J. Inher. Metab. Dis. 12 Suppl.

1 (1989) 42-54

Acute Metabolic Encephalopathy: A Review

of Causes, Mechanisms and Treatment
R. SURTEES and J. V. LEONARD
Department of Child Health, Institute of Child Health, London, WC1, UK

Summary: Acute encephalopathy is a relatively common problem: one

of the causes is metabolic disorders. A detailed history, examination and
investigations performed during the acute illness (blood sugar, blood gases,
plasma ammonia, blood lactate, plasma ketones, plasma amino acids, liver
function tests, and urinary organic acids) should identify those patients in
whom a metabolic disorder is likely. More detailed studies may be needed to
establish a precise diagnosis.
The mechanism of the acute brain dysfunction is multifactorial. Factors
that contribute include changes in blood flow and, initially, a disturbance in
neurotransmitter function followed by failure of energy metabolism and
cellular depolarization. Treatment of these conditions is largely supportive,
with especial attention to the management of cerebral perfusion pressure.

Acute encephalopathy is a rapid decrease in conscious level (over hours or days),

not secondary to ictal nor syncopal episodes. The differential diagnosis is wide
Table 1 Differential diagnosis of acute encephalopathy

1. Trauma
2. Infection (meningitis/encephalitis)
3. Space-occupying lesion
4. Ingestion of drugs or toxins (including lead-poisoning)
5. Parainfectious encephalitis and mycoplasma encephalopathy
6. Hypoxia/ischaemia (including near-miss sudden infant death syndrome and migraine)
7. Hypertension
8. Cerebral vasculitis (including haemolytic-uraemic syndrome)
9. Metabolic
10. Others: toxic-shock encephalopathy syndrome
haemorrhagic shock encephalopathy syndrome
remote effects of tumour

(Table 1) and includes metabolic disorders. Faced with a sick child it is important
to identify any underlying metabolic disorder rapidly. These can be conveniently
divided into six broad diagnostic groups (Table 2). There is considerable overlap
between these groups, and if patients fall into more than one group this will increase
the clinician's suspicions. These categories will be discussed but, although it is
recognized that fluid and electrolyte shifts are important in the pathogenesis of

42

Journal of Inherited Metabolic Disease. ISSN 0141-8955. Copyright© SSIEMand KluwerAcademic

Publishers, PO Box 55, Lancaster, UK. Printed in The Netherlands.
Acute Metabolic Encephalopathy 43

Table 2 Metabolic causes of acute metabolic encephalopathy and the initial investigations

Disturbances of glucose homeostasis glucose (B,U), gases (B)

Metabolic acidosis gases (B), lactate (P), ketones (U)
Hyperammonaemia ammonia (P)
Hepatic failure liver function and enzymes (P) clotting studies
(B)
Electrolyte disturbance urea and electrolytes (P) creatinine (P)
Mitochondrial encephatopathy lactate (B, U)
B = blood, P = plasma, U = urine. In all cases in which the diagnosis is not certain plasma
(5 mL) and urine 20 mL should be deep frozen in aliquots
The investigations listed represent the basic minimum and in many centres other investi-
gations may be able to be done at an early stage

metabolic encephalopathy these will not be considered; discussion will be confined

to encephalopathy after the immediate neonatal period.
If a metabolic disorder is suspected it is essential to obtain a detailed past and
family history together with the basic investigations listed in Table 2. These
represent the bare minimum and both plasma and urine should be deep frozen so
that they can be analysed later if necessary.

INVESTIGATION AND DIAGNOSIS

Disorders of glucose homeostasis
Hypoglycaemia: It is widely accepted that hypoglycaemia is defined as a blood
glucose concentration of less than 2 mmol L -1 although recent electrophysiological
studies suggest that the value should be 2.5mmolL -1 (Koh et al., 1988). The
possibility of hypoglycaemia should always be considered when conscious level is
disturbed, even in the absence of symptoms of adrenergic counter-regulation. Most
commonly the disturbance of consciousness is only transient, often secondary to a
convulsion. However some disorders may present with encephalopathy (see Table
3) and, regardless of the cause, if there are complications such as cerebral oedema
there may be prolonged disturbance of consciousness. The differential diagnosis of
acute metabolic encephalopathy and hypoglycaemia can be divided into three broad
categories, endocrine, metabolic and hepatic (Table 3). The history and clinical
examination may give important clues, for instance endocrine causes might be
suggested by the birthweight, micropenis and subsequent growth of the child, while
massive hepatomegaly suggests a defect in glycogen metabolism.
The cause of hypoglycaemia should always be sought. The most useful diagnostic
information is that obtained from samples taken when the child is hypoglycaemic.
These are sent for endocrine (insulin, cortisol, growth hormone) and metabolic
tests (blood free fatty acids, [5-hydroxybutyrate, lactate and alanine, and urine
organic acids) as well as tests of liver function. The results of these may give a
precise diagnosis and if not they at least enable a broad category of cause to be
identified.
If the results are not helpful or the samples are not collected during the acute

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44 Surtees and L e o n a r d

Table 3 Causes of hypoglycaemia and acute encephalopathy

Endocrine
Hypopituitary coma
Metabolic
Organic acidaemias:
Maple syrup urine disease
Methylmalonic acidaemia
Acetoacetyl-CoA thiolase deficiency
Propionic and isovaleric acidaemias (more rarely)
Fat oxidation defects:
Medium, long-chain and multiple acyl-CoA dehydrogenase deficiencies
3-Hydroxy-3-methylglutaryl-CoA lyase deficiency
Others (defects not fully characterized)
Drugs and toxins:
Alcohol
Oral hypoglycaemic agents
Salicylates
Hepatic
Fulminant liver failure
Reye's syndrome
This table gives the causes of illnesses presenting with acute encephalopathy (as defined
above) and hypoglycaemia. Any cause of hypoglycaemia may be responsible for transient
symptomatic (or even asymptomatic) central nervous system dysfunction; most commonly
this presents as a fit. Regardless of the cause of hypoglycaemia, prolonged symptoms can
also result in acute encephalopathy (see, for instance, Leonard and Dunger, 1978) and in
this situation the differential diagnosis is much wider

episode, the child should be investigated after recovery by studying the metabolic
response to fasting using the same investigations as listed above (Saudubray et al.,
1981). Based on the results of the tests, further appropriate studies should be
undertaken to determine the precise cause. These are beyond the scope of this
article (see Aynsley-Green and Soltesz, 1985; appropriate chapters in Stanbury et
al., 1983).
Hyperglycaemia: Diabetes mellitus presenting as acute metabolic encephalopathy
should be clear from the history, but it should be noted that hyperglycaemia and
glycosuria can also occur with ketoacidosis due to organic acidurias. This may rarely
be a presenting feature. However hyperglycaemia is most commonly secondary to
high glucose intake given to control metabolic disturbance. We have also seen
hypergtycaemia complicating severe illness in organic acidaemias caused by acute
pancreatitis (maple syrup urine disease, methylmalonic acidaemia and isovaleric
acidaemia; unpublished observations).

Metabolic acidosis
Metabolic acidosis is common in sick children regardless of the cause and in most
is secondary to poor tissue perfusion. A metabolic cause is more likely if there

J. Inher. Metab. Dis. 12 Suppl. 1 (1989)

Acute Metabolic Encephalopathy 45

have been previous episodes; the acidosis persists after correction of shock; if there
is metabolic acidosis without shock; or persistent ketosis. It can be particularly
difficult to recognize an underlying metabolic disorder if the patient has other
complications such as acute cardiomyopathy, The inherited disorders that may
present with acidosis are listed in Table 4.

Table 4 Acute metabolic encephalopathy and metabolic acidosis

Defects in glucose homeostasis:

Defects of gluconeogenesis (glucose 6-phosphatase and fructose 1,6-bisphosphatase
deficiences)
Organic acidaemias:
Maple syrup urine disease
Methylmalonic, propionic, 3-methylcrotonyl and isovaleric acidaemias, etc.
Multiple acyl CoA dehydrogenase deficiency and ethylmalonic-adipic aciduria
Holocarboxylase synthase deficiency
Defects in ketone body utilisation:
3-Oxoacid-CoA transferase deficiency
Acetoacetyl-CoA thiolase deficiency
Congenital lactic acidoses:
Pyruvate dehydrogenase deficiency
Deficiencies of the respiratory chain complex

The diagnosis is based on both the clinical findings and the blood glucose, lactate
and 3-hydroxybutyrate with the urine organic acids. In some patients, particularly
congenital lactic acidoses and ketone body utilization defects, the diagnosis may
only be established by studying the metabolic responses to fasting and glucose
loading once the child has recovered from the acute illness (Saudubray et al., 1987).
The diagnosis should be confirmed by enzyme analysis in fibroblasts or other
appropriate tissue.

Hyperammonaemia
In healthy adults and children venous plasma ammonia is usually less than
40 ~molL -I, but this may rise to 100~molL -I with systemic illness or shock.
However, the relationship between plasma ammonia concentrations and neurologi-
cal symptoms is not good. In patients with inherited disorders encephalopathic
symptoms may develop at ammonia concentrations of around 100~molL -~ but
some patients with urea cycle disorders may have no symptoms at much higher
concentrations (200~tmolL-I). However as a general guide, at ammonia concen-
trations of 100-200 ~tmol L -a vomiting, ataxia and irritability occur. Higher levels
of ammonia arc usually associated with increasing stupor, often alternating with
delirium and progressing to coma.
The differential diagnosis of acute hyperammonaemic encephalopathy is given
in Table 5 and the investigations to elucidate the cause can be deduced from this
list (Leonard, 1984).

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46 Surtees and L e o n a r d

Table 5 Hyperammonaemia and acute encephalopathy

Inherited disorders of the urea cycle:

Carbamyl phosphate synthase deficiency
Ornithine carbamoyl transferase deficiency
Citrullinaemia
Arginosuccinic aciduria
Arginase deficiency (rarely)
Organic acidaemias:
Propionic and methylmalonic acidaemias particularly
Other inherited disorders:
HHH syndrome
Hyperlysinaemia
Fat oxidation defects (medium and long-chain and multiple acyl-CoA dehydrogenase
defects)
Liver disease:
Any cause of severe chronic liver disease
Infective
Ischaemic
Drugs and toxins (e.g. valproate therapy, unripe Ackee fruit)
Wilson's disease
Reye's syndrome
Other:
Urinary tract infection with stasis
Asparaginase therapy
Leukaemia

Liver disease
Acute hepatic encephalopathy is characterized by confusion, depressed conscious
level, prominent motor abnormalities (tremor, asterixis, hyperactive stretch re-
flexes) and neuro-ophthalmological changes (normal pupils and brisk ocular re-
sponses). This may complicate either acute fulminant hepatic disease or acute
deterioration in chronic hepatic disease regardless of the underlying cause. Liver
disease should be suspected if liver enzymes are markedly raised and liver function
deranged (low albumin and fibrinogen, raised bilirubin). The presence of encepha-
lopathy, raised liver enzymes and a normal bilirubin suggests Reye's syndrome;
liver biopsy in this disease shows pathognomic changes (Partin et al., 1979). Detailed
diagnosis of the other causes is outside the scope of this article (see Russell et al.,
1987; Fraser and Arieff, 1985), but of particular importance is acute Wilson's
disease in older children which needs to be diagnosed urgently because of the
importance of giving specific therapy.

Mitochondrial encephalopathy
Patients with defects in the respiratory chain or of pyruvate dehydrogenase are
increasingly recognized, and may occasionally present acutely with encephalopathy.
These include Leigh syndrome (Pincus, 1972), Alpers syndrome (Gabre~ls et aI.,

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A c u t e Metabolic Encephalopathy 47

1984) and MELAS (myoclonus epilepsy, lactic acidosis and stroke-like episodes)
syndrome (Montagna et al., 1987). Although Leigh and Alpers syndromes can only
be diagnosed with certainty at post-mortem it is possible to establish the likely
diagnosis in life from the clinical course, raised lactate concentrations (which may
only be evident in cerebrospinal fluid) and characteristic changes on computerized
tomography or magnetic resonance imaging of the brain (van Erven et al., 1987).

MECHANISMS
The pathogenesis of acute metabolic encephalopathy is probably always multifact-
orial, with the more global effects of alterations in blood flow and intracranial
pressure acting in concert with more specific defects in one or more metabolic
pathways. Despite much interest and research, little is known about the interplay
of such factors and their impact upon the many different cell types in the central
nervous system.
It is likely that the initial symptoms and signs of acute metabolic encephalopathy
are caused by disordered neurotransmission and that only in the later stages of the
illness by energy failure and depolarization of cell membranes. All forms of acute
metabolic encephalopathy, with the exception of the mitochondrial encephalopath-
ies, are probably readily reversible in the early stages but with increasing duration
of the encephalopathy or repeated episodes permanent brain damage (Martin and
Schlote, 1972; Kendall et al., 1983) becomes more likely. This review concentrates
upon the disturbances secondary to hyperammonaemia and hypoglycaemia. Mech-
anisms of permanent brain cell damage following acute metabolic encephalopathy
and secondary structural damage that may complicate treatment (such as central
pontine myelinolysis) will not be discussed. The mechanisms that may cause
hepatic encephalopathy are also outside the scope of this article, except for the
consideration of those applicable to hyperammonaemia.

Hypoglyeaemia
The mechanisms of hypoglycaemic encephalopathy are likely to vary depending
on the disorder responsible for the reduced blood glucose concentration. Not only
is the major substrate for brain energy metabolism reduced but in some disorders
'toxic' metabolites may interfere directly with neurological function.
Cerebralperfusion pressure: Studies in man (della Porta et al., 1964) and animals
(Norberg and Siesj6, 1976) show that total cerebral blood flow rises during hypogly-
caemia but animal studies also show that there is a regionally selective loss of
antoregulation of cerebral blood flow (Ghajar et al., 1982). Therefore a fall in
systemic blood pressure during hypoglycaemia may well cause some regional
underperfusion. Some causes of hypoglycaemia ('toxic') may lead to cerebral
oedema because of accumulation of fatty acids (and possibly organic acids) in the
cells and, in theory, the large electrolyte shifts across cell membranes due to
hypoglycaemia per se may also cause cerebral oedema. Whilst measured fluid shifts

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48 Surtees and Leonard

have been small in 'isolated' hypoglycaemia, when 'toxic' metabolites are formed
cerebral oedema may become a major problem.
Effect on brain energy metabolism: Hypoglycaemia should have marked effects
upon cerebral energy metabolism because glucose is the main (and ordinarily
the sole) substrate for brain energy metabolism and the brain has high energy
requirements but slender substrate stores. In animals (Lewis et al., 1974) and man
(Koh et al., 1988) there is a critical blood glucose concentration below which
neurological dysfunction occurs.
Hypoglycaemia causes a fall in brain concentrations of glycolytic and tricarboxylic
acid cycle intermediates (Norberg and Siesj6, 1976; Lewis et al., 1974) and also a
fall in the high energy phosphate nucleotide pools (Chapman et al., 1981). The
fall in the high energy phosphate nucleotide pools occurs before a detectable
fall in cerebral metabolic rates and may be due to an uncoupling of oxidative
phosphorylation, perhaps by accumulation of intramitochondrial free fatty acids.
However, energy failure and subsequent generalized cellular depolarization occur
only when spontaneous brain electrical activity ceases, and cannot explain the
major symptoms of brain dysfunction during hypoglycaemia.
Neurotransmitter metabolism: Hypoglycaemia causing pre-coma results in drastic
changes in amino-acid (Lewis et al., 1974), acetyt-chotine (Gibson and Blass, 1976)
and monoamine (Siesj6, 1988) metabolism. It has been suggested that the symptoms
of hypoglycaemia that occur before development of energy failure are due to the
disruption of neurotransmission caused by such disordered metabolism (Siesj6 and
Plum, 1972). In addition, the marked deamination of amino acids to provide carbon
skeletons for oxidation during hypoglycaemia causes brain ammonia to rise to
levels seen in hyperammonaemic coma (Ghajar et al., 1982); this may further
impair synaptic transmission (see below).

Hyperammonaemia
Cerebralperfusionpressure: The effect of hyperammonaemia upon cerebraI blood
flow seems variable; however, there is an increase in cerebral blood flow (Voorhies
et al., 1983) in primates with acute hyperammonaemia, the vasodilation is probably
due to a direct effect of ammonia on vascular smooth muscle. However since there
is also a rise in intracranial pressure there may be no increase in perfusion
pressure. A rise in intracranial pressure and cerebral oedema may complicate
hyperammonaemia due to any cause and it has been suggested that this is due to
the osmotic effects of the large increase in brain glutamine (Watson et al., 1985).
In hepatic encephalopathy, cerebral oedema is found in 80% of deaths (Ware et
al., 1979).
Blood-brain barrier: Ammonia crosses the blood-brain barrier by diffusion, and
consequently the brain ammonia concentration increases in proportion with that of
blood. Hyperammonaemia appears to alter the properties of the blood-brain
barrier. In rats there is a selective increase in the uptake of tryptophan (perhaps
because of linked glutamine efflux) and a decrease in lysine uptake. The enhanced

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A c u w Metabolic Encephalopathy 49

uptake of tryptophan will increase brain serotonin and may have effects upon some
of the vegetative functions of the brain (Mans et al., 1987).
Effect on brain energy metabolism: Many experiments have shown that animals
in coma secondary to acute hyperammonaemia have depletion of ATP and phospho-
creatine, although this may show marked regional variation (McCandless and
Schenker, 1981). The mechanism by which hyperammonaemia depletes energy
stores is not well understood, nor is it known why some areas of the brain should
be more vulnerable than others.
The brain lacks the urea-cycle enzymes carbamyl phosphate synthase and orni-
thine carbamoyl transferase; therefore detoxification of ammonia in this organ
relies upon the formation of glutamine from glutamate, and ultimately from a-
ketoglutarate. One hypothesis, that ammonia interferes with the brain tricarboxylic
acid cycle by draining ct-ketoglutarate (Bessman and Bessman, 1955), has now
been disproved by the demonstration that in acute hyperammonaemia in animals
the brain a-ketoglutarate levels are normal or raised. However, in one study
in children with urea cycle disorders a negative correlation between plasma ct-
ketoglutarate and ammonia has been shown (Batshaw et al., 1980).
The adult brain relies upon the oxidation of glucose to carbon dioxide to provide
energy and the cytoplasmic N A D H produced must be regenerated as NAD ÷ by
the mitochondrial electron transport chain. Cytoplasmic N A D H cannot cross the
mitochondrial membrane and instead the reducing equivalents are transported via
shuttles. Of particular interest is the malate-aspartate shuttle, because its activity
in brain is closely linked to the tricarboxylic cycle and glutamate is an integral part
of the shuttle. In acutely hyperammonaemic rats, symptoms, occuring before
changes in the high energy phosphate intermediates are noted, are accompanied
by changes in the cytosolic and mitochondrial NADH/NAD + ratio and by decreased
aspartate and glutamate with raised pyruvate and alanine (Hindfield et al., 1977).
Initial symptoms of hyperammonaemia may be due to decreased shunting of
reducing equivalents and a decrease in excitatory neurotransmitters (aspartate and
glutamate). Eventually the reduced turnover of the shuttle will cause a slowing of
the tricarboxylic cycle and a fall in high energy phosphate intermediates.
Electrophysiology: In addition to the marked biochemical effects of hyperam-
monaemia there are also effects on the electrophysiological properties of synapses.
In theory ammonia should have a potassium-like depolarizing effect upon the
axon, but this requires a much higher ammonia concentration than that seen in
hyperammonaemic encephalopathy (Alger and Nicoll, 1983). However, marked
effects upon central nervous system excitatory and inhibitory synapses are seen at
ammonia concentrations more likely to be achieved in encephalopathy (Raabe,
1987). At excitatory synapses ammonia probably exerts its effect by depleting the
glutamine within presynaptic vesicles. Glutamine is the source for glutamate in the
synaptic vesicles (Bradford and Ward, 1976), and raised ammonia concentrations
also inhibit glutaminase activity. At inhibitory synapses ammonia prevents the
hyperpolarizing inhibitory potential at the post-synaptic neurone by decreasing
the chloride-dependent hyperpolarization triggered by calcium-influx or neuronal
depolarization (Raabe and Lin, 1985).

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50 Surtees and L e o n a r d

Metabolic acidosis and mitoehondrial disorders

Acidosis increases cerebral blood flow, although any benefit from this is offset by
the rise in intracranial pressure due to the osmotic effects of the abnormal metab-
olites. This is further complicated by the fluid loss from the circulation that occurs
secondarily to the diuresis induced by the excretion of abnormal metabolites. In
methylmalonie acidaemia many patients have a renal concentrating defect which
exacerbates the hypovolaemia and dehydration.
Although short-chain fatty acids are known to cause uncoupling of oxidative
phosphorylation in brain mitochondria (Ahmed and Schofield, 1961), coma induced
by an infusion of these does not seem to be due to impaired cerebral energy
metabolism (Walker et al., 1970). It seems likely that disordered neurotransmission
is responsible for the initial symptoms and it is known that ketoacids and short-
chain fatty acids affect the metabolism of both excitatory and inhibitory amino-acid
neurotransmitters (Tashian, 1961; Lopez-Lahoya et al., 1981).
The pathogenesis of acute encephalopathy in mitochondrial disorders is not
known. It is possible that increased energy demands exceed the residual activity of
the respiratory chain with failure in brain energy metabolism.

TREATMENT
The management of acute metabolic encephalopathy is largely general, with little
specific therapy. The general management of acute metabolic encephalopathy is
outlined in Table 6.
Table 6 General management of acute metabolic eneephaiopathy

1. Supportive
Maintain oxygenation
Maintain circulation
Maintain normal body temperature
Prevent agitation
2. Corrective
Electrolyte, calcium and phosphate imbalance
Acidosis
Seizures
Prevent protein and fat catabolism
3. Reduce raised intracranial pressure
Restrict fluids to ,.=]maintainance
Intubation and controlled ventilation
Monitor intracranial pressure
Intracranial pressure >20 mmHg or cerebral perfusion pressure <40 mmHg use mannitol
0.25-0.5gkg 1 then frusemide lmgkg -1
Consider pentobarbitone or thiopentone

The maintenance of an adequate circulation (with monitoring of the arterial and

venous pressures) is of especial importance because cerebral vascular autoreguta-
tion is often lost in these disorders. Electrolyte disturbance may be prominent in

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Acute Metabolic Encephalopathy 51

methylmalonic acidaemia and hepatic failure and hypovolaemia should be cor-

rected - but fluid overload avoided as it can exacerbate cerebral symptoms. It is
essential to prevent further protein and fat catabolism which frequently generate
the abnormal toxic metabolites in these diseases; this can be achieved by infusing
glucose using concentrated solutions at 75-100 g m -2 day -I (2.5-3.5 g kg -~ day -1)
plus insulin if hyperglycaemia becomes a problem. Acidosis should be corrected
with sodium bicarbonate and if this is ineffective or hypernatraemia develops
bicarbonate peritoneal dialysis should be instituted (Leonard, 1985).
Patients with inherited metabolic disorders are at particular risk of cerebral
oedema and care needs to be taken to reduce the risk of this developing. Fluid
overload should be avoided and in general any patient who is seriously ill should
be electively intubated and hyperventilated. This is particularly important before
any procedure or drugs that may compromise respiratory reserve such as peritoneal
dialysis. For any child who is clearly seriously ill, careful thought should be given
to monitoring the intracranial pressure before encephalopathy develops. Suspicious
signs are a deteriorating level of consciousness despite treatment and, in addition,
any of the following: (1) insensibility to pain; (2) extensor hypertonus; (3) sluggishly
reacting, dilated pupils; (4) abnormal respiratory pattern; (5) circulatory changes;
(6) spontaneous limb cycling. In early stages fluid restriction, elective intubation and
hyperventilation may be sufficient. The decision to monitor intracranial pressure is
easier now that reliable transducers can be easily inserted at the bedside. Measures
to consider to reduce intracranial pressure are summarised in Table 6.

Specific therapy
Hypoglycaemia: Hypoglycaemia should be immediately corrected with a bolus
of glucose intravenously (after collecting blood for diagnostic investigations) fol-
lowed by an infusion. Glucose therapy may need to be continued for some time
before improvement of encephalopathy is seen in 'toxic' hypoglycaemia, but may
cause a rapid reversal of symptoms in hypoglycaemia due to substrate deficiency.
Specific treatment may be used to prevent further episodes including hormone or
drug therapy.
ttyperammonaemia: Excretion of ammonia in urea cycle disorders can be en-
hanced by treatment with sodium benzoate and phenylacetic (or phenytbutyric)
acid. Benzoate combines with glycine to form hippuric acid and phenylacetate
combines with glutamine to form phenylacetylglutamine, both of these compounds
are readily excreted in the urine and therefore reduce the total nitrogen load on
the urea cycle. Additionally the urea cycle itself can be primed with arginine, and
in arginosuccinic aciduria and citrullinaemia this will reduce plasma ammonia
concentrations (Brusilow, 1985; Walter and Leonard, 1988).
Regardless of cause, very high ammonia levels (500-700~tmolL -1) or a poor
response to therapy indicate that dialysis should be considered, haemodialysis being
more effective than peritoneal.
Organic acidaemia: Glycine increases the excretion of isovaleric acid since it is
conjugated to form isovalerytglycine which is readily excreted in the urine. Carnitine

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52 Surtees and L e o n a r d

may increase the efflux of organic or fatty acids from the mitochondria, thereby
reducing the toxic effects upon the energy metabolism and promoting their excretion
(Wollff et al., 1986). If the toxicity is severe, dialysis will help to reduce the organic
acid toad and ameliorate the encephatopathy.
L i v e r disease: Acute Wilson's disease requires prompt therapy to reduce the total
copper load of the body. Measures used with some success include albumin infusion
and ptasmapheresis, and more recently peritoneal dialysis against penicillamine
(de Bont et aI., 1985) and liver transplantation (Sokol et aL, 1985),
In other forms of hepatic encephalopathy attempts to ameliorate the metabolic
disturbance have met with rather limited success. The use of branched-chain
amino or keto-acids, glutamate and y-aminobutyric acid antagonists have all been
suggested.

CONCLUSIONS
It is important to recognize acute metabolic encephalopathy at the earliest stage
possible and to institute treament to prevent permanent neurological damage.
Unfortunately, despite the very extensive literature on the mechanisms of acute
metabolic encephalopathy, very little of this information has yet been used in the
management of patients presenting acutely, and much of the treatment remains
supportive rather than specific.

REFERENCES
Ahmed, K, and Schofield, P. G. Studies on fatty acid oxidation 8. The effects of fatty acids
on metabolism of rat brain cortex in vitro. Biochem. J. 81 (1961) 45-53
Alger. B. E. and Nicoll, R. A. Ammonia does not selectively block IPSPs in rat hippocampal
pyramidal cells. J. Neurophysiol. 49 (1983) 1381-1391
Aynsley-Green, A. and Soltesz, G. Hypoglycaemia in infancy and childhood. Current
Reviews in Paediatrics, Vol. 1, Churchill Livingston, Edinburgh and London, 1985, pp.
151-161
Batshaw, M. L., Walser, M. and Brusilow, S. Plasma a-ketoglutarate in urea cycle enzy-
mopathies and its role as harbinger of hyperammonemic coma, Pediatr. Res. 14 (1980)
1316-1319
Bessman, S, P. and Bessman, A. N. The cerebral and peripheral uptake of ammonia in liver
disease with an hypothesis for the mechanism of hepatic coma. J. Clin. Invest. 34 (1955)
622-628
de Bont, B., Moulin, D., Stein, F., van Hoof, F, and Lauwerys, R. Peritoneal dialysis with
D-penicillamine in Wilson disease. J. Pediatr. 107 (1985) 545-547
Bradford, H. F. and Ward, H. K. On glutaminase activity in mammalian synaptosomes.
Brain. Res. 110 (1976) 115-125
Brusilow, S. W. Inborn errors of urea synthesis. In Lloyd, J. K. and Scriver, C. R. (Eds.),
Genetic and Metabolic Disease in Paediatrics, Butterworths, London, 1985, pp. 140-165
Chapman, A. G., Westerberg, E. and Siesj6, B. K. The metabolism of purine and pyrimidine
nucleotides in rat cortex during insulin-induced hypoglycaemia and recovery. J. Neuro-
chem. 36 (1981) 179-189
van Erven, P. M. M., Cillesen, J. P. M., Eekhoff, E. M. W., Gabre6ts, F. J. M., Doesberg,
W. H., Lemmens, W. A. J. G., Slooff, J. L., Renier, W. O. and Ruitenbeek, W. Leigh

J. h2her. Metab. Dis. 12 Suppl. 1 (1989)

Acute Metabolic Encephalopathy 53

syndrome, a mitochondrial encephalo(myo)opathy. Clin. Neurol. Neurosurg. 89 (1987)

217-230
Fraser, C. L. and Arieff, A. I. Hepatic encephalopathy. N. Engl. J. Med. 313 (1985) 865-
873
Ghajar, J. B. G., Plum, F. and Duffy, T. E. Cerebral oxidative metabolism and blood flow
during acute hypoglycaemia and recovery in unanaesthetised rats. J. Neurochem. 38
(1982) 397.409
Gabre6Is, F. J. M., Prick, M. J. J., Trijbets, J. M. F.. Renier, W. O., Jaspar, H. H. J.,
Jansen, A. J. M. and Sloof, J. L. Defects in citric acid cycle and the electron transport
chain in progressive poliodystrophy. Acta Neurol. Scand. 70 (1984) 145-154
Gibson, G. E. and Blass, J. P. Impaired synthesis of acetylcholine in brain accompanying
mild hypoxia and hypoglycaemia. J. Neurochem. 27 (1976) 37-42
Hindfield, B., Plum, F. and Duffy, T. E. Effect of acute ammonia intoxication on cerebral
metabolism in rats with portocaval shunts. J. Ctin. Invest. 59 (1977) 386-396
Kendall, B. E., Kingsley, D. P. E., Leonard, J. V., Lingam, S. and Oberholzer, V. G.
Neurological features and computed tomography of the brain in children with ornithine
carbamoyl transferase deficiency. J. Neurol. Neurosurg. Psychiatr. 46 (1983) 28-34
Koh, T. H. H. G., Aynsley-Green, A., Tarbit, M. and Eyre, J. A. Neural dysfunction
during hypoglycaemia. Arch. Dis. Child. 63 (1988) 1353-1358
Leonard, J. V. Hyperammonaemia in childhood. In Clayton, B. E. and Round, J. M.
(Eds.), Chemical Pathology and the Sick Child, BlackwelI, Oxford, 1984, pp. 96-119
Leonard, J. V. The early detection and management of inborn errors presenting acutely in
the neonatal period. Eur. J. Pediatr. 143 (1983) 253.257
Leonard, J. V. and Dunger, D. B. Hypoglycaemia complicating feeding regimes for glycogen
storage disease. Lancet 2 (1978) 1203-1204
Lewis, L. D., Ljundgren, B., Ratcheson, R. A. and Siesj6, B. K. Changes in the carbohydrate
substrates, amino acids and ammonia in the brain during insulin-induced hypoglycaemia.
J. Neurochem. 23 (1974) 65%671
Lopez-Lahoya, J., Garcia, M. L., Benavides, J. and Ugarte, M. Inhibition by methylmalon-
ate of glycine uptake by synaptosomes from the rat spinal cord. J. Neurochem. 36 (1981)
325-327
McCandless, D. W. and Schenker, S. Effects of acute ammonia intoxication on energy stores
in the reticular activating system Exp. Brain Res. 44 (1981) 325-330
Mans, A., Biebuyk, J. and Hawkins, R. Brain tryptophan abnormalities in hyperammona-
emia and liver disease. In Bender, D. A., Joseph, M. H., Kochen, W. and Steinhart, H.
(Eds.). Progress in Tryptophan and Serotonin Research 1986, Walter de Guyter, Berlin,
1987, pp. 207-213
Martin, J. J. and Schlote, W. Central nervous system lesions in disorders of amino-acid
metabolism: a neuropathological study. J. Neurol. Sci. 15 (1972) 49-76
Montagna, P., Gallassi, R., Medori, R., Govone, E., Eeviani, M., di Mauro, S., Lugaresi,
E. and Andermann, F. MELAS syndrome: characteristic migrainous and epileptic fea-
tures and maternal transmission. Neurology 38 (1988) 751-754
Norberg, K., Siesj6, B. K. Oxidative metabolism of the cerebral cortex of the rat in severe
insulin-induced hypoglycaemia. J. Neurochem. 26 (1976) 179-189
Partin, J. C., Bove, K., Partin, J. S. and Schubert, W. K. Liver and muscle ultrastructure
in Reye's syndrome. In Crocker, J. F. S. (Ed.), Reye's Syndrome, Vol. II Grune and
Stratton, New York, 1979, pp. 215-232
Pincus, J. H. Subacute necrotising encephalomyelopathy (Leigh's disease): a consideration
of clinical features and etiology. Dev. Med. Child. Neurot. 14 (1972) 87-101
della Porta, P., Maiolo, A. T., Negri, V. U. and Rosella, E. Cerebral blood flow and
metabolism in therapeutic insulin coma. Metabolism 13 (1964) 131-140
Raabe, W. Synaptic transmission in ammonia intoxication. Neurochem. Pathol. 67 (1987)
145-166
Raabe, W. and Lin, S. Pathophysiology of ammonia intoxification. Exp. Neurol. 87 (1985)
519-532

J. Inher. Metab. Dis. 12 Suppl. 1 (1989)

54 Surwes and Leonard

Russell, G. J., Fitzgerald, J. F. and Clark, J. H. Fulminant hepatic failure. J. Pediatr. 111
(1987) 313-319
Saudubray, J. M., Marsac, C., Limal, J. M., Dumurgier, E., Charpentier, C., Ogier, H.
and Coud6, F. X. Variation in plasma ketone bodies during a 24-hour fast in normal and
in hypoglycaemic children: relationship to age. J. Pediatr. 98 (1981) 904-908
Saudubray, J. M.0 Specola, N., Middleton, B., Lombes, A., Bonnefont, J. P., Jakobs, C.,
Vassault, A., Charpentier, C. and Day, R. Hyperketotic states due to inherited defects
of ketolysis. Enzyme 38 (1987) 8090
Siesj6, B. K. Hypoglycaemia, brain metabolism, and brain damage. Diabetes Metab. Rev.
4 (1988) 113-144
Siesj6, B. K. and Plum, F. Pathophysiology of anoxic brain damage. In Gaull, G. E. (Ed.),
Biology of Brain Dysfunction, Plenum Press, New York, 1972, pp. 319-372
Sokol, R. J., Francis, P. D., Gold, S. H., Ford, D. M., Lure, G. M. and Ambruso, D. R.
Orthotopic liver transplantation for acute fulminant Wilson disease. J. Pediatr. 107 (1985)
549-552
Stanbury, J. B.. Wyngaarden, J. B., Fredrickson, D. S., Goldstein, J. L. and Brown, M. S.
(Eds.). The Metabolic Basis of Inherited Disease, 5th edn., McGraw-Hill Book Co., New
York, 1983
Tashian, R. E. Inhibition of brain glutamic dehydrogenase by phenylalanine, leucine and
valine derivatives: a suggestion concerning the neurological defect in phenylketonuria
and branched-chain ketoaciduria. Metabolism 10 (1961) 393-402
Voorhies, T. M., Ehrlich, M. E., Dully, T. E., Petito, C. K. and Plum, F. Acute hyperam-
monaemia in the young primate: physiologic and neuropathotogic correlates. Pediatr.
Res. 17 (1983) 970-975
Walker, C. O., McCandless, D. W., McGarry, J. D. and Shenker, S. Cerebral energy
metabolism in short chain fatty acid induced coma. J. Lab. Clin. Med. 76 (1970) 569-
583
Walter, J. H. and Leonard, J. V. Inborn errors of the urea cycle. Br. J. Hosp. Med. 38
(1987) 176-183
Ware, A. J., d'Agostino, A. and Combes, B. Cerebral oedema: a major complication of
massive hepatic necrosis. Gastroenterology 76 (1979) 123-131
Watson, A. J., Karp0 J. E., Walker, W. G., Chamber, T., Risch, V. R. and Brusilow, S. W.
Transient idiopathic hyperammonaemia in adults. Lancet 2 (1985) 1271-1274
Wollff, J. A., Caroll, J. E,, Thuy, L. P., Haas, R. and Nyhan, W. L. Carnitine reduces
fasting ketogenesis in patients with disorders of propionate metabolism. Lancet 1 (1986)
28%291

J. lnher. Metab. Dis. 12 Suppl, 1 (1989)