Approach to Acute confusion “altered mental status”

One of the commonest reasons for patients to present to the hospital is an acute confusional state. This may be known as “altered mental status” or simply “confusion”. The list of potential causes and differential diagnosis is very broad. The general approach still applies here:

  1. Is this an acute confusional state or are we dealing with something else?
  2. Where is the area of dysfunction or lesion?
  3. What caused the dysfunction?
  4. What is the investigation and treatment plan?

Distinguishing the presentations and localizing the dysfunction:
Acute confusion may represent encephalopathy. This is also known as delirium. The anatomical substrate is global cerebral dysfunction or bihemispheric dysfunction. There are other presentations that need to be distinguished because the approach and underlying cause are different. The most important of these is aphasia and coma. Because ischemic stroke should not be missed in the case of aphasia, and structural causes of coma should not be miss-labeled as severe encephalopathy. Also, acute amnesia for example with transient global amnesia needs to be distinguished from encephalopathy.
The cardinal feature of encephalopathy is inattention and difficulty with concentration. This can be assessed various ways; by asking the patient to do “serial 7s” which involves sequentially subtracting 7 from 100 and saying the result out load e.g. 93, 86, 79, 72 etc. Naming the days of the week backwards is another test of attention and concentration.
In more severe cases of encephalopathy disorientation (to time, place, or person) and lethargy develops. Later on psychosis in the form of visual hallucinations or even delusions may occur. If very severe the patient can become obtunded and slip into a coma with non-structural cause. So there is overlap between severe encephalopathy and non-structural causes of coma. Although most patients with encephalopathy will have milder disturbances of level of consciousness. Distinguishing encephalopathy from aphasia is important and at times difficult. Patients with encephalopathy may have difficulty with naming. Expressive aphasia is fairy straight forward to distinguish from encephalopathy as speech is non-fluent with expressive aphasia. However, the difficulty arises with distinguishing receptive aphasia from encephalopathy. Both conditions can lead to non-sensical fluid speech. Both conditions may cause difficulty in following complex commands such as “touch your left ear with your right thumb”. Try a simple one step command without miming or demonstrating non-verbally such as “stick our your tongue” or “close your eyes”, or simple 2 step commands  such as “show me two fingers”. Patients with encephalopathy should be able to follow simple 1 step commands unless it is very severe, patients with expressive aphasia will not due to lack of comprehension. Also assess the patients visual fields by response to visual threat if they have a quadratinopsia or hemianopsia this suggests a focal lesion and aphasia is more likely. So in summary suspect encephalopathy if the patient has inattention and difficulty with concentration but is able to follow single step commands and has no evidence of focal lesions such as drift or visual field defect.
Acute memory disturbances such as transient global amnesia can seem like encephalopathy. In this rather unusual condition the patient will have sudden loss of ability to form short-term memories, and this lasts for 24 hours. The patient is attentive and has normal language, visual fields, cranial nerve and limb function. However, the patient will have usually complete inability to form short-term memories. They may also not know where they are or what is going on? They often repeat a question “where am I?” “what is going on?” They can carry a conversation and attend to your verbal and non-verbal ques. However, if you leave the room for several minutes and then return, classically, the patient will not remember having met you! This is an acute disturbance of short-term memory and the anatomically substrate is the limbic system, so technically it is not an encephalopathy. Posterior cerebral artery infarct with involvement of the hippocampus and medial temporal lobe structures, as well as complex partial seizures, can mimic this condition.
Etiological assessment:
The vast majority of cases of encephalopathy are due to systemic illness that disturb the overall function of the brain. Conditions such as hyponatremia, hypernatremia, hypoglycemia, hyperglycemia and non-central nervous system infections top the lists of causes. Even fever or hypothermia can cause enough global dysfunction to manifest as encephalopathy. So while the patient has a neurological presentation, the underlying cause of the illness in non-neurological. The infectious causes such as urinary tract infections and pneumonia are often asymptomatic and occult in these patients.
Previous neurological disease such as prior stroke, and dementia can predispose patients to developing encephalopathy when they have an intercurrent systemic condition such as a urinary tract infection, electrolyte dysfunction or renal failure.
There are some neurological causes of encephalopathy. Stroke in non-eloquent areas of the brain or areas that have multiple cortical projections such as the frontal lobes and  the thalamus respectively can present with encephalopathy as the only sign. Also neurological conditions with bilateral cerebral dysfunction such as hydrocephalus, subdural hematoma and traumatic brain injury typically present with encephalopathy.
Temporal features are important in encephalopathy. The onset and progression of most encephalopathy due to systemic illness is days to 2 weeks. The dysfunction can persist as long as there is systemic dysfunction. Also, it takes a while, several days, for the brain to recover once the underlying systemic illness is treated. In some cases the brain may accumulate residual cognitive dysfunction, although this is usually subtle. There is a group of conditions that are collected under the term subacute encephalopathy, which is the same as rapidly progressive dementias. These conditions manifest over weeks or months. Therefore the onset and progression is slower than encephalopathy due to systemic disease and faster than usual causes of dementia which progress over years. The subacute encephalopthies encompass an uncommon group of conditions such as autoimmune or paraneoplastic limbic encephalitis, chronic meningitis, Creutzfeldt Jakob disease, Hashimoto’s encephalitis and central nervous system vasculitis. They require extensive investigations and significant clinical expertise to manage. It is important to think of these conditions in patients with encephalopathy who are not responding after treatment of systemic illness, and also in patients who present with this subacute time course.
Below we outline some of the causes of encephalopathy and other confusional states, as well as some considerations for testing.

Acute encephalopathy a.k.a. Acute confusional state due to systemic illness a.k.a. Delirium:

  • This is a disorder of consciousness where there is an impairment in attention and concentration and usually also impairment in the level of consciousness
  • It is a clinical diagnosis with a change from baseline, plus impairment of attention or concentration
  • Electroencephalography EEG can support the diagnosis by showing dysregulated EEG. There is loss of the normal posterior dominant rhythm (loss of normal wakefulness) and loss of normal sleep architecture. Also the alpha:delta ratio is decreased corresponding with severity of the encephalopathy
Investigations to consider as appropriate:
  • Pulse oximetry
  • ABG
  • Blood tests:
    • Complete/full blood count, ESR (infection), U&E (hyponatremia), Ca++, phosphate, albumin (hypercalcemia), glucose, liver enzymes, TFT
  • Urinalysis
  • Urine microscopy culture, sensitivity
  • CXR: pneumonia
  • Head CT
  • LP: meningitis, encephalitis, carcinomatous meningitis,
  • Blood cultures, syphilis serology, HIV serology
  • Toxicology screen
  • MRI brain +contrast: carcinomatous meningitis
Treatment of encephalopathy:

Treatment is by addressing the underlying condition but there are general measure that are helpful.

  • Maintain normal diurnal variation and rhythm: Single room, dim lights at night, good lighting during the day
  • Nurse in semi-upright or upright position to prevent aspiration, unless contraindicated
  • Correct fluid & electrolyte imbalances

Stop unnecessary medications especially:

  • Antimuscarinics (anti M1)

Consider antipsychotic agents if necessary and if conservative measures  fail

  • Address sleep deprivation, hearing impairments & visual impairments
Rapidly progressive dementia, investigations to consider:


  • Features of CJD, CNS vasculitis, paraneoplastic encephalopathy/encephalomyelitis

CT thorax, abdomen & pelvis:

  • Occult neoplasm

Blood tests:

  • Vasculitis screen
  • HIV, syphilis, Lyme serology
  • Mercury, lead, arsenic
  • Thiamine, vitamin B12 levels
  • Paraneoplastic antibodies/autoimmune antibodies: Anti-Hu (ANNA-1), CV2 (CRMP5), Ma2/Ta, amphiphysin, Yo, Ri, Zic4, voltage gated potassium channel (VGKC), anti-NMDA antibodies
  • Thyroid function tests TFTs & anti-thyroglobulin or anti-thyroperoxidase antibodies: Hashimoto’s encephalopathy

EEG: features of CJD, Hashimoto’s encephalopathy

  • Protein 14-3-3 & S100 protein: CJD
  • CMV PCR: CMV encephalitis in AIDS patients

Tests for: CJD, Diffuse Lewy body disease, corticobasalganglionic degeneration,

Causes of encephalopathy (delirium):

Primary Neurological:


  • Fever
  • Septic encephalopathy:
    • Pneumonia
    • Urinary tract infection (UTI)
    • Septicemia
  • Organ failure:
    • Respiratory failure
    • Hepatic encephalopathy
    • Renal failure
  • Medications:
    • Benzodiazepines (overdose or withdrawal), Anticholinergics, Opioids
    • Many more
  • Drugs of abuse:
  • Endocrine:
    • Hyperthyroidism, hypothyroidism (myxoedema coma)
    • Hyperglycemia (Diabetic ketoacidosis, Hyperosmolar nonketotic hyperglycemia), hypoglycemia
  • Electrolyte imbalances:
    • Hyponatremia
    • Hypercalcemia (>3.7 mmol) and Hypocalcemia
    • pH abnormalities: acidosis, alkalosis
  • Shock from any cause:
    • Septic shock
    • Hypovolemic shock
    • Cardiogenic shock
    • Neurogenic shock
  •  Nutritional:
  • Hematological:
    • Diffuse intravascular coagulation (DIC)
    • Thrombotic Thrombocytopenic Purpura (TTP)
  • Hypothermia and hypothermia
  • Global cerebral ischemia a.k.a. anoxic-ischemic encephalopathy (usually causes coma)
  • Others:
    • Pancreatitis, Vasculitis

Causes of subacute encephalopathy (rapidly progressive dementia):


Central nervous system vasculitis:

Chronic meningitis:

Prion disease:


Amnesic disorder:

Investigations as to consider as appropriate

  • Infarction of; hippocampus, medial temporal lobe, anteriomedial nucleus of the thalamus or basal forebrain.
  • Tumour in temporal lobe

CT: subarachnoid hemorrhage (very uncommon), evidence of occult trauma
EEG: complex partial seizure
LP +CSF analysis: HSV encephalitis, paraneoplastic limbic encephalitis, subarachnoid hemorrhage,
Blood tests:

  • Carboxyhemoglobin: high in CO poisoning
  • B1 thiamine level

Causes of amnesia (short list):

Causes of amnesic state (longer list by duration):

Sudden onset:

Subacute onset:

Slowly progressive:

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