This week in Neurology® Highlights of the January 13 issue
A multidisciplinary study of patients with early-onset PD with and without parkin mutations This study indicates that carriers of parkin mutations are clinically indistinguishable from other early-onset patients. Nevertheless, parkin patients had significantly lower daily doses of dopaminergic treatment and greater delay in the development of levodopa-related fluctuations. See p. 110; Editorial, p. 106
Comorbidity delays diagnosis and increases disability at diagnosis in MS The authors studied over 8,000 patients with MS and observed longer delays in diagnosis and more disability at diagnosis in patients with pre-existing chronic conditions. This indicates that physicians seeing patients with chronic
MRI correlates of cognitive decline in CADASIL: A 7-year follow up study This paper investigates which of the MRI hallmarks in CADASIL are associated with cognitive decline. The authors found that increase in lacunar infarcts, microbleeds and ventricular volume, but not white matter lesions or atrophy, are associated with cognitive decline in CADASIL. See p. 143
Surrogate consent for dementia research: A national survey of older Americans Alzheimer disease clinical research often involves subjects who have lost their ability to consent; however, surrogate consent for dementia research remains controversial. This paper discusses a national survey of older Americans, which reveals broad public support for surrogate-based dementia research. See p. 149
conditions and new neurologic symptoms must be circumspect about attributing those symptoms to the existing conditions. See p. 117; Editorial, p. 108
Postmenopausal hormone therapy and subclinical cerebrovascular disease: The WHIMS-MRI Study The authors examine the association of conjugated equine
Cerebral microbleeds are a risk factor for warfarin-related intracerebral hemorrhage Underlying microbleeds on brain MRI are an independent risk factor for incident warfarin-related intracerebral hemorrhage. This study provides new radiological information on prognosis after long-term warfarin medication. See p. 171
estrogen-based hormone therapy (HT) versus placebo and silent cerebrovascular disease as a mechanism for negative effects of HT on cognition in older women. HT is not associated with increased lesion volume on brain MRI conducted 8 years after randomization to HT. See p. 135
Postmenopausal hormone therapy and regional brain volumes: The WHIMS-MRI Study The authors found that older women randomized to conjugated equine estrogen-based hormone therapy (HT) versus placebo have smaller hippocampal and frontal volumes on MRI assessed a mean of 8 years after
SPECIAL ARTICLES
Practice Parameter: Evaluation of distal symmetric polyneuropathy: Role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review) Practice Parameter: Evaluation of distal symmetric polyneuropathy: Role of laboratory and genetic testing (an evidence-based review) These papers outline the accuracy and usefulness of laboratory, genetic, and autonomic testing, as well as nerve and skin biopsy in the evaluation and management of patients with distal symmetric polyneuropathy. See p. 177 & p. 185
randomization. HT effects on regional volumes are most pronounced in women with lower cognitive function at baseline or higher ischemic lesion burden. See p. 135
Podcasts can be accessed at www.neurology.org
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105
EDITORIAL
Parkinson disease(s) Is “Parkin disease” a distinct clinical entity?
Christine Klein, MD Katja Lohmann, PhD
Address correspondence and reprint requests to Dr. Christine Klein, Department of Neurology, University of Lu¨beck, Ratzeburger Allee 160, 23538 Lu¨beck, Germany christine.klein@neuro. uni-luebeck.de
Neurology® 2009;72:106–107
The discovery of several monogenic forms has clearly established Parkinson disease (PD) as an etiologically heterogeneous condition.1 However, initial high expectations of well-defined genotype–phenotype correlations have remained largely unmet, both at the clinical and at the pathologic level.2 To date, very few studies have systematically addressed the natural history of genetic PD, resulting in an almost complete lack of longitudinal data on genetic vs non-genetic forms. Likewise, it is currently unknown whether the frequency and type of nonmotor signs, a well-recognized feature of idiopathic PD, might help differentiate genetic from idiopathic PD. These considerations are of major importance as they will not only improve our general understanding of the various forms of PD but will likely also impact on a better prediction of the individual patient’s prognosis, on recommendations for genetic testing, and on the choice of therapeutic options including type and doses of antiparkinsonian medication and potential treatment of nonmotor signs. Parkin mutations are the most common known cause of early-onset parkinsonism3,4 and appear to be associated with a slower disease progression and an overall better response to dopaminergic treatment.5 In their article on a multidisciplinary study of patients with early-onset PD with and without Parkin mutations, Lohmann and colleagues confirm their previous observation of a more favorable disease course in the mutation carriers who maintained an excellent response to lower doses of L-dopa than patients without mutations.6 The novelty of this study lies in the detailed assessment of cognitive function and psychiatric features of affected and unaffected Parkin mutation carriers vs patients with idiopathic early-onset PD.6 Patients with Parkin mutations did not differ from patients without mutations with respect to occurrence of cognitive impairment, nor regarding specific behavioral or psychiatric symptoms that had previously been suggested as a key feature of “Parkin disease.”7
However, the lack of observed clinical differences between mutation carriers and noncarriers might, at least in part, be attributed to the relatively young age of many of the carriers of two or one mutated Parkin alleles, raising the possibility that the full-blown picture of the disease has not yet developed. As discussed by Lohmann et al.,6 another limitation of their study represents the relatively small sample size (21 patients with and 23 without Parkin mutations). This may also explain why they did not detect the well-established observation of an earlier age at onset in mutation carriers compared to patients without a Parkin mutation and why many of their comparisons yielded nonsignificant differences. A previous investigation focusing on special clinical features in a series of 24 Parkin mutation carriers emphasized early instability, autonomic failure, early or atypical dyskinesias, and recurrent psychosis as part of the phenotypic spectrum of “Parkin disease.” 7 While all of these signs may occur in individual Parkin mutation carriers, none of them seems to hold up as a red flag that may be generally attributed to patients with Parkin mutations.6 Indeed, a systematic literature review on cognitive and psychiatric features in Parkin mutation carriers found the rates for depression (31%), anxiety (26%), hallucinations (7%), and dementia (5%; unpublished data) to be comparable to or even lower than those reported for patients with idiopathic PD.8 Adding a further level of complexity, it has been suggested that the type and localization of Parkin mutations may play a role in shaping different Parkin-associated phenotypes.9 This potential source of bias needs to be considered when assessing phenotype– genotype correlations, as was accounted for by Lohmann and colleagues in their previous study.5 In spite of the aforementioned caveats, an increasing body of evidence suggests that Parkin disease is indeed characterized by a particularly benign disease
See page 110 e-Pub ahead of print on November 5, 2008, at www.neurology.org. From the Department of Neurology, University of Lu¨beck, Germany. C. Klein is supported by a Lichtenberg grant from the Volkswagen Foundation and recipient of a career development award from the Hermann and Lilly Schilling Foundation. Disclosure: The authors report no disclosures. 106
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course with slow progression, excellent treatment response, and few, if any, additional motor and nonmotor signs. What we do not know at this point is whether Parkin disease is clinically different from PINK1 or DJ-1 disease and whether Parkin mutation carriers employ certain, particularly effective compensatory mechanisms counteracting the effects of their neurodegeneration. Finding answers to these intriguing questions will require a combined approach of large-scale, longitudinal clinical studies, biomarker development, and an improved understanding of the pathways and mechanisms involved in “Parkin disease” and other forms of PD.
3.
4.
5.
6.
7.
8. REFERENCES 1. Klein C, Schlossmacher MG. Parkinson disease, 10 years after its genetic revolution: multiple clues to a complex disorder. Neurology 2007;69:2093–2104. 2. Marras C, Lang AE. Changing concepts in Parkinson disease: moving beyond the decade of the brain. Neurology 2008 (in press).
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Lu¨cking CB, Du¨rr A, Bonifati V, et al. Association between early-onset Parkinson’s disease and mutations in the parkin gene. N Engl J Med 2000;342:1560–1567. Hedrich K, Eskelson C, Wilmot B, et al. Distribution, type, and origin of Parkin mutations: review and case studies. Mov Disord 2004;19:1146–1157. Lohmann E, Periquet M, Bonifati V, et al. How much phenotypic variation can be attributed to parkin genotype? Ann Neurol 2003;54:176–185. Lohmann E, Thobois S, Lesage S, et al., and the French Parkinson’s Disease Genetics Study Group. A multidisciplinary study of patients with early-onset PD with and without parkin mutations. Neurology 2009;72:110–116. Khan NL, Graham E, Critchley P, et al. Parkin disease: a phenotypic study of a large case series. Brain 2003;126: 1279–1292. Schrag A, Schott JM. Epidemiological, clinical, and genetic characteristics of early-onset parkinsonism. Lancet Neurol 2006;5:355–363. Hampe C, Ardila-Osorio H, Fournier M, Brice A, Corti O. Biochemical analysis of Parkinson’s disease-causing variants of Parkin, an E3 ubiquitin-protein ligase with monoubiquitylation capacity. Hum Mol Genet 2006; 15:2059–2075.
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EDITORIAL
Selection bias in observational studies Out of control?
Christopher A. Beck, PhD
Address correspondence and reprint requests to Dr. Christopher A. Beck, Department of Biostatistics and Computational Biology, University of Rochester Medical Center, 601 Elmwood Ave, Box 630, Rochester, NY 14642
[email protected] Neurology® 2009;72:108–109
Bias comes in many flavors. Observational studies are especially prone to its many forms, mainly due to the investigator’s lack of control over the study. Selection bias may result when a study fails to select a representative sample from the population of interest, limiting the applicability of the study’s results.1,2 In this issue of Neurology®, Marrie et al.3 report an analysis of questionnaires completed by participants of the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry,4 a self-report database for patients with multiple sclerosis (MS). They obtained demographic and clinical information from a questionnaire participants completed at the time of enrollment in the registry, and comorbidity information from a follow-up questionnaire in 2006. The study suggested that comorbidity lengthens the delay between onset and diagnosis of MS, and that comorbidity increases the severity of disability at diagnosis. However, after accounting for the delay in diagnosis, the association between comorbidity and disability at diagnosis diminished and in most cases became no longer significant. In other words, the delay in diagnosis partly mediated the effect of comorbidity on disability at diagnosis. For this study, 16,141 NARCOMS participants were eligible to receive the comorbidity questionnaire, and 8,983 (55.7%) responded. The authors restricted their primary analyses to the 2,375 (26.4%) responders who had enrolled in the registry within 2 years of diagnosis. Given the low response rate from registry participants, what is the population to which these results can be generalized? Ideally, this would be the general MS population, but bias in the selection of the sample may be an issue in the external validity of the study results. There are at least three sources of bias in the current study; the authors noted and addressed all three. These include the use of a disease registry database,5 nonresponse to the comorbidity questionnaire,6 and the restriction to subjects who enrolled in the registry within 2 years of diagnosis. The authors addressed the first two of these by comparing the characteristics of their sample to all NARCOMS participants and to MS subjects nationally, and found minor differences in race, gender, socioeconomic
status, type of insurance coverage, disease course, and therapies used. The most concerning difference between their sample and other patients with MS relates to the restriction to patients enrolled in the registry within 2 years of diagnosis. This restriction was necessary in order to assume that demographic and disability data from the enrollment questionnaire would not have changed between diagnosis of MS and enrollment in the registry. This resulted in a sample of patients with milder disability and shorter duration of disease than the general MS population, potentially limiting the generalizability of the association detected between comorbidity and disability at diagnosis. However, the finding that comorbidity lengthens diagnostic delay is supported by additional analyses based on all responders to the comorbidity questionnaire. Thus, the generalizability of this association does not appear to be limited by the restriction to subjects who enrolled in the registry within 2 years of diagnosis. Effective prevention of selection bias can be achieved using random sampling. This technique selects subjects independently and randomly from the population, with each subject having an equal chance of being selected. In research involving humans, a truly random sample is nearly impossible since subjects have to agree to participate in a study. The extent of selection bias in these studies should be assessed by comparing volunteers and non-volunteers whenever possible.7,8 Even randomized clinical trials are not immune to selection bias. Such studies use randomization in the assignment of treatments to enrolled subjects, but not in the selection of subjects to be enrolled. This results in treatment groups that tend to be comparable to each other in all respects, but potentially different from the general population. These treatment groups would be affected equally by any bias in the sample selection. In this case, if the purpose of the trial is to compare the efficacy of the treatments, selection bias is only a concern if the treatment effect interacts with any characteristics that differ between the sample and the population.9 The effect of selection bias should be carefully considered in the interpretation of results based on nonrandom
See page 117 From the Department of Biostatistics and Computational Biology, University of Rochester Medical Center, NY. Disclosure: The author reports no disclosures. 108
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samples, and any extrapolations should be made with extreme caution. Although selection bias can never be completely controlled, its effect can be minimized and better understood through proper study design and execution. Marrie et al. recognize these issues, and although the generalizability of their results do not appear to be compromised, they are correct in concluding that their findings require replication in population-based cohorts.
4.
5. 6.
7. REFERENCES 1. Ellenberg JH. Selection bias in observational and experimental studies. Stat Med 1994;13:557–567. 2. Williams WH. How bad can “good” data really be? Am Stat 1978;32:61–65. 3. Marrie RA, Horwitz R, Cutter G, Tyry T, Campagnolo D, Vollmer T. Comorbidity delays diagnosis and increases disability at diagnosis in MS. Neurology 2009;72:117–124.
8.
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The Consortium of Multiple Sclerosis Centers. North American Research Committee on Multiple Sclerosis Patients Registry. Available at: www.mscare.org/cmsc/CMSC-NARCOMSInformation.html. Accessed August 7, 2008. Dambrosia JM, Ellenberg JH. Statistical considerations for a medical data base. Biometrics 1980;36:323–332. Rupp I, Triemstra M, Boshuizen HC, Jacobi CE, Dinant HJ, van den Bos GAM. Selection bias due to non-response in a health survey among patients with rheumatoid arthritis. Eur J Public Health 2002;12:131–135. Kim SYH, Holloway RG, Frank S, et al. Volunteering for early phase gene transfer research in Parkinson disease. Neurology 2006;66:1010–1015. Coronary artery surgery study (CASS): a randomized trial of coronary artery bypass surgery. Comparability of entry characteristics and survival in randomized patients and nonrandomized patients meeting randomization criteria. J Am Coll Cardiol 1984;3:114–128. Piantadosi S. Clinical Trials: A Methodologic Perspective, 2nd ed. New York: Wiley; 2005.
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ARTICLES
A multidisciplinary study of patients with early-onset PD with and without parkin mutations E. Lohmann, MD S. Thobois, MD, PhD S. Lesage, PhD E. Broussolle, MD, PhD S. Tezenas du Montcel, MD, PhD M.-J. Ribeiro, PhD P. Remy, MD, PhD A. Pelissolo, MD B. Dubois, MD L. Mallet, MD P. Pollak, MD, PhD Y. Agid, MD, PhD A. Brice, MD The French Parkinson’s Disease Genetics Study Group*
ABSTRACT
Objective: To establish phenotype– genotype correlations in early-onset Parkinson disease (EOPD), we performed neurologic, neuropsychological, and psychiatric evaluations in a series of patients with and without parkin mutations.
Background: Parkin (PARK2) gene mutations are the major cause of autosomal recessive parkinsonism. The usual clinical features are early-onset typical PD with a slow clinical course, an excellent response to low doses of levodopa, frequent treatment-induced dyskinesias, and the absence of dementia.
Methods: A total of 44 patients with EOPD (21 with and 23 without parkin mutations) and 9 unaffected single heterozygous carriers of parkin mutations underwent extensive clinical, neuropsychological, and psychiatric examinations. Results: The neurologic, neuropsychological, and psychiatric features were similar in all patients, except for significantly lower daily doses of dopaminergic treatment and greater delay in the development of levodopa-related fluctuations (p ⬍ 0.05) in parkin mutation carriers compared to noncarriers. There was no major difference between the two groups in terms of general cognitive efficiency. Psychiatric manifestations (depression) were more frequent in patients than in healthy single heterozygous parkin carriers but did not differ between the two groups of patients.
Conclusion: Carriers of parkin mutations are clinically indistinguishable from other patients with Address correspondence and reprint requests to Prof. Alexis Brice, INSERM UMR S_679, Hoˆpital Pitie´-Salpeˆtrie`re, 47 boulevard de l’Hoˆpital, F-75013 Paris, France
[email protected] young-onset Parkinson disease (PD) on an individual basis. Severe generalized loss of dopaminergic neurons in the substantia nigra pars compacta in these patients is associated with an excellent response to low doses of dopa-equivalent and delayed fluctuations, but cognitive impairment and special behavioral or psychiatric symptoms were not more severe than in other patients with early-onset PD. Neurology® 2009;72:110–116 GLOSSARY CPRS ⫽ Comprehensive Psychopathological Rating Scale; EOPD ⫽ early-onset Parkinson disease; FAB ⫽ Frontal Assessment Battery; MADRS ⫽ Montgomery-Asberg Depression Rating Scale; MDRS ⫽ Mattis Dementia Rating Scale; MINI ⫽ Mini International Neuropsychiatric Interview; MMSE ⫽ Mini-Mental State Examination; TMT ⫽ Trail Making Test; UPDRS ⫽ Unified Parkinson’s Disease Rating Scale; WCST ⫽ Wisconsin Card Sorting Test.
Mutations in the parkin gene are considered to be the predominant cause of early-onset Parkinson disease (EOPD) particularly when the family history is compatible with autosomal recessive inheritance.1,2 Parkin-linked PD has a broad range of clinical phenotypes, some atypical, but is generally early-onset parkinsonism, with a slow clinical course, excellent response to low doses of levodopa, frequent treatment-induced dyskinesias, and no dementia.3,4 Cognitive function remains normal in the majority of patients,3-6 but behavioral disorders have been reported, including anxiety, psychosis, panic attacks, depression, and disturbed sexual, behavioral, and obsessive-compulsive disorders.4,5,7-9 Editorial, page 106 e-Pub ahead of print on November 5, 2008, at www.neurology.org. *The French Parkinson’s Disease Genetics Study Group members are listed in the appendix. Authors’ affiliations are listed at the end of the article. Supported by INSERM/AP-HP (PCR02006-P011104), the NIH grant NS41723-01A1, and the European commission (EU Contract No.LSHMCT-2003-503330/APOPIS). Disclosure: The authors report no disclosures. 110
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Mutations have been found in the homozygous or compound heterozygous state, compatible with recessive transmission, but occasionally as single heterozygous mutations.2,5,10 In these patients, it is still not clear whether a second mutation outside the open reading frame of the gene may be overlooked or whether some heterozygous mutations are sufficient to cause the disease.11 To establish pheno– genotype correlations in EO parkinsonism, we performed a clinical study of 21 patients with and 23 patients without parkin mutations. We expected behavioral or psychiatric problems in parkin mutation carriers because neuropathologic studies of parkin patients show severe generalized loss of dopaminergic neurons in the substantia nigra pars compacta that would greatly decrease dopaminergic efferents to the limbic and sensory-motor systems. In addition, although it is generally assumed that parkin gene mutations carriers have no dementia, systematic assessment of cognitive functions in this population was not performed. We aim to fill this gap. Additionally, we evaluated 9 healthy sibs of our patients with single heterozygous parkin mutations. METHODS Forty-four patients with isolated or familial earlyonset parkinsonism (⬍45 years) recruited in Paris (n ⫽ 25), Grenoble and Lyon (n ⫽ 19) underwent neurologic, neuropsychological, and psychiatric evaluation. The inclusion criteria for PD were at least two of the parkinsonian triad of signs (bradykinesia, rigidity, rest tremor) and at least 30% improvement under levodopa therapy, in familial or isolated cases. Exclusion criteria were the existence of extensor plantar reflexes, ophthalmoplegia, early dementia, or early autonomic failure. There were 13 women and 31 men; mean age at onset was 33.1 years ⫾ 8.3 (12– 44) and mean disease duration was 17.4 years ⫾ 7.8. (5–34). Twenty-five patients had known family histories of PD. Among the 44 patients originating from France (n ⫽ 41), Asia (n ⫽ 2), and North Africa (n ⫽ 1), 21 had homozygous or compound heterozygous parkin mutations and 23 patients no parkin mutations. Five female and four male heterozygous parkin carriers originating from France (n ⫽ 7) and North Africa (n ⫽ 2), healthy sibs of the parkin patients, also participated in the study. Their age at examination was 47.9 years ⫾ 12.6 (28 – 68). A standardized form was used to assess the history of the disease in the patient and the family, the clinical signs, additional diseases, and the response to present treatment. All patients were evaluated with the Unified Parkinson’s Disease Rating Scale (UPDRS) I to VI, with and without treatment (“on” and “off” state), except UPDRS I and IV, which were evaluated only in the “off” state. The “off” state was usually reached after interruption of antiparkinsonian medication for at least 12 hours, and the best “on” state was obtained after administration of a single su-
Table 1
Parkin mutations in affected and unaffected carriers
Mutations in unaffected heterozygous carriers (n ⴝ 9)
Mutations in affected carriers (n ⴝ 21)
ex8-9del/N (2 patients)
ex8-9del/ex8-9del
ex3-4del/N
ex6dupl/c.255delA (2 patients)
ex3dupl/N
ex5del/Cys411Arg (4 patients)
ex2-3del/N
ex5del/c255delA
ex2tripl/N
ex4del/Met1stop (2 patients)
promotor-ex1del/N (2 patients)
ex3-6del/Arg275Trp
Met1stop/N
ex3-4del/Arg275Trp (3 patients) ex3del/Arg275Trp ex3del /c.202-203delAG ex3del/promotor-ex1del (2 patients) ex3dupl/ex3dupl ex3del/ex3del (2 patients)
prathreshold dose of levodopa (50 mg higher than the usual effective morning dose). The response to treatment was calculated from the “off” and “on” values of UPDRS III. We used the conversion factors proposed by Thobois12 to calculate the daily levodopa dose-equivalent taken by the patients. Neuropsychological and psychiatric tests were performed while the patients received their usual treatment. The MiniMental State Examination (MMSE) and the Mattis Dementia Rating Scale (MDRS) were used to assess global intellectual efficiency. Verbal episodic memory was investigated with the Grober and Buschke test to control for effective encoding and to facilitate retrieval with the same semantic cueing, providing a comparison between free and cued recall. Two parallel forms of the Grober and Buschke test were used to control test-retest effects. Executive functions were assessed with the simplified version of the Wisconsin Card Sorting Test (WCST), the category and literal fluency test, the Trail Making Test (TMT), the Frontal score, and the Frontal Assessment Battery (FAB). The psychiatric evaluation was based on the Montgomery-Asberg Depression Rating Scale (MADRS), the Comprehensive Psychopathological Rating Scale (CPRS), and a standardized Mini International Neuropsychiatric Interview (MINI). Molecular analysis of the parkin gene was performed by denaturing high performance liquid chromatography and sequencing and semiquantitative multiplex PCR as described before.13 The G2019S mutation of the LRRK2 gene and mutations in the DJ-1 and Pink1 genes were excluded in all patients.14 Data are expressed as the mean ⫾ SD (range) or percentage (n). Group comparisons were made using the Kruskal-Wallis test for quantitative variables and the Fisher exact test for qualitative variables. When significant differences were detected, post hoc comparisons were performed with a Bonferroni correction for multiple comparisons. For the delay before dyskinesia, dystonia, and fluctuations, Kaplan-Meier estimations were obtained. The Sidak correction for multiple comparisons was applied by discipline (clinical, psychiatric, neuropsychological). The SAS 8.1 Neurology 72
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Table 2
Clinical characteristics of patients with Parkinson disease (PD) with parkin and without parkin mutations PD patients with parkin mutations (n ⴝ 21)
PD patients without parkin mutations (n ⴝ 23)
Age at onset, y
31.1 ⫾ 8.3 (12–44)
34.9 ⫾ 6.2 (16–44)
PD duration, y
17.4 ⫾ 7.8 (5–34)
12.9 ⫾ 7.7 (4–34)
UPDRS I (/16) UPDRS II off (/52) UPDRS II on (/52)
2.1 ⫾ 1.9 (0–6)
2.3 ⫾ 1.8 (0–6)
12.1 ⫾ 6.4 (2–23)
17.3 ⫾ 8.2 (6–34)
4.3 ⫾ 4 (0–17)
5 ⫾ 4.1 (0–16)
UPDRS III off (/108)
32.4 ⫾ 16.2 (7–63)
UPDRS III on (/108)
10.2 ⫾ 6.5 (1–24)
12.4 ⫾ 9.7 (1–37)
5.2 ⫾ 3.1 (0–12)
7.3 ⫾ 3.5 (2–17)
UPDRS IV (/23)
40.2 ⫾ 16.6 (19–70)
Hoehn and Yahr off (/5)
2.6 ⫾ 0.8 (1–4)
2.8 ⫾ 0.9 (1–5)
Hoehn and Yahr on (/5)
1.5 ⫾ 0.9 (0–3)
1.4 ⫾ 0.9 (0–3)
Schwab and England off (0–100%) Schwab and England on (0–100%)
78.1 ⫾ 12 (50–90) 91.9 ⫾ 8 (80–100)
Daily doses of levodopa equivalent, mg/d*
636 ⫾ 462 (120–2,150)
Daily doses of levodopa, mg/d
528 ⫾ 439 (50–2,000)
Duration of treatment, y
13.2 ⫾ 6.5 (4–31) (n ⫽ 20)
Occurrence of dyskinesia Delay before dyskinesia after treatment, y† Occurrence of dystonia
89.6 ⫾ 11.9 (60–100) 1139 ⫾ 451 (300–1,900) 778 ⫾ 343 (300–1,700) 9.9 ⫾ 6.3 (0.3–20) (n ⫽ 19)
71.4% (n ⫽ 15) 12 (8–16) 52.4% (n ⫽ 11)
Delay before dystonia after treatment, y†
17 (10–23)
Occurrence of fluctuations
57.1% (n ⫽ 12)
Delay before fluctuations after treatment, y*†
63.9 ⫾ 19.9 (20–90)
14 (9–28)
60.9% (n ⫽ 14) 10 (6–20) 52.2% (n ⫽ 12) 13 (7–20) 95.7% (n ⫽ 22) 5 (4–8)
*p ⬍ 0.05. †Data are expressed as the median (95% CI), otherwise they are mean ⫾ SD (range). UPDRS ⫽ Unified Parkinson’s Disease Rating Scale.
statistical package (SAS Institute, Cary, NC) was used for the analyses. The study was approved by the Ethical Committee of the Salpeˆtrie`re University Hospital Paris, France, and all patients gave their written informed consent.
Twenty-one out of 44 patients with EOPD had homozygous or compound heterozygous parkin mutations (table 1). Nine healthy sibs of the patients with parkin mutations had a single heterozygous mutation (table 1). Age at examination did not differ significantly among the three groups (47.5 years ⫾ 9.1 for affected parkin mutation carriers, 48.0 years ⫾ 8.0 for affected nonmutation carriers, and 47.9 years ⫾ 12.6 for unaffected single heterozygous carriers). Age at onset (31.1 years ⫾ 8.3 vs 34.9 years ⫾ 6.2) and disease duration (17.4 years ⫾ 7.8 vs 12.9 years ⫾ 7.7) were similar in patients with and without parkin mutations (table 2). Clinical characteristics RESULTS
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such as mentation, behavior, and mood (UPDRS I), activities of daily living (UPDRS II, “off” and “on” drug), parkinsonian motor disability (UPDRS III, “off” and “on” drug), Hoehn and Yahr Scale (UPDRS V), and the Schwab and England Scale (UPDRS VI) were also similar in patients with and without parkin mutations (table 2). However, the daily levodopa dose equivalents were significantly lower in patients with parkin mutations than in noncarriers (636 mg ⫾ 462 vs 1,139 mg ⫾ 451), although the duration of treatment was similar (13.2 years ⫾ 6.5 vs 9.9 years ⫾ 6.3). The UPDRS IV scores, which evaluate levodoparelated complications, did not differ between the two groups, but the delay before the appearance of levodopa-related fluctuations after treatment was significantly shorter in noncarriers than in patients with mutations (median: 5 years 95% CI [4 –18] vs 14 years [9 –28]). One affected non-mutation carrier but none of the patients with mutations had orthostatic hypotension, and none of the patients in either group had urinary incontinence. Patients from both groups had problems with sleep, such as sleep disruption, daytime sleepiness, or sleep behavior disorder (16/23 non-mutation carriers vs 10/21 parkin mutation carriers, data not shown), but the difference was not significant. Careful neurologic examination revealed no parkinsonism in the sibs with single heterozygous parkin mutations. Detailed neuropsychological examinations, including the MMSE, MDRS, Grober and Buschke test, WCST, TMT, FAB, and frontal score, did not detect any significant differences among the three groups (table 3). The results of the MDRS and the FAB were significantly different among the three groups, but after the Sidak correction for multiple comparisons, the difference was no longer significant. Four patients carrying two parkin mutations, one healthy heterozygous mutation carrier and one non-mutation carrier, had MDRS scores below the threshold of 136/144. The patient without parkin mutations (SPD-150) was a 55-year-old man, who started PD at age 33 and developed epilepsy during the 24-year evolution of his disease. The low cognitive efficiency of the patient (MMSE: 24/30 and MDRS: 110/144) was attributed to either his epileptic status or his carbamazepine treatment. The psychiatric profiles obtained with the MADRS, CPRS, and MINI tests were similar in patients with and without parkin mutations. Interestingly, patients tended to experience more depressive episodes and had higher MADRS scores (p ⫽ 0.2) than unaffected heterozygous parkin carriers (table 4). Additionally, six patients without and three pa-
Table 3
Neuropsychological evaluations of patients with Parkinson disease (PD) with and without parkin mutations and unaffected heterozygous parkin carriers (ⴙⴚ) PD patients with parkin mutations, n ⴝ 21 28.4 ⫾ 1.5 (25–30)
MMSE (/30) Mattis Dementia Rating Scale (/144)
138.5 ⫾ 4.1 (n ⫽ 19) (126–143)
PD patients without parkin mutations, n ⴝ 23
Healthy carriers of heterozygous parkin mutations, n ⴝ 9
28.4 ⫾ 2.1 (23–30)
29.5 ⫾ 0.9 (28–30)
139.0 ⫾ 6.7 (110–144)
142.4 ⫾ 1.4 (n ⫽ 8) (132–144)
Grober and Buschke 28.8 ⫾ 4 (n ⫽ 19) (20–34)
Free recall
30.2 ⫾ 5.0 (18–38)
35.1 ⫾ 6.2 (n ⫽ 8) (28–48)
Total recall
46.7 ⫾ 1.6 (n ⫽ 19) (43–48)
46.3 ⫾ 2.7 (37–48)
45.1 ⫾ 5.8 (n ⫽ 8) (31–48)
Delayed recall
10.9 ⫾ 2.5 (n ⫽ 19) (6–15)
11.8 ⫾ 2.4 (7–16)
13.3 ⫾ 1.3 (n ⫽ 8) (12–16)
Delayed total recall
15.7 ⫾ 0.6 (n ⫽ 19) (14–16)
Frontal score (/60)
15.8 ⫾ 0.5 (14–16)
15.6 ⫾ 1.1 (n ⫽ 8) (13–16)
54 ⫾ 5.6 (n ⫽ 18) (43–60)
54.7 ⫾ 5.3 (n ⫽ 21) (41–60)
54.4 ⫾ 10.3 (n ⫽ 8) (30–60)
17 ⫾ 1 (n ⫽ 18) (13–18)
16.5 ⫾ 1.5 (n ⫽ 22) (12–18)
17.9 ⫾ 0.4 (n ⫽ 8) (17–18)
Frontal Assessment Battery (/18) MCST
5 ⫾ 1.5 (n ⫽ 19) (1–6)
Categories Perseverations
1.7 ⫾ 2.8 (n ⫽ 18) (0–11)
5.3 ⫾ 1.1 (n ⫽ 21) (3–6)
6.0 (n ⫽ 8) (6–6)
1.3 ⫾ 2.3 (n ⫽ 21) (0–10)
0.6 ⫾ 1.4 (n ⫽ 8) (0–4)
Lexical fluency Category
20.7 ⫾ 5.1 (n ⫽ 18) (12–32)
Literal
12.8 ⫾ 4.1 (n ⫽ 18) (2–18)
21 ⫾ 7 (2–31)
23.3 ⫾ 6.0 (n ⫽ 8) (15–31)
13.2 ⫾ 4.9 (n ⫽ 22) (3–20)
13.1 ⫾ 3.6 (n ⫽ 8) (9–20)
MMSE ⫽ Mini-Mental State Examination; MCST ⫽ Modified Card Sorting Test.
tients with parkin mutations had MADRS scores ⬎15; five affected non-mutation carriers and three affected mutation carriers had scores ⬎18. However, the mean scores for both groups were not significantly different.
Table 4
This is one of the most detailed clinical studies to combine neurologic, neuropsychological, and psychiatric investigations to establish phenotype– genotype correlation in early-onset parkinsonism. We expected to find particular behavioral
DISCUSSION
Psychiatric evaluation of patients with Parkinson disease (PD) with and without parkin mutations and unaffected heterozygous parkin carriers PD patients with parkin mutations, n ⴝ 21
PD patients without parkin mutations, n ⴝ 23
MDE
43% (9)
48% (11)
MDE with melancholic features
10% (2)
9% (2)
Healthy carriers of heterozygous parkin mutations, n ⴝ 9
MINI 33% (3) 0
Dysthymia
6% (1)
4% (1)
0
Suicidality
14% (3)
4% (1)
0
Manic episode
14% (3)
4% (1)
0
Panic disorder
14% (3)
22% (5)
0
Agoraphobia
19% (4)
4% (1)
0
Social anxiety disorder
14% (3)
17% (4)
0
Obsessive-compulsive disorder
5% (1)
17% (4)
0
Posttraumatic stress disorder
10% (2)
4% (1)
0
Generalized anxiety disorder
33% (7)
26% (6)
11% (1)
CPRS (390)
34.1 ⫾ 29.2 (0–95)
42.7 ⫾ 27.7 (5–110)
17.1 ⫾ 15.3, n ⫽ 7 (4–44)
MADRS (30)
8.8 ⫾ 6.5 (0–21)
12.8 ⫾ 7.2 (2–28)
4 ⫾ 3.2, n ⫽ 7 (2–11)
None of the subjects were alcohol/substance abusers or had psychotic disorders, anorexia/bulimia nervosa, or antisocial personality disorders. MINI ⫽ Mini International Neuropsychiatric Interview; MDE ⫽ major depressive episode; CPRS ⫽ Comprehensive Psychopathological Rating Scale; MADRS ⫽ Montgomery-Asberg Depression Rating Scale. Neurology 72
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or psychiatric pattern and maybe cognitive disorders in parkin mutation carriers because neuropathologic studies of these patients have shown severe generalized loss of dopaminergic neurons in the substantia nigra pars compacta13 that would greatly decrease dopaminergic efferents to the limbic and subcorticalfrontal and sensory-motor systems. The 21 patients with and 23 patients without parkin mutations were appropriately matched for age at onset (31.1 years ⫾ 8.3 vs 34.9 years ⫾ 6.2) and disease duration (17.4 years ⫾ 7.8 vs 12.9 years ⫾ 7.7). Detailed clinical evaluations including UPDRS I–VI, with and without treatment, did not detect any significant differences between the two groups. The daily doses of levodopa were also similar in parkin mutation and non-mutation carriers (528 mg ⫾ 439 vs 778 mg ⫾ 343), but after calculation of the daily levodopa dose equivalents,12 a significant difference between the groups was observed: parkin mutation carriers improved to the same extent as noncarriers (68.4% ⫾ 13.1 vs 70.2% ⫾ 18.6, data not shown) with significantly lower daily levodopa dose equivalents (636 mg ⫾ 462 vs 1,139 mg ⫾ 451). Previous studies have already shown in large cohorts of patients that parkin carriers had more levodopa induced dyskinesias, brisk reflexes, onset with foot dystonia,3,15-17 and a better response to low doses of medication, even after a long evolution of the disease,4,5 although none of these studies compared patients matched for age and disease duration. Our study confirms that parkin patients have very good responses to low doses of antiparkinsonian treatment. Furthermore, our parkin mutation carriers did not have more levodopa-induced complications than noncarriers, but the delay before the appearance of fluctuations after initiation of treatment was significantly longer in parkin mutation carriers than in patients without parkin mutations (14 years ⫾ 5.1 vs 5 years ⫾ 1.4). This delay in the development of levodopa-related dyskinesia was probably a result of the significantly lower doses of medication, but, curiously, the delay between the development of levodopa-related dyskinesias and dystonia did not differ between the two groups (10 vs 12 years and 13 vs 17 years, table 2). Interestingly, we show that dysautonomia, orthostatic hypotension, and urinary incontinence, which are absent in patients with parkin mutations, are also rare in the other early-onset PD cases. All unaffected single heterozygous mutation carriers, with ages ranging from 28 to 68, had normal detailed neurologic examinations. Statistically significant reductions in [18F]fluorodopa uptake have been observed in carriers of a single heterozygous parkin mutation15,18 compared to controls, and some were reported to have 114
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subtle extrapyramidal signs, such as resting tremor, reduced arm swing, or a mask-like face.3,4,15,18 It cannot be excluded that these healthy single heterozygous mutation carriers will develop parkinsonian symptoms in the future, but six of them are already more than 15 years older than the age at onset of their affected sibs. This observation supports the hypothesis that a single, even truncating, mutation may not be sufficient to trigger PD. These unaffected sibs of affected parkin mutation carriers are useful controls, however, for neuropsychological and psychiatric evaluations, because they share genetic and environmental factors but not the disease with their affected sib. Neuropsychological examinations did not reveal major differences in general cognitive efficiency (MMSE, Mattis DRS, episodic memory, Grober and Buschke test) or executive functions (frontal score and FAB) in patients with and without parkin mutations and unaffected heterozygous parkin carriers. This is consistent with and confirms, with more detailed neuropsychological evaluations than in previous studies, that cognitive function remains normal in the majority of patients with parkin mutations,4,5,19 even after 45 years of evolution.4 Additionally, we showed that patients with early-onset PD without parkin mutations do not have cognitive decline even after more than 30 years of disease evolution. However, it is interesting to note that only one patient without a parkin mutation, who also has epilepsy, four patients with parkin mutations, and one healthy single heterozygous parkin carrier had abnormal results on the MDRS (⬍136), although the groups did not differ significantly after the Sidak correction for multiple testing. Functional or structural abnormalities in the caudate nucleus have been postulated to play a role in frontal-subcortical cognitive impairment or dementia in patients with basal ganglia disease. Interestingly, several studies3,15,17,18,20-22 reported that the decrease in [18F]fluorodopa uptake in nigrostriatal terminals in the caudate nucleus is generally greater in patients with parkin mutations than in patients without this mutation. This pattern of nigrostriatal dysfunction might result in a different neuropsychological profile. However, this discussion remains speculative and the results must be confirmed by further studies with larger patient groups. Behavioral disorders, including anxiety and psychosis, panic attacks, depression, disturbed sexual behavior, and obsessive-compulsive disorders, have been reported with variable frequency in patients with parkin mutations,4,5,7-9 and were suggested to be a distinctive feature of parkin disease.4 Dopaminergic dysfunction in cortical areas which might contribute to the psychiatric disorders, as postulated for patients with idiopathic PD,23 has been demonstrated in 13 homozygous or compound heterozygous parkin mutation carriers using
PET with 11C-raclopride.22 However, our detailed psychiatric examinations including MINI, MADRS, and CPRS did not detect any significant qualitative or quantitative differences between parkin mutation carriers and noncarriers. Psychiatric manifestations were present in both groups of patients, but at a similar rate. They were less frequent, however, in the unaffected heterozygous parkin carriers, supporting the hypothesis that dopaminergic dysfunction or antiparkinsonian drugs might account for their greater frequency in patients. Nevertheless, they do not appear to be more frequent in parkin-related parkinsonism than in other early-onset patients. The large spectrum of parkin gene defects, which differ in their predicted consequences on the function of the protein, also raises the question of their role in the variability of the phenotype. Despite the large number of parkin mutation carriers included, the number of cases in each of the genotype specific groups was too small for a specific neurologic, neuropsychological, or psychiatric pattern to emerge. The results of this detailed clinical study indicate that patients with PD with parkin mutations are clinically indistinguishable from other early-onset patients. Severe generalized loss of dopaminergic neurons in the substantia nigra pars compacta in these patients is associated with an excellent response to low doses of levodopa-equivalent and delayed fluctuations. Their neuropsychological performance is not distinctive. Interestingly, behavioral problems and psychiatric symptoms, which have been considered to be markers of parkin disease, are observed at similar rates in both groups of early-onset patients and are more frequent in these patients than in unaffected heterozygous parkin mutation carriers. AUTHORS’ AFFILIATIONS From INSERM (E.L., S.L., Y.A., A.B.), UMR_S679 Neurologie & The´rapeutique Expe´rimentale, Paris; AP-HP (E.L., B.D., Y.A., A.B.), Pitie´-Salpeˆtrie`re Hospital, Department of the Nervous System Disorders, Paris; UPMC Univ Paris 06 (E.L., S.L., Y.A., A.B.), UMR_S679, Paris; University of Lyon I and INSERM UMR 864 and The Pierre Wertheimer Neurological Hospital (S.T., E.B.), Department of Neurology, Lyon; AP-HP (S.T.d.M.), Pitie´-Salpeˆtrie`re Hospital, Department of Public Health, Unit of de Biostatistics and Medical Information and Unit of Medical Research, Paris; UPMC Univ Paris 06 (S.T.d.M.), EA3974 Modelisation in Clinical Research, Paris; CEA (M.-J.R.), I2BM, Service Hospitalier Fre´de´ric Joliot, Orsay; CEA (P.R.), I2BM, URA-CEA-CNRS 2210, Orsay; CHU Henri Mondor (P.R.), AP-HP et Faculte´ de Me´decine Paris 12, Cre´teil; AP-HP (A.P.), Pitie´-Salpeˆtrie`re Hospital, Department of Psychiatry, Paris; INSERM UMR 610 Neuroanatomie Fonctionnelle du Comportement et de ses Troubles (B.D.), Paris; AP-HP (B.D.), Pitie´Salpeˆtrie`re Hospital, Centre de Re´fe´rence sur la Maladie de Pick, Paris; Inserm Avenir Group IFR 70 Behaviour (L.M.), Emotion and Basal Ganglia, Center of Clinical Investigation, Paris; Department of Clinical and Biological Neurosciences (P.P.), University Hospital of Grenoble; AP-HP (Y.A.), Pitie´-Salpeˆtrie`re Hospital, Clinical Investigation Center, Paris; and AP-HP (A.B.), Pitie´-Salpeˆtrie`re Hospital, Department of Genetics and Cytogenetics, Paris, France.
ACKNOWLEDGMENT The authors thank the patients and their families; Ce´line Chamayou and Aure´lie Funkiewiez for the neuropsychological data, Ce´cile Behar and Mirce´a Polosan for psychiatric advice, Merle Ruberg for critical reading of the manuscript, and the DNA and Cell Bank of the IFR 070 for sample preparation; and the nurses of the Centre d’Investigation Clinique who provided care for the patients.
APPENDIX The French Parkinson’s Disease Genetics Study Group: Y. Agid, A.-M. Bonnet, M. Borg, A. Brice, E. Broussolle, Ph. Damier, A. Deste´e, A. Du¨rr, F. Durif, E. Lohmann, M. Martinez, C. Penet, P. Pollak, O. Rascol, F. Tison, C. Tranchant, M. Ve´rin, F. Viallet, M. Vidailhet, and J.-M. Warter (deceased).
Received March 10, 2008. Accepted in final form June 27, 2008. REFERENCES 1. Kitada T, Asakawa S, Hattori N, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998;392:605–608. 2. Periquet M, Latouche M, Lohmann E, et al. Parkin mutations are frequent in patients with isolated early-onset parkinsonism. Brain 2003;126:1271–1278. 3. Khan NL, Brooks DJ, Pavese N, et al. Progression of nigrostriatal dysfunction in a parkin kindred: an [18F]dopa PET and clinical study. Brain 2002;125:2248–2256. 4. Khan NL, Graham E, Critchley P, et al. Parkin disease: a phenotypic study of a large case series. Brain 2003;126: 1279–1292. 5. Lohmann E, Periquet M, Bonifati V, et al. How much phenotypic variation can be attributed to parkin genotype? Ann Neurol 2003;54:176–185. 6. Lucking CB, Brice A. Alpha-synuclein and Parkinson’s disease. Cell Mol Life Sci 2000;57:1894–1908. 7. Tassin J, Durr A, de Broucker T, et al. Chromosome 6-linked autosomal recessive early-onset Parkinsonism: linkage in European and Algerian families, extension of the clinical spectrum, and evidence of a small homozygous deletion in one family. The French Parkinson’s Disease Genetics Study Group, and the European Consortium on Genetic Susceptibility in Parkinson’s Disease. Am J Hum Genet 1998;63:88–94. 8. Wu RM, Shan DE, Sun CM, et al. Clinical, 18F-dopa PET, and genetic analysis of an ethnic Chinese kindred with early-onset parkinsonism and parkin gene mutations. Mov Disord 2002;17:670–675. 9. Yamamura Y, Hattori N, Matsumine H, Kuzuhara S, Mizuno Y. Autosomal recessive early-onset parkinsonism with diurnal fluctuation: clinicopathologic characteristics and molecular genetic identification. Brain Dev 2000;22 suppl 1:S87–91. 10. West A, Periquet M, Lincoln S, et al. Complex relationship between Parkin mutations and Parkinson disease. Am J Med Genet 2002;114:584–591. 11. Klein C, Lohmann-Hedrich K, Rogaeva E, Schlossmacher MG, Lang AE. Deciphering the role of heterozygous mutations in genes associated with parkinsonism. Lancet Neurol 2007;6:652–662. 12. Thobois S. Proposed dose equivalence for rapid switch between dopamine receptor agonists in Parkinson’s disease: a review of the literature. Clin Ther 2006;28:1–12. 13. Lesage S, Magali P, Lohmann E, et al. Deletion of the parkin and PACRG gene promoter in early-onset parkinsonism. Hum Mutat 2007;28:27–32. Neurology 72
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Lesage S, Lohmann E, Tison F, Durif F, Durr A, Brice A. Rare heterozygous parkin variants in French early-onset Parkinson disease patients and controls. J Med Genet 2008;45:43–46. 15. Hilker R, Klein C, Ghaemi M, et al. Positron emission tomographic analysis of the nigrostriatal dopaminergic system in familial parkinsonism associated with mutations in the parkin gene. Ann Neurol 2001;49:367–376. 16. Ishikawa A, Tsuji S. Clinical analysis of 17 patients in 12 Japanese families with autosomal-recessive type juvenile parkinsonism. Neurology 1996;47:160–166. 17. Lucking CB, Chesneau V, Lohmann E, et al. Coding polymorphisms in the parkin gene and susceptibility to Parkinson disease. Arch Neurol 2003;60:1253–1256. 18. Khan NL, Horta W, Eunson L, et al. Parkin disease in a Brazilian kindred: manifesting heterozygotes and clinical follow-up over 10 years. Mov Disord 2005;20:479–484.
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Lucking CB, Durr A, Bonifati V, et al. Association between early-onset Parkinson’s disease and mutations in the parkin gene. N Engl J Med 2000;342:1560–1567. Portman AT, Giladi N, Leenders KL, et al. The nigrostriatal dopaminergic system in familial early onset parkinsonism with parkin mutations. Neurology 2001;56:1759–1762. Sawle GV, Leenders KL, Brooks DJ, et al. Doparesponsive dystonia: [18F]dopa positron emission tomography. Ann Neurol 1991;30:24–30. Scherfler C, Khan NL, Pavese N, et al. Striatal and cortical pre- and postsynaptic dopaminergic dysfunction in sporadic parkin-linked parkinsonism. Brain 2004;127:1332– 1342. Williams-Gray CH, Foltynie T, Brayne CE, Robbins TW, Barker RA. Evolution of cognitive dysfunction in an incident Parkinson’s disease cohort. Brain 2007;130: 1787–1798.
Learn. Earn. Network. 2009 AAN Annual Meeting: An Excellent Value • Learn about the latest scientific advances in neurology • Earn valuable CME credit and fulfill Maintenance of Certification requirements • Network with your peers at exciting social events all week long • Enjoy the convenience and value of all this and more—in just one meeting Early registration and hotel deadline is March 20, 2009. Register today at www.am.com/AM2009.
Calling All New and International Members! Don’t miss these FREE AAN Annual Meeting events designed just for you: • New Member Information Session Sunday, April 26 / 5:00 p.m. to 6:00 p.m. Learn about the AAN, its resources and benefits, and network with Academy leaders. • International Attendee Summit Monday, April 27 / 7:00 a.m. to 9:00 a.m. Meet Academy leaders and make your voice heard on matters most important to you. Learn more at www.aan.com/specialevents.
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Comorbidity delays diagnosis and increases disability at diagnosis in MS
R.A. Marrie, MD, PhD R. Horwitz, MD G. Cutter, PhD T. Tyry, PhD D. Campagnolo, MD T. Vollmer, MD
Address correspondence and reprint requests to Dr. Ruth Ann Marrie, Health Sciences Center, GF 543, 820 Sherbrook Street, Winnipeg, MB, R3A 1R9, Canada
[email protected] ABSTRACT
Background: Comorbidity is common in the general population and is associated with adverse health outcomes. In multiple sclerosis (MS), it is unknown whether preexisting comorbidity affects the delay between initial symptom onset and diagnosis (“diagnostic delay”) or the severity of disability at MS diagnosis.
Objectives: Using the North American Research Committee on Multiple Sclerosis Registry, we assessed the association between comorbidity and both the diagnostic delay and severity of disability at diagnosis. In 2006, we queried participants regarding physical and mental comorbidities, including date of diagnosis, smoking status, current height, and past and present weight. Using multivariate Cox regression, we compared the diagnostic delay between participants with and without comorbidity at diagnosis. We classified participants enrolled within 2 years of diagnosis (n ⫽ 2,375) as having mild, moderate, or severe disability using Patient Determined Disease Steps, and assessed the association of disability with comorbidity using polytomous logistic regression.
Results: The study included 8,983 participants. After multivariable adjustment for demographic and clinical characteristics, the diagnostic delay increased if obesity, smoking, or physical or mental comorbidities were present. Among participants enrolled within 2 years of diagnosis, the adjusted odds of moderate as compared to mild disability at diagnosis increased in participants with vascular comorbidity (odds ratio [OR] 1.51, 95% CI 1.12–2.05) or obesity (OR 1.38, 95% CI 1.02–1.87). The odds of severe as compared with mild disability increased with musculoskeletal (OR 1.81, 95% CI 1.25–2.63) or mental (OR 1.62, 95% CI 1.23–2.14) comorbidity. Conclusions: Both diagnostic delay and disability at diagnosis are influenced by comorbidity. The mechanisms underlying these associations deserve further investigation. Neurology® 2009;72: 117–124 GLOSSARY BMI ⫽ body mass index; EDSS ⫽ Expanded Disability Status Scale; MS ⫽ multiple sclerosis; NARCOMS ⫽ North American Research Committee on Multiple Sclerosis; NINDS ⫽ National Institute of Neurological Disorders and Stroke; NMSS ⫽ National Multiple Sclerosis Society; OR ⫽ odds ratio; PDDS ⫽ Patient Determined Disease Steps.
Comorbidity is common in the general population1; it influences a broad range of health outcomes, including diagnostic delays and disease severity.2–5 Potentially, individuals with preexisting chronic illnesses are diagnosed earlier because of more frequent medical contacts.5 Conversely, preexisting disease may mask the symptoms of a new disease, negatively affect access to care, or prevent the consideration of etiologies other than the preexisting disease for new signs and symptoms.6 Comorbidity is common in multiple sclerosis (MS) at diagnosis.7 It is unknown, however, whether preexisting comorbidity affects the delay between symptom onset and diagnosis or the Supplemental data at www.neurology.org Editorial, page 108 e-Pub ahead of print on October 29, 2008, at www.neurology.org. From the Department of Medicine (R.A.M.), University of Manitoba, Winnipeg, Canada; Department of Medicine (R.H.), Stanford University, CA; Department of Biostatistics (G.C.), University of Alabama at Birmingham, AL; and Division of Neurology (T.T., D.C., T.V.), Barrow Neurological Institute, Phoenix, AZ. Supported partly by NIH, National Institute of Child Health and Human Development, Multidisciplinary Clinical Research Career Development Program Grant K12 HD04909. The NARCOMS Registry is supported by the Consortium of Multiple Sclerosis Centers. Disclosure: Author disclosures are provided at the end of the article. Copyright © 2009 by AAN Enterprises, Inc.
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severity of disability at diagnosis. Previous work suggested that greater disability early in the disease course is a negative prognostic factor for long-term disability,8,9 and diseasemodifying therapies are most effective early in the disease course, when disability is mild.10 Thus, comorbidity-associated differences in time to diagnosis or disability at diagnosis would be important prognostically and therapeutically. Using the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry, we aimed to determine the association between preexisting comorbidities or health behaviors on the degree of disability at MS diagnosis, as measured using Patient Determined Disease Steps (PDDS), and on the delay between symptom onset and diagnosis. We hypothesized that NARCOMS participants with preexisting comorbid illness or health behaviors would have more disability at diagnosis, after accounting for potential confounders. METHODS Study design and population. The NARCOMS Registry is a self-report registry for patients with MS,11 approved by the institutional review board at St. Joseph’s Hospital and Medical Center. At enrollment, participants provide demographic and clinical information, including date of birth, age at initial symptom onset, and age at and year of diagnosis. In October 2006, 18,000 active participants were eligible to receive the Fall Update Questionnaire. Per participant preference, we mailed a paper questionnaire (6,757) or e-mailed an invitation to complete the questionnaire online (11,243). To maximize response rates, we used a first-class postcard, two e-mail reminders, and a reminder in a lay publication provided quarterly to NARCOMS participants. We queried NARCOMS participants regarding physical and mental comorbidities. Questionnaire development is outlined on the Neurology® Web site at www.neurology.org. Participants indicated the presence or absence of a comorbidity and, if present, the year of diagnosis. Participants also reported past and present smoking status, height, and past and present body weight using questions from the Behavioral Risk Factor Surveillance Survey.12 Based on a literature review, we classified physical comorbidities as very likely to be accurately self-reported, moderately likely to be accurately self-reported, and least likely to be accurately reported.13,14 For the primary study, eligible participants were those living in the United States with complete data regarding date of birth, age at symptom onset, age at diagnosis, and age at symptom onset ⱖ16 years and ⬍60 years (n ⫽ 16,141). These criteria were intended to reduce heterogeneity in diagnostic testing and access to care, permit determination of the onset of the comorbidity in relation to MS onset and diagnosis, and limit heterogeneity due to differences in prognosis among persons with earlyor late-onset MS.15,16 118
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For this analysis, we grouped comorbidities into categories: physical, mental, vascular, autoimmune, visual, musculoskeletal, and gastrointestinal (see Neurology® Web site). Too few participants reported comorbid cancer for individual analysis. The validity of self-reported diagnoses is variable, being reasonably accurate for well-defined, chronic conditions requiring ongoing care but less accurate for diseases with less explicit diagnostic criteria.13,14 To account for this, we also created a category for any physical comorbidity, which included only those conditions very likely to be accurately self-reported based on literature review,13,14 including diabetes, hypertension, heart disease, breast cancer, colon cancer, rectal cancer, and lung cancer. Body mass index (BMI) was calculated from self-reported height and weight. Overweight was defined as a BMI ⱖ25 kg/m2 and ⬍30 kg/m2, and obesity was defined as a BMI ⱖ30 kg/m2.17 Participants were categorized according to the presence or absence of comorbidity at MS symptom onset and diagnosis.
Delay between symptom onset and diagnosis. For each participant, we calculated the delay between initial symptom onset and diagnosis (diagnostic delay) in years. Associations between the diagnostic delay and the presence or absence of comorbidity, and other covariates were analyzed with Wilcoxon or Kruskal–Wallis tests, or by using large-sample Z tests and CIs. We constructed a series of multivariate Cox proportional hazards models with diagnostic delay as the dependent variable and comorbidity categories as the independent variables.18 Covariates included sex, age at symptom onset, and year of symptom onset as independent variables.19 Year of symptom onset was categorized as ⱕ1980, 1981–1984, 1985–1989, 1990 –1994, 1995– 1999, or ⱖ2000. Age at symptom onset was categorized as ⱕ25, 25–39, or ⱖ40 years based on previous work regarding the diagnostic delay distribution in Denmark.20 We did not use income, education, or region of residence data for this model because there was sizeable potential for change in these variables between symptom onset, MS diagnosis, and registry enrollment. The proportional hazards assumption was tested using time-dependent covariates and graphical methods.21
Disability at diagnosis. To determine whether preexisting comorbidity influenced the degree of disability at diagnosis, we restricted the analysis to participants enrolled in the NARCOMS Registry within 2 years of diagnosis (n ⫽ 2,375); this allowed the use of demographic and disability data from the enrollment questionnaire. We assumed that changes in these variables were small or none in such a short time interval, based on previous examination of registry participants (data not shown).19 We report the characteristics of this subgroup and those of the whole sample, because this restriction truncates the distribution of diagnostic delay in patients with more recent symptom onset. PDDS is a self-reported surrogate measure of the Expanded Disability Status Scale (EDSS).22 Using PDDS, participants were classified as having mild (EDSS ⱕ3), moderate (EDSS 4 –5.5), or severe (EDSS ⱖ6) disability.23 Using polytomous logistic regression, we assessed the association between comorbidity and severity of disability at diagnosis after adjustment for potential confounders. Polytomous logistic regression is a technique used when the dependent variable is a categorical variable with greater than two classes but not necessarily monotonically ordered.24 The natural ordering of the data is lost, but all available data are used when calculating parameter estimates. Thus, we compared the odds of having moderate disability as compared with mild disability, and the odds of having severe disability as compared with mild disability. We report adjusted odds ratios (ORs) and 95% CIs as measures of association between comorbidity
Table 1
Demographic and clinical characteristics of the entire study population and of the disability at diagnosis subcohort
Entire population, n ⴝ 8,983
Disability at diagnosis subcohort, n ⴝ 2,375
Female
6,811 (75.8)
1,946 (81.9)
Male
2,172 (24.2)
429 (18.1)
White
8,442 (94.3)
2,237 (94.6)
Black
218 (2.4)
50 (2.1)
Other
293 (3.3)
78 (3.3)
Characteristic Sex, no. (%)
Race, no. (%)
Education, no. (%) 40 y >25 y and
