Kohler disease

Rationale: Duchenne muscular dystrophy (DMD) leads to progressive, generalized paresis, and to respiratory failure in the second decade of life. The assumption that severe physical disability precludes an acceptable quality of life is common, but has not been specifically evaluated in DMD.

Objectives: The purpose of this study was to investigate the quality of life in relation to physical disability, pulmonary function, and the need for assisted ventilation in DMD.

Methods: In 35 patients with DMD, aged 8-33 yr, we assessed physical disability by a score ranging from 9 (no disability) to 80 (complete dependence on care and technical aids), pulmonary function, and health-related quality of life by Short-Form 36 of the medical outcome questionnaire.

Measurements and Main Results: All patients required a wheelchair and help for dressing and eating. Fourteen patients were on long-term noninvasive positive-pressure ventilation. In ventilated patients, mean ± SD FVC was 12 ± 10 % predicted, and the physical disability score was 65 ± 7. Corresponding values in spontaneously breathing patients were 48 ± 25 % predicted, and 51 ± 7, respectively (p

Conclusions: Quality of life in DMD is not correlated with physical impairment nor the need for noninvasive positive-pressure ventilation. The surprisingly high quality of life experienced by these severely disabled patients should be taken into consideration when therapeutic decisions are made.

Keywords: chronic respiratory failure; hypoventilation; muscular diseases; noninvasive ventilation

Duchenne muscular dystrophy (DMD) leads to progressive muscle weakness of legs and arms, and respiratory and cardiac failure (1). Most patients become wheelchair-bound and dependent on others for their daily activities during the second decade of life (2). In advanced stages of the disease, chronic respiratory failure develops, and assisted mechanical ventilation is administered. Compared with historical controls, noninvasive positive-pressure ventilation (NIPPV) has increased the median survival of patients with DMD by several years to currently more than 25 yr (3-5). Only a few studies have addressed the health-related quality of life (HRQL) in patients with DMD. In an early investigation, 80 severely disabled patients with DMD on long-term assisted ventilation via a tracheostomy or a mask had a positive affect, and their life satisfaction was greater than anticipated by their caregivers (6). In a more recent study, 13 of 23 patients with DMD treated by nasal mask ventilation for chronic respiratory failure completed an HRQL questionnaire within 3 to 72 mo after starting assisted ventilation (3). Their health perception was superior to that of patients with chronic obstructive lung disease on noninvasive ventilation. Similarly, the mental component summary of the Short-Form 36 of the medical outcome questionnaire (SF-36) in 17 patients with DMD on noninvasive ventilation was higher than corresponding values in patients with chronic obstructive lung disease in another study (7). Although knowledge of the perceived quality of life in patients with chronic illness requiring a high level of care is essential because it may influence therapeutic decisions (8), a detailed analysis of quality of life in patients with DMD in relation to their physical performance, pulmonary function, and need for assisted ventilation has not previously been performed. Therefore, we investigated HRQL, physical disability, and respiratory impairment in stable patients with DMD with and without requirement for assisted ventilation. Some of the results of these studies have been reported in the form of an abstract (9).

METHODS

Patients

All patients with DMD living or attending school in a facility specialized in the care of patients with muscular dystrophies, the Mathilde-Escher-Heim, Zurich, were prospectively enrolled. According to the concepts of the Swiss health care system, patients with advanced neuromuscular disease are generally cared for by their relatives at home as long as feasible. Patients requiring a level of support that cannot be provided at home are admitted to one of the few institutions that offer services comparable to those of the Mathilde-Escher-Heim. The latter provides schooling and lodging as needed. School graduates have the opportunity to undergo professional training in information technology using special computer equipment. Some patients living in their parents' homes are brought in for daytime care. Others are full-time residents in the institution, and live together in groups of three to five patients who share a flat. They are attended by social workers, nursing staff, and physiotherapists.

In all patients, the diagnosis of DMD was based on standard criteria comprised of progressive symmetrical muscle weakness and other signs and symptoms starting before the age of 5 yr, elevated serum creatinin kinase activity, muscle biopsy and genetic analysis, and, in some, a family history consistent with X-linked recessive inheritance (10).

Informed consent of patients and their parents was obtained. The protocol was approved by the ethics committee of the University Hospital of Zurich.

Measurements

A physical examination, including measurement of body weight and body length, was performed. Body length was used for calculation of body mass index and reference values of pulmonary function. It was measured by a flexible ruler fitted along the contours of the body, from the head, along the vertebral spine and the backside of the legs, to the heels to account for kyphoscoliosis and leg contractures.

Spirometry was performed in sitting position with a flow meter attached to a flanged rubber mouthpiece with the nose occluded (Vmax; SensorMedics, Yorba Linda, CA) (11). Sniff nasal pressure (SNIP) at functional residual capacity and maximal expiratory pressure (MEP) at total lung capacity were measured (Pmax mouth pressure monitor; P.K. Morgan, Rainham-Gillingham, Kent, UK). Reference values for ages up to 17 yr (12, 13) and above (14, 15) were computed. Arterial blood gas analysis was performed on a sample drawn in sitting position during spontaneous room-air breathing, with the exception of patients requiring continuous ventilatory support (AVL Medical Systems AG, Diessenhofen, Switzerland).

Cardiac function was assessed clinically by ECG and echocardiography. Cardiac involvement was assumed if there were rhythm or conduction abnormalities, abnormal repolarization, a decreased left-ventricular ejection fraction, or abnormal ventricular cavity dimensions or wall motion (16).

Physical disability (i.e., the inability to perform activities of daily living [ADL] and the dependence on support by others and on technical aids) was evaluated with a score specifically developed by one of the authors (L.B.) for assessment of the course of illness in DMD. Some aspects are similar to the index of independence in ADL described by Katz and colleagues (17). Disability was evaluated by assessing the following eight aspects of daily life in a standardized way (see online supplement): mobility without technical aids, mobility with technical aids, transfers (e.g., from bed to wheelchair), static body control, changes of body position, dressing, feeding, and breathing. Each aspect was rated with up to 10 points, with higher scores reflecting greater disability. The sum score of all eight domains was computed as a measure of overall disability and of dependency on care; its maximal value was 80 points. The score had been prospectively applied over several years in a subset of the patients. These data are presented with the evaluation of all patients at the time of this study to illustrate that the score reflects the progressive disability in DMD.

The SF-36 was completed during an interview with each patient (18). Transformed scores for each domain and the physical and mental component summaries were computed (19). Reference values from an age- and sex-matched U.S. population (18), and from a German population (20), were used for comparison.

Data Analysis

Data are expressed as means ± SD. Comparison of results between groups was performed by unpaired t tests. A probability of p

RESULTS

Thirty-five male patients with DMD were enrolled. Of these, 18 patients spent the nights in the home of their parents and attended school at the Mathilde-Escher-Heim, whereas 17 full-time residents lived at the institution and went to school or worked there. All were wheelchair-bound due to advanced paresis of the legs and arms. Thoracolumbar scoliosis was apparent in 34 patients (97%), and spinal stabilization surgery had been performed in 24 patients (69%). Some patients required intermittent treatment for musculoskeletal pain with nonsteroidal antiinflammatory drugs, but none received narcotic, psychotropic, or antidepressant drugs.

Fourteen patients were on chronic NIPPV by nasal or face mask. Long-term assisted ventilation had been initiated in patients with chronic hypoventilation (daytime Pa^sub CO^sub 2^^ ≥ 50 mm Hg with appropriately compensated pH, or mean nocturnal transcutaneous PCO^sub 2^ > 50 mm Hg and oxygen saturation 5% of the night) and consistent symptoms, such as headaches, restless sleep, and excessive sleepiness (21). At the time of the study, none of the patients met criteria for invasive ventilation via tracheostomy (uncontrollable airway secretions, repeated aspiration [21]) or preferred this intervention over mask ventilation. The VPAP II ventilator (ResMed, North Ride, Australia) was used in the bilevel positive airway pressure S/T or T-mode, with inspiratory pressures of 12-22 cm H2O, expiratory pressures of 3-5 cm H2O, and respiratory rate of 12-20 breaths/min. Six patients applied NIPPV during the night only, two patients during the night and occasionally during the day (

Spirometric volumes (FVC, FEV^sub 1^) in patients not requiring NIPPV were reduced to about one-half of the predicted value, whereas the corresponding values of patients on NIPPV were only about one-tenth of the predicted value. In patients without NIPPV, the reductions of maximal respiratory pressures (SNIP and MEP) from predicted values were more pronounced than the reductions of lung volumes, but SNIP and MEP (% predicted value) were still significantly greater than in patients requiring NIPPV (Table 1). Spirometry and measurement of maximal respiratory pressures were not feasible in all patients due to ventilator dependency or difficulty in cooperation.

Cardiac evaluation had been performed clinically and by ECG in all 35 patients, and in 28 patients by echocardiography. No cardiac abnormalities were found in 25 patients (71%). In 10 patients (29%), cardiomyopathy was suspected in the ECG, and confirmed by echocardiography (mean ± SD left-ventricular ejection fraction, 36 ± 12%). The age of patients with and without cardiomyopathy was not statistically different (mean age, 21.3 ± 5.8 vs. 18.2 ± 5.7 yr; p = 0.12). The scores of the SF-36 domains and of the disability scale were similar in patients with and without cardiomyopathy (p > 0.05 for all comparisons; data not shown).

Disability and dependence on others and technical aids was assessed in 34 patients (Table 2). The disability sum scores were plotted over time for 29 patients in whom at least two assessments, separated by at a least 1 yr, were available (Figure 1A). The relentlessly progressive course of the illness is evident. At the time of the current evaluation of respiratory function and quality of life, patients on NIPPV were more disabled in each evaluated aspect of daily living (Table 2) and had higher disability sum scores than patients without NIPPV (although there was some overlap; Figure 1B). Due to the advanced generalized paresis, the scores reflecting reductions in mobility, transfer, and body control were particularly high. The "mobility without technical aid" scores of 10 and the "transfer" scores of ≥ 8 in all patients on NIPPV reflected their need for a wheelchair and their complete dependency on others for mobility. Similarly, they were all entirely unable to dress without help. The need for assistance in eating and drinking was more variable (Table 2).

As expected, HRQL was low in the SF-36 domains representing physical function (the physical functioning scores were near zero) and, to a lesser extent, in domains representing problems with work and everyday activities as a result of physical health (moderate reduction in role-physical values; Table 3). Other aspects of well-being, such as general and mental health, emotions, social functioning, and pain, were not impaired according to the patients' judgment, and corresponding domain scores were close to the values observed in populations without chronic illness (Figure 2) (18).

To compare the health profile of patients with DMD with values of a reference population, the scores of U.S. males, ages 18-24 yr (18), were subtracted from the measured scores in patients with DMD, and these differences are plotted in Figure 2. Thus, this figure illustrates the deviations in the domain scores of the studied population from the reference. German reference values (20) are also shown in Figure 2. Despite their greater limitation in pulmonary function and in ADL, the patients on NIPPV rated their HRQL similar to patients without NIPPV (Table 3 and Figure 2). To further evaluate a potential effect of physical disability on HRQL, correlation analysis was performed on the SF-36 physical and mental component summaries versus the disability summary score. The Pearson correlation coefficients were r = -0.326, p = 0.06, and r = -0.031, p = 0.862, respectively. The correlation of the physical and mental component summaries versus FVC (% predicted) as a measure of respiratory impairment also revealed no statistically significant correlation (Pearson correlation coefficients, r = 0.084, p = 0.646, and r = -0.268, p = 0.138, respectively). The course of respiratory impairment and HRQL as a function of age is illustrated in Figure 3.

DISCUSSION

The main finding of our study is that patients with DMD of various ages with advanced general muscle weakness and paresis perceive a high quality of life despite their chronic progressive illness, which makes them highly dependent on others and technical aids. Patients believe that the problems with ADL due to their health status are relatively minor, although they are aware of their major limitation in physical functioning. With the exception of domains directly linked to the loss of muscle strength, the HRQL of patients with DMD is independent of the degree of physical disability and respiratory impairment, and similar to that in reference populations (18, 20). Our observations have important clinical implications, as they contradict the still common assumption of a low HRQL of patients with advanced disability and respiratory impairment, an assumption that may influence therapeutic decisions (8).

This study provides the first detailed account of the quality of life in patients with DMD of various ages and degrees of disability and respiratory impairment. The use of a generic HRQL questionnaire allows comparisons with other populations with and without chronic illnesses. Simonds and coworkers (3) assessed HRQL with the SF-36 questionnaire in 13 patients with DMD on nasal mask ventilation. Because no numeric data were provided, a quantitative comparison with our study is not feasible. In a survey of HRQL in patients with chronic lung disease, kyphoscoliosis, and various neuromuscular diseases on domiciliary NIPPV, data on 17 patients with DMD were not reported separately, with the exception of the SF-36 mental component summary (7). The mean value of that component was 59.6, similar to the values of 60 and 62 that we found in patients without and with NIPPV (Table 3). Compared with patients with chronic obstructive lung disease and kyphoscoliosis in the cited report (7), patients with DMD in the current study had much lower physical functioning scores, but perceived less role limitation by physical and mental problems, and scored higher in mental health and social functioning (Table 3). The scores in all SF-36 domains, except physical functioning, in the patients with DMD studied in the current investigation were also considerably higher (by 7 to 52 points) than corresponding scores we had obtained in patients with severe pulmonary emphysema undergoing lung volume reduction surgery (22). This may relate to better coping abilities in patients with DMD adapting themselves to a progressive limitation since early childhood (Figure 4); patients with chronic obstructive lung disease may experience greater difficulties in handling the limitations imposed by a chronic illness acquired in adulthood. Another possibility is the very supportive and empathetic care given to the younger patients with DMD by their parents and their caregivers. Furthermore, perception of health status, and expectations on achievable goals in life, may differ between patients according to their illness and the time of its manifestation. Mental retardation as a possible confounding factor was not specifically examined in the current study, but was not prominent, as all patients attended at least primary school, and some underwent professional education in information technology. HRQL might also be influenced by certain medications, but none of our patients received psychotropic, antidepressant, or long-term analgetic drugs. An easy access to technical aids and activities that provide social contacts and independence might have contributed to the high HRQL perceived by the patients. Most of them own an electro-wheelchair, and some own a cellular phone. They have the opportunity to participate in electro-wheelchair hockey training and tournaments (Figure 4), participate in excursions, holiday camps, and other leisure time activities.

The lack of a correlation between physical disability scores, lung function impairment, and SF-36 mental and physical component summaries in patients with DMD of a broad age range (Figure 3) is in accordance with the notions discussed above. It corroborates data from a longitudinal evaluation of 45 patients, aged 25-60 yr, with various distal and proximal muscular dystrophies other than Duchenne, showing only moderate correlations between dependence with regard to ADL (17) and quality of life (23). The score we used for assessment of physical disability in DMD shares some similarities with the ADL, which was designed to evaluate disability and effects of rehabilitation in the elderly (17). However, our score incorporates some aspects typical of DMD (i.e., the consequences of progressive generalized muscle weakness). The score tracked the course of illness well, and asymptotically approached maximal values corresponding to the complete loss of mobility, ventilator dependence, and requirement of care by others (Figure 1).

Evaluation of pulmonary function revealed that the SNIP and MEP were relatively more reduced than spirometric lung volumes (Table 1), a finding consistent with an early impairment of SNIP preceding reductions in vital capacity in motoneuron disease (24).

In 80 severely disabled patients with DMD on long-term ventilation via tracheostomy or mask, the hardship associated with chronic ventilator dependence was significantly overestimated by health care professionals compared with the patients' own assessments, demonstrating a relatively positive attitude and health perception of patients with DMD, despite their physical dependence, and underlining the subjective nature of quality of life (6). Although our cross-sectional study allows no definitive conclusion with regard to the effect of NIPPV on HRQL, the nearly normal values of SF-36 scores in domains other than physical function and physical role limitation (Table 3) suggest that assisted ventilation does not adversely affect the perceived health status.

In conclusion, patients with DMD perceive a high HRQL independent of the degree of their physical disability, their respiratory impairment, and their dependence on NIPPV. Because medical professionals tend to underestimate the high HRQL perceived by the patients with DMD, these observations should be taken into consideration when decisions on mechanical ventilation and other life-sustaining therapies are made.

Conflict of Interest Statement: None of the authors have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

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Malcolm Kohler, Christian F. Clarenbach, Lukas Böni, Thomas Brack, Erich W. Russi, and Konrad E. Bloch

Pulmonary Division, Department of Internal Medicine, University Hospital of Zürich, Zürich, Switzerland

(Received in original form March 1, 2005; accepted in final form June 8, 2005)

Supported by grants from The Lung League of Zurich, Switzerland.

Correspondence and requests for reprints should be addressed to Konrad E. Bloch, M.D., Pulmonary Division, Department of Internal Medicine, University Hospital of Zürich, Raemistrasse 100, CH-8091 Zürich, Switzerland. E-mail: pneubloc@ usz.unizh.ch

This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Am J Respir Crit Care Med Vol 172. pp 1032-1036, 2005

Originally Published in Press as DOI: 10.1164/rccm.200503-322OC on June 16, 2005

Internet address: www.atsjournals.org

Copyright American Thoracic Society Oct 15, 2005
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