Reversible causes of Dementia

&
Delirium
Presenter : Dr. Udayan Majumder
Resident in Psychiatry, RIMS
 Reversible Dementias
 DSM-5 defines Major neurocognitive disorder as a
significant cognitive decline from previous level of
functioning in one or more cognitive domains:
 Complex attention
 Executive function
 Learning and memory
 Language
 Perceptual motor, or social cognition

 Not accountable to any other psychiatric illness like

depression, other mood disorders and psychosis
 What are reversible dementias?
• “Reversible dementias” are conditions that may well be
associated with cognitive or behavioral symptoms that can
be resolved once the primary etiology is treated

• Confusion over the term “reversible dementia” as many

metabolic causes of dementia overlap with delirium

• Treatable dementias may be untreatable after a delay in

diagnosis

• The common feature among all causes is that the treatment

of offending agent results in improvement in
cognitive functioning.
 Facts and figures
• Prevalence highly variable, with a number of studies
reporting a range between 8% and 40%

• Approx. 12% of patients presenting to specialist services

with symptoms of dementia have treatable/reversible
causes

• 18% in patients < 65 years but only 5% in those > 65 years

• The Indian study by Srikanth found reversible causes

account for 18% of all dementias. Three most common
causes were central nervous system (CNS) infections ,
NPH, and Vitamin B12 deficiency
•
 Central nervous system infection
• Chronic bacterial meningitis :
Common cause in neurology ward, variable dementic changes
found with other cardinal features, potentially reversible with
proper antimicrobial and supportive Mx

• Neurosyphilis :
Late syphilis presents as dementia, tabes dorsalis, general
paresis, sensory ataxia, and bladder / bowel disturbances.
MCI can be reversed following adequate treatment

• AIDS-dementia complex, HIV encephalopathy :

Difficulties in concentration and memory followed by apathy,
social withdrawal, and motor dysfunction. HAART , in particular,
is effective in reversing the cognition, as claimed by studies
 Contd.
• Neurocysticercosis (NCC) :
Clinically more aggressive form that can present as reversible
dementia in some cases . A study shows 15.5% of them had
dementia & 78.5% had a reversal of symptom 6 months
following treatment

• Other potential causes :

• HSV Encephalitis
• Lymes disease
• Tubercular meningitis
• Cryptococcal meningiis
• JC virus infections
 Normal Pressure Hydrocephalus
• Clinical triad of ataxia, urinary incontinence, and dementia

• Prevalence of is in the range of 0.2-2.9%. Individuals > 80 years,

prevalence rises to > 5.9%

• Frontal and subcortical deficits such as psychomotor slowing and

impaired attention, executive, and visuospatial dysfunction can
be the earliest cognitive signs

• Differentiating feature from Alzheimer’s dementia is severe

impairment of frontal lobe function while memory disturbance
and orientation are relatively spared

• Rapid reversal of symptoms following CSF tap in mild or VP

shunt in moderate to severe cases. May not be totally reversible
in late diagnosis or elderly individuals
 CNS tumors & SOLs
• Reports of chronic subdural hematoma (SDH) giving rise to
reversible dementia are reported

• Common causes are meningiomas, metastasis and prolactinomas

among the ICSOLs for reversible neuro-cognitive symptoms

• Usual clinical features include altered sensorium, focal neurological

deficits, and memory disturbances

• 50% of individual reach premorbid level of functioning following

surgery

• Reversible following the surgical removal of tumors

 Nutritional causes
 Thiamine Deficiency :

• Thiamine has been known to have an important role in memory

and emotion

• Deficiency can result in Wernicke-Korsakoff syndrome is usually

seen in chronic alcoholics and severely malnourished

• Triad of ophthalmoplegia, ataxia and acute confusion

• Korsakoff amnesia then follows with cognitive impairment in the

form of retrograde and anterograde amnesia

• Early detection and treatment of Wernicke’s can reverse cognitive

impairment
 Contd.
 Vit B12 defficiency :
• Common cause of macrocytic anemia and can result in a plethora
of neuropsychiatric symptoms

• Low levels are associated with neurodegenerative conditions and

cognitive impairment some of which may meet criteria for
dementia

• Reduce the rate of cortical atrophy and improvement in cognitive

function in individuals with preexisting vitamin deficiency

• Other vitamin deficiencies that can result in cognitive impairment

in elderly are niacin and folic acid deficiency
 Drugs
• Steroids can develop dementia-like cognitive symptoms that occur
without the occurrence of psychosis, reversible on tappering and
stopping

• Drugs with anticholinergic effects lead to dementia on long term use

• Antidepressants, antipsychotics, atropine, carbamazepine, first

generation antihistamines, and antimuscarinics, etc

• 21% of total cases of dementia are reversible in nature

• Prolonged use of BZD has an adverse effect on cognition specially in

the elderly population

• Other drugs are Valproate, chemotherapeutic agents, Thalidomide,

although the evidence is limited
 Endocrine causes
• Hypothyroidism, clinical & subclinical is one of the common
causes of reversible dementia, evident by studies

• Hyperthyroidism or elevated levels of thyroid hormones are

also known to cause dementia

• Cushing’s syndrome, can cause cognitive impairment, due to

hippocampal atrophy following hypercortisolemia

• Recurrent episode of hypoglycemia can lead to cognitive

impairment

• Other metabolic causes of reversible dementia are hypo and

hyperparathyroidism, Wilson’s disease, Paraneoplastic
syndrome
 Depression
• Although not entirely a true dementia, this condition is worth
mentioning as many cases of depression may be mistaken for
dementia

• Pseudo-dementia, as it is called, occurs in patients with a history of

depression

• Clinical testing may reveal memory impairment that is far less than
what is reported by the patient

• Treatment with antidepressants will lead to a reversal of symptoms

 Sleep apnea
• Obstructive sleep apnea (OSA) is a common clinical sleep
disorder that affects cognition in few patients

• OSA induced hypoxia with sympathetic vasoconstriction may

produce the final effects

• Patients with OSA had reduced hippocampal volume when

associated with cognitive impairment

• Treatment with continuous positive airway pressure produces

reversibility of pathological findings in hippocampal volume
 Investigations
• No supplement to the detailed history and clinical examination

• Any atypical case such as early age of onset,

disproportionate symptoms that do not fit in a definite
syndrome, the presence of a comorbid medical condition that
are known to cause reversible dementia should raise the
probability of reversible dementia

• Clinical examination may be aided by a variety of laboratory

investigations
Contd.
 CONCLUSION
• Although degenerative and vascular etiologies form a major group of
dementias in elderly, quite a few of them do present with reversible
causes

• Nutritional deficiencies, NPH, endocrine problems are the more

common causes of reversible dementias

• At times, patients may be misdiagnosed as having dementias when

they maybe actually having delirium

• These conditions are worth knowing for neurologist and

psychiatrist alike as early detection and treatment of them can
improve the quality of life of patients.
DELIRIUM
Delirium
Delirare: to be
crazy
De lira: to leave the
furrows
Early Descriptions

“ they move the face, hunt in “Sick people…lose their judgment

empty air, pluck nap from the and talk incoherently…when the
bedclothes…all these signs are violence of the fit is abated, the
bad, in fact deadly” judgment presently returns…”

Hippocrates:400 BCE Celsus: 1st Century BCE

 Delirium
• Synonyms: acute confusional state, organic brain
syndrome, encephalopathy, terminal agitation, acute
brain failure, toxic metabolic encephalopathy,
cerebral insufficiency
• Often mistaken for depression, anxiety, or dementia

Core symptoms:
The core symptoms of delirium include a disturbance of consciousness
that is accompanied by a change in cognition that develops rapidly,
usually hours to days, and tends to fluctuate during the course of the
day
 Hospital Length of Stay
increases Rs / $
Mortality and Morbidity
Nursing home placement from hospital
Caregiver burden
Nursing care
Cognitive and functional decline

Delirium is harmful
 Facts and figures
• Most incidence and prevalence rates reported in the
elderly
• The prevalence at hospital admission 14 - 24 %
• People experience it at end of life 85%
• General medical in-patients 10-30%
• Critical care units 16%
• Cardiac care Units 16-34%
• Orthopedic surgery units 33%
• Terminally ill cancer patients 22-28%
 Risk factors
• Predisposing factors
1. Age > 65yrs, Male sex
2. Dementia, H/O Delirium, Depression
3. Functional dependence, Immobility
4. Hearing or visual disturbances
5. Dehydration, Malnutrition
6. Psychoactive, anticholinergic drugs, alcohol
7. Coexisting medical conditions
 Risk factors contd.
• Precipitating factors
1. Medications
2. Stroke (non-dominant hemisphere), IC bleed,
neuroinfections
3. Intercurrent illnesses
4. Cardiac and orthopedic surgeries
5. Long ICU stay, sleep deprivation, bladder catheter,
physical restraints, pain, emotional stress
Medications
• Opioids • Lithium

• Corticosteroids • H2 Blockers
• Benzodiazepines • NSAIDs
• Anticholinergics • Metoclopramide
• Diuretics • Alcohol/drug use
• Tricyclics or withdrawal
Pathophysiology
• Still remains poorly understood
• Disruptions in different areas of brain (non-
dominant side)
• PFC, subcortical stuctures, thalamus, basal
ganglia, frontal and temporoparietal cortex,
fusiform cortex, and lingual gyri
Neurotransmission

Inflammation Chronic stress

Neurotransmission
1. Acetylcholine

a) Cholinergic activity related with REM sleep, attention,

arousal,memory
b) Administration of anti-cholinergic drugs can induce
delirium
c) Serum anti-cholinergic activity is increased in patients with
delirium
d) Physostigmine reverses delirium associated with
anticholinergic drugs
e) Cholinesterase inhibitors appear to have some benefit even
in cases of delirium that are not induced by drugs
Contd.
2. Dopamine
a) Dopaminergic excess to contribute to delirium, possibly its
regulatory influence on the release of acetylcholine
b) Dopaminergic drugs (L-dopa) are recognized as
precipitants of delirium
c) Dopamine antagonists (e.g., antipsychotic agents) effectively
treat delirium symptoms

3. Glutamate
a) Excitatory neurotoxicity effects cause neuronal death
b) NMDA antagonists (ketamine & phencyclidine)are
associated with delirium
 Contd.
3. GABA
a) Contributing to delirium secondary to BDZ and alcohol
withdrawal
b) Hepatic encephalopathy has been associated with
increased serum ammonia and GABA levels
4. Serotonin
a) May contribute, evidence less developed
b) Interactions with the cholinergic and dopaminergic
pathways
5. Oxidative Metabolism
a) Disturbance in brain oxygen supply versus demand
b) Impaired oxidative metabolism in metabolic disorders
Contd.
6. Blood brain barrier alterations
a) CNS response to systemic inflammation during a state of
blood–brain barrier compromise
b) Chemokines have been associated with delirium by
disrupting the BBB
c) Trauma, primary hyperparathyroidism and delirium
tremens
7. Ammonia
a) Ammonia induce and aggravate astrocyte swelling,
initiating cascade of events leading to delirium
 Contd.
8. Cytokines, IL-1,2,6, TNF-Alpha & IF-gamma,
may contribute by increasing the permeability of
the BBB and altering neurotransmission

9. Chronic stress brought on by illness or trauma

activates sympathetic nervous system and HPA
axis, resulting in increased cytokine levels and
chronic hypercortisolism, ultimately to delirium
 Clinical Subtypes: Delirium

Less likely to
be diagnosed

Mixed
• Confusion • Confusion
• Agitation • Somnolence
• Hallucinations • Fluctuates • Withdrawn
• Myoclonus between • Decreased PMA
• Mood lability • Mimic severe depression
both
Hyperactive Hypoactive
DSM-5
• Specify if
1. Acute – lasting a few hours or day
2. Persistent- lasting weeks or months
• Specify if
1. Hyperactive
2. Hypoactive
3. Mixed level of activity

• Associated feature supporting diagnosis :

• Disturbance in sleep wake cycle

• Emotional disturbance like anxiety, fear, depression, euphoria, anger,

irritability and apathy. There may be rapid and unpredictable shift from
one state to another.

 OTHERS - Other specified delirium, Unspecified delirium

 Warning Signs of Delirium
• Acute change in mental status

• Presence of medical illness

• Visual hallucinations

• Fluctuating levels of consciousness

• Acute onset of psychiatric symptoms without prior

history of psychiatric illness
Contd.
• Acute onset of new or different psychiatric symptoms
with history of prior psychiatric illness

• Patient described as “confused” or “disoriented”

• Diffuse slow waves or epileptiform discharges on

electroencephalogram.
SCALES
• Confusion Assessment Method (CAM) and CAM-
ICU for critically ill patients

• Severity of delirium –

1. Delirium Rating Scale (DRS)

2. Memorial Delirium Rating Scale (MDRS)

DIFFERENTIAL DIAGNOSIS
• Depression
• Dementia
• Schizophrenia
• Adjustment disorders,
• Anxiety disorders,
• Agitated depression
• Mania
COURSE AND PROGNOSIS
• By the third hospital day, approximately one-half the patients who are
diagnosed with delirium have been diagnosed.

• Symptoms of delirium usually last 3 to 5 days, but there is slow

resolution of symptoms contributing to persistent symptoms of delirium
at 6 to 8 weeks for severely ill patients.

• Symptom resolution is frequently incomplete by hospital discharge, with

as many as 15 percent of patients remaining symptomatic of delirium at 6
months.

• In general, studies suggest that the increased mortality risk associated

with delirium was maintained at 12, 24, and 36 months with a risk ratio
of at least 2 at all time points.

• Additionally, at 24 months, the increased risk of cognitive and functional

impairment remained.
PRIMARY PREVENTION
• Minimization of polypharmacy.

• Anti cholinergic, hypnosedative and opioid medications

should be used sparingly in the elderly.

• Maintain hydration and nourishment and ensure

sufficient sleep.

• Caregivers and nursing staff must be trained to

recognize delirium.
Secondary prevention
• Early diagnosis and treatment

• Improved recognition of the condition.

• It is recommended that all acutely ill elderly patients

should have a brief mental test on admission to
increase the rate of detection of delirium.

• Environment modifications, close monitoring to

prevent further morbidity and mortality.
 MANAGEMENT
Basic algorithm
1. Taper or discontinue non-essential medications.

2. Close observation.
3. Monitor vital signs and fluid intake and outputs.

4. Complete history and perform initial laboratory studies

5. Implement environment and psychosocial interventions

6. Pharmacological treatment as indicated.

7. Physical restraints are used only as a last resort
LABORATORY EVALUATION
Basic Investigation :  Additional Laboratories
Based on History,
1. CBC Examination, Laboratories:
2. Serum chemistry 1. Toxicology screen
3. Urine analysis 2. Drug levels
4. ECG 3. Vitamin B12 & folate
5. CXR 4. Thyroid tests
6. ABG 5. Ammonia levels
6. Blood-urine cultures
 EEG
• Slowing of the posterior dominant rhythm and
increased generalized slow-wave activity (80-90) %

• As delirium worsens and as the EEG background

rhythm reaches 5 to 6 Hz or less, reactivity is lost.

• The magnitude of change in frequency of the

posterior dominant rhythm is more important than the
absolute frequency.
NEUROIMAGING
• Structural brain imaging may detect acute or sub-acute conditions,
such as

• Subarachnoid hemorrhage

• Subdural hematomas

• Intracranial tumors

• Vascular changes, including stroke

 NCCT & MRI of brain mostly recommended

 fMRI, PET, SPECT --- limited scope in Indian scenerio

NON PHARMACOLOGICAL INTERVENTION
• Ensure effective communication & reorientation (e.g.
explaining where the person is, who they are, and what
your role is)

• Promoting day activity

• Maintaining quite, well-lit environment

• Staff continuity

• Avoiding room and bed changes

• Providing hearing and visual aids

 Contd.
• Encouraging personal items

• Limiting visits especially for hyperactive delirium patients,

• Remove noxious stimuli (e.g., catheters, pumps, etc.)

• Normal sleep–wake cycles can be promoted by the use of day

time activity and environmental cues (such as windows and
clocks)

• Interruptions of sleep should be minimized when possible

• Adequate nutrition
PHARMACOLOGICAL INTERVENTION
General principles

• Keep the use of sedatives and antipsychotics to a minimum.

• Use one drug at a time.

• Titrate doses to effect.

• Review at least every 24 hours. Once an effective has been

established, a regular dose should be prescribed.

• Maintain at an effective dose and discontinue 7–10 days after

symptoms resolve.

Maudsley prescribing guidelines

Contd.
• Psychoactive medications are indicated for delirium
associated with drug withdrawal or for behaviors that
pose a safety risk for the patient and others.

• Two general classes of agents—

• Antipsychotics and

• Benzodiazepines
Contd.
• Haloperidol - Preferred drug. Potent & fewer anti cholinergic and
hypotensive side effects.

• Therapy should be monitored closely for side effects.

• Haloperidol can be administered through oral, IM/IV routes though IV

route is not approved by USFDA

• Second-generation antipsychotics, such as risperidone, clozapine,

olanzapine, quetiapine, ziprasidone, and aripiprazole, may be
considered.

• For patients with Parkinson's disease and delirium who require

antipsychotic medications, clozapine or quetiapine have some support
in the literature.
Advances in Psychiatric Treatment (2008), vol. 14, 292–301, BJPsych advances
Benzdiazepines
• Benzodiazepines are also used in the management of
delirium to sedate the agitated patient.

• When the agitation is associated with sedative-hypnotic and

alcohol withdrawal, benzodiazepines are the treatment of
choice.

• Dosing : Lorazepam –0.5–3 mg a day and as needed every

4-6 hrs.

• BZD may worsen delirium and may cause respiratory

depression.
 Contd.
Cholinestrase inhibitors

• Donepezil 5mg OD, very little evidence

• Rivastigmine 3-9 mg OD, very little experience, usually used in

chronic delirium as an adjunct to antipsychotics.

Others

• Melatonin 2mg OD used to correct sleep wake cycle

• Sodium valproate, some case reports of its use when

antipsychotics and benzodiazepenes are not effective.
Maudsley prescribing guidelines
 Electroconvulsive Therapy
• It has been used as a last resort for delirious patients
with severe agitation who are not responsive to
pharmacotherapy.

• The ECT is usually given en bloc or daily for

several days, sometimes with multiple treatments
per day

• Effective in agitated and disruptive patients

Sleep–Wake Cycle
• Delirium is frequently complicated by changes in
the sleep–wake cycle.

• Sedating medicines – bedtime

• Stimulating medicines or caffeine in morning

• Brief, judicious use of sedating agents, such as

Zolpidem CR or Trazodone, to reset the sleep–wake
cycle may be appropriate.
 AFTER CARE
• Many patients are discharged before their symptoms are fully
resolved.

• Problems with attention and orientation are especially

persistent (Levkoff et al, 1994)

• Depression, post traumatic stress disorder (PTSD) are

recognized as psychological sequelae.
 Take home message
• Delirium is complex neuropsychiatric syndrome that is
common in all health care settings.

• The field is hampered by poor detection.

• Psychiatrists can play a pivotal role in the diagnosis

and treatment of delirious patients.

• Typical neuroleptic drugs remain the cornerstone of

treatment.
Contd.
• Cognitive impairment of delirium is not entirely
reversible in all patients.

• During delirium there is significant risk for progression

of underlying dementia.

• Symptoms of delirium frequently persists beyond the

acute phase of treatment, therefore post-discharge
treatment plans must focus on reducing ongoing risk
factors and managing residual functional impairment.
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THANK YOU