Acta Padiat Scand 57: 153-156, 1968

CASE REPORT

HYPOTHALAMIC HYPERPHAGIA, OBESITY AND DISTURBED BEHAVIOUR IN ACUTE LEUKEMIA

Y . Barak and E. Liban

From the Departments of Pediatrics “A” and Pathology, Kaplarz Hospital, Rehovot, Israel

The incidence of leukemic involvement of the central nervous system has markedly increased since the advent of antileukemic chemotherapy, and is now about 20% of all leukemic patients (9), reaching approximately 30 % in children (6). Usually the clinical picture consists of headache, vomiting, meningeal signs, papilledema, cranial and peripheral nerve palsies. Rarely, peculiar symptoms such as hyperphagia, excessive weight gain and behaviour disturbances are observed. In the case of acute lymphatic leukemia presented herein, these were the only symptoms of severe ineningocerebral involvement, confirmed at autopsy.

CASE REPORT A boy, four year old, was admitted to the “Kaplan Hospital’’ in November 1964 because of enlarged cervical lymph nodes, which appeared one month prior to his admission.

On examination, enlarged lymph nodes in cervical, axillar and inguinal regions of both sides were found. The lymph nodes were fairly well defined, firm, not tender. The spleen and liver were palpated 3 cm below the costal margin.

Laboratory findings. Hemoglobin 13.9 g / 100 ml, leuco- cytrs count 53,000/mm7 with 10% neutrophils, 4% eosinophils, 20 % lymphocytes and 66 lymphoblasts. Platelet count 45,000/mm7. Smears of bone marrow were typical of acute lymphatic leukemia. Chest X-Ray re- vealed enlargement of mediastinal lymph nodes.

The course and main hematological data are presented in Fig. 1. Treatment was started with 6-mercaptopurine (2.5 mg/kg/day). The patient responded well and 3 weeks later the enlarged nodes had almost disappeared and the spleen and liver had receded to the costal margin: no leukemic cells were found in the blood films and the platelets had returned to normal.

11 - 682876 Acta Pzdiot Scand 57

At the beginning of January 1965, after a remission of one month, the patient was readmitted, showing signs of acute illness and petechiae and ecchymoses on the skin. Once again enlarged tender lymph nodes were found in the cervical, axillar and inguinal regions, together with hepatosplenomegaly. Blood count showed hemo- globin 13.6 g/100 ml, platelets 32,000 and leucocytes 246,000 with 45 % blasts. Treatment with hydrocortisone (10 mg/kg/day), 6-mercaptopurine (2.5 mg/kg/day) and chloramphenicol (750 mg/day) was instituted and within 2 weeks a second remission had been brought about. Treatment with hydrocortisone, 6-mercaptopurine and chlorarnphenicol was discontinued, and meticorten (2 mg/kg/day) was introduced.

At the end of January 1965 new changes appeared. Quite suddenly his appetite increased enormously into definite hyperphagia, eating 12 eggs a day and demanding tremendous servings. Excessive weight gain of about 4 kg in two weeks was noted, and he became obese. At the same time his behaviour became bizzare, alternating from periods of rage, restlessness and unreasonable crying to periods of frozen immobility. Neurological examination and fundoscopy were negative. Treatment with corti- costeroids was stopped few days later, being thought to be the cause of these new changes.

From the beginning of March, the patient’s condition deteriorated progressively. Edema of hands and legs and hydrothorax were noted, the latter leading t o marked respiratory distress. Repeated peripheral blood examina- tion remained however essentially normal. In spite of a further therapeutic trial with methotrexate (2 .5 mg/day) the child died 4’i2 months from the date of his first admission.

AUTOPSY FINDINGS At postmortem the typical picture of acute lymphatic leukemia was found, with generalized involvement of almost all internal organs. On macroscopic examination of the brain no changes were noted, the meninges were thin and translucent, the ventricles not dilated. On microscopic examination however, the subarachnoidal space was found filled by lymphocytes and lymphoblasts,

Acta Prediut Scand 57

154 Y . Baralc and E . Lihan

I I I 1 I I I I I J O l l l l7ll2 C l l / @ 5 1811 712 2112 313 I413 O L T L 4l i I lr .4

Fig. 1. Hemoglobin levels, leucocyte counts, weight curve and therapy given during the course of the disease. The dashed parts of the vertical lines represent the proportion of immature white blood cells. Diuril= Chlorothiazide; ME= methotrexate.

Fig. 2. Diffuse and perivascular leukemic infiltrations of the medial hypothalamus. (H. and E. x 50.)

Fig. 3 . Higher magnification of the same region, showing reduced number of nerve cells and their degenerative changes. (H. and E. x 176.)

Acta Pediat Scand 57

Acute leukemia 155

which penetrated into the adjacent brain tissue in the form of perivascular cuffings. These meningeal infiltra- tions were more extensive at the basal parts of the brain than in the region of the convexities. Diffuse intracerebral leukemic infiltrations were observed in the floor and lateral walls of the third ventricle involving the nuclei of the medial hypothalamus. In these hypothalamic nuclei many nerve cells disappeared and those that remained ievealed degenerative changes (Figs. 2 and 3). Diffuse leukemic infiltrations of various intensity were also seen in the region of the optic chiasm, the mammillary body, the pons and among the fibers of the trigeminal, facial and acoustic nerves.

DISCUSSION

The presence of unusual hyperphagia, marked obesity and behaviour disturbances in the present case was first thought to be related to the treat- ment with corticosteroids. The autopsy finding, however, of severe leukemic infiltration of the

hypothalamus indicates a more plausible mech- anism.

As is well known (2) , the hypothalamus pos- sesses the mechanism controlling feeding be- haviour; its more lateral area is designated as “feeding center”, the more medial as “satiety center”. These centers have probably the function of facilitating and inhibiting of feeding reflexes. Experimentally produced lesions in the lateral hypothalamus resulted in aphagia, and lesions in the medial hypothalamus, especially in or near the ventromedial nucleus, resulted in increased food intake and obesity. This hyperphagia was assumed to be a release-phenomenon brought about through destruction of an inhibitory mech- anism.

The development of this “hypothalamic syn- drome” in cases of acute lymphatic leukemia is apparently rare. Only 14 cases presenting this

Table I . “Hypothalamic syndrome” in cases of acute leukemia

Age Type of Treatment with Leukemic involvement Authors (years) Sex leukemia Stage corticosteroids Clinical features of C . N. S. (at autopsy)

Sansone 12 (1954) [81

De-Toni 2

Heaney et al., 5 (1954) MI

cited by Fertman (1954) PI

(1957) [lo] Sullivan 4

4

Allies 6 (1958) 111

(1960) [Ill

(1965) [6] cases

(1960) I91

Zuelzer et al. I

Haghbinetal. + 4

Shaw eral. 5

Bastrup- 3 Madsen et al. (1963) P I

M

M

M

F

F

M

M

F

M

M

AC. lymphatic

Ac. lymphatic

Ac.

Ac.

lymphatic

lymphatic

Ac . lymphatic

Ac.

Ac .

Ac.

Ac .

Ac.

lymphatic

myeloid

lymphatic

lymphatic

lymphatic

Ac. lymphatic

Remission No Obesity, meningeal Meninges, hypophysis, symptoms and signs olfact. bulb, optic

chiasma, tracts and nerves

Remission 4 months before Obesity (25 kg), Not performed complication meningeal symptoms

and signs

Not stated No Obesity ( 2 5 kg), hypogenitalism

Remission Not stated Obesity, hirsutism

Remission No

Remission No

Obesity, headache, vomiting

Obesity, drowsiness, strabismus

Not stated Not stated Obesity (12 kg)

Remission Prednisone 3 Hyperphagia,

Remission No Papilledema, hyper- phagia, obesity

Not stated Not stated Hyperphagia, obesity, behaviour disturbances

behaviour

weeks initially obesity

Remission 4 months before Obesity, disturbed

Hypothalamus, hypophysis

Hypothalamus

Hypophysis, tentorium, anterior lobe of hypophysis

Not performed

Meninges, hypophyseal stalk, hypothalamus

Not performed

Not stated

Hypothalamus

Medulla oblongata, mesencephalon, hypothalamus

Acta Ptediat Scand 57

156 Y . Barak and E . Liban

complication have been reported up to date (Table 1).

On analysis of these cases certain clinical and pathological features emerge. The “hypothalamic syndrome” nearly always occurred in cases of acute lymphatic leukemia, prevalently among boys from 2 to 12 years of age. The weight gain, when stated, reached from 4 to 25 kgs during the disease. In the majority of the cases it became apparent during hematological remission. This may be due to the blood-brain barrier, which does not allow the antileukemic drugs to reach effective therapeutic levels in the cerebrospinal fluid (3, 6). In most of the cases corticosteroid therapy was not applied, thus giving strong sup- port to the assumption that these agents do not contribute to the appearance of the “hypothalamic syndrome”. In most cases other neurological and endocrinological changes were noted, while in few i t appeared as a single sign of meningo- cerebral leukemic involvement. At autopsy exami- nation the whole or part of the hypothalamus was found infiltrated by leukemic cells and very often the meninges and other parts of the brain were involved as well. The lack of additional neurological signs observed in some cases may be explained by the uneven distribution of the in- filtrations, which in such cases were more ex- tensive in the hypothalamus than in the other parts of the brain. It must be stressed however, that according to the recent experiments by Ma- bel et ul. (7) , increased ventricular pressure alone causes hyperphagia in normal rats, due to its effect on the intact ventromedial area of the hypothalamus.

It may be then concluded, that this hypo- thalamic syndrome might be the single sign of cerebral involvement in children suffering from acute leukemia. Its recognition can be of value in the early diagnosis and correct treatment of such complications, and may also avoid unneces- sary interruption of treatment with cortico- steroids.

SUMMARY

Hyperphagia with excessive weight gain and be- haviour disturbances without other neurological signs appeared during a remission of acute lym-

,phatic leukemia in a 4 year old boy. At autopsy, in addition to leukemic involvement of almost all

Acta Padiat Scand 57 ’

organs, extensive infiltrations were noted in the medial hypothalamus, the meninges and in some other parts of the brain. 14 similar cases collected from the literature were reviewed. The conclusion was drawn, that the “hypothalamic syndrome” may be the only sign of extensive cerebral leu- kemic involvement. Its recognition may be of value in early diagnosis and correct treatment of cerebral leukemic complications.

REFERENCES 1. Allies, F.: Adipositas und Polyphagie bei Leukimie.

Mschr Kinderheilk, 106: 237, 1958. 2. Annnd, B. K., Dua, S. & Shoenberg, K.: Hypothala-

mic control of food intake in cats and monkeys. J Phq’siol (London), 127: 143, 1955.

3. Bustrup-Madsen, P. & Greisen, 0.: Hypothalamic obesity in acute leukemia. Acta Haernar, 29: 109, 1963.

4. De Toni, G.: Mschr Kinderheilk, 102: 135, 1954. 5. Fertman, M. B,: Newer concepts of experimental

obesity. Arch Intern Med , 95: 794, 1955. 6. Haghbin, M. & Zuelzer, W. W.: A long-term study

of cerebrospinal leukemia. J Pediat, 67: 23, 1965. 7. Mabel, J. A,, Baile, C . A. & Mayer, J.: Hyperphagia

induced by ventt-icular pressure and :pentobarbitone in normal and hypothalamic obese rats. Luncet, 11: 473, 1966.

8. Sansone, G.: Pathomorphosis of acute infantile leu- kemia treated with modern therapeutic agents; “Meningoleukemia” and Frohlich’s obesity. Ann Pae- diat, 183: 33, 1954.

9. Shaw, R. K., Moore, E. W., Freireich, E. J. & Tho- mas, L. B.: Meningeal leukemia. Neurology, 10: 833, 1960.

10. Sullivan, M. P.: Intracranial complications of leu- kemia in children. Pediatrics, 20: 757, 1957.

11. Zuelzer, W. W. & Flatz, G.: Acute childhood leu- kemia. A ten-year study. Amer J Dis Child, 100: 886, 1960.

Submitted Aug. 10, 1967 Accepted Sept. 1, 1967

(E. L.) Dept. of Pathology Kaplan Hospital Rehovot Israel

Key words: Acute leukemia, hypothalamic symptoms, disturbed behaviour