THE JOURNAL OF NERVOUS AND MENTAL DISEASE Copyright © 1976 by The Williams & Wilkins Co. Ve Print ADULT “FAILURE-TO-THRIVE”’ SYNDROME BERNARD MESSERT, M.D.,* ARTHUR E. KURLANZIK, M.D., anp DAVID R. THORNING, M.D.? The analogy between the ‘‘failure-to-thrive” syndrome of childhood and a symptom complex seen in adult neurology is described. Adults presenting with a variety of central nervous system diseases occasionally seem to follow an unusual stereotyped course resulting in intractable weight loss, wide varia- tions in temperature, and a tendency to intractable decubitus ulcerations in a setting of decreased levels of consciousness. Sudden death occurs unexpect- edly. This syndrome can be observed following cerebral thrombosis, traumatic encephalopathy, degenerative central nervous system disorders, and encepha- litis. The pathophysiology is thought to result from the random aggregate of lesions rather than a verifiable discrete hypothalamic deficit. Over a number of years, we have ob- served a few patients who, in spite of a wide variety of central nervous system (CNS) diseases, seem to follow an unusual and yet fairly stereotyped clinical course which seems to include the following features: a) irreversible relentless weight loss refractory to a high caloric intake; b) wide tempera- ture swings, both above and below normal, unrelated to the presence or absence of infection; c) decrease in the level of con- sciousness; d) rapid onset of decubitus ulcerations not usually seen in a good nursing setting; and e) sudden death. Five such cases are described. None of the patients showed any evidence of gas- trointestinal dysfunction. Neither vomit- ing nor diarrhea was ever a feature of the clinical course. Patients whose course might have been complicated by underly- ing metabolic, toxic, or primary infections were not considered for this study. All patients required nasogastric or pha- ryngostomy feedings complemented by in- travenous fluids as needed. Daily intake exceeded the recommended allowance for adults. Commercial tube feeding formulas provided complete nutritional support and ‘From the Neurology and Laboratory Services, Veterans Administration Hospital, and the Depart- ment of Neurology, University of Wisconsin. Send reprint requests to Dr. Messert, Chief, Neu- rology Service, 2500 Overlook Terrace, Madison, Wisconsin 53705. ? Present address: VA Hospital, Seattle, Washing- ton 98108. 401 at least 1000 calories/liter, the average daily consumption being 2 to 3 liters. It is our hope that we will stimulate interest for further study of this most peculiar syndrome. CASE REPORTS Case 1. A 50-year-old, white male had the sudden onset of complete quadriplegia in No- vember, 1973. This had been preceded in the previous 3 months by transient basivertebral ischemic episodes. Up to that time the patient had been in good health except for mild, un- treated hypertension. On admission, the neurological examination was typical of the “locked-in” syndrome. The patient appeared mentally alert and in no acute distress. He was 6 feet tall and weighed 172 pounds; blood pressure was 144/90, pulse 80/ minute and regular, and temperature was 98.6 degrees. General examination was normal. The patient lay in bed alert but mute and followed the examiner with his eyes but had limited conjugate lateral eye movements. Bilateral fa- cial, tongue, palate, and pharynx weakness were present. There was a dense right hemiplegia, lesser degree of left hemiplegia, brisk deep tendon reflexes, bilateral Babinski signs, and dysmetria on attempted movement of the left upper extremity..The hospital course lasted 9 weeks. Febrile episodes were associated with hyperventilation and tachycardia, and_per- sisted after apparent control of the original urinary tract infection. One outstanding aspect of his course was a malignant weight loss which 402 occurred in spite of a daily caloric intake which exceeded 4000 calories. At the time of death 2 months after admission, the patient had lost 62 pounds and weighed 110 pounds. No vomiting or diarrhea was ever present during the hospital course. The patient remained fully conscious during the entire hospitalization. He died unex- pectedly, at a time when no exacerbation of his medical problems seemed present. Postmortem examination of the brain re- vealed bilateral ischemic necrosis in the para- median distribution of the basis pontis with preservation of the tegmentum pontis (Figure 1). There was severe atherosclerotic involve- ment of the basilar artery with a 3-cm occlusion 3 mm from its origin (Figure 2). Both the pontine lesion and the occlusive thrombus had histopathological changes consistent with the clinical course of 4 months’ duration. Descend- ing degeneration of the corticospinal tracts was seen in the medulla and was more severe on the left. No gross microscopic lesion was seen in the lower medulla or hypothalamus; however, there was an unusual intraneuronal and perineuronal edematous vacuolation involving the paraven- tricular (Figure 3) and supraoptic (Figure 4) nuclei bilaterally. Case 2. A 61-year-old, white male was trans- ferred to our institution for the evaluation of a subacute clinical course characterized by de- mentia, pseudobulbar palsy, axial rigidity, shuffling gait, decreased vertical gaze, inconti- nence, and increased tone in all of his extremi- ties without cogwheeling or tremor. Olivopon- tocerebellar atrophy was suspected clinically. The hospital course which lasted only 1 month was complicated by a urinary tract infection which was treated. The patient none- theless had marked temperature swings with no other apparent cause being found. He was found dead in bed, unexpectedly. The patient was 5 feet 5 inches tall and his average weight over the years had been 145 pounds. On admission to a chronic care facility in April, 1971, his weight was 146 pounds. On December 4, 1972 on admission to our service, he weighed 116 pounds, and 2 weeks later weighed 104 pounds. This weight loss occurred in spite of very adequate nutrition with high caloric intake in the absence of any gastrointes- tinal disorder. At postmortem, the general examination was within normal limits except for aspiration pneu- B. MESSERT et al. monia. The neurological postmortem examina- tion showed occlusion of the right posterior cerebral artery without infarction. There was diffuse cortical atrophy with increase in the size of the lateral ventricles especially in the frontal and parietal areas. Microscopic examination showed neuronal drop-out and senile plaques. There was atrophy of the inferior olivary nuclei as well as atrophy of the granular and Purkinje cell layers of the cerebellum. This was felt to be compatible with a diagnosis of olivopontocere- bellar atrophy. UHI I 8 HU % Fic. 1. tion in tk mental le ADULT ‘‘FAILURE-TO-THRIVE’’ SYNDROME TMM 6 | p | o Ul) tj Fic. 2.0 ing the basil Case 3. A 67-year-old, white male admitted in May, 1972 for evaluation of a sudden onset of right hemiparesis. In December, 1969, he had had an onset of transient right extremity numb- ness, speech arrest, and focal seizures. He had a left frontal abnormality on EEG and brain scan; cerebral angiography showed an anterior choroi- dal artery blush. Seizures were controlled with diphenylhydantoin (Dilantin). For 1 week prior to readmission, he had several brief episodes of dizziness as well as weakness and numbness of all four extremities. 403 On admission, he appeared well nourished, was 5 feet 7 inches tall and weighed 180!2 pounds. He wag confused, had a bilateral internuclear halmoplegia and a mild right hemiparesis. neurological deficit progressed to a com- quadriplegic state in which respiration eye movements were the only residual itary movements possible. An initial bout 1eumonia was treated successfully but the mt developed repeated temperature spikes out any other obvious source of infection z found. A RISA cisternography as well as a 1 scan were normal. Spinal fluid examina- were unremarkable. ,on after admission, the patient developed re bedsores which progressed in spite of 2ssive medical and surgical therapy. He n to show signs of severe cachexia in spite dequate alimentation. An EMG showed ralized polyneuropathy. In spite of these lems, his neurological deficit improved »what but wide temperature fluctuations inued to be present. One month later he found dead; weight at the time of death was nated at 120 pounds. ystmortem examination revealed an old, ed myocardial infarction, mucopurulent chitis, and bilateral bronchopneumonia. liver and spleen were congested. There were ple decubiti and diffuse muscle atrophy. fixed brain weighed 1530 g. The meninges » thickened with some lymphocytic and morphonuclear leukocytic infiltration. 7e was a complete occlusion of the basilar ry 1 cm from its origin. Multiple bilateral ccts of the pons, cerebrum, and cerebellum » found. There was Wallerian degeneration ughout the lateral columns of the spinal . Examination of the brachial plexus re- ed nerve bundle demyelination. ase 4. This was a 24-year-old, white male who had a rather sudden onset of “strange” behavior with withdrawal, irritability, and headaches. Because of his family’s suspicion of drug ingestion, he was admitted to a local detoxification center; by the next morning, however, he was comatose and was transferred to a local hospital. He had a mild fever and a purpuric rash. Lumbar puncture on three occa- sions showed elevated proteins, greater than 300 mg per cent. The remainder of the CSF and the rest of the laboratory studies were normal. Carotid angiography was not diagnostic. A tra- 404 B. MESSERT et al. Figs. 3 4) nuclei s ADULT ‘‘FAILURE-TO-THRIVE’’ SYNDROME cheotomy was performed and he was then transferred to the Madison VA Hospital. On admission, he was febrile, the tempera- ture being 103 degrees. There was a mild, resolving skin rash felt to be livedo reticularis. The remainder of the general examination was normal. On neurological examination, the pa- tient was comatose, responding only to painful stimuli with bilateral decerebrate posturing. His neck was supple; reflexes were brisk with bilateral Babinski signs. He had a mild leukocy- tosis and slight elevation of SGOT. LP revealed a protein of 608 mg per cent with 10 to 20 lymphocytes per high power field. All cultures as well as viral titers were negative. A PEG and repeat left carotid and left brachial angiogram were normal. A RISA scan was normal. Two months after admission, he remained deeply comatose and alternated between states of de- cortication, decerebration and total flaccidity. He rapidly developed joint contractures. A suprapubic cystostomy and feeding pharyngos- tomy were performed. A repeat PEG at this time showed massive ventricular dilation (Fig- ure 5). Shortly thereafter, he began to develop recurrent episodes of urinary tract infection, aspiration pneumonia, and septicemia. Only the first such episode was treated with antibiot- ics; he recovered from the others without treat- ment. He began to develop widely fluctuating Fic. Repeat associat 405 temperatures between 99 degrees and 106 de- grees which were apparently unrelated to the presence or severity of his infectious processes. His weight, which was 114 pounds on admis- sion, began to decline rapidly in spite of over 3 liters of tube feedings per day. The patient survived 2 months in this condition until he was found dead in bed. An autopsy was not per- formed. Case 5. A 42-year-old, chronic alcoholic was found unconscious at the site of a one-car accident. He was comatose with an internuclear ophthalmoplegia and skew deviation of the eyes, and signs of decortication and decerebra- tion were present. A full work-up including contrast studies was nonrevealing. During an 8-month hospitalization, he showed a continu- ous intractable weight loss associated with mus- cle mass wasting; this occurred in spite of adequate nasogastric feeding. The patient was finally discharged to a nursing home in an irreversible chronic vegetative state, weighing 112 pounds from a premorbid weight of 180 pounds, having lost over 65 pounds. DISCUSSION The above cases are examples of diffuse CNS damage secondary to trauma, proba- ble encephalitis, vascular disease, or idi- opathic degenerative changes. Although all 406 levels of the neuraxis were involved, the posterior fossa was the most severely and widely affected. It is highly unlikely that a single, specific localized lesion can be evoked to explain all or part of this syn- drome as has been recently suggested (27). More likely, however, is that this clinical syndrome is a nonspecific manifestation of different etiological and diffuse geographic nervous system pathology, t.e., this syn- drome may reflect a final common path- way of neurological dysfunction. Fre- quently when presented with such a ca- chetic patient, a diagnosis of malignant neoplasia is considered and a search for a primary tumor is undertaken (27). Our clinical formulation is based upon certain diversified clinical data. The first, and probably most interesting, is the simi- larity between our cases and a well defined pediatric syndrome descriptively termed “failure-to-thrive.”’ Although this syn- drome is readily identified clinically, it has many possible etiologies which run the gamut of acquired and congenital disease of all major organ systems, including the nervous system (21). Most children with CNS disease lose weight because of nonspecific factors such as anorexia and vomiting. There is, how- ever, an interesting subgroup first de- scribed by Russell in 1951 as ‘ta dience- phalic syndrome of emaciation in infancy and childhood” (81). This syndrome, termed ‘ta syndrome of paradoxes” (31) is seen in children between the ages of 2 months and 4 years (33). These patients are emaciated to the point of appearing terminally ill, yet have a ravenous appe- tite, are active, some even overactive, and at times even appear euphoric (31). The neurological examination is mentioned only in light of the paucity of findings, nystagmus being the most common sign (4). Most patients are dead within 1 to 1! years (9). Most of these cases are caused by tu- mors, usually astrocytomas (33), in the region of the anterior hypothalamus. There is a case reported presumed to be second- ary to third ventricular dilatation as a consequence of hydrocephalus from a mid- line cerebellar mass lesion (16), and a case B. MESSERT et al. associated with nonprogressi’ atrophy (20). This syndrome, then, is not absolutely specific for intrinsic hypotha- lamic disease although it is quite sugges- tive. Emaciation is not an uncommon mani- festation of hypothalamic disease (6) al- though its pathophysiology is obscure. Ref- erence to the experimental literature paints a deceptively simple picture. It is known that if the area around the ventro- median nuclei of the hypothalamus is de- stroyed in the rat or cat, the animal over- eats and becomes obese (2, 3). If the areas in the lateral hypothalamus at the same latitude as the ventromedian nuclei are destroyed bilaterally, the animals display anorexia and secondary weight loss (2, 3). It appears that a “‘satiety center” in the ventromedian nuclei of the hypothalamus exerts its influence via the laterally situ- ated “feeding centers,” for if the animal is rendered hyperphagic by destroying the ventromedian nuclei and then both lateral nuclei are destroyed, the animal will ab- ruptly stop eating (2, 3). These changes are reversible in some animals (36, 37). The situation in man, however, is not that simple. Cases of extensive hypotha- lamic damage without any weight changes have long been known (10); rarely precise clinicopathological correlations like those described above have been seen in humans (38). In a report of patients with hypotha- lamic disease of diverse etiologies including neoplasm, inflammation, and degenera- tion, Bauer (6) noted anorexia in four cases, bulimia in five cases, obesity in 15 patients, and emaciation in 11; of the 26 cases with alteration in body weight, only nine had appetite changes. Furthermore, changes in appetite, when present, did not always correlate with the expected weight change, so that some anorectic patients became obese and some bulimic patients became emaciated. This last situation is the one encountered in the diencephalic syndrome, although occasionally the pa- tient will continue to eat ravenously and become obese (20). Was hypothalamic disease the cause of our patients’ severe weight loss? This ques- ADULT “‘FAILURE-TO-THRIVE’’ SYNDROME tion is unanswerable at this time. Unfortu- nately, in only one case (case 1) was detailed examination of the hypothalamus undertaken, and we failed to demonstrate unequivocal pathological changes. We were obviously unable to assess our patients’ appetites because of their far advanced state of neurological deterioration. All pa- tients received more than adequate nutri- tion, yet all lost a significant amount of weight; none became obese. Since all of our patients had evidence of diffuse CNS disease, the presence or ab- sence of a single lesion, as for example, in the hypothalamus, cannot be given abso- lute specificity for any one sign or symp- tom. We postulate that these changes are due to a random aggregation of diffuse pathological changes. Of note is that there is evidence in animals of areas of CNS outside the hypothalamus which function in weight control (22, 36). Another body of clinical data which will help to better define this syndrome in- volves ‘trophic changes” in CNS disease. For at least the past 125 years, reference has been made to the contralateral, occa- sionally with accompanying ipsilateral flaccidity, muscle wasting and skin changes seen in patients with parietal lobe disease. Critchley (12) discusses this sub- ject at some length and lists six principal etiological theories. Quincke in 1893 ad- vanced the most tenable theory when he postulated that a cortical center exerts a trophic influence on peripheral muscula- ture. Although well defined functionally, the nature of this trophic force is still an enigma (7). Many clinicians no longer feel that the CNS lesion(s) which results in muscle atrophy and trophic skin changes resides exclusively in the parietal lobe. Gordon (23) in 1927 mentioned three other areas which may function as ‘trophic centers”: the head of the caudate nucleus, the ante- rior segment of the internal capsule, and the internal portion of the lenticular nu- cleus. In one study (18), two out of four patients with hemiplegia accompanied by muscle atrophy had no signs of impaired sensation, while four other patients with hemiplegia without muscle atrophy had hemihypesthesia. The parietal lobes, therefore, are not the only part of the CNS capable of being a “trophic center.” The nature of these ‘trophic centers” has been elaborated on through elec- trodiagnostic tests. These provide evidence for lower motor neuron dysfunction in the form of fibrillations, positive waves, and polyphasic muscle potentials (7, 30) with (11) or without (30) decreased nerve con- duction velocities. These findings have not been universal, and electrodiagnostic tests in these patients have been normal (22, 32). Muscle biopsies have not been helpful in localizing the process (12, 18). Complete postmortem examinations in these pa- tients have shown in some cases extensive degenerative changes involving anterior horn cells, anterior and posterior spinal roots, peripheral nerves (5, 8), afferent tracts such as the spinocerebellar tracts and lateral spinothalamic tract (8), and cranial nerve nuclei (5). In spite of all of these data, the nature of this trophic proc- ess still eludes us. It is interesting to postulate that the muscle wasting seen in our patients may be secondary to loss of these trophic factors. The same may be said about the massive skin decubiti so prominent in our case 3. Bedsores are extremely rare on our unit because of our nurses’ experience with chronic bedridden patients; our case 3, however, developed marked skin ulcers which were refractory to all medical and surgical therapy. Again, it is impossible to prove this hypothesis at this time. Only case 3 had an electrodiagnostic study, and this demonstrated a generalized polyneu- ropathy. This same case at autopsy showed Wallerian degeneration of the lateral col- umns of the spinal cord and nerve bundle demyelination on microscopic examination of the brachial plexus. The major area of consideration relevant to these patients’ weight loss and muscle wasting involves the possible role of the adrenal cortex. Although our data here are sparse, consideration from this viewpoint raises several possible modes of therapy. It is well known that Cushing’s syndrome is associated with a myopathy (1) and that prolonged steroid administration, espe- 408 cially the fluorinated compounds, produces muscle atrophy (25). The mechanisms by which this occurs are unknown (28); di- phenylhydantoin, however, has been found to be an effective treatment of steroid- induced myopathy in animals (24) and man (35). We recently began to examine the role of the adrenal cortical hormones in this syn- drome. We examined the 8:00 a.m. and 4:00 p.m. serum cortisol levels of neurologi- cal patients without any features of this syndrome and found normal values, and in our most recent patient (case 5) with the longest survival, serum cortisol levels were markedly elevated. The reason for investigation along these lines related to data concerning diphenyl- hydantoin’s effect on the pituitary-adrenal system. Diphenylhydantoin acts centrally to stimulate the pituitary-adrenal system and produce changes in adrenocortical secretion that are characteristic of a ho- meostatic reaction (26, 29). Animals sacri- ficed after chronic diphenylhydantoin ad- ministration have shown adrenal cortical hypertrophy (34). In addition, diphenyl- hydantoin will increase the cortisone-low- ered seizure threshold in animals (13). Of note is that a case reported of a woman with anorexia and weight loss secondary to a hypothalamic tumor was found at au- topsy to have adrenal cortical atrophy (38). The above data raise the speculation that diphenylhydantoin might be tried in treatment of this syndrome. This is pure speculation and more work should be done. The remaining aspects of our proposed syndrome involve the wide temperature swings which occurred at times without identifiable cause, the unusual evidence of decubitus ulcers, and the sudden death. Variations in body temperature, espe- cially hyperthermia, which is secondary to various pathological changes in the vicinity of the hypothalamus are rare but docu- mented (10, 13, 14, 17). They are also known to occur during surgical procedures in and around the third ventricle (17). The hypothalamus is not the only area of the CNS which functions in the regulation of body temperature. Hyperthermia has been associated with cervical cord lesions (33). B. MESSERT et al. In cats, various unilateral or bilateral corti- cal ablations produced abnormal tempera- ture regulation (13). Whether or not some of the wide temperature fluctuations seen in our cases can be attributed to “central causes” is indeterminate, but remains an interesting point for speculation. It is well known that decubitus ulcera- tions tend to occur in areas deprived of sensory innervation when these areas are subjected to trauma, pressure, or excessive temperature changes. In addition, decubiti are seen in areas of autonomic denervation. These factors are most commonly present in myelopathies with sensory and motor denervation, and in paralysis of circulatory cutaneous reflexes. Decubitus ulcerations are also seen, if less frequently, in periph- eral neuropathies and occasionally in he- miplegic limbs in cases of parietal lobe destructive lesions. 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