Central nervous system sarcoidosis with alveolar hypoventilation

Central

Nervous

with Alveolar JERE

System Sarcoidosis Hypoventilation”’

J. DAUM, M.D.,? HALL G. CANTER,

M.D.

and SOL KATZ, M.D.

Washington, D.C.

S

and 3.5 gm. per cent globulin; alkaline phosphatase 5.4 Bodansky units; prothrombin concentration 60 per cent. The bromsulfalein excretion test showed 60 per cent retention in 45 minutes. Biopsy specimens of the liver, right scalene lymph node and main stem bronchus of the right lung revealed noncaseating granulomas. A Kveim test result was positive. Both the intermediate tuberculin (purified protein derivative) and histoplasmin skin tests produced 5 mm. induration. Pulmonary function tests revealed a vital capacity of 4,825 cc. ; timed vital capacity at 1 second 70 per cent, at 2 seconds 83 per cent and at 3 seconds 89 per cent. The maximum breathing capacity was 136 L. per minute. Arterial blood gas analysis showed a pH of 7.40, pCO2 46 mm. Hg, and ~02 67 mm. Hg. A diagnosis of sarcoidosis was made. Following discharge from the hospital the patient continued to drink approximately 7 to 8 quarts of water per day. Cold intolerance developed during the winter and he noted increased fatigability. In August 1963 he became aware of decreased libido and decreased hair growth on his chin. In contrast to his usual pattern of shaving every other day, he now shaved every fifth day. He also noted a decrease in the size of both testes. Hypothalamic symptoms such as narcolepsy and bulemia were denied. The patient was hospitalized again in January 1964 for evaluation of pituitary insufficiency. Physical examination revealed sparse body hair, including the beard area. He was slightly obese. The penis was normal in size. Bilateral small firm testes were felt and there was minimal prostatic tissue. Daily water intake varied from 6,180 to 9,140 cc. with a urinary output ranging from 5,650 to 9,950 cc. The specific gravity of all specimens of urine was 1.003. A HickeyHare test result was positive: the osmolality of the urine was 108 mOsm. before the intravenous infusion of 1 L. of 2.5 per cent saline solution and 110 mOsm. following the infusion. After 5 units of vasopressin tannate was given intramuscularly, the osmolality of the urine rose to 430 mOsm. The baseline 17-hydroxysteroid and 17-ketosteroid excretions were normal, 7.93 and 8.0 mg. per 24 hours, respectively. He had a

of the central nervous system is uncommon and when it occurs usually presents as leptomeningitis, cranial nerve palsy or brain tumor. The occurrence of posterior pituitary insufficiency has been reported frequently but insufficiency of the anterior pituitary is most uncommon. Alveolar hypoventilation as a manifestation of central nervous system sarcoidosis has not been recorded, to our knowledge. This report describes two patients with sarcoidosis and evidence of central nervous system involvement. Both had alveolar hypoventilation on a central basis and one had associated anterior and posterior pituitary insufficiency. ARCOIDOSIS

CASE

REPORTS

CASE I. This thirty-four year old Negro male pharmacist (J. L., V. A. Hospital, Washington,D. C., No. 010610) was treated for moderately advanced pulmonary tuberculosis of the upper lobe of the left lung in 1953. His last positive sputum for tubercle bacilli was in September 1953. Serial films of the chest revealed that the lesion in the upper lobe of the left lung had remained stable since February 1954. In May 1962, a chest roentgenogram demonstrated bilateral hilar lymphadenopathy and irregular linear fibrotic strands scattered throughout both lung fields. At the time of hospitalization in June 1962, the patient’s only symptoms were dryness of the mouth and the need to drink large quantities of fluid to keep his mouth moist. He had associated polyuria. Physical examination was noncontributory. The hematocrit was 46 per cent and the white blood cell count 15,400 cells per cu. mm., with a normal differential. The specific gravity of the urine on admission was 1.018 and on July 9 was 1.005 in a random specimen. Chemical analysis of the blood revealed a urea nitrogen of 12 mg. per cent; total protein 7.5 gm. per cent with 4 gm. per cent albumin,

* From the Medical Service and Pulmonary Laboratory, V. A. Hospital, Washington, D. C. and the Department of Medicine, Georgetown University School of Medicine, Washington, D. C. Manuscript received July 22, 1964. t Present address: 4977 Battery Lane, Bethesda, Maryland. VOL.

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Sarcoidosis and Alveolar Hypoventilation-Daum

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though the pCO2 was decreased during voluntary hyperventilation. ings point to a central abnormality for alveolar hypoventilation.

FIG. 1. Case I. Chest film obtained on admission showing parenchymal and hilar sarcoidosis in addition to residual tuberculosis in the upper lobe of the left lung.

normal response to metopirone and ACTH stimulation. The 24-hour 1131-uptake was 10 per cent; basal metabolism was - 19 per cent; and serum proteinbound iodine 4.5 fig. per cent. The response to TSH stimulation was normal. Biopsy of the testes revealed testicular atrophy. The 24-hour urinary gonadotropin excretion was less than 5 mouse units. The responses to both intravenously administered insulin and tolbutamide were normal. Serum total protein was 8.7 gm. per cent, with 2.8 gm. per cent albumin and 4.9 gm. per cent globulin. Serum calcium was 10.5 gm. per cent and serum phosphorus 4.5 mg. per cent. An electrocardiogram revealed nonspecific changes in the T wave. The electroencephalogram and visual fields were normal. Roentgenograms of the skull, including laminograms of the sella turcica, were within normal limits. The spinal fluid contained no cells; the sugar was 66 mg. per cent and the protein 30 mg. per cent. A chest roentgenogram revealed bilateral hilar adenopathy and increased linear markings in both lungs, especially in the upper lobe of the left lung (Fig. 1.) Results of the pulmonary function tests, arterial blood studies and response to carbon dioxide inhalation obtained during the second admission are recorded in Table I. Comment: The pulmonary studies showed a restrictive ventilatory abnormality and alveolar hypoventilation. This was unexpected since this type of pulmonary involvement is usually associated with normal or increased alveolar ventilation. The ventilatory response to carbon dioxide inhalation was markedly impaired al-

significantly These findas the cause

CASE II. This forty year old Negro male cook (E. C., V. A. Hospital, Washington, D. C., No. 013991) was well until August 1963 when dyspnea on exertion and a dry nonproductive cough developed. A chest roentgenogram revealed abnormalities and he was referred to the hospital. Positive findings in the system review included flashing lights in the right eye for several months and a 45 pound weight gain. The patient had recently noted an increase in breast size and a decrease in testicular size. He had been married twelve years and had no children. He shaved only twice a week. On physical examination his height was 72 inches, arm span 82 inches, and lower segment measurement 39 inches. There was bilateral parotid swelling and prominence of the lacrimal glands. Gynecomastia was quite marked. Acute anterior uveitis was present in the right eye. Coarse rales were present in the lower fields of both lungs. The liver was palpable 2 fingerbreadths below the right costal margin. A sparsity of body hair was noted. There was a female escutcheon. The penis was of normal size but the testes were pea-sized and firm. The prostate was small. The hematocrit was 44 per cent and the white blood cell count 7,300 cells per cu. mm., with a normal differential. Chemical analysis of the blood showed a fasting blood sugar of 80 mg. per cent; total protein 7.9 gm. per cent, with 4.4 gm. per cent albumin and 3.5 gm. per cent globulin; serum glutamic oxaloacetic

FIG. 2. Case II. Chest film demonstrating infiltrations

diffuse nodular

and hilar adenopathy.

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A. Results

I

of Verrtilatory

Test.\ I

Case I Data ~_

895

et al.

Case II

PI Predicted

Actual

5.35

2.42

~~~~~. ~____~~_

Vital capacity (L.). Timed vital capacity (%) lsec..... 2sec...... .._.... 3sec............................. Maximum voluntary ventilation (I../min.). ._. ._. _.

I

Predicted _~__.___/ 5.10

Actual ~~~.~~~~~. ~~~~ _~~~.._ 2.10

: I

82 94 97

82 89 94

82 94 97

/

76 91 100

185

95

172

(

55

B. Results of Arterial Blood Gas Analysis CASE II

CaseI Data

Rest, room air breathing. Rest, 100% oxygen breathing. Exercise, room air breathing. Voluntary hyperventilation.

7.43 7.43 7.38 7.63

47 49 47 24

72 554 72 107

PH

PC02 (mm. H8)

PO2 (mm. Hg)

7.40 7.40 7.41 7.58

51 49 51 31

70 500 69 107

Response to 5% COt inhalation1 (L./min./mm. Hg pCOz) (A;a201>

transaminase

0.481

45

units;

alkaline

phosphatase

/

4.6

Bodansky units; and cholesterol 196 mg. per cent. The bromsulfalein excretion test showed retention of 23.5 per cent at 45 minutes, The 24-hour 1131uptake was 37 per cent and the protein-bound iodine 7.6 pg. per cent. The baseline 17-hydroxysteroid excretion was normal as were the ACTH stimulation and metopirone test results. The 24-hour urinary gonadotropin excretion was more than 5 mouse units and less than 50 units per 24 hours. Biopsy specimens of the liver, left scalene lymph node and bronchus in the lower lobe of the right lung revealed noncaseating granulomas. A biopsy specimen of the right gastrocnemius muscle showed normal striated muscle. A biopsy specimen of the right testicle did not reveal any evidence of spermatogenesis or marked Leydig cell hyperplasia consistent with Klinefelter’s syndrome. Smears of the buccal mucosa showed 6 to 8 per cent of the cells contained a single chromatin body at the nuclear membrane. A chromosome study demonstrated an XXY pattern. A chest roentgenogram indicated diffuse involvement of both lungs with 1 to 3 mm. nodular densities and the hilar regions were markedly enlarged. (Fig 2.) The electrocardiogram VOL.

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/

/

was normal. An x-ray series of the skull did not reveal any abnormalities. Spinal fluid pressure, cell count, sugar and protein were all normal as was an electroencephalogram. The Wechsler adult intelligence scale revealed an I.Q. of 52. The results of the pulmonary function tests are recorded in Table I. Because of extensive sarcoidosis the patient was given corticosteroids. Repeat chest films obtained seven months later revealed complete clearing of the nodular densities in the lung, however alveolar hypoventilation persisted. Comment: Ventilatory function tests demonstrated primarily a restrictive abnormality. Arterial blood gas analysis revealed moderate hypoxemia, alveolar hypoventilation and compensated respiratory acidosis. There was no significant change in pCOs during exercise or high oxygen breathing. The ventilatory response to carbon dioxide inhalation was half of normal. However, voluntary hyperventilation lowered the pCOz by 20 mm. Hg. These findings suggest a primary abnormality in respiratory

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Hypoventilation-Daum

FIG. 3. Drawing of brain stem showing proximity to bilateral, paired respiratory centers (expiratory,

regulation rather than the lungs or thorax.

a mechanical

defect

of

COMMENTS

The finding of alveolar hypoventilation caused by central nervous system involvement in these two patients with sarcoidosis was unexpected. The pulmonary lesions which they demonstrated were neither of the type nor extent which would be expected to cause hypoventilation, but rather hyperventilation. Therefore, to determine the cause of hypoventilation additional studies were performed. Ventilatory tests revealed some restrictive impairment in both patients. Both showed a reduced ventilatory response to the inhalation of carbon dioxide. The normal response is a rise of 1.5 L. per minute or more in minute volume for each millimeter of mercury rise in pCOz. To rule out a pulmonary or thoracic cause for the impaired response to carbon dioxide inhalation both patients were asked to hyperventilate voluntarily. They were able to lower pCOz considerably by this maneuver, suggesting a central defect in respiratory regulation of their as a cause alveolar hypoventilation. These patients should not be classified as

et al.

of median eminence (M. E.) E. C., and inspiratory, I.C.).

examples of the primary hypoventilation syndrome [I]. The clinical features of this syndrome include easy fatigability, somnolence, cyanosis, polycythemia, an abnormal electrocardiogram suggesting right ventricular preponderance, usually cardiomegaly, little or no dyspnea and carbon dioxide retention without an obvious cause. In the patients described herein neither are all the clinical criteria for this diagnosis fulfilled nor is the cause of their hypoventilation unexplained. It is postulated that a sarcoid lesion or lesions located in the region of the hypothalamus and/or medulla altered the of the respiratory regulating responsiveness mechanism. Since the anatomic location of these suspected lesions cannot be proved except by exploratory craniotomy or autopsy, the diagnosis remains a clinical one. However, the coincidental finding of pituitary insufficiency in one patient with alveolar hypoventilation (J. L.) strongly suggests a lesion in the region of the hypothalamus. It has been established that respiration is not controlled by a single sharply defined respiratory center [2]. Central respiratory regulating neurons are found in the cerebral hemispheres, in the ponS, in the medullary reticular formation AMERICAN

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and the superficial regions of the brain stem near the lateral margins of the fourth ventricle [.3]. It has been shown by brain transections that no characteristic respiratory effects occur until the anterior border of the pons is reached. The centers responsible for automatic adjustment of respiration to metabolic requirements are located in the pons and upper two thirds of the medulla. Control of the spontaneous rhythmic respiratory act appears to be located within the medulla itself since respiratory rhythmicity continues even when the medulla is deprived of connections with higher centers or with the afferent fibers in the vagus, glossopharyngeal or auditory nerves. The median eminence, which is important in pituitary function, is situated in the vicinity of the medullary inspiratory centers. (Fig. 3.) In this region are also located the inferior reticular nucleus and the expiratory centers, which are dorsal to the inspiratory centers. A lesion in this area could result in both pituitary and respiratory dysfunction. Sarcoid lesions located in other areas of the central nervous system were not apparent in either of these patients. Such involvement might include localizing signs of a cerebral tumor, evidence of diffuse leptomeningitis or lesions involving the cranial nerves. Lesions of these types are usually associated with increased concentrations of protein in the spinal fluid. The cerebrospinal fluid and electroencephalograms were normal in both patients. Although alveolar hypoventilation has not been reported, numerous cases of pituitary insufficiency due to central nervous system sarcoidosis have been described [4-141. Recent work in the field of neuroendocrinology [15] has defined areas in the hypothalmus which have been designated as endocrine regulation areas. The median eminence, which is located in the area of the medullary inspiratory center (Fig. 3), acts as a neural gland whose secretions are liberated into the hypophyseal-portal circulation and regulate anterior lobe cells. The hypothalamus, therefore, may be the factory for pituitary hormones and the pituitary gland a mere storehouse. Anterior lobe insufficiency due to sarcoidosis is usually preceded by clinical manifestations of diabetes insipidus. In anterior pituitary insufficiency there is usually a sequential loss of first the gonadotropic followed by the thyrotropic and lastly adrenotropic activity. VOL.

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Patient J. L. demonstrated loss of gonadotropic and thyrotropic function. The symptoms of decreased libido, decreased facial hair and progressive decrease in testicular size correlated well with the biopsy finding of bilateral testicular atrophy. Symptoms of cold intolerance were consistent with a radioactive iodine uptake of 10 per cent, and a normal TSH stimulation test implicates higher tropic release centers as the site of the deficiency. The metopirone and ACTH stimulation tests were both normal, indicating normal adrenotropic and adrenal cortical activity. SUMMARY

Two patients with sarcoidosis and evidence of central nervous system involvement are described. Both had alveolar hypoventilation on a central basis. Although the exact location of the lesion cannot be proved, the association of pituitary insufficiency in one of the patients suggests sarcoid involvement of the medullary-hypothalamic area. REFERENCES 1. RODMAN, T., RESNICK, E., BERKOWVZ, I)., FENNELLY, J. and OLIVIA, J. Alveolar hypovcntila-

tion due to involvement of the respiratory center by obscure disease of the central nervous system. Am. J. Med., 32: 208, 1963. 2. BARD, P. Medical Physiology, 11th ed., p. 614 St. Louis, 1961. C. V. Mosby Co. 3. MITCHELL, R. A., MASSION, W., CAREM, C. T. and SEVERINGHAUS,J. W. Fourth ventricle respiratory chemosensitivity and the area postrema. I:ed.Pm., 19: 374, 1960. 4. PENNELL, W. H. Boeck’s sarcoid with involvement of the central nervous system. Arch. Neural. & Psych&, 66: 728, 1951. 5. TILLGREN, J. Diabetes insipidus as a symptom of Schaumann’s disease. Brit. J. Dermat., 47: 223, 1935. 6. KRAUS, E. J. Sarcoidosis (Boeck-Besnier-Schaumann disease) as a cause of pituitary syndrome. J. Lab. & Clin. Med., 28: 140, 1942-1943. 7. GLASS, S. J. and DAVIS, S. Granuloma of the pituitary associated with panhypopituitarism. J. Clin. Endocrinol., 4: 489, 1944. 8. BARBER, H. N. Benign lymphogranuloma of Schaumann with apparent involvement of the anterior pituitary. P&-Roy. Sm. Med., 39: 92, 1945. 9. BLEISCH. U. R. and ROBBINS. S. L. Sarcoid-like granuioma of the pituitary gland. Arch. Znt. lzilfd., 89 : 877, 1952. 10. LONGCOPE, W. T. and FREIMAN, D. G. A study of sarcoidosis: based on a combined investigation of 160 cases including 30 autopsies from the John Hopkins Hospital and Massachusetts General Hospital. Medicine, 31: 1, 1952. 11. ASZKANAZY, C. L. Sarcoidosis of the central nervous system. J. Neuropath. & Exper. .$~eurol., 11 : 392,

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12. OWEN, T. K. and HENNEMAN, J. Diffuse sarcoidosis associated with hypopituitarism failure. &it.

and terminal renal

M. J., 2: 1141, 1954.

13. JACKSON, A. and HOOD, T. R. Sarcoidosis with involvement of the pituitary gland. Ann. ht. Med., 49: 467, 1958.

et al.

14. SELENKNOW, H. A., TYLER, H. R., MATSON, D. D. and NELSON, D. M. Hypopituitarism due to hypothalamic sarcoidosis. Am. J. M. SC., 238: 456, 1959.

15. REICHLEIN, S. Neuroendocrinology. Med., 269: 1182. 1963.

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