of ADHD history


580


and narcolepsy, using the most conservative estimate (WURS > 46) at 8% to 15% of the NG. This joint prevalence was shown to be more than 8 to 15 times greater than what would be expected if there was no connection. In addition, previous evidence suggested that patients with depression might have inflated WURS scores (e.g., Ward et al., 1993). A major strength of the current study is that we were able to show that none of the WURS scores in our data were significantly inflated by the presence of depression. Therefore, our study concludes that there is a significant co-occurrence of self-reported ADHD childhood symptomatology among adult narcoleptics, and this warrants future research. Although there were no significant relationships noted between WURS score and the prevalence of genes predisposing individuals to narcolepsy, it was noted that 64% of NG tested were HLA-DQB1*0602 carriers, compared with the 36% that were noncarriers. However, for the genetic marker HLA-DR2, only 28% were carriers whereas 72% were noncarriers. Only six of the 23 (26.08%) NNR registrants who were tested for both, tested positive for both. This distribution appears to be in contrast to those reported in the literature as previous evidence suggests that more than 85% of individuals with narcolepsy and cataplexy are the HLADQB1*0602 carriers, and this predisposition is most often accompanied by the presence of the HLA-DR2 (Mignot, 1998). However, as only 23 of the 161 NNR registrants (14.28%) were tested for both markers, we may not have a large enough sample size to determine that this is an important finding. In fact, it is possible that the lack of genetic testing for all of the narcoleptics in this study may be a reason for insignificant findings between genetic markers and the WURS score. Further research could elucidate this. In addition, recent research has suggested the involvement of a hypothalamic hypocretin/orexin dysregulation in ADHD (Cortese, Konofal, & Lecendreux, 2008), hypersomnia (Nishino & Sagawa, 2010), and in narcolepsy (De la HerranArita, Guerra-Crespo, & Drucker-Colin, 2011). Future work on this system may elucidate common genes shared with ADHD and the narcolepsy/hypersomnia spectrum. Results from this study also revealed a significant relationship between MSLT latencies and WURS score, such that adults with greater childhood ADHD symptomatology, indicative of ADHD history, had shorter MSLT latencies. Thus, a diagnosis of narcolepsy and objective sleepiness was significantly paired with a childhood history of ADHD. Finally, it is worth mentioning that 27 questionnaires from narcoleptics in the NNR returned to the lead investigator were not completed following the directions provided. Thus, they were not able to be scored and were excluded from this study. It is noteworthy to mention that an inability to accurately follow directions is diagnostic (part of the diagnostic criteria) of ADHD. However, without sufficient sample data returned from these individuals, it is unclear

whether or not they demonstrated notable ADHD-specific symptoms and if their inability to follow directions is indicative of ADHD symptomatology.

Conclusion A significantly greater presence of self-reported childhood ADHD symptoms was noted in adult narcoleptics than controls. In addition, joint prevalence calculations, using the most conservative estimate, divulged more than 8 to 15 times greater than would be expected in the general population for comorbidity of ADHD and narcolepsy within this narcoleptic population. Among the narcoleptics, those individuals with a greater score of the WURS, indicative of childhood ADHD symptomatology, also had shorter sleep-onset latencies in the MSLT. This suggests greater sleepiness in adult narcoleptics with a history of childhood ADHD. It is likely that the research community needs to revisit the notion that narcolepsy and ADHD are mutually exclusive disorders. It may be that ADHD history is common among narcoleptics, whereas narcolepsy may be no more common in an ADHD population than in the general population. In such a case, a subtype of ADHD may lead to narcolepsy or its atypical variant hypersomnia. If this is the case, it may be more fruitful to explore this relationship in a narcoleptic/hypersomniac population, rather than an ADHD population. Future research is warranted to elucidate the connection between clinically significant retrospective history of self-reported childhood ADHD symptomatology and an adult diagnosis of narcolepsy or hypersomnia.

Appendix Below, we present three case studies taken from data acquired from the larger Narcolepsy Group (NG) population. These case studies are instances where there was a formal diagnosis of ADHD among the NG population. Their background and reported Wender Utah Rating Scale (WURS) score are detailed below. Interestingly, there were no male adults with formal diagnoses of ADHD, especially because ADHD is more common among males. Perhaps this is due to the fact that there was a much smaller sample of male adults than female adults in this study.

Case Study 1 This was a 46-year-old female narcoleptic with a history of ADHD. She was treated with methylphenidate from ages 12 to 18 for ADHD. Methylphenidate was resumed at age 30 with a new diagnosis of narcolepsy. In addition, she had a history of migraines, asthma, chronic bronchitis, and endometriosis. She had a score of 79 on the WURS and a formal diagnosis of ADHD with no history of depression.


581

Modestino and Winchester

Case Study 2 This was a 53-year-old female narcoleptic with a history of ADHD, autoimmune connective tissue disorder, migraines, back injury with chronic pain, three cervical fusions, three knee surgeries, and a history of broken toes, fingers, and ribs. She had a score of 53 on the WURS and a formal diagnosis of ADHD with no history of depression. She had a family history of ADHD and narcolepsy, and was positive for the narcolepsy gene HLA-DQB1*602. Her father had both narcolepsy and ADHD. “My father had ADD, and like me, fell asleep if he wasn’t eating or moving.”

Case Study 3 This was a 63-year-old female narcoleptic with a history of ADHD that was diagnosed 10 years prior to the diagnosis of narcolepsy at about age 50. She had allergies, low blood pressure, and slow heart rate. Two of her three siblings had diagnoses of dyslexia and her father’s mother had symptoms of narcolepsy. She had a score of 33 on the WURS and a formal diagnosis of ADHD with no history of depression. As previously noted, her score of 33, less than 36, would not have qualified for a retrospective history of childhood ADHD. Thus, this put into question the scoring of ADHD in this study. Authors’ Note This research was conducted with the National Sleep Foundation’s National Narcolepsy Registry (NNR) of narcoleptic registrants. This closed database is now housed at the Center for Narcolepsy, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, under the direction of Dr. Emmanuel J. Mignot, MD, PhD. The data for the normals were collected by Frederick William Reimherr, MD, and associates from the Mood Disorders Clinic in the Department of Psychiatry at the University of Utah School of Medicine.

Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

Notes 1. It is important to note that, here, the registrants were never made aware that this study’s aim was to retrospectively investigate the possibility of ADHD-specific childhood symptoms in the Narcolepsy Group (NG), thus, yielding a single-blind protocol. 2. The National Narcolepsy Registry (NNR) returned a few hundred envelopes to the lead investigator, so there is no way

to determine the exact amount of NNR registrants who were actually sent this package. 3. Using the short version in German, the Wender Utah Rating Scale–k (WURS-k), which includes only 21 key questions needed for scoring, scores of 30 or greater can be used as a cutoff for ADHD (Sobanski, Schredl, Kettler, & Alm, 2008). In addition, one standard deviation above the mean for normalcy is a score of 29 (Ward, Wender, & Reimherr, 1993). Thus, using a score of 30 as a cutoff can be justified.

References Allen, R. P., Singer, H. S., Brown, J. E., & Salam, M. M. (1992). Sleep disorders in Tourette’s syndrome: A primary or unrelated problem? Pediatric Neurology, 8, 275-280. American Psychiatric Association. (1994). Diagnostic and Statistical Manual of Mental Disorders (4th ed.). Washington, DC: Author. American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders (4th ed., text rev.). Washington, DC: Author. Brown, T. E., & McMullen, W. J., Jr. (2001). Attention deficit disorders and sleep/arousal disturbance. Annals of the New York Academy of Sciences, 931, 271-286. Brumback, A. R. (2000). Weinberg’s syndrome: A disorder of attention and behavior problems needing further research. Journal of Child Neurology, 15, 478-480. Chiang, H.-L., Gau, S. S.-F., Ni, H.-C., Chiu, Y.-N., Shang, C.-Y., Wu, Y.-Y., & Soong, W.-T. (2010). Association between symptoms and subtypes of attention deficit hyperactivity disorder and sleep problems/disorders. Journal of Sleep Research, 19, 535-545. Coogan, A. N., Dobrean, A., Donev, R. M., Mateescu, L., Müller, U., Thome, J., & Voinescu, B. I. (2012). Adult attention deficit hyperactivity disorder: Translating research into practice. Attention Deficit and Hyperactivity Disorders, 4, 41-51. Cortese, S., Konofal, E., & Lecendreux, M. (2008). Alertness and feeding behaviors in ADHD: Does the hypocretin/orexin system play a role? Medical Hypotheses, 71, 770-775. Dahl, R. E., Holttum, J., & Trubnick, L. (1994). A clinical picture of child and adolescent narcolepsy. Journal of the American Academy of Child & Adolescent Psychiatry, 33, 834-841. De la Herran-Arita, A. K., Guerra-Crespo, M., & Drucker-Colin, R. (2011). Narcolepsy and orexins: An example of progress in sleep research. Frontiers in Neurology, 2, 1-8. Drake, M. E., Hietter, S. A., Bogner, J. E., & Andrews, J. M. (1992). Cassette EEG sleep recordings in Gilles de la Tourette syndrome. Clinical Electroencephalography, 23, 142-146. Duane, D. D. (1991). To the editor. Journal of Pediatrics, 118, 489-490. Gajaria, A., Yeung, E., Goodale, T., & Charach, A. (2011). Beliefs about attention-deficit/hyperactivity disorder and response to stereotypes: Youth postings in Facebook groups. Journal of Adolescent Health, 49, 15-20. Gau, S. F. S., Kessler, C. R., Tseng, W., Wu, Y., Chiu, Y., Yeh, C., & Hwu, H. (2007). Association between sleep problems and symptoms of attention-deficit/hyperactivity disorder in young adults. Sleep, 30, 196-201.


582


Kotagal, S., & Swink, T. D. (1996). Excessive daytime sleepiness in a 13-year-old. Seminars in Pediatric Neurology, 3, 170-172. Mignot, E. (1998). Genetic and familial aspects of narcolepsy. Neurology, 50(Suppl. 1), S16-S22. Mohsenin, V. (2009). Narcolepsy—Master of disguise: Evidencebased recommendations for management. Postgraduate Medicine, 121, 99-104. Navelet, Y., Anders, T., & Guilleminault, C. (1976). Narcolepsy in children. In C. Guilleminault, W. Dement, & P. Passouant (Eds.), Narcolepsy (pp. 171-177). New York, NY: Spectrum. Nevsimalova, S. (2009). Narcolepsy in childhood. Sleep Medicine Reviews, 13, 169-180. Nishino, S., & Sagawa, Y. (2010). The neurochemistry of awakening: Findings from sleep disorder narcolepsy. International Review of Neurobiology, 93, 229-255. Oosterloo, M., Lammers, G. J., Overeem, S., de Noord, I., & Kooij, J. J. S. (2006). Possible confusion between primary hypersomnia and adult attention-deficit disorder. Psychiatry Research, 143, 293-297. Palm, L., Persson, E., Bjerre, I., Elmqvist, D., & Blennow, G. (1992). Sleep and wakefulness in preadolescent children with deficits in attention, motor control and perception. Acta Paediatrica, 81, 618-624. Rossini, E. D., & O’Connor, M. A. (1995). Retrospective selfreported symptoms of attention-deficit hyperactivity disorder: Reliability of the Wender Utah Rating Scale. Psychological Reports, 77(Pt. 1), 751-754. Sobanski, E., Schredl, M., Kettler, N., & Alm, B. (2008). Sleep in adults with attention deficit hyperactivity disorder (ADHD) before and during treatment with methylphenidate: A controlled polysomnographic study. Sleep, 31, 375-381. Stein, M. A., Sandoval, R., Szumowski, E., Roizen, N., Reinecke, M. A., Blondis, T. A., & Klein, Z. (1995). Psychometric characteristics of the Wender Utah Rating Scale (WURS): Reliability and factor structure for men and women. Psychopharmacology Bulletin, 31, 425-433. Stores, G. (2009). Latest advances in psychiatry. Misinterpretation of sleep disorders. Errors in the recognition and diagnosis

of sleep disorders. Progress in Neurology and Psychiatry, 13(6), 24-33. Sultan, S. G., Bertrim, S. E. A., Kimoff, R. J., & Baltzan, M. (1998). “Syndrome Z”: A description of a possible narcolepsy spectrum disorder. Sleep, 21(Suppl.), 88. Walters, A. S., Silvestri, R., Zucconi, M., Chandrashekariah, R., & Konofal, E. (2008). Review of the possible relationship and hypothetical links between attention deficit hyperactivity disorder (ADHD) and the simple sleep related movement disorders, parasomnias, hypersomnias, and circadian rhythm disorders. Journal of Clinical Sleep Medicine, 4, 591-600. Ward, M. F., Wender, P. H., & Reimherr, F. W. (1993). The Wender Utah Rating Scale: An aid in the retrospective diagnosis of childhood attention deficit hyperactivity disorder. American Journal of Psychiatry, 150, 885-890. Weinberg, W. A., & Brumback, R. A. (1990). Primary disorder of vigilance: A novel explanation of inattentiveness, daydreaming, boredom, restlessness and sleepiness. Journal of Pediatrics, 116, 720-725. Weinberg, W. A., & Harper, C. R. (1993). Vigilance and its disorders. Neurological Clinics, 11, 59-78. Yoss, R. E. (1970). The inheritance of diurnal sleepiness as measured by pupillography. Mayo Clinic Proceedings, 45, 426-437.

Author Biographies Edward J. Modestino, PhD, is a cognitive neuroscientist and faculty member at Atlantic University in Virginia Beach, Virginia. His main research interests include neuroimaging and electrophysiology of attention, and neurophenomenology of consciousness and altered states of consciousness. Jeanna Winchester, PhD, is a clinical cognitive neuroscientist. Working closely with Dr. Carl Cotman, PhD, at the University of California at Irvine, her research has focused on clinical interventions in Alzheimer’s disease, ranging from cognitive behavioral to exercise-based clinical trials.


Journal of Attention Disorders

Journal of Attention Disorders

Suggest Documents