Medical Diseases and Metabolic Encephalopathies

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Neurological emergencies in medical diseases (secondary brain
injury), e.g., renal coma, hepatic coma, salt and water imbalance,
disturbance of glucose metabolism, other endocrinal causes of
coma, disturbances of calcium and magnesium metabolism,
drugs and intoxication, represent a good part of the patient
population in the neurocritical care unit. Understanding the
underlying mechanisms of secondary brain injury which include
hypoxia, hypoperfusion, reperfusion injury with free radical
formations, release of excitatory amino acids and harmful
mediators from injured cells, and electrolyte and acid base
changes from systemic or regional ischemia, are very important
for proper management of such conditions. Management rules
will be specified according to each cause and pathogenesis.
Metabolic encephalopathies are a group of neurological deficits
affecting the brain causing delirium, confusion, or coma, caused
by different mechanisms involving toxin production or
interference with metabolic biochemical processes. Metabolic
encephalopathies are usually multifactorial in origin, and are
important complications of many diseases of patients treated in
critical care units. Confusion is clinically defined as the inability

to maintain a coherent stream of thought or action. Delirium is a
confusional state with superimposed hyperactivity of the
sympathetic limb of the autonomic nervous system with
consequent signs including tremor, tachycardia, diaphoresis,
and mydriasis. Acute toxic-metabolic encephalopathy (TME),
which encompasses delirium and the acute confusional state, is
an acute condition of global cerebral dysfunction in the absence
of primary structural brain disease (Chen 1996).
Examination of the Encephalopathic Patient
1. Mental state assessment
a. Level of consciousness using Glasgow Coma Scale (GCS),
b. Memory and attention by Mini-Mental State
Examination (MMSE),
c. Mood (depression, elation, mania or irritability),
d. Hallucination, which is usually visual.
2. Physical examination
a. Temperature,
b. Pulse (for tachycardia),
c. Pupillary dysfunctions and extraocular movements,
N.B. pupillary functions are ones that last and resist
changes in metabolic encephalopathies.
d. Respiratory pattern,
e. Motor response,
N.B. during examination of motor response look for
presence of asterixis, which are drops of fully extended
wrists for less than one second with re-extension again.
3. Investigations
a. CSF examination,
b. Full metabolic scanning of the blood,
c. Neurophysiologic tests, e.g., EEG, evoked potentials,
i. EEG patterns in metabolic encephalopathies are not
specific (e.g., triphasic waves in hepatic
encephalopathy). On the other hand, multifocal

spikes are specific to lithium intoxication (Kaplan
2011).
ii. Brain stem auditory evoked potentials (BAER) are
resistant to metabolic changes.
d. Neuroimaging, e.g., CT scan, MRI.
General Pathophysiology
Normal neuronal activity requires a balanced environment of
electrolytes, water, amino acids, excitatory and inhibitory
neurotransmitters, and metabolic substrates (Earnest 1993). In
addition, normal blood flow, normal temperature, normal
osmolality, and physiologic pH are required for optimal central
nervous system function. Complex systems, including those
mediating arousal and awareness and those involved in higher
cognitive functions, are more likely to malfunction when the
local body environment is deranged (Young 1998).
All forms of acute metabolic encephalopathy (ME) interfere
with the function of the ascending reticular activating system
and its projections to the cerebral cortex, leading to impairment
of arousal and awareness. Ultimately, the neurophysiologic
mechanisms of ME include interruption of polysynaptic
pathways and altered excitatory-inhibitory amino acid balance
(Lipton 1994). The pathophysiology of ME varies according to the
underlying etiology.
Hepatic Encephalopathy
Hepatic encephalopathy (HE) appears as a complication of
fulminant hepatic failure (FHF) and in chronic liver failure.
Initially it is characterized by minor mental and personality
changes with some cognitive impairment. With disease
progression there are obvious motor abnormalities and
increasing loss of consciousness until deep coma.
Etiology of fulminant hepatic failure includes viruses, drugs
(such as halothane, acetaminophen, valproate and INH), and

acute fatty liver in pregnancy, toxins (such as amatoxins and
phosphorus), Wilson disease and Rye’s syndrome.
Pathophysiology of hepatic encephalopathy includes
neurotoxins (like ammonia, short- and medium-chain fatty
acids, mercaptans, phenols, etc), and altered neurotransmission
(due to benzodiazepine-like substances, and neurotransmitters’
hypothesis including 5-HT and glutaminergic transmission). This
may end in cerebral edema (Young 1998).
All of the following conditions may precipitate hepatic
encephalopathy:
– Increased GIT protein absorption like in GIT hemorrhage or
increased dietary protein
– Drugs like benzodiazepines or INH
– Renal dysfunction
– Catabolic states like infections and surgery
– Dehydration, hypokalemia, constipation
– Chronic hepatopathies which can present with FHF, e.g.,
cirrhosis with portal hypertension, portal vein thrombosis,
Wilson disease, ornithine carbamoyltransferase deficiency
and chronic valproate hepatopathy
Complications of hepatic encephalopathy (HE)
Epilepsy may complicate hepatic encephalopathy in 10–30% of
cases, related to hypoglycemia. Cerebral edema may complicate
hepatic encephalopathy in 80% of cases. Bleeding and renal
dysfunction (i.e., renal failure in presence of normal-sized
kidney (hepatorenal syndrome), with urine sodium
concentration below 20 mmol/L, while the urine is
hyperosmolar) may complicate hepatic encephalopathy also.
This syndrome is reversible with normalization of renal
functions. Another form of renal dysfunction is pre-renal
azotemia. Hypotension and derangement of acid base balance
with acidosis is reported with cerebral edema and alkalosis, and
is found with vomiting and hypokalaemia in cases of hepatic
encephalopathy.

Table 9.1 – Differences between FHF and chronic hepatic
encephalopathy
Feature FHF Chronic HE
History
Onset
Mental state
Precipitation
History of liver disease
Acute
Mania → coma
Viral infection or
hepatoxin
No
Insidious or subacute
Blunted → coma
GIT hemorrhage,
exogenous protein,
uremia
Yes
Symptoms
Nausea & vomiting
Signs
Liver
Nutritional state
Ascitis
Common
Small, soft, tender
Normal
Absent
Unusual
Large, firm, painless
Cachectic
May be present
Lab tests
Transaminases
Coagulopathy
Very high
Present
Normal or slightly high
Often present
Table 9.2 – Clinical staging of hepatic encephalopathy
Grade Consciousness Intellect Behavior Motor Psychometric
0-1 Normal Normal Normal Normal Poor performance
1 Inverted sleep
Insomnia
Hypersomnia
Short
attention
Low
perception
Impaired
calculation
Anxiety
Apathy
Irritability
Low
monotonous
voice
Incoordination
Poor hand
writing
Tremors
Prolonged
2 Slow response
Lethargy
Disorientation
for time
Disinhibition
Disobedience
Asterixis
Ataxia
Dysarthria
Hyperreflexia
Very prolonged
3 Confusion
Delirium
Paranoia
Semistupor
Disorientation
for place
Amnesia
Perseverate
Bizarre
behavior
Hyperreflexia
Nystagmus
Rigidity
Yawing
Incontinence
Unable to
perform
4 Coma, arousal to
pain
Coma
unresponsive
None absent Decorticate /
Decerebrate
posturing

Treatment of hepatic encephalopathy
Fulminant Hepatic Failure (FHF). First of all, patients must be
nourished by intravenous infusion of glucose 20–40%, then be
given retention enema with 250 ml lactulose in 750 ml
electrolyte solution, neomycin 2 g 2-3x daily, along with fresh
frozen plasma (FFP) for coagulopathy. Plasma exchange can be
used daily, until the prothrombin time is near normal (Quick
score prolonged below 25%) or patient is awake. Hypotension
must be treated with volume expanders. GIT bleeding is the
second cause of death in FHF, administration of H2 antagonists or
proton pump inhibitors may help. Cerebral edema is treated by
20% manitol, 100 ml every 8 hours in absence of renal failure, but
steroids are contraindicated. In cases of metabolic
encephalopathy due to organ failure, transplantation may be an
option. In In case of acetaminophen-induced fulminant hepatic
failure, gastric lavage, forced diarrhea and N-acetyl cysteine
infusion of 150 mg/kg diluted with glucose solution may help.
Hepatic encephalopathy in chronic liver disease. Most
porto-systemic encephalopathies (PSE) occur as a consequence
of dietary mistakes, GIT bleeding, hemorrhage, infection,
alkalosis or hypokalemia as a result of diuretic therapy.
Hepatic encephalopathy in this case can be managed by a diet
restricted in proteins, allow 30-40 g/day. Lactulose can be given
at about 60-180 ml, in divided doses, to give 2-3 soft stools daily.
In addition, neomycin (2 g twice daily) and flumazenil (a
benzodiazepine receptor antagonist) should be given in 2 mg
dose infused in 15 minutes (Onyekwere 2011).
Renal Encephalopathies
The most disabling feature of both renal failure and dialysis is
encephalopathy. It is probably caused by the accumulation of
renal toxins. Other important causes are related to the
underlying disorders that cause renal failure, particularly
hypertension. The clinical manifestations of renal (uremic)
encephalopathy spans from mild confusional states to deep

coma, and movement disorders such as asterixis may be
associated. Cognitive impairment is considered to be the major
indication for the initiation of renal dialysis with or without
subsequent transplantation. Sleep disorders including restless
legs syndrome are also common in patients with kidney failure.
Renal dialysis is also associated with neurologic complications
including acute dialysis encephalopathy and chronic dialysis
encephalopathy, formerly known as dialysis dementia (Seifter
2011).
Five major syndromes of CNS affection are seen in renal failure.
– Acute renal failure: asterixis, myoclonus, seizures,
irritability and raised deep tendon reflexes.
– Chronic renal failure: early personality changes,
polyneuropathy.
– Dialysis disequilibrium syndrome: usually when there is
rapid hemodialysis, it presents by headache, lethargy,
nausea and vomiting.
– Chronic dialysis encephalopathy (dialysis dementia): always
late in the course of chronic renal failure. It gives dysarthria,
deterioration in memory, progressing to myoclonus,
mutism, coma and death (Seifter 2011).
– Renal transplantation: patients with renal transplantation
may experience encephalopathy (soon) after
transplantation. Immunosuppressive drugs, like
cyclosporine and acyclovir may produce confusion, lethargy
and coma at toxic levels. (Later) after transplantation,
primary CNS lymphoma becomes a major concern in
patients developing symptoms of brain dysfunction.
Management of acute and chronic renal failure is by
hemodialysis; dialysis disequilibrium syndrome is managed by
prolonging the time of dialysis; management of chronic dialysis
encephalopathy is by renal transplantation

Fluid and Electrolyte Imbalance
Osmolarity disorders
Hypernatremia: Hypernatremia indicates a deficit of body
water relative to sodium concentration. Clinically, it is similar to
hyponatremia where encephalopathy possibly develops, due to
dehydration. Usually, hypernatremic patients are hypovolemic.
Common causes of hyponatremia are
– Pure water loss (in renal diabetes insipidus and external
insensible losses via the skin and lungs).
– Combined water and sodium loss (in renal osmotic diuresis
combined with inadequate water intake, and external
excessive sweating).
– Inadequate sodium gain (in cases of excessive sodium
administration, like hypertonic solutions; adrenal
hyperfunction, like hyperaldosteronism, Cushing
Syndrome; and intake of exogenous steroids).
Hypernatremia should be corrected slowly. When volume
depletion with circulatory insufficiency is predominant,
vigorous treatment with isotonic saline solution is mandatory.
When the cause is diabetes insipidus, administer 2-5 units of
aqueous vasopressin, or 1-5 mcg of desmopressin (DDAVP)
should be given subcutaneously or intranasally. When
hypernatremia is due to excessive gain, hypotonic (0.45%) saline
is used to replace, in part, additional water deficits.
Hyponatremia: Three types of hyponatremia are described:
Hypovolemic hyponatremia: patients with low intake of sodiumcontaining
fluids and have attempted replacement with free
water may present with encephalopathy.
Hypervolemic hyponatremia: usually seen in congestive heart
failure or hypoalbuminemia. This condition can be treated with
fluid restriction, a wise use of diuretics as well as treatment of
the primary cause.
Euvolemic hyponatremia: This condition is seen in syndromes of
inappropriate secretion of ADH (SIADH) adrenal insufficiency,
hypothyroidism, severe psychogenic polydipsia, and

hypoglycemia; also in pancreatitis with hyperlipidemia and
hyperproteinemia. The degree of encephalopathy produced by
hyponatremia depends on the rate of fall of serum sodium rather
than its value.
All cases of euvolemic hyponatremia are treated with fluid
restriction (800-1000 ml/d) and removal of precipitants (Young
1998).
Central pontine myelinolysis (CPM): Due to rapid correction
of hyponatremia by more than 10 meq/d. Clinically, patients
present with quadriparesis and cranial nerve dysfunction over
several days, which may be followed by encephalopathy. The
maximal lesion is seen in the basis pontis, but supratentorial
white matter is also affected.
Syndrome of inappropriate secretion of antidiuretic
hormone (SIADH): It is a common syndrome in neurological
diseases; it leads to hyponatremia and increases salt
concentration in urine (>20 mmoI/L). Serum ADH is high. Causes
of SIADH include
– Malignant neoplasms likes oat-cell carcinoma of lung, and
Hodgkin disease
– Non-malignant pulmonary diseases, e.g., TB, emphysema,
pneumothorax
– CNS diseases like subarachnoid hemorrhage, cerebral
venous thrombosis, encephalitis, and meningitis, and PNS
diseases like Guillain-Barré syndrome.
– Use of drugs like vincristine, carbamazepine, tricyclic
antidepressants, etc.
Slow correction of hyponatremia by IV 3% sodium solution is
recommended. IV 100 cc given over one-hour interval, until
serum sodium level reach 125 mmol/l. Do not exceed correction
rate of 2 mmol/h.
Hypercalcemia: The encephalopathy of hypercalcemia is not
different from any metabolic encephalopathy except in early
anosmia.

Other findings in hypercalcemia are myopathy, polyuria,
pruritis, nausea and vomiting. Patients start to complain at
serum calcium level of 13 mg/dl, when abnormal EEG changes
start to appear. Patients suffering from hyperparathyroidism
may manifest seizures independent of serum calcium level due
to elevated serum parathormone.
Management: Hypercalcemia is corrected by saline diuresis,
augmented with furosemide, followed by a choice of
mithramycin steroids, phosphate or etidronate.
Encephalopathy in Diabetic Patients
Hypoglycemia: Clinically, patients who develop hypoglycemia
are graded:
– At 20 mg/dl, immediate loss of consciousness in adults and
children, neonates resist hypoglycemia better,
– At 45 mg/dl, confusion, irritability. Sometimes unexplained
focal lesions appear with hypoglycemia.
Management: give IV glucose at 1 g/kg body weight, plus
thiamine 1 mg/kg to prevent Wernicke’s encephalopathy (Quinn
2002).
Nonketotic hyperosmolar hyperglycemia (NHH): Usually
occurs in diabetic patients whose insulin production is adequate
to inhibit lipolysis, but insufficient to prevent hyperglycemia,
which result in a marked osmotic diuresis. Diuresis leads to
dehydration and hyperosmolarity. In such situations, serum
glucose may rise to 800-1200 mg/dl, and serum osmolarity may
exceed 350 mOsm/L, which may invite development of brain
edema.
Osmolarity= 2(Na+K) + (glucose/18) + (BUN/2.8)
Clinically, patients present with encephalopathy, focal
neurological signs, and partial seizures that do not respond to
conventional antiepileptic medication. Such encephalopathy
must be treated by rehydration.
Management: Normal saline is infused slowly to correct
hypotension and improve osmolality, in addition to insulin

infusion at the rate of 10 IU/h, with regular checking of plasma
glucose, since these patients are very sensitive to insulin.
Glucose should be added to saline when plasma glucose is
approximately 300 mg/dl (Quinn 2002).
Diabetic ketoacidosis (DKA): About 80% of DKA patients have
encephalopathy and 10% are comatose. Management: Like NHH,
but with higher amounts of insulin. If there is evidence of brain
edema mannitol is used. If there is evidence of electrolyte
imbalance, mandate correction. The use of IV sodium
bicarbonate to compensate for metabolic acidosis is debatable
(Quinn 2002).
Hypoxic Ischemic Encephalopathy (HIE)
Following cardiac or respiratory arrest, CO poisoning or
cyanide poisoning, one of four clinical syndromes might appear:
– Global encephalopathy
– Memory loss
– Postanoxic Parkinsonism
– Lance-Adams syndrome (intention myoclonus)
Findings predicting good prognosis are preserved pupillary
responses, preserved roving eye movement, decorticate posture
or better at initial examination. We predict good prognosis when
we find in clinical examination after 24 hours, motor withdrawal
from noxious stimuli or improvement of 2 grades in eye
movement. Also, finding motor withdrawal or better, and
normal spontaneous eye movements at 72 hours examination,
carries a good prognosis. Also, when a patient obeys commands
at the 1-week examination.
Management is by hyperventilation and osmotic diuresis, for
cerebral edema. Seizure control is live saving and has an impact
on prognosis, as patients suffering from GTCS have a better
outcome than those who suffer from myoclonic seizures.
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Septic Encephalopathy
Septic encephalopathy is a frequent sequel of severe sepsis, with
no definite therapeutic strategies available that can prevent
associated neurological dysfunction and damage. It is caused by
a number of processes, such as direct bacterial invasion, toxic
effects of endotoxins, inflammatory mediators, impairment of
microcirculation, and neuroendocrine changes. The exact
cellular and molecular mechanisms remain an enigma. Several
mediators of inflammation have been assigned a key role in
etiogenesis of encephalopathy, including cytokines, chemokines
and complement cascade. With the observations that brain
dysfunction in such sepsis disorders can be alleviated by
regulation of the cytokines and complements in various species
of animals, optimism is building for a possible therapy of the
sepsis-damaged brain (Jacob 2011).
Early aggressive treatment with antibiotics is key, along with
modulators of cytokines and complements and antiinflammatory
medicines (Jacob 2011).
Drug-induced Encephalopathies
Commonly implicated drugs in encephalopathy etiology include
salicylates, tricyclic antidepressants, lithium, sedatives,
neuroleptics, methyldopa, amantadine, acyclovir, digitalis,
propranolol, hydantoins, etc (Jain 2001).
Drug-induced delirium results from disruption of the normal
integration of neurotransmitters, including dopamine,
acetylcholine, glutamate, gamma-aminobutyric acid (GABA),
and/or serotonin (Young 1998).