Papilledema in chronic respiratory acidosis

Papilledema in Chronic Respiratory Acidosis* Report of a Case, with Studies on the Blood -Cerebrospinal Fluid Barrier for Carbon Dioxide FELICE MANFREDI, M .D .,t CHARLES R . MERWARTH, M .D ., CHARIEs E. BUCKLEY, III, M .D . and HERBERT 0 . SIEKER, M .D .

Durham, North Carolina INCE Cameron J1] first described papilledema in respiratory acidosis in 1933, a score of similar cases have appeared in the English literature . Recently, C onn et al . [2] and Austen and co-workers [3f reported cases of this syn-

the lower respiratory tract, including whooping cough . At age thirty-six she had bilateral pneumonia and was told afterwards that she had asthma . She had a chronic cough productive of moderate amounts of whitish sputum. which she attributed to smoking approximately one package of cigarettes per day for over forty years . Five years preceding admission she had a single episode of frank hemoptysis . Chest roentgenogratns and sputum examination at that time revealed no abnormalities . In the last several years she had been bothered by intermittent wheezing and had been short of breath with such household activities as sweeping and with climbing one flight of stairs . Her symptoms were increased with frequent infections of the respiratory tract and in the year preceding admission she required antibiotic therapy on three occasions . At no time did she have difficulty with mentation, increased somnolence, tremor, peripherall edema or orthopnea . Headaches occurred infrequently, and the only visual disturbance was two transient episodes of gray vision occurring in the two weeks preceding admission . During this period of time she was taking small doses of cortisone derivatives prescribed by her local physician for control of wheezing . In 1957 the patient was admitted to the Neurosurgical Service for investigation of low back pain which was thought to be secondary to hypertrophic arthritis . On that occasion tormosity of the retinal veins was noted bilaterally but funduscopic examination was otherwise within normal ]imits . On physical examination, temperature was 37 .6'c . . pulse 94, respiration 22, and blood pressure 125/80 with 15 nun . Hg paradox . The patient was a moderately obese white woman who complained of back pain . She was oriented, and her mental function was intact as tested by serial sevens, general knowledge and recall . There was a moderate dusky discoloration of the mucous membranes . The conjunctivas were

S

drome with predominant neurologic manifestations . To date, the pathophysiology of papilleclema in pulmonary insufficiency is a subject for speculation [1 -41 . It is the purpose of this paper to report a case of papilledema and retinopathy associated with respiratory acidosis . Over a three month period serial and simultaneous determinations were made of arterial blood gases and cerebrospinal fluid pH and pCO2 . The resolution of the eyeground changes under appropriate therapy for the underlying pulmonary disease was followed with fundus photographs . These findings were correlated with the progressive changes observed in arterial blood and spinal fluid pH and pCO 2 . The data obtained in this patient permit a more complete understanding of the possible pathogenesis acidosis .

of papilledema

in respiratory

CASE REPORT

S . L ., a fifty-five year old white woman, was adcoined to the Medical Service of Duke Hospital on September 2 . 1959, for investigation of papilledema . The patient was initially seen in the outpatient department because of low back pain . At the time of the examination essentially asymptomatic bilateral papilledcma with retinal hemorrhages was discovered, and she was hospitalized for further evaluation . After careful and repetitive questioning the following history was obtained . As a child, the patient had had frequent infections of

suffused . The pupils were regular and reactive with

'' From the Department of Medicine, Duke University Medical Center, Durham, North Carolina . This study was supported (in part) by a grant from the American Heart Association and (in part) from the Life Insurance Medical Research Fund . f American Heart Association Research Fellow . JANUARY

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Acidosis-Manfredi et al .

1B Fm . 1 . Eyeground photographs A, right and B, left eye taken on September 10, 1959 .

FIG . 2 . Posteroanterior and left lateral views of the the

normal extraocular movements . Peripheral visual fields were intact but there was minimal enlargement of the central blind spot . Visual acuity was 20,1 300 o .u . without glasses, and corrected was 20/25 o .dA and 20/30 o .s . The fundi showed florid bilateral papilledema with indistinct disc margins and large fresh hemorrhages clustered around both discs . The retinal veins were engorged and tortuous . (Fig . 1 .) The neck was supple and without venous distention . The anteroposterior chest diameter was increased . Breath sounds were distant and inspiratory and expiratory wheezes were heard throughout both lung

fields. There was no physically detectable eardiomegaly . The second pulmonic sound was louder than the second aortic sound . No murmurs or gallops were heard . The liver was not palpable . There was moderate scoliosis of the dorsolumbar spine with tenderness over the right sacroiliac region . The nail beds were dusky but clubbing was absent . There was no peripheral edema. Neurologic examination, except for the finding of papilledema, was within normal limits . Laboratory data revealed a hemoglobin of 18 .5 gm . per cent, a hematocrit of 56 per cent, and a white count of 7,150 per cu . mm . with a normal differential . AMERICAN JOURNAL OF MEDICINE



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3B Fm . 3 . Eyagrnund photographs A, right eye and B, left eye taken on September 2'I, 1959, 3.

Urine pH was 5 and 5 .5 . CO, combining power was 38 .5 mEq ./L . and other serum electrolytes were within normal limits . Blood urea nitrogen was 9 mg . per cent . The result of a glucose tolerance test was normal . A chest roentgenogram revealed bronchovascular thickening and moderate emphysema . (Fig . 2 .) '1 he electrocardiogram showed low voltage in the frontal plane with delayed progression of the QRS complex across the precordium and inverted T waves in leads V, through V 4 ; the QRS loop was broad and of indeterminate axis . Skull films and electroencephalogram did not show any abnormalities . Urinary excretion of 17-hvdroxvketosteroids and 17-ketosteroids was also normal . Venous pressure was 136 mm- of water . A lumbar puncture on September 9 revealed an initial pressure of 200 mm . of water, but the patient was not well relaxed . Five mononuclear cells, 70 rng . per cent of protein, and a negative colloidal gold curve were observed . On September 16 the spinal fluid pressure was 135 mm . of water . Vital capacity and maximum breathing capacity were 84 and 54 per cent of predicted normal . The helium washout time was prolonged to nine minutes . Arterial blood studies revealed oxygen unsaturation, with a pH of 7 .25, and a pCO_, of 97 .5 mm . Fig . Following six minutes of breathing 5 per cent carbon dioxide in air, the minute volume of ventilation increased 5 .85 L. and the tidal volume increased approximately 300 ml . The patient was treated with nebulized Isupreic and Alevaire,® using an intermittent positive pressure breathing device . Expectorants and a ten-day course of tetracycline were also administered . On this therapeutic program there was a gradual decrease in wheezing and dyspnca, with simultaneous improvement of the fundi . The disc margins became more distinct, and there was resorption of the hemorrhages. (Fig . 3 .) I&NUARY

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On the eighth and the fifteenth day of hospitalization simultaneous determinations of arterial blood gases and cerebrospinal fluid pH and pCO, were obtained . Blood oxygen content and saturation were measured by the photometric method of Iliekam and Frayser [5] . The pH of whole blood was measured with a Cambridge model R pH meter with enclosed glass electrode . Measurements were corrected to

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Fm . 4 . Serial determinations on arterial blood and spinal fluid.



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5A 5B FIG . 5 . Eyeground photographs A, right eye and B, left eve taken on November 30, 1959 . 37°c. using Rosenthal's factor [6] . Cerebrospinal fluid pH was measured with the same apparatus at room temperature . No temperature correcting factor was applied to these readings, since on four occasions they were found to be comparable (within 0 .01 units) to the values obtained at 37°c . on a Cambridge model R pH meter equipped with an anaerobic chamber and a constant temperature bath . Total carbon dioxide content of blood and spinal fluid was determined by the method of Van Slyke and Neill [7] . Plasma carbon dioxide content was calculated from whole blood carbon dioxide content, pH and hemoglobin, using the line chart of Van Slyke and Sendroy [8] . Carbon dioxide tension of blood and cerebroTABLE I ARTERIAL BLOOD-SPINAL FLUID GRADIENTS FOR PH AND PCO2 Date 1959

Blood

Cerebrospinal Fluid

Difference

I PH 9/9

7 .28

9/16

7 .29

11/30

7 .41 1

7 .32 - -7 .31 7 .32 1 PCOs mm . Hg

-0 .04 -0 .02 +0 .09

spinal fluid was calculated using the HendersonHasselbalch equation and a pK' of 6 .13 for spinal fluid . All determinations were made in duplicate . The results obtained are illustrated in Figure 4 and Table I . The arterial oxygen saturation was 82 .9 per cent and remained essentially unchanged (September 9 and 16) . A progressive rise in arterial pH with a corresponding fall in pCOs was noted . The spinal fluid showed no significant variation in these parameters . The arterial blood-cerebrospinal fluid pH gradient was negative on the two determinations (minus 0 .04 and minus 0 .02) ; the corresponding pCO2 gradients were positive (plus 4 and plus 3 mm . Hg) . Just before discharge (September 21) the arterial pH was 7 .36 . On November 30 the patient was seen in the outpatient department for follow-up . She had been doing well, except for one episode of bronchopulmonary infection which had responded promptly to antibiotic therapy . On examination of the chest the breath sounds were again distant, and occasional inspiratory rhonchi were heard . The striking improvement of the fundi is shown in Figure 5 . Arterial blood showed an oxygen saturation of 89 .1 per cent, pH 7 .41, and pCOs 54 mm . Hg . Spinal fluid obtained simultaneously revealed a pH of 7 .32 and a pCOs of 54 .2 mm . Hg . The arterial-spinal fluid gradients for pH and pCOs were now opposite to the ones found on previous determinations, being plus 0 .09 for pH and minus 0 .2 for pCOs . (Fig. 4 and Table I.) COMMENTS

9/9

59 .7

55 .4

+4 .3

9/16

62 .0

58 .9

+3 .1

11/30

54 .0

54 .2

This case presents several interesting aspects . Although a history of respiratory disease was documented on initial evaluation of the patient, its significance was not appreciated . Her presenting complaint was severe back pain . Dyspnea AMERICAN JOURNAL OF MEDICINE



Papillederna in Respiratory Acidosis was not noted, but exertion had been limited by the back pain . The pulmonary findings on physical evaluation were not of a magnitude usually associated with respiratory acidosis or with its neurologic complications . Other possibilities considered more likely were brain tumor, particularly of the infratentorial angiomatous type [10], primary polycythemia [11-13], diabetic retinopathy and papillitis . These were excluded by appropriate studies . Papilledema secondary to withdrawal of steroids [14] was also considered unlikely . In retrospect, a more accurate history was obtained when the rocntgenograms and the pulmonary function studies indicated the presence of a significant degree of lung disease and the arterial blood gases revealed evidence of respiratory acidosis . Striking and maintained improvement on adequate therapy substantiated the diagnosis . Papilledema in this patient occurred with only modest respiratory symptoms and signs . Arterial blood gas determinations on the day of admission would have delineated the degree of pulmonary insufficiency and clarified the diagnostic difficulties . The importance of this laboratory information in patients with papilledema and any suggestion of lung disease should be emphasized . Multiple factors have been implicated by various investigators as possible causes of papilledema in respiratory insufficiency [1-4,11, 14-1i] . In our patient there was no evidence of congestive heart failure, primary polycvthemia or significant elevation of cerebrospinal fluid pressure . She did, however, manifest a marked degree of carbon dioxide retention . There is extensive clinical and experimental evidence in the literature to demonstrate that hypercapnia increases cerebral blood flow and produces edema of the brain [3,15,15-23] . In our patient papilledema was not secondary to increased intracranial pressure which would he expected with diffuse cerebral edema . The mechanism by which metabolic and circulatory derangements result in the eyeground changes is poorly understood . Apparently, hypercapnia and possibly hvpoxemia can alter cerebral and retinal metabolism resulting in papilledema and retinopathy . As far as it can be ascertained, no observations of pH or PCO 2 gradients between spinal fluid and arterial blood have been made in patients with papilledema from respiratory acidosis . General agreement is found in the literature that spinal fluid pH is lower than arterial blood pH . although this difference has not been as yet satisfactorily explained [24-26] . The spinal fluid pH appears to be regulated JANUARY

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primarily by the carbon dioxide tension . It has been shown that this gas diffuses readily across the blood-brain barrier in physiologic as well as in experimental conditions whereas the combined form of carbon dioxide is transferred across the barrier at a much slower rate [25-29] . It would appear that under normal conditions carbon dioxide in the gaseous form flows from brain tissue to cerebral venous blood and cerebrospinal fluid, and hence into the systemic circulation, with a total tension drop of approximately 15 mm . Ilg [24,30] . In our patient during the initial period of treatment, when the eyeground changes were still prominent, the arterial blood pH was persistently lower and the pCO 2 higher than the respective spinal fluid values . These findings must be considered as actual reversion of the normal gradients, since the p11 and pCO 2 differences are definitely outside the limits of error expected for the methods used in the respective determinations . When the respiratory insufficiency was corrected, the eyeground lesions regressed, and at this time both gradients were reversed toward normal directions, i .e ., pH lower and pCO 2 higher in cerebrospinal fluid than in arterial blood . With pulmonary insufficiency and attendant arterial carbon dioxide retention, the normally existing spinal fluid-arterial blood pCO 2 gradient may be reversed . Brain tissue is capable of absorbing large quantities of carbon dioxide [31] . The reversed gradient may therefore persist over a long period of time . until a saturation point is reached in the brain tissue or until arterial hypercapnia is corrected by improving the pulmonary function . The toxic effect of carbon dioxide accumulation within the brain substance may be responsible for local vasodilation, increased cerebral blood flow, increased vascular permeability, and possibly altered cell metabolism resulting in papilledema and retinopathy . Since in this patient arterial oxygen saturation returned toward normal values concomitantly with the progressive correction of hypercapnia, the role of hypoxemia in the pathogenesis of papilledema from respiratory acidosis cannot be defined . SUMMARY

A case of papilledema and retinopathy associated with pulmonary insufficiency in a fifty-five year old woman with chronic bronchitis and emphysema is reported . This presentation exemplifies the diagnostic difficulties encountered in identifying the underlying disorder in

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cases of papilledcma and retinopathy secondary to lung disease, since the pulmonary symptoms of this patient, as well as her chest findings on physical examination and roentgenograms, were not prominent. Repeated studies were made of arterial blood gases and cerebrospinal fluid pH and pCO 2 during a three month period . The progressive resolution of the eyeground lesions was correlated with improved respiratory function . Hypercapnia and hypoxemia have been suss peeled as the cause of papilledema in respiratory acidosis . The results of this study suggest that in respiratory acidosis accumulation of carbon dioxide in brain tissue, as reflected by inversion of the normal carbon dioxide tension gradient between cerebrospinal fluid and arterial blood, may he related to the development of papilledema and retinopathy . REFERENCES

Marked papilloedema in pulmonary emphysema . Brit. J . Ophth ., 17 : 167, 1933 . 2 . CONN, H . O ., DUNK, J . P., NEWMAN, H. A . and BELKIN, G . A . Pulmonary emphysema simulating brain tumor . Am . J. Med., 22 : 524, 1957 . 3 . AUSTEN, F. K ., CARMICHAEL, M . W . and ADAMS, R . D . Neurologic manifestations of chronic pulmonary insufficiency . New England J. Med., 257 : 579, 1957 . 4 . SIMPSON, T . Papilloedema in emphysema . Brit . M. J ., 2 : 639, 1948 . 5 . HICxAM, J . B . and FRAVSER, R. Speetrophotomctric determination of blood oxygen . J. Biol . Chem ., 180 : 457, 1949 . 6 . ROSENTHAL, T . B . Effect of temperature on pH of blood plasma in vitro . J. Biot . Chem ., 173 : 25, 1948 . 7 . PETERS, J . P. and VAN SLVKF., D . D . Quantitative clinical chemistry . In : Methods, vol . 2 . Baltimore, 1932 . William & Wilkins . 8 . VAN SLVKF., D . D . and SENDROY, J., JR . Studies of gas and electrolyte equilibria in blood ; line charts for graphic calculations by Henderson-Hasselbalch equation, and for calculating plasma carbon dioxide content from whole blood content . J . Biol . Chem ., 79 : 781, 19289 . HASTINGS, A . B . and SLNDROY, J ., JR . The effect of variation in ionic strength on the apparent first and second dissociation constants of carbonic acid . J . Bid . Chem ., 65 : 445, 1925 . 10. STARR, G . F ., STROEBEL, C . F ., JR . and KEARNS, T . P . Polycythemia with papilledema and infratentorial vascular tumors Ann . tot . Med., 48 : 978, 1958 . It . MEADOWS, S . P. Papilloedema associated with chronic bronchitis, emphysema and polycythemia . Proc . Roy . Soc . Med., 40 : 555, 1947 . 12 . LUCAS, W. S . Erythremia or polycythemia with chronic cyanosis and splcnomegaly . Arch . Inl . Med., 10 : 597, 1912 . 13 . DREW, J . N . and GRANT' . F . C. Polvcvthemia as a ncurnsurgical problem . Arch . Neurol . & Psychiat ., 54 : 25, 1945 . 14. DEEs, S . C . and MORAY, It . W ., JR . Occurrence of 1 . CAMERON, A . J .

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pscudotumor. cerebri (benign intracranial hypertension) during treatment of children with asthma by adrenal steroids . Pediatrics, 23 : 1143, 1959 . 15 . McMICHAEL, J. and LENNOX, B . Letter to editor . Lancet, 2 : 1057, 1949 . 16 . PA'1TERSON, J . L ., HEYMAN . A . and DONE, 1'. W . Cerebral circulation and metabolism in chronic pulmonary emphysema . Am . J . Med., 12 : 382, 1952 . 17 . SCHFINBERG, P., BLACKBURN, I ., SASI .AW, M ., RICH, M . and BAUM, G . Cerebral circulation and metabolism in pulmonary emphysema and fibrosis with observations on the effects of mild exercise . J. Clirs_ Invest ., 32 : 720, 1953 . 18 . WOLFF, H . G. and LENNOX, W. G . Cerebral circulation . No . Effect on pial vessels of variations in oxygen and carbon dioxide content of blood . Arch . .Veurol. & Psychiat ., 23 : 1097, 1930 . 19 . COBB, S . and FRFMONT-SMITH, F . Cerebral circulation . xvi . Changes in human retinal circulation and in pressure of cerebrospinal fluid during inhalation of mixtures of carbon dioxide and oxygen . Arch . Neural . & Psychiat ., 26 : 731, 1931 . 20 . LENNOX, W . G. and GIBES, E. L . The blood flow in brain and leg of man and the changes induced by alteration of blood gases . J. Clin. Invest ., 11 : 1155, 1932 . 21 . WRITE, J . C ., VERLOT, M., SELVERSTONE, B ., and. BEECHER, II . K. Changes in brain volume during anesthesia : the effects of anoxia and hypercapnia. Arch . Surg ., 44 : 1, 1942 . 22 . KETY, S . 5 . and Scimmi', C . F . The effects of alteredd arterial tensions of carbon dioxide and oxygen on cerebral blood flow and cerebral oxygen consumption of normal young men . J. Clin . Invest ., 27 : 484, 1948 . 23 . SIMPSON, T. Acute respiratory infection in emphysema . Brit . M. J., 1 : 297, 1954 . 24 . 85101 . A. T . and KARELITZ, S . The carbon dioxide tension of cerebrospinal fluid . J. Biel . Chem ., 71 : 119 . 1926 . 25 . Rouix, E . D., WHALEY, R. D ., Catnip, C . H ., BICKELMANN . A . G . and TRAVIS . D. M . Acid-base relations between spinal fluid and arterial blood with special reference to control of ventilation . J. Appl . Physiol ., 13 : 385, 1958 . 26 . LEUSEN, 1 . R . Acid-base equilibrium between blood and cerebrospinal fluid . Am . J. Physiol., 176 : 513, 1954 . 27 . DAVSON, H . Physiology of the Ocular and Cerebrospinal Fluids . Boston, 1956 . Little, Brown and Co_ 28 . GESELL, R . and HERTZMAN, A . B . The regulation of respiration . iv . Tissue acidity, blood acidity and pulmonary ventilation . A study of the effects of semipcrmeability of membranes and the buffering action of tissues with the continuous method of recording changes in acidity . Am. J . Physiol., 78 :: 610, 1926 . 29 . COLLIP, J . B . and BACKUS, P . L . The alkali reserve of the blond plasma, spinal fluid and lymph . Am . .I . Phy,dol ., 51 : 551, 1920 . 30, GIBBS, E . L ., LENNOX, W . G ., NLMS, L, F. and Gians, F. A . Arterial and cerebral venous blood . Arterialvenous differences in man . J . Riot . Chem ., 144 : 325, 1942 . 31 . NICHOLS, G ., JR . Serial changes in tissue carbon dioxide content during acute respiratory acidosis . J . Clin . Invest ., 37 : 1111, 1958 . AMERICAN JOURNAL OF MEDICINE