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1 (1989) 42-54
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
Table 2 Metabolic causes of acute metabolic encephalopathy and the initial investigations
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
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.
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).
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.,
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
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
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).
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
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
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.
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