Epidemiology – PLOS Currents Huntington Disease http://currents.plos.org/hd Sat, 15 Sep 2018 23:34:16 +0000 en-US hourly 1 https://wordpress.org/?v=4.5.3 The Prevalence of Juvenile Huntington’s Disease: A Review of the Literature and Meta-Analysis http://currents.plos.org/hd/article/the-prevalence-of-juvenile-huntingtons-disease-a-review-of-the-literature-and-meta-analysis/ http://currents.plos.org/hd/article/the-prevalence-of-juvenile-huntingtons-disease-a-review-of-the-literature-and-meta-analysis/#respond Fri, 20 Jul 2012 10:13:57 +0000 http://currents.plos.org/hd/?post_type=article&p=4305

Introduction

Huntington’s disease (HD) is an autosomal dominant, neurodegenerative disorder with onset usually, but not exclusively, between 35 and 50 years of age1 . Onset ? the age of 20 is classified as juvenile onset Huntington’s disease (JHD), which can be further divided into childhood (0-10 years) and adolescent (11-20 years) onset. Although there are many similarities with the adult form of the disease, JHD has a clinically distinct presentation; the dominant motor feature being a parkinsonian type syndrome of rigidity, dystonia and bradykinesia, rather than chorea234 . In addition, childhood cases may also present with cerebellar signs, epilepsy, myoclonus and spasticity56 . Behavioural problems and cognitive decline are also common in JHD46 , with additional features of developmental delay and autism in childhood cases5 .

The causative mutation in HD has been identified as an expanded CAG repeat sequence in the first exon of the HTT gene 7 . A CAG repeat of ? 40 is unequivocally fully penetrant, with CAG repeats of 36-39 showing reduced penetrance8 . JHD is usually associated with a CAG repeat of ? 60 repeats in approximately 50% of cases9 , with childhood onset often exhibiting a repeat size of ? 80510 . However, consistent with findings in adult cases,CAG repeat size does not always correlate with age of onset in JHD5 .

The prevalence of HD is considered to be approximately 4-10 cases per 100,000 in Caucasian populations11but this may be higher15 . Such variability may be accounted for in part by differences in methods of ascertainment, prevalence method used (period or point prevalence) and diagnostic/age of onset criteria. Low prevalence rates of less than 1 case per 100,000 have been reported in Japanese populations1112 . Well developed medical services in Japan mean under-ascertainment is unlikely12.. More recently, Warby et al (2011)16 have summarised prevalence data from around the world and discussed the reasons for low prevalence in some countries. Prevalence in African and American black populations is also considered to be lower than in white populations1718 . However this may represent under-ascertainment12 , with studies employing more extensive methods reporting equivalent rates19 . Juvenile onset HD is considered to be extremely rare, with few clinicians ever seeing more than one case. In 1981, Hayden summarised the prevalence of JHD, expressed as a percentage of the total number of HD cases surveyed11 . Presented by country, a mean of 5.7% of HD cases were found to be of juvenile onset, with a range of 1-9.6%. Childhood onset was rarer than adolescent onset, with means of 1.3% and 4.4%, respectively. These findings are consistent with the widely accepted belief that JHD is indeed a rare form of the disease.

Although Hayden’s work has been the first and only summary of the epidemiology of JHD known to the authors, there are several limitations in combining and interpreting the data in this way to obtain an estimate of the proportion of JHD cases. The first concerns the pooling of data from different types of studies, such as those reporting period with those reporting point prevalence. Secondly, data are included that are published in more than one paper. Furthermore, the Hayden report includes studies which, due to differences in country and year of study, report prevalence in populations with different age-sex structures. This potentially introduces a bias; lower life expectancies artificially raise the proportion of cases with juvenile onset as patients with adult onset are more likely to die prematurely from unrelated causes. The aim of the current study is therefore to update and expand Hayden’s work, exploring the impact of study level factors on the estimated proportion of HD cases with juvenile onset.

Methods

We searched the MEDLINE and EMBASE databases for the period 1981-May 2011. The following search terms were used in the title and abstract field:

Huntington’s AND disease AND Prevalence

Huntington’s AND disease AND Population

Huntington’s AND disease AND Epidemiology*

Huntington’s AND disease AND Incidence

Huntington*AND Prevalence

Huntington*AND Population

Huntington*AND Epidemiology*

Huntington*AND Incidence

Juvenile AND Huntington*

(* indicates searches including unlimited truncations of the target word)

Studies that did not include a defined HD population were excluded. Literature reviews were included if they provided information on the total number of HD cases surveyed. Studies were excluded if they did not include information on ages of onset, number of juvenile cases, or patients with onset before age 21. We only used published data once. Articles not written in English were excluded, the one exception being the German language Panse study20 as it was included in the original Hayden study. For each study, data relating to the total number of HD cases and total number of juvenile cases were extracted. In addition, the number of cases with childhood (onset 0-10 years) and adolescent (11-20 years) was extracted if available. For each study the proportion of HD cases with juvenile onset was calculated and expressed as a percentage.

Sub-group analyses. Studies were subdivided based on methodology, year of publication and country studied. Study methodology was defined as either “multiple methods of ascertainment” or “HD roster/clinic population”. Of these, the most accurate estimates of prevalence were considered to be from studies with multiple methods of ascertainment. Therefore, studies meeting this criterion were used for all further sub-analyses. To account for any biases relating to age-based population structure, studies were further divided by economic status as defined by the World Bank21 . To account for any time related changes in population structure and to gain an accurate estimate of the current prevalence of JHD, the final sub-group analysis was conducted using studies published between 1980 and 2011.

Statistical analysis. Within each sub-group, study results were pooled in a meta-analysis. Proportions were first transformed using the Freeman-Tukey double arc-sin transformation before being combined. A random effects model was assumed for each meta analysis due to the heterogeneity in the study characteristics. For each meta-analysis the I2 value is reported as a measure of statistical heterogeneity. Confidence intervals presented for each individual study were computed using the exact binomial method. All analyses were conducted using the “meta” package in R 2.13.1 22 .

Results

The search criteria produced a total of 1594 articles. Of these, 48 studies met the inclusion criteria. These studies were combined with those reported by Hayden11 , increasing the total number of studies to 59. The study by van Dijk et al2 was excluded as this literature survey was specifically searching for articles with JHD cases and did not define a denominator total HD population. Although the aim of the study was to update Hayden’s work we also included the paper by Julia Bell 1948 23 .

The pooled data presented in the Cameron and Venters paper24 , which originally included data from their own sample (Scotland) plus that of Bickford and Ellison (Cornwall)25and Pleydell (Northamptonshire)2627 , has been disaggregated to recreate counts in the three study populations. No JHD cases were reported in the Bickford and Ellison paper25 and this was therefore excluded. Therefore, only the data from Pleydell2627 and Cameron and Venters24 are included in our review. Although the counts of JHD cases in the Cameron and Venters paper are not explicitly reported, these were deduced by calculating the number of cases reported in the two Pleydell2627studies.

Cases in the Hayden South African study28were categorised by ethnicity into white, mixed and black populations recognising that the white South African population has a mortality distribution similar to that in countries listed as high income, whereas the mixed population has a mortality distribution similar to countries in the upper middle income group (no cases were reported in the black population). To avoid double counting of data in the meta-analysis, the overall total for South Africa was not included. This produced a revised total of 62 studies. A summary of these studies is presented in an appendix.

The results of the meta-analysis are presented as a forest plot in Figure 1. The black population data from Hayden28 were excluded for purposes of the statistical analysis since there were no HD cases reported. The overall pooled proportion of JHD cases was 4.92% (95% confidence interval (CI) 4.07% to 5.84%), with a range of 1-15%.

Fig. 1: Forest plot of all studies used in this anlysis

Sub-analyses. Table 1 below summarises the results of a number of sub-group analyses of the data which are described below.

HD roster or clinic. Thirty-five studies reported data obtained from either a HD roster or clinic population which are summarised in Fig 2. It is possible that a centre which uses a roster approach may have some patients included in different studies but our final analysis was based on studies which used multiple methods of ascertainment (MMA) so this is is less likely to be a problem.

Fig. 2: Forest plot of studies from a roster or clinic

Multiple methods of ascertainment (MMA). There were 25 studies applying MMA summarised in Fig 3.

Fig. 3: Forest plot of studies which used multiple methods of ascertainment (MMA)

Income status. The World Bank21 classification of countries was used to subdivide the studies, the majority (22 studies) came from the high income group. By comparison, three studies came from the upper middle income group, two came from Venezuela1044 and the third study was that of Hayden28, where the data from the White South African population was included in the high income analysis and data from the mixed population was included in the middle income group. Fig 4 summarises these studies from high income countries.

Fig. 4: Forest plot of studies using MMA from high income countries

Post 1980 studies. Of the MMA studies, 14 were published between 1980 and 2011. Ten were conducted in high income and three in the upper middle income. As above, the final study was that of Hayden28, where the data from the white South African population was included in the high income analysis and data from the mixed population was included in the upper middle income group. The forest plot for studies from high income countries is shown in Fig 5 and the forest plot for studies from upper middle income countries is shown as Fig 6.

Fig. 5: Forest plot of post 1980 studies using MMA from high income countries

Fig. 6: Forest plot of post 1980 studies using MMA from upper middle income countries

Table 1

Summary of Meta-Analyses

Study type number Mean
%
95%
Confidence
Interval
Range
%
All studies 62 4.92 4.07-5.84 1-15
HD clinic/Roster 35 4.94 3.85-6.16 1-15
Multiple Metods
of Ascertainment
MMA
25 5.32 4.18-6.60 1-15
MMA + High Income 22 4.70 3.71-5.80 1-12
MMA + Upper
Middle Income
3 9.95 6.37-14.22 6-15
MMA + Post 1980 +
High Income
11 4.81 3.31-6.58 1-10
MMA + Post 1980 +
Upper Middle Income
3 9.95 6.37- 14.22 6-15

Data on childhood and adolescent onset cases was available for 42 studies, representing 475 cases. Of these, 111 (23.4%) and 364 (76.6%) were childhood and adolescent onset, respectively. Only seven studies found a higher proportion of childhood onset cases, with two studies reporting equal numbers. Therefore in 76% of studies, adolescent onset occurred more frequently than childhood onset. When we consider just the most recent studies of the highest quality from the high income group (the MMA-post 1980 studies), the pattern is similar with 40 out of 50 (80%) cases being of adolescent onset.

Discussion

Main results. In the meta-analysis of all the studies identified in this review we estimate the proportion of JHD cases to be 4.92% (95% CI 4.07% – 5.84%). In order to expand on Hayden’s original work11 and produce more robust estimates of the proportion of JHD cases, the potential sources of bias associated with the various studies were considered. We identified 35 studies which were based on clinic lists or rosters (Figure 2); and 25 studies which used multiple methods of ascertainment (Figure 3). These gave mean estimates of the proportion of 4.94% and 5.32% respectively. A clinic list or roster approach may downwardly bias the proportion of JHD cases if it is perceived that the clinic serves mainly adult patients. Studies with multiple methods of ascertainment are more likely to give a robust estimate.

Most studies were conducted in Europe and North America so the effect of considering geography was minimal (Figure 4); however, the three studies from economically less developed countries (Figure 5) were effectively from the South African black population and Venezuela. The longitudinal study of families from the area around Lake Maricaibo has been important in that it contributed to the original localisation of the gene to chromosome 4 and for an understanding of the natural history of the condition 104480 The mean proportion of JHD cases from these three studies was 9.95% (95% CI 6.57% – 14.22%). If the age of death was lower in the general population in which these cases live, then those with HD who were destined to develop the condition later in life may not manifest as they die of other causes; consequently the proportion of JHD cases will be higher. In addition, the patients with HD living around Lake Maricaibo are a relatively closed community so it is possible that this also has an effect on the proportion of JHD cases. These three studies were reported after 1980.

Eleven studies were reported after 1980, which used multiple methods of ascertainment, and were from economically more developed countries; these gave a slightly lower proportion of 4.81% (95% CI 3.31% – 6.58%) and may be considered the most robust estimate to use when considering European and North American populations.

Implications for Research. At present, there is no treatment to alter the natural history of HD. As soon as treatments become available which do alter the natural history of HD, then it will be important to assess their effects on patients at the more extreme end of the phenotypic spectrum. If a faster rate of disease progression can be demonstrated in this group of patients, then any compound which affects the natural history of HD may show an effect more quickly.

In June 2010, the UK population was estimated to be 62.3 million79 . If we assume the prevalence of HD is approximately 4-10 per 10011121314 , in the UK and we also assume some degree of under-ascertainment; therefore, using a figure of 100 HD patients per million would imply that there are around 6,230 patients with HD in the UK, so we should expect to see approximately 300 cases with an onset under the age of 20 years (95% CI 205 – 411). Identifying these patients represents a considerable challenge.

Conclusion

We have presented a review of the proportion of cases with JHD from 62 studies. Using data from 25 studies after 1980 which were mainly fromNorthern Europe suggests that the mean proportion of JHD cases is just less than 5%.

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Huntington’s like conditions in China, A review of published Chinese cases http://currents.plos.org/hd/article/huntingtons-like-conditions-in-china-a-review-of-published-chinese-cases-2/ http://currents.plos.org/hd/article/huntingtons-like-conditions-in-china-a-review-of-published-chinese-cases-2/#respond Wed, 15 Feb 2012 10:48:26 +0000 http://currents.plos.org/hd/?post_type=article&p=2091

Introduction

Huntington disease (HD) has been mainly reported in the West and, to date, knowledge on HD in China is very sparse. It has been claimed, that the incidence is very low, however, well-conducted epidemiological studies are lacking. Furthermore, the phenotype in HD patients has not been well characterized, and it may well be that it is influenced by ethnic background. We have therefore performed an analysis of the literature on HD China by systematically retrieving appropriate reports to describe the clinical manifestations of the disease in this country.

Methods

Items including Huntington’s disease, Chinese equivalents of the terms: hereditary chorea, chronic progressive chorea, and hysterical chorea were used as keywords to search articles published in the China National Knowledge Infrastructure. Pre-indexing did not reveal any systematic evaluation, prospective or retrospective cohort study regarding HD in China. Case series and individual reports published between January 1 st , 1980 and April 30 th , 2011 were included, but reviews and experimental studies on HD excluded. Case reports with non-definite clinical diagnosis or repetitive contents were excluded. Information was extracted about family history, involuntary movements, including the region involved, cognitive disturbances, and psychiatric symptoms. Results of imaging and neurophysiological studies, and of genetic testing were included, where available.

Literature inclusion

A total of 230 articles related to HD were collected; 136 were excluded since they reported identical data and basic studies; 94 studies involving 547 patients were selected (Table 1). Of these, 306 cases ad to be excluded due to incomplete clinical data. In total, 279 patients were included (157 males and 122 females), with an age of onset of 6-70 years. Of these cases, 236 cases (96.8%) included a family history. A total of 89 patients were noted to have come from a precise region, 16 were from the South, and the remainder were from the North (82.0%), including 15 from Henan Province, 14 from Shandong Province, and 8 from Hebei Province.

Table 1. Reports included in the present survey

Year of publication First author Male Female Molecular testing Ref.
N Age at onset N Age at onset
1980 Wancong Gao 0 na 1 na na [11]
1980 Linde Liu 1 42 1 27 na [12]
1980 Wenshi Li 2 37 to 42 1 54 na [13]
1980 Xiongya Wu 1 51 1 47 na [14]
1983 Qian Xu 5 15 to 44 3 7 to 8 na [15]
1984 Zian Chen 4 32 to 39 1 32 na [16]
1985 Xiaolian Du 2 5 to 40 3 16 to 19 na [17]
1985 Jixue Feng 0 na 1 41 na [18]
1985 Shuyou Fang 4 28 to 46 1 24 na [19]
1986 Guiqing Wang 2 28 to 58 1 28 to 58 na [20]
1986 Honglin Fu 0 na 3 34 na [21]
1986 Hua Shao 1 39 0 na na [22]
1987 Wenjun Chen 1 31 0 na na [23]
1988 Shicheng Pei 1 43 0 na na [24]
1988 Shuqiang Bu 0 na 2 34 to 37 na [25]
1988 Keqing Ding 3 41 to 55 1 45 na [26]
1988 Zhiyuan Ha 1 28 1 30 na [27]
1989 Yongqian Xing 5 20 to 35 3 25 to 43 na [28]
1989 Xuesong Tu 0 na 1 na na [29]
1989 Fuyuan Shao 1 7 0 na na [30]
1990 Yuxiang Xu 4 17 to 42 1 35 na [31]
1990 Chuandong Wu 2 17 to 36 0 na na [32]
1990 Jiaxi Huang 0 na 4 34 to 40 na [33]
1991 Zhaoxiang Zeng 0 na 1 31 na [34]
1992 Ke Fan 4 27 to 38 2 38 to 56 na [35]
1992 Changdao Sun 3 24 to 30 2 21 to 25 na [36]
1992 Chengyu Chen 4 27 to 47 0 na na [37]
1993 Fengying Hou 1 47 0 na na [38]
1994 Yanjun Gao 1 48 0 na na [39]
1994 Qishan Dong 1 42 1 38 na [40]
1994 Yuejin Huang 0 na 1 42 na [41]
1995 Xiaomei Yao 0 na 2 46 to 47 na [42]
1995 Xiuhua Fan 1 47 0 na na [43]
1995 Chenghao Chu 4 10 to 65 1 20 na [44]
1995 Jiying Wang 0 na 1 32 na [45]
1995 Ronghua Yong 1 60 1 48 na [46]
1996 Kun Liu 0 na 1 42 na [47]
1996 Zhaozhong Shen 2 na 0 na na [48]
1997 Meiju Hou 1 36 0 na na [49]
1997 Jiaming Xia 3 18 to 35 2 18 na [50]
1997 Wenhua Sun 0 na 1 25 na [51]
1998 Xiangming Fang 5 18 to 40 0 na na [52]
1998 Weizhou Liu 1 23 0 na na [53]
1998 Yujin Zhang 6 24 to 50 4 30 to 55 na [54]
1998 Xiaoping Yang 2 30 to 40 2 13 to 33 na [55]
1998 Kai Feng 1 56 0 na na [56]
1998 Zuozhi Gao 2 33 to 54 1 34 na [57]
1998 Xiaoping Zeng 3 43 to 54 1 45 na [58]
1998 Yuchen Sun 1 42 2 45 to 46 na [59]
1999 Weiguo Yang 0 na 1 39 na [60]
1999 Guilan Wang 0 na 1 8 na [61]
1999 Bin Liu 4 32 to 45 3 34 to 38 na [62]
2001 Xi Zhang 1 50 0 na na [63]
2001 Jing Chen 1 24 0 na na [64]
2001 Wen Li 2 21 to 26 3 25 to 26 na [65]
2001 Qinglin Dong 4 23 to 36 2 30 to 32 na [66]
2001 Huizhi Fan 0 na 1 32 na [67]
2001 Liansheng Xu 5 29 to 54 5 32 5o 52 na [68]
2002 Jing Liu 3 28 to 46 5 35 to 50 na [69]
2002 Benqiang Deng 1 66 0 na na [70]
2002 Ye Tian 1 70 1 40 na [71]
2003 Liqun Fang 1 31 0 na na [72]
2003 Huize Ma 2 31 to 52 3 33 to 45 na [73]
2003 Yuhai Zhao 2 22 to 40 1 30 N CAG repeats [74]
2004 Feng Tian 1 54 2 38 to 50 na [75]
2004 Mingbing Chen 1 32 0 na na [76]
2004 Weiwei Dong 1 14 0 na na [1]
2004 Jun Chen 2 52 2 44 to 54 na [76]
2004 Jiamu Wu 2 31 to 33 0 na na [77]
2004 Beilei Zhu 1 28 0 na Genetic test (no N CAG repeats) [78]
2005 Liyan Guo 0 na 1 32 na [79]
2006 Shiyong Zhang 0 na 1 52 na [80]
2006 Huamei Wang 2 41 to 48 0 na na [81]
2006 Fang Lin 4 421 to 58 0 na na [82]
2006 Baorong Zhang 3 30 to 45 5 18 to 36 N CAG repeat [83]
2006 Zhilin Shi 2 33 to 45 1 45 Genetic test (no N CAG repeats) [84]
2007 Yuan Liu 3 33 1 17 N CAG repeats [85]
2007 Yanchun Geng 2 28 to 29 0 na na [86]
2008 Wei Xu 3 25 to 36 2 27 to 45 Genetic test (no N CAG repeats) [87]
2008 Jin Yu 1 41 4 32 to 45 na [88]
2008 Ning Wang 1 na 2 na N CAG repeat [89]
2008 Zhouri Li 2 40 to 43 1 41 na [90]
2008 Yiming Feng 1 33 0 na na [91]
2009 Xingwang Song 2 41 to 57 4 6 to 58 N CAG repeat [92]
2009 Qiuhong Zheng 2 50 to 60 3 41 to 60 na [93]
2009 Meiying Cai 1 30 2 35 to 45 N CAG repeat [94]
2009 Weijie Liu 0 na 1 37 na [95]
2010 Meihua Zhu 0 na 1 35 na [96]
2010 Ge Gao 3 36 to 42 0 na N CAG repeat [97]
2010 Jing Ma 0 na 1 46 na [98]
2011 Min Li 0 na 1 51 na [99]
Total 157 122

Most (65%) of the patients had onset in middle age (Table2), with a mean of 35.8 years (± 11.8), mean age at death was 45.6 years (± 13.5, range 13–69), and mean course from onset to death was of 11.6 years (± 5.6, range 3–30). Around 9 % had a juvenile onset. The study included 115 families. Paternal inheritance was more often found than maternal inheritance (Table 2), and age of onset with paternal inheritance was lower than maternal inheritance (34 ± 10 versus 37 ± 10 years, P < 0.05). The age at death (46 ± 15 vs. 50 ± 10 years), and the course of disease (12 ± 6 vs. 12 ± 4 years), were not significantly different. In addition, no difference was found between male and female patients in terms of age of onset, death age (47 ± 14 versus 46 ± 12 years), and course of disease (12 ± 6.0 vs. 10.7 ± 5.0 years). Within the cohort, 55 patients death were reported, of which three were due to suicide.

Table 2. Clinical features of the reported patients

N of total with available data %
Inheritance
Paternal 127/194 65.5
Maternal 67/194 34.5
Anticipation 42/59 71.2
Age at onset (yr)
< 20 24/279 8.6
30–55 182/279 65.2
Presentation at onset
Abnormal movements 146/196 52.3
Generalized 94/146 64.4
Head and face 20/146 13.7
Upper limbs 29/146 19.8
Lower limbs 3/146 2.1
Psychiatric disorder 45/196 16.1
Cognitive impairment 5/196 1.8
Course
Abnormal movements 242/243 99.6
Psychiatric disorder 85/243 35.0
Cognitive impairment 165/243 67.9

The most frequent presentation at onset were abnormal movement found in more than half of the patients (Table 2), with a predilection for the face and upper limbs when it was not generalized. In the course of the disorder most patients developed abnormal movements, followed by psychiatric symptoms and cognitive impairment (Table 2). There were some specific features in single patients, for example, one displayed speech impairment, instability of gait and cognitive impairment, with no obvious involuntary movement [1]. Dysarthria and dysphagia was also reported during the course in 26 % of the patients. One single patient had epilepsy at onset.

Laboratory investigations

In a total of 48 patients with electroencephalograms, 34 (70.8%) had abnormal curves, mostly with mild slowing. In a total of 16 patients undergoing cerebrospinal fluid examination, three (18.8%) displayed abnormally increased protein levels. In a total of 89 patients undergoing cranial imaging, 80 (90.0%) presented with abnormalities of varying extent, including 65 (73.0%) with brain atrophy and lateral ventriculomegaly, 2 (2.2%) with selective caudate nucleus atrophy, and 26 (29.2%) with brain atrophy, lateral ventriculomegaly, and caudate nucleus atrophy. IT15 gene detection was reported positive in 38 patients, of which CAG repeats were clearly reported in 33 of the cases. The number of CAG repeats was greater in patients with a younger age of onset (mean of 61 in patients with onset before versus 46 with age of onset after 30).

Discussion

The prevalence of HD is quite variable, with figures varying between 0.5 (Finland) [2], 1 (Croatia [3]) and 10 (German speaking European countries [4]) per 100 000 in Europe, and with high local prevalence in some communities, like in Venezuela (almost 700 in the Lake Maracaibo region [5]. It is usually thought that the prevalence in Asia is lower, however, fewer data than in the West have been reported so far. In Japan reported estimations ranged between 0.1 [6] and 0.7 [7]. Earlier estimation in Hongkong are within the same range [8], however, no data have been so far reported for mainland China. The present survey of Chinese literature on HD shows that the disease is indeed present in this country, but does not provide precise clues on the prevalence of the disorder. It also suggests a higher prevalence in Northern China, however this may also be a report bias. The number of juvenile cases reported seems higher than in other regions of the world and there is a male predominance in overall prevalence. However, the mean age of onset is otherwise consistent, but the course seems shorter with absence of the gender difference reported earlier [9]. The majority of patients had a positive family history, and only five cases were determined to be sporadic. Moreover, the number of cases due to paternal inheritance was significantly greater than that from maternal inheritance, with a significantly younger age of onset with paternal inheritance, which was in accordance with previously published results. Only one case among the 20 with juvenile onset was reported to have epileptic seizure, which is in contrast to the literature, reporting up to 30% of them. Studies have suggested that the suicide rate of HD patients is significantly greater than healthy individuals, in particular in early or advanced stages [10]. Only three patients were reported to have committed suicide, however, data regarding suicide in China are not available for comparison. In general the other aspects were similar to the reports in other populations. However, only a small number had a molecular confirmed diagnosis, but the trend to earlier age of onset with higher triplet repeat numbers is found here also.

In conclusion, ethnic differences among Chinese with HD as compared to other populations are possible. However, the use of appropriate clinical assessment tools and molecular genetic testing in a larger cohort of patients is urgently needed. For this reason a Chinese Huntington’s disease network is going to be launched.

Competing interests

The authors have declared that no competing interests exist

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Current Pharmacological Management in Juvenile Huntington’s Disease http://currents.plos.org/hd/article/current-pharmacological-management-in-juvenile-huntingtons-disease-2/ http://currents.plos.org/hd/article/current-pharmacological-management-in-juvenile-huntingtons-disease-2/#respond Mon, 06 Feb 2012 06:02:48 +0000 http://currents.plos.org/hd/?post_type=article&p=2145

Introduction

Huntington’s disease (HD) is a dominantly inherited, neurodegenerative disorder, due to a (CAG)n repeat expansion in the HTT gene [1] . In the majority of HD cases, onset is in adult life.

Juvenile HD (JHD)is defined as onset under 20 years of age [2] and represents approximately 1-10% of cases [3] [4] [5] [6] [7] . There is an inverse correlation between the age at onset of disease and the number of (CAG)n repeats [8] [9] [10] .

Adult HD is characterised by a triad of clinical features including: chorea, cognitive decline and psychiatric disturbance or behavioural disturbance [11] . However, in JHD, particularly in those with onset in the first decade, chorea is less likely to be present and instead, patients are more likely to present with rigidity, bradykinesia, dystonia and gait disorder, ie. parkinsonian features [7] [11] [12] [13] [14] [15] [16] [17] . In addition, JHD patients are more likely to develop epilepsy than adult-onset cases [18] . The spectrum of features at presentation can also include ataxia, dysarthria, dysphagia, deterioration in school performance or severe behavioural problems [11] [14] [19] [20] .

There is currently no effective disease-modifying treatment for either adult onset HD or JHD; therefore, clinical care is symptomatic and supportive. The very different presentation means that different treatments are likely to be used in the management of JHD versus adult onset HD. Given the rarity of the condition, each treating clinician is unlikely to have seen more than a few cases and there are no treatment guidelines. Therefore, gathering together the limited information available is of significant benefit to both families and physicians and helps form the basis of future trials.

For UK families affected by JHD, we composed a questionnaire, to be completed by the family, listing their child’s symptoms and treatments. The study received M-REC and local R&D approval. Patients were identified through the Patient’s Support Group and Hospital Clinicians (Neurologists and Clinical Geneticists).

As a second phase, we collated data on medications prescribed for JHD patients enrolled in the European Huntington’s Disease Network REGISTRY study (excluding the UK). We used monitored case report forms from the European Huntington’s Disease Research Network (EHDN) REGISTRY project. This is a multinational observational study see www.euro-hd.net/html/registry [21] . All medications were grouped according to the WHO ATC classification.

In the UK, 40 questionnaires were sent out and seven families responded. 38 REGISTRY patients with JHD were identified.

In the UK cohort, the most common symptoms reported by the families were speech difficulties(7), dysphagia(6), stiffness/spasticity(6), sleeping difficulty(5), pain(4) and behavioural problems(4) . Equivalent data from REGISTRY was not available.

When the data was combined the median number of medications prescribed was four, with an arithmetic mean of five (range 1-16) (Fig 1).

Fig. 1: No of agents prescribed to each patient (combined data)

In REGISTRY, the most commonly prescribed agents were anti-psychotics, anti-depressants, anti-parkinsonianmedications and anti-epileptics (Fig 2). In the UK, the anti-psychotic was the most commonly prescribed agent (Fig 3).

Fig. 2: Classes of medicines prescribed (European Data)

Fig. 3: Classes of medicines prescribed (UK data)

The most commonly prescribed individual medication was Valproic acid (anti-epileptic), followed jointly by: Tiapride (anti-psychotic), Dopa and Dopa derivatives (anti-parkinsonian) and Tocopherol (vitamin preparation) (Fig 4).

Fig. 4: The most commonly prescribed medicines, arranged by group

Discussion

The most commonly prescribed medication in our cohort was the anti-psychotic agent (24/45 individuals). In the UK group, the family member completing the questionnaire was asked to give the indication for each medication, and for anti-psychotics this included: agitation, behavioural problems and psychiatric disturbances, none of which are listed as diagnostic features of JHD. This is important as it is recognised that children presenting with behavioural or psychiatric problems often experience a significant delay in receiving a diagnosis of JHD [14] , and our data would infer that such problems are common in this age group affected by HD.

Anti-depressants and anti-parkinsonian agents were also frequently prescribed (n=17 and n=15 respectively) and some (n=7) were taking a combination of anti-parkinsonian medications and anti-psychotics. This odd regime often reflects the combination of dystonia and parkinsonism seen in JHD, although whether it is a useful combination is unclear especially given the recognised parkinsonian side-effects of anti-psychotics [22] . This side-effect is less frequent with the atypical anti-psychotics than in first generation anti-psychotics, but does still occur and it may be difficult to distinguish from disease progression.

The most commonly prescribed individual medication was Valproic acid (8), reflecting consistency in anti-epileptic prescribing. This is in-line with prescribing practice in the management of childhood epilepsy of all causes [23] ; Valproic acid is widely used as first-line therapy for generalised seizures with a strong evidence base to support its efficacy [24] . At present, as there is no disease-modifiying therapy available, the optimum management of JHD encompasses the optimum management of the associated symptoms.

Five patients were prescribed in excess of eight types of medications. The highest number of medications for any one patient was sixteen, raising issues of polypharmacy. This is a particularly important issue in a group of patients with swallowing difficulties. Three patients were on three or more anti-pyschotic agents or anti-parkinsonism agents simultaneously: which highlights the fact that many cases of JHD appear to be refractory to pharmacotherapies.

An apparent difference in prescribing habits was noted between the two populations of patients studied: within the UK, opioids were prescribed whereas in the REGISTRY group they were not, this may be due to variations in national restrictions [25] . For certain individuals with JHD, pain can be a feature and from our own experience this can be difficult to manage and the input of a specialist pain team or palliative care specialists can be invaluable [26] .

The diagnostic features of HD presenting in the first decade are a family history of HD, often in the father (though onset in the child may precede onset in the parent), and two or more of the following: declining school performance, seizures, oral motor dysfunction, rigidity and gait disorder [27] . We analysed the data based on age of diagnosis (Fig 4); we hypothesized that those who were older at diagnosis may have a profile more akin to adult JHD with a lower incidence of rigidity, dystonia and epilepsy. We therefore divided patients into three groups, those diagnosed at 10 years of age or under (n=6), those diagnosed between 11 to 15 years of age (n=12) and those diagnosed between 16 to 20 years (n=26). The age at diagnosis was unknown in one case (n=1). We observed that those who were diagnosed at 10 years or under were significantly more likely to be prescribed a muscle relaxant than those diagnosed between ages 11-20 years (Fisher’s exact test, p=0.01). There was no apparent trend between younger age at diagnosis and the frequency of prescription of anti-epileptics or anti-parkinsonian agents.

Fig. 5: Comparison of medications prescribed in JHD at different ages

Conclusions

We set out to identify which medications were being prescribed for symptomatic relief in JHD; this has not been done before. We identified that anti-psychotics were the most commonly prescribed agent and that anti-depressants and anti-parkinsonian medications were also frequently prescribed in the JHD group.

JHD patients have complex needs. The diversity of their problems means they are often prescribed medications which exceed the area of expertise of a single hospital specialist. Their medications require regular review by a team of experts, in the face of evolving symptoms. Polypharmacy is an issue in this group, highlighting a potential need for reviewing and stopping medicines, especially when they appear to be ineffective.

Identifying current practice is only a first step towards establishing an evidence base for treatment guidelines. JHD is a rare condition which means that international collaboration is essential to gather information on the effectiveness of symptomatic management. Projects such as REGISTRY are vital in order to establish such information. Ultimately we would hope that it will be possible to use such a database to identify affected patients and conduct a randomised trial on the effectiveness of different symptomatic treatments in this form of HD.

Competing Interests

The authors have declared that no competing interests exist.

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Aspiration pneumonia and death in Huntington’s disease http://currents.plos.org/hd/article/aspiration-pneumonia-and-death-in-huntingtons-disease-2/ http://currents.plos.org/hd/article/aspiration-pneumonia-and-death-in-huntingtons-disease-2/#respond Mon, 30 Jan 2012 11:17:23 +0000 http://currents.plos.org/hd/?post_type=article&p=2771

Introduction

Huntington’s disease (HD) is a progressive neurodegenerative autosomal dominant disease characterized by disturbed movements, changes in behaviour, and cognitive decline. Although the motor disturbances are both choreatic and hypokinetic, chorea is the most characterizing. Choreatic movements are irregular, unwanted involving not only the limbs and the trunk but also the respiratory and buccolingual muscles. HD is caused by a CAG repeat expansion of the HTT gene on the short arm of chromosome 4. The mutant protein huntingtin causes neurodegeneration in the brain, particularly in the caudate nucleus and putamen. The mean age at onset is in the third and fourth decade of life and the disease duration about 15-20 years. [1] Death usually results from respiratory complications. Studies to the cause of death in HD found that the primary cause (variation of 33%-85.7%.) of death is pneumonia. [2] [3] [4] [5] [6] [7] None of the reported studies mentioned any details about the type of pneumonia. Pneumonia has several causative factors of which aspiration seems an important one. Pneumonia can be classified into different types, such as community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP), chemical pneumonia, and aspiration pneumonia. Although the exact percentage is unknown, most HD patients have dysphagia, especially in the advanced stage of the disease, therefore, aspiration is the most likely cause of the fatal pneumonia. The aim of the present study is to find out how often aspiration pneumonia is the primary type of fatal pneumonia in HD.

Materials and Methods

The records of all deceased HD patients from the Leiden University Medical Center (LUMC) brainbank in the Netherlands were collected. The diagnosis of HD was confirmed by family history and post-mortem pathological investigation, and since 1993 in most cases by DNA analysis. From all files the following information was collected: DNA confirmation, gender, year of birth, year of death, age at onset, location of death, naturally death, total body autopsy, described primary cause of death, other described underlying causes of death, repeated pneumonias, special remarks. The special remarks contained all available information about the type of pneumonia and the macroscopic description of the content of the lungs at autopsy. The clinical data from the patients were analyzed, when available, especially for dysphagia.

Statistical analysis

Descriptive statistics was used to obtain results, and Chi-square distribution was used to compare different variables. (SPSS 18.0)

Results

Two hundred twenty four charts of deceased HD patients were reviewed, of which 216 (111/104 male/female, one unknown) had records available, 147 listed a cause of death (Table 1), which was pneumonia in 81 (55%) cases. 38 of those 81 cases had an autopsy that included a description of the lungs. Of those 38 cases, 12 had gastric juices or food in the lungs, and 4 had giant cells, reaction which we defined as “death due to aspiration pneumonia”, 17/38 had hyperemia, which we defined as “possible aspiration pneumonia”, and only 5 showed bacteria or viruses, which was defined as “primary infectious pneumonia”. For the cause of death aspiration pneumonia, no significant difference was found for gender and aspiration (χ 2 =.995). From all 216 records, in 69 cases no primary cause of death was given. In 15/69 records the clinical information revealed information about dysphagia, and in 8/69 records information about repeated pneumonias in the end stage was present. In 4/69 records, a description of the microscopy revealed of giant cells and hyperemia in the lungs.

Table 1: Primary cause of death in 147 patients with Huntington disease
Cause of death N=147 100%
Known Cause:
-pneumonia 81 55.1
-suffocation 6 4.1
-pulmonary embolism 6 4.1
-cachexia 11 7.5
-cardiac diseases 16 10.9
-other neurological diseases 3 2.0
-shock/sepsis 7 4.8
-suicide 2 1.4
-euthanasia 5 3.4
-other causes 10 6.8

Discussion

With the information available, we found it plausible that significant more patients died from aspiration pneumonia, instead of a primary infectious pneumonia. It is most likely that dysphagia is the causative factor for this aspiration pneumonia. The relation between dysphagia leading to aspiration pneumonia is confirmed in patients with Parkinson disease (PD) and in elderly people. [8] [9] The leading cause of death in PD is aspiration pneumonia, for as much as 70%. And these patients also suffer from dysphagia. [8] [10] [11] In elderly people it is found that dysphagia is a common problem, and that dysphagia is the major pathophysiologic mechanism leading to aspiration pneumonia. [9] [12] Another interesting point is that it is likely that patients who died from an infectious pneumonia, still died because of aspiration. Because in most cases the cultures consisted of the staphylococcus aureus, klebsiella and candida albicans. When patients aspirate their saliva, patients can develop pneumonia, especially patients in the last stage of HD, who are mostly cachectic, in bad condition and with a poor resistance. Previous studies to the role of chronic conditions, health behaviors, and nutritional status have shown that these factors increases the risk of pneumonia.[13] [14] [15] On investigating the files of the deceased HD patients, a large proportion of the files, 32% did not contain the primary cause of death. Therefore, it seems that the files of the deceased HD patients are relatively inaccurate in recording causes of death. Other studies have also shown an inaccuracy rate. Haines and Conneally [4] had an overall rate of 66%. Alderson [16] found an overall accuracy rate of 61%. Thus, our overall rate of 68.1% is not unusual. Because of this overall rate, it seems likely that more patients died of aspiration pneumonia. Some of these patients were described with suffering from dysphagia, and repeated pneumonias in their last period of life. As said these issues have influence on developing aspiration pneumonia. To conclude, our data suggest that aspiration pneumonia is the most prominent primary cause of death in HD, which is in accordance with the literature. As the source data showed to be rather incomplete, lacking information about the clinical status of the patients regarding dysphagia, we started to develop a dysphagia assessment scale to get better insight in the prevalence of dysphagia and its consequences for the development of pneumonia.

Competing interests

The authors have declared that no competing interests exist.

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Seven-year clinical follow-up of premanifest carriers of Huntington’s disease http://currents.plos.org/hd/article/seven-year-clinical-follow-up-of-premanifest-carriers-of-huntingtons-disease-2/ http://currents.plos.org/hd/article/seven-year-clinical-follow-up-of-premanifest-carriers-of-huntingtons-disease-2/#respond Mon, 28 Nov 2011 10:12:07 +0000 http://currents.plos.org/hd/?post_type=article&p=3559

Introduction

Huntington’s disease (HD) is a hereditary neurodegenerative disease that becomes manifest in midlife and is characterised by motor disturbances, cognitive decline and behavioural dysfunction. HD is caused by the abnormal expansion of a trinucleotide (CAG) repeat in the gene for the protein huntingtin [1]. The genetic defect leads to cerebral cell death, especially in the basal ganglia. Although the clinical diagnosis of HD is based on the first appearance of motor signs, a positive family history and confirmation by DNA-testing, subtle changes in motor function, cognition and behaviour are known to precede manifest disease. Detecting these very early changes is of importance in the development of instruments to monitor early therapeutic intervention trials and to obtain more insight into the phase of clinical disease onset.

Cross-sectional reports showed that carriers of the HD gene mutation without manifest motor signs (further labelled as carriers) perform significantly worse than non-carriers on certain motor scores, neuropsychological tests and behavioural assessments [2][3][4][5][6][7][8][9][10][11]. Furthermore, some studies showed relationships between fewer years to estimated onset of diagnosable clinical disease and worse motor and cognitive function [2][7][12][13][14].

Longitudinal follow-up is however necessary to really understand the pattern of evolving motor, cognitive and behavioural abnormalities in the phase of HD clinical onset. First of all, to find out if clinical markers that are sensitive in detecting premanifest abnormalities show a decline over time and might be suitable as outcome measures in future therapeutic trials. Secondly, to monitor whether carriers, converting to manifest HD, display specific clinical changes. To date, several longitudinal studies have been undertaken. The duration of follow-up however has been brief in the vast majority of longitudinal studies and results show discrepancies. In accordance with other studies we failed to demonstrate clinical markers for premanifest HD in our previous 3-year follow-up study [15][16][17]. Others did detect a significant decline over time in motor function, executive function, attention and memory [18][19][20][21]. The longest follow-up study to date (10 years) demonstrated that the most rapid decline on motor and cognitive domains was found in individuals approaching clinical disease onset [13]. With the present observational study we aim to give more insight in the clinical onset phase of the disease as the number of reports on clinical decline in premanifest HD using long-term follow-up with a comprehensive assessment battery is limited. The objective was to follow a premanifest HD carrier group for 7 years in order to determine if our assessment battery detects subtle clinical changes preceding diagnosable clinical HD. Furthermore, we examined whether the rate of decline on motor, cognitive and behavioural measures could be related to estimated proximity to diagnosable clinical disease.

Methods

Participants

In the original study, 134 participants were included (46 premanifest carriers, 88 non-carriers). They were referred to the Leiden University Medical Centre (LUMC) Department of Clinical Genetics, for predictive testing, and consented to participate in a three-year clinical follow-up study [17]. Non-carriers were at-risk individuals who, after predictive testing, proved to have a CAG-repeat lenght of fewer than 27. Carriers were considered to be premanifest in the absence of unequivocal motor signs on the Unified Huntington’s Disease Rating Scale (UHDRS) [22]. A neurologist who was blind to genetic status and trained in the administration of the UHDRS performed the motor examination and filled in a score ranging from 0-3 (0= normal, 1= minor soft signs, 2= probable HD, 3= unquestionable HD). Carriers with a rating of 3 at baseline were diagnosed with HD and excluded from the study. One hundred six participants (33 carriers, 73 non-carriers) attended all follow-ups in the three-year period. Seven years after the start of the original study these participants were invited to take part in an additional follow-up. Twenty-nine carriers and 44 non-carriers consented to continue follow-up. Four carriers and 29 non-carriers did not re-enter the study after the original three year follow-up. One non-carrier was excluded for analyses since he had a minor stroke. This seven year follow-up study, therefore, reports on 29 carriers who were premanifest at baseline, and 43 non-carriers who served as controls. Carriers who where rated as unquestionable HD on the UHDRS after seven years were considered converters to manifest HD. The study was approved by the local Medical Ethical Committee. Written informed consent was obtained from all participants.

Procedure

All participants were evaluated with the UHDRS, including motor and behavioural assessment, and an extensive set of neuropsychological tests covering global cognitive function, memory, language and executive function (Tables 2 and 3) [17] [22]. The number of estimated years to clinical diagnosis (EYTD) was calculated using a CAG- and age-based predictive model designed by Langbehn et al. [23].

Motor assessment

The UHDRS motor rating was filled in by a neurologist (range 0-3). A Total Motor Score (TMS) was calculated by summing all motor items of the UHDRS [17] . Analysis of TMS subscales was restricted to eye movement, voluntary movement and chorea [22] .

Neuropsychological assessment

Neuropsychological tests included Mini Mental State Examination (MMSE) [24]; Wechsler Adult Intelligence Scale-Revised (WAIS-R) [25] subtests Information, Digit span, Arithmetic, Picture arrangement, Block design; Wechsler Memory Scale (WMS) [26] ;Verbal fluency (FAS) [27]; Boston naming test [28]; Symbol Digit Modalities Test (SDMT) [29]; Trail Making Test, consisting of a simple (TMT-A) and a more complex (TMT-B) version [30]; Stroop colour-word test [31]. Reaction time measures were both derived from a simple reaction time paradigm and a complex ‘choice’ reaction time paradigm (go/no go paradigm) [32]. A psychologist administered the cognitive tests [17].

Behavioural assessment

Behavioural and mood complaints were limited to the total behavioural score (TBS) that was obtained by adding the products of the frequency and severity for each item from the behavioural assessment of the UHDRS, administered by a psychologist [11]. Analysis of individual items from the behavioural assessment were restricted to four frequently reported neuropsychiatric symptoms; sadness, anxiety, aggression and irritability [33].

Statistical analysis

SPSS for Windows (release 16.0) was used for data analysis. Cross-sectional group differences at baseline and after 7 years were analysed with parametric or non-parametric tests when appropriate. Clinical group comparisons were corrected for age at assessment using ANCOVA. For longitudinal analyses we used the method reported by Solomon et al. (2008) since it accounts for slight differences in follow-up period (Solomon et al., 2008). For each clinical score the change over the 7-year period was calculated for each participant. This Rate of Change (further labelled as RoC) was computed as follows: RoC= (score 2 – score 1 )/ (age 2 -age 1 ). Differences in RoC between carriers and non-carriers were analysed using ANCOVA with correction for age at baseline. To assess the relationship between EYTD and RoC, Pearson correlation coefficients were calculated. The level of statistical significance was set at p= 0.01. A more liberal level of significance of 0.01<p *le; 0.05 was also reported to be of marginal interest to maximize any opportunity of finding trends towards group differences. Effect sizes are displayed as partial eta squared values ( ), eta squared values () and r-values.

Results

Group characteristics at study entry

The mean time interval between baseline and seven-year follow-up was 7.3 years (range 6.3-8.5 years). The group characteristics are described in Table 1. Carriers were younger than non-carriers (p = .015, = .082). No group differences emerged for gender and education.

Table 1. Characteristics of carriers and non-carriers at baseline

Carriers
n=29
Non-carriers
n=43
P
Male/female a 11/18 18/25 ns
Age (years) 37.9 (9.1) 43.8 (10.4) .015*
Education (years) 12.0 (2.9) 11.9 (2.8) ns
CAG repeat length b 42.9 (39-49) 20.7 (16-30)
Estimated years to clinical diagnosis (EYTD) b 15.6 (4.3-36.4)

Values in the table are means with SD or range b between parentheses. Independent t-tests were used except where Pearson -test was used a . *p= .05, **p =.01.

Cross-sectional Results

Carriers did not differ from non-carriers with respect to the UHDRS motor rating at baseline (p= .99, r= -0.002) or after seven years (p= .12,r= -0.192) (Table 2). Five carriers (17%) converted to unquestionable HD on the UHDRS during follow-up. Two converters were rated as normal at baseline. Three converters were rated as probable HD at baseline. One carrier who was rated as probable HD at baseline was rated as normal after 7 years. Three non-carriers were rated as probable HD at baseline and five after 7 years. None of the non-carriers was rated as unquestionable HD. From the three carriers where motor assessment was missing at baseline, two were rated as normal after 7 years and one carrier showed minor soft signs.

Mean clinical scores are displayed in Table 3. At baseline, carriers showed more complaints in aggression than non-carriers (p= .024, = .073). They also performed worse on the WAIS-R arithmetic subsection (p= .031, = .065), SDMT (p=.002, = .128), TMT-A (p= .006, = .104), TMT-B (p= .024, = .072), Stroop word (p= .008, = .097) and Stroop interference (p=.01, = .089). After seven years carriers additionally showed more motor abnormalities compared to non-carriers on the UHDRS TMS (p= .012, = .096), and on the UHDRS eye movement (p= .026, = .076), voluntary movement (p= .029, = .073) and chorea subsection (p= .005, = .118). Also, worse scores on the MMSE (p= .015, = .083), WMS memory quotient (p= .001, = .147), WMS concentration (p= .001, = .161), WMS logical memory (p= .025, = .07) WMS visual reproduction (p= .042, = .059) and Stroop colour (p= .009, = .097) emerged in carriers. Cross-sectional differences at baseline on aggression and Stroop word could not be demonstrated after seven years.

Without the five carriers who converted to manifest HD, baseline differences remained, except for TMT-B (p= .144, = .033). In the analyses after seven years, differences remained only on UHDRS TMS (p= .04, = .071) WMS memory quotient (p=.007, = .105), WMS concentration (p=.006, = .114) and Stroop colour (p= .027, = .075).

Table 2. Frequencies of UHDRS motor ratings in carriers and non-carriers at baseline and after 7 years

Carriers Non-carriers (n= 29) (n= 43) UHDRS rating Baseline Seven years Baseline Seven years
Normal 19 15 29 24
Minor soft signs 3 5 9 8
Probable HD 4 4 3 5
Unquestionable HD 5

Values are expressed as number. UHDRS= Unified Huntington’s Disease Rating Scale. Out of 29 carriers 3 motor assessments were missing at baseline. Out of 43 non-carriers two motor assessments were missing at baseline and six at follow-up.

Table 3. Mean (SD) performances on motor, behavioural and cognitive assessment at baseline and seven-year follow up in carriers and non-carriers

Baseline Carriers Non-carriers P Seven years Carriers Non-carriers P
Motorb
UHDRS TMS 6.9 (7.8) 6.3 (5.7) .124 .037 8.0 (15.5) 2.8 (2.7) .012* .096
Eye movement 2.2 (3.3) 1.9 (2.8) .113 .039 1.8 (4.2) 0.9 (1.3) .026* .076
Voluntary movement 2.1 (2.1) 1.9 (2.0) .135 .035 2.1 (3.9) 0.9 (1.3) .029* .073
Chorea 1.2 (2.5) 0.9 (2.1) .363 .013 2.6 (5.2) 0.5 (0.8) .005** .118
Behaviourb
UHDRS TBS 9.0 (13.4) 5.2 (7.2) .484 .007 9.6 (13.1) 8.1 (12.6) .786 .001
Sadness 1.9 (2.8) 1.3 (2.2) .989 .00 2.0 (3.2) 2.0 (3.0) .436 .009
Anxiety 1.3 (2.7) 1.0 (1.9) .702 .002 1.8 (2.8) 1.3 (2.5) .873 .00
Aggression 1.5 (3.0) 0.2 (0.8) .024* .073 1.6 (3.0) 0.8 (2.3) .558 .005
Irritability 1.4 (2.8) 1.0 (2.1) .696 .002 1.6 (2.7) 1.7 (2.7) .383 .011
Neuropsychology
MMSE, total score 28.2 (1.1) 28.6 (1.3) .248 .019 28.3 (1.3) 29.0 (1.2) .015* .083
WAIS-R Information 10.4 (3.0) 10.8 (1.8) .932 .00 10.6 (2.8) 10.9 (2.0) .899 .00
Digit span 8.1 (2.6) 8.9 (2.2) .076 .045 8.4 (3.0) 9.3 (2.1) .078 .044
Arithmetic 10.6 (3.3) 12.3 (2.5) .031* .065 10.6 (3.4) 12.4 (2.6) .023* .073
Picture arrangement 8.8 (2.5) 9.2 (2.6) .217 .022 9.3 (2.7) 9.2 (3.1) .347 .013
Block design 11.8 (3.0) 11.7 (2.9) .591 .004 11.6 (3.3) 11.9 (2.9) .118 .036
WMS, memory quotient a 115.2 (15.6) 122.1 (14.7) .062 .05 113.8 (19.0) 127.8 (15.3) .001** .147
Concentration 7.7 (1.8) 8.4 (1.2) .107 .037 6.8 (2.1) 8.4 (1.2) .001** .161
Logical memory 9.4 (3.1) 10.1 (3.2) .237 .02 8.2 (3.3) 10.0 (3.6) .025* .07
Visual reproduction 11.1 (2.3) 11.2 (2.2) .686 .002 10.2 (3.3) 11.2 (2.2) .042* .059
Associative learning 18.0 (2.2) 18.0 (2.6) .719 .002 17.2 (2.9) 17.5 (3.0) .600 .004
Verbal fluency (FAS) 33.7 (9.4) 34.2 (11.5) .869 .000 34.8 (14.0) 37.4 (12.0) .387 .011
Boston naming test 26.6 (2.6) 26.1 (4.6) .712 .002 27.1 (2.5) 27.7 (2.0) .308 .015
SDMT, total score 48.2 (10.8) 53.2 (10.1) .002** .128 53.3 (15.8) 58.7 (10.5) .006** .103
TMT-A, seconds b 38.3 (14.8) 31.2 (9.4) .006** .104 33.0 (17.6) 28.4 (9.4) .035* .063
TMT-B, seconds b 59.6 (22.9) 51.4 (17.4) .024* .072 66.1 (47.1) 52.1 (23.2) .017* .079
Stroop colour 74.0 (11.7) 77.4 (10.8) .054 .053 71.5 (14.6) 77.6 (13.3) .009** .097
Stroop word 95.5 (16.5) 103.4 (14.4) .008** .097 96.1 (20.4) 101.2 (15.7) .086 .043
Stroop interference 42.1 (10.4) 45.2 (8.5) .01** .089 41.5 (9.8) 45.6 (8.8) .001** .150
Reaction time simple, milliseconds b 428.5 (70.5) 422.2 (63.7) .298 .017 484.6 (113.5) 455.8 (80.2) .135 .036
Reaction time complex,milliseconds b 568.1 (84.8) 552.7 (85.0) .146 .033 640.8 (127.6) 615.0 (106.2) .112 .041

Mean scores (SD). Raw scores are displayed except for WMS memory quotient, which is calculated with a correction for age. ANCOVA corrected for age except for a . *p= .05, **p =.01. Effect sizes are displayed as partial eta squared ( ) values. Higher scores correspond with worse performance b . UHDRS= Unified Huntington’s Disease Rating Scale. TMS= Total Motor Score. TBS= Total Behavioural Score. MMSE= Mini Mental State Examination, WAIS-R= Wechsler Adult Intelligence Scale-Revised. WMS= Wechsler Memory Scale, SDMT= Symbol Digit Modalities Test (number correct), TMT= Trail Making Test (sec), Reaction time simple= Reaction time single stimulus conditions (milliseconds), Reaction time complex= Reaction time complex conditions (milliseconds).

Longitudinal Results

The Rates of Change (RoC) on the motor, behavioural and cognitive tests are displayed in Table 4. Carriers demonstrated a greater rate of decline compared to non-carriers on the UHDRS TMS (p= 0.024, = .083) and chorea subsection (p= .008, = .114), the WMS memory quotient (p= .015, = .084), WMS concentration (p= .007, = .101) and WMS visual reproduction (p= .045, = .057). Without the carriers who converted to manifest HD, the only remaining significant decline in carriers compared to non-carriers was on WMS concentration (p= .041, = .063).

Table 4. Mean (SD) Rate of Change (RoC) in carriers and non-carriers between baseline and 7-year follow-up

Carriers Non-carriers (n= 29) (n=43) RoC RoC P
Motorb
UHDRS TMS 0.217 (1.440) -0.475 (0.639) .024* .083
Eye movement -0.037 (0.401) -0.141 (0.294) .431 .011
Voluntary movement 0.012 (0.375) -0.149 (0.252) .103 .045
Chorea 0.235 (0.523) -0.052 (0.328) .008** .114
Behaviouralb
UHDRS TBS 0.164 (2.178) 0.380 (1.485) .634 .003
Sadness 0.025 (0.581) 0.093 (0.313) .634 .003
Anxiety 0.079 (0.556) 0.043 (0.326) .554 .005
Aggression 0.019 (0.457) 0.084 (0.321) .388 .011
Irritability 0.039 (0.493) 0.091 (0.375) .401 .010
Neuropsychological
MMSE, total score 0.012 (0.213) 0.057 (0.200) .319 .014
WAIS-R Information 0.030 (0.236) 0.007 (0.129) .706 .002
Digit span 0.048 (0.260) 0.057 (0.225) .994 .000
Arithmetic -0.006 (0.321) 0.016 (0.296) .728 .002
Picture arrangement 0.067 (0.255) 0.004 (0.314) .745 .002
Block design -0.028 (0.314) 0.035 (0.228) .156 .029
WMS, memory quotient -0.265 (1.813) 0.760 (1.593) .015* .084
Concentration -0.134 (0.236) 0.004 (0.148) .007** .101
Logical memory -0.170 (0.369) -0.015 (0.298) .065 .049
Visual reproduction -0.129 (0.327) 0.008 (0.313) .045* .057
Associative learning -0.119 (0.330) -0.046 (0.368) .656 .003
Verbal fluency (FAS) 0.187 (1.181) 0.428 (1.131) .174 .027
Boston naming test 0.074 (0.193) 0.211 (0.622) .351 .013
SDMT, total score 0.709 (1.440) 0.723 (0.780) .827 .001
TMT-A, seconds b -0.781 (2.073) -0.375 (1.105) .446 .008
TMT-B, seconds b 0.860 (4.552) 0.088 (2.364) .172 .027
Stroop colour -0.325 (1.478) 0.027 (0.985) .125 .034
Stroop word 0.112 (1.730) -0.369 (1.409) .300 .016
Stroop interference -0.077 (1.201) 0.071 (0.775) .470 .008
Reaction time simple, milliseconds b 6.706 (11.411) 4.229 (7.995) .627 .004
Reaction time complex, millisecondsb 7.893 (8.229) 8.953 (12.164) .796 .001

Mean RoC (SD). ANCOVA corrected for age at baseline. *p .05, **p .01. Effect sizes are displayed as partial eta squared () values. Positive scores indicate an improvement over time and negative scores indicate deterioration over time, except for b where positive scores indicate deterioration and negative scores indicate an improvement. RoC= Rate of Change. UHDRS= Unified Huntington’s Disease Rating Scale. TMS= Total Motor Score. TBS= Total Behavioural Score. MMSE= Mini Mental State Examination, WAIS-R= Wechsler Adult Intelligence Scale-Revised. WMS= Wechsler Memory Scale, SDMT= Symbol Digit Modalities Test (number correct), TMT= Trail Making Test (sec), Reaction time simple= Reaction time single stimulus conditions (milliseconds), Reaction time complex= Reaction time complex conditions (milliseconds).

Associations between estimated years to clinical diagnosis and Rates of Change

Table 5 shows that proximity to estimated clinical diagnosis (EYTD) in carriers was associated with a greater rate of decline on WAIS-R Information (p= .033, = .397), WMS memory quotient (p= .024, = .426), WMS concentration (p= .034, = .396), WMS logical memory (p= .016, = .444), WMS visual reproduction (p= .012, = .461) and Reaction time complex condition (p= .046, = -.410). Excluding the carriers who converted to manifest HD, associations remained between EYTD and rate of decline on WMS memory quotient (p= .045, = .421), WMS logical memory (p= .028, = .448) and WMS visual reproduction (p= .005, = .553).

Table 5. Correlations between estimated years to clinical diagnosis (EYTD) and rate of Change (RoC) in carriers

EYTD RoC r-value P
Motor assessment b
UHDRS TMS -.266 .189
Eye movement -.264 .193
Voluntary movement -.218 .286
Chorea -.222 .276
Behavioural assessment b
UHDRS TBS -.043 .828
Sadness -.137 .486
Anxiety .104 .598
Aggression -.241 .217
Irritability .062 .753
Neuropsychological assessment
MMSE, total score .233 .224
WAIS-R Information .397 .033*
Digit span .082 .672
Arithmetic .338 .073
Picture arrangement .124 .529
Block design .267 .170
WMS, memory quotient .426 .024*
Concentration .396 .034*
Logical memory .444 .016*
Visual reproduction .461 .012*
Associative learning -.002 .990
Verbal fluency (FAS) .089 .645
Boston naming test .130 .501
SDMT, total score .289 .129
TMT-A, secondsb -.171 .376
TMT-B, secondsb -.328 .082
Stroop colour .166 .398
Stroop word .345 .067
Stroop interference -.022 .910
Reaction time simple, millisecondsb -.214 .315
Reaction time complex, millisecondsb -.410 .046*

Pearson correlation coefficients (r-value) with *p ≤ .05. RoC= Rate of Change. Positive scores indicate an improvement over time and negative scores indicate deterioration over time, except for b where positive scores indicate deterioration and negative scores indicate an improvement. UHDRS= Unified Huntington’s Disease Rating Scale. TMS= Total Motor Score. TBS= Total Behavioural Score. MMSE= Mini Mental State Examination, WAIS-R= Wechsler Adult Intelligence Scale-Revised. WMS= Wechsler Memory Scale, SDMT= Symbol Digit Modalities Test, TMT= Trail Making Test, Reaction time simple= Reaction time single stimulus conditions, Reaction time complex= Reaction time complex conditions.

Discussion

This longitudinal study with a follow-up of seven years demonstrated a significant decline in motor functioning, memory, and concentration in premanifest carriers of the HD gene mutation. Cognitive changes over time could be primarily ascribed to carriers who converted to manifest HD.

Cross-sectional results at baseline were comparable to previous studies demonstrating abnormalities in carriers in executive function, specifically attention, cognitive flexibility, psychomotor speed, and inhibitory processes, as assessed with WAIS-R arithmetic, SDMT, TMT and Stroop [5][6][34]. Without the carriers who converted to manifest HD during the study, cognitive abnormalities at baseline could still be demonstrated. This indicates that subtle cognitive deviations, especially on executive functions, are present, even long before the onset of HD motor signs and may be related to early deficits in the basal-ganglia circuitry [15][35]. After seven years additional cross-sectional differences emerged, with carriers showing more motor abnormalities on the UHDRS motor section and worse performance on memory and concentration tasks from the WMS, compared to non-carriers [2][6][7][10][13].

Remarkably, we could not demonstrate a significant decline on the executive tasks that proved sensitive for the earliest cognitive manifestations of HD at baseline. Also, we did not find an association between estimated years to clinical diagnosis and rate of change on these tasks. Practice effects on these type of tasks and familiarity with the test procedures might compensate for subtle cognitive deficits [19]. This is important for the interpretation of longitudinal data. A follow-up study by Paulsen et al. (2001) [36] showed an improvement on executive tasks in individuals at-risk for HD and a decline in converters. This is in accordance with our finding that differences between groups at follow-up, could be ascribed in particular to carriers who converted to manifest HD during the study. Indeed, previous longitudinal studies that did demonstrate a decline on these tasks displayed a much higher rate of carriers converting to manifest HD [20][21][36][37]. Duff et al. (2007) suggest that the amount of individual practice effects in longitudinal studies might provide valuable information on cognitive status and predict long-term cognitive outcome [38].

The WMS memory quotient shows an absence of practice effects in carriers compared to non-carriers, suggesting cognitive dysfunction in carriers. Indeed, we did demonstrate a decline in memory function and concentration on the WMS compared to non-carriers. These changes over time could be attributed to the carriers who converted to manifest HD, except for the decline on the concentration subtest. Also, when estimations of age at clinical diagnosis were used, an association with rate of change on the WMS could be demonstrated. Memory decline in individuals approaching clinical disease onset is confirmed by other studies [7][12][13]. The fact that we could not detect cross-sectional differences between carriers and non-carriers at baseline on memory tasks is in line with the observation by Snowden at al. (2002) that memory function shows a precipitous decline around the time of clinical onset [20]. Perhaps, concentration changes evolve more slowly and precede the effect on memory tasks. It can be argued, however, that the concentration subtest of the WMS does not reflect selective attention but rather general cognitive slowing, since it is a timed task.

Interestingly, many longitudinal studies reported mainly on motor and executive tasks, specifically psychomotor speed and cognitive flexibility [21][36][39]. This is also reflected in the broadly used UHDRS cognitive section that is highly influenced by motor speed. Our findings confirm the importance of these tasks in detecting premanifest abnormalities. However we advocate the addition of memory tasks for this purpose since memory decline may be a sign of conversion to manifest HD and these tasks have the advantage to lack the motor component.

Behavioural changes could not be demonstrated in the current study. Complaints about aggression on the UHDRS behavioural section at baseline disappeared in subsequent years and confirm the variability in occurrence of psychiatric symptoms [17]. Furthermore, as many objective, quantitative cognitive tasks are available, these are more prominently represented in the present study design. In current studies, more attention is paid to behavioural and mood changes using extensive batteries of neuropsychiatric questionnaires including the Problem Behaviours Assessment for Huntington Disease (PBA-HD) [40][8]. Also, in motor functioning more continuous measures of motor function should be included in clinical studies since reliability of the UHDRS motor assessment is somewhat limited, especially when motor signs are very subtle [41]. This is reflected in the large number of non-carriers in our study that are rated with minor soft signs or probable HD. Converters to manifest HD in the current study mainly developed signs of chorea. We suggest that the appearance of subtle choreatic movements is an important specific feature for the motor examiner when diagnosing unquestionable HD. In a recent study, quantitative voluntary neurophysiological motor tasks proved sensitive for subtle motor deficits in carriers more than a decade before estimated clinical onset and might be used more commonly in premanifest HD research [8].

In the evaluation of longitudinal results of the current and previous studies, many discrepancies appear. Heterogeneity in closeness to clinical disease onset within and between studies and differences in the studied measures are probably the most important factors. Follow-up studies should show international uniformity in inclusion criteria and assessment protocol. Furthermore, longitudinal studies combining clinical and biological measures will provide more insight into the processes underlying clinical changes and may lead to a combination of measures suitable for objectively tracking premanifest HD. Ongoing international, multi-centre, multidisciplinary trials are an important example in improving research on the subject and in realising fast recruitment of study samples with sufficient power. PREDICT-HD [6], TRACK-HD [8] COHORT [42] and REGISTRY [43] are longitudinal observational studies on clinical and biological markers in the evolution of HD. Longitudinal data on these impressive studies will contribute substantially to the knowledge on the phase of onset of HD.

Conclusion

Standardized motor assessments and objective memory and concentration tasks prove sensitive for change, specifically in the phenoconversion phase. Executive tasks were found to be sensitive for subtle cognitive abnormalities in premanifest HD, a decline over time could, however, not be demonstrated on these tasks. Strengths of the current study are the lengthy follow-up and the comprehensive assessment battery, enabling us to detect changes over time. For the purpose of therapeutic trials, however, suitable instruments are still needed to track changes over shorter intervals. Extended follow-up periods appear useful only for clinical purposes since information about clinical disease onset and progression is of crucial importance in improving the psychosocial support for patients and their families. Because of discrepancies between studies and the discontinuous evolvement of clinical changes, uniformity in international research through multi-site collaborative research models will improve premanifest HD research substantially and point to a selection of specific clinical measures sensitive to change in premanifest HD.

Acknowledgements

None

Funding information

None

Competing interests

The authors have declared that no competing interests exist.

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No evidence of impaired gastric emptying in early Huntington‘s Disease http://currents.plos.org/hd/article/no-evidence-of-impaired-gastric-emptying-in-early-huntingtons-disease/ http://currents.plos.org/hd/article/no-evidence-of-impaired-gastric-emptying-in-early-huntingtons-disease/#respond Wed, 16 Nov 2011 14:28:20 +0000 http://currents.plos.org/hd/?post_type=article&p=2821

Introduction

Weight loss is a main feature in Huntington’s disease (HD) and was found to be manifest even at early stages of the disease. [1][2][3][4][5] Multifactorial causes, such as decreased caloric intake due to dysphagia and a higher energy expenditure due to increased motor activity have been discussed as being a possible reason for weight loss especially at the advanced stages of the disease. [6][7][8][9][10] Using a whole body indirect calorimetry in both early stage HD patients and the R6/2 transgenic mouse model of HD, Goodman and colleagues were able to demonstrate that patients with early HD tended to have a negative energy balance for reasons not related to their movement disorder, which was paralleled in the transgenic R6/2 mice. [4] This leads to the assumption of an increased metabolic rate as a main reason for weight loss in HD, which is supported by other experiments in the transgenic R6/2 mice. [4][11][12] In a study investigating the direct relation between the number of CAG repeats in the mutant huntingtin gene and weight loss, Aziz and colleagues found a correlation between both of these factors and discussed a hypermetabolic state as being a reason for weight loss, occurring even at early stages of the disease. [13] They discussed a hypermetabolic state as being likely to stem directly from interference of the mutant protein with cellular energy homeostasis and thus reflecting fundamental pathologic mechanisms underlying HD and not to be secondary to hyperactivity. Since mutant Huntingtin (mtHtt) is not only expressed in the brain of HD patients, but also in the gastrointestinal (GI) tract, a recently published study investigated the GI tract in the R6/2 mice model for HD. This study describes a loss of enteric neuropepitdes, a decreased mucosal thickness and villius length and also an impaired gut motility, diarrhea, and malabsorption of food, suggesting that GI dysfunction plays an important role in weight loss in HD mice. [14]

In addition, gastrointestinal dysfunction is discussed as being the main reason for weight loss in Parkinson’s disease (PD). [15] In a study using a solid meal and the 13 C-sodium octanoate breath test for measurement of gastric emptying in patients with PD, Goetze and colleagues found 88% of PD patients suufered from delayed gastric emptying when compared with controls. The severity of motor impairment was associated with gastroparesis. [16] Several other studies confirm an impaired gastric emptying in PD, some of them with a rate of 100% of PD patients. [16][17][18][19][20][21] One study describes a 60% delay in gastric half emptying time in the PD patient group after a solid test meal using the non-invasive 13 C-sodium octanoate breath test for evaluation of gastric emptying. [17] Neuropathological findings suggest enteric dysfunction to be one of the initial pathophysiological events in PD. [16][22] Central and enteric nervous system involvement in PD is discussed as being a pathophysiologic basis for this dysfunction. [15]

Autonomic nervous dysfunction was found to be present in HD, too. [23] Thus, the aim of the current study was to investigate gastric emptying in early HD patients without medication as a possible additional reason for weight loss by using the well-established 13 C-octanoate breath test. [16][17][18][19][20][21][24]

Methods

Participants

11 manifest HD patients with genetically confirmed diagnosis and without any medication in at clinically early stages of the disease (Shoulson stage I/II) and 11 controls were recruited from the HD centre Bochum, Germany. [25] Participants with known concurrent gastrointestinal diseases or previous operations of the gastro-intestinal tract were excluded, as well as patients with other severe diseases, diabetes mellitus, severe respiratory dysfunction, and malignancies. Also participants with concurrent liver diseases or excessive alcohol consumption (50 g/d of ethanol) were excluded. All participants had lab parameters for ALT, AST, LDH, cholesterol and triglycerides within the normal range, as well as normal findings for the ultrasonography of the upper abdomen. Pregnant and breast-feeding women were excluded. All HD participants underwent neurological investigation and were scored according to the UHDRS items “motor scale” (MS), “total functional capacity” (TFC) “independence scale” (IS) and the items verbal fluency test, symbol digit test, interference test, color naming and color reading which were summarized as “cognitive score” (CS). [26] Fine motor skills were additionally measured by simple (tapping; higher motor impairment leads to lower test results) and complex (pegboard; higher motor impairment leads to higher test results) instrumental movement tests. [27][28][29][30] The severity of depressive symptoms was assessed by using the Beck’s depression inventory (BDI) and Hamilton depression rating scale. [31][32] Clinical characteristics of all HD patients are given in table 1. In addition we calculated the disease burden score (DBS = [CAG repeat – 35.5] x age) for each subject. [33] The study was approved by the ethic committee of the Ruhr-University Bochum, Germany (registration-number 2719). Participants gave informed written consent according to GCP/ICH.

Parameter HD Participants Controls
Age [yr] 42.4 ± 8.4 (29-57) 48.9 ± 9.6 (38-69)
Gender (male/female) 3/8 3/8
BMI 22.5 ± 3.5 (16-30) 26.5 ± 6.4 (19-42)
Weight [kg] 63.6 ± 14.1 (42-85) 84.5 ± 22.5 (54-128)
Height [cm] 166.8 ± 10.1 (153-183) 178.2 ± 9.4 (164-190)
AO motor 39 ± 8.6 (25-51)
AO psychiatric 38 ± 20.9 (29-50)a
CAG expanded 45 ± 2.9 (42-51)
Disease burden score 386.59 ± 66.06 (273-483)
Disease duration [yr] 4.2 ± 2.5 (0.1-9)
UHDRS MS 30.8 ± 18.7 (5-72)
UHDRS TFC 10.2 ± 1.9 (7-12)
UHDRS IS 81.8 ± 9.8 (70-100)
UHDRS CS 195.1 ± 79.0 (98-346)
Verbal fluency 22.5 ± 18.2 (4-69)
SDMT 27.2 ± 10.6 (16-44)
Stroop color 47.1 ± 17.1 (26-74)
Stroop word 68.1 ± 22.8 (32-100)
Stroop interference 29.5 ± 16.1 (10-59)
Hamilton 12.8 ± 10.0 (1-26)
Beck depression inventory 12.3 ± 13.4 (0-39)
Tapping dominant 129.2 ± 44.8 (47-198)
Tapping non dominant 99.4 ± 33 (38-161)
Pegboard dominant [sec] 68.6 ± 24.8 (42.2-120.9)
Pegboard non dominant [sec] 80.9 ± 40.2 (43.9-184.0)

Table 1: Clinical characteristics of 11 HD patients and 11 matched controls; values are given as mean ± SD; range (min-max) in brackets; Abbreviations: BMI – body mass index, yr – years, AO – age at onset, a n = 6; UHDRS – unified Huntington´s disease rating scale, MS – motor score TFC – total functional capacity, IS – independence scale, CS – cognitive sum score, SDMT – symbol digit modalities test; sec – seconds. * – significant differences.

Test meal and 13C-octanoate breath test technique

The 13 C-octanoate breath test was used in the same way as described earlier. [16][17][18][34] In summary: After an overnight fasting each participant received a solid test meal consisting of an egg omelet of one egg, 60 g of white bread, 5 g of margarine and 150 ml of water (14 g of proteins, 26 g of carbohydrates and 9 g of fat, 241 kcal) labeled with 100 mg of 13C-sodiumoctanoate (chemical purity of 99,7 % and an isotopic purity of 99,1 %) at 8 AM. Breath samples, which were expired in close aluminized plastic breath bags of 50 ml content were obtained before substrate administration at baseline and after 10, 20, 30, 45, 60, 75, 90, 105, 120, 135, 150, 165, 180, 200, 220 and 240 minutes. The subjects were kept in a relaxed sitting position during the octanoate breath test (OBT). Physical activity was restricted during the test. All subjects consumed their test meal within 10 minutes. The 13 C/ 12 C isotope ratio of the breath samples was analysed by isotope-selective nondispersive infrared spectrometer (NDIRS). The results were both expressed as delta (δ) value per mil (‰) and delta over baseline (dob = δ s – δ 0 ). Definition of the δ-value: δ s = (R S /R PDB -1) x 1000 [‰] with R s = 13 C/ 12 C isotope ratio in CO 2 in breath and R PDB = 0.0112372 = isotope ratio in reference (PDB = PeeDeeBelmnite, South Carolina; δ 0 = isotope ratio at baseline).

Mathematical analysis of 13CO2 excretion curves and statistical analysis

As regards the measuring of the proportion of the 13 C-sodium octanoate given by mouth that is metabolised the results were expressed as a percentage dose of 13 C recovered (PDR) over time for each time interval from which the cumulative PDR (cPDR), obtained by numerical integration from PDR values, was calculated for each time interval. This calculation is based on the formula as proposed by Ravussin. [35] CO 2 production rate was assumed as being 300 mmol per unit of body surface area per hour. The body surface area was calculated using the Haycock weight-height formula. [36] The evaluation of the OBT for gastric emptying was done by non-linear regression analysis of the 13 CO 2 -excretion curves (PDR) with the formula PDR(t) = at b e -ct . The expression ln a, as gastric emptying coefficient (GEC) is a reliable parameter to describe the rate at which the stomach empties. The percentage of 13 CO 2 cumulative values was fit using a model given by the formula cPDR(t) = m(1-e -kt ) ß , where y is cPDR at time t in hours and m, k and ß are regression estimated constants, with m being the total amount of 13 CO 2 when time is infinite. Half gastric emptying time (t 50 ) was calculated by taking PDR(t) equal to m/2 in the PDR equation which is expressed as t 50 = (-1/k)ln (1-2 -1/ß ). The Lag phase is expressed as t lag = 1/klnß. [37] Statistical analysis was carried out as a descriptive evaluation of GEC, t 50 (min), tl ag (min) and t peak (min) and characteristics of participants (mean ± SD).

Gastroparesis Cardinal Symptom Index (GCSI) and Short-Form Leeds Dyspepsia Questionnaire (SF-LDQ)

The well-validated Gastroparesis Cardinal Symptom Index (GCSI) was used for clinical evaluation of gastroparesis symptoms. GCSI quantifies nine symptoms in the three different subscales: nausea and vomiting, postprandial fullness, and bloating. [38] In addition patients were asked about the frequency and severity of their stomach complaints, heartburn, burping and nausea symptoms according to the Short-Form Leeds Dyspepsia Questionnaire (SF-LDQ). [39]

The data analysis and statistics were performed by using the commercial software program SPSS statistics 19. All measured parameters and clinical data were first analysed descriptively and they were when presented as mean ± SD. Normality of distribution of the data was tested with the one-sample Kolmogorov-Smirnov test. Data were analyzed using the independent t-test for comparison between HD participants and controls. Pearson correlation analysis was used for exploratory statistical calculations of the normal distributed data.

Results

As expected HD participants had a lower body mass index compared to controls. One HD patient had underweight with a body mass index of 16. There were however, no significant differences between groups concerning any of the clinical data (table 1). Breath test results and clinical data showed normal distribution except for gender.

Results of the 13 C-sodium octanoate breath test are given in table 2. 13 CO 2 -excretion curves (PDR) and the percentage of 13 CO 2 cumulative values (cPDR) showed normal excretion of 13 C. For PDR only PDR max for the maximum amount of 13 CO 2 -excretion reached during testing time is listed in table 2. There were no significant differences compared to controls for the values decisive for the evaluation of gastric emptying, such as PDR max , cPDR, GEC, t 50 (min) and tl ag (min; see table 2). Compared to standard values given in literature, the most important parameters t 50 and tl ag were within normal range (t 50 < 200 min and tl ag <130 min; no data is available in literature for GEC, cPDR and PDR max ) and none of the patients had abnormal breath test results (see figure 1). [24]

OBT Parameter Results HD Results Controls
PDR max 9.76 ± 2.866.32 – 14.18 9.85 ± 2.615.58 – 14.09
cPDR 23.64 ± 7.92(14.72 – 37.0) 25.38 ± 7.92(15.51 – 34.94)
GEC 2.96 ± 0.84(0.95 – 3.77) 2.89 ± 0.36(2.42 – 3.27)
t 50 129.26 ± 38.84(77.15 – 197.60) 135.88 ± 22.27(95.74 – 167.47)
t lag 85.45 ± 25.14(55.95 – 123.42) 80.74 ± 17.33(56.31 – 109.05)

Table 2: 13 C-sodium octanoate breath test results; values are given as mean ± SD; range (min-max) in brackets, Abbreviations: PDR max for the maximum amount of 13 CO 2 -excretion reached during testing time [%]; cPDR – cumulative exhaled 13 CO 2 (cPDR [%]) after 240 minutes; GEC – gastric emptying coefficient; t peak – time to highest exhaled 13 CO 2 value [min]; t 50 – half gastric emptying time [min]; t lag – Lag phase [min]. * – significant differences.

Fig. 1: Gastric emptying of solids measured by 13 C sodium octanoate breath test presented as individual lag phase (tl ag ) and gastric half emptying time (t50) in 11 HD participants (controls not shown). The normal t 50 range reported from literature (<200 min) is shown by the dotted line. A normal t lag range is reported to be below 130 min. [24]

Gastroparesis Cardinal Symptom Index (GCSI) was 0.3855 (SEM ± 0.48; range 0 – 1.28) and Short-Form Leeds Dyspepsia Questionnaire (SF-LDQ) was 0.8182 (SEM ± 1.83; range 0 – 6) for HD participants. Thus, both questionnaire results were in line with published data from healthy controls, without clinical evidence of gastroparesis or dyspepsia. [38][39] GCSI was 0.3027 (SEM ± 0.30; range 0 – 0.83) and SF-LDQ was 2.273 (SEM ± 2.195; range 0 – 7) for controls. Differences were not significant (data not shown).

Explorative correlation analysis of breath test results given in table 2 with clinical symptoms from table 1 showed no significant correlation, except for the cognitive sum score and t 50 (p 0.018, r -.692) and tl ag (p 0.019, r -.688), as well as for PDR max and the total functional capacity (TFC; p 0.014, r .712; no analysis of the cognitive subtests was done; see figure 2). Especially no correlation to motor symptoms was found.

Fig. 2: A strong relation can be seen between gastric emptying of solids measured by 13 C sodium octanoate breath test

A strong relation can be seen between gastric emptying of solids measured by 13 C sodium octanoate breath test, presented as individual t lag (a) and t 50 (b) in minutes and the cognitive sum score of the UHDRS (t 50 – p 0.018; r – .692 and t lag – p 0.019; r – .688), as well as for PDR max (c) and total functional capacity (TFC; p 0.014, r .712).

The correlation analysis of GCSI and SF-LDQ with clinical symptoms showed no significant correlation with any of the clinical characteristics from table 1.

Discussion

Several factors such as dysphagia, an increased motor activity, an increased metabolic rate and hypermetabolic state have been discussed as contributing to weight loss even at early stages of HD. In addition, a recently published study also suggested gastrointestinal tract dysfunction as a reason for weight loss in a Huntington mouse model, similar to findings for Parkinson’s disease (PD). [14][15][21] Several studies describe a delay in gastric emptying for 88% or even for up to 100% of PD patients. [16][17][18][19][20][21] Contrary to this, in our pilot study on HD patients did not provide any evidence of impaired gastric emptying by using a solid meal and the 13 C-sodium octanoate breath test. There were no significant differences compared to controls and also compared to standard values given in literature all parameters were within normal range. In addition, we had no clinical evidence of gastroparesis or dyspepsia symptoms by using the “Gastroparesis Cardinal Symptom Index” and “Short-Form Leeds Dyspepsia Questionnaire” in our cohort. Thus, our data contrast with data for PD, but also with data for HD mice.

As a possible explanation, gastric emptying may only contribute to weight loss more severe stages of HD. R6/2 HD mice usually show a very rapid course of the disease. A recent published study investigating the GI tract in a R6/2 mice model carrying a mean of 204 CAG-repeats describes several GI abnormalities, including an increased water content in R6/2 compared to feces in wild type mice from 8 weeks of age. The fecal output as a percentage of food intake however, was only significantly increased at 12 weeks, but not at 8 weeks. [14] This indicates that the occurrence of malabsorption of nutrients plays an important role in weight loss in HD mice only in the end stage. The study did not investigate early stages of the disease prior 8 weeks in the mice model.

An earlier study from our group describes a high prevalence of gastritis or esophagitis as an accidental finding during PEG-placement, as a possible indication of gastrointestinal tract dysfunction in HD patients at advanced stages of the disease. [40] The findings in this study were also correlated with the duration and severity of the disease, also suggesting that gastrointestinal tract dysfunction might occur later in the course of the disease. We presumed that influences from the disease itself as well as secondary mechanisms like medication and general disability may contribute. [40] It was also the case in this study that the focus was not on early symptomatic patients.

To summarize, the pilot data from our study suggest that impaired gastric emptying is not an early event in HD when compared to PD. We can not exclude that gastric emptying contributes to weight loss at more advanced stages of the disease.

Surprisingly, we found a significant correlation for the cognitive sum score und the total functional capacity of the UHDRS and breath test results, such as t 50 (47.8% of variance), tl ag (47.4% of variance) and PDR max which usually shows the most precise quantification (50.6% of variance; see figure 2). This was not expected, since OBT results were within normal range. Cognitive decline, however, is a very early event in the course of HD. [41] In fact the cognitive sum score from our HD participants showed a broad range from 98-346 points with a mean of 195.1 points indicating a cognitive impairment in most of the patients. It is well known that the performance in UHDRS cognitive tests declined during disease progression, as did the functional capacity (TFC), which is highly dependent on cognitive tasks. [42][43] A decrement in mitochondrial function is discussed as contributing to age-dependent functional deficits in neurons and myocytes in normal aging and other neurological disorders, such as Alzheimer’s disease, accompanied with a cognitive decline. [44][45][46] Mitochondrial dysfunction is well known in HD and seems to be a relevant and early feature in the pathology. [47][48][49] Mutant htt (mtHtt) tends to aggregate in cytoplasm and nucleus of neurons as well as non-neuronal tissues including the liver. [50][51][52][53][54][55] Within the mitochondria, octanoic acid undergoes b-oxidation. Octanic acid generates acetyl coenzyme A which enters the Krebs cycle and is oxidized to CO 2 . Therefore breath tests based on octanoate, usually used to assess gastric emptying, should also reflect mitochondrial function. [56] Thus, one can speculate that a correlation of OBT results with results of cognitive tasks might reflect a parallel decline in cognitive and mitochondrial function.

To our knowledge this is the first study dealing with gastrointestinal track dysfunction in HD in vivo. A limitation of our study is the relative small number of participants. To exclude drug effects we only included patients without any medication and without serious comorbidities. On the other hand, due to the fact that this is a very rare group of patients it is a strength of our study that we can exclude medication effects.

Competing interests

The authors declare that they have no competing interests.

Ethics

The local ethics committee of the university approved this study.

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An International Survey-based Algorithm for the Pharmacologic Treatment of Irritability in Huntington’s Disease http://currents.plos.org/hd/article/an-international-survey-based-algorithm-for-the-pharmacologic-treatment-of-irritability-in-huntingtons-disease/ http://currents.plos.org/hd/article/an-international-survey-based-algorithm-for-the-pharmacologic-treatment-of-irritability-in-huntingtons-disease/#respond Fri, 02 Sep 2011 14:30:04 +0000 http://currents.plos.org/hd/?post_type=article&p=2897

Introduction

Huntington’s disease (HD) is a neurodegenerative disorder with an autosomal dominant hereditary pattern, caused by an elongated CAG repeat on chromosome 4 [1]. HD is clinically characterized by motor dysfunction, neuropsychiatric symptoms, and cognitive impairment leading to dementia at end-stage. Onset of clinical symptoms most commonly occurs between the ages of 30 and 50 years, and follows a progressive course with an average disease duration of 20 years. No treatment is available to delay onset or to slow progression of the disease.

Irritability is a frequently reported neuropsychiatric disorder in HD, in addition to depression, anxiety, apathy, and obsessive-compulsive behaviors [2]. HD irritability has been defined as a temporary psychologic state characterized by impatience, intolerance, and reduced control over temper, which can progress to angry and aggressive verbal or behavioral outbursts [3]. Estimates of irritability vary from 31% to 65% according to studies using different methods of sampling and measurement [4] [5]. A study comparing self and care-partner assessment shows a higher reported incidence for irritability when information is obtained from care-partners [6], suggesting a component of lack of awareness in patients. However, many are aware and recognize that they are too easily provoked, and take more time to calm down after provocation [7]. Irritability can precede the onset of motor symptoms of HD [8] and it occurs over all stages of disease. However, measures of irritability do not track with disease progression [7] [9]. Further, patients differ in the degree to which they experience irritability: some “feel” irritable, some exhibit mild irritability without further behavioral manifestations, while the behavior of others can escalate to physical aggression.

At all levels of severity, it is vital to recognize irritability as part of the disease process, and not to mischaracterize patients as difficult, stubborn, or “character disordered” which adds to strain experienced by patients and families. Early recognition and treatment of this symptom is important because irritability behaviors that escalate can be a tipping point in terms of care partner burnout and subsequent need to institutionalize HD patients.

Box 1. Abbreviations for drugs and drug classes

AED mood stabilizing anti-epileptic drug
APD antipsychotic
BZD benzodiazepine
CMI clomipramine
SNRI serotonin-norepinephrine reuptake inhibitor
SSRI selective serotonin reuptake inhibitor
TCA tricyclic

Though behavioral interventions have not been studied, or drugs officially approved to manage irritability in HD, it is generally accepted that behavioral interventions, APDs, SSRIs, AED’s, and other drugs are useful in treatment of these symptoms [10]. However, a recent Cochrane review of symptomatic treatments for HD concluded that no treatment recommendations could be made based on evidence from the research literature [11]. Lacking an adequate evidence base to guide treatment, we surveyed current clinical practice among an international group of HD experts to ascertain practice-based preferences. Recognizing the limits of expert opinion, and with the expectation that future clinical research will provide evidence-based information, we present survey results to provide direction for the management of irritability in HD.

Methods

The irritability survey was one of three symptom surveys developed by three core groups of nine psychiatrists and neurologists drawn from the European Huntington’s Disease Network (EHDN) and North American Huntington Study Group (HSG), and an HD family representative. Concurrent surveys were developed for obsessive-compulsive behaviors and chorea in HD. These three specific symptoms were chosen by core group consensus as those in greatest need of expert guidance relative to other symptoms of HD, including depression, anxiety, sleep disorder, and psychotic behaviors, for which clinical practice follows guidelines developed for these conditions in the general population. Data on coincident surveys for the treatment of obsessive-compulsive behaviors and chorea are presented in separate reports [12] [13].

The survey for HD irritability was developed by four core group psychiatrists from different geographic areas who have had extensive experience treating behavioral symptoms in HD. Questions were constructed electronically. Subsequently the survey was sent by email link to a larger international group of 66 EHDN and HSG physician leaders from HD specialty centers in 11 European countries, 10 U.S.A states, 4 Canadian provinces, and 3 Australian states. Experts were selected by the combined EHDN and HSG core groups as being knowledgeable in treating HD symptoms. Follow-up email or telephone reminders were used to encourage survey participation. Respondents were sent a small honorarium after completing the survey.

The survey consisted of 51 multiple-choice questions with 680 alternative answers, and the option to add comments. Questions addressed respondents’ demographics and their patterns of pharmacological treatment. By core group consensus, the survey focused on 5 drug classes (SSRIs, APDs, AEDs, BZDs, and tricyclic antidepressants (TCAs)) and 4 specific drugs (propranolol, clomipramine (CMI), buspirone, and mirtazapine), that have been used to treat HD irritability. In iterative fashion, each drug/drug class was addressed separately through additional questions covering the following: patterns of use (first choice, alternative monotherapy, adjunctive therapy, not an appropriate use, insufficient experience), perceived effectiveness (very effective, effective, somewhat effective, minimally effective), and preferred drugs within each class. Branching logic utilized in the survey prevented the answering of questions if a respondent did not choose a specific treatment as first or alternative monotherapy, or indicated having no experience with a particular treatment. However, branching logic allowed a respondent to check more than 1 drug or drug class as first or alternative therapy, or to check no drug as first choice. Questions also covered augmentation and switch strategies, timing of dose titration, and preferred drugs when other behavioral symptoms comorbid to irritability were present.

Following analysis of survey data, the core group presented results and a proposed algorithm for the treatment of irritability to a broader group of international HD experts attending the 2010 EHDN and HSG meetings for the purpose of obtaining further review.

Results

Of the 66 expert clinicians contacted, 55 responded. Not all respondents answered all individual questions. Of these 55 expert respondents, 26 were from Europe, 23 from the United States, 4 from Canada,and 2 from Australia. Most respondents were neurologists (39) or psychiatrists (10). There were 2 respondents who were double boarded in neurology and psychiatry and 2 respondents in neurogenetics. Clinical experience was quite substantial among the surveyed experts: over half reported treating more than 100 HD patients annually.

Practice patterns by drug or drug class: The first set of treatment questions concerned drug selection and was phrased as follows: “Assuming there are no comorbid symptoms to influence your decision, what is your practice pattern with the use of [drug or drug class] for the treatment of irritability in Huntington’s disease?” Drugs/drug classes included SSRIs, APDs, AEDs, BZDs, and tricyclic antidepressants (TCAs)) and 4 specific drugs (propranolol, clomipramine (CMI), buspirone, and mirtazapine. Alternative usage included: first choice, alternative monotherapy, adjunctive therapy, not an appropriate use, or insufficient experience. Interpretation of this first set of questions was complicated by limitations in the survey branching logic which allowed for the respondent to check more than 1 first choice or no first choice. Five respondents checked no first choice, while 2 had more than 1 first choice. See figures 1-3 and table 1.

Fig. 1: Choice of irritability drug across all geographic regions. Vertical axis is number of responses. See box 1 for abbreviations.

Fig. 2: Choice of irritability drug, European respondents. Vertical axis is number of responses. See box 1 for abbreviations.

Fig. 3: Choice of irritability drug, North American and Australian respondents. Vertical axis is number of responses. See box 1 for abbreviations.

Table 1. Choice of drug for treating irritability across all geographic regions. N is number of responses. Percentages are relative to N. See box 1 for abbreviations.

Drug or drug class N First choice Alternative monotherapy Adjunctive therapy Inappropriate Insufficient experience
SSRI 53 57% 23% 21% 0% 0%
APD 52 21% 31% 44% 4% 0%
AED 51 14% 27% 49% 0% 10%
CMI 51 2% 12% 18% 8% 61%
mirtazapine 50 0% 28% 24% 6% 42%
BZD 50 0% 16% 72% 10% 2%
TCA 50 0% 16% 16% 32% 36%
propranolol 50 0% 12% 26% 16% 46%
buspirone 50 0% 6% 20% 14% 60%

Results from this set of questions, when no comorbid symptoms influenced treatment decisions revealed some variation in practice patterns. Across all geographic regions SSRIs were most frequently chosen as the first drug for treating mild to moderate HD irritability. Though a less frequent choice than the SSRIs overall, APD usage for treatment of mild or moderate irritability was more common in Europe than in North America and Australia. AEDs were less frequently endorsed as first choice drug. When combining monotherapy choices (first and alternative), SSRIs were most frequently endorsed (80%), followed by APDs (53%) and AEDs (43%). No respondent chose buspirone, mirtazapine, propranolol or TCAs as first choice drugs, but each was cited as an alternative monotherapy choice by a minority of respondents. Many cited lack of experience with these drugs for treating irritability. The BZDs were most frequently used as an adjunctive drug. Though many (43%) were not familiar with the use of mirtazapine for irritabilty, half of those familiar with the drug chose it as an alternative monotherapy.

Perceived efficacy of drug choice: Most experts indicated that efficacy of APDs was somewhat higher than SSRIs. Table 2 summarizes expert views about the relative efficacy of surveyed drugs.

Table 2. Expert opinion of drug efficacy for treating irritability. N is number of responses. Percentages are relative to N. See box 1 for abbreviations.

Drug or drug class N Very Effective Effective Somewhat Effective Minimally Effective
SSRI 51 14% 43% 37% 6%
APD 50 18% 50% 32% 0%
AED 45 7% 31% 58% 4%
CMI 16 12% 19% 56% 12%
mirtazapine 26 0% 19% 77% 4%
BZD 45 4% 29% 58% 9%
TCA 16 0% 19% 56% 25%
propranolol 18 0% 11% 50% 39%
buspirone 13 0% 8% 54% 38%

Perceived benefit of high dose SSRI optimization: Respondents were also asked about SSRI dosing optimization for treating irritability in HD to upper limits of manufacturer recommended dosage for depression. Though all respondents perceived a level of increased effectiveness with higher dosing, the degree of effectiveness varied widely. Subsequent to the survey, the Federal Drug Administration issued a directive to change manufacturer recommended high dosage of citalopram from 60 mg to 40 mg per day, based on an increase in heart arrhythmias, and lack of larger dose benefit in treating depression. However, for treatment of irritability, six respondents reported beneficial result in selected patients exceeding the highest dose recommended for depression.

Dosing interval choices: Respondents were asked about dosing titration intervals for the drug/drug class alternatives. Preferred titration intervals varied greatly within each drug or drug class. See table 3.

Table 3. Choice of dosing titration intervals for drugs used to treat irritability. N is number of responses. Percentages are relative to N. See box 1 for abbreviations.

Drug or drug class N 1-2 weeks 2-4 weeks 4-6 weeks 6-12 weeks
SSRI 52 12% 33% 44% 12%
APD 49 33% 33% 24% 10%
AED 45 18% 42% 33% 7%
CMI 16 6% 12% 75% 6%
mirtazapine 26 8% 50% 35% 8%
BZD 44 55% 20% 11% 14%
TCA 17 0% 41% 47% 12%
buspirone 13 15% 31% 46% 8%

Adding or switching drugs for inadequate response to initial drug choice: The next set of iterative questions regarded strategies for adding or switching drug when an initial drug choice failed to adequately treat irritability in HD in the setting of no comorbid symptom to influence choice. The most notable result to this set of questions is that no consistent pattern was demonstrated for either SSRI or APD, the preferred initial choices. When SSRI was chosen as initial monotherapy but gave no or only partial benefit, the experts reported adding: an APD (30%), AED (16%) or BZD (7%), or switching to another SSRI (14%), or switching to an APD (12%), AED (7%), or BZD (5%). Similarly when an APD was chosen as initial monotherapy and did not give adequate response, the experts reported switching to another APD (28%), adding an SSRI (15%), AED (15%) or BZD (11%), or switching to an AED (8%) or SSRI (6%).

Table 4. Alternate choice of drug for treating irritability when inadequate response to initial therapy. N is number of responses. Percentages are relative to N. Alternate listed only if chosen by 5% or more of respondents. See box 1 for abbreviations.

Initial therapy N Alternate therapy if inadequate response Percentage of experts choosing this alternate therapy
SSRI 43 add APD 30%
add AED 16%
switch to another SSRI 14%
switch to APD 12%
switch to AED 7%
add BZD 7%
switch to BZD 5%
APD 36 switch to another APD 28%
add SSRI 19%
add AED 19%
add BZD 11%
switch to AED 8%
switch to SSRI 6%

Specific drugs favored within class: Preferred drugs within class for use in HD irritability included the SSRIs citalopram (35%), sertraline (25%) and paroxetine (15%); the APDs olanzapine (51%), risperidone (32%), and quetiapine (30%). Sulpiride and tiapride available only in parts of Europe were preferred by 7 European respondents. Insufficient experience was reported by many for clozapine, aripiprazole, ziprasidone, and pimozide. A high percentage of respondents (83.7%) preferred second-generation over first-generation antipsychotics. AED preferences included valproate derivatives (74%) and carbamazipine (23%), with a few others choosing each of the following: lamotrigine, gabapentin, topiramate and levetiracetam.

Other choices: The mood stabilizer lithium was an option for treating HD irritability. Only one expert rated lithium to be his/her first choice, but a substantial number of experts (23.6%) had no experience in using lithium for HD irritability, and 17.4% rated it as inappropriate. Only one respondent reported using benzodiazepines (BDZs) as first choice of treatment for irritability in HD. Most respondents prescribed BDZs as adjunctive therapy (70.6%). No one endorsed propranolol as a first-choice medication, 6 chose it as alternative monotherapy, and 13 as adjunctive therapy for irritability in HD. Almost half of the experts reported insufficient experience with propranolol for this indication.

Preferred medication choices for irritability with comorbid psychiatric symptoms: Given comorbid depression, anxiety, or perseverative behaviors, an SSRI was the first choice of the experts for treating HD irritability. Antipsychotic drugs were the first choice when comorbid psychosis, aggression, impulsivity, or hypersexuality were present. When patients who were irritable also suffered from insomnia, the favored medication choices were BDZs or mirtazapine. See figure 4 and table 5.

Fig. 4: Choice of irritability drug, North American and Australian respondents. Vertical axis is number of responses. See box 1 for abbreviations.

Table 5. Choice of drug for treating irritability that occurs with a given comorbid symptom. Percentages are relative to the number of experts who provided information for any symptom x drug combination (47). The last column is the sum of the previous two; the percentages do not always match precisely because of roundoff. The table only includes drugs chosen by 10% or more of the experts. See box 1 for abbreviations.

Comorbid symptom Drug or drug class First choice Alternative monotherapy First choice or alternative
depression SSRI 87% 13% 100%
SNRI 17% 57% 74%
mirtazapine 6% 49% 55%
TCA 2% 38% 40%
AED 4% 23% 28%
CMI 2% 23% 26%
anxiety SSRI 55% 23% 79%
BZD 19% 23% 43%
SNRI 6% 36% 43%
mirtazapine 4% 30% 34%
buspirone 6% 26% 32%
TCA 6% 23% 30%
AED 6% 11% 17%
APD 2% 15% 17%
CMI 2% 15% 17%
OCBs SSRI 47% 19% 66%
CMI 19% 26% 45%
APD 23% 19% 43%
SNRI 2% 28% 30%
AED 4% 13% 17%
TCA 2% 13% 15%
mirtazapine 2% 9% 11%
psychosis APD 94% 2% 96%
aggression APD 77% 13% 89%
AED 19% 23% 43%
SSRI 15% 26% 40%
BZD 6% 19% 26%
SNRI 2% 23% 26%
mirtazapine 0% 17% 17%
TCA 2% 9% 11%
impulsivity APD 43% 21% 64%
SSRI 30% 23% 53%
AED 19% 21% 40%
BZD 4% 23% 28%
SNRI 4% 21% 26%
mirtazapine 0% 11% 11%
buspirone 0% 11% 11%
insomnia BZD 30% 34% 64%
mirtazapine 30% 30% 60%
TCA 11% 34% 45%
SSRI 13% 26% 38%
APD 9% 26% 34%
SNRI 2% 17% 19%
AED 2% 13% 15%
buspirone 2% 9% 11%
hypersexuality APD 45% 21% 66%
SSRI 17% 26% 43%
AED 6% 17% 23%
SNRI 4% 19% 23%
BZD 0% 17% 17%
TCA 0% 15% 15%

Discussion

Though irritability is common in HD and several medication classes are employed in clinical practice to treat irritability in HD, only a few small studies are available. Further, these studies are hard to compare, with varying definitions of irritability and measurement tools utilized, and most patients in these reports were using additional medications which may have influenced results. Among these studies are: a single report on the use of an SSRI [14], a few other studies on various APDs, olanzapine alone [15], olanzapine and valproate [16], another on haloperidol and lithium [17], and more recently on nabilone, a cannabinoid most often used in treatment of nausea caused by cancer chemotherapy [18]. All of these studies represent a low level of evidence and give little guidance for treatment.

In an earlier survey (results not reported) experts agreed that behavioral intervention that includes education for patients and their families on practical behavioral approaches is recommended prior to, and to accompany pharmacological interventions. Though there is no formal guidance on how to use these interventions in HD, we recommend several strategies, based on treatments used in traumatic brain injury. Box 2 summarizes helpful recommendations. It is important to address triggers and recommended behavioral strategies at each patient and care-partner visit.

Box 2. Key behavioral interventions for managing irritability.

Expectations Care partners should have appropriate expectations regarding a patient’s abilities and needs. Some HD patients with high levels of symptoms have great difficulty controlling irritability behaviors and should not be expected to consistently control symptoms.
Prevention If there are situations that trigger irritability behaviors (e.g., discussing driving ability or cigarette smoking), it is best to avoid these topics. It is best to set and maintain regular schedules and routines. Identify and address sources of physical and emotional distress such as pain, hunger, thirst, difficulty with communication, frustration with failing abilities, boredom and unexpected change in routine.
Redirection Redirection is the most common environmental strategy used. It may take the form of changing the subject, starting a new activity, moving to a different room, placing an interesting object (e.g., a coin) in the patient’s hand as a distraction, and the like.
Calm Response Confronting or arguing with the patient may escalate irritability severity to aggressive levels. Any discussion of the event triggering this behavior should wait till the patient is calmed.
Source : LEARNet Tutorial on Anger And Anger Management

Overall, the present survey reveals a variety of pharmacological treatment patterns, without clear consensus in many areas. Nevertheless, some practice patterns emerge as preferred by many of the experts, with SSRIs and APDs as the most favored medication classes.

When the irritability is severe and/or there is an urgent need for treatment, the experts favored starting either an atypical APD, or less frequently an AED such as valproate. When irritability in HD is not accompanied by psychotic symptoms and is not severe or urgent, an SSRI was favored as first choice of treatment. No consensus existed among the experts as to the duration of treatment required before onset of full clinical effect, but clinical experience would suggest the onset of SSRI benefit for irritability in HD occurs earlier than benefit for depression, so a range of 2 to 4 weeks was chosen by the authors to emphasize this point in the algorithm. Assessment of adherence is always important when there is an inadequate response. This is emphasized in the algorithm, as is dose optimization when lower doses produce only a partial response in treating irritability.

The experts widely agreed that an SSRI is the first choice for treating HD irritability when accompanied by depression. When residual depressive symptoms remain after optimizing the SSRI in an irritable HD patient, we recommend optimizing treatment of the depression first, before proceeding to augmentation or switch strategies for managing irritability. When irritability in HD is accompanied by impulsivity, aggression, or hypersexuality, most experts favored use of atypical APDs or less frequently AEDs. This finding is indicated in the decision node that directs clinicians to favor these two classes among the four medication classes recommended for combination therapy when monotherapy with an SSRI is insufficient to achieve a satisfactory response to irritability.

The use of second-generation APDs and AED drugs were favored over propranolol and BZDs, due to their greater perceived effectiveness. Few survey respondents use propranolol, despite its wide use in other neuropsychiatric settings such as traumatic brain injury [19]. A Cochrane review of pharmacologic treatment of agitation in acquired brain injury concluded that Beta-blockers had best efficacy [20]. Only a few survey respondents use, or were familiar with, buspirone for HD irritability despite early positive research reports [21] [22]. If two or more consecutive combination trials across at least two distinct classes fail to achieve a full response to irritability (with adequate dose, duration and adherence), referral to a specialist is recommended.

Based on the results of this international expert survey, a clinical practice algorithm for the treatment of irritability in HD was constructed. The authors do not mean to imply that following the steps most often chosen by experts will result in best outcomes. Treatment response varies greatly in HD, and is particularly hard to predict. The steps represented in the algorithm are meant to guide, not decide any individual’s treatment. Only the clinician can address the complexities of any specific patient, where treatment must be tailored to fit individual needs.

Algorithm

(Click on the figure for a printable, single page view of the algorithm).

Conclusions

Based on survey outcomes the experts agreed that behavioral interventions and education for patients and care partners are helpful in management of irritability in HD. There was good agreement among the experts that an an APD is first choice when irritability is expressed as aggressive behaviors. For less severe irritability, most of experts in the combined regions chose an SSRI as first choice drug. APDs were more often chosen as first choice drugs in Europe than North America and Australia for less severe irritability The SSRIs and APDs were perceived as similar in efficacy for treating non-urgent irritability, and each of these options was used to augment the other. AEDs were not frequently utilized as monotherapy, but were used as augmenting agents to both SSRI or APD when each was ineffective alone. There was agreement that BZDs are not substantially effective as monotherapy, but agreement on their use as adjunctive therapy, particularly when anxiety is a comorbid factor.

The results of the survey point out the need for further study of irritability in HD. Development of a standard definition of these symptoms in HD, along with a validated scale for assessment, would greatly advance understanding of these conditions. Review of the literature shows there is a pressing need for treatment studies to determine which psychopharmacological and behavioral treatments are most efficacious. Head to head comparisons of the most frequently used agents and augmenting strategies would provide practical information.

Limitations: Survey results are not a substitute for evidence-based study. Instead, these results present treatment options based on a synthesis of opinions from a large group of experts. However, selection of the experts surveyed was not systematic. The core group authors generated a list of expert clinicians based on their personal knowledge of individuals active in the clinical research networks. A systematic survey of all members of the EHDN and HSG, though less feasible, would have provided a larger and more diverse sample. Further, as shown in this survey, practice patterns were influenced by geographic location.

A potential limitation is the inherent design of this survey that asked experts to consider irritability as an isolated symptom, which is not a common presentation in clinical practice. Recall bias may also have occurred, with survey results limited by the accuracy of respondents’ recall, with potential for over- or underestimation of drug efficacy. SSRIs were listed first in the questionnaire, reflecting the authors’ own views but possibly biasing answers toward this class of medication. A random order of presentation for medication class, varied among participants, would have been methodologically more sound. Though we believe the survey questions were comprehensive, they did not cover every possibility and may have omitted other useful queries.

This project received funding support in part by Lundbeck Inc., an arrangement that could introduce bias. In an effort to limit this bias, HSG and EHDN core committee members and survey respondents had no knowledge of Lundbeck Inc. support during the survey process or data analysis.

Acknowledgements

The authors thank those HD experts who shared knowledge and participated in this survey: Karen Anderson, Tomasin Andrews, Anna Rita Bentivoglio, Kevin Biglan, Jodi Cori-Bloom, Raphael Bonelli, Jean-Marc Burgunder, Jang Ho Cha, Edmond Chiu, Peter Como, David Craufurd, Merit Cudkowicz. Matthias Dose, Richard Dubinsky, Erik van Duijn, Alexandra Durr, Mary Edmondson, Andy Feigen, Joaquim Ferreira, Mark Groves, Arvid Heiberg, Don Higgins, Stephen Hersch, Joseph Jankovic, Hans Jung, Karl Kieburtz, Barry Kremer, Pierre Krystkowiak, Martin Kucharik, Blair Leavitt, Ann Catherine Bachoid-Levi, Wayne Martin, Elizabeth McCusker, Ann Messer, Marsha Nance, Michael Orth, Oksena Osuchowersky, Susan Perlman, Asa Petersen, Josef Priller, Hugh Rickards, Raymund Roos, Adam Rosenblatt, Diana Rosas, Ann Rosser, Jan Roth, Burton Scott, Kathleen Shannon, Shiela Simpson, Ira Shoulson, Nicholas Stoy, Sarah Tabrizi, Francis Walker, Eric Wexler, Vicki Wheelock, Daniel Zielonka.

Further gratitude to Dr. Richard Dubinsky and Dr. Eric Wexler who provided expert advice in survey creation, CHDI Foundation for expert advice and technical assistance, and Ann Covalt for editorial assistance.

Funding sources

The Huntington’s Disease Society of America (HDSA), Huntington Society of Canada (HSC), European Huntington’s Disease Network (EHDN), and HD Drug Works (HDDW) provided funding for this project. Support from Lundbeck Inc. was provided by a one time unrestricted grant to HDDW. The combined funds from HDSA, HSC, EHDN, and HDDW provided stipend reimbursement for expert participation. To prevent bias, experts were kept unaware of the Lundbeck Inc. grant during survey and analysis portions of this project.

Competing interests

Dr. Goodman received unrestricted grant and consultant fees from Lundbeck, Inc. In 2009. Dr. Edmondson has received consultant fees from Lundbeck, Inc.

Author roles

    • Drs. Mark Groves (HSG) and Erik van Duijn (EHDN) shared equally in leading the construction and review of the survey questionaire, review of data analysis, writing of first draft and review of manuscript.

      • Drs. Karen Anderson and David Craufurd. Construction and review of survey questionnaire. Review of data analysis and manuscript.

      • Dr. Mary Edmondson. Review of data analysis and manuscript.

      • Dr. Dan van Kammen. Expert adviser. Review of data analysis and manuscript.Dr. Nathan Goodman. Data analysis.

              • Dr. LaVonne Goodman. Conception, organization and facilitator for execution of the project. Review of manuscript.

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                An International Survey-based Algorithm for the Pharmacologic Treatment of Chorea in Huntington’s Disease http://currents.plos.org/hd/article/an-international-survey-based-algorithm-for-the-pharmacologic-treatment-of-chorea-in-huntingtons-disease/ http://currents.plos.org/hd/article/an-international-survey-based-algorithm-for-the-pharmacologic-treatment-of-chorea-in-huntingtons-disease/#respond Fri, 02 Sep 2011 14:29:03 +0000 http://currents.plos.org/hd/?post_type=article&p=2929

                Introduction

                Huntington’s disease (HD) is a progressive neurodegenerative disorder transmitted by an autosomal dominant inheritance via an elongated CAG nucleotide repeat on chromosome 4 [1]. At present, there are no established therapies which have been shown to delay onset or alter progression of this disease. In addition to cognitive impairment and a wide variety of psychiatric features, HD is characterized by a combination of complex hyper-and hypokinetic motor syndromes that vary among affected individuals, and change over the stages of disease within a single individual. Hyperkinetic motor signs include involuntary chorea movements, which peak in early and mid-stage disease in adult onset individuals, and subsequently decline as the disease progresses. Dystonia is another involuntary motor disorder which occurs predominantly in later stage disease. Bradykinesia, or paucity of movement, is a voluntary motor impairment that is present very early in the course of disease and progresses steadily to end-stage akinetic rigidity. Except for the use of Botox for isolated dystonic reactions, chorea is the only motor symptom for which there are therapeutic options.

                Age of onset in HD can vary from early childhood [2] to advanced age [3], but most commonly occurs between the ages of 30 and 50 years. After onset the disease follows a progressive degenerative course with an average duration of approximately 20 years, when age of onset is between 20 and 50 years of age [4]. Chorea is an early and highly visible sign of the disease in approximately 90% of adult-onset HD patients, peaking at about 10 years after first emergence of this symptom, then gradually abating as the disease progresses. Chorea is mild or absent in juvenile onset disease and in 10% of adult onset patients. The pattern of choreic movements differs among individuals and can include facial pouting, grimacing, and lifting of alternate eyebrows; forward, backward, and rotational neck and trunk movements, upper and lower extremity asymmetric flexion or extension of both small and larger muscle groups, and frequent crossing of the arms and legs [5]. The gold standard definition for onset of HD remains an open debate (plos) Although it is now known that cognitive and behavioral symptoms may predate onset of motor signs in many patients [6], onset, as defined in PREDICT-HD is that point in time when the investigator is confident in the diagnosis of unequivocal motor signs. However, in clinical practice, due to its high visibility. chorea is the motor sign most often used as the clinical marker that defines onset of the disease in adults [7].

                Box 1. Abbreviations for drugs and drug classes

                It is generally agreed that drugs are available in clinical practice that can improve chorea [8] [9] [10]. However, as summarized in the 2009 Cochrane review “Therapeutic intervention for symptomatic treatment in Huntington’s disease,” there is a lack of sufficient efficacy studies for individual drugs, and lack of drug comparison studies to obtain clear clinical guidance regarding drug choice. The authors cite TBZ as the antichoreic medication with best available clinical evidence; but they were unable to give any specific recommendation about best medical practices for treating chorea [11]. Lacking an adequate evidence base, we surveyed an international group of HD experts to ascertain practice-based preferences. Within the limits of expert opinion, and with the expectation that future clinical research will provide better information, we present survey results, and propose an algorithm to guide the clinical management of chorea in HD. The goal of the algorithm is to concisely deliver relevant and expert knowledge to point-of-care medical providers, and to update when evidence-based recommendations emerge.

                Methods

                This chorea survey was one of three symptom surveys developed by 2 core groups of nine psychiatrists and neurologists drawn from the European Huntington’s Disease Network (EHDN) and the Huntington Study Group (HSG), and a HD family representative. Concurrent surveys were developed for obsessive compulsive behaviors and irritability symptoms in HD. These specific three symptoms were chosen as those in greatest need of expert guidance relative to other symptoms of HD, including depression, anxiety, sleep disorder, and psychotic behaviors, for which clinical practice follows guidelines developed for these conditions in the general population. Data on concurrent surveys for the treatment of irritability and obsessive compulsive behaviors is presented in separate reports [12] [13].

                Three neurologists from different geographic areas who had extensive experience treating chorea in HD, and an HD family member developed the chorea survey. Individual questions were framed to gather information on clinicians’ indications for drug treatment, drug selection, dosing, management of inadequate drug responses, treatment of side effects, and management of chorea when complicated by concurrent symptoms of the disease. Survey questions were developed electronically on software that utilized branching logic in queries. The survey was subsequently distributed by email link to a larger international group of EHDN and HSG physician leaders from HD specialty centers in 11 European countries, 10 U.S.A states, 4 Canadian provinces, and 3 Australian states. Experts were selected by the combined EHDN and HSG core group members as being knowledgeable in treating HD symptoms. Follow-up email or telephone reminders were used to encourage survey participation.

                The initial chorea survey contained 28 multiple choice questions with 168 alternative answers, with the option to add additional comments. Questions addressed respondents’ demographics, clinical indications for treating chorea, and patterns of pharmacologic treatment By core group consensus, the survey focused on 2 drug classes (APDs and BZDs) and 2 drugs (TBZ and amantadine) that have been used to treat chorea. In iterative fashion, each medication class was addressed separately through additional questions covering the following: patterns of use (first choice, alternative monotherapy, adjunctive therapy, not an appropriate use, insufficient experience), perceived effectiveness (very effective, effective, somewhat effective, minimally effective), preferred drugs within each class, and side effect profiles. Branching logic utilized in the electronic survey prevented the answering of questions if a respondent did not choose a specific treatment as first or alternative monotherapy, or indicated having no experience with a particular treatment, Questions also covered dose titration, preferred APDs, and preferred drug for chorea when comorbid behavioral symptoms were present. Due to an omission in the original survey that became apparent during data analysis, we distributed an addendum to the original survey, presenting 3 additional questions with 10 alternative answers specifically addressing the combination of APDs and TBZ. After completion of the first part of the survey, respondents received a small honorarium.

                Following analysis of survey data, we presented an algorithm for the treatment of chorea at the Spring 2010 EHDN conference and the Fall 2010 HSG symposium for final review by a broader group of international experts.

                Results

                The original survey was sent to a total of 66 international expert physicians, of whom 52 (79%) completed at least part of the survey. Respondents were predominantly from the United States of America (N=24) and Europe (N=22), with a few others based in Canada (N=4) and Australia (N=2). The majority of respondents were boarded in Neurology (N=41), psychiatry (9), or double-boarded in Neurology and Psychiatry (N=2). Three of nine psychiatrist respondents cited limited experience in treating chorea. Among the remaining 49 responders who answered the majority of questions, clinical experience was quite substantial: over half of the respondents reported treating more than 100 HD patients annually. The survey addendum was sent to the 49 respondents from the original survey, of whom 30 (61%) responded.

                Treatment indications: Respondents were first queried about factors that would warrant drug treatment of HD chorea. The most noted indications were stigma factors of patient embarrassment and social isolation, physical injury, loss of balance, and interference with employment or sleep. Interference with caregiver tasks rated highly, but family stigma factors of embarrassment and social isolation were not considered as compelling as treatment indications.

                Table 1. Percentage of respondents choosing specific indications for drug treatment of chorea.

                Indications for drug treatment of chorea Respondents affirming indication (%)
                Patient embarrassment 92%
                Physical injury due to chorea 88%
                Loss of balance 81%
                Interference with caregiver tasks 79%
                Social isolation 77%
                Interference with work 77%
                Interference with sleep 64%
                Family embarrassment 32%

                Practice patterns by drug or drug class: The first set of treatment questions concerned drug selection and was phrased as follows: “Assuming there are no comorbid symptoms to influence your decision, what is your practice pattern with the use of [drug or drug class] for the treatment of chorea in Huntington’s disease?” In iterative manner for each separate query on drug or drug class, respondents were asked to choose either (1) first choice, (2) alternative monotherapy, (3) adjunctive therapy, or (4) inappropriate, (5) insufficient experience. Interpretation of results for this set of questions was complicated by limitations inherent in survey software, which allowed the respondent to check more than one first choice, or to check no first choice. An additional complicating factor for this set of questions was that respondents were asked to consider chorea as an isolated symptom, which is an uncommon situation in real-world clinical practice, where comorbid symptoms strongly influence choice of chorea drug. See figures 1-3 and table 2.

                Fig. 1: Choice of chorea drug across all geographic regions. Vertical axis is number of responses. See box 1 for abbreviations.

                Fig. 2: Choice of chorea drug, European respondents. Vertical axis is number of responses. See box 1 for abbreviations.

                Fig. 3: Choice of chorea drug, North American and Australian respondents. Vertical axis is number of responses. See box 1 for abbreviations.

                Table 2. Choice of drug for treating chorea across all geographic regions. N is number of responses. Percentages are relative to N. See box 1 for abbreviations.

                Drug or drug class N First choice Alternative monotherapy Adjunctive therapy Inappropriate Insufficient experience
                APD 50 58% 34% 4% 2% 2%
                TBZ 50 30% 56% 8% 0% 6%
                BZD 50 6% 12% 26% 22% 34%
                amantadine 50 4% 10% 62% 22% 2%

                Results from this set of questions showed a lack of consensus about the first choice of chorea drug when analyzed across all geographic regions. APDs were the first choice of most European and North American respondents. However, due to limitations when using survey branching logic, 15% of respondents checked more than one first choice, and an equal number checked no first choice. We speculate that these clinicians had discomfort with a single first choice preference. Results also show a striking variation of first-choice drug across geographic regions. Although APDs were the first choice of the majority of both European and North American respondents, a greater number of HSG respondents from North America and Australia (43%) chose TBZ as first-choice drug, compared to only 11% of EHDN European respondents.

                When analysis of combined monotherapy choices (first and alternative) was performed, APDs scored only slightly higher (92.3%) than the combined numbers for TBZ (86.5%). Benzodiazepines were chosen as adjunctive therapy. However, respondents disagreed about the use of amantadine: A minority considered it useful as monotherapy or adjunctive therapy, while a smaller but not insignificant number of respondents considered its use inappropriate for the treatment of chorea, and several cited inexperience with its use.

                Perceived effectiveness of drug choice: Ratings for the perceived effectiveness of APD and TBZ for HD chorea were similar for these two treatment options. Experts rated APDs for the treatment of chorea as follows: “very effective” (20%), “effective” (64%), or “somewhat effective” (16%). No respondent perceived APDs as ineffective. Experts rated the perceived effectiveness of TBZ as follows: “very effective” (20%), “effective” (48%), and “somewhat effective” (28%). In contrast, most respondents who used either BZD or amantadine rated both medications as only “somewhat” or “minimally” effective as monotherapy.

                Preferred APD monotherapy for HD chorea: There was wide variation in APD choice. Olanzapine and risperidone were most preferred. Tiapride, a first generation neuroleptic not available in North America, was preferred by 50% of European respondents. Again, due to survey software limitations, several respondents checked more than one first choice. Regarding APD dosing for chorea, though specific dose range for individual drugs was not addressed, 92% of respondents preferred APD dosing lower than manufacturer recommended recommendations for treating psychosis.

                Table 3. APD of first choice (all geographic areas). APD listed only if chosen by more than two respondents.

                APD of first choice Respondents reporting (%)
                risperidone 43%
                olanzapine 39%
                tiapride* 29%
                haloperidol 24%
                quetiapine 12%
                aripiprazole 11%
                *Tiapride only available in certain European countries.

                Preferred BZD for adjunctive therapy: Clonazepam was the preferred BZD for adjunctive treatment of chorea by 79.5% of respondents, with several citing its lower addictive potential compared to other BZDs. Lorazepam was chosen by a minority (12.5%) of respondents.

                TBZ specific practice: Several questions focused specifically on TBZ, including contraindications, interval titration of dosage, frequency of depression as a side effect, and treatment strategy for TBZ-associated depression. Regarding contraindications: the great majority of respondents (90%) would not use TBZ with concurrent active depression, but indicated that past or treated depression was not a contraindication for use (88%). Given a past history of suicidal gesture, 24% would not use TBZ, while a larger fraction (48%) would not use the drug if a suicide attempt had been made at any time in the past. Regarding dose titration intervals: the minority of respondents (16%) chose the 1-2 week titration interval recommended by Lundbeck Inc., distributor of the drug in the United States. More respondents (50%) chose a 2-4 week titration interval, and 26.5% chose an interval of more than 4 weeks. Regarding TBZ-associated depression: respondents reported the perceived frequency of occurrence as follows: “very frequently” (4%), “frequently” (14%), “somewhat frequently” (36%), and “infrequently” (38%). When depression occurred with TBZ, 26% of respondents decreased TBZ dosage, while 10.2% added or increased dosage of an antidepressant without changing TBZ dosage. A larger number of respondents (34.7%) did both: decreased TBZ dosage and added or increased antidepressant therapy. A minority of respondents (20%) discontinued TBZ. When depression occurred, most respondents (69.5%) reported that it was more likely to occur in the first two months of TBZ therapy, but many cited lack of long-term experience with TBZ.

                Frequency of perceived side effects due to APDs or TBZ: Respondents rated the frequency of observed side effects associated with APDs and TBZ (Table 4). When comparing APDs and TBZ, experts reported that sedation and cognitive decline appeared to occur at similar frequencies (less than a 3% difference). Apathy, Parkinsonism, metabolic syndrome, and tardive dyskinesia side effects were perceived to be higher for APDs than for TBZ. However, depression was frequently cited as a side effect of TBZ. Akathisia (motor or psychic restlessness) was reported as a side effect for both types of agent at similar frequencies. Due to an error of omission in the survey queries, swallowing disorder associated with APDs and TBZ could not be compared.

                Table 4. Side effects reported as occurring “very frequently” or “frequently” with APDs and TBZ. See box 1 for abbreviations.

                Side effect Drug or drug class Respondents reporting (%)
                Sedation APD 48%
                TBZ 46%
                Depression APD Not queried
                TBZ 26%
                Parkinsonism APD 18%
                TBZ 13%
                Apathy APD 18%
                TBZ 13%
                Cognitive impairment APD 10%
                TBZ 10%
                Swallowing disorder APD Not queried
                TBZ 4%
                Akathisia (motor and psychic restlessness) APD 10%
                TBZ 8%
                Metabolic syndrome APD 8%
                TBZ Not queried
                Tardive dyskinesia APD 4%
                TBZ 0%

                First choice of drug when comorbid symptoms are present: Though the majority of survey questions concerned the treatment of chorea as an isolated symptom, it is more common for HD patients to present with multiple symptoms that may influence choice of drug. APDs were the universal first-choice drug for treating chorea when it occurs in the setting of comorbid symptoms of psychotic or aggressive behaviors, and active depression. If poor compliance was suspected, APD was preferred over TBZ.

                Combining APDs and TBZ: Following the original survey, additional information was solicited about the clinical practice experience of combining APDs with TBZ. Though a smaller number (32) of the original {49) respondents who cited experience with treating chorea responded to the appended question, most of this subset (75%) had experience combining APDs and TBZ. The majority of those who had used the combination (80%) cited the need to control chorea and concurrent comorbid symptoms. A smaller fraction (40%) had used the combination to treat severe chorea not adequately controlled by a single drug. As for each agent independently, experts combining APDs and TBZ reported Parkinsonism, apathy, and akathisia as the most common side effects.

                Discussion

                Indications for drug treatment: Drug treatment decisions for HD chorea have the goal of improving quality of life. However in practice, assessing the benefit of treatment on quality of life is difficult because there have been no chorea studies that have used quality of life as a measure, and lack of studies on chorea’s impact on stigma or motor dysfunction. Further, assessing side effects of chorea drugs, which include apathy, Parkinsonism, and worsening cognition are difficult to separate from signs of disease progression. There has also been general disagreement about the impact of chorea, citing the lack of patient awareness [14] as a rationale to forgo treatment. However, subsequent studies have shown that lack of self-awareness occurs more broadly across the spectrum of HD symptoms including dyskinesia [15] as well as cognitive, social, emotional and functional abilities [16], for which lack of awareness would not influence treatment decisions.

                Impact of chorea on motor dysfunction: Studies have shown that chorea negatively impacts motor function for accuracy of movement, reaction time, and gait regulation [17] [18] [19]. However, HD is a mixed movement disorder with hypokinetic components that also negatively impact function. So it is difficult to assess the relative contribution of chorea and hypokinetic components in total motor dysfunction, particularly in early or middle stages of adult onset disease when chorea is more prominent [20]. In contrast, bradykinesia begins early in adult onset disease [21], and correlates with decline in functional capacity over the entire course of disease [22]. Bradykinesia and rigidity are the dominant motor impairments in juvenile onset [23] and late-stage adult onset patients. Late stage bradykinesia is a strong predictor of nursing home placement [24].

                Although direct clinical research is lacking on chorea’s functional impact as an isolated symptom, even in those with severe chorea, there are several studies suggesting that chorea may play an independent role in functional disability. The suppression of chorea improved writing speeds by 50% [25] . Chorea score was a major factor in impairment of motor tracking, or of accurately completing a motor task [20]. In a retrospective analysis of CARE-HD study participants, severity of chorea independently correlated with functional disability among a subgroup least affected by non-chorea symptoms [26]. In very-early-disease subjects in the TRACK-HD study, motor scores were more highly associated with earliest functional decline in HD than cognitive or behavioral scores. Among the separate motor components, chorea scores showed the highest correlation with loss of function [27]. In later-disease subjects, severity of chorea was an independent predictor of fall frequency and gait disturbance in HD, and more highly correlated to number of falls than voluntary motor impairment [28].

                Survey results support a trial of drug treatment for motor component dysfunction when HD chorea causes difficulty performing motor tasks at the workplace, causes imbalance and falls, results in physical injury, or interferes with sleep.

                Impact of chorea on HD stigma: Though multiple factors are involved in HD stigma, chorea’s high visibility likely contributes to embarrassment and the social isolation of affected individuals and families. While there are no studies that have included quality of life measures in HD, related studies in other diseases suggest that stigma is high across the spectrum of chronic neurological disorders, particularly those that include visible motor components. Studies in epilepsy [29], multiple sclerosis [30], and Parkinson’s disease [31], indicate that stigma impacts quality of life in these disorders. Studies of the high stigma which occurs in Tourette Syndrome (TS) and related motor tics may more closely approximate the stigma related to chorea in HD [32]. Further, in both HD and TS , the movement disorders are often mistaken for alcohol intoxication which in turn may further increase the level of stigma [33].

                Stigma in HD can likely be assessed by use of a scale validated for use in other chronic neurologic disease [34], which suggests the type of interview question that might be asked: “Because of my illness: (1) I feel embarrassed in social situations, (2) people avoid me, (3) strangers tend to stare at me, (4) people seem to be uncomfortable with me.” The high frequency of stigma and discriminatory events that occur in individuals with a positive HD family history who have no symptoms has been documented in RESPOND-HD study [35]. It is unclear how substantially chorea of the affected family member contributes to stigmatization of unaffected family members. However, it may be a factor to consider in treatment decisions.

                Survey results strongly support drug treatment of chorea when stigma factors of embarrassment and social isolation affects the HD patient. In practice this type of information should regularly be elicited from patients. In contrast, there is minority support from the experts for treating the patient when HD stigma adversely affects family members.

                Chorea drug treatments: For the indications listed, this survey supports the use of drugs for the treatment of chorea with the goal of reducing symptom severity. Though not addressed specifically in the survey, there is general agreement that pushing therapy to eliminate chorea will cause unacceptable levels of side effects. Because each drug alternative has significant side effects, a careful evaluation of risk-benefit must be assessed for each individual prior to initiating drug therapy, and reassessed frequently both during drug titration and over the course of treatment. Because chorea severity decreases with later progression of disease, the need for chorea treatment should be reassessed over time. Further, the presence of comorbid symptoms should greatly influence the choice of drug for treating chorea.

                Antipsychotic drug treatment for HD chorea: Though it is an off-label use, the first choice of most international respondents for treatment of chorea is an APD. Importantly, APD use is strongly preferred when psychosis, depression, aggressive behaviors, or poor compliance are comorbid factors. Although the use of second generation APDs was generally preferred, tiapride a first generation APD was a frequent European choice, and the lower cost of haloperidol, a first generation APD was a factor in treatment choice for several respondents in all geographic areas. The choice of a specific APD was quite varied, which reflects the lack of evidence base to guide drug choice.

                Only small studies and case reports are available; there are no large placebo-controlled or head-to-head comparison studies of APDs for treatment of HD chorea. Chorea benefit was demonstrated in a small placebo-controlled trial of haloperidol [36]. Olanzapine has been used in small open label studies with variable benefit [37] [38] [39]. A few reports note benefit with risperidone [40] [41], and quetiapine [42]. Benefit was shown in small open label [43] and placebo-controlled [44] trials of tiapride, available in most countries in Europe. A study with clozapine suggested minimal benefit, and significant side effects [45]. Studies with aripiprazole, a third generation APD, found a reduction in chorea similar to that observed with TBZ [46]. In the only study to compare functional capacity differences between a second generation APD (clotiapine) and TBZ for treatment of chorea [47], 38 participants were followed for a minimum of 2 years. Loss of functional capacity was greater in the APD group (N=10) than that in the TBZ group (N=28). However this study is retrospective and assignment to APD or TBZ was not randomized. This points out the important need to study and compare potential treatment-related functional losses in a prospective and randomized manner.

                Importantly, survey respondents reported frequent APD side effects, including sedation, Parkinsonism, apathy, cognitive decline, and less frequently, akathisia, metabolic syndrome, and tardive dyskinesia. Though not specifically addressed in the survey, side effects may vary according to specific drug choice (Table 5). Because many of these symptoms occur as a consequence of disease progression, the contribution of drug side effects is difficult to assess. If APDs are used to treat chorea, it is important to reassess dose requirements as the disease progresses. Though dosage ranges for individual APDs were not addressed in the survey, respondents indicated that, in general, dosage less than that recommended for psychotic behaviors is preferred.

                Table 5. Side effect profiles for APDs used for HD chorea.

                APD Observed side effects
                olanzapine weight gain, metabolic syndrome, sedation, dry mouth
                risperidone hyperprolactinemia, weight gain, Parkinsonism
                quietapine weight gain, sedation, akathisia, dry mouth
                aripiprazole arrhythmias, akathisia, sedation, Parkinsonism
                haloperidol sedation, Parkinsonism, akathisia, tardive dyskinesia
                tiapride sedation, Parkinsonism

                Tetrabenazine treatment for HD chorea: In North America, when choice was not influenced by other factors, TBZ was preferred almost as highly as APDs for chorea treatment. In both North America and Europe, TBZ was a consistent alternative monotherapy choice. TBZ is the only drug that the U.S. Federal Drug Administration has approved for the treatment of HD chorea. TBZ is also available in Canada, Australia, Denmark, France, Germany, Ireland, Israel, Italy, New Zealand, Portugal, Spain, Switzerland, and the UK. The efficacy of this drug was shown in a double-blinded, placebo-controlled study conducted by the HSG, in which drug was given as tolerated up to 100 mg/day [48] . A 3.5 point change in chorea score, or a 23.5% reduction from baseline was demonstrated in the treated group (chorea score range is 0 to 28), with about 50% of the treated group achieving a 6-point or greater improvement compared to 7% showing this level of response in the placebo group. Importantly, however, more adverse events occurred in the treated group, including somnolence, insomnia, depressed mood, agitation, akathisia, and one suicide. However, after stable dosing was achieved, there was no significant difference in adverse events between the treated and placebo groups. During the 80-week open-label extension phase of this study, a similar side effect profile emerged [49]. No quality of life issues were measured in this or any other TBZ chorea drug trial. In the present survey, the perceived frequency of TBZ side effects, except for depression, was similar to or slightly lower than those perceived for APDs in treating chorea. For HD in general, and particularly with the use of TBZ for HD chorea, it is imperative to have heightened caution regarding depression and suicide risk. While studies suggest that risk of depression with TBZ is more likely to occur in those with pre-existing depression, it can also occur in those with no history of depression prior to TBZ [50]. As in the placebo controlled trial, survey responders reported more depression during the titration phase and first 2 months of stable dose TBZ treatment. However, functional capacity appeared to be better preserved in a small number of patients treated with TBZ than in those treated by an APD over a 2 year time period [47].

                The dosage after titration for the majority of participants in the HSG trial and open label extension was 50-75 mg/day, which was the dosage range preferred by the majority of survey respondents. Lundbeck Inc. recommends and will provide reimbursement for testing CYP2D6 metabolizer levels prior to increasing TBZ dose above 50 mg/day. In CYP2D6-poor metabolizers, concomitant use of strong inhibitors (paroxetine, fluoxetine, fluxoxamine) should be avoided, or TBZ dosage decreased.

                Benzodiazepine treatment for HD chorea: In a single study, high doses of clonazepam (up to 5.5 mg/day) were required to suppress chorea [51]. Survey respondents did not endorse use of BZDs as monotherapy, but thought BZDs an adjuctive therapy.

                Amantadine treatment for HD chorea: Two small placebo-controlled studies of amantadine for HD chorea provide conflicting results [52] [53]. When a meta-analysis of the combined trials was performed as part of the Cochrane review [11], the differences between treated and placebo groups did not reach significance. Similarly, survey respondents disagreed about the use of this drug. When chosen, amantadine’s most frequent use was as adjunctive therapy, though others thought its use inappropriate.

                Based on the results of this international expert survey, a clinical practice algorithm for the treatment of chorea in HD was constructed. The authors do not mean to imply that following the steps most often chosen by experts will result in best outcomes. Treatment response varies greatly in HD, and is particularly hard to predict. The steps represented in the algorithm are meant to guide, not decide any individual’s treatment. Only the clinician can address the complexities of any specific patient, where treatment must be tailored to fit individual needs.

                Algorithm

                (Click on the figure for a printable, single page view of the algorithm).

                Conclusions

                The expert respondents indicated a high level of agreement on treatment indications for chorea, including factors of stigma, impairments with work, sleep, safety and balance issues. But they strongly disagreed about the first choice of drug, with a wide difference between experts from Europe, who preferred APDs, and those from North America and Australia, who chose equally between APDs and TBZ as a first treatment choice. APD usage for chorea was strongly favored by all groups when comorbid psychosis, aggression, or depression symptoms were present, or poor compliance suspected. There was agreement that both APDs and TBZ are partially and variably effective, with similar side effect profiles for sedation, apathy, Parkinsonism, and akathisia, and that depression is a serious, but treatable adverse reaction for TBZ. APDs and TBZ were sometimes used together to control combinations of symptoms, or for chorea inadequately controlled by either APDs or TBZ alone. There was agreement that BZDs are not substantially effective as monotherapy, but agreement on their use as adjunctive therapy, particularly if anxiety is a comorbid factor. There was high level of disagreement about the use of amantadine, and agreement among users that this drug was not substantially effective.

                Survey results point out the important need for more study on the direct impact of chorea on motor function, and stigma factors in HD. Results also show the pressing need for drug comparison study, both for efficacy and for side effect profiling. There is also need for studies to address the side effect functional consequences of APDs and TBZ when used to treat chorea.

                Limitations: Survey results are not a substitute for evidence-based study. Instead, these results present treatment options based on a synthesis of opinions from a large group of experts. As shown in this survey , practice patterns are influenced by the practice experience learned in subspecialty training and/or geographic location. And although Lundbeck Inc, has created mechanisms for mitigating TBZ cost for low-income and non-insured individuals in the U.S, practice decisions were influenced by the cost and complexity of prescribing this drug in the United States. Recall bias may also have occurred, with survey results limited by the accuracy of respondents’ recall, with potential for over- or underestimation of both drug efficacy and drug side effects. This project received funding support in part by Lundbeck Inc., an arrangement that could introduce bias. In an effort to limit this bias, HSG and EHDN core committee members and survey respondents had no knowledge of Lundbeck Inc. support during the survey process or data analysis. Though we believe the survey questions were comprehensive, they did not cover every possibility and may have omitted other useful queries. Further, selection of experts surveyed was not systematic, but included those active in clinical research known to the authors.

                Acknowledgements

                The authors thank those HD experts who shared knowledge and participated in this survey: Karen Anderson, Tomasin Andrews, Kevin Biglan, Ann Catherine Bachoud-Levi, Jodi Cori-Bloom, Raphael Bonelli, Jean-Marc Burgunder, Jang Ho Cha, Edmond Chiu, Peter Como, Merit Cudkowicz. Matthias Dose, Richard Dubinsky, Alexandra Durr, Andy Feigen, Joaquim Ferreira, Mark Groves, Mark Guttman, Don Higgins, Stephen Hersch, Joseph Jankovic, Karl Kieburtz, Barry Kremer, Pierre Krystkowiak, Martin Kucharik, Blair Leavitt, Wayne Martin, Elizabeth McCusker, Marsha Nance, Michael Orth, Oksena Osuchowersky, Susan Perlman, Asa Petersen, Josef Priller, Ann Messer, Hugh Rickards, Raymund Roos, Adam Rosenblatt, Diana Rosas, Ann Rosser, Jan Roth, Kathleen Shannon, Burton Scott, Ira Shoulson, Shiela Simpson, Sarah Tabrizi, Erik van Dejin, Francis Walker, Eric Wexler, Vicki Wheelock, Daniel Zielonka.

                Funding sources

                The Huntington’s Disease Society of America (HDSA), Huntington Society of Canada (HSC), European Huntington’s Disease Network (EHDN), and HD Drug Works (HDDW) provided funding for this project. Support from Lundbeck Inc. was provided by a one time unrestricted grant to HDDW. The combined funds from HDSA, HSC, EHDN, and HDDW provided stipend reimbursement for expert participation. To prevent bias, experts were kept unaware of the Lundbeck Inc. grant.

                Competing interests

                Dr. LaVonne Goodman received unrestricted grant and consultant fee support from Lundbeck, Inc. in 2009.

                Author roles

                • Drs. Jean-Marc Burgunder, Mark Guttman, and Susan Perlman shared equally in construction and review of survey questionnaire, review of data analysis and manuscipt.

                • Dr. Dan van Kammen. Expert advisor, review of data analysis and manuscript.

                • Dr. Nathan Goodman. Data analysis.

                • Dr. LaVonne Goodman. Conception, organization and facilitator for execution of the project. Writing of the first draft and review of manuscript

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                http://currents.plos.org/hd/article/an-international-survey-based-algorithm-for-the-pharmacologic-treatment-of-chorea-in-huntingtons-disease/feed/ 0
                An International Survey-based Algorithm for the Pharmacologic Treatment of Obsessive-Compulsive Behaviors in Huntington’s Disease http://currents.plos.org/hd/article/an-international-survey-based-algorithm-p284k2gmahk5-9/ http://currents.plos.org/hd/article/an-international-survey-based-algorithm-p284k2gmahk5-9/#respond Fri, 02 Sep 2011 02:31:39 +0000 http://currents.plos.org/hd/article/an-international-survey-based-algorithm-p284k2gmahk5-9/

                Introduction

                Huntington’s disease (HD) is an inherited neurodegenerative illness characterized by a combination of motor, cognitive and behavioral abnormalities. A wide variety of behavioral disturbances have been described in HD patients, including perseveration and obsessive-compulsive symptoms. For the purposes of this discussion we use the single term, obsessive-compulsive behaviors (OCBs) to encompass this entire range of these symptoms. Research into OCBs in HD is limited; however reports suggest that OCBs occur in 20 to 50% of HD patients [1][2][3][4][5][6][7] . OCBs have also been reported in prediagnosed individuals who carry the HD gene expansion [8][9][10] . Similarly, case reports have described instances of OCBs [11][12] , and an instance of obsessive gambling in an HD pedigree [13] .

                Box 1. Interview Questions for Assessment of OCBs.

                Do you get stuck on certain ideas that seem to go through your head over and over?
                Do you like to have certain things done on a very definite schedule?
                Are you worried about dirt, infections, contamination, more than other people?
                Is it upsetting to you when things change unexpectedly?
                Do you like to collect things, especially items that other people might find worthless (e.g., empty cologne bottles, worn out clothing, old newspapers)?
                Do you like things arranged a certain way, for example, all the clothes in your closet must be in order by color? If so, do you get very upset if someone else moves things out of place?
                Are there certain actions that you do over and over?
                Do people say you ask the same questions over and over?

                OCBs are problematic because they are often difficult to recognize. However, it is vital to identify these symptoms, because mischaracterization of these patients as difficult, stubborn, or “character disordered” adds greatly to the strain experienced by patients and families. If these behaviors are untreated, they can lead to management problems, including aggression toward care partners, family members, and medical staff. Untreated OCBs can greatly complicate long-term care and nursing home placement. Box 1 gives examples of questions for use in the evaluation of OCBs.

                Box 2. DSM IV criteria for obsessions and compulsions.

                Obsessions
                Recurrent and persistent thoughts, impulses, or images that are experienced, at some time during the disturbance, as intrusive and inappropriate and that cause marked anxiety or distress
                The thoughts, impulses, or images are not simply excessive worries about real-life problems
                The person attempts to ignore or suppress such thoughts, impulses, or images, or to neutralize them with some other thought or action
                The person recognizes that the obsessional thoughts, impulses, or images are a product of his or her own mind (not imposed from without as in thought insertion).
                Compulsions
                Repetitive behaviors (e.g., hand washing, ordering, checking) or mental acts (e.g., praying, counting, repeating words silently) that the person feels driven to perform in response to an obsession, or according to rules that must be applied rigidly.
                The behaviors or mental acts are aimed at preventing or reducing distress or preventing some dreaded event or situation; however, these behaviors or mental acts either are not connected in a realistic way with what they are designed to neutralize or prevent or are clearly excessive.
                Source : (DSM-IV, American Psychiatric Association, 1994)

                Information obtained from care partners about OCBs is invaluable in any assessment since insight into these symptoms is often limited in HD patients. OCBs can be a tipping point in terms of care partner burnout and subsequent need to institutionalize HD patients. Offering a care partner the opportunity to discuss OCBs can be part of a more general discussion on caring for the person with Huntington’s disease. The OCBs seen in most patients with HD do not meet DSM criteria for Obsessive-Compulsive Disorder (OCD) as defined by DSM IV (Box 2), because patients often lack insight into the symptoms and are not troubled by them. The majority of OCBs in HD are better defined as perseverative behaviors. Perseveration is the uncontrolled repetition or continuation of a response (motor act, word, thought, activity, strategy, or emotion) in the absence of an ongoing occasion or rationale for the behavior [14] . Perseveration often results from a disruption of frontal-subcortical circuitry in conditions such as traumatic brain injury, schizophrenia, autism, Alzheimer’s disease, and frontal dementias such as HD.

                Even though the OCBs seen in most patients with HD do not fully meet DSM criteria for OCD, it is practical to group perseverative symptoms and obsessive and compulsive symptoms together because the behavioral and pharmacologic interventions are similar. Features of frontal lobe dysfunction, such as impulsivity, may complicate OCBs, as patients may have difficulty suppressing the urge to act on ideas or emotions, resulting in irritability or aggression. OCBs interfere with learning and adaptive behavior (interactions with others, on-task behavior, task shifting, mental flexibility). Pharmacologic treatment of perseverative behavior may “unblock” performance potential and result in improved overall functioning in activities of daily living [14] .

                Box 3. Abbreviations for drugs and drug classes

                AED mood stabilizing anti-epileptic drug
                APD antipsychotic
                BZD benzodiazepine
                CMI chlomipramine
                SNRI serotonin-norepinephrine reuptake inhibitor
                SSRI selective serotonin reuptake inhibitor
                TCA tricyclic

                Lacking an adequate evidence base to guide treatment of OCB’s in HD, we surveyed current clinical practice among an international group of HD experts to ascertain practice-based preferences. Recognizing the limits of expert opinion, and with the expectation that future clinical research will provide evidence-based information, we present survey results to provide direction for the management of OCBs in HD.

                Methods

                The OCB survey was one of three symptom surveys developed by three core groups of nine psychiatrists and neurologists drawn from the European Huntington’s Disease Network (EHDN), the Huntington Study Group (HSG), and an HD family representative. Concurrent surveys were developed for irritability and chorea in HD. These specific three symptoms were chosen by core member concensus as those in greatest need of expert guidance relative to other symptoms of HD including depression, anxiety, sleep disorder, and psychotic behaviors, for which clinical practice follows the guidelines developed for these conditions in the general population. Data on coincident surveys for the treatment of irritability behaviors and chorea are presented in separate articles [15][16] .

                The OCB survey was developed by five psychiatrists from different geographic regions, who have had extensive experience treating OCB symptoms in HD. Questions were constructed electronically. Subsequently the survey was distributed by email link to a larger international group of EHDN and HSG physician leaders from HD specialty centers in 11 European countries, 10 U.S.A states, 4 Canadian provinces, and 3 Australian states. Experts were selected by the combined EHDN and HSG core groups as being knowledgeable in treating HD behavioral symptoms. Follow-up email or telephone reminders were used to encourage survey participation. Respondents received a small honorarium after completing the survey.

                The OCBs survey consisted of 51 multiple-choice questions with 680 alternative answers, with the option to add comments. Questions addressed respondents’ demographics and patterns of behavioral and pharmacological treatment. By core group consensus, the survey focused on the use of 5 drug classes (SSRIs, APDs, AEDs, benzodiazepines (BZDs), and tricyclic antidepressants (TCAs)) and 2 specific drugs (clomipramine (CMI), and lithium) that have been used to treat OCBs in HD. In iterative fashion, each drug/drug class was addressed separately through additional questions covering the following factors: patterns of use (first choice, alternative monotherapy, adjunctive therapy, not an appropriate use, insufficient experience), perceived effectiveness (very effective, effective, somewhat effective, minimally effective), and preferred drugs within each class. Branching logic utilized in the electronic survey prevented the answering of questions if a respondent did not choose a specific treatment as first or alternative monotherapy, or indicated having no experience with a particular treatment. Questions also covered augmentation and switch strategies, timing of dose titration, and preferred drugs when other behavioral symptoms comorbid to OCB’s were present.

                Following analysis of survey data, the core group presented results and a proposed OCBs treatment algorithm to broader groups of international experts attending the 2010 EHDN and HSG annual meetings for the purpose of obtaining further expert opinion and review.

                Results

                Of the 66 expert clinicians contacted, 49 (75%) responded. Not all respondents answered all individual questions. Of these 49 experts, 21 were from Europe, 26 from North America, and 3 from Australia. Most respondents were neurologists (33) or psychiatrists (14), and 2 were double boarded in neurology and psychiatry. Most respondents reported seeing at least 50 HD patients per year; there were only 8 who reported seeing fewer than this number. Fourteen reported seeing 50-100 patients annually; 9 reported seeing 100-150 and 18 more than 150 patients per year.

                Behavioral Interventions : The first questions concerned non-pharmacological interventions for OCBs; specifically, respondents were asked treatment practice using cognitive behavioral therapy (CBT) in patients with either mild, moderate, or severe cognitive impairment. There was also a query about the perceived benefit of family education. Many respondents (23%) indicated having no experience with CBT for HD patients, but others (50%) reported that CBT was at least somewhat effective, but only in those with mild cognitive impairment. It was not endorsed for patients with moderate or severe cognitive impairment. However, 83% of respondents endorsed family education on OCBs.

                Practice patterns by drug/drug class : The next set of treatment questions concerned drug selection and was phrased as follows: “Assuming there are no comorbid symptoms to influence your decision, what is your practice pattern with the use of [drug or drug class] for the treatment of OCBs in Huntington’s disease?”

                An SSRI was first choice of most respondents for treatment of OCBs when no comorbid symptoms influenced treatment decisions. CMI was the next most frequently endorsed first choice, followed by APDs and AEDs. Considering all monotherapy choices (first and alternative) SSRIs were most frequently endorsed (89%). CMI also rated highly and was endorsed as monotherapy by 63% of respondents who had experience with this drug. The BZDs, TCAs (excluding clomipramine) and lithium were not chosen as first choice agent by any respondent. APDs and AEDs were often utilized as augmenting and adjunctive therapies. BZDs were most often used as adjunctive therapy when anxiety was a comorbid factor.

                Fig. 1: Choice of drug from OCBs across all geographic regions. Vertical axis is number of responses. See box 3 for abbreviations.

                Fig. 2: Choice of drug for OCBs, European respondents. Vertical axis is number of responses. See box 3 for abbreviations.

                Fig. 3: Choice of drug for OCBs, North American and Australian respondents. Vertical axis is number of responses. See box 3 for abbreviations.

                Table 1. Choice of drug for treating OCBs across all geographic regions. N is number of responses. Percentages are relative to N. See box 3 for abbreviations.

                Drug or drug class N First choice Alternative monotherapy Adjunctive therapy Inappropriate Insufficient experience
                SSRI 47 74% 15% 6% 2% 2%
                CMI 47 6% 57% 4% 4% 28%
                APD 47 4% 30% 49% 15% 2%
                AED 47 2% 11% 43% 17% 28%
                TCA 47 0% 11% 21% 32% 36%
                lithium 47 0% 2% 13% 28% 57%
                BZD 47 0% 0% 57% 38% 4%

                Perceived efficacy of drug choice : Most experts indicated that SSRIs are the most effective drug choice for treating OCBs in HD. For respondents experienced with clomipramine, efficacy ratings for this drug were similar to SSRIs. Table 1 summarizes expert views about the relative efficacy of the surveyed drugs.

                Table 2. Expert opinion of drug efficacy for treating OCBs. N is number of responses. Percentages are relative to N. See box 3 for abbreviations.

                Drug or drug class N Very Effective Effective Somewhat Effective Minimally Effective
                SSRI 46 4% 39% 48% 9%
                CMI 32 3% 41% 50% 6%
                APD 40 0% 33% 60% 8%
                AED 27 0% 7% 67% 30%
                TCA 15 0% 20% 73% 7%
                lithium 7 0% 0% 57% 50%
                BZD 28 0% 4% 75% 21%

                Perceived benefit of high dose SSRI optimization : Respondents were also asked about SSRI dosing optimization for treating OCBs in HD to upper limits of manufacturer recommended dosage for depression. Though all respondents perceived a level of increased effectiveness with higher dosing, the degree of perceived effect varied widely. Seven respondents reported beneficial results in selected patients using dosage exceeding that recommended by the manufacturer. Subsequent to the survey, the Federal Drug Administration issued a directive to change manufacturer recommended high dosage of citalopram from 60 mg to 40 mg per day due to increase in heart arrhythmias and lack of benefit of the higher dose for treating depression. However, seven respondents reported beneficial results for treating OCBs in selected patients using doses higher than that recommended for depression.

                Dosing interval choices : The respondents were asked about dose titration intervals for the drug/drug class alternatives. For both SSRI and CMI, the top two pharmacological agents for monotherapy, more of respondents reported they would increase from initial dose after 4-6 weeks, followed by 2-4 weeks as the second most endorsed option (Table 3).

                Table 3. Choice of dosing titration intervals for drugs used to treat OCBs. N is number of responses. Percentages are relative to N. See box 3 for abbreviations.

                Drug or drug class N 1-2 weeks 2-4 weeks 4-6 weeks 6-12 weeks
                SSRI 46 7% 28% 57% 8%
                CMI 32 9% 38% 47% 6%
                AED 26 15% 31% 50% 4%
                TCA 15 0% 20% 60% 20%
                BZD 27 41% 30% 19% 11%

                Adding or switching drugs for inadequate response to initial drug choice : The next set of iterative questions regarded strategies for either adding or switching drug when an initial drug failed to adequately treat OCBs in HD. The most notable result to this set of questions is that no consistent pattern was demonstrated. When SSRI was chosen as initial monotherapy but gave no or only partial benefit, the next step in management varied: switch to another SSRI (23%), switch to CMI (18%), add CMI (16%) or an APD (16%), switch to serotonin and norepinephrine reuptake inhibitor (SNRI) (14%). Less common choices (5% each) were: switch to an APD or add BZD. When CMI was chosen as initial monotherapy but gave no or only partial benefit, next step choices also varied and included: add an APD (41%), switch to SSRI (26%), add SSRI (11%), add an AED (11%), or switch to an APD (7%). Fewer than 5% chose any other option. In response to separate questions regarding APDs, AEDs, BZDs or TCAs (other than clomipramine), the majority of those surveyed reported they used all of these agents most frequently as adjunctive therapy.

                Table 4. Alternate choice of drug for treating OCBs when inadequate response to initial therapy. N is number of responses. Percentages are relative to N. Alternate listed only if chosen by 5% or more of respondents. See box 3 for abbreviations.

                Initial therapy N Alternate therapy if inadequate response Percentage of experts choosing this alternate therapy
                SSRI 44 switch to another SSRI 23%
                switch to CMI 18%
                add CMI 16%
                add APD 16%
                switch to SNRI 14%
                switch to APD 5%
                add BZD 5%
                CMI 27 add APD 41%
                switch to SSRI 26%
                add SSRI 11%
                add AED 11%
                switch to APD 7%

                Specific drugs favored within class : Respondents were asked about preferred drugs within class for treating OCBs in HD. Preferred drugs included the SSRIs: citalopram (35%), sertraline (25%), paroxetine (15%), fluoxetine (11%), the APDs: olanzapine (52%), risperidone (34%), quetiapine (23%), aripiprazole (21%), the AEDs: valproate derivatives (70%), carbemazepine (22%), lamotrigene (16%), topiramate (11%). When using BZDs, favored drugs were: clonazepam (60%), alprazolam (28%), lorazepam (27%). For a separate query regarding Lithium, most respondents reported insufficient experience using this agent for OCBs in HD (56%). Another 29% felt it was not an appropriate alternative. Only 14% reported using it as monotherapy.

                Preferred drug for OCBs given comorbid psychiatric symptoms : Respondents were asked, for each of the medication classes (SSRI, CMI, APBs, AEDs, BZDs, TCAs, lithium) about how selection of that drug would be affected by the presence of a given comorbid symptom occurring with OCBs. Comorbid symptoms queried included depression, anxiety, psychotic behaviors, aggressive or threatening behaviors, impulsivity, insomnia, or hypersexuality. Given comorbid depression, anxiety, impulsivity, or hypersexuality, SSRI drugs were most frequently chosen. Antipsychotic drugs were chosen when comorbid psychotic or aggressive behaviors occurred. See figure 4 and table 5.

                Fig. 4: Choice of drug for treating OCBs that occur with a given comorbid symptom. Blue bars indicate the number of experts who selected the drug as first choice; red bars indicate the number who selected the drug as alternative monotherapy. See box 3 for abbreviations.

                Table 5. Choice of drug for treating OCBs that occur with a given comorbid symptom. Percentages are relative to the number of experts who provided information for any symptom x drug combination (47). The last column is the sum of the previous two; the percentages do not always match precisely because of roundoff. The table only includes drugs chosen by 10% or more of the experts. See box 3 for abbreviations.

                Comorbid symptom Drug or drug class First choice Alternative monotherapy First choice or alternative
                depression SSRI 96% 2% 98%
                CMI 17% 38% 55%
                AED 0% 15% 15%
                APD 0% 11% 11%
                anxiety SSRI 70% 21% 91%
                BZD 19% 26% 45%
                CMI 9% 26% 34%
                AED 4% 9% 13%
                APD 0% 23% 23%
                psychosis APD 87% 11% 98%
                SSRI 9% 9% 17%
                aggression APD 66% 9% 74%
                SSRI 13% 21% 34%
                AED 13% 21% 34%
                CMI 4% 9% 13%
                BZD 0% 11% 11%
                impulsivity SSRI 32% 21% 53%
                APD 26% 19% 45%
                AED 15% 15% 30%
                CMI 9% 21% 30%
                BZD 4% 6% 11%
                insomnia BZD 26% 23% 49%
                SSRI 15% 26% 40%
                APD 11% 28% 38%
                CMI 4% 26% 30%
                hypersexuality SSRI 32% 15% 47%
                APD 15% 32% 47%
                CMI 4% 19% 23%
                AED 2% 13% 15%

                Discussion

                OCBs are problematic and deserve to be addressed in any comprehensive plan of care for a patient with HD. The high frequency of these symptoms in HD is not surprising, inasmuch as the distinctive neuropathological changes seen in HD (striatal degeneration) are similar to those hypothesized to underlie primary obsessive-compulsive disorder (OCD), namely dysfunction of cortico-striatal connections [17][18] . Dysfunction in the orbitofrontal cortex, which has extensive connections to the basal ganglia, has been reported in brain imaging studies of individuals with OCD [19][20] , while functional imaging studies have implicated both striatal and cortical abnormalities in patients with primary OCD. Post-pharmacological treatment studies suggest that normalization of caudate and orbitofrontal cortex activation [21][22] occurs following remission of OCD symptoms.

                Treatment studies : Formal studies to guide treatment of OCBs in HD are scarce. A Cochrane review of symptomatic treatment for HD concluded that no definitive recommendations could be made for treatment of any behavioral symptoms in HD, due to the lack of controlled studies [23] . Case studies of individual patients report some amelioration of OCBs with various medications including fluoxetine [24] , sertraline and olanzapine [25] , or olanzapine alone [26] . Despite the probable high frequency of these symptoms as described above, a survey of medication choices for 2128 HD patients showed that less than 2% were being prescribed medications specifically for OCBs [27] .

                Box 3. Key behavioral interventions for managing OCBs.

                Expectations It is important that family members and other care partners have appropriate expectations regarding a patient’s abilities and needs. Some HD patients with high levels of symptomotology have great difficulty controlling OCBs, and should not be expected to control their symptoms. They may not respond quickly and consistently to strategies listed below.
                Prevention If there are situations that evoke perseverative behaviors (e.g., discussing driving ability or cigarette smoking), then it is best to avoid these topics.
                Redirection Redirection is the most common environmental strategy used. It may take the form of changing the subject, starting a new activity, moving to a different room, placing an interesting object (e.g., a coin) in the patient’s hand as a distraction, and the like.
                Setting limits It is sometimes useful to set a limit to the perseverative activity and then insist on an end to the activity; however, this is unlikely to work for severely impaired patients or those with extremely poor insight.
                Dramatic termination It may be useful to dramatically end a topic or activity. For example, write the topic on a card, and tear up the card, saying, “We are done with that; it’s over; no more!” and then move on to a new activity.
                Gradually modifying the activity One possibility is for care partners to enter the activity with the patient and gradually add activities to redirect the behavior. For example, a patient who perseverates on rearranging objects in the house could gradually be directed to dusting the room.
                Ignoring If perseverative behavior has developed to gain attention from care partners or others, ignoring the behavior will stop reinforcing it positively. However, ignoring perseveration can lead to aggression or outbursts from patients who are frustrated, and may not be useful in many people with HD.
                Source : LEARNet Tutorial on Perseveration

                Behavioral interventions : Most of the experts surveyed agreed that behavioral interventions for patients with mild cognitive impairment, and education for family and care partners are helpful in managing OCBs. However, there is no formal guidance on how to use these interventions in HD. We recommend several strategies, based on treatments used in traumatic brain injury. Box 3 summarizes particularly helpful recommendations.

                Cognitive behavioral therapy : Cognitive behavioral therapy (CBT), which has established efficacy in primary OCD (APA practice guidelines for OCD, 2007) was endorsed by some of our experts. However, there have been no controlled studies of CBT in HD, and its usefulness may be limited by a patient’s lack of insight or cognitive deficits. Although a large number of our experts had no experience with using CBT for people with HD, those who did thought it could be somewhat useful in HD patients with mild cognitive impairment.

                SSRIs and CMI : In general, there was good agreement among the experts surveyed as to first choice of medication for treatment of OCBs Most respondents endorsed SSRIs as the drug of first choice, with clomipramine as a second option. Though fewer had experience with CMI, perceived efficacy of SSRIs and clomipramine was similar. Clomipramine is the tricyclic antidepressant with the highest serotonergic effects, in addition to its effects on norepinephrine. The authors suggest that efforts should be made to increase familiarity with using this medication among HD experts, because clomipramine has good efficacy for treatment of OCBs in the general population (APA OCD practice guidelines, 2007). Clomipramine was listed separately from other TCAs because of its particular efficacy for treatment of OCBs and its FDA approval for treatment of obsessive compulsive disorder. Other TCAs are not nearly as useful for OCBs, as was reflected in responses to survey questions on efficacy.

                Others : Olanzapine was the top antipsychotic chosen among respondents to this survey, mostly for augmentation use. It is possible that the selection of olanzapine as antipsychotic of choice by HD experts was influenced to some extent by its utility for treating other symptoms of HD, notably irritability and aggression. APA guidelines do not recommend a specific neuroleptic for use in OCD at this time.

                Recommended dosing titration intervals : Dosing titration interval was an area in which the authors disagree with survey results for some situations. For both SSRI and CMI, the top two pharmacological agents for monotherapy, the majority of respondents reported they would increase from initial dose after 4-6 weeks, followed by 2-4 weeks as the second most endorsed option. The authors feel that dosing changes can be made in 1-2 week intervals. The highest dosing level would be either the top dose recommended by the manufacturer, or the dose best tolerated. More rapid dose escalations are particularly important for treatment of OCBs since these behaviors, like anxiety disorders in general, require longer treatment periods at effective dose for pharmacological treatment to be successful. In the authors’ experience, treatment requires going to the highest recommended or tolerated dose.

                Based on the results of this international expert survey, a clinical practice algorithm for the treatment of OCBs in HD was constructed. The authors do not mean to imply that following the steps most often chosen by experts will result in best outcomes, Treatment response varies greatly in HD, and is particularly hard to predict. The algorithm steps are meant to guide, not decide any individual’s treatment. Only the clinician can address the complexities of any specific patient, where treatment must be tailored to fit individual needs.

                Algorithm

                (Click on the figure below for a printable, single page view of the algorithm).

                Conclusions

                Most experts agreed that behavioral interventions for patients with mild cognitive impairment, and education for family and care partners are helpful in management of OCBs. Further, there was good agreement among the experts that an SSRI is first choice of drug for treatment of OCBs, with CMI as a second option. SSRIs and CMI were perceived as similar in efficacy by the majority of respondents who answered these questions. However, many respondents indicated a lack of experience with CMI or other drug options. Both APDs and AEDs were utilized as augmenting agents when an SSRI or CMI was ineffective alone. There was agreement that BZDs are not substantially effective as monotherapy, but agreement on their use as adjunctive therapy, particularly if anxiety is a comorbid factor.

                The results of the survey point out the need for further study of OCBs in HD. A problem with study of OCBs is that there is not a good clinical or research definition of these behaviors. Development of a standard definition of these symptoms, along with a validated scale for assessment, would greatly advance understanding of these conditions. Review of the literature shows there is a pressing need for treatment studies to determine which psychopharmacological and behavioral treatments are most efficacious for OCBs. Ethically, a placebo-controlled study of medications would be problematic, given that many of the experts surveyed felt several agents had reasonable efficacy for these symptoms. Head to head comparisons of the most frequently used agents would provide practical information without depriving some patients of treatments that are felt to be useful.

                Limitations : Survey results are not a substitute for evidence-based study. Instead, these results present treatment options based on a synthesis of opinions from a large group of experts. However, selection of the experts surveyed was not systematic. The core group authors generated a list of expert clinicians based on their personal knowledge of individuals active in the clinical research networks. A systematic survey of all members of the European Huntington’s Network and the Huntington Study Group, though less feasible, would have overcome this problem and provided a larger and more diverse sample. As shown in this survey, practice patterns are influenced geographic location. Recall bias may also have occurred, with survey results limited by the accuracy of respondents’ recall, with potential for over- or underestimation of both drug efficacy and side effect frequency. SSRIs were listed first in the questionnaire, reflecting the authors’ own views but possibly biasing answers toward this class of medication. A random order of presentation for medication class, varied among participants, would have been methodologically more sound. Respondents were not asked about use of SNRIs as an independent class of medication, only about their use as second or third line choice or as an augmenting agent. Though we believe the survey questions were comprehensive, they did not cover every possibility and may have omitted other useful queries.

                This project received funding support in part by Lundbeck Inc., an arrangement that could introduce bias. In an effort to limit this bias, HSG and EHDN core committee members and survey respondents had no knowledge of Lundbeck Inc. support during the survey process or data analysis.

                Acknowledgements

                The authors thank those HD experts who shared knowledge and participated in this survey: Karen Anderson, Tomasin Andrews, Kevin Biglan, Jodi Cori-Bloom, Raphael Bonelli, Jean-Marc Burgunder, Jang Ho Cha, Edmond Chiu, Peter Como, Merit Cudkowicz. Matthias Dose, Erik van Duijn, Erik van Duijn, Mary Edmondson, Andy Feigen, Joaquim Ferreira, Mark Groves, Marc Guttman, Don Higgins, Stephen Hersch, Joseph Jankovic, Karl Kieburtz, Barry Kremer, Pierre Krystkowiak, Martin Kucharik, Blair Leavitt, Ann Catherine Bachoud-Levi, Wayne Martin, Elizabeth McCusker, Marsha Nance, Michael Orth, Oksena Osuchowersky, Susan Perlman, Asa Petersen, Josef Priller, Hugh Rickards, Raymund Roos, Adam Rosenblatt, Diana Rosas, Ann Rosser, Jan Roth, Burton Scott, Kathleen Shannon, Shiela Simpson, Ira Shoulson, Nicholas Stoy, Sarah Tabrizi, Francis Walker, Eric Wexler, Vicki Wheelock, Olga Yastrubetskaya, Olga Yastrubetskaya, Daniel Zielonka.

                Additional gratitude to Dr. Richard Dubinsky and Dr. Eric Wexler who provided expert advice in survey creation, CHDI Foundation for expert advice and technical assistance, and Ann Covalt for editorial assistance.

                Funding information

                The Huntington’s Disease Society of America (HDSA), Huntington Society of Canada (HSC), European Huntington’s Disease Network (EHDN), and HD Drug Works (HDDW) provided funding for this project. Support from Lundbeck Inc. was provided by a one time unrestricted grant to HDDW. The combined funds from HDSA, HSC, EHDN, and HDDW provided stipend reimbursement for expert participation. To prevent bias, experts were kept unaware of the Lundbeck Inc. grant.

                Competing interests

                Dr. Goodman received unrestricted grant and consultant fee support from Lundbeck, Inc. in 2009. Dr. Edmondson has received consultant fee support from Lundbeck, Inc.

                Author roles

                Drs. Karen Anderson, HSG core group member, and David Craufurd, EHDN core group member, shared equally in construction and review of survey questionnaire, review of data analysis, writing of first draft of manuscript, and review of manuscript. Drs. Mark Groves, HSG Core group member, and Erik van Duijn. EHDN Core group member. Construction and review of survey questionnaire. Review of data analysis. Review of manuscript. Dr. Mary Edmondson. Review of data analysis and manuscript. Dr. Dan van Kammen. Expert adviser. Review of data analysis and manuscript. Dr. Nathan Goodman. Data analysis. Dr. LaVonne Goodman. Conception, organization and facilitator for execution of the project. Review of manuscript.

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                http://currents.plos.org/hd/article/an-international-survey-based-algorithm-p284k2gmahk5-9/feed/ 0
                Self Reports of Day-to-Day Function in a Small Cohort of People with Prodromal and Early HD http://currents.plos.org/hd/article/self-reports-of-day-to-day-function-in-a-small-cohort-of-people-with-prodromal-and-early-hd/ http://currents.plos.org/hd/article/self-reports-of-day-to-day-function-in-a-small-cohort-of-people-with-prodromal-and-early-hd/#respond Thu, 11 Aug 2011 01:41:57 +0000 http://currents.plos.org/hd/?post_type=article&p=2953

                Introduction

                Huntington disease (HD) is an autosomal dominant, progressive neurodegenerative disorder in which losses of neurologic function continue until the end of the person’s life. The diagnosis of HD traditionally is made with onset of motor symptoms. This typically occurs in the fourth decade of life [1] , when individuals are employed and may be parenting minor age or young adult children. Cognitive, motor, sensory, physiologic, and neuroimaging markers of the earliest phase of this condition have been reported [2] , but clear descriptions of the effects of these changes on day-to-day function have not yet been possible due to limited sensitivity of existing measures [2] .

                In plain language, function refers to a person’s abilities to do their daily tasks and routines in their daily life. However, the concept of ability to perform daily tasks is used in a variety of ways. The FDA description of patient-reported outcomes in clinical trials includes measures of any aspect of a patient’s health status that document the effect of a disease on a person’s quality of life, which in turn may include the person’s ability to perform daily activities (FDA, 2006). In the public health arena, health related quality of life refers to the effect of chronic illness on a person’s day-to-day life [3] . The notion of function status is a component of a health-related quality of life model [4] , and it refers to the ability to perform tasks in multiple domains such as one’s physical, social role, and psychological function on a day-to-day basis [5] .

                The earliest phase described in HD is referred to as the prodrome, and research findings have documented features of the disease up to 15 years prior to the diagnosis [2] . Ongoing studies in the US and in Europe on prodromal HD (PREDICT-HD and TRACK-HD) [6] [7] use a variety of measures of functional assessments, including the UHDRS TFC scale [8] , SF 36 [9] , and Functional Assessment scale (FAS) [10] . However, these measures do not provide sufficient detail regarding specific functional deficits, nor do they assess factors that may contribute to these changes. The UHDRS TFC scale [8] is used in TRACK-HD and PREDICT-HD. In addition, TRACK-HD uses participant self reports on the SF 36 [7] . The SF 36 provides scales to measure physical and social aspects of functioning [9] . The TFC includes ratings by the person with prodromal HD or with the person’s companion, of a person’s self reported abilities to maintain their occupation, finances, domestic chores, activities of daily living, and whether the person resides at home with or without support or in a full time skilled nursing facility. The FAS [10] is a questionnaire of tasks related to occupation, finances, activities of daily living, domestic chores, level of care, and physical abilities.

                These global measures of functioning may not be sensitive to subtle changes in functional abilities that occur in prodromal HD. For example, when administered to 786 participants in PREDICT-HD, over 88% of participants scored at ceiling on the TFC or FAS. Among those participants, 5-7% reported some loss on questions about work and managing finances [2] . A separate analysis of 265 people who were diagnosed as having HD during their prospective participation in Huntington Study Group projects [11] identified that functional loss is strongly related to changes in motor scores; cognitive scores were also associated with decreased function regarding managing finances, driving safely, supervising children, and being able to volunteer; depression scores were related to loss of ability to engage in usual employment. Thus, measures to be used in upcoming clinical trials and in clinical assessments of people with prodromal HD would be needed that are sensitive to day-to-day real-life function. Although measures are under development to address specific components of function, including one’s work performance and quality of life [12] , no measure captures the full range of tasks that comprise the day-to-day life of people with prodromal HD.

                Research on the potential effect of interventions to delay or modify symptoms is limited by the absence of measures of day-to-day function activities across the prodromal and early diagnostic phases of HD. This includes those activities that may be diminishing at the time surrounding the time of diagnosis. Instruments are needed that document patient reported outcomes [13] . When developing these measures, qualitative methods such as interviews may be useful to identify relevant and appropriately worded items [14] . The purpose of this study was to systematically examine the range of day-to-day tasks and limits on the performance of day-to-day tasks reported by people with prodromal HD or recently diagnosed HD, in order to more completely characterize changes experienced in this time period for the development of patient reported outcome measures.

                As reviewed above, the available quantitative data has been queried with regards to day-to-day functions in prodromal and very early HD. Findings have suggested that the currently available measures lack sensitivity to prodromal and very early diseases. This limitation is expected since most functional scales were initially developed for neurodegenerative diseases to track stages of dementia. Only more recently have we had the ability to identify and track persons at high risk for neurodegenerative diseases through efforts such as Mild Cognitive Impairment and PREDICT-HD. Findings suggest that new information is needed to better develop the earliest functional changes that occur prior to formal diagnosis of neurodegenerative disease. The current study was designed to solicit qualitative data to assist with the development of more sensitive measures. In an effort to maximize the data obtained through the qualitative interviews, we created an algorithm to recruit prodromal research volunteers who are considered most close to receiving a formal motor diagnosis and who were most likely to experience early functional decline.

                Methods

                This is an exploratory study using descriptive qualitative methods and a single telephone semi-structured interview.

                Participants

                Sixteen people who were enrolled at one of two PREDICT-HD research sites participated in the IRB-approved telephone interviews. Participants were selected from the PREDICT-HD study based on one of the following criteria:

                (1) were considered to be “near” diagnosis based upon formula derived from CAG repeat length and current age [15] ; (2) received a motor diagnosis according to the UHDRS motor score within the last 12 months; (3) obtained a UHDRS total motor score of >10 at their most recent PREDICT-HD visit; or (4) were in the 75thpercentile of longitudinal change in UHDRS total motor score.

                The project received approval from The University of Iowa Institutional Review Board and the Centre for Addiction and Mental Health Research Ethics Board in Toronto, Canada. The majority of participants (11/16) were female. Six were from Canada and 10 from the US. The mean CAG length was 41.38 (SD 1.45) and range 38-44. Mean age was 65.6 (SD 10.0) and range 36.5-78.8. Twelve had been diagnosed at the time of the interview.

                Interview Guide and Data Collection

                A semi-structured interview guide (Figure 1) was developed by the authors for this project. Topics were selected based on a review of the literature, clinical experience of the research team, and prior interviews conducted during the development of an instrument focused specifically on ability to perform tasks at work. After completion of informed consent procedures, each person participated in a telephone interview conducted by a team member who is an experienced interviewer. Interviews ranged from 4-35 minutes, with the average being 13.5 minutes. The shorter interview times were for those participants who had no functional changes to report. All interviews were audiotaped and transcribed verbatim. Data saturation was reached after six interviews; after that we did not learn of other day-to-day function changes not previously mentioned by other participants.

                Figure 1. Day-to-Day Function Semi-Structured Interview Guide

                We are interested in learning how things are going in your day-to-day life. What is this like for you?

                Some people have told us they have noticed changes in their ability to do certain day-to-day tasks. I’ll ask you about some specific topics. [Probes for each question] In what areas do you need help, What do you do about this, Has anyone commented on your (fill in the topic)?

                1. Please tell me about your household chores. Do you ordinarily take care of your own home? What tasks do you ordinarily do? Have there been any changes in your ability to do these chores?

                2. Please tell me about getting to places you need to go. Do you ordinarily drive or use public transportation? Do you usually get around by yourself? Has there been a change in this? Have you stopped doing things because of problems getting around?

                3. Please tell me about shopping. Do you shop for things like groceries, items for your home, yourself, your car?

                4. Please tell me about cooking and meals at home. Do you ordinarily prepare meals at home?

                5. Please tell me about using the telephone. Do you ordinarily make calls, answer the phone?

                6. Please tell me about things you usually enjoy. Do you start these hobbies on your own? Do you enjoy them if someone else gets you started or takes you where you can enjoy that activity, e.g., going to church, going fishing, bowling?

                7. Please tell me about your ability to handle your finances. Do you ordinarily take care of these yourself?

                8. Please tell me about work. Do you ordinarily work for pay; is this full time work?

                9. Please tell me about being around, or interacting with, other people: In what areas do you see changes, e.g., avoid being around other people, become irritated or impatient with people

                10. Last question: What else would you like to tell me?

                Analysis

                Two authors followed qualitative descriptive analysis techniques [16] . The data were initially coded using NVivo 8 software [17] . Data were independently coded and reviewed until there was 100% agreement between the two authors.

                Results

                Fourteen of the 16 participants described one or more changes in performance of day-to-day tasks. Each participant reporting changes endorsed from 1-7 areas of function (Table 1). One person who did not endorse any of the 9 topics in the interview guide reported the presence of involuntary movements. Specific functional tasks and examples of statements are provided below. Participants are identified by a number only for the purpose of reporting the data.

                Table 1. Functional Changes (N=16)

                Driving 11
                Interactions 8
                Household chores 8
                Telephone 7
                Shopping 6
                Finances 5
                Paid work 4
                Cooking 4
                Hobbies 1
                Other-Motor 1

                Driving: The most commonly endorsed day-to-day change was driving (11/16). Participants referred to concerns about doing more than one thing at a time, being slower, and concerns about safety. For example, I can only, kind of, do one thing at a time now, I need to be alert to the driving solely; my reaction time is slower (1), and one of the kids was nervous of me driving. Because of that I have said that I won’t drive any of the grandkids (2).

                Interactions: When describing changes in interactions with others, participants described a variety of changes including lack of interest, anxiety, and irritability with others. I’m, um, a little less patient, sometimes I have to watch myself, you know; I have to watch the way I speak (3), and it’s not that I don’t feel social, it’s just . . . I get lazy and I don’t want to go out (4).

                Household chores: Respondents were aware they were not keeping up with their usual responsibilities, but described a lack of interest or initiative. I used to change the beds and now it’s not as often as I used to (5), You know, I could look at something, and you know, realize it was dusty, but . . . for that to register in my head that I, you know, had to clean a whole house . . . I just never thought about it (6), and it’s not important any more (7).

                Telephone: Respondents were reluctant to respond on the telephone when they weren’t prepared, and were selective when they did answer the telephone. Only if I know about it in advance. Spur of the moment . . . forget it . . . it’s like because it was unexpected . . . my brain’s not working that way (7), and I have it print out on my TV so I it tells me who it is . . . I don’t want to get into the conversation . . . you just don’t want to . . . initiate it (8).

                Shopping: Skills needed for shopping included being able to remember where to go for needed items, as well as what the items are. I make my list, and write it down . . . to make sure I remember to stop (8), and I forget things so I usually need to have a list for everything I’m going to need (1).

                Finances: Not being able to remember to take care of finances was mentioned by several; others also noted that they could not keep up with the processes of calculating and managing them. Anything concerning the bills, or anything like that, I can’t remember (3), uh, I just kind of don’t do it, I mean, I don’t know what happened (6), I’m not very good at it, you know, adding in my head anymore (5).

                Paid work: All respondents who left paid employment had done so voluntarily. Some stated they were able to retire due to having reached the requirements for full retirement, or for family reasons. Others specifically addressed an inability to do their jobs. I had to leave my job because . . . I just couldn’t work, like I just couldn’t . . . mentally . . . I couldn’t do it (3). I was falling behind (6).

                Cooking: Multiple demands in planning and executing preparing a meal were difficult for some participants. I think I make more of a mess . . . But for the most part it’s ok; it takes me longer to clean up . . . I just forget to do things (4).

                Hobbies and other topics: When asked about changes in hobbies or leisure activities, none of the respondents reported changes that were related to having prodromal HD. When asked if there were other things they had noticed, comments were offered about motor skills. Oh God, that’s bad too; I walk into walls (7), I guess what you call the involuntary movements . . . I definitely feel that it doesn’t mean it makes any changes in your ability to do things . . . it’s just something you have noticed over time, that’s all (9).

                Comments about Functional Changes

                In responding to queries regarding potential changes in ability to carry out day-to-day tasks in specific areas, all respondents provided information on factors that, they believed, made it difficult to do these tasks. These factors ranged from emotional to cognitive to physical stamina topics.

                Apathy/Fatigue:I get really tired . . . It’s not so much a physical thing; it’s a, like in your mind (10). I don’t have the excitement part of doing some things; it’s just not there (11).

                Cognition:Part of my trade was . . . always learning stuff; I couldn’t learn . . . I couldn’t remember anything anymore (4); Memory—it’s just gone. Like my short-term memory (3).

                Irritability:I always seem to have that real quick to anger (6). I’m a little short, a little cranky (12).

                Discussion

                This study examined self-reports of losses of abilities to perform day-to-day tasks in a small cohort of people in the prodromal HD or very early phase of HD and for whom scores on the UHRDS motor scale indicated a significant increase of motor decline. Findings indicate that changes in day-to-day task function vary in prodromal HD and those recently diagnosed with HD, but that when changes are experienced, they are more likely to be in the domains of tasks that require multiple cognitive, motor, and behavioral abilities. Driving is a good illustration of this because it is an activity that requires multiple domain skills and was the most frequently mentioned area of functional difficulty in this sample. Although few reports focus on components of day-to-day function in prodromal HD or early HD, the range of topics is consistent with those reported with less sensitive measures, specifically that of employment and managing finances [2] , which are endorsed by this cohort. In a study of changes in people with prodromal HD over a 12 month period, changes in function as measured by the TFC are reported to show greater change than controls, but this did not reach statistical significance [18] .

                A potential limitation of this study includes the possibility of early lack of insight that is a component of HD [19] that has also been found in persons with prodromal HD. As people with prodromal HD approached diagnosis, increasing discrepancies between self-ratings and companion ratings of apathy, disinhibition, and executive function have been documented [20] . On the other hand, self-report of cognitive impairment has been demonstrated to be a reliable indicator of mild cognitive impairment in studies of people in early stages of dementia [21] [22] .

                These findings suggest that day-to-day function may be impaired in some domains during the prodromal HD and recently diagnosed period, and that measures to document function must encompass the range of domains likely to be affected in prodromal HD. Data from these interviews were used in the development of items to assess day-to-day functioning by FuRST-pHD; and initiative to develop a rating scale for assessing symptoms and functional ability in prodromal and early HD. Further investigations may provide insight into factors associated with the domains in which people with prodromal HD perceive changes, as well as provide data to monitor progression of day-to-day function over time.

                Funding information

                This research is supported by the National Institutes for Health, National Institute of Neurological Disorders and Stroke (NS40068) and CHDI Foundation, Inc.

                Acknowledgments

                We thank the PREDICT-HD sites, the study participants, and the National Research Roster for Huntington Disease Patients and Families. The full list of those involved with the PREDICT-HD study is shown below.

                Competing interests

                The authors declare no competing interests.

                PREDICT-HD Investigators, Coordinators, Motor Raters, Cognitive Raters

                Active: September 2009-August 2010

                Thomas Wassink, MD, Stephen Cross, BA, Nicholas Doucette, BA, Mycah Kimble, BA, Patricia Ryan, MSW, LISW, MA, Jessica Wood, MD, PhD, Eric A. Epping, MD, PhD, and Leigh J. Beglinger, PhD (University of Iowa, Iowa City, Iowa, USA); Edmond Chiu, MD, Olga Yastrubetskaya, PhD, Joy Preston, Anita Goh, D.Psych, Chathushka Fonseka, and Liz Ronsisvalle (St. Vincent’s Hospital, The University of Melbourne, Kew, Victoria, Australia); Phyllis Chua, MD, and Angela Komiti, BS, MA (The University of Melbourne, Royal Melbourne Hospital, Melbourne, Australia); Lynn Raymond, MD, PhD, Rachelle Dar Santos, BSc, and Joji Decolongon, MSC, CCRP (University of British Columbia, Vancouver, British Columbia, Canada); Adam Rosenblatt, MD, Christopher A. Ross, MD, PhD, Barnett Shpritz, BS, MA, OD, and Claire Welsh (Johns Hopkins University, Baltimore, Maryland, USA); William M. Mallonee, MD, Greg Suter, BA, and Judy Addison (Hereditary Neurological Disease Centre, Wichita, Kansas, USA); Ali Samii, MD, and Alma Macaraeg, BS (University of Washington and VA Puget Sound Health Care System, Seattle, Washington, USA); Randi Jones, PhD, Cathy Wood-Siverio, MS, Stewart A. Factor, DO, and Claudia Testa, MD, PhD (Emory University School of Medicine, Atlanta, Georgia, USA); Roger A. Barker, BA, MBBS, MRCP, Sarah Mason, BSC, Anna Goodman, PhD, Rachel Swain, BA, and Anna DiPietro (Cambridge Centre for Brain Repair, Cambridge, UK); Elizabeth McCusker, MD, Jane Griffith, RN, Clement Loy, MD, David Gunn, BS, and Linda Stewart, RN (Westmead Hospital, Sydney, Australia); Bernhard G. Landwehrmeyer, MD, Michael Orth MD, PhD, Sigurd Süβmuth, MD, RN, Katrin Barth, RN, and Sonja Trautmann, RN (University of Ulm, Ulm, Germany); Kimberly Quaid, PhD, Melissa Wesson, MS, and Joanne Wojcieszek, MD (Indiana University School of Medicine, Indianapolis, IN); Mark Guttman, MD, Alanna Sheinberg, BA, and Irita Karmalkar, BSc (Centre for Addiction and Mental Health, University of Toronto, Markham, Ontario, Canada); Susan Perlman, MD and Arik Johnson, PsyD (University of California, Los Angeles Medical Center, Los Angeles, California, USA); Michael D. Geschwind, MD, PhD, Jon Gooblar, BA, and Gail Kang, MD (University of California San Francisco, California, USA); Tom Warner, MD, PhD, Maggie Burrows, RN, BA, Marianne Novak, MD, Thomasin Andrews, MD, BSC, MRCP, Elisabeth Rosser, MBBS, FRCP, and Sarah Tabrizi, MD, PhD (National Hospital for Neurology and Neurosurgery, London, UK); Anne Rosser, MD, PhD, MRCP, Kathy Price, RN, and Sarah Hunt, BSc (Cardiff University, Cardiff, Wales, UK); Frederick Marshall, MD, Amy Chesire, LCSW-R, MSG, Mary Wodarski, BA, and Charlyne Hickey, RN, MS (University of Rochester, Rochester, New York, USA); Oksana Suchowersky, MD, FRCPC, Sarah Furtado, MD, PhD, FRCPC, and Mary Lou Klimek, RN, BN, MA (University of Calgary, Calgary, Alberta, Canada); Peter Panegyres, MB, BS, PhD, Elizabeth Vuletich, BSC, Steve Andrew, and Rachel Zombor, MPSYC (Neurosciences Unit, Graylands, Selby-Lemnos & Special Care Health Services, Perth, Australia); Joel Perlmutter, MD, Stacey Barton, MSW, LCSW, and Amy Schmidt (Washington University, St. Louis, Missouri, USA); Zosia Miedzybrodzka, MD, PhD, Sheila A. Simpson, MD, Daniela Rae, RN, and Mariella D’Alessandro, PhD (Clinical Genetics Centre, Aberdeen, Scotland, UK); David Craufurd, MD, Ruth Fullam, BSC, and Elizabeth Howard, MD (University of Manchester, Manchester, UK); Pietro Mazzoni, MD, PhD, Karen Marder, MD, MPH, and Paula Wasserman, MA (Columbia University Medical Center, New York, New York, USA); Rajeev Kumar, MD and Diane Erickson, RN (Colorado Neurological Institute, Englewood, Colorado, USA); Vicki Wheelock, MD, Terry Tempkin, RNC, MSN, Nicole Mans, BA, MS, and Kathleen Baynes, PhD (University of California Davis, Sacramento, California, USA); Joseph Jankovic, MD, Christine Hunter, RN, CCRC, and William Ondo, MD (Baylor College of Medicine, Houston, Texas, USA); Justo Garcia de Yebenes, MD, Monica Bascunana Garde, Marta Fatas, BA, and Asuncion Martinez-Descales (Hospital Ramón y Cajal, Madrid, Spain); Wayne Martin, MD, Pamela King, BScN, RN, and Satwinder Sran, BSC (University of Alberta, Edmonton, Alberta, Canada); Anwar Ahmed, PhD, Stephen Rao, PhD, Christine Reece, BS, Janice Zimbelman, PhD, PT, Alexandra Bea, BA, Emily Newman, BA, and Alex Bura, BA (Cleveland Clinic Foundation, Cleveland, Ohio, USA).

                Steering Committee

                Jane Paulsen, PhD, Principal Investigator, Eric A. Epping, MD, PhD, Hans Johnson, PhD, Megan Smith, PhD, Janet Williams, PhD, RN, FAAN, Leigh Beglinger, PhD, James Mills, MS (University of Iowa Hospitals and Clinics, Iowa City, IA); Elizabeth Aylward, PhD (Seattle Children’s Research Institute, WA); Kevin Biglan, MD (University of Rochester, Rochester, NY); Blair Leavitt, MD (University of British Columbia, Vancouver, BC, Canada); Marcy MacDonald, PhD (Massachusetts General Hospital); Martha Nance, MD (Hennepin County Medical Center, Minneapolis, MN); and Cheryl Erwin, JD, PhD (University of Texas Medical School at Houston).

                Scientific Sections

                Bio Markers: Blair Leavitt, MDCM, FRCPC (Chair) and Michael Hayden, PhD (University of British Columbia); Stefano DiDonato, MD (Neurological Institute “C. Besta,” Italy); Ken Evans, PhD (Ontario Cancer Biomarker Network); Wayne Matson, PhD (VA Medical Center, Bedford, MA); Asa Peterson, MD, PhD (Lund University, Sweden), Sarah Tabrizi, MD, PhD (National Hospital for Neurology and Neurology and Neurosurgery, London); Beth Borowsky, PhD (CHDI); Andrew Juhl, BS, James Mills, MS, Kai Wang, PhD (University of Iowa); and David Weir, BSc (University of British Columbia).

                Brain: Jean Paul Vonsattell, PhD (Chair), and Carol Moskowitz, ANP, MS (Columbia University Medical Center); Anne Leserman, MSW, LISW, Lynn Schaul, BA, and Stacie Vik, BA (University of Iowa).

                Cognitive: Deborah Harrington, PhD (Chair), Gabriel Castillo, BS, Jessica Morison, BS, and Jason Reed, BS (University of California, San Diego), Michael Diaz, PhD, Ian Dobbins, PhD, Tamara Hershey, PhD, Erin Foster, OTD, and Deborah Moore, BA (Washington University Cognitive Science Battery Development); Holly Westervelt, PhD (Chair, Quality Control and Training, Alpert Medical School of Brown University), Jennifer Davis, PhD, and Geoff Tremont, PhD, MS (Scientific Consultants, Alpert Medical School of Brown University); Megan Smith, PhD (Chair, Administration), David J. Moser, PhD, Leigh J. Beglinger, PhD, Kelly Rowe, and Danielle Theriault, BS (University of Iowa); Carissa Gehl, PhD (VA Medical Center, Iowa City, IA); Kirsty Matheson (University of Aberdeen); Karen Siedlecki, PhD (Fordham University); Marleen Van Walsem (EHDN); Susan Bonner, BA, Greg Elias, BA, and Melanie Faust, BS (Rhode Island Hospital); Beth Borowski, PhD (CHDI); Noelle Carlozzi (University of Michigan); Kevin Duff, PhD (University of Utah); Nellie Georgiou-Karistianis (St. Vincent’s Hospital, The University of Melbourne, Australia); Julie Stout, PhD (Monash University, Melbourne, Australia); Herwig Lange (Air-Rahazentrum); and Kate Papp (University of Connecticut).

                Functional : Janet Williams, PhD (Chair), Leigh J. Beglinger, PhD, Anne Leserman, MSW, LISW, Eunyoe Ro, MA, Lee Anna Clark, Nancy Downing, RN, PhD, Joan Laing, PhD, Kristine Rees, BA, and Stacie Vik, BA (University of Iowa); Rebecca Ready, PhD (University of Massachusetts); Anthony Vaccarino, PhD (Ontario Cancer Biomarker Network); Sarah Farias, PhD (University of California, Davis); Noelle Carlozzi, PhD (University of Michigan); and Carissa Gehl, PhD (VA Medical Center, Iowa City, IA).

                Genetics: Marcy MacDonald, PhD (Co-Chair), Jim Gusella, PhD, and Rick Myers, PhD (Massachusetts General Hospital); Michael Hayden, PhD (University of British Columbia); Tom Wassink, MD (Co-Chair) Eric A. Epping, MD, PhD, Andrew Juhl, BA, James Mills, MS, and Kai Wang, PhD (University of Iowa); Zosia Miedzybrodzka, MD, PhD (University of Aberdeen); and Christopher Ross, MD, PhD (Johns Hopkins University).

                Imaging:Administrative: Ron Pierson, PhD (Chair), Kathy Jones, BS, Jacquie Marietta, BS, William McDowell, AA, Greg Harris, BS, Eun Young Kim, MS, Hans Johnson, PhD, and Thomas Wassink, MD (University of Iowa); John Ashburner, PhD (Functional Imaging Lab, London); Steve Potkin, MD (University of California, Irvine); and Arthur Toga, PhD (University of California, Los Angeles). Striatal: Elizabeth Aylward, PhD (Chair, Seattle Children’s Research Institute). Surface Analysis: Eric Axelson, BSE (University of Iowa). Shape Analysis: Christopher A. Ross (Chair), MD, PhD, Michael Miller, PhD, and Sarah Reading, MD (Johns Hopkins University); Mirza Faisal Beg, PhD (Simon Fraser University). DTI: Vincent A. Magnotta, PhD (Chair, University of Iowa); Karl Helmer, PhD (Massachusetts General Hospital); Kelvin Lim, MD (University of Ulm, Germany); Mark Lowe, PhD (Cleveland Clinic); Sasumu Mori, PhD (Johns Hopkins University); Allen Song, PhD (Duke University); and Jessica Turner, PhD (University of California, Irvine). fMRI: Steve Rao, PhD (Chair), Erik Beall, PhD, Katherine Koenig, PhD, Michael Phillips, MD, Christine Reece, BS, and Jan Zimbelman, PhD, PT (Cleveland Clinic); and April Bryant (University of Iowa).

                Motor: Kevin Biglan, MD (University of Rochester), Karen Marder, MD (Columbia University), and Jody Corey-Bloom, MD, PhD (University of California, San Diego) all Co-Chairs; Michael Geschwind, MD, PhD (University of California, San Francisco); Ralf Reilmann, MD and Zerka Unds (Muenster, Germany); and Andrew Juhl, BS (University of Iowa).

                Psychiatric: Eric A. Epping, MD, PhD (Chair), Nancy Downing, RN, PhD, Jess Fiedorowicz, MD, Robert Robinson, MD, Megan Smith, PhD, Leigh Beglinger, PhD, James Mills, MS, Kristine Rees, BA, Adam Ruggle, Stacie Vik, BA, Janet Williams, PhD, Dawei Liu, PhD, David Moser, PhD, and Kelly Rowe (University of Iowa); Karen Anderson, MD (University of Maryland); David Craufurd, MD (University of Manchester); Mark Groves, MD (Columbia University); Anthony Vaccarino, PhD and Ken Evans, PhD (Ontario Cancer Biomarker Network); Hugh Rickards, MD (Queen Elizabeth Psychiatric Hospital); Eric van Duijn, MD (Leiden University Medical Center, Netherlands); Irina Antonijevic, MD, PhD, and Joseph Giuliano (CHDI); Phyllis Chua (The University of Melbourne, Royal Melbourne Hospital); and Kimberly Quaid, PhD (Indiana University School of Medicine).

                Core Sections

                Statistics: James Mills, MEd, MS, Dawei Liu, PhD, Jeffrey Long, PhD, Wenjing Lu, Kai Wang, PhD, and Ying Zhang, PhD (University of Iowa).

                Recruitment/Retention: Martha Nance, MD (Chair, University of Minnesota); Anne Leserman, MSW, LISW, Nicholas Doucette, BA, Mycah Kimble, BA, Patricia Ryan, MSW, LISW, MA, Kelli Thumma, BA, Elijah Waterman, BA, and Jeremy Hinkel, BA (University of Iowa).

                Ethics: Cheryl Erwin, JD, PhD, (Chair, McGovern Center for Health, Humanities and the Human Spirit); Eric A. Epping, MD, PhD Janet Williams, PhD, Nicholas Doucette, BA, Anne Leserman, MSW, LISW, James Mills, MS, Lynn Schaul, BA, and Stacie Vik, BA (University of Iowa); Martha Nance, MD (University of Minnesota); and Lisa Hughes, MEd (University of Texas Medical School at Houston).

                IT/Management: Hans Johnson, PhD (Chair), R.J. Connell, BS, Karen Pease, BS, Ben Rogers, BA, BSCS, Jim Smith, AS, Shuhua Wu, MCS, Roland Zschiegner, Erin Carney, Bill McKirgan, Mark Scully, and Ryan Wyse (University of Iowa); Jeremy Bockholt (AMBIGroup).

                Program Management

                Administrative: Chris Werling-Witkoske (Chair), Karla Anderson, BS, Kristine Bjork, BA, Ann Dudler, Jamy Schumacher, Sean Thompson, BA, Leann Davis, Machelle Henneberry, Greg Ennis, MA, and Stacie Vik, BA (University of Iowa).

                Financial: Steve Blanchard, MSHA, Kelsey Montross, BA, and Phil Danzer (University of Iowa).

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