European Journal of Internal Medicine 25 (2014) 112–116

Contents lists available at ScienceDirect

European Journal of Internal Medicine
journal homepage: www.elsevier.com/locate/ejim

Review Article

A neurologist's approach to delirium: Diagnosis and management of toxic
metabolic encephalopathies
Vaishnav Krishnan ⁎, Lester Y. Leung, Louis R. Caplan
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, United States

a r t i c l e

i n f o

Article history:
Received 6 October 2013
Received in revised form 22 November 2013
Accepted 25 November 2013
Available online 10 December 2013
Keywords:
Delirium
Encephalopathy
Confusional state
Confusion
Metabolic encephalopathy

a b s t r a c t
Toxic metabolic encephalopathies (TMEs) present as an acute derangement in consciousness, cognition and behavior, and can be brought about by various triggers, including endocrine and metabolic disturbances, exogenous
toxins, pain and infection. Also referred to as “delirium” or “acute confusional states,” TMEs are characterized by
1) an altered level of consciousness and activity, 2) global changes in cognition with inattention, 3) a fluctuating
course with disturbances in the sleep-wake cycle, and 4) asterixis and myoclonus. The pathophysiology of this
syndrome is poorly understood. Imbalanced neurotransmitter signaling and pathologically heightened brain
inflammatory cytokine signaling have been proposed as candidate mechanisms. Focal brain lesions can also occasionally mimic TMEs. A neurological examination is required to identify the presence of focal findings, which
when present, identify a new focal lesion or the recrudescence of prior ischemic, inflammatory or neoplastic insults. Diagnostic testing must include a search for metabolic and infectious derangements. Offending medications
should be withdrawn. Magnetic resonance imaging, cerebrospinal fluid analysis and electroencephalography
should be considered in select clinical situations. In addition to being an unpleasant experience for the patient
and family, this condition is associated with extended hospital stays, increased mortality and high costs. In individuals with diminished cognitive reserve, episodes of TME lead to an accelerated decline in cognitive functioning. Starting with an illustrative case, this paper provides a neurologist's approach to the diagnosis, differential
diagnosis and management of toxic metabolic encephalopathies.
© 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

1. Introduction
Toxic metabolic encephalopathies (TMEs), variously known as “acute
confusional states,” “sepsis-associated encephalopathy,” “delirium,” or
“intensive care unit (ICU) psychosis” represent a serious and common
neuropsychiatric syndrome associated with morbidity, prolonged hospitalization and financial costs, as well as increased psychological distress
to the patient and family [1–3]. TMEs are canonical demonstrations of
how distributed central nervous system circuits responsible for arousal,
perception and focus are susceptible to systemic infectious, toxic or metabolic derangements. The brain's reaction to such derangements is often
relatively acute, and a variety of different irritants often produce the
same nonspecific behavioral reactions [4]. Nevertheless, perhaps due to
heterogeneities in symptomatology and presentation, this condition remains under-recognized [5], and it has spurred the generation of several
psychometric tools to assist with the rapid diagnosis of this condition [6].
TMEs often lead to persistent neurocognitive alterations even after
offending triggers have been addressed effectively [7]. While serving
on the neurology consult service in a multispecialty tertiary referral center, we obtained numerous consultations for “altered mental status.” The
specific questions ranged from concerns about nonconvulsive status or
⁎ Corresponding author. Tel.: +1 617 667 4700.
E-mail address: vkrish@bidmc.harvard.edu (V. Krishnan).

ischemic stroke to worries about the presence of undiagnosed dementia.
In this clinical review designed for internists, we provide a neurologist's
approach to the diagnosis and differential diagnosis of acute confusional
states.
2. Case
A 91 year-old woman with systolic congestive heart failure presented to the cardiology clinic. At baseline, she is physically and cognitively
independent. She was volume overloaded by examination, and so was
electively admitted for diuresis. Over the next 48 h, high dose
intravenous furosemide was administered with an appropriate treatment response. However, her serum creatinine increased from 1.0
to 1.8 mg/dL (estimated creatine clearance [CrCl] of 17 mL/min], and
her systolic blood pressures reduced from the 130–140 mm range to
90–100 mm. She was transferred to the cardiac care unit (CCU) for
milrinone therapy, which improved her renal function and blood pressures. However, on the second day of her CCU stay, she was noted to
be confused, paranoid, and tremulous with intermittent jerking movements in all four extremities. When mobilized by physical therapy
staff, she was unable to ambulate independently, and her knees
appeared to intermittently give way. A noncontrast computed tomography scan of her head identified mild cerebral atrophy without hemorrhage, and a comprehensive laboratory investigation showed only an

0953-6205/$ – see front matter © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ejim.2013.11.010

V. Krishnan et al. / European Journal of Internal Medicine 25 (2014) 112–116

elevated creatinine (1.3, CrCl 22 mL/min). Neurology was consulted for
“altered mental status with jerking movements.” On exam, the patient
was awake, alert and oriented only to her name. She was easily distracted and could not recall the months of the year backwards. She followed
commands and did not display paraphasias. Cranial nerve examination
was normal, and extremity movements were contaminated by intermittent myoclonic jerks that would affect one extremity at a time. The
strength of individual muscle groups was normal, but she displayed an
inconsistent and involuntary increase in tone. She had prominent bilateral asterixis. She was diagnosed with a toxic metabolic encephalopathy
and no further diagnostic testing or neuroimaging was undertaken.
Over the next several days, her mental status gradually improved as
her cardiac and renal parameters returned to baseline. On the day of
discharge five days later, her family noted that her responses were
still delayed, but she was oriented and much less distractible.
3. Pathophysiology
Unraveling the basic biology of metabolic encephalopathy and delirious states remains the subject of active translational investigation.
Hypoxia, hypoperfusion, infection, medications, alcohol withdrawal,
and other triggers all appear to give rise to similar neurophysiological
changes leading to global cognitive dysfunction of TMEs. Age and preexisting dementia are major risk factors for the development of delirious states, suggesting that diminished “cognitive reserve” remains a
key vulnerability factor [8]. For simplification, we identify three main
pathophysiological themes that deserve significant attention.
First, two main neurotransmitter systems have been implicated in
the clinical manifestations of acute confusional states. Reduced central
acetylcholinergic signaling can directly result in cognitive impairment:
this is exemplified by the iatrogenic development of delirium in vulnerable individuals following the administration of medications with
prominent anticholinergic activity. These include first generation antihistamines (e.g., diphenhydramine, meclizine), tricyclic antidepressants
(e.g., imipramine, amitriptyline) and antispasmodic agents for overactive bladder (e.g., tolterodine, oxybutynin). A rat model of low dose
atropine administration recapitulates the neurocognitive impairments,
electroencephalographic slowing and sleep impairments of typical
anticholinergic encephalopathic states [7,9], but has not yet been implemented more extensively to identify specific cholinergically innervated
brain regions that are responsible for behavioral impairments in metabolic encephalopathies [10]. The success of antidopaminergic agents in
addressing the hyperactivity and agitation of delirium have led
some to propose that excess dopaminergic signaling also plays a role.
In support of this theory is the observation that excess dopamine
supplementation in patients with Parkinson's disease can result in
delirium. Overall, both of these neurotransmitter systems are best
thought of as modulators rather than primary mediators of inattention
and disorientation.
Second, serum levels of a variety of proinflammatory cytokines (e.g.,
interleukin-8 and tumor necrosis factor alpha) and anti-inflammatory
cytokines (e.g., interleukin-10) appear to be elevated in patients
with acute confusional states [7]. Recent work has identified specific
panels of cytokines that seem to distinguish encephalopathy in
“inflamed” (i.e., those with infection or sepsis) versus “noninflamed”
patients [11]. Cytokines are thought to act on neurons through humoral
routes (by directly activating macrophages in regions that lack a functional blood brain barrier, such as the circumventricular organ) or
through the activation of cytokine receptors on vagal afferent neurons
[12,13]. Pro-inflammatory cytokines may act directly on endothelium
to result in impaired cerebrovascular autoregulation in sepsis [14].
Cytokines do cross the blood brain barrier, but with the advent of
more sensitive and quantitative cytokine assays, we are just beginning
to collect data on how cerebrospinal fluid cytokine levels may
predict the occurrence of delirium [15,16]. Preliminary experiments
using a model of polymicrobial sepsis in mice have shown that

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persistent brain elevations TNF-α (tumor necrosis factor-α) and IL-6
(interleukin-6) may be responsible for long-term neuropsychological
sequelae following bacterial infections [17].
Encephalopathy associated with kidney or liver failure is likely
related to an accumulation of unexcreted medications or toxic physiological metabolites (many of which have not yet been identified). Hepatic encephalopathy has traditionally been conceptualized as a direct
consequence of elevated ammonia levels [18], which itself is sufficient
to enhance glycolysis and depress mitochondrial function [19]. Patients
with minimal hepatic encephalopathy (MHE, cirrhotic patients who
have subtle impairments in cognitive function only detected with
neuropsychological testing) have been the subjects of functional magnetic resonance imaging studies. MHE patients demonstrated altered
functional connectivity in a number of “resting state networks” [20].
Resting state networks are interconnected cortical and subcortical
brain regions that are activated when a subject is awake and at rest
and demonstrate abnormal connectivity in a number of neurodegenerative conditions including early Alzheimer's disease. In contrast to
ammonia, the encephalopathy associated with renal failure (“uremic
encephalopathy” or “dialysis dementia”) may be related to the accumulation of “guanidino” compounds (including guanidinosuccinic acid and
methylguanidine) [21]. Associated electrolyte and acid-base derangements may also contribute, though less significantly [18].
For a given patient, one or many of these factors may be contributory. A premorbid dementia resulting in diminished cognitive reserve
[22], sensory deprivation (e.g., lack of hearing aids), together with environmental triggers that result in pain and involuntary immobilization
(e.g., use of restraints, urinary catheters), may all combine with the
above medical and iatrogenic etiologies to raise the risk and prolong
the course of metabolic encephalopathy [1].
4. Clinical manifestations and approach to physical examination
A relatively acute onset of new behavioral symptoms with a fluctuating course remains the key distinguishing feature between dementia
and toxic metabolic encephalopathies; hence, neurologists prefer the
term “acute confusional state.” The American Psychiatric Association
formally identifies delirium as having i) core features of rapid and
abrupt onset of impaired attention and altered sensorium, together
with ii) changes in “at least one cognitive domain” (e.g., recent memory
and orientation.) and iii) “associated features” (e.g., changes in sleep
wake cycle, worsening in the evening) [23].
Rather than describing patients as “altered,” it is preferable to report
specific alterations in i) activity (ranging from hypoactive abulia to
agitated delirium), ii) arousal (ranging from alertness to stupor), and
iii) cognition, which occurs within specific domains (attention, memory,
language, etc.) [24]. Perceptual disturbances such as audiovisual
hallucinations and delusions may be prominent features. Subtle difficulties with focus and attention are often the first sign of an ensuing
encephalopathy, and are characterized by delayed reaction time and
easy distractibility. Global inattention typically contaminates other abnormalities on mental status testing, such as difficulties with calculation, short-term recall and incorrect responses to simple orientation
questions.
Inattentiveness is typically followed by diminished arousal or
changes in the level of activity (ranging from severe agitation and hyperactivity to abulia, a hypoactive state with diminished spontaneity).
There have been efforts to distinguish between “hypoactive” and “hyperactive” delirious states. From studies of patients with focal lesions,
abulia has been linked to dysfunction within circuits connecting the
frontal lobes to basal ganglia structures, including the caudate and accumbens nuclei, thalamus and midbrain [25]. In contrast, focal lesions
in hyperactive patients typically disturb posterior circuits connecting
occipitoparietal cortices to limbic structures within the mesial temporal
lobe [26]. In patients without focal lesions, this distinction simply reflects a spectral response to the same underlying neurological insult

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[22]. The classical example of a hyperactive delirium without a focal lesion is delirium tremens, a syndrome of confusion, agitation, autonomic
hyperactivity, tremors and seizures which occurs in the setting of alcohol withdrawal [27].
Motor manifestations of metabolic encephalopathy tend to create
significant confusion among non-neurologists. Asterixis, a sudden loss
of postural tone, when occurring bilaterally, is a characteristic sign of
metabolic encephalopathies and is not specific to hepatic dysfunction.
Myoclonus, a brief twitch of a muscle or group of muscles, is another
commonly observed sign. When this affects the lower extremity muscles, it results in gait difficulties and postural instability. Together,
asterixis and multifocal myoclonus are often described as “shaking” or
“jerking” and are reported as “seizures” or “tremor.” Finally, one can
also observe paratonia or gegenhalten, a type of hypertonia where
patients display an inconsistent and involuntary increase in resistance
to passive extremity movements. Paratonia may also result in gait
difficulties.
When a toxic metabolic encephalopathy is strongly suspected, we
recommend clarifying the history from caregivers about the patient's
baseline cognitive abilities and the time course over which the change
in behavior occurred. Home and hospital medication lists require close
review to identify benzodiazepines, opiate narcotics or anticholinergics.
Given that paranoia and terrifying hallucinations can often be a prominent component of metabolic encephalopathies, one needs to approach
the patient gently and in a manner that would promote trust and collaboration. Rather than jumping directly to questions related to orientation
to place and date, we suggest first evaluating for the presence of difficulty with simple attentional tasks (such as recalling the months of the
year backwards, or a digit span test). Then, focus should be shifted
to demonstrating the presence or lack of signs of focal cortical dysfunction. Difficulties with language suggest focal dysfunction in the dominant frontal or temporal lobes and associated structures. These
may manifest as subtle paraphasic errors (such as “truck” instead of
“duck”), agrammatic or fragmented speech, or difficulties with fluency
and comprehension. Reading and writing can also be tested to assess
these language functions. Visual field testing is essential since this
may be the only elementary sign of a focal temporal and parietal lobe lesion. When possible, one needs to closely observe for the presence of
hemi-inattentiveness or hemineglect, which indicates a contralateral cerebral hemisphere lesion.
Stuporous patients may have negligible participation in formal mental status testing. Attention must then be shifted to testing cranial nerve
function and a sensorimotor examination to exclude focality or structural explanations for their stupor [28]. Focal deficits may reflect a
post-ictal phenomenon. A general physical examination is essential to
identify meningismus and a source of possible infection or pain.
5. Focal/structural lesions
A number of focal lesions can mimic the clinical features of toxic and
metabolic encephalopathies with very subtle localizing signs. Rather
than providing a comprehensive catalog, we list some common scenarios here and refer our readers to associated references:
• In patients with cardiovascular risk factors, the acute onset of altered
attentional processing, particularly when associated with extremes
in blood pressure, should raise suspicion for ischemic stroke or
intraparenchymal hemorrhage involving the non-dominant parietal
or temporal lobes [26,29,30]. A subtle hemiparesis with ipsilateral neglect may be the only clue.
• In patients at risk for cardioembolism, a shower of small emboli
may lead to a diffuse derangement in processing speed without
resulting in obvious focal signs. This extends to patients with atrial
fibrillation who are not on anticoagulation, valvular heart disease, or
following catheterization or surgical manipulation of the left heart
and aorta.

• Cerebral venous sinus thrombosis may occasionally result in bilateral
thalamic edema from venous congestion or infarction that can result
in an acute confusional state, stupor or coma [31,32]. A search for venous thrombosis must be undertaken when the patient has comorbid
conditions associated with systemic hypercoagulability, such as malignancy, sepsis, etc.
• The presence of confusion associated with vivid visual, tactile and auditory hallucinations may suggest damage in the distribution of bilateral posterior cerebral arteries [33]. Similarly, a form of hypertensive
encephalopathy known as posterior reversible leukoencephalopathy
syndrome (PRLS or PRES) can result in transient vasogenic edema in
occipitoparietal white matter and can result in confusion accompanied by cortical blindness or seizures [34]. PRES is often observed in
patients who are immunosuppressed on calcineurin inhibitors including tacrolimus.
• Encephalopathy may be caused by acute or chronic subdural hemorrhages, particularly in patients with known significant brain atrophy,
in alcoholics, and in patients who are maintained on anticoagulants
such as warfarin. Subdural hemorrhages along the vertex or at the anterior poles of the temporal lobes can irritate underlying cortex and
produce subtle seizures, manifesting as a classical fluctuating encephalopathy [28].
• The meningoencephalitis associated with the herpes simplex virus
(HSV) results in preferential damage to the mesial temporal lobes
and the medial orbitofrontal cortex, leading to language dysfunction,
seizures, short term memory loss, and an abulic encephalopathy [35].
6. Diagnostics, ancillary testing and the role of
neurologic consultation
A comprehensive metabolic and infectious investigation is likely to
identify an offending etiology in the vast majority of cases of TME. Testing
should include electrolyte panels, a complete blood count with differential, liver function tests, a urinalysis, a plain chest film, as well as blood
and urine cultures. Checking serum ammonia levels, arterial blood gases
and the examination of cerebrospinal fluid may be utilized selectively.
In parallel, one must review the patient's medication list to identify and
discontinue or avoid medications with known anticholinergic activity,
as well as opiate narcotics, corticosteroids, sedatives and other medications with sedative activity (e.g., cyclobenzaprine and gabapentin). In patients with dementia, sensory deprivation and immobility (i.e. through
wrist restraints and urinary catheterization) may be the sole precipitant
of an acute confusional state without metabolic or infectious derangements, and therefore these interventions need to be minimized.
When feasible, we recommend obtaining a noncontrast CT (computed
tomography) scan of the head. In addition to identifying hemorrhages
(including acute and chronic subdural hemorrhages), today's CT scans
can augment a clinical assessment of overall brain health. One may find
focal atrophy, or bilateral periventricular white matter hypoattenuation
(signifying chronic microvascular ischemic changes), both of which may
suggest a predisposition to the development of delirium. CT imaging
may also show prior small infarctions as circumscribed hypodensities or
larger infarctions as lobar encephalomalacia, and these findings may explain the recurrent development of focal neurological signs in conjunction
with an acute confusional state (“recrudescence”). To definitively diagnose acute ischemic stroke or to exclude new neoplastic lesions or conditions such as PRES, an MRI (magnetic resonance imaging) is essential.
Gadolinium contrast may be considered when neoplasia and focal infections or abscesses are highest on the differential. MR or CT venography
is a must when central venous sinus thrombosis is suspected.
Continuous video-electroencephalography (cvEEG) remains the
gold standard to diagnose nonconvulsive seizures or nonconvulsive status epilepticus (NCSE), the clinical manifestations of which can range
from a “twilight state” with intermittently delayed responsiveness to
coma [36]. EEG in the vast majority of TME cases will typically show
varied degrees of etiologically nonspecific diffuse slowing in the theta

V. Krishnan et al. / European Journal of Internal Medicine 25 (2014) 112–116

(3–7 Hz) or delta range (1–3 Hz), and may also have a few epileptiform
discharges or triphasic waves (a type of discharge canonically observed
in liver failure) [37]. These “abnormalities” should not be treated indiscriminately with anticonvulsant agents. The absence of epileptiform
discharges in the first 4 h of recording generally denotes that
nonconvulsive seizures are unlikely to be the explanation for persistent
confusion [38]. To avoid the unnecessary and excessive use of EEG, we
recommend that the cvEEG be strongly considered only in the following
clinical scenarios:
• Those with a known history of epilepsy or who have had a clinical
convulsion in the course of their confusional state.
• Patients younger than 18 [39].
• Patients with a history of acute or old brain injury (including trauma,
prior stroke or anoxia). Fresh blood products of acute intracranial
hemorrhages (including subarachnoid, intraventricular and subdural
hemorrhages) are especially prone to trigger seizures [40].
• Patients exposed to medications known to lower seizure threshold
(bupropion, tramadol, fluoroquinolones and metronidazole, among
others).
• Comatose or stuporous individuals with subtle ocular movement
abnormalities (e.g., nystagmus, bobbing) or unexplained, transient,
abrupt alterations in blood pressure or heart rate [41].
Overall, we recommend prompt neurologic consultation for those
patients suspected of TME when 1) a comprehensive laboratory and
pharmacologic evaluation has not identified any obvious culprit
derangements, 2) patients have a history of drug-refractory epilepsy
or structural brain disease with or without focal or lateralizing features
on their examination, and 3) MR imaging or continuous long term video
EEG is being strongly considered.
7. Management and prognosis
Foremost emphasis must be placed on elucidating the underlying
cause(s), and therapies should be targeted at remediating all identified
insults. In patients with poor cognitive reserve, very subtle derangements may be sufficient to trigger a TME (e.g., a slight hyponatremia).
Frequent doses of benzodiazepine therapy in conjunction with fluid
and thiamine supplementation remain the mainstay of therapy in the
management of the autonomic hyperactivity and seizures associated
with alcohol withdrawal [27]. Aside from alcohol withdrawal, when
convulsive seizures occur in the setting of a metabolic encephalopathy,
one may initiate anticonvulsant therapy at nonsedating doses to lower
the risk of seizures and avoid frequent benzodiazepine injections.
First- and second-generation antipsychotics, procholinergic agents and
benzodiazepines have been utilized to “treat” the confusion, agitation
and disorientation of acute confusional states. The use of antipsychotics
for delirium altogether remains controversial: their strong sedative
effects, which may be beneficial in agitation, can themselves perpetuate an encephalopathy. The risk of extrapyramidal symptoms (acute
dystonia, tremor and rigidity) and QTc prolongation necessitates a “start
low and go slow” approach when utilizing these agents. While first and
second generation antipsychotics may not differ in efficacy, the side
effects of first generation agents including haloperidol require more frequent monitoring [42,43]. For this reason, we urge avoidance of haloperidol and other first generation antipsychotics, particularly with repeated
use in high doses. A number of delirium prevention trials using “prophylactic” antipsychotic agents have not shown significant efficacy [42,44].
Prophylactic cholinesterase inhibition such as rivastigmine may in fact
lead to increased mortality [45]. As our knowledge of the basic neurobiological mechanisms of encephalopathic states continues to grow, we will
continue to require large-scale randomized pharmacologic treatment and
prevention trials to better answer this question.
The design of delirium prevention strategies has received more attention lately, as it can be argued that many cases of delirium may be
predictable [7]. A number of cost-effective multi-component delirium-

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prevention protocols have been successfully implemented [46–48].
These programs typically involve combinations of: early assessment of
bowel and bladder function, aggressive mobilization, intravenous hydration and close monitoring of electrolytes, medication review and
avoidance of polypharmacy, frequent pain assessments, structures to
enhance the quality of sleep, and pathways to improve deficits in vision
and hearing [2]. Much more emphasis needs to be placed on formalizing
and developing protocols for nonpharmacological methods such as the
Hospital Elder Life Program [47,49].
It has long been observed that demented patients who develop acute
confusional states remain somewhat more impaired following the resolution of the acute illness, and seem to display a “new baseline.” Among
patients with clinically diagnosed Alzheimer disease (AD), the occurrence of delirium during a hospitalization tends to accelerate ADrelated cognitive decline by approximately 50% [50,51]. Even among patients without dementia, the occurrence of delirium following cardiac
valve replacement surgery or coronary artery bypass grafting resulted
in a significantly lower likelihood of patients returning to their preoperative level of functioning [52]. As mentioned above, the field has a
limited understanding of the pathophysiological basis for such a phenomenon and will likely have to develop new neuroimaging and bioinformatic tools to further clarify such mechanisms.
8. Conclusions and future directions of research
Episodes of delirium or acute confusion represent a serious consequence of an underlying metabolic, infectious or inflammatory insult.
These are associated with prolonged hospitalization, heightened mortality and increased financial costs. Age, pre-existing dementia, multiple
medical comorbidities and polypharmacy are important risk factors. As
our population's burden of dementia continues to grow in the absence
of specific disease-modifying therapies, developing effective means to
prevent delirium-induced cognitive decline will be essential. First and
foremost, we need to promote a greater awareness of this condition
within all communities of health care providers. We must improve
our methods of identifying at-risk patients through the use of serological, cerebrospinal fluid and genetic analysis, and implement routine
nonpharmacological techniques to prevent and address delirium [7].
Only with a deeper understanding of the underlying molecular mechanisms can we begin to devise rationally designed medical treatments to
prevent and treat delirium [49]. Finally, higher quality clinical studies
are required to clarify the importance of i) phenomenologic distinctions
within delirium subtypes (hypoactive versus hyperactive), ii) the value
of prophylactic pharmacological therapy, and iii) potential therapies to
reverse persistent cognitive alterations.
Learning points
• Toxic metabolic encephalopathies (TMEs), also known as “delirium”
or “acute confusional states” represent an acute diffuse derangement
in cognitive functioning and can be brought about by a variety
of triggers, including infection, metabolic disturbances, pain and
dehydration.
• The clinical hallmarks of TME include inattentiveness and a fluctuating course, and may be associated with symmetric motor manifestations such as asterixis, myoclonus and paratonia.
• A comprehensive metabolic and infectious work up must be conducted in each patient with an acute confusional state. Focal findings on
the neurological examination, including hemiparesis, hemianopia,
cortical blindness or aphasia may suggest an underlying focal process
such as ischemic stroke, venous sinus thrombosis or hypertensive encephalopathy. Alternatively, they may represent the recrudescence of
old cerebral lesions. A noncontrast computed tomography scan
should be obtained to rule out “acute lesions” (e.g., hemorrhages
and abscesses) and can also augment one's clinical assessment of
overall brain health.

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V. Krishnan et al. / European Journal of Internal Medicine 25 (2014) 112–116

• In some, even after the derangement has been reversed, the occurrence
of this syndrome may lead to a persistent impairment in cognitive
functioning, setting up a “new baseline”.
• We suggest prompt neurological consultation in confused patients
with a history of structural brain disease and refractory epilepsy, so
that we may guide the use of electroencephalography and neuroimaging techniques.
• In patients with prominent agitation, low dose benzodiazepines and
second-generation antipsychotics should be judiciously employed
only in situations where the safety of the patient and caregivers is at
stake.
Conflicts of interests
The authors disclose no competing financial or other sources of conflict of interest.
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