Metabolic encephalopathy and metabolic coma

 
Contributors
G Bryan Young MD, author. Dr. Young of the University of Western Ontario has no relevant
financial relationships to disclose.
 
Gary R W Hunter MD, author. Dr. Hunter of the University of Western Ontario has no
relevant financial relationships to disclose.
 
Zachary N London MD, editor. Dr. London of the University of Michigan has no relevant
financial relationships to disclose.

Publication dates
Originally released July 17, 2007; last updated February 22, 2010; expires February 22, 2013

Historical note and nomenclature

  The term “metabolic encephalopathy” was coined by Kinnier Wilson in 1912 to describe a
clinical state due to various causes in which the brain's integrated activity is impaired in the
absence of structural abnormalities. Metabolic encephalopathy is, thus, not a diagnosis but a
syndrome of global cerebral dysfunction induced by systemic stress, and can vary in clinical
presentation from mild executive dysfunction or agitated delirium, to deep coma with
decerebrate posturing. There are also some differences in presentation depending on the
metabolic disorder.
  In this discussion we shall refer to those disorders due to vital organ failure, nutritional
deficiencies, electrolyte imbalances, hypoglycemia, hyperglycemia, endocrine disorders, and
systemic sepsis; the following are excluded: cardiac arrest and anoxic-ischemic
encephalopathy, direct CNS infections, exogenous toxins (including drugs, alcohol, and
poisons), hematological conditions, immune-mediated CNS diseases, and direct and indirect
effects of cancer on the nervous system.
  It should be understood that various metabolic disorders causing encephalopathy are
combined, rather than occur in isolation, especially in critically ill patients (Kunze 2002). This
reflects the interaction among various organ systems, causing multiple metabolic
derangements.

Clinical manifestations
  Metabolic encephalopathies may range in degree from a mild confusional state to coma, an
unarousable unconscious state. Delirium or acute confusional state is usually the earliest
recognized brain malfunction in metabolic encephalopathies. Patients may be either agitated,
usually with increased sympathetic nervous system activity, or quiet and withdrawn. The key
feature of delirium is impaired concentration and attention. Patients cannot keep on track with
mental tasks, eg, serial 7s or spelling “world” backwards, and are easily distracted. They may
or may not have hallucinations, often visual but sometimes auditory. These are more common
in withdrawal (from alcohol or drugs) states.
  Some clues that the problem is metabolic rather than due to a structural brain lesion include:
  The setting. Often there is a background of vital organ dysfunction or history of some event,
eg, toxic exposure that would upset the metabolic milieu of the brain, as opposed to a sudden
catastrophic event with instantaneous loss of consciousness, as might occur with trauma,
seizures, cardiac arrest, etc. There may also be clues from the general examination, eg,
jaundice, hyperventilation, signs of chronic pulmonary or cardiac disease, hypothermia or
hyperthermia, etc.
  Time course. Patients with metabolic encephalopathies are acute or recent in onset and tend
to fluctuate in the severity of their impairment of consciousness, such that they may be
coherent and obeying at one point, and a few hours later in a stupor, rousing only to vigorous
stimulation. This is in contrast to structural lesions such as strokes or tumors, which tend to
have static or progressive courses.
  Vital signs. Myxedema coma and Wernicke encephalopathy commonly cause hypothermia,
with temperatures below 35°C. Hypothyroidism slows the metabolism and respiratory rate (as
reflected in elevations of PaCO2 on blood gas determination: respiratory acidosis). Wernicke
encephalopathy produces metabolic lesions near the ventricular system, including the
hypothalamus, which can result in lowering of body temperature if the posterior
hypothalamus is involved. In some cases, this may be the only clue to the diagnosis in a
comatose patient. Hyperthermia is common in thyroid storm, in which metabolism is
accelerated. Agitated delirium is typically accompanied by increased sympathetic nervous
system activity, including hypertension, tachycardia, and perspiration. Hyperventilation
producing a respiratory alkalosis is characteristic of hepatic encephalopathy and early sepsis.
Metabolic acidosis from advanced sepsis, renal failure, diabetic ketoacidosis, or lactic
acidosis can also produce hyperventilation. Hyperventilation may also accompany lower
PaO2, as with cardiopulmonary disorders. Thus, the discovery of hyperventilation, along with
simple blood gas determination, narrows the diagnostic possibilities.
  Motor phenomena. Tremor, asterixis, and multifocal myoclonus are strongly suggestive of
a metabolic etiology in encephalopathic or delirious patients. The tremor is of an action-
postural type and commonly accompanies an agitated delirium, as in withdrawal states,
uremia, and the early phase of hepatic encephalopathy. Asterixis is a loss of postural tone,
best assessed by having the patient hold the arms outstretched, the wrists dorsiflexed, and the
fingers extended. The “flapping tremor” then appears, often asynchronously. Asterixis may
also affect truncal muscles, causing the head or body to drop forward. If they are supported in
a frog-leg position, the lower limbs may be affected as well. Although tremor and asterixis are
not seen in coma, multifocal myoclonus can be seen from delirium to coma. In the setting of
hepatic coma, multifocal myoclonus is usually an ominous sign and portends a poor
prognosis, although this is not universally true. The brief twitches occur in various muscles in
an asynchronous, non-rhythmic, helter-skelter fashion. They often involve the face and limbs
and may migrate from one side to the other. Multifocal myoclonus is often confused with
seizures but is generally resistant to the usual anticonvulsant drugs and has no epileptiform
EEG correlate. Levetiracetam and valproate may be useful in controlling multifocal
myoclonus, but it is often refractory to treatment unless the underlying cause is corrected.
  Neurologic examination. The mental status examination can provide important clues to the
metabolic nature of the brain dysfunction in noncomatose patients. Agitation with
hallucinations is common in withdrawal states, but can be found in some metabolic disorders,
such as acute intermittent porphyria and the early phase of acute liver failure.
  The cranial nerve reflexes are spared in most metabolic encephalopathies; these include
pupillary, corneal, vestibular-ocular, and pharyngeal reflexes. This is helpful in differentiating
metabolic disorders from most structural lesions. However, some structural lesions are
multifocal and can mimic metabolic brain diseases. A single structural supratentorial mass
lesion may cause a lateral displacement of the brain, causing coma before the pupillary light
reflex is affected on the same side. Such patients may show lateralized motor signs. Most
coma-producing posterior fossa lesions will alter at least some of the cranial nerve reflexes as
the pathways for these run through the rostral reticular formation that is compromised in coma
from such lesions. There are also reverse caveats, in that some metabolic disorders can affect
some cranial nerve reflexes. Wernicke encephalopathy, related to thiamine deficiency,
commonly causes loss of the vestibular-ocular reflex, even with caloric stimulation. This
relates to the site of “metabolic lesions,” which includes the vestibular nuclei at the floor of
the 4th ventricle. Other cranial nerve reflexes are spared–a helpful diagnostic clue. Parenteral
thiamine usually restores the vestibular-ocular reflex in Wernicke encephalopathy, another
helpful diagnostic and therapeutic point.
  Hepatic encephalopathy can produce a variety of false localizing signs, including conjugate
horizontal or vertical gaze deviations, dysconjugate downgaze, hemiparesis, severe spasticity
with sustained clonus, and a variety of abnormal postures including decortication to painful
stimuli. These may be seen in the setting of cerebral edema but can also occur purely due to
metabolic dysfunction with normal intracranial pressure. Other well-known metabolic mimics
of focal lesions include hypoglycemia and hyperglycemia. Hyperglycemia is also notorious
for producing movement disorders, namely hemichorea.
NTRODUCTION

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 [1]. An overview of TME in hospitalized patients will be
discussed here; a diagnostic approach to delirium is presented separately. (See "Diagnosis of
delirium and confusional states".)

TME is common among critically ill patients. Furthermore, TME is probably underrecognized
and undertreated, especially when it occurs in patients who require mechanical ventilation [2-4].
TME is usually a consequence of systemic illness, and the causes of TME are diverse. Most
TME is reversible, making prompt recognition and treatment important. Certain metabolic
encephalopathies, including those caused by sustained hypoglycemia and thiamine deficiency
(Wernicke's encephalopathy), may result in permanent structural brain damage if untreated.
Alcohol withdrawal syndromes must be excluded in patients with suspected TME. (See
"Management of moderate and severe alcohol withdrawal syndromes".)

PATHOPHYSIOLOGY

Normal neuronal activity requires a balanced environment of electrolytes, water, amino acids,
excitatory and inhibitory neurotransmitters, and metabolic substrates [5]. In addition, normal
blood flow, normal temperature, normal osmolality, and physiologic pH are required for optimal
central nervous system function [6]. Complex systems, including those mediating arousal and
awareness and those involved in higher cognitive functions, are more likely to malfunction when
the local milieu is deranged [5-7].

All forms of acute toxic-metabolic encephalopathy (TME) interfere with the function of the
ascending reticular activating system and/or its projections to the cerebral cortex, leading to
impairment of arousal and/or awareness [6]. Ultimately, the neurophysiologic mechanisms of
TME include interruption of polysynaptic pathways and altered excitatory-inhibitory amino acid
balance [8,9]. The pathophysiology of TME varies according to the underlying etiology:

 Cerebral edema contributes to acute fulminant hepatic encephalopathy and to hypo-

osmolar encephalopathies [7].
 Drug-induced delirium results from disruption of the normal integration of
neurotransmitters, including dopamine, acetylcholine, glutamate, gamma-aminobutyric
acid (GABA), and/or serotonin [7,10].
 Electrolyte derangements alter membrane excitability to produce TME [6,8].
 Nutritional disorders disturb cellular energy metabolism and may result in neuronal death
[5,6].
 Exogenous toxins, including carbon monoxide and cyanide, cause impaired
oxygen delivery and mitochondrial dysfunction [7].
It usually develops acutely or subacutely and is reversible if the systemic disorder is treated. If left
untreated, however, metabolic encephalopathy may result in secondary structural damage to the brain.
Most encephalopathies are present with neuropsychiatric symptoms, one in particular being depression.
However, mood disorders are often co-morbid with cardiovascular, liver, kidney and endocrine
disorders, while increasing evidence concurs that depression involves inflammatory and
neurodegenerative processes. This would suggest that metabolic disturbances resembling
encephalopathy may underscore the basic neuropathology of depression at a far deeper level than
currently realized. Viewing depression as a form of encephalopathy, and exploiting knowledge gleaned
from our understanding of the neurochemistry and treatment of metabolic encephalopathy, may assist
in our understanding of the neurobiology of depression, but also in realizing new ideas in the
pharmacotherapy of mood disorders. Forty-six patients developed 47 central and three peripheral
neurologic complications. The most common complications were cerebral hemorrhage, metabolic
encephalopathy, and CNS infections. All CNS infections occurred with allogeneic BMT Eleven of 16
hemorrhages were subdural hematomas, which were more frequent in autologous than in allogeneic
BMT, and in patients with acute myelogenous leukemia than in the remaining leukemia patients. Eight
of 11 subdural hematomas occurred in AML patients receiving autologous BMT When we compared
patient-, disease-, and transplant-related characteristics of these patients with those without subdural
hematoma, only platelet refractoriness correlated with an increased risk of subdural hematoma. The
actuarial probability of developing subdural hematoma was 44% in patients with platelet-refractory
disease and only 2.5% in the other patients. Ten patients with subdural hematoma did not have surgery
and eight had significant clinical improvement associated with reduction or resolution of the hematoma,
confirmed by CT scan in six patients. The subdural hematoma was the cause of death in only one
patient. The purpose of this study was to determine the pattern of neurologic characteristics, MR
imaging abnormalities, and brain neurometabolites in EMS METHODS: Sixteen patients with EMS and
CNS abnormalities and 12 control subjects underwent evaluation, including medical and neurologic
examination, proton MR spectroscopy, and MR imaging. RESULTS: Neurologic findings that were
increased in CNS-EMS included minor depression, amnesia, and intermittent confusion, although
fatigue, motor disorders, recurrent headache, major depression, and dementia also occurred, but at a
lesser significance. Self-reported disability was markedly increased in CNS-EMS MR imaging findings
included subcortical focal lesions, focal lesions in deep white matter, cortical atrophy, ventricular
dilatation, and diffuse and periventricular white matter abnormalities. MR spectroscopic findings
established two distinct spectral patterns: 1) increased choline-containing compounds, decreased N-
acetylaspartate, and increased lipid-macromolecules, consistent with inflammatory cerebrovascular
disease; and 2) increased glutamine, decreased myo-inositol, and decreased choline, consistent with
acute CNS injury or metabolic encephalopathy. CONCLUSION: Neurologic abnormalities, self-reported
disability, brain lesions, and MR spectroscopic abnormalities are common in CNS-EMS The pattern of
cerebral lesions and neurometabolites is consistent with widespread inflammatory cerebrovascular
disease. However, a subgroup of patients with CNS-EMS have neurometabolic changes consistent with a
metabolic encephalopathy identical or similar to hepatic encephalopathy.

Clinically, it presents as a progressive fatal neurologic syndrome that is not easily distinguished from
other feline neurologic conditions. Most cases of FSE have been reported in England, where it was first
detected in 1990, but a few cases have been reported from other European countries. To identify
possible cases of FSE in Italy, the Italian Ministry of Health funded a 2-year surveillance project during
which the brains from 110 domestic cats with neurologic signs were evaluated histologically for
spongiform encephalopathy and immunohistochemically to detect PrP sc. Although no cases of FSE were
found, the study proved useful in monitoring the Italian cat population for other neurologic diseases:
neoplasia, toxic-metabolic encephalopathy, granulomatous encephalitis, suppurative encephalitis,
trauma, circulatory disorders, degeneration, nonsuppurative encephalitis, and neuromuscular diseases.
Logistic regressions were applied on patient samples across and for separate etiologies.For stroke and
hemorrhage the ORs with 95% confidence intervals were: 2.05, 4.47, 10.29, for trauma: 1.63, 4.72,
12.89, anoxic: 8.03, 15.50, 5.93, post-operative: 10.66, metabolic encephalopathy: 2.12, 3.60, 7.71, and
all etiologies: 2.85, 6.53, and 8.79. Based on six N100 studies, five MMN studies, and six P300 studies,
the N 100, MMN, or P300, when present, significantly predicted awakening, P300 and MMN being
significantly better predictors than N100.Conclusions: The MMN and P300 appear to be reliable
predictors of awakening.Significance: The prognostic assessment of low responsive patients with
auditory ERP should take into account both MMN and P300. 2006 International Federation of Clinical
Neurophysiology. Published by Elsevier Ireland Ltd. Logistic regressions were applied on patient samples
across and for separate etiologies.For stroke and hemorrhage the ORs with 95% confidence intervals
were: 2.05, 4.47, 10.29, for trauma: 1.63, 4.72, 12.89, anoxic: 8.03, 15.50, 5.93, post-operative: 10.66,
metabolic encephalopathy: 2.12, 3.60, 7.71, and all etiologies: 2.85, 6.53, and 8.79. Based on six N100
studies, five MMN studies, and six P300 studies, the N 100, MMN, or P300, when present, significantly
predicted awakening, P300 and MMN being significantly better predictors than N100.Conclusions: The
MMN and P300 appear to be reliable predictors of awakening.Significance: The prognostic assessment
of low responsive patients with auditory ERP should take into account both MMN and P300. 2006
International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. Rarely, the drug
has been associated with severe hepatotoxicity. We present the case of a 13-year-old girl who
developed jaundice and profound liver dysfunction with rapid progression to metabolic encephalopathy
while receiving PTU therapy. She died despite extensive therapeutic measures including orthotopic liver
transplantation. He lost consciousness after taking acetazolamide for 9 days. There was no finding of
cerebro-vascular disease, electrolyte imbalance and severe liver dysfunction, however the
electroencephalograms and brain wave demonstrated metabolic encephalopathy. Serum concentration
of acetazolamide was 54 mug/ml suggesting acetazolamide cause consciousness disorder.

We utilized an antibody that selectively recognizes the neo epitope generated by caspase-3 mediated
cleavage of APP to determine if this proteolytic event occurs in senile plaques in the inferior frontal
gyrus and superior temporal gyrus of autopsied AD and age-matched control brains. Consistent with a
role for caspase-3 activation in AD pathology, alphaDELTACcsp-APP immunoreactivity colocalized with a
subset of TUNEL-positive pyramidal neurons in AD brains. AlphaDELTACcsp-APP immunoreactivity was
found in neurons and glial cells, as well as in small- and medium-size particulate elements, resembling
dystrophic terminals and condensed nuclei, respectively, in AD and age-matched control brains. There
were a larger number of alphaDELTACcsp-APP immunoreactive elements in the inferior frontal gyrus
and superior temporal gyrus of subjects with AD pathology than age-matched controls.
AlphaDELTACcsp-APP immunoreactivity in small and medium size particulate elements were the main
component colocalized with 30% of senile plaques in the inferior frontal gyrus and superior temporal
gyrus of AD brains. In some control brains, alphaDELTACcsp-APP immunoreactivity appeared to be
associated with a clinical history of metabolic encephalopathy.

This paper presents clinical and biochemical studies in three patients and unsuccessful prenatal
diagnosis in one case with combined D-2- and L-2-hydroxyglutaric aciduria. We suggest that these
patients, who displayed a phenotype of neonatal onset metabolic encephalopathy, present a third
variant of 2-hydroxyglutaric aciduria. However, neurologic symptoms with poor prognosis have been
regularly reported, mostly in Asian children affected by the severe dengue hemorrhagic fever/dengue
shock syndrome, and attributed to a non specific, anoxic or metabolic encephalopathy. Recently, first
isolations of dengue viruses from CSF or brain tissue, have renewed this concept. We report 3 dengue
fever cases with neurologic manifestations and favorable outcome. Occurrence in adult age, during
classic dengue fever, and neurologic sequellae were the three outstanding features. We point out the
proteiform expression of these neurologic changes and their low incidence rate. HAD is a metabolic
encephalopathy caused by productive viral infection of brain mononuclear phagocytes and sustained by
paracrine-amplified, inflammatory, neurotoxic responses. MP neurotoxins are, in large measure,
homeostatic secretory products that can have a negative effect on neuronal cell function when
produced in abundance. Proinflammatory cytokines, chemokines, platelet-activating factor, arachidonic
acid and its metabolites, nitric oxide, quinolinic acid, progeny virions, and viral structural and regulatory
proteins are all included as part of these cellular and viral toxic elements. In addition, neuronal damage
can occur directly by engaging specific receptors or through inducing widespread inflammatory activities
in brain tissue that ultimately induce neuronal demise. The mechanisms for immune- and viral-mediated
neural injury in HAD are made more striking by the effects of abused drugs on cognitive function. Early
symptoms are fatigue, apathy, clumsiness, and concentration deficits. Later a delirious syndrome with
generalized seizures and reduced vigilance may progress to coma. The pathophysiological processes that
lead to UE are not fully understood. There is a loss of synaptic function probably mediated by
parathyroid hormone. Imaging studies are unspecific and may be used to exclude other etiologies of
encephalopathy. EEG findings are consistent with a metabolic encephalopathy. Therapy of UE consists of
a normalization of the metabolic derangement, which in most instances leads to a full remission of all
neuropsychiatric symptoms. Once UE is effectively treated, if necessary also with repeated dialysis,
residual deficits are uncommon. In patients with permanent renal failure, renal transplantation is the
therapy of choice. Uremic neuropathy is a predominantly distal, axonal, sensory more than motor
neuropathy with burning dysesthesias. Patients with UNP also suffer from entrapment
mononeuropathies, most frequently the carpal tunnel syndrome due to a susceptibility for nerve
compression. An autonomic neuropathy is seen in up to 50% of the patients. Neurophysiological findings
comprise reduction of sensory and motor nerve conduction velocities, distal motor latencies and
amplitudes, as well as denervation consistent with an axonal neuropathy. Therapy of UNP consists of
effective dialysis or renal transplantation. Mild UNP can clinically resolve, but severe UNP responds only
partially and best to transplantation. Two syndromes associated with dialysis in patients with renal
failure are the dialysis disequilibrium syndrome, and dialysis encephalopathy. The former is
characterized by agitation, muscle cramps, nausea and migraineous headaches caused by a rapid
decrease of serum osmolarity with brain edema during dialysis. The latter is caused by aluminium
toxicity and manifests itself with speech disturbance, depression, myoclonus and epileptic seizures. In
the final stage patients are immobilized and mute. DDS is prevented by slow dialysis techniques. DE is
treated with a complete absence of oral aluminium intake and elimination by chelating agents.

Because findings from our laboratories have established that HIV-1 infection of astrocytes down-
regulates high affinity glial glutamate transporters, we further investigated whether secretory products
of HIV-1-infected astrocytes could contribute to a metabolic encephalopathy in neurons. We used a
xenogeneic system of rodent hippocampal neurons grown in compartmentalized cultures where rodent
astrocytes and hippocampal cell bodies from E18 embryos were plated in compartment 1. After 11-14
DIV, hippocampal neurites had migrated through a silicon grease barrier that excluded the passage of
small molecules, into compartment 2, which was devoid of glia. Conditioned media from HIV-1-infected
human fetal astrocytes or their sham-infected controls, or VSV HIV-1-infected murine astrocytes, or
their sham-infected controls was applied for 18-24 hours to neurites in compartment 2. As an index of
mitochondrial membrane potential, we measured 1 nM TMRE uptake in neurites from compartment 2
and found it to be abolished after treatment with CM from either HIV-1-infected or VSV HIV-1 infected
astrocytes, but not their uninfected controls. Dilution of HIV-1 infected CM with culture media restores
in part TMRE uptake. The types of RIST were with blood stem cells from an HLA-identical or one-locus
mismatched related donor, bone marrow from a matched unrelated donor, and unrelated cord blood
transplantation. The preparative regimens before RIST were busulfan 8 mg/kg plus fludarabine 150-180
mg/m2 or cladribine 0.77 mg/kg. We added 4 Gy TBI or rabbit antithymocyte globulin in UBMT, and 4 Gy
TBI in UCBT, GVHD prophylaxis incorporated cyclosporine or cyclosporine plus short-term methotrexate.
Diagnosis of CNS complications was based on clinical, radiological and microbiological findings. When
infectious or hemorrhagic etiologies were excluded, CNS complications were classified as metabolic
encephalopathy. CNS complications occurred in 19 of the 211 patients, with a median onset of 24 days.
The symptoms included unconsciousness, seizures and visual disturbances. The type of transplants were
BSCT from a related donor, UBMT and UCBT. The CNS complications were classified into 3 categories:
infectious, hemorrhagic, and metabolic encephalopathy. The etiology of metabolic encephalopathy were
cyclosporin, sepsis, and unknown. Concomitant conditions of metabolic encephalopathy included
hyponatremia, hypokalemia, hypomagnesemia and hypertension. Eight patients had fever at the onset
of CNS complications, and 2 were on steroid therapy for acute GVHD The complications promptly
improved in 7 patients, while 8 died without improvement within 30 days. The remaining 4 died
thereafter without improvement within 100 days. Multivariate analysis using a logistic regression model
revealed UCBT as a significant risk factor of early CNS complications. Conclusion: This study
demonstrates that early CNS complication is rather common in RIST, particularly when patients received
cord blood cells.

Early symptoms are fatigue, apathy, clumsiness, and concentration deficits. Later a delirious syndrome
with generalized seizures and reduced vigilance may progress to coma. The pathophysiological
processes that lead to UE are not fully understood. There is a loss of synaptic function probably
mediated by parathyroid hormone. Imaging studies are unspecific and may be used to exclude other
etiologies of encephalopathy. EEG findings are consistent with a metabolic encephalopathy. Therapy of
UE consists of a normalization of the metabolic derangement, which in most instances leads to a full
remission of all neuropsychiatric symptoms. Once UE is effectively treated, if necessary also with
repeated dialysis, residual deficits are uncommon. In patients with permanent renal failure, renal
transplantation is the therapy of choice. Uremic neuropathy is a predominantly distal, axonal, sensory
more than motor neuropathy with burning dysesthesias. Patients with UNP also suffer from entrapment
mononeuropathies, most frequently the carpal tunnel syndrome due to a susceptibility for nerve
compression. An autonomic neuropathy is seen in up to 50% of the patients. Neurophysiological findings
comprise reduction of sensory and motor nerve conduction velocities, distal motor latencies and
amplitudes, as well as denervation consistent with an axonal neuropathy. Therapy of UNP consists of
effective dialysis or renal transplantation. Mild UNP can clinically resolve, but severe UNP responds only
partially and best to transplantation. Two syndromes associated with dialysis in patients with renal
failure are the dialysis disequilibrium syndrome, and dialysis encephalopathy. The former is
characterized by agitation, muscle cramps, nausea and migraineous headaches caused by a rapid
decrease of serum osmolarity with brain edema during dialysis. The latter is caused by aluminium
toxicity and manifests itself with speech disturbance, depression, myoclonus and epileptic seizures. In
the final stage patients are immobilized and mute. DDS is prevented by slow dialysis techniques. DE is
treated with a complete absence of oral aluminium intake and elimination by chelating agents.

Patients with confirmed mold-exposure history completed clinical interviews, a symptom checklist,
limited neuropsychological testing, quantitative electroencephalogram with neurometric analysis, and
measures of mold exposure. Patients reported high levels of physical, cognitive, and emotional
symptoms. Ratings on the SCL-90-R were "moderate" to "severe," with a factor reflecting situational
depression accounting for most of the variance. Most of the patients were found to suffer from acute
stress, adjustment disorder, or post-traumatic stress. Differential diagnosis confirmed an etiology of a
combination of external stressors, along with organic metabolically based dysregulation of emotions and
decreased cognitive functioning as a result of toxic or metabolic encephalopathy. Measures of toxic
mold exposure predicted QEEG measures and neuropsychological test performance. QEEG results
included narrowed frequency bands and increased power in the alpha and theta bands in the frontal
areas of the cortex. These findings indicated a hypoactivation of the frontal cortex, possibly due to
brainstem involvement and insufficient excitatory input from the reticular activating system.
Neuropsychological testing revealed impairments similar to mild traumatic brain injury. In comparison
with premorbid estimates of intelligence, findings of impaired functioning on multiple cognitive tasks
predominated. A dose-response relationship between measures of mold exposure and abnormal
neuropsychological test results and QEEG measures suggested that toxic mold causes significant
problems in exposed individuals. Neurotoxicity is a well-recognized side effect of calcineurin inhibitors.
Rapamycin is considered to be significantly less neurotoxic than calcineurin inhibitors. The aim of this
study was to retrospectively analyze a group of post-liver transplant patients who had been converted
to rapamycin because of CNI-related neurotoxicity.Patients and methods. Orthotopic liver
transplantation was performed in 56 consecutive patients between April 1, 2003, and August 15, 2004.
Immunosuppression was administered with tacrolimus, mycophenolic acid, and corticosteroids.Results.
Seven patients were converted to rapamycin due to new-onset neurotoxicity or exacerbation of
previous neurological symptoms secondary to CNNone of the patients had toxic levels tacrolimus at the
time of symptoms, which persisted despite reduction of CNI dose. The indications for conversion were:
peripheral neuropathy; seizure; metabolic encephalopathy; and central pontine myelinolysis. All
patients showed improvement or resolution of their neurological symptoms after conversion to
rapamycin. Two patients died, the first due to a hypoxic event and the second due to central pontine
myelinolysis with limited improvement and a family decision to withdraw care. There were no
complications directly attributed to rapamycin. Specifically, there were no thrombotic events, wound
complications, or biliary leaks. Three patients had a rejection episode that was successfully treated with
pulse corticosteroids and low-dose tacrolimus.Conclusions. Rapamycin can be safely used in OLT
recipients with severe neurological symptoms ascribed to or exacerbated by CNIs. Rapamycin
monotherapy may be inadequate to control rejection early after transplantation.

Objective: To describe electroencephalographic differences between TWs and GNCSE Methods: We

retrospectively compared the electroencephalograms of two groups of patients presenting with
decreased level of consciousness; those with TWs associated with metabolic encephalopathy and those
with GNCSE We studied the following: demographics, etiology and EEG morphological features. All EEGs
were classified blindly by two expert EEGers. Agreement between experts and concordance with clinical
diagnosis were measured. We analysed 87 EEGs with TWs and 27 EEGs with GNCSE Agreement between
experts and concordance with clinical diagnosis were excellent. When compared to TWs, epileptiform
discharges associated with GNCSE had a higher frequency, a shorter duration of phase one, extra-spikes
components and less generalized background slowing. Amplitude predominance of phase two was
common with TWS. Lag of phase two was absent in all cases of GNCSE but present in 40.8% of patients
with TWs. Noxious or auditory stimulation frequently increased the TWs while it had no effect on the
epileptiform pattern. However, critical basic science and clinical research did not progress until the DSM
III criteria clearly defined delirium 20 years ago. The term delirium then replaced many nonspecific
entities, such as acute confusion state, acute brain syndrome, metabolic encephalopathy, and toxic
psychosis. This review discusses the epidemiology, risk factors, interventions, causes, management, and
outcomes of delirium. Seventeen of these patients experienced 19 neurological complications during the
course of their disease. Fourteen had nervous system metastases or invasion. Nonmetastatic
complications, including CNS infections and new onset of seizures secondary to metabolic
encephalopathy were seen in 5 cases. By the time of the final analysis of the results, 8 of the 17 patients
with neurological complications had died. 7 had either been lost to follow-up or were in the terminal
stage of their disease, and 2 were in remission. Both of the patients who were in remission had
dumbbell neuroblastoma, and 1 of them, with congenital DNB, also had neurological sequelae,
characterized by paraplegia and neurogenic bladder. Neurological complications occurred in 68% of NB
and GNB cases. Metastatic complications were more common than nonmetastatic complications and
had a poor prognosis. Neurological complications were the primary cause of mortality in this study,
mortality being related to neurological complications in 63% of cases, and the final outcome was worse
than expected. HAD is a metabolic encephalopathy caused by productive viral infection of brain
mononuclear phagocytes and sustained by paracrine-amplified, inflammatory, neurotoxic responses. MP
neurotoxins are, in large measure, homeostatic secretory products that can have a negative effect on
neuronal cell function when produced in abundance. Proinflammatory cytokines, chemokines, platelet-
activating factor, arachidonic acid and its metabolites, nitric oxide, quinolinic acid, progeny virions, and
viral structural and regulatory proteins are all included as part of these cellular and viral toxic elements.
In addition, neuronal damage can occur directly by engaging specific receptors or through inducing
widespread inflammatory activities in brain tissue that ultimately induce neuronal demise. The
mechanisms for immune- and viral-mediated neural injury in HAD are made more striking by the effects
of abused drugs on cognitive function.
efinition
Metabolic encephalopathy describes temporary or permanent damage to the brain that happens
when the body’s metabolic processes are seriously impaired. Most cases occur when the liver
cannot act normally to remove toxins from the bloodstream.

The Brain

Copyright © 2005 Nucleus Communications, Inc. All rights reserved. www.nucleusinc.com

Causes
Metabolic encephalopathy occurs during significant metabolic derangements, after some types of
poisoning, and during diseases such as cirrhosis or hepatitis that slow or stop liver function.

It can also happen during medical conditions that cause blood circulation to bypass the liver.
These problems keep the liver from removing toxins like ammonia, which build up in the blood
as part of normal metabolism. High levels of these toxins can temporarily or permanently
damage the brain, causing metabolic encephalopathy.

Risk Factors
A risk factor is something that increases one’s chance of getting a disease or condition.

 In people who already have liver problems, the risk of metabolic encephalopathy
increases by:
o Low oxygen levels in the blood
o Infections
o Major surgery
o Any serious illness that causes changes in the body’s chemical make-up or
metabolism
o Use of certain medicines, such as sedatives and narcotics
o Bleeding within the intestines
o Persistent vomiting or diarrhea that lowers blood potassium levels
 Metabolic encephalopathy also happens to people without liver problems who suffer
sudden liver failure due to poisoning, develop severe electrolyte imbalances, or for other
reasons.

Symptoms
The symptoms of metabolic encephalopathy include:

 Confusion or agitation
 Changes in behavior and personality
 Forgetfulness
 Disorientation
 Insomnia
 Muscle stiffness or rigidity
 Tremor (particularly a flapping tremor of the hands)
 Difficulty speaking
 Uncontrollable movements, or, rarely, seizures
 Stupor or coma

These problems can develop quickly, and may all resolve when the metabolic encephalopathy is
reversed. However, prompt treatment is required to save a patient that has lapsed into a coma.

Diagnosis
Metabolic encephalopathy is a very serious problem that can quickly become a medical
emergency. Hospitalization is always required. Doctors will perform a detailed physical
examination to assess the patient’s neurologic condition.

Blood tests usually show high blood ammonia levels and other significant abnormalities related
to the failing liver and possible causes for the ensuing encephalopathy. An electroencephalogram
(EEG; a reading of electrical activity in the brain) may be useful to determine how seriously the
brain is affected.

Treatment
During hospitalization, the doctor and hospital staff will work to treat the problems that caused
the metabolic encephalopathy in an effort to remove or neutralize toxins that have built up in the
bloodstream. Reversing the underlying problem is necessary to treat the encephalopathy, but it
does not guarantee that there will not be residual brain injury if the condition was severe enough
or persisted long enough to cause permanent damage.

A low-protein diet is usually prescribed to help lower blood ammonia levels (the body creates
ammonia when it metabolizes and uses protein). Special tube feedings may be needed and life
support machines may be required, especially in the case of coma.

In cases of metabolic encephalopathy due to chronic liver failure (eg, cirrhosis patients), strong
consideration is often given for liver transplantation.

Prevention
Appropriate early treatment of liver problems may prevent metabolic encephalopathy in some
people. If you have longstanding liver problems you should see your healthcare provider
immediately if you develop confusion or any type of behavior change.