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The incidence of delirium has been estimated between 5-40% for hospitalized patients
in general and between 11-80% for critically ill patients. Other studies have reported a
lower incidence of about 30%, after the exclusion of patients maintained in purposeful
drug-induced sedation.
Many etiologies of acute encephalopathy can be easily detected with neuroimaging as a
well visualized structural lesion (ischemic stroke, intracerebral or subarachnoid
hemorrhage, tumor etc). A frequent reason for a Neurological consultation, however,
remains the non-structural, metabolic syndrome and its management considerations.
This will be the focus of this chapter.
ETIOLOGY AND RISK FACTORS
The various etiologies of metabolic encephalopathy are presented in Table 1. In general,
there could be divided into drug intoxication or withdrawal (frequently from illegal
drugs), electrolyte and glucose abnormalities, major organ dysfunction (such as liver,
kidneys, lungs, endocrine), nutritional deficiencies, exposure to extraneous toxins,
paraneoplastic syndromes and sleep or sensory deprivation.
Risk factors that have been associated with delirium in hospitalized, critically ill patients
include [1]:
Older age (more than 70 years),
Male gender,
Poor functional status,
Malnutrition,
Substance abuse
Pre-morbid medical conditions or cognitive impairment
Polypharmacy, including medications that affect neurotransmitters (such as
anticholinergic or dopaminergic)
Physical restraints
Visual or hearing impairment
Prior history of delirium
DIAGNOSIS
Despite the protean symptomatology of delirium, specific diagnostic criteria have been
developed, which are presented in Table 2. The diagnosis can be missed in mild forms,
but any presentation which includes alteration in the level of consciousness (agitation or
sedation), attention impairment (distractability, perseveration), fluctuation of the
symptoms in time and severity (with worsening during the night or reversal of sleepwake), presence of hallucinations, disorientation or perceptual distortions, as well as
disorganized thought process (occasionally incoherent speech or non-pre-existing
memory disturbances) should alert the physician of its presence.
Standardized delirium detection scales have also been used, but are not specific for the
etiology of the metabolic encephalopathy. These include the Confusion Assessment
Method for the Intensive Care Unit (CAM-ICU) [2] and the Intensive Care Delirium
Screening Checklist (ICDSC) [3]. Using these scales one can detect delirium, but cannot
necessarily differentiate between hepatic or septic or uremic encephalopathy, for
example, because all could present with similar signs and symptoms.
Therefore, a detailed history especially through relatives, by-standers or co-workers can
be of immense help, as well as review of previous hospital admission or clinic data. The
clinical exam would also reveal focality in the neurological part when structural brain
lesions are present, but in the vast majority of cases non-focal exam with alteration of
vital signs (tachycardia, hypotension, hypertension, tachypnea) in case of a metabolic
encephalopathy. A detailed systematic exam may also reveal clues for the etiology of
the encephalopathy. For example, fever and nuchal rigidity for meningitis, clammy pale
extremities with hypotension in shock, jauntice in hepatic encephalopathy, fruity breath
odor from acetone expiration in diabetic ketoacidosis, blue gum with lead, Meeslines
with arsenic and acrodynia with mercury intoxications [4]. One should not forget,
however, that even metabolic derangements can suggest focality, such as focal-onset
seizure with hypoglycemia or asymmetric ophthalmoplegia and ataxia with thiamine
deficiency.
A basic or extended laboratory workup may then reveal the cause (Table 3). One should
remember that many drug levels can be measured only in specialized laboratories,
therefore extra serum should be stored in case the culprit is not revealed after the
routine, first-pass evaluation. Electroencephalography (EEG) may show triphasic waves
which usually occur with hepatic or uremic encephalopathy, but are not specific.
Neuroimaging studies can also help to exclude structural lesions and also allow a safer
lumbar puncture, as well as occasionally narrow the potential etiologies of
toxometabolic encephalopathies. MRI of the brain may reveal specific findings in
conditions such as central pontine myelinolysis from rapid hyponatremia correction,
carbon monoxide poisoning, methanol, ethylene glucol, cyclosporine or metronidazole
toxicity. MR spectroscopy can be used to detect the decreased choline and myoinositol
and the increased glutamine and glutamate in hepatic encephalopathy, but the clinical
application of these findings are questionable [5].
GENERAL TREATMENT FOR ACUTE METABOLIC ENCEPHALOPATHIES
Treating delirium is considered a medical emergency. Assessment of airway, breathing
and circulation is always the first step, followed by a detailed neurological examination
in parallel with laboratory and neuroimaging studies. The identification of the
underlying cause is of utmost importance. Preventing measures in order to avoid
escalation of symptoms, such as patient reorientation, noise reduction, avoidance of
unnecessary procedures, decrease of restraint use, promotion of sleep or exposure to
daylight and limiting sensory deprivation (glasses, hearing aids) are also helpful. Pain
Clinically, the syndrome starts with subtle mental and emotional changes and can
progress to full blown delirium, seizures and coma. Motor phenomena, such as action
tremor, asterixis, hypereflexia, myoclonus, as well as anorexia and, in longstanding
cases, peripheral neuropathy can also be part of the clinical evolution. Neuroimaging
may reveal diffuse cerebral atrophy and the EEG generalized slowing with triphasic
waves, paroxysmal frontally-predominant high voltage delta waves and occasionally
paradoxical accentuation of the background rhythm with eye opening [14].
Therapeutic measures include renal replacement therapy, with reversal of the
symptoms and signs within days or weeks and renal transplantation, having the same
beneficial effects. Correction of anemia with erythropoietin with target hemoglobin of
11-12g and of potential thiamine deficiency with B1 supplementation may also lead to
cognitive improvement [14,17].
Pulmonary encephalopathy
This can occur in patients with chronic respiratory insufficiency frequently complicated
by congestive heart failure and systemic or pulmonary infection. But it can also occur in
more acute or chronic conditions, where from brain to muscle the neurorespiratory
control of gas exchange is impaired. Brainstem lesions affecting the respiratory center,
such as stroke, hemorrhage or compression, upper spinal cord injuries,
polyneuropathies, such as Guillain-Barre syndrome or critical illness polyneuropathy,
neuromuscular junction blockade, such in myasthenia gravis or Lambert-Eaton
syndrome, myopathies affecting the diaphragms or intercostal muscles, are
characteristic examples.
The pathophysiological basis is hypoxia and/or hypercapnea. As oxygen availability to
the brain is decreased (decreased oxygenation, ventilation or hemoglobin carrying
capacity, such as with carbon monoxide [CO] poisoning) or CO2 is increased, cerebral
vasodilation ensues and cerebral blood flow increases, with ICP elevation. CO also
affects the respiratory chain by binding to cytochrome c oxidase, worsening tissue
hypoxia and creating deleterious reactive O2 species [18].
Although the clinical presentation of pulmonary encephalopathy may not differ from
other types of delirium, occasionally papilledema is present if more chronic cases. Also a
milder, indolent form, mainly with cognitive impairment only proven by
neuropsychologic battery tests, may be present as in sleep apnea patients.
Additionally, CO poisoning may have a biphasic course. Initially symptoms of confusion,
difficulty concentrating, dizziness, nausea, headache may present with 20-30% carboxyhemoglobin (COHg) concentrations. Higher levels of COHg lead to ataxia, hallucinations,
stupor and coma, with death usually occurring at levels of 80% or higher. Survivors who
recover, 10-30% may develop extrapyramidal signs, memory loss, incontinence and
psychotic behavior 3-240 days later. MRI in these delayed cases shows symmetrical
bilateral putaminal or entire basal ganglia hyperintensities or symmetrical bilateral
white matter changes in T2 with decreased ADC values (suggesting cytotoxic
component) [14].
days) and benzodiazepines (either fixed dosing or symptom triggered regimens). For
resistant cases propofol infusion or barbiturates can be used. Because intracranial
hemorrhage is also prevalent in alcoholics, neuroimaging should be obtained for newonset seizures, if the neurological exam confirms focality or if overt trauma is present.
Wernickes encephalopathy
Wernickes encephalopathy can result from alcoholism, but also from malnutrition,
cancer, chemotherapy or liver or kidney disease. Inattentiveness, indifference, impaired
memory, disorientation and disordered perception are common, but the most
characteristic signs are from the eyes, including nystagmus, lateral rectus palsy
(occasionally bilateral), conjugate horizontal gaze palsy or complete ophthalmoplegia.
Truncal ataxia is present in 80% of patients and peripheral neuropathy is also common.
The amnestic syndrome of Korsakoffs frequently emerges after the initiation of
treatment and improvement of the acute Wernickes signs. The ocular symptoms
improve within few hours to days with thiamine 50-100 mg/day administration, but the
ataxia less often.
Pancreatic encephalopathy (PE)
PE occurs in 1.7-35% of patients with acute pancreatitis. It begins within 2 weeks after
acute pancreatitis, usually between day 2 to 5, and clinically does not differ from other
encephalopathies. Although this entity remains controversial and many believe that is
incorporated within the SAE spectrum (because many of these patients also have signs
of sepsis or SIRS), others believe that it entails a different pathophysiology and
potentially future treatment options [20].
More specifically, it has been hypothesized that levels of pancreatin (including trypsin,
elastin enzyme, lipase and phospholipase A2) enter the circulation, where activated PLA2
transforms encephalin and lecithin into highly cytotoxic hemolytic encephalin and
hemolytic lecithin. Both damage the blood-brain-barrier, dissolve the phospholipid
structure of the cell membrane, hydrolyze mitochondria and cause demyelination and
vasogenic edema. PLA2 also passes through and has potent neurotropism, destroying
the phospholipid layers of brain cells, and causing brain cell cytotoxic edema.
Inflammatory cytokines, which increase after acute pancreatitis and also alter the
permeability of the BBB, and systemic disturbances, such as hypoxia, hypotension,
disseminated intravascular coagulopathy or fat embolism may also contribute to the
delirium.
Interestingly there is no clear correlation between the severity of pancreatitis (amylase
levels) and the incidence of PE. Higher lipase levels have been reported in the CSF of
patients with PE, but this is rarely performed.
Hypoglycemic encephalopathy
Because of the brain dependence on glucose as its primary energy source, hypoglycemia
(serum glucose < 40 mg/dL) may lead to serious sequelae. Depending on the baseline
daily glucose levels, symptoms can occur at higher (diabetics) or lower (patients with
very tight glycemic control) glucose levels than this [25]. Severe hypoglycemia can occur
in Type 1 or Type 2 diabetics and most commonly is associated with insulin therapy (or
sulfonylurea overdose in Type 2). In modern ICUs, the implementation of tighter
glycemic control protocols has led to emergence of frequent hypoglycemic events and
increased risk of death [26].
The neuroglucopenic symptoms and signs associated with either postprandial or fasting
hypoglycemia are due to sympathetic system activation and secretion of catecholamines
(cold perspiration, lightheadedness, tachycardia) and are followed by dysfunction of the
nervous system (headache, confusion, tremor, stupor, seizures), which can be global or
focal, mimicking stroke. When hypoglycemia becomes severe and prolonged, coma and
decorticate or decerebrate posturing from selective brain damage occur, with some
brain areas, such as the dentate gyrus of the medial temporal lobe, the superficial layers
of the neocortex and the basal ganglia, being more susceptible to injury.
Treatment should be fast with administration of 50 ml of DW 50% IV, followed by DW
5% infusion. Glucagon administration although also effective may be underutilized [27].
Hyperglycemic encephalopathy
It can occur either in the context of diabetic ketoacidosis (DKA) or, more commonly, of
nonketotic hyperosmolar hyperglycemia (NKH). Encephalopathy may occur at serum
glucose levels > 300 mg/dL in DKA or > 600 mg/dL in NKH and the degree of impairment
of consciousness may correlate with the degree of serum osmolality changes.
Alterations in electrical activity within the ascending reticular activating system with
multiple neurotransmitter derangements, as well as cerebral edema due to fast
therapeutic interventions to correct hyperglycemia, have been implicated in the
pathophysiology of the encephalopathy [14].
Neurologic symptoms and signs occur more frequently with NKH and progress from
confusion and lethargy to stupor and coma. Focal neurologic deficits mimicking stroke
or transient ischemic attack (hemiplegia, aphasia, speech arrest, visual changes) or
hemichorea-hemiballismus can also occur with KNH [14]. Additionally, reflex seizures
due to limb movement (even passive), then followed by refractory period, during which
movement will not activate them can also be seen with NKH [28].
Treatment of the severely contracted volume with normal saline, IV insulin
administration and correction of the profound electrolyte derangements usually
improves the encephalopathy.
NMDA-receptor encephalopathy
This condition is caused by the presence of serum or CSF antibodies against brain Nmethyl-D-aspartate receptors. Most patients are female (80%) and in most the presence
of these antibodies should be considered paraneoplastic syndrome, because ovarian
teratomas can be found in 26-59%. Only 2% of patients may have another type of tumor
(neuroblastoma or Hodgkins lymphoma [29]. However, there is another group of
antibody-positive patients with encephalopathy without detection of neoplasms despite
extensive evaluations (non-paraneoplastic syndrome) [30]. The younger the patient, the
less chances a tumor will be found [29].
Symptoms and signs can be divided into a prodromal phase (headache, fever, vomiting,
diarrhea), early phase after few days (with psychiatric symptomatology, such as anxiety,
delusions, paranoia, echolalia or seizures) and late phase (where movement disorders,
such as choreoathetoid, orofacial movements, myoclonic or oculogyric crises and
opisthotonus or autonomic instability with hyperventilation, tachycardia, pyrexia or
sialorrhea, predominate). Lower initial NMDAR antibody levels and less frequent
confusion, agitation, amnesia and reduced consciousness may be found in nonparaneoplastic than paraneoplastic patients [30].
CSF may show initially lymphocytic pleocytosis, elevated protein and oligoclonal bands.
Diagnosis is made when antibodies are detected in CSF or serum, although after
treatment only CSF may remain positive. EEG may show diffuse or rhythmic delta
activity or non-convulsive status epilepticus and MRI is non-diagnostic in the majority.
First step in treating these patients is removal of the teratoma if present. Subsequently,
IVIG or plasma exchange or immunosuppression with methylprednisolone or rituximab
plus cyclophosphamide will lead to improvement, but in 20-25% of patients recurrence
will eventually mandate chronic immunosuppression [29].
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Toxins
Metabolic
Endocrine
Neoplastic
Nutritional
Miscellaneous
TABLE 2. DSM-IV-TR Diagnostic criteria for delirium due to a general medical condition
[31]
A. Disturbance of consciousness (i.e., reduced clarity of awareness of the environment)
with reduced ability to focus, to sustain, or to shift attention.
B. A change in cognition (such as memory deficit, disorientation, or language
disturbance) or the development of a perceptual disturbance that is not better
accounted for by a preexisting, established, or evolving dementia.
C. The disturbance develops over a short period of time (usually hours to days) and
tends to fluctuate during the course of the day.
D. There is evidence from the history, physical examination, or laboratory findings that
the disturbance is caused by the direct physiological consequences of a general medical
condition.
Grade 2
Grade 3
Grade 4