Pathophysiology of Encephalopathy

N. LATRONICO, G.F. BussI, A. CANDIANI

The metabolic complexity of the central nervous system (CNS) makes it de-
pendent upon the functional integrity of other body systems for the adequate
provision of essential nutrients and elimination of toxins. It is therefore not
surprising that various metabolic effects on the CNS are secondary to sys-
temic diseases. These are situations in which a diffuse brain malfunction is
clinically evident, despite the evidence of structural brain alteration is lacking.
It is only when the metabolic disorder has been profound that structural
changes occur, thus accounting for the permanent neurological deficits that
some patients exhibit.
Attention and cognitive functions such as perception, thinking and memory
are affected early. Alertness tends to fluctuate between agitation and lethargy,
but in severe cases stupor and coma may ensue. Noteworthy, focal motor signs,
abnormalities of pupillary reactivity and of ocular movements are exceedingly
rare even in deep coma [1].
Numerous endogenous conditions, including fluid and electrolytes disorders,
hypoglycaemia, diabetes and pancreatitis, liver and renal failure, cancer, hyper-
and hypothermia, nutritional and hypoxic disorders may be responsible for a
metabolic encephalopathy in the critically ill patient [1, 2].
Septic encephalopathy (SE) defines a clinical picture characterised by the
impairment of the alertness and cognitive function, which is described in pa-
tients with sepsis. A structural brain alteration is not evident on neuroradiologi-
cal investigations, and the clinical signs may be fully reversible, provided the
systemic infection is timely dominated and complications are avoided. So de-
fined, the SE fulfils the definition of metabolic encephalopathy, although other
authors classify it among the inflammatory CNS disorders [1]. Systemic inflam-
mation has a key role in promoting the multiple organ dysfunction syndrome
and a systemic inflammatory response syndrome, either due to infection (sepsis)
or not, is a recognised [3-5] although still a debated entity [6]. However, local
signs of inflammation within the CNS are lacking [7].

A. E. Baue et al. (eds.), Sepsis and Organ Dysfunction

© Springer-Verlag Italia 2000
78 N. Latronico, G.F. Bussi, A. Candiani

The neuronal function, not strictly the neuron, is involved

The loss of the highest integrative cerebral functions in SE is compatible with a
diffuse dysfunction of neurons. Also the fact that electroencephalogram (EEG)
correlates well with the severity of SE [8] points to the functional involvement
of the neuron, the EEG-generating cell. The available evidence indicates that the
major determinants of the neuronal function - the cerebral blood flow, the
blood-brain barrier, the cerebral environment and the neuron itself - are altered
in SE.

The supply of oxygen and nutrients

Cerebral blood flow (CBF) is reduced in dogs [9] and humans [10, 11] with se-
vere sepsis. The cerebral metabolic rate of oxygen (CMR0 2) is increased in
dogs probably as a consequence of gross endotoxin blood-brain barrier damage
and passage of hydrogen ions and catecholamines into the brain. This imbalance
between demand (increased) and supply (reduced) makes the brain vulnerable to
hypoxia, and can be prevented by propanolol pretreatment [9]. In humans, the
CMR02 seems reduced, however only one study actually measured it in 6 pa-
tients [11]. In this study, decreased oxygen consumption was paralleled by EEG
slowing, suggesting normal coupling between metabolic activity and blood
flow. Microthrombosis is also reported [1], however this seems a finding of ad-
vanced, complicated disease, while encephalopathy is an early event [12].
Wijdicks and Stevens in a retrospective series of 84 patients found that the
development of SE was associated with hypotension [13]. Two out of 14 patients
developing SE had widespread ischaemic cortical damage on neuropathological
examination. However, criteria for hypotension (timing, severity, duration) are
not presented, and those for SE were only clinical, a low sensitive method com-
pared to EEG [1, 8]. Eidelman et al. in a prospective study could not find an as-
sociation between hypotension and SE, which was instead associated with in-
creased mortality, bacteraemia, and renal and hepatic dysfunction [2].
Hypoxic-ischaemic damage by a number of causes is likely to aggravate an
already altered brain. However, no convincing evidence supports its role in initi-
ating SE.

The blood-brain barrier (BBB)

A breakdown of the BBB has since long been postulated after studies showing
an increased permeability with the passage of colloidal iron oxide [14], 14C_
amino acids [15], horseradish peroxidase [16] and 125I-albumin [17] in septic an-
imals, as well as the increased cerebro-spinal fluid level of proteins in septic hu-
mans [8].
Pathophysiology of Encephalopathy 79

Recently, Papadopoulos et al. showed increased oedema around cortical mi-

crovessels, but not around larger vessels [18]. On the contrary, the endothelial
cells appeared normal with morphologically intact mitochondria and intercellu-
lar tight junctions.
To summarise, the mechanism(s) by which BBB permeability is increased
remains obscure: increased pinocytosis or molecular alteration of the occludins,
the tight-junction constituent proteins, are possible explanation [18]. The
perivascular oedema may affect the supply of oxygen and nutrients to the brain,
and may contribute to the symptoms of SE.

The cerebral environment

Astrocytes are not just framework cells
The neuronal function is strictly dependent on the maintenance of appropriate
chemical and physical cerebrospinal fluid (CSF) properties. For example, the re-
duction of CSF osmolality greatly increases the neuronal excitability, and
seizure is a common complication of acute hyponatraemia [19]. The BBB has a
central role in the maintenance of cerebral homeostasis, and so the astrocytes.
However, it is now clear that astrocytes also have intense metabolic activity.
Studies over the last 15 years have buried the image of astrocytes as "stodgy,
merely supportive, and unresponsive ugly sister of neurons" [20]. Their impor-
tance in removing glutamate and aspartate, the two major excitatory amino
acids (EAA), is crucial in preventing neurotoxicity [20, 21] (Fig. 1), a role that
Lugaro had intuited at the beginning of this century:
"Every nervous termination suffers a chemical modification and this chemi-
cal modification in tum gives stimulus to another neuron. If this is true, the in-
terneuronal articulation would be at the center of the chemical exchange, and
therefore would comprise in all the most proximal, vacant interstitial spaces, a
region for infiltration of the protoplasmatic prolongations of feathery extensions
of the neuroglia [the astrocytes], perhaps with the purpose of collecting and in-
stantly processing the smallest amount of waste product" (Lugaro, 1907) [22].
Astrocyte swelling was demonstrated by Clawson et al. in endotoxaemic rab-
bits [14]. This result has been recently confirmed in Papadopoulos' study, in
which a substantial astrocyte damage with gross swelling of perivascular end-
feet and their rupture and detachment from microvessel endothelial cell wall
was clearly present [18]. Disruption of BBB is a likely explanation for these al-
terations [23], which in tum may profoundly alter CSF composition by increas-
ing the extracellular glutamate concentration. This latter has been estimated to
be approximately 0.6 fJ,mollL, and substantial excitotoxic damage is expected to
occur when the glutamate concentration reaches 2 to 5 fJ,mollL. Since the astro-
cytes (and neurons) contain 10 mmol of glutamate per litre, the potential for dis-
aster is obvious [21] (Fig. 1).
 80 N. Latronico, G.P. Bussi, A. Candiani

Ammonia

Glutamate

Glutamate 0.6 lJllloVL

Glutamate

Ammonia

Fig. 1. Glutamate-glutamine shuttle: the presynaptic neuron (pre) stimulates the post-synaptic neu-
ron (post) by means of glutamate. Extracellular glutamate concentration must be kept below 2-5
~mol/L, and it is therefore aminated to glutamine by glutamine synthetase (GS) in the astrocyte
(A). Glutamine is then partly deaminated to glutamate by glutaminase (GLM) to restore the neu-
ronal pool, and partly conveyed to the blood. The glutamine passage across the blood-brain barrier
(BBB) is coupled with entrance of neutral amino acids

In summary, the alteration of neuronal environment, particularly EAA cyto-

toxicity, is a conceivable operating mechanism in SE. To date, however, only in-
direct evidence is available to support this view.

Neurotransmitter imbalance
Aromatic (AAA: phenylalanine, tyrosin, tryptophan) and sulfur-containing
amino acids (taurine, cysteine, methionine) are increased in plasma from septic
animals and humans. Conversely, the branched chain amino acids (BCAA: va-
line, leucine, isoleucine) and y-aminobutyric acid (GABA) are reduced. This
pattern is similar to that seen in hepatic encephalopathy, and is thought to be
due to enhanced muscle proteolysis coupled with a hepatic failure to handle
these breakdown products [15, 24-28].
AAA are precursors for brain neurotransmitters, and their brain uptake is in-
creased during sepsis [26-28] (Fig. I). GABA is a major inhibitory neurotrans-
Pathophysiology of Encephalopathy 81

mitter in the CNS, and an increase in GABA-A receptors density has been
demonstrated in septic rodents [29].
The result is a neurotransmitter imbalance with concomitant activation of the
GAB A and serotoninergic inhibitory systems and inhibition of the cate-
cholaminergic activating system [28-30] (Fig. 2).

Muscle ProteolYSitand liver dysfunction

Increased plasmatic levels of AAA

BLOOD Tryptophan Phenylalanine Tyrosine

I

BRAIN
+~
GABA Serotonin Pheny lethilamine, phenylethanolamine
~l
Dopamine
Octopamine Norepinephrine
Tyramine

+ Inhibitory + Weak (false) activating - Activating

neurotransm itters neurotransmitters neurotransmitters

Sensorium Impaired immuno-

depression mediated systemic
inflammation
Fig. 2. Alterations of plasma and brain aromatic amino acids (AAA, phenylalanine, tyrosin, tryp-
tophan), and their supposed effect on consciousness [24-30) and immunity [31)

There is general agreement that plasma amino acids alterations are caused
by subtle liver dysfunction, probably an early as well as underestimated prob-
lem due to the complexity of diagnostic approach [15, 25-28]. It is worth citing
that the brain amino acids derangement, particularly the noradrenergic system,
may in tum profoundly affect the immune-mediated systemic inflammatory re-
sponse [31].
The alteration of plasma and brain amino acids profile may explain some of
the consciousness alterations seen in SE patients, and BCAA infusion has been
shown to restore brain amino acids and neurotransmitter profile towards normal.
However, direct proof that BCAA ameliorate the symptoms of SE is lacking.
82 N. Latronico, G.F. Bussi, A. Candiani

The neuron
In Papadopoulos' study dark, shrunken neurons were seen in the frontal cortex
of pigs after 8 hours of sepsis, They were not present in control sham-operated
animals, and therefore they were not an artifact [23], Furthermore, the cyto-
plasm of other neurons appeared dilute, The authors speculate that a cytotoxic
event could be operating. Taken together with the described astrocyte alter-
ations, it is possible that astrocytes fail to keep the extracellular excitatory
amino acids concentration low. When excitotoxic levels are reached, cellular
(neurons and astrocytes) necrosis ensues, thus liberating massive amount of ex-
citatory amino acids, and creating a vicious, self-propagating circle.
As already cited, at present cytotoxicity is only a sound hypothesis still to be
tested. Whatever the mechanism(s) of neuronal damage, the Papadopoulos' re-
sults are important, since they demonstrate that neurons are directly damaged in
an early phase of sepsis.

Conclusions
The available evidence suggests that the blood-brain barrier, the brain environ-
ment, the neuron itself, and in advanced state the brain energy supply - that is,
all the major determinants of the neuronal function - are altered in SE. Ultra-
structural and functional investigations are needed to validate the on-going hy-
potheses and put them in a rank order.

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