Martino D, Aniello MS, Masi G, Lamberti P, Lucchese V, Lamberti S, Livrea P, Berardelli A, Defazio G. Validity of Family History Data on Primary Adult-Onset Dystonia. Arch Neurol. 2004;61(10):1569-1573. doi:10.1001/archneur.61.10.1569
Copyright 2004 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2004
To our knowledge, no study has assessed the validity of family history data provided by probands with adult-onset dystonia.
To measure the sensitivity and specificity of interviewing patients with primary adult-onset dystonia as a method for obtaining information on dystonia in first-degree relatives.
Seventy probands with primary adult-onset dystonia were asked to identify first-degree relatives who had dystonia. Available relatives were then directly examined by a trained neurologist. The validity of the probands’ reports was tested against the neurologists’ diagnoses.
Among 300 first-degree relatives who were examined, 26 received a diagnosis of dystonia. Only 7 of the 26 were identified by the probands’ reports. Among the 274 relatives free of dystonia, the probands reported 5 as having dystonia. The probands’ reports therefore yielded a sensitivity of 27.0% and a specificity of 98.2%.
Because the family history method yields low sensitivity and incurs a risk of misclassification, it is of limited use in family studies of adult-onset dystonia. The only valid means of ascertaining dystonia among relatives remains neurological examination of at-risk subjects.
Current evidence indicates that genetic factors are among the causes of primary adult-onset dystonia.1,2 Obtaining accurate information about dystonia in family members is therefore increasingly important in clinical practice and in research. Physicians in general practice may need to seek more familial information on patients with dystonia, for example by including genetic testing and assessing the risk in other family members. In the research field, familial information is crucial for valid testing of genetic hypotheses and for assessing the contribution of familial and environmental risk factors to dystonia and their interaction.
In theory, the most valid means of assessing the familial occurrence of dystonia is clinical examination of at-risk relatives, but this approach is often impractical because of limited resources. Information on dystonia in the family is often obtained indirectly, by asking the probands to identify dystonia among relatives. Although evidence suggests that probands with adult-onset dystonia underreport dystonia in their relatives,3,4 no studies have addressed the question systematically, to our knowledge.
In this article, we investigated whether asking patients with adult-onset dystonia to report a family history of dystonia is a valid (sensitive and specific) method for assessing the presence of dystonia in first-degree relatives.
Probands were identified during a 12-month period among consecutive outpatients with primary adult-onset dystonia attending the Movement Disorders Clinic at the Department of Neurological and Psychiatric Sciences and living no more than 3 hours’ traveling distance from the medical center. The study was approved by the local ethics committee. Inclusion criteria were a diagnosis of focal, segmental, or multifocal dystonia according to published criteria5; age at dystonia onset (defined as the time of first symptoms) older than 20 years; and duration of disease longer than 1 year. Exclusion criteria were clinical and laboratory findings (including serum ceruloplasmin determination and imaging studies) suggesting secondary causes of dystonia5 and specific referral for familial dystonia.
Patients were asked about vital status and demographic information of parents, siblings, and children. Thereafter, we repeated the following question for each living family member separately: “Does your relative have movements or postures in certain parts of the body that he or she cannot control (in particular, forceful closure of both eyelids; jaw opening, closing, or deviation with or without tongue movements; movements of the head or neck or abnormal position of the neck and shoulders; and sustained movements or blocks of the hand or fingers, making writing or other manual tasks difficult to perform)?” The same physician (M.S.A.) interviewed all patients.
After the interview, each proband was asked to participate in a family study. Probands were told that dystonia may be sometimes so mild that neither the affected subjects nor their close family and friends may be aware of symptoms; conversely, examination by an expert physician has a greater chance of identifying dystonia even in apparently asymptomatic subjects. A neurologist (D.M.) blinded to previous interviews and trained in movement disorders visited at home all first-degree relatives giving informed consent. Family members underwent complete neurological examination, including triggering maneuvers for dystonic movements or postures in asymptomatic subjects. Subjects were asked to repeatedly open and close their eyes or their mouth, look upward and downward, speak, walk, read, and perform manual tasks, including spontaneous and dictated writing. Definite dystonia was diagnosed when slow dystonic movements and abnormal postures occurred at rest or were activated by specific tasks. Blepharospasm (BSP) was defined as tonic or clonic episodes of involuntary eyelid closure associated with signs of orbicularis oculi muscle contraction, such as lowering of the brows beneath the superior orbital margin (Charcot sign). Oromandibular dystonia was diagnosed when spasms of the tongue, mandible, or floor of the mouth muscles were associated with involuntary jaw deviation, closing, or opening. Cervical dystonia was diagnosed when slow dystonic movements or abnormal neck postures were associated with head jerks. Finally, limb dystonia was diagnosed when slow dystonic movements and awkward postures developed at rest or were activated by specific tasks. Increased blinking with no evidence of Charcot sign, features suggesting so-called apraxia of eyelid opening,6 unusual tight hand gripping with writing, and isolated focal action tremor7 were not assigned a diagnosis of definite dystonia because their diagnostic value is unclear. Coexistence of postural tremor and dystonia in the same body region did not exclude the diagnosis of definite dystonia. Diagnoses made on site were confirmed through direct or videotape examination by 2 senior neurologists (A.B. and G.D.) expert in dystonia, blinded to the previously assigned diagnoses. Each affected relative was also asked about awareness of dystonia and interference of dystonia (yes or no) with at least 1 of the following activities of daily living: reading, writing, watching television, walking, shopping, performing manual tasks, housework, or outside jobs.
Probands’ reports of dystonia in relatives served as the screening, and the relatives’ diagnosis of dystonia based on clinical examination served as the reference standard. Sensitivity was defined as the proportion of relatives who screened positive at the probands’ interviews among those given a diagnosis of dystonia based on direct clinical examination. Specificity was defined as the proportion of relatives who screened negative on the probands’ interviews among those who were judged normal on clinical examination.
t Test and χ2 test were used for statistical analysis. P<.05 was considered to be statistically significant.
During the study period, 91 patients met the eligibility criteria, of whom 70 agreed to participate in the study. The group who declined included 2 subjects with no living first-degree relatives and 8 subjects who disagreed with most of their relatives. The remaining 11 probands preferred not to explain their refusal. Patients who participated in the study and those who did not had similar demographic and clinical features (Table 1).
The 70 probands participating in the study produced a potential population of 523 first-degree relatives, of whom 377 were alive and 300 were examined (Table 2). Of the 300 relatives who were examined, 26 (8.7%) from 19 families were diagnosed as having definite focal or segmental dystonia (Table 3). Of the 26 relatives in whom dystonia was diagnosed, the probands identified only 7 (code numbers 1, 2, and 4-8 in Table 3); probands’ reports therefore yielded an overall sensitivity of 27.0%. Five (code numbers 1, 4, 5, 7, and 8 in Table 3) of the 7 affected relatives identified by probands’ reports and 6 (code numbers 9, 10, 11, 15, 24, and 26 in Table 3) of the 19 affected relatives identified only by clinical examination had the same type of dystonia as the proband (P = .17, χ2 test). Three affected relatives (code numbers 13, 14, and 17 in Table 3) were unaware of dystonia (none were identified by probands’ reports), 20 (code numbers 1-4, 7, 9-12, 15, 16, and 18-26 in Table 3) were aware of dystonia but reported no interference with activities of daily living (4 were identified by probands’ reports), and 3 (code numbers 5, 6, and 8 in Table 3) reported interference with some activity of daily living (all were identified by probands’ reports). Interference of dystonia with activities of daily living was significantly more frequent in the relatives of probands reporting a family history of dystonia (Table 4).
Probands’ reports identified not only the 7 relatives with dystonia included in Table 3 but also 5 relatives who did not have dystonia on examination. They included a woman with orofacial movements triggered by dentures that she did not wear on examination, a man with hemifacial spasm, a man with increased blinking but no BSP, a man with kinetic bilateral hand tremor, and a woman with dry eye complaints but no BSP. Because 5 of the 274 relatives free of dystonia were mistakenly reported by the proband as having dystonia, the probands’ history reports yielded an overall specificity of 98.2%.
To check possible determinants of sensitivity or specificity related to the proband or the relatives, probands were stratified according to median age (62 years), median years of schooling (5 years), and distribution of dystonia, whereas relatives were subdivided according to their relationship to the proband (Table 5). Differences between strata assessed by the χ2 test (when appropriate, the Yates correction was used) did not achieve statistical significance.
Our findings show that patients with primary adult-onset dystonia do not accurately report the dystonia histories of their first-degree relatives. The low sensitivity (27.0%) of family history information indicated a high proportion of false-negative responses. The high specificity (98.2%) resulted from 5 relatives incorrectly labeled as having dystonia among 274 relatives free of dystonia. Although limited, the risk of misclassifying relatives affected by movement disorders other than dystonia should be considered when interpreting findings from probands’ interviews.
In our series, there were no significant differences in sensitivity and specificity associated with sex, age, education level, and type of dystonia of the probands, as well as the affected relative’s relationship to the proband. This may have been partly caused by the small number of affected relatives, despite the large size of the study sample. Increasing the power of investigation may be difficult owing to the rate of dystonia in first-degree relatives and the low penetrance of the condition.1,3,4,8
Other studies systematically measuring the accuracy of family history information on adult-onset dystonia are lacking. In the study conducted by Leube et al,3 who examined 51 first-degree relatives of 17 patients with adult-onset dystonia, patients underreported dystonia in their families, but the investigators gave no sensitivity and specificity estimates. The sensitivity of the probands’ interviews is higher for adult-onset dystonia (27.0%) than for essential tremor (16.7%),9 but lower than for epilepsy (87%),10 Alzheimer disease (64%),11 and migraine(44%).12 Overreporting of family history of dystonia in comparison with essential tremor probably relates to the fact that the validity of family history data on essential tremor was assessed in a cohort that included first-degree and second-degree relatives.9 Underreporting of family history of focal or segmental dystonia compared with epilepsy10 and Alzheimer disease11 probably relates to the lack of drama associated with a seizure and the mildness of dystonia in relatives. This view receives support from 2 observations in our study: first, most affected relatives were unaware of dystonia or their dystonia did not appreciably interfere with activities of daily living, and second, awareness of dystonia and interference with activities of daily living were significantly more common in the relatives of probands who correctly identified dystonia in relatives.
This study has several strengths. First, it was large. A study of this size was only possible in the context of an investigation on the familial aggregation of dystonia, which justified the funding needed for contacting a large number of first-degree relatives directly. The primary results of our study on the familial aggregation of dystonia will be reported elsewhere. Second, our series was probably representative of primary adult-onset dystonia. Except for the large number of patients who had BSP, our case population had demographic and clinical features similar to those in previous series.3,4,8,13,14 The predominance of BSP has been noted in another large Italian series14 and a community-based sample15 and might suggest differences in the clinical expression of adult-onset dystonia across countries. Finally, dystonia status for each relative was based on clinical examination by trained neurologists who used stringent diagnostic criteria.
Our study has limitations. First, the family history method was imperfect and had a potential flaw. We used a single question about dystonia and repeated the same question for each family member. Theoretically, some family members might have not understood the question. However, no significant difference in sensitivity and specificity was found when probands were stratified by education level. Asking additional questions about the symptoms of dystonia might have increased the sensitivity of the method. However, our aim was to assess the validity of family history data from the vantage point of clinical practice. Second, 23.1% (21/91) of eligible subjects declined to participate in the study. If patients who were excluded were less or more aware of their family history than those who were included, our estimates of sensitivity and specificity could be biased. Yet, case subjects who were included were similar to those excluded for several variables, including sex, age, education level, family size, age at dystonia onset, and distribution of dystonia. An open question is whether differences in other factors influenced our findings. Third, our validation study might have been affected by differences between relatives who were examined and those who were not. Because of our probands’ advanced age, we were unable to examine most of their parents. Owing to the late onset of dystonia, probands might have had a greater opportunity to observe the development of dystonia in older subjects. This is a common problem in late-onset disorders.
Two observations prevent us from generalizing our findings to the entire population with adult-onset dystonia. First, our series included only a few probands with upper limb dystonia, and none of them had affected relatives. Second, we did not address the issue of laryngeal dystonia in family members, because it often cannot be diagnosed solely by clinical examination, but requires detailed otolaryngologic and speech-language assessment.16
Despite the foregoing limitations, this study may have important implications for clinical practice and design and interpretation of studies investigating familial aggregation of primary adult-onset dystonia. Our findings counsel against considering family history information on adult-onset dystonia as valid. In particular, probands’ interviews tend to bias information in 2 ways. First, they may be insensitive. Second, they incur the risk of misclassifying relatives affected by movement disorders other than primary dystonia. The only valid means of ascertaining dystonia among relatives is neurological examination of at-risk subjects. Because this approach is often impractical, we need to develop and validate alternative screening instruments (eg, standardized interview of relatives) like those successfully used in other movement disorders such as Parkinson disease and essential tremor.17,18
Correspondence: Giovanni Defazio, MD, Department of Neurological and Psychiatric Sciences, University of Bari, Piazza Giulio Cesare 11, 1-70124 Bari, Italy (email@example.com).
Accepted for Publication: March 17, 2004.
Author Contributions:Study concept and design: P. Lamberti, Livrea, Berardelli, and Defazio; acquisition of data: Martino, Aniello, Masi, Lucchese, and S. Lamberti; drafting of the manuscript: Aniello, Masi, Lucchese, and S. Lamberti; critical revision of the manuscript for important intellectual content: Martino, P. Lamberti, Livrea, Berardelli, and Defazio; statistical analysis: Martino and Defazio; obtained funding: P. Lamberti and Berardelli; administrative, technical, and material support: Aniello, Masi, Lucchese, and S. Lamberti; study supervision: Livrea.
Funding/Support: This work was supported by grants from the Benign Essential Blepharospasm Research Foundation, Beaumont, Tex, and from the Italian Ministry of Health, Rome.