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(Chest. 1999;115:1539-1545.)
© 1999 American College of Chest Physicians

Micturitional Disturbances Are Associated With Impaired Breathing Control in Multiple Sclerosis*

Rob van Klaveren , MD, PhD; Tine Buyse , MD; Luc Van De Gaer , MD; Jan Meekers , MD; Felicien Rochette and Maurits Demedts , MD, PhD, FCCP

* From the Department of Pulmonology (Drs. van Klaveren, Buyse, and Demedts, and Mr. Rochette), University Hospital Gasthuisberg, K.U. Leuven, Leuven, Belgium; the Multiple Sclerosis and Rehabilitation Center (Dr. Van De Gaer), Overpelt, Belgium; and the Maria Hospital Noord Limburg (Dr. Meekers), Campus Maria Middelares, Lommel, Belgium.


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
Study objectives: To investigate whether the localization of multiple sclerosis (MS), the duration of the disease, and the level of neurologic functioning in patients with MS predispose them to disturbed breathing control.

Design: Case-control study.

Setting: Outpatient pneumology department of a university hospital.

Patients: Twenty-three MS patients and 51 healthy control subjects.

Measurements and results: Resting mouth occlusion pressure at 0.1 s after onset of inspiratory effort (P0.1) was measured during the hypercapnic response (HCR) and the hypoxic response (HR) in all subjects. The Kurtzke expanded disability status scale and the functional system score were used to describe the level of neurologic functioning of the MS patients. Predictors of HCR and HR were assessed by multiple regression analysis. Low maximal inspiratory pressure (MIP) values correlated with low resting P0.1 values (r = 0.44; p = 0.05), although in neuromuscular diseases, high resting P0.1 values are usually found to compensate for low MIPs. Detrusor-sphincter dyssynergia (DSD) was the only predictor for lower ventilatory HCR (p = 0.006; r2 = 0.52), lower P0.1 HCR (p = 0.004; r2 = 0.47), lower ventilatory HR (p = 0.04; r2 = 0.28), and lower P0.1 HR (p = 0.04; r2 = 0.10); low MIPs and pyramidal tract involvement had no role.

Conclusions: (1) Impaired control of breathing in some MS patients is related mainly to central defects. (2) DSD is the most important predictor of disturbed ventilatory control, presumably because the micturition and pneumotaxic center are closely related and located in the rostral pons. (3) No relationship with the duration of the MS disease could be demonstrated, which can be explained by the variable course of MS itself.

Key Words: detrusor-sphincter dyssynergia • hypercapnic response • hypoxic response • pneumotaxic center • micturition center • pons


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
Multiple sclerosis (MS) is a disease of unknown etiology, characterized pathologically by widespread patches of demyelination in the nervous system, followed by gliosis.

The primary cause of MS is unknown. Several neurologic systems can be involved, which can lead to a wide variety of neurologic disturbances, including autonomic dysfunction.

Respiratory dysfunction has already been reported as a common feature in MS patients, even in the presence of normal spirometric values.1 2 3 4 5 6 7 8 9 In particular, reduced maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) are frequently encountered and appear to correlate with the stage of pyramidal and brainstem disease.1 Although several authors have reported on the spirometric and respiratory pump abnormalities in MS patients, studies on the control of breathing are scarce. Tantucci et al7 found an impaired ventilatory response to CO2 in MS patients, which should alert the clinician to the possible existence of disturbances in automatic breathing and the increased risk of death during sleep. However, to our knowledge, the neurologic defect(s) that predispose MS patients to develop impaired breathing control have not been identified.

The aim of the present study, therefore, was to measure the ventilatory pressure and the mouth occlusion pressure at 0.1 s after onset of inspiratory effort (P0.1) during the hypercapnic response (HCR) and the hypoxic response (HR) in 23 patients with moderate-to-severe MS and to investigate whether there is a relationship among the duration of MS, the localization of the disease, the severity of the neurologic defects, and the control of breathing in these patients.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusions
 References
 
Subjects
The study population consisted of 23 MS patients (8 men, 15 women; mean age [± SD], 49.0 ± 10.1 years and 40.0 ± 13.0 years, respectively) from the Multiple Sclerosis Rehabilitation Center Overpelt. They all met the MS criteria of Poser et al10 for the definite diagnosis of MS. The MS patients were compared with 51 healthy white volunteers (26 men, mean age 42.4 ± 12.4 years; and 25 women, mean age 40.1 ± 13.7 years), most of them employees of the hospital, with no history of cigarette smoking or cardiopulmonary disease. They took no medication. Informed consent was obtained from each subject.

Clinical Assessments
The patients were interviewed with special emphasis on tobacco use, pulmonary symptoms, and medications. The Kurtzke expanded disability status scale (EDSS) and the functional system score (FSS) were used to describe the level of neurologic functioning.11 The EDSS provides an overall score ranging from 0 (indicating normal neurologic findings) to 10 (indicating death from MS). The FSS yields specific information on the grade of involvement of the following neurologic functions: pyramidal, sensory, cerebellar, brainstem, sphincter, visual, and mental. These impairments are expressed with a score ranging from 0 to 5 or 0 to 6. The scores were assigned by a neurologist with no knowledge of the results of the pulmonary function tests and respiratory drive measurements. In 1984, the International Federation of Multiple Sclerosis Societies defined a minimal data set for neurologic signs, physical disabilities, and social impact of MS.11 The EDSS and FSS have been used since then in clinical trials. The functional systems are mutually exclusive in terms of neuroanatomy, but together they comprise all neurologic abnormalities on examination that can be attributed to MS lesions.11 Since 1984, this validated score has been used universally. The EDSS correlates well with both frequency and severity of involvement for all FSS functions.11

Pulmonary Function Tests
Pulmonary function tests included static and dynamic volumes (vital capacity [VC]), FEV1, plethysmographic volumes (total lung capacity [TLC]), and residual volume (RV). Flow-rate measurements included peak expiratory flow (PEF) and the maximal expiratory flow when 50% and 75% of the VC has been exhaled. The single-breath transfer factor of the lung for carbon monoxide (TLCO) was measured, as were airway resistance (Raw) and specific airway conductance. Static MEP and MIP were measured according to the techniques described previously.1 Each patient performed at least three trials and the best performance was used for analysis. The measurements were carried out according to the criteria of the American Thoracic Society and the European Respiratory Society.12 The European Respiratory Society's prediction equations, which represent those of the European Community for Steel and Coal, were used for lung volumes and TLCO. For Raw, 0.22 kPa/L/s was used as the upper limit of normal. The MEP and MIP were expressed as a percentage of the predicted values of Rochester and Arora,13 which were very similar to the normal values obtained in our laboratory. All lung function tests were performed with the subject in a sitting position in a body plethysmograph (Medgraphics System 1085/d; Medical Graphics; St. Paul, MN). The normal control subjects did not undergo lung function testing except for a measurement of the VC.

Respiratory Drive Measurements
For respiratory drive measurements, control subjects and MS patients sat in a comfortable chair, in a quiet acclimated room, with their eyes closed. They breathed via a mouthpiece through a low-resistance valve (Hans Rudolph; Kansas City, MO), wearing a nose clip. For the P0.1 measurement, the inspiratory side of the valve was occluded at random after four to eight breaths during expiration by an inflatable balloon shutter (Medgraphics RPM modulus; Meda SA; Antwerp, Belgium). The P0.1 was measured 0.1 s after start of the inspiration at functional residual capacity.14 The average value of four breaths preceding each occlusion was used for the recordings of the respiratory frequency (FR), inspired tidal volume (VT), inspiratory time (TI), expiratory time, and minute ventilation, using the Medgraphics equipment previously mentioned (Medical Graphics; St. Paul, MN). Flows and volumes were measured by a heated pneumotachograph calibrated with a 3-L syringe at different flow rates. A fast-response paramagnetic oxygen sensor and a CO2 infrared photometer (Datex Normocap 200; Meda SA) recorded the inspiratory and expiratory O2 and CO2 concentrations breath by breath. Air was sampled from the mouthpiece (flow rate, 180 mL/min) and was returned to the expiratory side of the circuit. The accuracy for CO2 analysis was 1.5 mm Hg (± SD), and for oxygen, 1.5 mm Hg (± SD). The analyzers were calibrated before each test with standard gas mixtures. Saturation was measured by a finger pulse oximeter (model 920; Healthdyne Technologies; Marietta, GA) with an accuracy of 3% (± SD) between 70% and 100%. The dead space of the circuit was about 100 mL.

Study Protocol
Before the HCR and HR tests were performed, basal respiratory parameters of each subject were collected during a 5-min period after at least 1 min of adaptation to the mouthpiece. Subsequently, all subjects underwent an HCR test, and 15 min later an HR test. The HCR test was performed according to the rebreathing method of Read,15 starting with a gas mixture of 7% CO2 and 93% O2. The HCR test was completed within 3 min, when CO2 had reached 9%. The slopes of the ventilatory and occlusion pressure response of the HCR test were determined for each subject by linear regression analysis. The HR test was performed using the rebreathing method of Rebuck and Campbell.16 A rebreathing bag was filled with a volume equal to the subject's VC plus 1 L of a mixture containing 7% CO2, 23% O2, and 70% N2. After 1 min of adaptation to the mouthpiece, the subject was switched to the gas mixture and was started with two VC maneuvers to facilitate equilibration with the gas mixture in the bag. The recordings were started when end-tidal CO2 had reached the mixed-venous plateau (7%). To maintain the CO2 at this level, the flow through the CO2 absorber was manually adjusted by varying the pump speed. During rebreathing, the end-tidal O2 concentration was decreased from 23% to at least 6% during a 3- to 6-min period, but the test was interrupted earlier if the subject experienced intolerable discomfort.

Statistical Analysis
For statistical analyses, we used linear and multiple regression analyses, Pearson correlations, and unpaired t tests with appropriate computer software (SAS/STAT package, version 6; SAS Institute; Cary, NC). Linear regression analysis was used for the determination of the slope of the HCR and HR curve. Stepwise backward multiple regression analysis (level of significance, 0.10 for retaining and adding) was used to investigate the impact of the neurologic dysfunction (FSS and EDSS), MIP, and MEP on baseline breathing control, the HCR, and the HR. The level of significance was set at 0.05.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusions
 References
 
Subjects
Apart from their smoking habits and minor differences in mean age, body surface area, and body mass index, the MS patients and control subjects were comparable. Their characteristics are presented in Table 1 . Five male and eight female MS patients smoked. Data were missing for sphincter function in two men, HCR in one man, and HR in one man, leaving five male subjects for the regression analysis shown in Figure 1 . Although the mean duration of MS was not significantly longer in men than in women, men with MS had a higher degree of disability (mean EDSS score, 5.5 ± 2.8) than women (mean EDSS score, 3.0 ± 2.0), as shown in Table 2 . The men also had a 1.6-fold higher score for pyramidal involvement, a 4.3-fold higher brainstem damage score, and a 2.2-fold higher score for sphincter dysfunction than the female patients. Although all MS patients suffered from impaired respiratory muscle function, in terms of lower MIP, MEP, and PEF values (Tables 2 and 3 ), it was more pronounced in the men. Apart from a lower CO transfer factor, results of the other lung function tests were normal.


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  		Table 1. Characteristics of 23 MS Patients and 51 Control Subjects*

 


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  		Figure 1. Relationship between the ventilatory (Ve) and occlusion pressure (P0.1) HCR and HR and the degree of sphincter dysfunction (Kurtzke11 FSS score range, 0 to 6). {circ} = individual women with MS; {blacktriangleup} = individual men with MS.

 

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  		Table 2. Duration of Disease, Respiratory Muscle Strength, and Neurologic Disability Scores in Male and Female MS Patients*

 

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  		Table 3. Pulmonary Function Test Results for the MS Patients*

 
Drive and Timing Components of Breathing at Rest
When all MS patients were studied together, it appeared that they had a 1.2-fold shortened TI and a 1.1-fold increased FR compared with the control subjects. When the male and female subjects were studied separately, women with MS showed a 1.3-fold lower TI and a 1.2-fold higher FR compared with female control subjects, whereas drive and timing components in men with MS did not differ from those in male control subjects (Table 4 ).


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  		Table 4. Baseline Ventilation and HCR and HR Indices in MS Patients and Control Subjects*

 
There was no evidence by multiple regression analysis that the shortened TI and increased FR values in MS patients were related to neurologic defects (Table 5 ). However, MS patients breathed with a larger VT when their FSS for sensory defects was higher (Table 5) . The MIP and P0.1 values showed an inverse relationship with the FSS for pyramidal tract damage. The MIP values correlated positively with the resting P0.1 values (r = 0.44; p = 0.05).


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  		Table 5. Relationship Between Baseline Ventilatory, HCR, and HR Indices and the FSS in MS Patients

 
Ventilatory Control During Hypercapnia and Hypoxia
When the HCR and HR of all MS patients together were compared with those of the control subjects, no differences were found other than a 1.4-fold lower ventilatory HCR in the MS patients. When the same comparisons were made by sex, no differences were detected between the male MS patients and the control subjects; however, the female MS patients showed a 1.9-fold higher ventilatory HR and a 2.7-fold higher occlusion pressure HR compared with female control subjects (Table 5) . The ventilatory HCR and occlusion pressure HCR in MS patients did not differ from those in the control subjects. A positive correlation was found between the ventilatory HCR and occlusion pressure HCR (r = 0.48; p < 0.05), and between the ventilatory HR and occlusion pressure HR (r = 0.71; p < 0.001).

Multiple stepwise regression analysis for all MS patients together and all neurologic FSS, MIP, and MEP values showed that the lower the ventilatory HCR, occlusion pressure HCR, and ventilatory HR were, the higher the FSS for bladder sphincter dysfunction. For the occlusion pressure HR, only a nonsignificant relationship with brainstem damage could be demonstrated (Table 5) . Correlation analyses also showed a relationship between the sphincter dysfunction score and the hypercapnic and hypoxic responsiveness, but they did not reach the level of significance for the HCRs (Fig 1) . No correlations were found between the ventilatory HCR and the FSS for pyramidal involvement (r = 0.17). The same was found for the correlations between the occlusion pressure HCR and pyramidal involvement (r = 0.19), the ventilatory HR and pyramidal involvement (r = -0.12), and the occlusion pressure HR and pyramidal involvement (r = -0.15). There was no correlation between the degree of sphincter dysfunction and the degree of pyramidal tract involvement.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusions
 References
 
In the first part of the study, we investigated drive and timing components of ventilation at rest in 23 patients with moderate-to-severe MS. As has been demonstrated by others, we found no significant impairment in lung function, but our patients showed a reduction in MIP and MEP values of up to 24% and 36%, respectively. MIP and resting P0.1 values were positively correlated, which is an important finding because it means that P0.1 as a fraction of MIP (P0.1%MIP) remained normal. Usually, in COPD and in a number of neuromuscular disorders, MIP is very low and P0.1%MIP is high. In contrast to the significantly higher P0.1 values at rest found by Tantucci et al,7 in our study, mean P0.1 values in MS patients at rest did not differ from those in the control group, and the decreased MIP values were not accompanied by increases in P0.1. This indicates that the central breathing control in these patients is already impaired. As the motor neurons of the pyramidal tract are involved in activating the inspiratory muscles and the diaphragm, it is evident that pyramidal tract involvement will lead to lower MIP and P0.1 values. Whether this predisposes to impaired breathing control in our MS patients will be discussed below.

In the second part of our study, we investigated the differences in HCR and HR between the MS patients and the control subjects, and we tried to find out if these differences are dependent on the duration of the MS disease and the localization and grade of neurologic impairment. Because the HCR and HR are age-, gender-, and stature-dependent,17 the MS patients were divided by gender and compared with 51 age-, height-, and gender-matched control subjects. Although White et al18 demonstrated that there was a difference between the follicular and luteal phase in women for the HR, but not for the HCR, we did not adjust the HR data for menstrual status because the differences found by White et al18 were small. Because we did not take menstrual cycles into account in either the control or patient group, a comparison between the two groups in our study appears to be justified. The male MS patients tended to have lower HCR and HR responses, but the female MS patients showed higher responses, which reached significance for the HR. A possible explanation is that the female MS patients, who were much less affected by MS than the male MS patients (lower EDSS and FSS), were able to increase their respiratory drive and to compensate for a reduced MIP.

To identify the possible underlying neurologic defects responsible for these differences between the HCR and HR of male and female MS patients, correlation analyses and multiple backward regression analyses were performed on all subjects combined. This revealed that there was a negative correlation between the grade of the sphincter dysfunction and the HCR (p values were not significant) and HR (p < 0.05), which was confirmed by multiple backward regression analyses (Table 5) . For the occlusion pressure HR only, a negative relationship with brainstem lesions was demonstrated. At first glance, the relationship between disturbed ventilatory control and bladder sphincter dysfunction appears to be coincidental. However, from MRI studies in patients with pontine hemorrhages, we know that the pontine micturition center is located in the dorsolateral tegmentum of the rostral pons, including the pontine reticular nucleus and the reticular formation adjacent to the medial parabrachial nucleus and the locus ceruleus.19 Lesions in this area cause neurogenic vesicourethral dysfunctions, or detrusor-sphincter dysynergia (DSD). From studies in cats and MRI studies in man, we know that the pneumotaxic center is also located in the pons, more precisely in the ventrolateral part of the rostral pons.20 21 22 Auer et al23 described two MS patients with Ondine's curse who died during their sleep. Autopsy showed that they had plaques in the areas controlling automatic breathing in the medullary reticular formation.

Although we cannot support our findings with MRI or autopsy data, there are several indirect arguments in favor of disturbances in central breathing control in our patients. First, the P0.1%MIP was not increased, as usually occurs in neuromuscular disease. Second, correlation and multiple regression analyses showed that MIP and pyramidal tract involvement did not emerge as predictors of the responsiveness to hypercapnia and hypoxia; this excludes spinal cord disease as a causative factor for the disturbed breathing control in our MS patients. Last, the fact that the pneumotaxic and micturition centers are anatomically and functionally so closely related20 22 supports our finding that MS patients with DSD are more prone to disturbances in ventilatory control. DSD can, however, also be caused by spinal lesions of the pyramidal tract, but no correlation was found between the degree of pyramidal tract lesions and the degree of sphincter dysfunction in our patients. These results provide us with indirect evidence that the DSD in our MS patients is mainly related to supraspinal (pontine) lesions, which has also been found by others.24

The mechanism by which MS lesions in the pontine pneumotaxic center might lead to diminished chemosensitivity is unknown. From animal studies, it is known that the pneumotaxic center has a tonic excitatory input on the inspiratory off-switch neurons, which subsequently inhibit inspiratory motoneurons. However, the effect of lesions in the pneumotaxic center on ventilatory chemosensitivity in awake animals is not known. Because the central mechanism of breathing control is very complex,25 and sometimes considered to be a "black box,"26 it is almost impossible to speculate about the mechanism by which pons lesions might lead to the impaired HCRs and HRs found in our study.

In our studies, no clear differences have been found between the ventilatory and occlusion pressure responses. This finding is not unexpected, because MS lesions in the brainstem will also interrupt the motor (reticulospinal) pathways to the phrenic, intercostal, and accessory respiratory muscle nerves. Therefore, determination of both the occlusion pressure and the ventilatory response will not help us to differentiate between pontine and suprapontine lesions. We did not demonstrate any relationship with the duration of MS, which can be explained by the variable course of the disease.


   Conclusions
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
References
 
We therefore conclude the following: (1) impaired control of breathing in some MS patients is mainly related to central defects; (2) DSD is the most important predictor of disturbed ventilatory control, presumably because the micturition and pneumotaxic centers are closely related and located in the rostral pons; and (3) no relationship with the duration of MS could be demonstrated, which can be explained by the variable course of MS itself.


   Footnotes
 
Correspondence to: Rob van Klaveren, MD, PhD, Department of Pneumology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium; e-mail: rob.van.klaveren@uza.uia.ac.be

Abbreviations: DSD = detrusor-sphincter dyssynergia; EDSS = expanded disability status scale; FR = respiratory frequency; FSS = functional system score; HCR = hypercapnic response; HR = hypoxic response; MEP = maximal expiratory pressure; MIP = maximal inspiratory pressure; MS = multiple sclerosis; P0.1 = mouth occlusion pressure at 0.1 s after onset of inspiratory effort; P0.1%MIP = P0.1 as a fraction of MIP; PEF = peak expiratory flow; Raw = airway resistance; TI = inspiratory time; TLC = total lung capacity; TLCO = single-breath transfer factor of the lung for carbon monoxide; VC = vital capacity; VT = inspired tidal volume

Received for publication June 16, 1998. Accepted for publication January 15, 1999.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 

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