Spirometry in Amyotrophic

Lateral Sclerosis

Robert J. Fallat, MD; Barbara Jewitt; Michael Bass, MD; Barbara Kamm; Forbes H. Norris, Jr, MD

\s=b\Clinical evaluation and pulmonary function tests were performed in 218 patients with motor neuron disease, mainly amyotrophic lateral sclerosis (ALS). Serial studies were obtained in 103 patients, in 31 until death from ALS. Most patients, regardless of the pattern of motor neuron involvement, had characteristic abnormalities in pulmonary function, including reduced forced vital capacity (FVC) and maximum voluntary ventilation (MVV). Reductions in the FVC and MVV to as low as 50% were commonly missed by clinical evaluators. Spirometry is therefore of value in detecting early involvement of respiratory neurons. Progressively greater reductions in the FVC and MVV in all the fatal cases indicate that serial spirometry has prognostic value in ALS. (Arch Neurol 36:74-80, 1979) most r~p hedisease

sclerosis

motor

neuron

amyotrophic

lateral

common

is

(ALS), in which

motor sys¬

damage occurs both extensively and rapidly so as to culminate in death within an average of three years.1"3 The muscles of the thoracic cage and the diaphragm are ultimately involved in all ALS cases and may be the earliest involved muscles in some cases. Patients with ALS usually die from such respiratory problems as tem

hypoventilation causing hypoxemia, hypercarbia, or both; aspiration pneu¬ monias; other pneumonias; and occa¬ sionally pulmonary emboli.1"" Although respiratory function plays such an important role in the progno¬ sis of these patients, there have been few reports of pulmonary function studies in ALS.1"7 Indeed pulmonary

function in other neuromuscular dis¬ ease has been reported from only small series, with the exception of the studies of poliomyelitis,8 muscular dystrophy,1' and parkinsonism.1" The purpose of this report is to analyze the lung function in 218 motor neuron patients, 103 of whom were studied serially. Correlation of lung function Accepted for publication Jan 19,

1978. From the Institutes of Medical Sciences, Pacific Medical Center, San Francisco. Reprint requests to Institutes of Medical Sciences, 2200 Webster St, San Francisco, CA 94115 (Dr Norris).

with the progression of neuromuscu¬ lar disease and the usefulness of such studies in diagnosis, prognosis, and management of ALS are presented. METHODS

There were 218 patients with motor disease seen from January 1971 to September 1974: 156 men and 62 women ranging in age from 19 to 78 years (mean age, 56 years). Serial studies were obtained on 103 of the patients for periods varying from 1 to 40 months through September 1975. Ninety patients were followed until death from ALS, and 31 of these had serial studies. In each case, the diagnosis was estab¬ lished from a history and physical exami¬ nation by two or more independent neurol¬ ogists and confirmed by characteristic findings at electromyography and muscle neuron

biopsy. Typically negative findings were examinations of cerebrospinal fluid, heavy metal screening, myelography, and other relevant tests whenever appropriate. Amyotrophic lateral sclerosis was present in 192 patients. Progressive bulbar palsy, a form of ALS with early and predominant bulbar involvement, was present in five cases. The lower motor disease, progressive muscular atrophy, was present in 16 patients, and the predominantly upper motor neuron disease, primary lateral scle¬ rosis, affected five patients.

The date of onset in each case was taken the time of first severe weakness. Some ALS patients have cramps, undue fatigue, or fasciculation months or even years earlier, but this date is usually harder to specify so we relied on the onset of weak¬ as

sign, fasciculation, selected functional

and

spasticity,

and

abilities, such as cough¬

ing, changing position, and sitting up. A normal score was 100, of which six points for normal breathing and coughing were directly related to breathing. In each case, within days of the NMS, pulmonary function studies were per¬ formed. Spirometry was done with a roll¬ ing drum spirometer. Maximum expiratory flow volume loops were obtained on an X-Y mechanical recorder and simultaneously analyzed by computer. Residual volume (RV) was measured both by neon dilution during the single-breath, carbon monoxide diffusing capacity (D,CO)12 and by closedcircuit helium dilution on the initial study.11 Spirometry, including maximum voluntary ventilation (MVV), was done at each follow-up visit, and D..CO and RV determined when significant changes oc¬ curred. Arterial blood was obtained in subjects with evidence of more severe ventilatory abnormalities; measurement of 0L, and CO, tensions and pH were done with an electronic blood gas analyzer. Predicted normal values for forced vital capacity (FVC), forced expired volume in one second (FEV,), and male total lung capaci¬ ty (TLC) were taken from Kory et al,14 the predicted TLC for females from Goldman and Becklake,1 the midmaximal flow rate (MMFR) from Schmidt et al,1" and the MVV predicted values from Grimby and Soderholm.17 The DLCO predicted was based on a formula derived in our laborato¬ ry and is based on the simultaneous total '

lung capacity measurement: predicted D,.CO 13.67

+

4.36

=

TLCBTI,S 0.20

age

-

ness.

Each

patient's general neuromuscular

status was quantitated, using a neuromus¬ cular score (NMS) previously detailed as the ALS score.11 Briefly, this score was based on points given for selected exami¬ nation characteristics, such as Babinski's Table 1—Initial

_

Pulmonary

where BTPS is the body temperatureadjusted pressure saturation. RESULTS

A summary of the initial

pulmonary

function results is shown in Table 1

Function in Motor Neuron Disease Mean (% of Predicted) ( ± SD) 218 3.2(1.2) 80(23) 204_82 (38)_67 (27) 208 138(40) 2.5(0.7)

_Mean ( ± SD)

Forced vital capacity (FVC), liters Maximum voluntary ventilation, liters/min Residual volume, liters Total lung capacity, Functional residual capacity, liters Forced expiratory volume in 1 s (FEV,), liters

liters_208_5.6(1.4)_94(19) 208

3.5(0.9)

111(24)

218 79(24) 2.5(0.9) FEV,/FVC, %_218_78(11.6)_.___ 182 Diffusing capacity, ml/min/mm Hg 28(7.2) 103(23)

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—I-1-1-1-1-1-1-1-,-1-1-r

50

] No

100 150 Percent Predicted

200

| Airway

Obstruction

Airway Obstruction

Shaded Area is Normal

80

I

70

Airway Obstruction -

S

50-

CB

CJ

No

Airway Obstruction

listed in Table 1. Solid areas represent patients with obstructive lung disease; these account for only a minority of high RV observed. Dots represent mean value; bars, ±1 SD.

40 30 2010

rrril

h

— -1-1-1-1-1-1-1-1

50

100

Neuromuscular Score

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~

150

Airway Obstruction

Fig 1 .—Histograms of pulmonary functions

CL

-°

~

100 Percent Predicted

Range

No Airway D Obstruction

60

50

additional 15

100

with FEV,/FVC classified as having airway obstruction based on curvature of flow volume loops (Fig 3, A) and low flow rates at lower lung volumes; therefore, there are 42 cases considered to have airway obstruction, shown as solid symbols in Fig 1. Analysis of the flow volume loops of 120 patients with residual volumes greater than 120% showed that airway obstruction was a probable cause of the high residual volume in 38 cases, as evidenced by decreased FEV, or curvature in the expiratory portion of the curve (Fig 3, A). There were 75 patients unable to give full expiration, as evidenced by premature inhalation in the final portion of the curve (Fig 3, B), or by curves that showed the errat¬ ic patterns found in many ALS patients (Fig 3, C). In the remaining seven cases with high residual volume, airway obstruction was not evident from the flow volume loops (Fig 3, D); these patients probably had small airway disease, as they were all smok¬ ers and objectively had prolonged helium-mixing times. The most consistently and signifi¬ cantly reduced measurement was the maximum voluntary ventilation. The mean of 67% ± 27 was the lowest of all the variables; in the 204 cases, 133 or 67% were below the predicted range (less than 80%); 14 of the cases did not have an MVV measurement because of their severe disability and inability to perform this most laborious of the ventilatory tests (requiring the pa¬ tient to breathe as fast and as hard as possible for at least 12 seconds). cases

greater than 70% y

ÒZ c:

CD O t_ CD

CL

FVC Percent

MVV Percent

NMS

—r—

10

20 0 20 0 10 Months After Initial Study

-Alive -Dead

10

20

120 100

200

50

TLC Percent 0

0 0 20 10 Months After Initial Visit

——

—

10

20

Fig 2.—Change in pulmonary function and NMS after initial evaluation in surviving and nonsurviving ALS patients. Hatched areas are normal ranges. Note more marked decline in FVC and MVV and rise in RV in fatal cases. Table 2 gives correlation coefficients and statistical comparisons of slopes. and

Fig 1. These results include all the

types of

disease (eg, primary lateral sclerosis) as well as ALS because the same pattern of abnormalities was seen in all the motor

neuron

subtypes. Lung Volumes and Spirometry The initial FVC was low, with a mean for the entire group of 80% of the predicted value (Table 1). Of the 218 subjects, 106 had an FVC less than 80% predicted, which is approximately 2 SD below the normal range (Fig 1).

The RV was high (mean, 138%); 66% of the patients were more than 2 SD above the mean for normals (ie, greater than 120%). The distribution of functional residual capacity (FRC) shows only slight skewing to the high side of normal (mean, 111%; Table 1),

which in part may be due to the presence of airway obstruction as indicated by the solid areas in Fig 1. The distribution of TLC was only slightly low (mean, 94%; Table 1), but there is a definite progression to a lower TLC with progression of the disease as seen by the decreased TLC in those who died (Fig 2). Airway obstruction was not promi¬ nent; only 37 of the patients had an FEV,/FVC (forced expired volume in one second/forced vital capacity) less than 0.70 (Fig 1). Only 27 of these cases had other evidence of airway obstruction, such as curvature of the flow volume loops (Fig 3, A) or delayed helium mixing time; the low FEV,/FVC in the remaining ten was related to their weak and uncoordi¬ nated expiratory effort (Fig 3, C). An

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Gas

were

Exchange

Arterial blood gas measurements were obtained in 30 of the ambulatory patients with markedly reduced venti¬ latory capacity (MVV < 60%). Normal Po. tensions (greater than 80 mm Hg) were found in 19. Eight had slightly lower Po, tension of 70 to 80 mm Hg, consistent with their ages. Three with associated obstructive airway disease had lower values of 61 to 67 mm Hg. Only one patient had Paco., elevation to 52 mm Hg, and even he had a normal Pao2 of 80 mm Hg. This patient had an FVC of 18% and the MVV was impossible for the patient to perform. He died at home that

evening.

Several other patients developed respiratory acidosis and hypoxemia as a result of complicating factors such as infections, congestive heart failure,

surgery, so their blood gas values not reported here. Generally, on recovery, the values returned to the or

are

Vital

Capacity

VC, L

3.8

(91)

2.5

(52)

RV, L

2.9 (165)

3.7

(290)

6.7 (108) 4.2 (165)

6.3 (106) 4.0 (141)

TLC, FRC, L L

FEV/FVC MVV, L/min

65 86

(62)

(61)

3.6

(79)

(122) 4.7 (76) 3.5 (136)

3.1

(184) (105) (159)

2.6 2.1

4.2

62

96 92

6.7

(53)

85

(34)

49

150

(96)

Fig 3.—Variation in characteristics of forced vital capacity are shown as flow vs volume curves. A, Subject with distinct airway obstruction. Note marked curvature compared to Fig 3, D. Also note low FEV,/FVC and high RV and TLC. , Inability of this patient to fully exhale is seen by initiation of inspiration when expiratory flow is still quite high. Repeated efforts all result in the same early inspiration. C, Extremely erratic expiratory effort in patient with bulbar ALS. There is sudden decrease in flow to zero, apparently caused by occlusion of glottis by dyscoordinated muscles. D, Normal-appearing expiratory flow volume curve, but patient still has unexplained high RV.

previous levels. One subject had an idiosyncratic drug reaction resulting in

increased

muscular

weakness,

pulmonary congestion, and acute res¬ piratory failure. He subsequently had a sustained chronic respiratory acido¬

sis that was controlled by use of a chest cuirass at home. Some details of this case are reported elsewhere.18 Serial Studies

It is

patients

recognized that

Table 2.—Linear Regression of Functional Characteristics With Time (Comparison of Survivors With Nonsurvivors)

some

ALS than

have slower courses others.' '" Our ALS patients were arbitrarily divided into two groups: those alive and those dead by Septem¬ ber 1975. Although the living group was biased by the inclusion of more recent cases, it also included more slowly progressive cases while the dead group tended to include the

rapidly progressive cases. Linear regressions with time for the pulmonary functions of these two groups are given in Table 2. Figure 2 shows that initially there was little

difference between the groups. Subse¬ quently, there were differences in the declines in FVC and MVV and rise in RV. Although the correlation coeffi¬ cients are low, there are statistically

No. of Patients

No. of Studies

Correlation Coefficient

Slope*,

73

224 79

-.11

-0.51 -1.28

217 77

-.03

23

•03

-0.16 -1.8