A syndrome of periodic hypothalamic discharge

A Syndrome

of Periodic

Hypothalamic

Discharge* SHELDON

M.

WOLFF,

M.D., RICHARD

C.

and RONALD

ADLER, H.

M.D.,?

THOMPSON,

ELSWORTH

R.

BUSKIRK,

PH.D.$

PH.D.

Bethesda, Maryland

L

ESIONS, most frequently neoplasms, in and around the hypothalamus have been associated with a variety of endocrinopathies [Z-5]. Precocious puberty or hypogonadism are the ones most commonly noted, but panhypopituitarism with secondary adrenal insufficiency is not infrequently observed. Hyperadrenocorticism with histologic changes of the hypothalamus has also been reported [S]. Cyclic production and release of hormones is characteristic of endocrine regulation of physiologic control mechanisms. These cycles, in the absence of an endocrinopathy that disturbs a normal cycle, may be readily apparent, as is reported herein. Neurologic disease with hypothalamic lesions has been observed to be recurrent [7j but is usually either constant or progressive. It is, therefore, of considerable interest to describe a disease state involving a suspected hypothalamic lesion together with periodic and augmented release of corticotrophin and adrenal cortical hormones. The case presented herein probably involves a distinct aberration in the hypothalamic-pituitary-adrenal axis characterized by periodic release of corticotrophin and adrenal cortical hormones in association with a distinct and recurrent group of clinical signs and symptoms. CASE REPORT A fourteen year old boy of Greek-German parentage was admitted to the clinical service of the National Institute of Allergy and Infectious Diseases in August 1961 for study of his recurrent fever. He was the product of a prolonged labor and high forceps

delivery. Until age five he had recurrent bronchiolitis and multiple infections of the upper portion of the respiratory tract which were extensively investigated at age two with cultures, roentgenograms and bronchoscopy. All yielded negative results. Frequent episodes of nausea, vomiting and fever were noted during infancy and early childhood and were usually ascribed to viral gastroenteritis. He was thin until six years of age but then rapidly became obese. At the age of six he began to have recurrent episodes of nausea, vomiting, fever, mental depression and marked weight loss, lasting three to five days and recurring irregularly every one and a half to three months. Although the patient denied pain, the family stated that he had gritted his teeth so much that his four lower front teeth loosened and had to be removed. During the intervals between attacks he rapidly regained the lost weight, attended school and was thought to be a normal child. Four years prior to admission to the National Institutes of Health the episodes became periodic and recurred every three weeks. The periodicity was so striking that the family made no social or other plans for the anticipated time of the attacks. The patient is the son of a marine officer, and he has been hospitalized on many occasions in both military and civilian hospitals for his illness. On two occasions he was admitted to service hospitals because of moderate electrolyte imbalance. Six years prior to admission chlorpromazine was given, with suppression of the disease for four months. Many other therapeutic trials were unsuccessful. Two years before admission a pneumoencephalogram demonstrated cortical atrophy and slight ventricular dilatation. One year later an electroencephalogram was interpreted as normal. He was given barbiturates and diphenylhydantoin in sufficient dosage to produce ataxia without change in his clinical state. His intelligence quotient two years prior to admis-

* From the Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, and the Metabolic Diseases Branch, National Institute of Arthritis and Metabolic Diseases, National Institutes of Health, Bethesda, Maryland. Part of this manuscript was presented at the meeting of the American Federation for Clinical Research, Atlantic City, New Jersey, April 29, 1962 T71. Manuscript received Mav 15. 1963. t Present address:‘Department’of Pediat&s, Johns-Hopkins University School of Medicine, Baltimore, Maryland. $ Present address: Human Performance Research Laboratory, Pennsylvania State University, University Park, Pennsylvania. 956

AMERICAN

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Periodic Hypothalamic

Discharge-

650’

0

2b

957

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VI 40

$0

&

loo HOSPITAL

GO

I40

160

DAYS

FIG. 2. Clinical features during the first admission. Note that with each attack there was hypertension, fever and weight loss. PEG is pneumoencephalogram and was associated with fever only.

FIN. 1. Distribution of fat of the patient, a fourteen year old boy, on admission to the National Institutes of Health. sion was reported as 110. At that time a diagnosis of schizophrenia was suggested, and he began two years of intensive psychotherapy. His family took part in the program for one year. No change occurred in the pattern of his disease despite these psychotherapeutic attempts. There was no history of a similar illness in his family although his maternal grandmother had been institutionalized in Greece for an alleged psychosis. One week prior to admission to the National Institutes of Health the patient was admitted to the National Naval Medical Center with a typical episode of fever, depression, nausea and constant vomiting. A gastrointestinal series on the night of admission demonstrated “pylorospasm with marked The episode lasted five days. A gastric dilatation.” repeat gastrointestinal series when he was afebrile was interpreted as being within normal limits. On admission to the National Institutes of Health, physical examination revealed an obese young boy in no distress. The obesity was slightly centripetal in VOL.

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distribution (Fig. I), but there was no “buffalo hump,” and the contour of the supraclavicular areas was normal in appearance. There were purple striae over the abdomen and buttocks and beginning pubertal hair growth. The blood pressure, pulse, temperature and respirations were all in the normal range. Both breasts were pendulous, but no mammary tissue was palpable. His genitalia were small but thought to be consistent with early adolescent development in an obese male subject. The remainder of the complete physical examination revealed no additional abnormalities. During the first admission to the hospital he had seven episodes which usually began in the morning. (Fig. 2.) Each attack lasted four to five days and was separated by periods of from nineteen to twenty-five days. On one occasion a pneumoencephalogram induced a fever which temporarily interrupted his periodicity; his regular cycle was re-established after three days. Each episode was characterized by marked mental withdrawal and depression, but he was always oriented as to time and place. He had marked nausea, vomiting and thirst. At times he was noted to become flushed and was described as having “facial plethora.” He perspired normally and had no difficulty in lacrimation. On one occasion he had an erythemaeruption over his trunk. He tous, “pityriasis-like” always denied abdominal pain and never had diarrhea. The rectal temperature began to rise early in each episode and usually reached a high of 39Oc. (Fig. 2.) However, on one occasion it was 40”~. Rectal temperature began to decrease during the third day and was usually normal by the fifth day.

958

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Hypertension was a constant and striking feature of each episode. Maximum blood pressures attained were 160 mm. Hg systolic and 120 mm. Hg diastolic. During one episode he had profound orthostatic hypotension with disappearance of blood pressure and marked elevation in pulse rate and presyncope upon assuming an upright position. During an attack he might have a sustained tachycardia with pulse rate as high as 140 beats per minute. His usual weight before an attack was 75 kg. However, during an attack he would rapidly lose from 5 to 10 kg. of body weight. During some of the episodes he was allowed no fluids orally and was under constant nursing surveillance so that adequate measurements of fluid balance could be made. A twelve hour gastric secretion collection at the onset of an episode yielded a total volume of 1,320 ml. as compared to 150 ml. during an afebrile period. Almost all of the weight loss during the episodes could be accounted for by loss of water due to vomiting, urination and sweating. During the episodes a leukocytosis was observed, the highest white blood cell counts being recorded early in the attack; the maximum on one occasion was 17,750 per cu. mm. The differential white blood cell count always showed a marked “shift to the left” during the episode. On the first day of one episode 79 per cent polymorphonuclear leukocytes were seen. The erythrocyte sedimentation rate (Westergren) usually was within normal limits even when he was ill, with an occasional slight elevation during an attack to 18 to 20 mm. per hour. There were no changes in hematocrit, hemoglobin or platelet counts during the episodes. Multiple urinalyses were within normal limits. The specific gravity, when afebrile, averaged about 1.010, but during an episode he would concentrate to a maximum of 1.033. During a Fishberg concentration test, the maximum specific gravity reached 1.033. The blood urea nitrogen was 8 mg. per cent when he was afebrile, but during one febrile episode it reached a maximum of 18 mg. per cent (normal in this laboratory up to 22 mg. per cent) although his usual febrile level was below 15 mg. per cent. The following were within normal limits at all times: serum calcium, phosphorus, alkaline phosphatase, total proteins, amylase and liver function test results. Urinary alpha amino nitrogen [S] (maximum of 187.2 mg. per twenty-four hours) and serial urinary 5-hydroxyindole acetic acid [9] were likewise normal, with no change during the episode. Chromatograms of the urine for coproporpyrins, uroporphyrins and porphrobilinogen were negative on three different occasions. Results of a n-xylose tolerance test, serum vitamin A and carotene determinations were within normal limits. Cultures of blood, urine and cerebral spinal fluid revealed no growth (including fungus cultures). Multiple stool examinations for blood, ova and parasites revealed Endolimax nana on one occasion.

Discharge--

WC@ et at.

Serum Venereal Disease Research Laboratory test results, cold agglutinins, salmonella, brucella and pasteurella tularensis agglutinins were negative. Serum Coombs’ test result, cryoglobulin test result, urinary urobilinogen and red blood cell osmotic fragilities, all carried out when the patient was febrile and afebrile, demonstrated no abnormalities. Lupus erythematosus preparations, Fz and deoxyribose nucleic acid bentonite flocculation test results were repeatedly negative. No skin reactivity was noted to intermediate purified protein derivative, coccidioidin, blastomycin and histoplasmin skin tests. The results of an immunochemical test [70] demonstrated normal levels of serum ceruloplasmin. When afebrile, the serum haptoglobin was 77 mg. per cent and during an episode 116 mg. per cent. Plasma fibrinogen levels were within normal limits when the patient was afebrile and slightly elevated (up to 550 mg. per cent) when febrile (normal up to 400 mg. per cent). Electrocardiograms were normal. Chest roentgenograms, oral cholecystograms, barium enema, intravenous pyelogram and skull roentgenograms were all within normal limits. Some demineralization of bone was noted in these studies. Gastrointestinal series submitted from the National Naval Medical Center were read as demonstrating a markedly dilated stomach with spasm of the pylorus during an attack. Six days later, when the patient was afebrile, results of the gastrointestinal series was thought to be within normal limits. Serum sodium, potassium and chloride levels were measured on a number of nonconsecutive days when the patient was afebrile and serially through some episodes. On occasion in the middle of an attack, the serum potassium level would fall to a low of 3 mEq. per L. while the carbon dioxide combining power reached 36 mEq. per L. at a corresponding time. Serum sodium and chloride were always within normal limits. When the patient was afebrile, an overnight twelve hour gastric aspiration resulted in a total acidity of 27 degrees, no free acid, sodium of 95 mEq. per L., potassium of 10.4 mEq. per L. and chloride of 113 mEq. per L. in a total volume of 150 ml. Beginning at the onset of an episode, twelve hour gastric aspiration yielded a total volume of 1,320 ml., a total acid of 12 degrees, no free acid, sodium of 68 mEq. per L., potassium 18 mEq. per L. and a chloride of 73 mEq. per L. In respect to serum lipids (Table I) there was usually a rise in total cholesterol [77] during an episode, which was accounted for almost entirely by an increase in the esterified fraction. Triglycerides [72] decreased during each episode while the phospholipids [ 731 and plasma free fatty acids increased [ 741. The urinary excretion of amines (Table II) was studied and 3-methoxy-4-hydroxymandelic acid [ 751 was normal when the patient was afebrile but elevated when he was febrile. Urinary dopamine level AMERICAN

JOURNAL

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Periodic TABLE SERUM

Lipid

1 LIPIDS

During

Total cholesterol (mg. %) Free cholesterol (mg. %) Phospholipids (mg. %). Triglycerides (mg. X) Free fatty acid (plasma, mEq./ml.).

.

Hypothalamic

Attack

Before

T

220 .

Attac!.

2;: 6S 1.35-0.96

I

0.31

-I

197 52 209 159

0.34

[76] was slightly but not abnormally elevated. Both urinary epinephrine and norepinephrine values [ 771 were elevated during the episodes. Normetanephrine and metanephrine [78] were within normal limits. The intravenous infusion of 0.025 mg. of histamine when the patient was normotensive did not elevate the blood pressure. When he was hypertensive during an episode, the infusion of 5 mg. of Regitine@ intravenously did not lower the blood pressure. Multiple neurologic examinations were within normal limits. Ophthalmologic examination, including tests of visual fields, did not demonstrate any abnormalities. Routine skull roentgenograms were normal when the patient was afebrile and febrile. Multiple lumbar punctures, both when the patient was well and when ill, failed to demonstrate any abnormalities, including quantitative sugar, protein, chlorides and serologic test results. Opening pressure was always normal, and only two white blood cells were seen on one occasion. Smear, bacterial and fungus cultures revealed no microorganisms. Fractional pneumoencephalograms with labial laminograms showed no shit of the ventricles, however, the left lateral ventricle was somewhat larger than the right. There was bilateral prominence of the subarachnoid pathways. (Fig. 3.) These findings were thought to be consistent with some dilatation of the left lateral ventricle and cortical atrophy. Comparison of these films with the pneumoencephalograms made elsewhere eighteen months previously demonstrated that there had been no change or progression. Patients with periodic fever frequently indicate symptomatic sensations that they interpret as poor cold tolerance. Some insist that exposure to cold will precipitate a febrile episode, In view of this background and the abnormal pneumoencephalogram, a systematic evaluation of several aspects of the patient’s thermoregulation was made. An open-system hood method was employed to measure oxygen consumption. The volume of air drawn through the hood, including the subject’s expired air, was measured continually with a large wet-test air meter. An aliquot of the total stream was diverted to the following: (1) a modified Beckman F-3 analyzer for oxygen; and (2) a modified Baird (infrared) plant stream analyzer for carbon dioxide analysis. This system has been described in more detail elsewhere [79]. Rectal temperature was measured with a flexible thermistor VOL.

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catheter and an appropriate resistance bridge. Skin temperatures were measured with a Stoll-Hardy dermal radiometer. Body fat content was determined from skinfold measurements made with a modified vernier caliper [ZU]. Oxygen consumption was calculated from the appropriate gas concentrations and wet-test meter readings and corrected to conditions of standard temperature and pressure, dry (STPD). Mean weight skin temperature was calculated using the following weight factors: 0.12, forehead; 0.18, chest; 0.16, abdomen; 0.08, upper part of the arm; 0.06, forearm; 0.03, fingers; 0.18, thigh; 0.14, calf; 0.05, toes. Insulation of body = ‘c. per kcal. per (M2. hour) = Ta - MWST per 0.76 M when Tn = rectal temperature, MWST = mean weight skin temperature and M = heat production in kcal. per (M2. hour) and 0.76 is a constant correction for evaporative heat loss. Skin conductance = kcal. per (M2. hour) per “c. = M ~/TR - MWST when 5[kcal. per (M2. hour)] is a constant for respiratory plus evaporaative heat loss. Heat debt = kcal. = (MBTt, MBTo,~~)(O.~~ X kg. body weight) when MBT = mean body temperature; to = start of the exposure, time zero; trzo = time, 120 minutes; MBT = 0.33 MWST + 0.67 Ta; 0.83 = the average specific heat of body tissue. Figure 4 shows the metabolic response (oxygen consumption) during the course of three different exposures to cold. Considerable variability is apparent between the responses that are illustrated. For example, the earliest and most sustained response occurred on September 12, 1961, which was only two days after termination of fever. Since the exposure on September 12 was at 15.5’c., the warmest used, the pronounced metabolic activity was not only surprising but proved to be in excess of 2 standard deviations (S.D.) above the response normally expected at 10”~. for a normal subject with comparable body fat content. On October 31, 1961, another interesting feature was noted. A prolonged bout of shivering took place which lasted approxiTABLE CHEMICAL

AND

ADRENOMEDULLARY

_ I DURING

Date

Urine Volume

Norepinephrine

(cc.1

(PP.)

g/25/61 9/29/61

Normaivaluesat24hr

Non: slightly Regitinc

From elevated, infusion

900 500

II

PHYSIOLOGIC

AN

REFLECTIONS

OF

FUNCTION ATTACK

Normetanephrine and Metanephrine

Epinephrine (pg.1

VMA (me.1

(mg.) __~_

120 89

34 28

10-80

O-20

0.77 . <1.3

7.8 7.0 --. 2-6

-

September 9 to September 29 dopamine level histamine provocative test results were negative, while the patient was hypertensive was negative.

was and

960

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Hypothalamic

Discharge-

Wolf et al.

FIG. 3. Lateral view of pneumocepl~alogr~In to show prominrncc of the subarachnoid pathways.

JS 8 33350-

_/’

,,“+PsD /’

MINUTES

FIG. 4. Change in oxygen consumption (AVo,) and rectal temperature (ATR) during two hours exposure to an ambient air temperature of 10” or 15.5”~. Only shorts were worn for clothing. Arrows indicate where the onset of shivering occurred. Since each cold exposure took place on a different day, zero or reference Vo, is indicated for each exposure. Rectal temperature was approximately 37.7”~. for all exposures. On August 22,1962, the patient was being treated with dexamethasone.

FIG. 5. Average heat production at two hours and heat debt accumulated in two hours in relation to per cent body fat when the patient was exposed to air temperatures of 10” or 15.5”~. The solid regression lines and the dashed lines, representing plus and minus 2 S.D., were established from previous experiments on normal subjects [27]. The plus and minus term in each regression equation represents the standard error of the slope. AMERICAN

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mately thirty minutes. Another bout of shivering failed to generate for a full fifteen minutes, then a second bout started. This phenomenon of pronounced shivering followed by complete cessation of shivering and a return to resting metabolism has not been seen in normal male subjects. Following treatment with dexamethasone shivering failed to occur, and no metabolic response was noted during the two hours of exposure to 10’~. For normal persons as obese as the patient, this response falls within the normal range. (Fig. 5.) On October 31 a marked decrease in core temperature, as represented by rectal temperature, was observed. On this day, metabolic activity followed the cyclic pattern mentioned in the preceding paragraph. A fall in core temperature of this rapidity and magnitude has never been observed in a normal subject, and it resembles the poikilothermic response seen in a dog with a surgically induced hypothalamic lesion. Review of the heat exchange measurements indicates a periodic variability in reaction to the cold exposure which exceeded normal variation. In addition, several atypical events occurred such as shivering with abnormal periodicity, a striking fall in rectal temperature on only one occasion and a marked metabolic response in the warmest of the two environments. Glucose metabolism was studied on two days when the patient was afebrile and febrile; 100 gm. of glucose was given orally and blood drawn at appropriate intervals. The response on both occasions revealed “flat” curves; the maximum values were 96 mg. per cent at thirty minutes and 93 mg. per cent at one hour, respectively. Early in two episodes, when the patient was fasting, he was noted to be hyperglycemic (168 and 164 mg. per cent). Therefore, 35 gm. of glucose was administered intravenously, while he was afebrile and again at the onset of an episode. Results of the latter test were interpreted as being compatible with a diabetic type response with the values at thirty and sixty minutes being 270 and 220 mg. per cent, respectively. (When the patient was afebrile these values were 120 and 61 mg. per cent.) Buccal mucosa smears stained with orcein were “chromatin negative” and thus compatible with a male sex pattern. Cultures of peripheral white blood cells revealed a normal number and appearance of chromosomes. ENDOCRINE

STUDIES

Serum protein-bound iodine and butanolextractable iodine levels could not be determined due to recently administered iodinated contrast media for roentgenography. Plasma thyrotrophin levels [ZZ] were within normal limits (8 milliunits per cent) both during and VOL.

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DEXAMETHASONE

i-1

8

L12

Y Y E

LlLLlLLuuLLLl/-IL-l-ll 2

4

6

8

IO 12

I 2

4

6

8

IO 12 14 16

DAYS FIG. 6. Urinary electrolyte determinations which illustrate the decrease in sodium excretion during the episode and the increase in potassium excretion with a diminution as the episode progresses. Total creatinine excretion did not vary greatly, since volume decreased during the attacks. Aldosterone levels (urinary excretion values) for control days were 4.6 pg. per 24’ and 4.2 pg. per 24”, during early attack 27.6 pg. per 24” and during late attack 2.7 pg. per 24”.

between episodes. Tests for urinary excretion of gonadotrophin [23] yielded positive results at 12 mouse units and negative results at 50 mouse units, when the patient was well and positive results at 12 mouse units and negative results at 24 mouse units when he was febrile. As previously noted, on one occasion the patient had slight hypokalemia and alkalosis. Hypernatremia or hyperchloremia was never noted, even though these parameters were followed daily during some episodes. Urinary excretion of creatinine, measured daily through a number of afebrile and febrile periods, was normal. Sodium excretion immediately decreased (Fig. 6) and almost disappeared with the onset of the febrile period and did not return to normal levels until the end of the period. However, he had a kaliuresis (Fig. 6) during the initial few days of the episode.

Periodic

Hypothalamic

DAY-3

FIG. 7. Urinary excretion of steroids during the first Note the hyperresponsiveness to ACTH admission. infusion and the suppression of excretion with 2 mg. of dexamethasone per day when the patient was afebrile. The elevation of steroid excretion during the episodes was associated with a lack of suppression when both 2 mg. and 8 mg. were given intramuscularly for two days each. The response to SU-4885 represents a “normal pituitary reserve.” The PEG (pneumoencephalogram) was associated with a slight elevation of urinary 17-ketosteroids and fever.

Urinary and serum osmolarities [Zd] were followed daily through an afebrile and a febrile period. The serum averaged 288 mOsm. per L. when the patient was well and during the attack reached a maximum of 300 mOsm. per L. The urinary values averaged 340 mOsm. per L. when he was well and attained a maximum of 1,090 mOsm. per L. (average of 850) during the episode. Urinary excretion of aldosterone [25] revealed a normal excretion of 4.6 and 4.2 pg. per twenty-four hours when the patient was afebrile. Elevated levels of 27.6 pg. were found during the first day of an episode, but excretion fell to low levels of 2.7 pg. per twenty-four hours by the fourth day. The aldosterone secretion rate [ZS] of 51 pg. per twenty-four hours when he was well was within normal limits as was the secretion rate of 65 pg. per twenty-four hours following an exogenously administered dose of endotoxin. When the patient was afebrile, there was a normal excretion of 17-hydroxycorticoids [27] and 17-ketosteroids [28]. However, during the episodes there was an abrupt increase in the twenty-four hour excretion of both on the first day; the 17-hydroxycorticoid level rose to a high of 85 mg. and the 17-ketosteroids to a high of 66 mg. (Fig. 7.) The rise in the urinary steroid

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Wolf et al.

level began on the first day of the attack and then gradually decreased but remained elevated through the last day of an episode. On the day following an episode the urinary steroids were usually within the normal limits. When the patient was afebrile, the infusion of 50 units of ACTH in 1 L. of 5 per cent dextrose in water for eight hours was accompanied by an accentuated response in the urinary steroids. This test was repeated, and the excretion of 17-hydroxycorticoids was 67.2 and 63.1 mg. per day, of 17-ketosteroids 23.3 and 15.7 mg. per day. Following nine months of exogenous dexamethasone administration (second admission) the test was repeated, and the following results were obtained: The day prior to the infusion the excretion of 17-hydroxycorticoids totaled 2.1 mg., that of 17-ketosteroids was 5.4 mg.; however, on the day of the test the excretion was increased sevenfold with an excretion of 14 mg. per twenty-four hours (17-hydroxycorticoids) and 11.5 mg. per twentyfour hours (17-ketosteroids). W-4885 (2-methyl-l, 2bis-(3 pyridil)-l-propanone), 500 mg. every six hours orally over a period of forty-eight hours, demonstrated a “normal pituitary reserve” when the patient was afebrile [29]. This test was not performed when he was febrile. Paper chromatography of an extract of urine (febrile) revealed blue-tetrazolium reacting substance with the same relative mobility as that of tetrahydrocortisone and tetrahydrohydrocortisone. Plasma diurnal cortisol [27] levels (Table III) when the patient was afebrile were within normal limits. After nine months of exogenous dexamethasone administration the plasma cortisol levels (afebrile) were low, as expected. TABLE PLASMA

ACTH

Data

Plasma ACTH

(milliunits

%)

Plasma cortisol (gamma %) ... Noon ....................... Midnight. .................. Noon ....................... Midnight ................... * Dexamethasone

III

AND

CORTISOL

Normal

Before Attack

During Attack


0.48 0.38

0.79*

5-25

0* 1* 8.2 4.2

1.98*

9.57* 6.96* 6.09*

5.57*

therapy.

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During the episodes, however, despite continued administration of exogenous steroid, the plasma cortisol levels were elevated, over the levels (suppressed) when he was afebrile. When the patient was afebrile, the administration of 0.5 mg. of dexamethasone every six hours for forty-eight hours rapidly suppressed the urinary excretion of 17-hydroxycorticoids. (Fig. 7.) However, during an episode the administration of both 0.5 and 2 mg. of dexamethasone every six hours for forty-eight hours intramuscularly, did not suppress the urinary excretion of steroids (Fig. 7), suggesting an autonomous pituitary hypersecretion [30]. Plasma ACTH levels [31] determined on two occasions when the patient wasafebrile were 0.48 and 0.38 milliunits per cent (normal up to 0.5). (Table III.) Following eight months of exogenous dexamethasone therapy these studies were repeated during two episodes, and the results revealed elevated levels of 1.98 and 0.79 milliunits per cent. It is of interest that following a pneumoencephalogram he had fever for three days, which disrupted his usual periodicity. (Fig. 7.) During these three febrile days he did not have all the other manifestations of an episode. The only changes observed were a leukocytosis and a rise in his urinary 17-ketosteroid level to 16 mg. per twenty-four hours. (Fig. 7.) THERAPY

The rapid gain in weight prior to an episode, indicating water storage, together with the massive loss in water during an attack, suggested that perhaps in some undefined way excess water accumulation might play a role in the development of the patient’s illness. Therefore, therapy was initiated with 400 mg. of spironolactone and 1.5 gm. of chlorothiazide per day. Although this treatment delayed accumulation of body water until shortly prior to the next episode, he rapidly gained weight to his usual level before an attack and had an episode on schedule. Since the data accumulated demonstrated that cyclical hypersecretion of his adrenal cortex was intimately associated with his disease, possibly secondary to a hypothalamic or pituitary disturbance, it was decided to attempt to suppress the patient’s adrenocortical function exogenously. Therefore, he was given 4 mg. of dexamethasone a day orally when afebrile. Over a period of months the dose of dexamethasone VOL.

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was gradually reduced to 0.5 mg. every eight hours orally, and there were no further attacks for five and a half months. He then had a typical episode. The steroid therapy was continued, and at seven months he had to be readmitted because of two attacks separated by twenty days, with concomitant increase in urinary excretion of steroids. The attacks resembled those during the first admission, except as noted previously. Following the last attack the dose of dexamethasone was increased to 3 mg. a day, and there were no further episodes until nine weeks later when the dose had been decreased to 1.5 mg. a day. Each attack while he was receiving steroids was accompanied by an increase in urinary excretion of steroids even though the adrenal glands had been suppressed for months. Since 3 mg. of dexamethasone per day produced changes typical of Cushing’s syndrome, dexamethasone was not given for long term therapy; instead 1 mg. of reserpine per day was tried because of possible hypothalamic inhibition by this drug, while the dexamethasone was gradually reduced. On reserpine therapy, he remained asymptomatic for nine weeks and then had a typical episode, followed in two weeks by another. The reserpine therapy has, therefore, been discontinued, and other therapeutic trials will be undertaken. COMMENTS

In the literature a wide variety of clinical disorders have been classified as “periodic disease” [32]. During the past few years such diseases as familial Mediterranean fever [33] and etiocholanolone fever [34] have been separated from this general category into separate nosologic disorders. It has been our experience in the study of a group with these unusual recurrent fevers that extensive evaluation can lead to placement of some of these patients into well recognized disease categories [35]. Even so, the patient described herein would appear to represent a unique and hitherto unreported complex of symptoms and findings. The anterior portion of the pituitary gland (and thus release of corticotrophin) has been identified as being at least partially under control of the hypothalamus [36,37] through neurohumoral mechanisms. Mild histologic changes of the hypothalamus [6] have been found in four patients with Cushing’s syndrome, but in these instances the disease was constant and not periodic. In the vast majority of patients with

Periodic

Hypothalamic

hypothalamic disorders and abnormalities of corticotrophin release the resulting disorder is one of hyposecretion of corticotrophin. The past history of this patient suggests that his disease started early in life, perhaps even in infancy. The etiology of the central nervous system lesion may be secondary to a birth injury or even an undiagnosed infectious disease of early infancy. The long history and stability of the lesion as established by pneumoencephalograms would suggest that it is not a neoplastic lesion increasing in size, although a cystic malformation in the ventricular floor or region of the hypothalamus cannot be excluded. The studies in the metabolic chamber demonstrated that on one occasion his reactivity was almost poikilothermic and not unlike that of a dog with surgical ablation of a portion of the hypothalamus [38]. Indeed, the results obtained in the metabolic chamber suggest definite derangement of the thermoregulatory mechanism. Many of the clinical findings suggest that hyperadrenocortism of an intermittent type is playing a role in this patient’s illness; the psychic changes during the episode and the hypertension for example. One of the most striking features of the illness is its periodicity. The cycle seemed to be triggered not by environmental or exogenous changes but by some internal mechanism. It is inviting to postulate that with the accumulation of water before the febrile period, an increased intracerebral or ventricular pressure occurred which either triggered a sensitized hypothalamic area or activated a relatively quiescent lesion. Since all of the findings cannot be explained on the basis of excessive ACTH secretion and hyperadrenocorticism, it seems probable that other hypothalamic nuclei are involved in addition to those related to ACTH release. The fever could be explained on the basis of an elevated plasma unconjugated etiocholanolone; measurements of this steroid are currently being carried out. However, involvement of the thermoregulatory mechanisms in the hypothalamus by the primary lesion is probable. Recurrent fever has been reported in a young man with Gushing’s syndrome, but the periodicity and extent of the fever were not reported

WI.

The massive vomiting could be due to hypersecretion of the adrenomedullary amines, which can cause gastric dilatation [40] and result in vomiting. Since the studies suggest that the

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elevation in the amines was not of the magnitude seen in pheochromocytoma [47], we would suggest that this was secondary to the severe “stress” of the episode. The hypertension is more likely clue to hypercorticism than to elevations of the catecholamines. The change in plasma free fatty acid is probably secondary to the secretion of epinephrine [&I. The cause of the alterations of the serum triglycerides is not known. The marked granulocytosis may perhaps be due to increased secretion of cortisol [43] or etiocholanolone [a]. Fibrinogen has been reported not to rise with fever associated with central nervous system lesions [45]. Nevertheless, this may be the case in the patient described herein, and the fibrinogen elevation is merely a reflection of an “acute phase reactant” type of response. Failure to respond to the administration of large doses of anticonvulsants and the normal electroencephalograms suggests that this patient does not have an epileptiform disorder. The lack of mental retardation and absence of lacrimation abnormalities would seem to substantiate that this is not an aberrant form of the Riley-Day syndrome [&I. The marked change in glucose metabolism may be due to cortisol hypersecretion or may be part of the primary disorder. Fever, per se does not seem to alter glucose metabolism in the manner noted in this patient [35]. The normal secretion of both thyrotrophin and gonadotrophin would suggest that corticotrophin is the major hormone of the anterior part of the pituitary gland altered in this condition. The hypokalemia and alkalosis would appear also to be related to the hypersecretion of the adrenocortical hormones. The absence of hypernatremia and hyperchloremia and the patient’s ability to concentrate urine normally in the face of water deprivation suggests that the mechanism governing antidiuretic hormone secretion was not altered by the disease. The elevated urinary levels of aldosterone and the concomitant kaliuresis, with decrease in sodium excretion early in the episode, could be partially explained by hypersecretion of ACTH or perhaps to the massive loss of water and shift of fluid. The latter could also explain the lowering of the aldosterone excretion late in the episode. The levels of plasma ACTH, urinary 17-hydroxycorticoids and 17-ketosteroids reported herein have not been noted in other

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patients undergoing a maximal “stress.” The hyperresponsiveness of the adrenal cortex to ACTH, when the patient was afebrile, leads to the postulate that secondary to the frequent stimulus afforded by his disease the adrenal underwent compensatory functional glands hypertrophy. The failure of a daily dose of 8 mg. dexamethasone during episodes to suppress excretion of the metabolites of the adrenal cortex suggests that the lesion was “autonomous.” The demonstration of elevated plasma ACTH levels is interpreted to mean that the adrenal hyperfunction was not autonomous but that the lesion was either in the pituitary gland or higher in the central nervous system. Since chromatography of the urine revealed the 17-hydroxycorticoids to be qualitatively but not quantitatively “normal, ” it would appear that this disease is not secondary to a hydroxylation defect at the adrenocortical level. Suppression of the pituitary gland with high dose of exogenous steroid, when the patient was afebrile, led to disappearance of attacks, whereas lower doses allowed a relapse to occur. Therefore, one might conclude that the suppressive effect was dose-related. Increasing the dose again possibly suppressed the secretion of a corticotrophin releasing factor (since the lesion appears to be above the pituitary gland) or ACTH. Although it is also possible that dexamethasone had an “anti-inflammatory” efl’ect on the primary lesion responsible for the disease, we believe this to be unlikely. The fact that when the patient broke through the lower dose of steroids, had an elevated plasma ACTH and increased his steroid output, despite more than nine months of exogenous steroids in high dosage, would appear to confirm the postulate that the lesion is intimately related to the hypothalamic-pituitary-adrenal axis and is autonomous. The partial clinical response to reserpine therapy, a drug which can have effects on the hypothalamus, again strongly supports the concept that this disorder has its primary site in the hypothalamus. Although we have failed to find reports of similar disease complexes in the literature, two reports deserve special mention. The first, by Engel and Aring [47,48], described a seventeen year old boy (at the time of death) who had recurrent (not periodic) episodes clinically similar to those described herein but with abnormal neurologic findings. The triggering VOL.

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mechanism in their patient seemed to be emotional disturbance. The patient appeared to have hypogonadism and was of small stature, but no endocrine data were reported. The lesion was a cystic soft degeneration of the right lateral thalamus, the dorsomedial nucleus and the internal medullary lamina, but it did not appear to involve the hypothalamus. In 1958 Graham described five adolescent male subjects with periodic psychotic episodes [49] which he attributed to abnormalities of the diencephalon (“pituitary diencephalon”), perhaps secondary to organic intracerebral damage. The patients were all obese, underdeveloped and clinically hypogonad, although the latter manifestation was not investigated by appropriate laboratory tests. One of the patients had slight elevations in temperature during the episodes. endocrine studies were not Unfortunately, reported. There are examples in the literature [50,57] of “transient” Cushing’s syndrome. However, these latter cases were not periodic or cyclic. If the patient described herein does indeed represent a case of “periodic” Cushing’s syndrome, one must add to the list of possible mechanisms for the development of Cushing’s syndrome, a fixed hypothalamic lesion reflecting thermoregulatory dysfunction in addition to hyperadrenocorticism. SUMMARY

A fourteen year old boy is described who has had cyclical manifestations of nausea, vomiting, fever, emotional disturbance and marked weight change. Associated findings during the attacks were facial plethora, hypertension, abnormal glucose tolerance, elevated plasma ACTH and adrenal hyperfunction. The results of roentgenologic and physiologic studies are compatible with a lesion of the central nervous system, with periodic release of ACTH resulting in a clinical disease secondary to hyperadrenocorticism. The studies reported reaffirm the role of the hypothalamus in certain homeostatic mechanisms. The disease process was effectively suppressed with exogenous dexamethasone treatment during two periods of administration. Acknowledgment: We wish to thank the following investigators for studies carried out on the patient: L. Laster (o-xylose test, serum carotene and vitamin A), B. Blumberg (haptoglobin), N. R. Shulman (fibrinogen), D. Fredrickson

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(lipids), A. Sjoerdsma (urinary amines), J. Whang (chromosomes), R. Bates (thyrotrophin), G. Ross (gonadotrophin), G. Bryan (urine and serum osmolarities), B. Kliman (aldosterone), F. Bartter (plasma cortisol) and R. Ney (plasma ACTH). Capt. T. E. Cone, MC, USN, kindly referred this patient to us. The following doctors saw the patient and made many helpful suggestions: G. Bryan, B. Klirnan, G. Liddle and F. Bartter. Both Dr. Bartter and Dr. V. Knight read the manuscript and offered valuable criticisms. ADDENDUM

Following submission of this manuscript, the patient continued to have characteristic episodes of his disease. Therefore, in August 1963, he was begun on a regimen of 100 mg. chlorpromazine every six hours orally. This dosage was associated with somnolence, and it was reduced to 50 mg. every eight hours, which was followed by an abortive episode on August 22, 1963. The dose of chlorpromazine was then increased to 300 mg. every day and in October 1963, dextroamphetamine (15 mg. each morning) was added. Since late August 1963, he has had only one day of nausea and vomiting (in September 1963) and has been able to return to school on a full time basis.

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