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1274
ENCEPHALOPATHY AND FATTY
DEGENERATION OF THE VISCERA
ACID-BASE OBSERVATIONS
HAMISH SIMPSONM.B. Edin., M.R.C.P.E., D.C.H., D.Obst.
LECTURER, DEPARTMENT OF CHILD LIFE AND HEALTH,UNIVERSITY OF EDINBURGH
ENCEPHALOPATHY associated with fatty degeneration ofthe viscera in children is becoming increasingly recognised.Reye et al. (1963) described 21 cases from Australia, andsince then similar cases have been reported from GreatBritain, South Africa, New Zealand and Czechoslovakia(Corlett 1963, Elliott et al. 1963, Maloney 1963, Utianand Wagner 1963, Stejskal and Kluska 1964). Utian et al.(1964) subsequently published a more detailed account oftheir cases and described the condition as white liverdisease. Further reports have appeared from workers inthe United States (Golden and Duffell 1965, Randolphet al. 1965) and New Zealand (Becroft 1966).
Clinically, the main features of this syndrome are
vomiting, convulsions, and coma, usually preceded by anupper-respiratory-tract infection. Hypoglycaemia andraised serum-transaminases are the most constant bio-chemical abnormalities. Fatty change in the liver andkidneys, and cerebral oedema are the major postmortemfindings.
I describe here the clinical, biochemical, and patho-logical features of fourteen such cases recognised in
Edinburgh since 1952, eleven being in the past 3 years,and give the acid-base disturbances encountered in the sixlatest cases.
Clinical Features
Table I summarises the clinicopathological features ofthe fourteen cases. There were nine females and five
males, aged 3 months to 6 years. Eight were under6 months. Ten of these children had previously beenhealthy, and on admission to hospital all were wellnourished. One (case 1) had had mumps 4 weeks beforeadmission, two (cases 5 and 8) had had otitis media whenaged 3 months and 2 months respectively, and one (case 13)had been an influenza contact. A history of previousconvulsions was obtained only in patient 12, who had twofebrile convulsions when aged 6 months. No history ofpoisoning was obtained in any case, although one patient(case 1) had been given salicylates (600 mg.) beforeadmission.
In eight patients an upper-respiratory-tract infectionhad preceded the main symptoms which most often startedabruptly 7-10 days later. Although vomiting was common
(eleven cases), it was seldom copious but was " coffee-ground " in three patients. Eleven children became
pyrexial during their illness but six were apyrexial onadmission to hospital. In seven patients the liver wasenlarged and firm. Convulsions and coma were constantfeatures. The types of convulsions varied, focal twitchingof a slow rhythmic nature being most common.
Generalised convulsions occurred in four patients, whileone (case 5) had carpopedal spasm suggestive of tetany.Muscle tone and tendon reflexes were increased in twelvecases but flaccidity and diminished reflexes alternated withspasticity in eight. The pupils were often dilated andunresponsive to light. Ventilation was abnormal in ten
patients, hyperpnoea occurring in all. Shallow or irregularrespirations were also observed at some stage in seven ofthese children, and apnoeic attacks in four.
Blood-glucose was estimated in nine cases, and in eight thelevel fell below 25 mg. per 100 ml. at some stage in the illness.The serum-glutamic-pyruvic-transaminase (S.G.P.T.), estimatedin six patients, was increased in each case, initial values varyingfrom 48 to 1050 Sigma-Frankel units per ml., whilst theserum-glutamic-oxaloecetic-transaminase (S.G.O.T.), measuredin four patients, ranged from 160 to 860 Sigma-Frankel unitsper ml.The serum-potassium, measured in twelve cases, was above
normal in cases 7 and 8, the levels on admission being 7-7 and6-8 mEq. per litre, respectively. There were no other electro-lyte abnormalities, but the carbon-dioxide-combining powerwas below normal in every case (normal range 21-25 mEq. perlitre). The highest blood-urea-nitrogen was 50 mg. per 100 ml.(in case 3).The cerebrospinal fluid was examined in ten cases. Low
glucose levels were noted in those cases which had not beengiven glucose therapeutically before lumbar puncture, butotherwise there were no biochemical abnormalities. The cell-count was increased to 30 lymphocytes per c.mm. in case 6, butno growth was obtained in culture of the fluid.
Blood-cultures in seven cases and virology studies in fivewere also unhelpful. A neutrophil leucocytosis was a constantfinding.
Treatment usually consisted of anticonvulsants (fourteencases), intravenous glucose (ten cases), and hydrocortisone(nine cases). In two earlier cases lactate had been given tocorrect " acidosis " but latterly, lactate and bicarbonate weredeliberately withheld until acid-base measurements were
available. Assisted ventilation was used in the treatment offour patients (cases 1, 4, 6, and 8). Ten of the fourteen patientsdied, 24 hours (on average) after admission to hospital. Ninenecropsies were performed, and in all of them the liver wasthe main organ affected, a severe fatty change being the out-standing finding. Of the four survivors, one (case 5) is severelymentally retarded, but the others have recovered without
apparent residual neurological impairment.
TABLE I-SUMMARY OF CLINICAL AND PATHOLOGICAL FEATURES
1275
Acid-base MeasurementsMethodsAcid-base measurements were made in cases 1-6 as soon as
the diagnosis was suspected (which was within 6 hours ofadmission in all except case 5). Disturbances of ventilation inchildren admitted with convulsions had most often suggestedthe need for this investigation. Heparinised capillary blood-samples were obtained from the previously warmed heel.
Subsequent samples were taken as determined by clinical
progress.The pH, carbon-dioxide tension (Pco2) in mm. Hg, and
standard bicarbonate in mEq. per litre were measured by theRadiometer ’ G297/G2 ’ glass electrode and ’ PHM 27 ’ meter,using the interpolation method (Sigaard-Andersen et al. 1960)for PC02 and standard bicarbonate.
ResultsThe results of initial acid-base measurements are shown in
table 11. pH values ranged from 6-85 to 7-47 and were belownormal in cases 2, 3, and 6. Pc02leve1s were normal in cases 3and 6 and below normal in the remaining cases. Standard
TABLE II-INITIAL ACID-BASE MEASUREMENTS
bicarbonate values were invariably below normal, the lowestbeing 6-0 mEq. per litre in case 6.
Case-reportsCase 1
A 5-year-old child who was admitted on account of vomitingand headache of 1 day’s duration. She had recovered from
mumps four weeks earlier. On examination she was comatosewith rapid deep respirations. Her pupils were dilated and non-reactive, and fundi were normal. She was generally hypotonicwith extensor plantar responses. Although the liver was notenlarged, her S.G.P.T. was 680 Sigma-Frankel units per ml.Convulsions started within 1 hour of admission when her
blood-glucose was 20 mg. per 100 ml. These were controlledwith glucose intravenously and anticonvulsants. Her initial
pH was 7-39, PC02 22 mm. Hg, and standard bicarbonate17 mEq. per litre. Several hours later she became cyanosedand apnceic. An emergency tracheotomy was performed butshe died soon afterward despite assisted ventilation. At
necropsy the liver showed gross fatty change whilst the brainwas pale and swollen with slight, non-specific microscopicchanges. Early bronchopneumonic changes were present inthe lungs.
Case 3An 11-week-old baby who had been ill for one day with
breathlessness, refusal of feeds and loose stools. Whenexamined he was comatose, pyrexial (104°F, 40°C) andrespirations were rapid and shallow. He was generally hypo-tonic with diminished tendon reflexes. Examination was
otherwise unremarkable. Soon after admission his blood-glucose was 12 mg. per 100 ml., his pH 7-18, and standardbicarbonate 14.0 mEq. per litre. His PC02 was normal, 40mm. Hg (fig. 1). Hypoglycasmia was controlled with intra-venous glucose and steroids, and his metabolic acidosis wascorrected with intravenous bicarbonate. After 18 hours,generalised convulsions started at a time when his blood-glucose, pH, and serum-calcium were normal. The convul-sions were controlled by barbiturates. He remained uncon-scious for 3 days and for some time afterward showed noresponse to visual stimuli. His sisht did return. however. and
he has subsequently de-veloped normally withoutfurther convulsions.
Case 4A 4-week-old baby
admitted with a 3-dayhistory of vomiting,hmmatemesis, and gen-eralised convulsionswhich occurred on the
day of admission. Whenexamined she was
apyrexial, comatose, andgenerally hypotonic. Herbreathing was labouredand irregular, and theliver edge was just pal-pable. Systematic exami-nation was otherwise
unrevealing. Her blood-glucose was then 65 mg.per 100 ml. (’Dextro-stix ’). She was treatedwith 10% glucose intravenously. Despite this, her blood-glucose fell to 6 mg. per 100 ml. within 4 hours. Her pH wasthen 7-44, PC02 21 mm. Hg, and standard bicarbonate 17 mEq.per litre (fig. 2)-i.e., she had mixed respiratory alkalosis andmetabolic acidosis. 24 hours later her breathing was still
laboured, and her acid-base status unchanged. At 36 hoursshe suddenly became apnoeic. Her pH had fallen to 7-0 whilsther PC02 had risen to 100 mm. Hg (she was then breathing40% oxygen). Assisted ventilation with the Bird respiratorpartially corrected this respiratory acidosis, but improvementwas only temporary. Progressive circulatory collapse supervened,and she died the next day. At necropsy there was no evidenceof respiratory obstruction to account for her sudden respiratoryfailure. The liver showed a severe fatty change, confirmedmicroscopically. The brain and meninges were normal.Case 5
A 5-month-old baby who had been ill for one day withvomiting, cough, and dyspnoea. She was stuporose on admis-sion, with dilated unreactive pupils, nystagmus, and extensorplantar responses. Respirations were regular and rapid, and herliver was three fingerbreadths enlarged. Convulsions startedsoon after admission, when her blood-glucose level was 10 mg.per 100 ml. She improved after intravenous glucose, hydro-cortisone, and anticonvulsants. After 21 hours in hospital herbreathing was rapid and deep. Her pH was then 7-47, PC02
Fig. 1-Case 3: capillary pH, Pco2, andstandard bicarbonate at varioustimes after admission to hospital.
, .!.V’ "Q;.J crmoo
Fig. 2-Case 4: capillary pH, Pco., and standard bicarbonate atvarious times after admission to hospital.
1276
Fig. 3-Case 5: capillary pH, PC02, and standard bicarbonate at various times after admission to hospital.Convulsions occurred intermittently throughout the period shown.
17 mm. Hg, and standard bicarbonate 17-0 mEq. per litre
(fig. 3), again a mixed respiratory alkalosis and metabolicacidosis. Over the next 24 hours her breathing becamestridulous and convulsions restarted. Her pH rose to 7-58 andher Pco2 fell to 11 mm. Hg. She was thought to have alkalotictetany. Endotracheal intubation was carried out and her dead-
space increased by arranging an empty soda-lime canister inseries with the endotracheal tube. This allowed her to rebreathecarbon dioxide and thus raised her PC02.Improvement was dramatic. As the pH fell, convulsions and
stridor stopped, but deep breathing continued even when thePC02 had returned to normal. She continued to rebreathecarbon dioxide in this way for 48 hours, by which time herbreathing was more normal. During that period, however,a metabolic alkalosis developed. Her pH rose to 7-55, and herstandard bicarbonate to 30 mEq. per litre whilst her PC02remained relatively normal. The only intravenous therapy atthis point was 10% glucose, and her alkalosis was attributed tocopious loss of gastric secretions after haematemesis. It wascorrected with physiological saline solution and 2% ammoniumchloride given intravenously. This child survived but is
epileptic and shows severe mental retardation. Other investi-
gations carried out included S.G.P.T. (1050 Sigma-Frankel unitsper ml.) and S.G.O.T. (860 Sigma-Frankel units per ml.).Glucose tolerance and leucine sensitivity tests were normal
during the recovery phase of her illness.
Discussion
The clinical picture was remarkably uniform and
characteristic, and corresponds closely with previousdescriptions (Reye et al. 1963, Utian et al. 1964, Becroft1966). Utian et al. (1964) emphasised the hypoglycaemiawhich was often uninfluenced by infusions of glucose. Inthe present series hypoglycaemia was the commonest bio-chemical abnormality but was not always accompanied byconvulsions, which occurred even when blood-glucosewas normal. Moreover, correction of hypoglycsemiaseldom stopped convulsions. Latterly blood-glucose levelswere monitored frequently using dextrostix (Ames), evenin patients in whom the initial levels had been normal.
Serum-transaminases were usually notably raised whencompared with the moderate increase which may beassociated with " febrile " convulsions, bronchiolitis, andcirculatory failure. The high serum-potassium in cases 7
and 8 are not easy to
explain, but may havebeen associated withmetabolic acidosis
(Sigaard-Andersen1962) or respiratoryacidosis (Giebisch et al.1955). Unfortunately,pH measurements werenot made in either casebut both of these child-ren died and at necropsytheir livers showed
typical fatty infiltration,whilst the adrenal glandsshowed no evidence ofhyperplasia. The initialacid-base measurements
(table n) showed widev,ariation, pH levelsvarying from 6-85 to
7-47. Every case had ametabolic acidosis withreduced standard bicar-bonate but only in cases2,3, and 6 were pH levels
below normal. In case 2 the metabolic acidosis was partiallycompensated by the respiratory alkalosis due to hyper-ventilation, but in all remaining cases respiratory alkalosiscompensated for metabolic acidosis to such an extent thatthe resultant pH was either normal (case 1) or increased(cases 4 and 5). Thus, it would have been irrational tohave treated cases 1, 4;, and 5 with lactate or bicarbonate,although clinically they had " acidotic " respirations.The ventilatory disturbances are not readily explained.
Respiratory alkalosis may occur in patients with hepaticcoma (Vanamee et al. 1956), but the underlying mechanismis uncertain. It could be argued that acidosis was thestimulus to overbreathing in case 2, but this was not so incases 4 and 5 in which pH values were above normal.Moreover, cases 3 and 6 were strikingly acidotic, butneither was hyperventilating. It seems more likely thathyperventilation was a feature of cerebral disorder, ratherthan primarily due to the metabolic upset.The changing acid-base status sometimes encountered
in individual cases is shown in follow-up studies-e.g.,one patient (case 4) was initially alkalotic with a pH of 7-44and a PC02 of 20-0 mm. Hg, but later developed severerespiratory acidosis, the pH falling to 7-0 while the Pco2rose to 100 mm. Hg (fig. 2). In case 5 the rebreathing ofcarbon dioxide corrected the respiratory alkalosis presentby increasing the PC02- Clinically deep respirations con-tinued, however, but this was not unexpected as carbondioxide is the most powerful ventilating stimulant, pro-vided there is no central respiratory depression (Haldaneand Priestley 1905). Metabolic alkalosis also developed inthe same patient but was corrected with ammoniumchloride. This therapy carried a risk of precipitatinghepatic coma with ammonium ion, but at that stage thepatient was not jaundiced and her serum-transaminaseswere not known.The necropsy findings were identical to those described
previously (Reye et al. 1963). The aetiology of this con-dition remains obscure, but possible factors have recentlybeen discussed by Becroft (1966). In most reports virusinfections or poisoning have been considered, but in theseries described here virology studies were unhelpful and
1277
no toxicological studies were undertaken. As in other
series, the prognosis was poor, and only four childrensurvived. Their diagnoses were based on clinical featuresonly, as liver biopsy was not done. In three of these cases,however, acid-base abnormalities were recognised andtreated, and this may have improved the prognosis.
SummaryThe clinical, biochemical, and pathological features of
fourteen children with encephalopathy and fatty infiltra-tion of the viscera are reported. The most constant acid-base disturbance encountered during the management ofsix of these cases was metabolic acidosis, often associatedwith respiratory alkalosis due to hyperventilation. Theresultant pH values varied widely. These abnormalitiescould not have been predicted clinically, and the seriesserves to stress the imporance of acid-base measurementsas a guide to therapy in such patients.
I thank Prof. J. 0. Forfar, Dr. T. T. S. Ingram, and Dr. D. C.Flenley for their advice and helpful criticisms of this paper; Dr.T. E. Isles and Mr. E. Skedd for assistance with the biochemicalestimations; Dr. A. D. Bain who carried out the necropsies andallowed access to the pathological records; and Dr. J. McC. Murdochand Dr. A. J. Keay for allowing me to include cases 1 and 9,respectively.
REFERENCES
Becroft, D. M. O. (1966) Br. med. J. ii, 135.Corlett, K. (1963) Lancet, ii, 937.Elliott, R. I. K., Mann, T. P., Nash, F. W. (1963) ibid. p. 882.Giebisch, G., Berger, L., Pitts, R. F. (1955) J. clin. Invest. 34, 231.Golden, G. S., Duffell, D. (1965) Pediatrics, Springfield, 36, 67.Haldane, J. S., Priestley, J. G. (1905) J. Physiol., Lond. 32, 225.Maloney, A. F. J. (1963) Lancet, ii, 1122.Randolph, M., Kranwinkel, R., Johnston, R., Gelfman, A. (1965) Am. J. Dis.
Child. 110, 95.Reye, R. D. K., Morgan, G., Baral, J. (1963) Lancet, ii, 749.Sigaard-Andersen, O. (1962) Scand. J. clin. Lab. Invest. suppl. no. 66.
— Engel, K., Jorgensen, J., Astrup, P. (1960) ibid. 12, 172.Stejskal, J., Kluska, V. (1964) Lancet, i, 615.Utian, H. L., Wagner, J. M. (1963) ibid. ii, 1010.
— — Sichel, R. J. S. (1964) ibid. ii, 1043.Vanamee, P., Poppell, J. W., Guckshan, A. S., Randall, H. T., Roberts, K. E.
(1956) Archs intern. Med. 97, 762.
ACUTE PYELONEPHRITIS
INCIDENCE OF REINFECTION IN 100 PATIENTS
P. J. LITTLEM.B. N.Z., M.R.C.P.LECTURER IN MEDICINE
H. E. DE WARDENERM.B.E., M.D. Lond., F.R.C.P.
PROFESSOR OF MEDICINE
From the M.R.C. Renal Infection Group, Department ofMedicine, Charing Cross Hospital Medical School, Fulham
Hospital, London W.6
WE describe here the progress of 100 patients for up toeighteen months after an attack of acute pyelonephritis,and describe the effect of treatment on the reinfection-rateand symptomatic relapse.
Patients and MethodsAcute pyelonephritis was diagnosed when there was loin
pain and tenderness, a body temperature above 100°F (37-8°C)and an infected urine. Most patients also had dysuria andfrequency, and some had rigors. Patients known to havehypertension, persisting defects in renal function, or an
abnormal pyelogram were excluded. 85 of the patients under-went intravenous pyelography. 61 of the 100 were admitted tohospital for measurement of endogenous-creatinine clearanceand for assessment of their ability to concentrate and acidify theurine; the treatment of these patients was organised in a
RELAPSE-RATES AT SIX AND EIGHTEEN MONTHS IN RELATION TO
PREGNANCY AND TO TREATMENT
* p<O,OO5. tp>0.1. p>O’2.
controlled trial in which patients were treated with either along or a short course of antibacterial agents. These 61 patientsincluded 14 pregnant women, 44 non-pregnant women, and3 men. The remaining 39 patients were not admitted tohospital; they were all women who had had pyelonephritisduring pregnancy, and were followed up in the antenatalclinic.
Treatment was designed to eliminate infection as well asrelieve symptoms. Short-term treatment consisted of seven-to-fourteen days treatment with a urinary antiseptic or anti-biotic to which the organism was sensitive. Long-term treat-ment consisted of one-to-eighteen months’ treatment withantibacterial agents; each patient was given four or five drugsand was instructed to take one drug each week in rotation.Drugs were continued for as long as they were acceptable tothe patient.
Urine samples were cultured quantitatively (Bradley andLittle 1963). In patients receiving short-term treatment urinecultures were performed one-to-fourteen days after treatmentwas stopped and then at monthly intervals. In 3 patientsthe initial course of treatment did not render the urine sterile.These patients were given another short course of treatment.In patients on long-term treatment urine cultures were per-formed at monthly intervals.Most patients were followed up for eighteen months. This
report is mainly concerned with the interval between the attackof acute pyelonephritis and the first episode of reinfection. Theincidence of such reinfection has been expressed as a per-centage of the total number of patients still under observationat monthly intervals after the attack of acute pyelonephritis.
Results
The results are shown in the table.
Whole Group (100 Patients)By the end of the first month, 23% of the patients were
reinfected. 50% of the 84 patients still under observationwere reinfected by four-and-a-half months. At eighteenmonths, 77% of the patients were reinfected.
17 of the 48 patients who became reinfected, and whowere not treated immediately, had symptoms of urinary-tract infection during the next three months.
Short-term treatment (65 patients).-29 of the patientswere reinfected by the end of the first month. 50% of the54 patients still under observation were reinfected at
four and a quarter months, and at eighteen months, 83%were reinfected.
Long-term treatment (35 patients).-2 (5°°) of these
patients were reinfected by the end of the first month.50% of the 30 patients still under observation werereinfected at five and a quarter months, and at eighteenmonths, 69% were reinfected.Of the 19 who became reinfected, 13 were still being
prescribed antibiotics when the infection developed. Itwas not possible to determine how many patients hadstopped taking the tablets.
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