Approach to Altered Sensorium - Harrison's Principles of Internal Medicine, 22nd Edition (2025)

Terminology and Definitions

• Confusion - reduced comprehension, coherence, and capacity to reason
• Delirium - acute confusional state (hallmark = attention deficit)
• Stupor - patient arousable only with vigorous stimulation
• Coma - unresponsive, unarousable state

PART I: DELIRIUM (Acute Confusional State)

Clinical Features

• Altered sleep-wake cycles
• Perceptual disturbances (hallucinations, delusions)
• Affect changes
• Autonomic instability (HR and BP fluctuations)

Patients often fluctuate between subtypes along a spectrum. Hypoactive delirium is frequently overlooked on medical wards and in the ICU.

Risk Factors (Table 29-1 in Harrison's)

• Age >65 years
• Pre-existing cognitive impairment/dementia
• Severe illness, functional dependence
• Sensory deprivation (vision/hearing loss)
• Dehydration, malnutrition

Laboratory and Diagnostic Evaluation (Table 29-2)

• History - special attention to medications (including OTC and herbals)
• General physical + neurologic examination
• CBC, electrolyte panel (Ca, Mg, Phosphorus), LFTs (with albumin), renal function tests

• Systemic infection screen: UA + culture, chest X-ray + respiratory pathogen tests, blood cultures
• ECG
• ABG
• Serum/urine toxicology screen (earlier in young patients)
• Serum B12, folate, thiamine levels

• Brain CT or MRI
• EEG (essential when NCSE is suspected or etiology remains unclear)
• LP - CSF analysis (meningitis, encephalitis)
• Autoimmune/paraneoplastic antibody panel
• Thyroid function, cortisol, ammonia

Per Harrison's: "No single algorithm will fit all delirious patients due to the staggering number of potential etiologies." If a clear precipitant (e.g., offending medication) is identified, further testing may not be required.

Management of Delirium

• Reorientation by nursing staff and family
• Visible clocks, calendars, outside-facing windows
• Sensory aids: glasses, hearing aids
• Sundowning prevention: daytime activities, quiet dark nights, limit nocturnal interruptions
• Melatonin before bed to promote sleep
• Mimic home environment: familiar objects, bedding, clothing
• Family visits throughout the day
• Maintain nutrition, hydration, manage pain, incontinence, skin breakdown
• Minimize "tethers" (Foley catheters, nasal cannulas, telemetry) that restrict movement

• Reserve for severe agitation endangering the patient or staff
• Low-dose haloperidol remains standard; atypical antipsychotics (quetiapine, olanzapine) are alternatives
• Avoid benzodiazepines except in alcohol/sedative withdrawal delirium - they worsen most other causes
• Dexmedetomidine in the ICU setting

PART II: COMA

Anatomy and Physiology

1. Widespread abnormalities of both cerebral hemispheres, or
2. Reduced activity of the reticular activating system (RAS) - neurons in the upper brainstem and thalamus

Herniation Syndromes

FIGURE 30-1 - Types of cerebral herniation: (A) uncal; (B) central; (C) transfalcial; (D) foraminal

Differential Diagnosis of Coma (Table 30-1)

• Intoxications: alcohol, sedatives, opiates
• Metabolic: anoxia, hyponatremia, hypernatremia, hypercalcemia, DKA, NKHH, hypoglycemia, uremia, hepatic coma, hypercarbia, Addisonian crisis, thyroid states, nutritional deficiency
• Severe systemic infections: pneumonia, septicemia, typhoid fever, malaria, Waterhouse-Friderichsen syndrome
• Shock from any cause
• Status epilepticus / NCSE / postictal states
• Hyperperfusion syndromes: hypertensive encephalopathy, eclampsia, PRES
• Severe hyper/hypothermia
• Concussion
• Acute hydrocephalus

• Hemispheral hemorrhage (basal ganglionic, thalamic) or large MCA infarction with secondary brainstem compression
• Brainstem infarction (basilar artery thrombosis/embolism)
• Brain abscess, subdural empyema
• Epidural/subdural hemorrhage, brain contusion
• Brain tumor with surrounding edema
• Cerebellar and pontine hemorrhage/infarction
• Widespread traumatic brain injury
• Metabolic coma in the setting of preexisting focal damage

• Bacterial meningitis
• Subarachnoid hemorrhage
• Viral/fungal/tubercular meningitis
• Carcinomatous meningitis

Approach to the Comatose Patient

Initial Priorities

History

1. Rapidity of onset and circumstances
2. Antecedent symptoms - confusion, weakness, headache, fever, seizures, dizziness, diplopia, vomiting
3. Medication, drug, or alcohol use
4. Chronic medical diseases (liver, kidney, lung, heart)

General Physical Examination

Neurologic Examination

• Spontaneous movements, yawning, swallowing, moaning = near-normal arousal
• Lack of movement on one side or externally rotated leg = hemiplegia (or hip fracture)
• Subtle twitching of finger/foot/face = seizure activity
• Multifocal myoclonus = metabolic disorder (uremia, hypoxemia, drug intoxication, prion disease)

• Pressure on bony prominences or pinprick
• Purposeful abduction-avoidance = intact corticospinal system
• Posturing (decerebrate/decorticate) = severe corticospinal damage

Brainstem Reflexes

FIGURE 30-3 - Brainstem reflex examination: pupillary light reflex (midbrain/CN III), corneal reflex (pons CN V-VII), oculocephalic/caloric reflexes (pons CN VI-VIII, via MLF), respiratory pattern (medulla)

Preserved brainstem reflexes = bihemispheric localization (toxic/metabolic) Abnormal brainstem reflexes = brainstem lesion OR herniation from supratentorial mass

• Spontaneous roving conjugate movements = intact brainstem, coma from bihemispheral disease
• Oculocephalic reflex (doll's eyes): Eyes deviate opposite to head rotation if intact; absent in brainstem lesions
• Oculovestibular reflex (cold calorics): Cold water in ear → eyes tonically deviate toward that ear if brainstem intact; absent/dysconjugate = brainstem lesion
• Conjugate eye deviation toward the side of a hemiplegia = ipsilateral frontal lobe or contralateral pontine lesion ("eyes look toward the lesion" for hemisphere, "eyes look away from the lesion" for pontine)

• Cheyne-Stokes breathing = bihemispheral or metabolic
• Central neurogenic hyperventilation = midbrain-upper pons lesion
• Apneustic breathing = caudal pontine damage
• Ataxic breathing = medullary damage (pre-terminal)

Investigations in Coma

• Blood glucose - check immediately (and give empirical dextrose if hypoglycemia suspected)
• Empirical thiamine 100 mg IV before glucose in malnourished/alcoholic patients
• CT head - first-line neuroimaging (exclude mass lesion before LP)
• LP - if no cause apparent; indispensable for meningitis/encephalitis (blood cultures and antibiotics first if meningitis suspected, then proceed to imaging)
• EEG - NCSE must be excluded; essential when etiology is unclear
• Standard labs: CBC, electrolytes, glucose, renal/liver function, ABG, toxicology screen

Prognosis

• Drug/metabolic coma with preserved brainstem reflexes: generally good prognosis with treatment
• Hypoxic-ischemic coma: Absent cortical SSEP responses and high serum neuron-specific enolase (NSE) at established intervals = strong indicator of poor outcome
• Traumatic coma: GCS at 6 hours, age, pupillary responses are key prognostic markers
• ~10% of traumatic vegetative patients may show functional MRI cortical activation to commands; ~15% of acutely brain-injured unresponsive patients show EEG activation

Serial examinations and multimodal prognostication are advised. Avoid premature prognostic conclusions from single data points.

Brain Death

• Complete and irreversible cessation of all brain functions including the brainstem
• Prerequisites: known proximate cause, absence of confounders (hypothermia, drugs, metabolic)
• Clinical exam: coma, absence of all brainstem reflexes, apnea test
• Confirmatory tests when clinical exam is incomplete: EEG, cerebral angiography, SSEP, nuclear perfusion scan

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