MASSACHUSETTS GENERAL HOSPITAL

Neuropsychology Laboratory
Vincent-Burnham 827
Boston, MA 02114

Tel. (617) 726-3274 Fax (617) 726-2353

Delirium and Altered Mental Status

David Caplan, M.D., Ph.D.
Professor of Neurology
Harvard Medical School

No disclosures
Topics

Incidence, Importance
Characteristics and Classification
Time course and Etiology
ED management
Incidence and Importance
“Delirium” and “altered mental state”
-- are common in ED -- 7 - 10% of older ED patients
(Han et al, 2010)
-- often reversible but
-- can be signs of medical/neurological life-threatening
emergencies
-- can be signs of diseases that can lead to significant
morbidity if not treated promptly
Emergency physicians miss 57% to 83% of cases of delirium (!)

Discharged ED patients in whom delirium was missed by the

emergency physician were more likely to die at 6 months
compared to patients in whom delirium was recognized
(30.8% versus 11.8%)
Characteristics and Classification
Nomenclature/typology not settled

My preferred classification is along two axes:

Type
– hyperactive, hypoactive, mixed, restricted
Time course
– chronic, subacute, acute
 Presentations

Level Hyperactive conditions

of
Conscious- Hypoactive conditions
ness
Mixed

Content Restricted symptoms

of
Conscious-
ness
Presentations

Hyperactive conditions -- confusion, inappropriate behaviors,

agitation, delusions, hallucinations, delirium, seizures

Hypoactive conditions -- drowsiness, lethargy, stupor, coma

-- “quiet delirium” (pt is “pleasantly confused”)

Mixed – alteration between hyper- and hypo-active states

Restricted symptoms – limited to some cognitive areas

Hyperactive conditions

Symptoms -- confusion, inappropriate behaviors, agitation,

delusions, hallucinations, delirium, seizures

Point to cortical pathology

1. Under-activity of areas that inhibit and monitor
thoughts and behaviors (mostly frontal lobes)
2. Over-activity of cortex, especially following depression
(withdrawal -- delirium tremens; reversal of narcotic
OD with Naloxone)

Brain stem lesions do not produce hyperactive syndromes

Hypoactive conditions (drowsiness, lethargy, stupor, coma)

-- “hypoactive delirium” – confusion, disorientation,

in a normally awake patient

-- anatomy covered by Marty Samuels – bi-hemispheric

or brain stem

-- hemisphere pathogenesis can be

-- cortical depression (toxic, metabolic)
-- cortical excitation (subclinical seizures)
Mixed conditions

-- patients frequently alternate between hyperactive and hypoactive

state in hours

-- if hyperactive state occurs, pathology is cortical

Restricted symptoms
-- can be confused with more general ΔMS (fluent aphasia, TGA)
-- can be part of either hyperactive or hypoactive presentations
-- associated with localized cortical lesions
-- point to focal pathology

The four A’s

aphasia – dominant hemisphere (L), perisylvian
agnosia – inferior temporal
apraxia -- dominant hemisphere (L), parietal
amnesia – medial temporal

neglect -- nondominant hemisphere (R), parietal

many others

hypoactive delirium – confusion, disorientation,

in a fully awake patient
Time course and Etiology
Three time courses – chronic, subacute, acute

Chronic – months to years

Subacute – weeks to months
Acute – minutes to weeks
Chronic (time course of months to years)
-- can present
-- as Chief Complaint (“not an emergency”)
-- as exacerbation of symptoms
aggression, wandering, chronic drowsiness, agitation,
hallucination, delusions, somnolence
-- as comorbidity, with new CC

The question is – is this a change?

-- “acute-on-chronic” ΔMS
IF clearly longstanding and unchanged, the df dx is in the domain
of dementing disease

-- degenerative – AD, LDB, FTD, CBD, SMA, PSP

-- vascular – multi-infarct, Binswanger’s, CAA,
CADASIL
-- systemic -- uremia, CHF, hepatic, thyroid …
-- nutritional – B12, B1 …
-- infectious – HIV, GPI, TB . . .
-- immune -- SLE, Sjogren’s, paraneoplastic …
-- demyelinating
-- neoplastic – primary, secondary
-- structural – NPH …
-- other
Subacute time course (weeks to months)

-- a tricky category
-- history is often hard to establish
-- when did symptoms really start? Is this “chronic”?

-- many diseases that are not common

 TRAUMA
•  Diffuse axonal injury, hemorrhage
•  Chronic subdural hematoma
•  Chronic traumatic encephalopathy

Courtesy of Jeremy Schmahmann

 INFLAMMATION / INFECTION
•  Creutzfeld-Jakob disease
•  post-Herpes simplex encephalitis
•  HIV dementia, and opportunistic infections
•  focal cerebritis/abscess (including toxoplasma)
•  Progressive multifocal leukoencephalopathy
•  Lyme encephalopathy (with or without meningitis)
•  Chronic meningitis (TB, cryptococcus, cysticercosis)
•  Syphilis (GPI, gumma, vasculitic)
•  Parenchymal sarcoidosis
•  Subacute sclerosing panencephalitis
•  Whipple’s disease of the brain

Courtesy of Jeremy Schmahmann

 NEOPLASTIC
•  Tumor - benign (frontal meningioma, clivus chordoma
invading medial temporal structures)
•  Tumor - malignant, 1º / 2 º
•  Paraneoplastic limbic encephalitis
–  Note - there may be NO tumor
–  Hu (SCLC), Ri, CV2, Ma2 (testicular), NMDA
(teratoma), AMPA, VGKC
•  Radiation necrosis
•  Cancer chemotherapy
•  Intravascular lymphoma

Courtesy of Jeremy Schmahmann

 VASCULAR

•  Multi-infarct dementia
•  Binswanger's encephalopathy
•  Amyloid dementia
•  Focal vascular syndrome (thalamic, inferotemporal, frontal)
•  Triple border zone watershed infarction (post - cardiac bypass)
•  Diffuse hypoxic / ischemic injury
•  Posterior reversible encephalopathy syndrome (PRES)
•  CADASIL (cerebral autosomal dominant arteriopathy with
subcortical infarcts, leukoencephalopathy, migraine)
•  Mitochondrial disease (Mitochondrial encephalopathy with lactic acidosis
and stroke-like episodes, MELAS)

Courtesy of Jeremy Schmahmann

 AUTOIMMUNE
•  Non-paraneoplastic limbic encephalitis
–  VGKC Ab
•  Systemic lupus erythematosus
•  Isolated angiitis of the nervous system
•  Temporal arteritis
•  Wegener's granulomatosis
•  Polyarteritis nodosa
•  Hashimoto encephalopathy (Steroid responsive
encephalopathy syndrome [SREAT] – may need IVIG)
•  Susac Syndrome

Courtesy of Jeremy Schmahmann

 DRUGS / TOXINS
•  Medications: neuroleptics, benzodiazepines, anticonvulsants,
dopaminergic agents, antidepressants, beta blockers,
histamine / dopamine blockade, methotrexate
•  Substances of abuse:
–  Alcohol (Korsakoff, Marchiafava-Bignami)
–  PCP
–  Heroin: “Chasing the Dragon” leukoencephalopathy
–  mescaline
–  marijuana psychosis
•  Toxins: lead, mercury, arsenic
•  Carbon monoxide, cyanide – globus pallidus lesions

Courtesy of Jeremy Schmahmann

 DEMYELINATING
•  Multiple sclerosis, Schilder's, Balo's sclerosis
•  Acute disseminated encephalomyelitis (ADEM)
•  Delayed post-hypoxic leukoencephalopathy
•  Leukodystrophy with axonal spheroids (myelin and axons)
•  Adrenoleukodystrophy
•  Metachromatic leukodystrophy
•  Electricity-induced demyelination
•  Decompression sickness demyelination

Courtesy of Jeremy Schmahmann

 OBSTRUCTIVE (or mechanical)
•  Normal pressure hydrocephalus
•  Obstructive hydrocephalus
•  Sagging Brain Syndrome

Courtesy of Jeremy Schmahmann

Some uncommon - but not vanishingly rare -
disorders that cause dementia
•  HunBngton's disease
•  Fragile X Tremor Ataxia Syndrome
•  Gordon Holmes Syndrome
•  Spinocerebellar Ataxias
–  SCA 1 – corBcal, subcorBcal as well as cerebellar
–  SCA 2 – can resemble PD
–  SCA 3 (Machado-Joseph Disease)
–  SCA 17 – resembles HD
•  Langerhans cell hisBocytosis
•  Niemann-Pick Type C

Courtesy of Jeremy Schmahmann

UCSF Non-prion diagnoses in 67 patients initially suspected of having CJD

Neurodegenerative N=26 39%

CBD 8, FTD 7, DLB 4, AD 5, PSP 2
Autoimmune N = 15 22%
Hashimoto 4, MS 1, Antibody mediated 9
Infectious N=4 6%
Psychiatric N=4 6%
Malignancy N=4 6%
Toxic/metabolic N=3 4%
Vascular N=3 4%
Unknown N=8 12%
Geschwind et al. Ann Neurol. 2008 July ; 64(1): 97–108

Courtesy of Jeremy Schmahmann

Acute (time course minutes to hours/days)

-- often present to ED

-- etiology can be suspected from aspects of presentation but

always requires lab for dx or confirmation

-- df dx as vast as for subacute ΔMS

Harrington and
Vardi, 2014

Selected
causes of
delirium
Gower et al, 2012 – I WATCH DEATH
Don’t overlook the obvious

-- pain
-- consBpaBon
Q: What do I need to make sure I catch in the first day?

Han et al, 2010 – WHHHHIMPS
 Management
Q: What quesBons in history and physical best differenBate badness from nonbadness?

A: Acute changes in mental state are all potenBally bad

DetecBon is key

The most important part of the history is: “when did change begin?”

Physical signs indicaBng CNS disease point to “bad” disease


Detection

Diagnosis is obvious in many cases; subtle symptoms and

signs can be hard to spot

Inouye et al (1990) – Confusion Assessment Method (CAM)

-- Specificity 63% - 100%
-- Sensitivity 46% - 95%
-- Up to 10 minutes to administer
EXAM

-- Vital Signs
-- General exam
-- rash, signs of medical disease (liver failure, petechiae) . . .
-- CNS exam
-- level of consciousness
-- content of consciousness
-- focal cognitive neurological signs
-- aphasia, amnesia, perception disorder (neglect)
-- eye exam (fundi, pupils, EOMs)
-- focal non-cognitive neurological signs (weakness, posturing)
-- possible seizures
-- meningismus
Meningismus

-- nuchal rigidity
Meningeal irritation C-spine disease
-- throughout range of motion -- endpoints only
-- all directions -- extension/flexion only

-- Kernig’s sign
thigh is flexed at the hip
knee at 90 degree angles
extension of knee is painful

-- Brudzinski's sign
pt supine
involuntary lihing of the legs with head flexion
Kernig’s sign
Brudzinski's sign
MANAGEMENT OF ACUTE ΔMS

-- labs
-- CBC, ESR, electrolytes, renal fxn, liver fxn, TSH, EKG,
oximetry, U/A, CXR, tox screen

-- rapid treatment (before labs back): glucose, thiamine, naloxone

Management of acute ΔMS – issues

MRI

Q: Do all these paBents need MRI?

A: No guidelines that I know of

My view:

All patients with acute ΔMS need MRI unless

-- there is a credible explanation for their ΔMS
and
-- they improve with treatment

This often requires observation overnight or admission

Management of acute ΔMS – issues

EEG

No official guidelines exist

University Teaching Hospital in Zambia issued “Evidence-Based

Guidelines for EEG UBlizaBon” (2011)

“An urgent EEG is indicated in all unconscious paBents suspected of

non-convulsive status epilepBcus or subclinical seizures. This includes
comatose or obtunded inpaBents of unclear eBology especially those
in whom seizures preceded the onset of coma.”

Case – recurrent confusional state

Obtain EEG in pts with undiagnosed ΔMS

MANAGEMENT OF ACUTE ΔMS
– issues

LP

“If you think of doing a spinal tap, do one”

Basically correct, but there are a few considerations

-- yield
-- dangers
-- timing
 Yield – very low in some studies, never high

Van de Beek et al (2004)

Majed et al (2009)
-- surveyed all pts in ED in general hospital in Arras, France, in 2004, 2005
-- 46,486 visits, 247 LPs (0.53%)
Majed et al (2009)

63.6% of posiBve LPs à asepBc meningiBs

1/126 PCRs for HSV posiBve
DANGERS

-- HerniaBon
-- Headache

Warshaw and Tanzer (1993)

-- A significant majority of these paBents will not benefit
from an evaluaBon of their CSF.
-- delays in the appropriate treatment
-- agitated, confused, older paBents are not easy subjects for the LP
procedure.
-- The use of sedaBon to perform diagnosBc procedures in elderly
confused older paBents can significantly distort the clinical
picture.
-- TraumaBc LPs are not uncommon in this situaBon (44/79 negaBve LPs)

“Examina'on of CSF is difficult to jus'fy for all cases of delirium and

fever in the older pa'ent”
Current MGH in-paBent guidelines (under development)

LP indicated in paBents with ΔMS (altered level of consciousness,
lethargy, personality change)

AND ONE OF

-- fever > 100.4
-- seizure without pre-exisBng epilepsy
-- new focal deficit

My view:
-- not specific enough (ΔMS and new focal deficit à stroke)
-- not sensiBve (ΔMS and meningismus à meningiBs)

 So when to do LP?

Warshaw and Tanzer (1993) “If you think of doing a spinal tap, do one”
“ExaminaBon of CSF is difficult to jusBfy for
all cases of delirium and fever in the older
paBent”
My VERY UNOFFICIAL suggesBon

In paBents with acute ΔMS

-- have a high index of suspicion for CNS infecBon (special atenBon to HSV)
-- LP if
-- history, exam, first line labs do not give very likely diagnosis
-- meningismus
-- fever and new focal sign
TIMING

Concern for herniaBon

-- papilledema NOT reliable, especially in pts > 50
-- CT ohen performed prior to LP
-- Majed et al (2009) -- 89.9% pts had CT prior to LP

CAUSES DELAYS
Majed et al (2009)
All pts
-- mean ED-to-CT Bme = 2 hours
-- mean ED-to-LP Bme = 6 hours

Pts arriving between midnight – 6 am
-- mean ED-to-CT Bme = 7 hours
-- LP delayed for 10 hours in some cases
Tunkel et al (2004) Infectious Disease Society of America