ENCEPHALOPATHY
AND
FATTY
CHANGE
IN
THE
LIVER
AND
KIDNEY
Gerald S. Golden, M.D., and David Duffell, M.D.
Department of Pediatrics and the Department of Laboratory Medicine, University of Minnesota, Minneapolis, Minnesota
(Submitted August 31; accepted December 26, 1964.)
PRESENT ADDRESS: (G.S.G.), Department of Neurology, Albert Einstein College of Medicine, Bronx,
New York.
67
Pr.rnriucs, Vol. 36, No. 1, July 1965
EYE AND CO-WORKERS1 in Australia have recently described an illness in
chil-dren that may represent a new clinicopatho-logical entity. The outstanding clinical
fea-tures in their group of 21 children were
disturbed consciousness, fever, convulsions, and vomiting. Seventeen of these patients
died and at autopsy all had similar gross and microscopic findings. These consisted of fatty change without necrosis in the liver and kidneys, cerebral edema, and fat drop-lets in the capillary endothelial cells of the
brain.
Within weeks of this report several letters to the editor of Lancet from Great 23
South Africa,4 and New ZeaIand appeared reporting personal experiences with at least
31 similar cases. Brain and Hunter,6 Curry
Ct al., and Anderson8 have also described patients who probably had a related illness. Utian et al.#{176}have subsequently published
a more complete analysis of their cases from South Africa.
A 6-month-old child with a similar clini-cal course and pathological findings was
re-cently seen at necropsy in the University of Minnesota Hospitals. This appears to be
the first reported case from the United States.
CASE REPORT
BR, a 6-month-old American Indian female from southwestern Minnesota, was seen by her family physician on September 5, 1963, for high fever and a generalized seizure. Physical examination revealed pharyngitis, rhinorrhea, and scattered rllonchi throughout both lung fields. She was treated with one injection of AP Bicillin. On ex-amination two days later, the temperature was 100.2 per rectum and there was some clearing of the rhonchi. Therapy was begun with a mixture of
novobiocin and tetracycline. She was admitted to a community hospital on September 10 because of continuing fever and irritability. By the next morning the child was lethargic, but the physical examination was otherwise unchanged. Neurologic examination was unrevealing and there were no signs of meningeal irritation.
Laboratory studies showed the hemoglobin to be 10.6 gm/100 ml and WBC 15,800 with 7% bands, 65% polymorphonuclear leukocytes, and 28% lym-phocytes. Urinalysis revealed pH 6, trace albumin, and no reducing substance. The urinary sediment showed 3 RBC and 5 WBC per high powered field. The chest x-ray was normal and a Mantoux test was negative. A lumbar puncture was performed
with the removal of clear fluid. Analysis revealed
37 mononuclear cells, sugar 15 mg/100 ml, protein 59 mg/100 ml, and chloride 93 mEq/1. Smears for pyogens and acid-fast bacilli were negative.
Because of the suspicion that the patient might have tuberculous meningitis, transfer to the
Uni-versity Hospitals was arranged. During the trip, the patient began to vomit and apparently aspi-rated and died during one episode. The body was brought to the University of Minnesota Hospitals for postmortem examination.
Past medical history revealed that the infant had been seen by a physician on July 17, 1963, for a cough and temperature of 104.6#{176}F (40.3#{176}C). At that time the hemoglobin was 13.4 gm/100 ml and the WBC was 3,000. She was treated with Signe-mycin and Robitussin and responded well. She re-mained in good health until the onset of the
pres-ent illness.
Autopsy Findings
GROSS: The body was that of a well-developed and well-nourished female Indian infant weighing 10 kg. A small amount of dark vomitus was pres-ent in the mouth. The anterior fontanel measured 3 X 3 cm and was scaphoid. No lymphadenopathy was present and no organs could be palpated through the abdominal wall. No fluid was present in the pleural, pericardial, or peritoneal cavities. There were multiple, small to moderate-sized petechial hemorrhages on the epicardial surface
68 ENCEPHALOPATHY
F;. 1. Corneal section of brain showing slight engorgement of vessels and minimal swelling.
the left ventricle. The trachea and larger bronchi
contain(d a small amount of dark greenish-black material similar to that seen in the niouth. There
were a few enlarged, dark, firm tracheobronchial
IvIliph nodes.
The liver weighed 279 gm (normal 200 gui). On
ChIt section, the parenchyma was yellow, greasy, and firm, but the lobules appeared uniform and
normal ill size. The gallbladder contained a small
amount of bile, and the external biliary tree was
lLLteIlt throughout.
The kidneys were normal in size and
configura-tiohl. On cut section the cortex appeared pale, and tile cortex and medulla were sharply demarcated.
1’xternal examination of the brain and spinal
cord showed mild engorgement of the cerebral
vessels. The leptomeninges were translucent
throughout. Coronal sections of the cerebral
hemi-spheres, brain stem, cerebellum, and spinal cord
revealed only moderate vascular engorgement,
mainly in the white matter. Only minimal swelling
of the brain was present (Fig. 1). There were no other significant gross findings at autopsy.
MICROSCOPIC: Hematoxylin and eosin-stained sections of the liver revealed a normal lobular architecture (Fig. 2). Almost all of the parenchymal
cells throughout the liver lobules contained clear vacuohes of varying size (Fig. 3). This alteration did not have a specific distribution within the lobules. There was no necrosis, scarring, inflammatory re-action, or areas of parenchymal regeneration. Sudan III stains on frozen sections of formalin-fixed tissue
revealed that the vacuoles contained lipid. Sections of the kidney showed swelling of the epithelial cells of the proximal convoluted tubules. Small clear vacuoles were present in the basal por-tion of almost all of the epithelial cells of the proximal convoluted tubules (Fig. 4), and Sudan
III stains revealed large amounts of lipid in these
cells. Some lipid was also present in the epithelial cells of the loops of Ilenle. Tile kidneys otherwise appeared normal.
Multiple sections of tile cerebral hemispheres revealed no evidence of an active inflammatory
process in the leptomeninges or parenchyma. There was exaggeration of the perineuronal spaces, some scattered shrunken neurons, and an occasional rather large glial cell nucleus. The significance of these changes is difficult to evaluate, since post-mortem autolysis can mimic cerebral edema or early ischemia, and glial cell nuclei are often more
prominent in the infant brain as compared to the
adult. No definite eosinophilic necrosis or
vacuo-lation of neurons was observed and the mvelin ap-peared well preserved in all regions. There was
en-gorgement of the vessels throughout the cerebral parencyhma but no hemorrhage was seen. Sections of tile basal ganglia, hippocampus, mid-brain, pons,
cerebeliar hemisphere, medulla and spinal cord
were otherwise without special change.
ARTICLES 69
Fic. 2. Section of liver showing normal architecture and uniform vacuolar change in the parenchymal cells. (H. & E., x140)
Fic. 3. Section of liver at higher magnification showing clear vacuoles in the parenchymal cells and absence of necrosis and inflammation. (H. & E.,
70 ENCEPHALOPATHY
Fic. 4. Section of kidney showing clear vacuoles in the basal portion of the epithelial cells of the proximal convoluted tubules. (H. & E., x400)
vessels. Sudan III stains, however, revealed the presence of tiny lipid droplets in many of the endo-thelial cells of the capillaries in the brain and spinal cord. (Fig. 5A and B) No fat was seen in the vascular lumens and there were no lipid containing macrophages in the parenchyma adjacent to the capillaries. Lipid droplets were also present in the endothelial cells of some of the arterioles and arteries. In addition, small fatty droplets appeared to be present in some of the smooth muscle cells of these vessels. There was an occasional lipid-con-taming macrophage in the perivascular space of a few of the larger vessels in the white matter, but these did not appear to be related to obvious parenchymal degeneration. No sudanophilic
ma-terial was observed in the neurons.
Sections of the lungs revealed patchy areas of atelectasis. A few alveoli near the pleura were par-tially filled with macrophages. No abnormalities
were seen on histologic examination of the
re-mainder of the autopsy material.
Lipid stains of other tissues revealed no unusual deposition of fat other than that in the liver and kidney. Fatty droplets in vascular endothelial cells and smooth muscle cells were not found anywhere except in the vessels of the central nervous system.
BACTERIOLOGY: All premortem cultures of the cerebral spinal fluid were sterile, including those
for acid-fast bacilli. Cerebral spinal fluid culture obtained immediately postmortem was also sterile.
Postmortem cultures of the leptomeninges, lymph node, liver, spleen, and lung revealed no acid-fast bacilli.
An ECHO virus, type 11, was isolated from tissue removed at autopsy. This consisted of repre-sentative specimens of gastro-intestinal tract, lung, liver, spleen, adrenal, heart, and lymph nodes. Unfortunately, because of technical problems, the virus was isolated from a homogenate of the en-tire specimen.
REVIEW OF THE LITERATURE
The report of 21 children by Reye et al.’
was the first attempt to define a new entity. Their series consisted of 14 girls and 7 boys,
aged 5 months to 8% years. There was an unusual age distribution, two-thirds of the patients being under 2 years of age; the
remainder over 5 years. The children ini-tially appeared to have some type of mild upper respiratory infection and after sev-eral days showed clinical deterioration with
ARTICLES
71
FIG. 5a. Frozen section of cerebral white matter stained with Sudan III showing lipid droplets in capillary endothelium. (x400)
Fic. 5b. Frozen section of cerebral white matter stained with Sudan III showing lipid
72 ENCEPHALOPATHY
In addition to the constant symptoms of a profoundly disturbed state of
conscious-ness and vomiting, some abnormality of respiratory rhythm was found in every child but one. Neurological findings were present in many of the group. Hypertonia or increased deep tendon reflexes were found
in 16, dilated pupils in 10, and abnormal plantar responses in about one-half of the group. Twelve patients had significant hepatomegaly, and in 6 the liver was felt
to be abnormally firm.
Thirteen of 19 patients showed a decrease in cerebral spinal fluid glucose. Nine pa-tients had blood glucose determinations,
and in 6 of them, the value was below
50 mg/100 ml. Nine of 12 patients had blood urea nitrogen values greater than
40 mg/100 ml although the authors felt that
this might be secondary to dehydration in
5 of the patients. SGOT, SGPT, and
pro-thrombin time were abnormal in all pa-tients in whom these studies were made. Electroencephalography revealed gross
gen-eralized abnormalities in the 6 patients tested.
Seventeen patients came to autopsy and
the findings were remarkably similar. Grossly the brain was swollen and appeared moist and edematous. The liver was slightly
enlarged and presented a uniform bright yellow color. The kidneys had a somewhat widened cortex and the cut surfaces were
pale.
Microscopic sections of the liver showed
striking fatty changes involving every cell
of every lobule in a quite uniform manner. There was,
despite
the magnitude of thesechanges,
no evidence
of necrosis
of hepatic
parenchymal cells and no significant
in-flammatory reaction in any area.
The epithelium of the renal proximal
convoluted tubules was likewise involved
in a severe fatty change without necrosis.
Loops
of Henle
were involved to someex-tent, but the distal convoluted tubules and
collecting tubules were for the most part
spared.
Microscopic examination of the brain showed some swollen neurons, astrocytes,
and
oligodendroglia.
There
was,
however,
no
inflammatory
reaction in the centralnervous system parenchyma or meninges
and
no
degeneration of the myelin wasfound.
Fat droplets were present in somecapillary endothelial cells, but there were no fat emboli. A few neurons were found
to contain
a
number of sudanophilicgran-ules.
Although
no etiology
for this clinical
and
laboratory complex could be determined,
it was felt that the findings had sufficient
consistency to define a previously un-described entity.
Several letters to the editor of Lancet were written concerning this report by
Reye.1 Elliott et al.3 reported that they had
seen 5 cases of this entity. Corlett5 reviewed the cases of encephalitis at the Aukland
Hospital
in 1960 to 1961 and found 2 cases,age 4 and 16 months. Maloney,2 in
Edin-burgh, reported seeing 6 or possibly 8 simi-lar cases since 1954, all but one of which was fatal. The oldest patient was 14 months
of age. Swelling of the brain and fatty changes in the liver were the major autopsy
findings.
Utian and Wagner,44’ Brain and Hun-ter,6 Curry et a1., and Anderson8 also re-ported experiences with apparently similar
cases.
The case presented has many features in common with the illness in children
de-scribed by Reye.1 The infant had a mild upper respiratory tract infection and several
days later showed central nervous system
depression. Although extensive laboratory data are not available, the low cerebral spinal fluid sugar and negative cultures are findings in common with the previously re-ported cases. Many of the neurological
symptoms described by Reye were not
pres-ent in this case probably because the
clini-cal course
of the
patient
was
short
due
to
death from aspiration of vomitus. The au-topsy findings of fatty change in the liver and proximal convoluted tubules of the
ARTICLES
73were fewer definite changes in the neurons
and glial cells of the central nervous system. The morphologic alterations in these cells, including the sudanophilic granules,
de-scribed by Reye may in part have been re-lated to periods of anoxia secondary to con-vulsions which were numerous in many of
the patients in his series. The patient in this report did not have repeated or prolonged convulsive episodes.
The isolation of an ECHO virus, type 11,
from the patient’s tissue is quite interesting, as this type has been associated with gastro-intestinal disease#{176} and central nervous
sys-tem 12 in children.
Unfortu-nately, however, the isolate in this case was obtained from a tissue pool which contained
gastrointestinal tract as one of the
speci-mens. ECHO viruses of many kinds,
in-eluding type 11, may be found in the gastro-intestinal tract of children undergoing
ron-tine stool examination13 or from infants in
a vel1-baby clinic. For this reason it would be impossible to attach etiologic significance to the presence of this virus.
The cerebral spinal fluid sugar content, 90% of which is glucose, tends to roughly
parallel the blood sugar level but is also dependent upon the permeability of the blood-brain barrier and the presence of glycolysis in the CSF.15 In the absence of
proven microorganisms or morphologic
evi-dence of a breakdown in the blood-brain
barrier, the presence of hypoglycorrhachia in these patients is probably a manifestation of the low blood sugar. Many of the clinical
symptoms in these patients could be
ex-plained by a low blood sugar. The patho-logical changes, however, that have been described in cases of hypoglycemiabo are not at all similar to the morphologic alterations in this patient.
Popper and Schaffnerl7 state that diffuse fatty changes in the liver can be secondary to nutritional, toxic, or endocrine causes.
There was no evidence for inadequate nu-trition in the patient. There also was no
clinical symptomatology or pathologic find-ings suggestive of endocrine disease. A toxic etiology for the disease is suggested by the
combination of hepatic, central nervous
system, and renal findings. Reye and his co-vorkers undertook fairly extensive en-vironmental investigations, but were unable
to discover exposure to known toxic agents in any of their cases.
Drug-induced fatty liver has been de-scribed following tetracycline ingestion in
human beings.18 i:i The patient did receive
a compound containing this antibiotic, hut the doses used were well below those
re-ported to cause this complication.
SUMMARY
Reports of a new syndrome, the chief manifestations of which are hypoglycor-rhachia, disturbances of the state of
con-sciousness, and vomiting, are reviewed and a case presented. The pathological mani-festations are quite consistent and include
massive fatty infiltration of the liver without necrosis, fatty changes in the epithelium of the proximal convoluted tubules of the
kidney, and deposits of fat in the endo-thelium of many of the cerebral vessels. Although a toxic etiology has been sug-gested, no known cause is really apparent
at the present time.
REFERENCES
1. Reye, R. D. K., Morgan, G., and Baral, J.: Encephalopathy and fatty degeneration of the viscera. Lancet, 2:749, 1963.
2. Maloney, A. F. J.: Encephalopathy and fatty degeneration of the viscera. Lancet, 2:1122,
1963.
3. Elliott, R. I. K., Mann, T. P., and Nash, F. W.: Encephalopathy and fatty degeneration of the viscera. Lancet, 2:882, 1963.
4. Utian, H. L., and Wagner, J. M. :
Encephalop-athy and fatty degeneration of the viscera.
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4a. Utian, H. L., Wagner, J. M., and Sichel,
R.
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7. Curry, A. S., Cuttman, H. A. N., and Price, D. E.: A urinary pteridine in a case of liver
failure. Lancet, 1:885, 1962.
74
ENCEPHALOPATHY
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9. Sommerville, R. C.: Enteroviruses and diar-rhoea in young persons. Lancet, 2:1347, 1958.
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15. Petersdorf, R. C.: Why does the sugar dis-appear from the C.S.F. in meningitis? Amer.
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A., Norman, R. M., and Russell, D. M.: Creenfield’s Neuropathology. 2nd Ed. Bal-timore: Williams and Wilkins Co., 1963, pp. 252-254.
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