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Parkinson's Disease

Overview

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Pathophysiology

The Dopamine-Acetylcholine Imbalance

• Inhibitory dopaminergic neurons (from substantia nigra)
• Excitatory cholinergic neurons (within neostriatum)

Basal Ganglia Circuit Disruption

• Direct pathway (D1 receptors): dopamine is excitatory - facilitates movement
• Indirect pathway (D2 receptors): dopamine is inhibitory - reduces the brake on movement

Alpha-Synuclein and Lewy Bodies

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Clinical Features

Motor Symptoms (the classic tetrad)

Other Motor Manifestations

• Masked facies (hypomimia) - reduced facial expression, decreased blink rate
• Micrographia - progressively smaller handwriting
• Hypophonia - soft, monotone voice with hurried muttering quality
• Festinating gait - small, shuffling steps; difficulty initiating (freezing), tendency to lean forward (anteropulsion) or backward (retropulsion)
• En bloc turning - turning without normal torso twist
• Myerson's sign - inability to suppress blinking when glabella is repeatedly tapped (non-specific)
• Dysphagia - recognized by Parkinson himself in 1817; subjective prevalence ~35%, objective up to 82%; involves oral, pharyngeal, and esophageal phases; silent aspiration in 15-33%

Non-Motor Symptoms (often precede motor symptoms)

• Autonomic: orthostatic hypotension, constipation, urinary urgency, sexual dysfunction, seborrhea
• Sleep: REM sleep behavior disorder (RBD) - often an early prodromal marker
• Olfactory: hyposmia/anosmia (may predate motor symptoms by years)
• Neuropsychiatric: depression (most common psychiatric disturbance), anxiety, apathy, psychosis (typically medication-induced visual hallucinations in ~40%, delusions in ~16%)
• Cognitive: mild executive dysfunction is common early; dementia occurs in 15-40% later in the course

Note on psychosis: In PD, hallucinations are usually fleeting and nocturnal, motor symptoms virtually always precede psychosis, and psychosis is generally medication-induced. This distinguishes it from Dementia with Lewy Bodies (DLB), where psychosis is a core feature occurring even without medications. - Bradley and Daroff's Neurology in Clinical Practice

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Diagnosis

Supporting features:

• Asymmetric onset
• Good response to levodopa
• Progressive course over 5-15 years

Investigations:

• DaT SPECT (dopamine transporter scan): shows reduced uptake in the striatum; useful when diagnosis is uncertain
• MRI brain: typically normal in idiopathic PD; used to exclude structural causes

Red flags suggesting alternative diagnoses:

• Early postural instability (before 3 years)
• Rapid progression
• Symmetrical onset
• No response to levodopa
• Early falls, early dementia, early autonomic failure, supranuclear gaze palsy, cerebellar signs

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Pharmacological Treatment

1. Levodopa + Carbidopa (first-line, most effective)

• Reduces peripheral conversion of levodopa to dopamine (preventing nausea, vomiting, cardiac arrhythmias)
• Increases CNS availability of levodopa
• Allows a 75% reduction in levodopa dose

• Wearing-off phenomenon: as neuronal loss progresses, the drug effect duration shortens between doses
• On-off fluctuations: unpredictable swings between mobile ("on") and immobile ("off") states
• Dyskinesias: involuntary choreiform movements, typically at peak dose
• Nausea, orthostatic hypotension, psychosis

2. COMT Inhibitors (adjunct to levodopa)

• Increase central levodopa uptake
• Raise brain dopamine levels
• Reduce "wearing-off" effects

3. MAO-B Inhibitors

4. Dopamine Receptor Agonists

• Longer duration of action
• Lower risk of dyskinesia
• Useful in patients with levodopa fluctuations
• Initial monotherapy in younger patients delays dyskinesia

5. Anticholinergic Agents

6. Amantadine

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Non-Pharmacological and Surgical Treatment

Exercise and Physiotherapy

Deep Brain Stimulation (DBS)

• Advanced PD with motor fluctuations refractory to medical therapy
• Intolerable levodopa-induced dyskinesias
• Preserved cognitive function

Repetitive Transcranial Magnetic Stimulation (rTMS)

Swallowing and Speech Therapy

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Complications and Prognosis

• Disease progression is typically insidious, over 5-15 years
• Many patients die of other causes (given late onset) rather than directly from PD
• Leading causes of death in advanced PD: aspiration pneumonia, falls/trauma, immobility complications
• Dementia (PD dementia) occurs in 15-40% of patients late in the course
• PD dementia shares pathological overlap with DLB (both are "synucleinopathies")

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Key Differential Diagnoses

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Recent Evidence (2024-2026)

• Exercise for motor symptoms (PMID: 39880702, 2025 network meta-analysis): Specific exercise modalities significantly improve motor outcomes - exercise should be considered a core therapeutic component, not optional.
• Virtual reality for balance (PMID: 40142335, 2025 meta-analysis): VR combined with conventional therapy improves balance compared to conventional therapy alone.
• Anxiety management (PMID: 40568748, 2025): Anxiety affects up to 50% of PD patients and remains undertreated; a recent meta-analysis reviewed pharmacological and non-pharmacological approaches.

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Parkinson's Disease

Harrison's Principles of Internal Medicine, 22nd Edition (2025)

Authors: C. Warren Olanow, Anthony H.V. Schapira, Christine Klein

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Epidemiology

• Estimated ~10.8 million people with PD worldwide; expected to double within 20 years due to population aging
• Mean age of onset: ~60 years (but can occur in the 20s, especially with pathogenic gene mutations)
• Lifetime risk: ~3% for men, ~2% for women
• Frequency increases steeply with age

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Pathology

1. Degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc)
2. Reduced striatal dopamine
3. Lewy pathology - intraneuronal proteinaceous inclusions (Lewy bodies in cell bodies; Lewy neurites in axons) that stain positive for alpha-synuclein (Fig. 446-1)

• Cholinergic neurons of the nucleus basalis of Meynert (NBM)
• Norepinephrine neurons of the locus coeruleus (LC)
• Serotonin neurons of raphe nuclei
• Neurons of the olfactory system, cerebral hemispheres, spinal cord, and peripheral autonomic nervous system

Premotor Stage ("Body-First vs. Brain-First" PD)

1. Based on neuronal alpha-synuclein accumulation staging
2. Based on alpha-synuclein deposition + distribution of neurodegeneration + pathogenic gene variants

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Etiology and Pathogenesis

Genetics

Putative Mechanisms of Cell Death

• Oxidative stress (increased free radicals from dopamine metabolism)
• Mitochondrial dysfunction (Complex I deficiency in SNc)
• Proteasomal/lysosomal dysfunction - failure to clear alpha-synuclein aggregates
• Neuroinflammation - activated microglia in SNc
• Apoptosis as a final common pathway

MPTP Model

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Clinical Features

Cardinal Motor Features (TABLE 446-1)

Diagnosis - UK Brain Bank Criteria & MDS Criteria

• Supportive criteria (features increasing diagnostic confidence)
• Absolute exclusion criteria
• Red flags (must be counterbalanced by supportive criteria)

Imaging

In atypical parkinsonism (MSA, PSP): striatal dopamine depletion can also be seen, so DaT imaging does NOT reliably distinguish PD from atypical parkinsonism. However, FDG-PET of basal ganglia/thalamic network may help - PD shows decreased GPI activity with increased thalamic activity (opposite in atypical parkinsonism).

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Differential Diagnosis

Atypical Parkinsonism (TABLE 446-3 from Harrison's)

Wilson's disease must always be ruled out in young-onset parkinsonism, as progression can be prevented with copper chelators.

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Treatment

LEVODOPA - The Gold Standard

"Levodopa remains the most effective symptomatic treatment for PD and the gold standard against which new therapies are compared." - Harrison's 22e

• Carbidopa (USA - Sinemet)
• Benserazide (most other countries - Madopar)
• Prevent peripheral levodopa conversion to dopamine, reducing: nausea, vomiting, orthostatic hypotension (mediated via area postrema dopamine receptors outside the BBB)

• Standard oral levodopa/carbidopa (Sinemet)
• Controlled-release (Sinemet CR / Madopar HP)
• Long-acting oral formulation (Rytary)
• Levodopa/carbidopa/entacapone combined (Stalevo)
• Levodopa-carbidopa intestinal gel - continuous intra-intestinal infusion
• Continuous subcutaneous infusions of levodopa
• Inhaled levodopa - absorbed through pulmonary alveoli (approved on-demand therapy for off periods)

Motor Complications of Levodopa (Fig. 446-6)

1. Wearing-off phenomenon: Duration of benefit per dose progressively shortens. Initially, benefit lasts many hours (the "long-duration response"). Eventually, benefit approaches the drug's half-life (60-90 min).
2. On-off phenomenon: Rapid, unpredictable switches between the "on" state (drug working) and "off" state (parkinsonism returns).
3. Dyskinesias: Involuntary choreiform/dystonic movements, typically at peak dose during "on" periods.

• Inhaled levodopa (Inbrija)
• Subcutaneous apomorphine injection (Apokyn)
• Sublingual apomorphine (Kynmobi)

Other Pharmacological Agents

Neuroprotection - The Major Unmet Need

"A neuroprotective or disease-modifying therapy that slows or stops disease progression remains the major unmet therapeutic need." - Harrison's 22e

• Agents preventing toxic alpha-synuclein species formation or accumulation
• LRRK2 inhibitors
• GCase (GBA1) enhancers
• GLP-1 agonists (developed for diabetes; anti-inflammatory and pro-mitochondrial effects; results in double-blind trials have been inconsistent)

Surgical Treatment

• Primary targets: subthalamic nucleus (STN) or globus pallidus interna (GPi)
• STN-DBS: reduces all cardinal motor features; often allows levodopa dose reduction
• GPi-DBS: particularly effective for dyskinesias
• Indications: Advanced PD with motor fluctuations refractory to optimized medical therapy; intolerable dyskinesias; preserved cognitive function
• Contraindications/poor candidates: Significant dementia, prominent non-dopaminergic features (freezing, falls), active psychiatric illness, unrealistic expectations
• Focused ultrasound thalamotomy (non-invasive): now available as an alternative for tremor-predominant PD

Emerging / Experimental Therapies (Harrison's 22e)

• Japan (Kyoto University): Phase 1/2 trial since 2018; 7 patients treated
• USA: FDA approved first clinical trial of ESC-derived dopamine neurons; 10 patients in Phase 1
• Europe: Trial of ESC-derived neurons began 2023; 4 patients on low dose with no acute adverse effects

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Non-Motor Management

• Depression: Most common psychiatric disturbance; SSRIs are first-line (though may worsen motor symptoms); tricyclics as alternative
• Psychosis: Visual hallucinations in up to 40% - usually medication-induced; clozapine (low dose) or pimavanserin (5-HT2A inverse agonist, does not worsen parkinsonism) are options
• Dementia: 15-40% develop dementia; rivastigmine (ChEI) has some evidence
• Autonomic: Orthostatic hypotension (fludrocortisone, midodrine, droxidopa); constipation; urinary dysfunction
• Sleep/RBD: Melatonin or low-dose clonazepam for RBD
• Anosmia: No treatment; important as a premotor marker

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PARKINSON'S DISEASE

Harrison's Principles of Internal Medicine, 22nd Edition — Chapter 446

C. Warren Olanow | Anthony H.V. Schapira | Christine Klein

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1. DEFINITION & EPIDEMIOLOGY

• 2nd most common age-related neurodegenerative disease (after Alzheimer's)
• First described by James Parkinson in 1817 as "shaking palsy"
• Prevalence: ~10.8 million worldwide; expected to double in 20 years
• Mean age of onset: ~60 years; can occur in 20s with gene mutations
• Lifetime risk: 3% men, 2% women
• ~15% of cases are familial; the rest are sporadic

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2. PATHOLOGY (FIGURE 446-1 - Harrison's)

Gross pathology

Microscopic pathology

Three hallmark pathological features:

1. Degeneration of dopaminergic neurons in the SNc (substantia nigra pars compacta)
2. Reduced striatal dopamine
3. Lewy pathology — intraneuronal alpha-synuclein aggregates as:
   • Lewy bodies (in cell bodies)
   • Lewy neurites (in axons)

Nondopaminergic involvement (explains nonmotor features):

• Cholinergic neurons of nucleus basalis of Meynert (NBM) → dementia, cognitive dysfunction
• Norepinephrine neurons of locus coeruleus (LC) → depression, sleep
• Serotonin neurons of raphe nuclei → mood disorders
• Olfactory system → anosmia
• Dorsal motor nucleus of vagus → autonomic dysfunction
• Peripheral autonomic nervous system, GI tract → constipation, gastroparesis
• Spinal cord and cerebral hemispheres

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3. ETIOLOGY AND PATHOGENESIS

A. Genetics (TABLE 446-4 — Harrison's)

B. Environmental Factors

• MPTP (methyl-phenyl-tetrahydropyridine) — contaminant of illicit synthetic heroin; caused acute PD syndrome in California addicts in 1980s
  • MPTP → oxidized (by MAO-B) to MPP+ → mitochondrial Complex I inhibitor → selective dopamine neuron death
  • Importantly: MPTP/MPTP-like compounds have NOT been linked to sporadic PD
• Risk factors (inconsistent evidence): pesticides, rural living, farming, well water, solvents
• Possible protective factors: caffeine, cigarette smoking, NSAIDs, calcium channel blockers

C. Pathogenetic Mechanisms

1. Oxidative stress — free radical production from dopamine metabolism
2. Mitochondrial dysfunction — Complex I deficiency in SNc
3. Proteasomal/lysosomal failure — impaired clearance of alpha-synuclein aggregates
4. Neuroinflammation — activated microglia in SNc
5. Apoptosis — final common pathway

D. Braak Staging (Alpha-synuclein spread)

• Anosmia, constipation, RBD precede motor symptoms by years to decades
• These are now classified as premotor PD, not just risk factors
• Concept of "body-first" vs "brain-first" PD based on where pathology initiates

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4. CLINICAL FEATURES (TABLE 446-1 — Harrison's)

A. Cardinal Motor Features (TRAP)

B. Other Motor Features

• Micrographia — progressively smaller handwriting
• Masked facies (hypomimia) — reduced facial expression
• Reduced eye blinking
• Drooling (sialorrhoea)
• Hypophonia — soft, monotone voice
• Dysphagia — oral, pharyngeal, esophageal
• Freezing of gait — sudden arrest of movement ("feet glued to the ground"); major cause of falls; may respond to sensory cues (marching, stepping over imaginary line, singing)
• Festinating gait — small, shuffling, rapid steps; anteropulsion; reduced arm swing; en bloc turning
• Retropulsion — backward stepping on pull test

C. Non-Motor Features

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5. DIAGNOSIS

Clinical Criteria

• Core: Bradykinesia + rigidity
• Plus: rest tremor, asymmetry of onset, good response to levodopa

• Core: Motor parkinsonism (bradykinesia + rigidity/tremor)
• Three additional categories:
  1. Supportive criteria (increase diagnostic confidence)
  2. Absolute exclusion criteria
  3. Red flags (must be counterbalanced by supportive criteria)
• Two certainty levels: Clinically Established PD and Clinically Probable PD

Supportive Criteria for PD (Harrison's)

• Clear beneficial response to dopaminergic therapy
• Rest tremor
• Anosmia
• Cardiac sympathetic denervation on MIBG scintigraphy

Red Flags (suggest atypical parkinsonism):

• Early postural instability or falls (within first 3 years)
• Early dementia (within first 1 year = DLB)
• Absence of rest tremor
• Symmetrical onset
• Poor or no response to adequate levodopa trial
• Early prominent autonomic failure
• Supranuclear gaze palsy (downward gaze palsy → PSP)
• Cerebellar signs
• Pyramidal signs

Investigations

• Shows reduced and asymmetric striatal dopamine transporter uptake
• Most affected: posterior putamen (with relative sparing of caudate)
• Does NOT reliably distinguish PD from atypical parkinsonism (both show reduced DaT)

• PD: decreased GPI activity + increased thalamic activity
• Atypical parkinsonism: reverse pattern

• Alpha-synuclein seed amplification assay (SAA) — detects misfolded alpha-syn in CSF/skin/olfactory epithelium; highly sensitive and specific; increasingly used for early/premotor diagnosis

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6. DIFFERENTIAL DIAGNOSIS

Classification of Parkinsonism (TABLE 446-2 — Harrison's)

Key Distinguishing Features

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7. TREATMENT

A. LEVODOPA — The Gold Standard

"Levodopa remains the most effective symptomatic treatment for PD and the gold standard against which new therapies are compared." — Harrison's 22e

• Carbidopa (USA) — brand: Sinemet
• Benserazide (Europe) — brand: Madopar
• Purpose: block peripheral levodopa conversion → prevent nausea, vomiting, orthostatic hypotension (from area postrema dopamine receptors that lie outside the BBB)

Motor Complications of Chronic Levodopa

1. Wearing-off effect
   • Duration of benefit per dose shortens progressively
   • Initial "long-duration response" (hours/days) → eventually approaches drug half-life (60-90 min)
   • Due to loss of dopaminergic storage capacity as neurons degenerate
2. On-off phenomenon
   • Rapid, unpredictable switches: "on" (drug working) ↔ "off" (parkinsonism returns)
   • Patients may remain in "off" state for hours despite a levodopa dose
3. Dyskinesias
   • Involuntary choreiform/dystonic movements
   • Typically at peak dose (peak-dose dyskinesias)

• Inhaled levodopa (Inbrija) — fastest acting
• Subcutaneous apomorphine injection (Apokyn)
• Sublingual apomorphine (Kynmobi)

B. MAO-B INHIBITORS

C. DOPAMINE AGONISTS

• Longer duration of action
• Lower risk of dyskinesias
• Used as initial monotherapy in younger patients to delay dyskinesias

D. COMT INHIBITORS

E. AMANTADINE

• NMDA glutamate receptor antagonist (also mild dopaminergic + anticholinergic)
• Uses: mild early PD symptoms; crucially — treatment of levodopa-induced dyskinesias in advanced PD

F. ANTICHOLINERGICS

• Benztropine, trihexyphenidyl
• Primarily for tremor in younger patients
• Avoid in elderly — anticholinergic burden (confusion, memory impairment, urinary retention, constipation)

G. NEUROPROTECTION (Major unmet need — Harrison's 22e)

"A neuroprotective or disease-modifying therapy that slows or stops disease progression remains the major unmet therapeutic need."

• Anti-alpha-synuclein therapies (prevent aggregation/accumulation)
• LRRK2 inhibitors
• GBA1/GCase enhancers
• GLP-1 agonists (anti-inflammatory, pro-mitochondrial) — results in double-blind trials have been inconsistent

H. SURGICAL TREATMENT

1. Motor cortex lesions → improved tremor but caused motor deficits → abandoned
2. VIM thalamotomy → reduced tremor, no hemiparesis, but no benefit for bradykinesia/rigidity
3. Posteroventral pallidotomy (GPi lesion) → improved rigidity, bradykinesia, tremor + markedly reduced dyskinesias; but bilateral lesions → dysphagia, dysarthria, cognitive impairment
4. STN lesions → anti-parkinsonian + reduced levodopa need, but risk of hemiballismus

• Electrode implanted into target → connected to subcutaneous stimulator over chest wall
• Disrupts pathological neurophysiological signals without making a brain lesion
• Fully reversible and adjustable (voltage, frequency, pulse duration, electrode configuration)
• Suitable for bilateral procedures safely

• Severe tremor refractory to medications
• Motor fluctuations / dyskinesias not controlled by drug adjustments
• Good cognitive function
• Good levodopa response (except for tremor)

• Surgical: hemorrhage, infarction, infection
• Hardware: lead displacement, lead break, skin ulceration
• Stimulation: ocular/speech abnormalities, paresthesias, depression, rarely suicidality

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8. MANAGEMENT OF NONMOTOR FEATURES (Harrison's 22e)

Harrison's explicitly states: "Nondopaminergic features (especially falls and dementia) are the primary source of disability and main reason for hospitalization and nursing home placement in the levodopa era."

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9. CURRENT MANAGEMENT ALGORITHM (Harrison's 22e)

DIAGNOSIS OF PD
      |
      ├── No functional disability → MAO-B inhibitor (rasagiline/selegiline)
      |                              [potential neuroprotection + mild symptom relief]
      |
      ├── Functional disability present:
      |         |
      |         ├── Age <60 / Cognitively intact → DA AGONIST first
      |         |   (delays dyskinesias; longer duration of action)
      |         |
      |         └── Age >70 / Cognitively impaired → LEVODOPA first
      |             (most effective; agonists poorly tolerated in elderly)
      |
      ├── Motor complications develop (wearing-off/dyskinesias):
      |         → Adjust levodopa dosing/intervals
      |         → Add COMT inhibitor (entacapone/opicapone) for wearing-off
      |         → Add amantadine for dyskinesias
      |         → On-demand therapies for off periods (inhaled levodopa, apomorphine)
      |
      └── Refractory motor complications → Consider DBS (STN or GPi)

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10. PROGNOSIS

• Progression typically over 5-15+ years
• Nondopaminergic features (dementia, falls, autonomic failure) cause the most late disability
• Dementia ultimately affects up to 80% of patients
• Leading cause of death: aspiration pneumonia; complications of immobility; falls

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11. KEY EXAM FACTS AT A GLANCE

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SEPSIS AND SEPTIC SHOCK

PG Exam Long Answer — Based on Surviving Sepsis Campaign (SSC) 2026 + Harrison's 22e (Chapter 315)

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1. DEFINITIONS (Sepsis-3, 2016 — Still Current)

Note: The term "severe sepsis" (Sepsis-2) has been eliminated — it is no longer used. All patients with organ dysfunction from infection are now called "sepsis."

Previous Definitions (Historical Context)

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2. SOFA SCORE (Sequential Organ Failure Assessment)

• RR ≥22 breaths/min
• GCS <15 (altered mentation)
• SBP ≤100 mmHg

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3. EPIDEMIOLOGY

• ~11 million deaths per year worldwide from sepsis
• ~10.8% of all deaths globally are attributable to sepsis
• ~88% community-onset (within 48h of hospitalization); 12% hospital-onset (after 48h)
• Most common organisms: S. aureus, E. coli, Klebsiella, Streptococcus, P. aeruginosa
• Most common source: Urinary tract (48.9%), respiratory (32.9%), intraabdominal (13.6%), skin/soft tissue (10.3%)
• ~53% of US sepsis cases are culture-positive
• Hospital mortality: sepsis ~25-30%; septic shock >40%

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4. PATHOPHYSIOLOGY

A. Dysregulated Host Response

B. Haemodynamic Profile in Septic Shock

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5. CLINICAL FEATURES

Motor Presentation

• Fever (>38°C) or hypothermia (<36°C) — hypothermia is ominous
• Tachycardia >90/min; tachypnoea >20/min
• Hypotension — SBP <90 mmHg or MAP <65 mmHg
• Altered mental status — confusion, agitation, drowsiness
• Oliguria — UO <0.5 mL/kg/h
• Warm, flushed skin (early) → mottled, cold peripheries (late, worsening shock)

Organ Dysfunction Manifestations

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6. INVESTIGATIONS

Immediate (within minutes)

• Blood cultures — ≥2 sets from different sites BEFORE antibiotics (but do not delay antibiotics beyond 1h for cultures)
• Serum lactate — key biomarker; lactate >2 mmol/L suggests tissue hypoperfusion
• CBC, CRP, procalcitonin — procalcitonin guides antibiotic de-escalation
• LFTs, RFTs, coagulation profile, ABG
• Urinalysis + urine culture
• Chest X-ray (portable)
• Serum glucose, electrolytes

Additional

• Sputum culture, wound cultures, drain fluid — based on suspected source
• Echocardiography (bedside/POCUS) — to assess cardiac function and guide resuscitation
• CT abdomen/pelvis — if intraabdominal source suspected
• Lumbar puncture — if CNS infection suspected

Biomarkers

• Lactate: Single most important biomarker; >4 mmol/L = very high risk (= "cryptic shock" even without hypotension)
• Procalcitonin: Guides antibiotic de-escalation and duration; elevated in bacterial sepsis
• CRP: Less specific but widely used

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7. SSC 2026 GUIDELINES — MANAGEMENT

Published: March 23, 2026 | Prescott HC, Antonelli M et al. | Crit Care Med + Intensive Care Med

129 statements; 46 NEW statements; endorsed by 24 professional societies

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A. INITIAL RESUSCITATION

Hour-1 Bundle (SSC) — Actions within the FIRST HOUR:

1. Measure serum lactate — re-measure if initial >2 mmol/L
2. Obtain blood cultures (≥2 sets) BEFORE antibiotics
3. Administer broad-spectrum antibiotics (within 1h of septic shock recognition; within 3h of sepsis without shock)
4. Administer 30 mL/kg IV crystalloid bolus for sepsis-induced hypoperfusion/hypotension
5. Start vasopressors if hypotension persists after or during fluid resuscitation — target MAP ≥65 mmHg

Fluid Resuscitation (SSC 2026 - Updated):

Key 2026 change: Balanced crystalloids (Lactated Ringer's or Plasmalyte) are NOW recommended over normal saline — this was not in the 2021 guidelines.

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B. VASOPRESSORS (SSC 2026)

• Target MAP ≥65 mmHg — STRONG recommendation (preferred over higher targets such as 80-85 mmHg)
• In older adults: Lower MAP targets may be appropriate — NEW 2026 (reduces vasopressor-related harm)

• Peripheral vasopressor administration is acceptable initially rather than delaying while awaiting central venous access — Conditional recommendation

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C. ANTIMICROBIAL THERAPY (SSC 2026)

Timing:

7-8% increase in mortality for every 1-hour delay in appropriate antibiotic administration in septic shock (Harrison's 22e).

Antibiotic Selection:

• Avoid unnecessary anti-anaerobic coverage (e.g., metronidazole, piperacillin-tazobactam) when source is urinary or pulmonary — these disrupt gut microbiome and are associated with higher mortality

Antibiotic Optimization:

• Beta-lactams should be administered before vancomycin
• Prolonged infusion (extended infusion) of beta-lactams after the initial bolus — improves PK/PD target attainment
• De-escalation: Narrow antibiotics as soon as culture + sensitivity results available
• Duration guided by procalcitonin: Use PCT decline to guide stopping antibiotics (reduces duration safely)
• Target 5-7 days for most uncomplicated infections; not more than 7-10 days routinely

Blood Cultures:

• Obtain ≥2 sets before antibiotics when possible
• Do NOT delay antibiotics >1h to obtain cultures in septic shock

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D. SOURCE CONTROL

• Identify and control source as soon as possible
• Examples: Drain abscess, resect necrotic bowel, relieve biliary obstruction (ERCP/PTC), debride necrotizing fasciitis
• Remove potentially infected devices (central lines, catheters) promptly
• Source control should occur within 6-12 hours of diagnosis whenever feasible

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E. HAEMODYNAMIC MONITORING & RESUSCITATION TARGETS

• If lactate >2 mmol/L → remeasure within 2h
• Lactate-guided resuscitation is recommended over CVP-guided resuscitation
• ANDROMEDA-SHOCK trial: Capillary refill time (CRT) ≤3 sec can be an equivalent endpoint to lactate clearance

• Passive leg raise (PLR) test — increase in CO ≥10% predicts fluid responsiveness
• Pulse pressure variation (PPV) ≥13% in ventilated patients
• Stroke volume variation (SVV)

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F. CORTICOSTEROIDS (SSC 2026)

Note on antipyretics: SSC 2026 recommends against using antipyretics/surface cooling to improve outcomes. This does not prohibit their use for comfort or in specific indications (neuro-ICU patients, post-cardiac arrest).

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G. MECHANICAL VENTILATION (Sepsis-associated ARDS)

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H. SEDATION & ANALGESIA IN SEPSIS

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I. RENAL REPLACEMENT THERAPY (RRT)

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J. GLUCOSE CONTROL (SSC 2026)

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K. DVT PROPHYLAXIS

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L. STRESS ULCER PROPHYLAXIS (SSC 2026 — Updated)

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M. NUTRITION (SSC 2026)

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N. BLOOD TRANSFUSION (SSC 2026)

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O. POST-SEPSIS CARE (NEW in SSC 2026)

• Psychological rehabilitation — depression, PTSD, anxiety are common post-sepsis
• Physical rehabilitation — early mobilisation in ICU; physiotherapy post-discharge
• Post-ICU follow-up clinic — structured review of physical, cognitive, and psychological sequelae
• PICS (Post-Intensive Care Syndrome) — cognitive impairment, physical disability, mental health issues
• Medication review — de-prescribe unnecessary medications started during ICU stay
• Long-term outcomes: 30-40% of survivors have significant long-term morbidity

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8. WHAT'S NEW IN SSC 2026 vs SSC 2021 — EXAM SUMMARY

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9. SEPSIS CARE BUNDLES (CMS SEP-1)

1. Measure lactate
2. Blood cultures before antibiotics
3. Broad-spectrum antibiotics
4. 30 mL/kg IV crystalloid for hypotension or lactate ≥4 mmol/L

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10. COMPLICATIONS OF SEPSIS

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11. KEY EXAM FACTS AT A GLANCE

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DYSLIPIDAEMIA

PG Exam Long Answer — Based on 2026 ACC/AHA Guidelines + 2025 ESC/EAS Focused Update + Harrison's Principles of Internal Medicine, 22nd Edition (Chapter 419)

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1. DEFINITIONS AND CLASSIFICATION

• Hypercholesterolaemia — elevated LDL-C (primary target)
• Hypertriglyceridaemia — elevated TG
• Low HDL-C
• Mixed hyperlipidaemia — elevated LDL-C + elevated TG
• Elevated Lp(a) — newly recognised independent risk factor

Fredrickson-WHO Classification

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2. LIPID METABOLISM — KEY CONCEPTS (Harrison's Ch. 419)

Lipoproteins and Apolipoproteins

Key Enzymes and Proteins

• LPL (Lipoprotein lipase) — on capillary endothelium; hydrolyses TGs in chylomicrons and VLDL; requires ApoC-II as cofactor, ApoA-V as facilitator; deficiency → massive hypertriglyceridaemia
• PCSK9 — secreted by liver; binds LDL receptor → targets it for lysosomal degradation → reduces LDL receptors on hepatocyte surface → raises LDL-C. Gain-of-function mutations → FH (ADH type 3); Loss-of-function mutations → protective, very low LDL-C
• CETP (Cholesteryl Ester Transfer Protein) — transfers CE from HDL to TG-rich lipoproteins; inhibition raises HDL
• HMG-CoA reductase — rate-limiting enzyme in cholesterol synthesis; target of statins
• Hepatic lipase (HL) — processes IDL to LDL; involved in HDL catabolism

Exogenous vs Endogenous Pathways

• Exogenous: Dietary fat → absorbed in duodenum/jejunum → chylomicrons (ApoB-48) → lymph → blood → LPL removes TG → chylomicron remnants → taken up by liver via ApoE/LDLR
• Endogenous: Liver secretes VLDL (ApoB-100) → LPL removes TG → IDL → either liver clearance (via ApoE) or further processed to LDL → taken up by LDL receptor on liver/peripheral cells

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3. PRIMARY (GENETIC) DYSLIPIDEMIAS

A. Familial Hypercholesterolaemia (FH)

• LDLR mutations (most common) — reduced LDL receptor expression/function
• APOB mutations — reduced ApoB-100 binding to LDL receptor (familial defective ApoB, FDB)
• PCSK9 gain-of-function — increased PCSK9 activity → receptor degradation (ADH type 3)

B. Familial Dysbetalipoproteinaemia (Type III Hyperlipoproteinaemia)

• ApoE2/E2 homozygosity → impaired chylomicron and VLDL remnant clearance
• Both cholesterol AND TG elevated (mixed dyslipidaemia)
• Palmar xanthomas (pathognomonic — orange-yellow creases on palms)
• Responds well to fibrates and statins

C. Familial Hypertriglyceridaemia

• VLDL overproduction or reduced LPL activity
• TG 200-500 mg/dL typically; risk of pancreatitis if >1000 mg/dL

D. Familial Combined Hyperlipidaemia (FCHL)

• Most common familial dyslipidaemia — 1-2% of population
• Overproduction of ApoB-containing lipoproteins (VLDL + LDL)
• Phenotype variable (IIa, IIb, or IV)
• Associated with metabolic syndrome; high ASCVD risk

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4. SECONDARY CAUSES OF DYSLIPIDAEMIA

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5. CLINICAL FEATURES

Physical Signs of Dyslipidaemia

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6. SCREENING AND INVESTIGATIONS

When to Screen (2026 ACC/AHA)

• All adults ≥20 years: Fasting lipid panel at least once
• Children: Screening between ages 9-11 (especially if FH suspected or family history of premature ASCVD)
• Screen earlier if: family history of FH, premature ASCVD, high-risk medical conditions

Lipid Panel Components

Additional Tests (2026 ACC/AHA — New Emphasis)

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7. CARDIOVASCULAR RISK ASSESSMENT

2026 ACC/AHA — PREVENT Equations (MAJOR CHANGE from 2018)

The Pooled Cohort Equations (PCE) are replaced by the new PREVENT-ASCVD equations (Predicting Risk of cardiovascular disease EVENTs)

Risk Categories (2026 ACC/AHA)

2025 ESC/EAS — SCORE2/SCORE2-OP

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8. LDL-C TREATMENT TARGETS

2026 ACC/AHA LDL-C Goals (MAJOR CHANGE — LDL targets restored after 2018 removed them)

"LDL goals are back — lower is better, lower for longer." — 2026 ACC/AHA

2025 ESC/EAS LDL-C Goals

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9. LIFESTYLE MODIFICATIONS (FIRST LINE FOR ALL PATIENTS)

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10. PHARMACOLOGICAL TREATMENT

A. STATINS (HMG-CoA Reductase Inhibitors) — FIRST LINE

• Doubling the statin dose produces only ~6% further reduction ("rule of 6%")
• Most LDL-lowering occurs at the starting dose

• Statin-associated muscle symptoms (SAMS): Myalgia (most common), myopathy (rare), rhabdomyolysis (rare but dangerous — check CK if myopathy suspected)
• Risk increased by: hypothyroidism, CYP3A4 inhibitors (e.g., clarithromycin, cyclosporin), high dose, elderly, renal/hepatic impairment, Asian patients
• Hepatotoxicity: Mild transaminase elevation common; clinically significant hepatitis rare — routine LFT monitoring no longer recommended by most guidelines
• New-onset type 2 diabetes: Small increased risk (especially high-intensity statins) — cardiovascular benefits far outweigh this risk
• Statin intolerance: If SAMS, try a different statin at lower dose before abandoning statin therapy

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B. EZETIMIBE — SECOND STEP

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C. PCSK9 INHIBITORS — THIRD STEP (Powerful; High Cost)

• FOURIER (evolocumab) — 27% RRR in MACE in secondary prevention
• ODYSSEY OUTCOMES (alirocumab) — 15% RRR in MACE post-ACS
• ORION trials (inclisiran) — sustained LDL-C reduction; non-inferior to antibodies

• Very high-risk ASCVD on maximally tolerated statin + ezetimibe if LDL still >55 mg/dL
• FH with inadequate response to statins ± ezetimibe
• With elevated Lp(a) ≥50 mg/dL (PCSK9 mAb specifically recommended — Class IIa, 2026)

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D. BEMPEDOIC ACID — NEW IN 2026 GUIDELINES

• Class I: In high-risk patients with statin-attributed muscle symptoms → add bempedoic acid and/or ezetimibe to achieve LDL <70 mg/dL
• Class IIa: In very high-risk ASCVD on maximally tolerated statin → add bempedoic acid (±ezetimibe ±PCSK9 mAb) to reach LDL <55 mg/dL
• Class IIa: In severe hypercholesterolaemia on maximally tolerated statin → add bempedoic acid

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E. FIBRATES (Fibric Acid Derivatives)

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F. OMEGA-3 FATTY ACIDS

KEY POINT: Only icosapent ethyl (pure EPA, no DHA) has demonstrated CV benefit in the statin era (REDUCE-IT). The DHA-containing omega-3 preparations have NOT shown benefit.

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G. NIACIN (Nicotinic Acid)

• Mechanism: Reduces hepatic VLDL secretion, ↑ HDL, ↓ TG, ↓ LDL
• Currently NOT recommended for routine use — HPS2-THRIVE and AIM-HIGH trials showed no added CV benefit over statin + significant flushing, hepatotoxicity, and new-onset DM
• May be considered in rare cases where alternative therapies unavailable

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H. BILE ACID SEQUESTRANTS (Resins)

• Mechanism: Bind bile acids in gut → prevent reabsorption → liver uses cholesterol for more bile acids → ↑ LDL receptor expression → ↓ LDL-C
• LDL-C ↓ 15-30%; may ↑ TG
• Avoid in hypertriglyceridaemia
• Can impair absorption of fat-soluble vitamins, other medications (take other medications 1h before or 4h after resin)
• Colesevelam also reduces blood glucose (approved for T2DM)

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I. SPECIAL AGENTS FOR RARE CONDITIONS

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11. TREATMENT ALGORITHM

ASSESS CARDIOVASCULAR RISK (PREVENT-ASCVD / SCORE2)
              |
    ┌─────────┴──────────┐
    │                    │
CLINICAL ASCVD       PRIMARY PREVENTION
    │                    │
    ├── Very High Risk    ├── PREVENT ≥10% (High Risk)
    │   LDL target <55   │   LDL target <70 mg/dL
    │                    │   Start HIGH-intensity statin
    └── Not Very High    │
        LDL target <70   ├── PREVENT 5-<10% (Intermediate Risk)
                         │   LDL target <100 mg/dL
STEP 1: HIGH-INTENSITY  │   MODERATE-to-HIGH intensity statin
STATIN                  │
(Atorvastatin 40-80mg   ├── PREVENT 3-<5% (Borderline Risk)
or Rosuvastatin 20-40mg)│   Use risk enhancers/CAC to decide
        |               │
     If LDL goal        └── PREVENT <3% (Low Risk)
     not achieved           Lifestyle only; consider statin
        |                   only if LDL very high (>190)
STEP 2: ADD EZETIMIBE 10mg
        |
     If LDL goal still
     not achieved
        |
STEP 3: ADD PCSK9 INHIBITOR
   Evolocumab / Alirocumab (biweekly SC)
   OR Inclisiran (every 6 months SC)
        |
     If statin-intolerant or still not at goal:
        |
STEP 4: ADD/SUBSTITUTE BEMPEDOIC ACID
   (±ezetimibe; no muscle risk; option in statin intolerance)
        |
     SPECIAL CASES:
   - TG ≥500 mg/dL: FIBRATE (fenofibrate preferred) to prevent pancreatitis
   - TG ≥135 mg/dL on statin + high CV risk: ICOSAPENT ETHYL 4 g/day
   - HoFH: EVINACUMAB + LDL apheresis
   - Elevated Lp(a) ≥50 mg/dL: PCSK9 mAb (reduces Lp(a) ~25-30%)

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12. LIPOPROTEIN(a) — Lp(a) — IMPORTANT 2026 UPDATES

What is Lp(a)?

• LDL particle with an additional protein — apolipoprotein(a) [apo(a)] covalently attached to ApoB-100
• Levels are genetically determined (90% heritable) by LPA gene on chromosome 6q26-27 — largely unaffected by diet/lifestyle
• Independent causal risk factor for ASCVD and calcific aortic valve disease
• High Lp(a) confers risk even with normal LDL-C

2026 ACC/AHA — NEW Class I Recommendation

Universal Lp(a) measurement at least ONCE in every adult — brings US practice in line with ESC/EAS

• Intensify statin therapy
• Lower LDL-C targets
• PCSK9 inhibitors reduce Lp(a) by ~25-30% — specifically recommended when Lp(a) ≥50 mg/dL + ASCVD if on maximally tolerated statin (Class IIa, 2026 ACC/AHA)
• Novel agents in trials: Pelacarsen (antisense), Olpasiran/Muvalaplin (siRNA/oral) — Lp(a) >90% reduction

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13. TREATMENT OF HYPERTRIGLYCERIDAEMIA

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14. SPECIAL POPULATIONS

Diabetes

• All patients with DM + ASCVD → high-intensity statin → LDL <55 mg/dL (ADA + 2026 ACC/AHA)
• Age 40-75, DM without ASCVD → moderate-intensity statin (at minimum)
• Statins associated with mild ↑ risk of new-onset T2DM — cardiovascular benefits outweigh this risk
• Small dense LDL particles in T2DM are more atherogenic (more easily glycated, more oxidised)

Chronic Kidney Disease (CKD)

• High cardiovascular risk; statins recommended
• Adjust doses: rosuvastatin dose reduction in severe CKD; avoid simvastatin 80 mg
• Dialysis patients: statin initiation de novo not recommended (4D, AURORA trials — no benefit); continue statin if already taking one

Elderly (>75 years)

• Secondary prevention: continue statin — clear benefit
• Primary prevention: individualise decision; 2026 guidelines allow lower MAP targets reflecting benefit-risk balance
• Start low, go slow; watch for drug interactions (polypharmacy)

Pregnancy

• Stop statins during pregnancy and breastfeeding (teratogenic — Category X)
• Bile acid sequestrants (cholestyramine) are safe in pregnancy
• PCSK9 mAbs — safety not established

HIV Patients (2025 ESC/EAS — New Section)

• HAART drugs (especially protease inhibitors) cause dyslipidaemia
• Statin interactions: simvastatin contraindicated with most PIs; rosuvastatin preferred; pravastatin safe
• HIV itself is a major independent ASCVD risk factor — treat aggressively

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15. WHAT'S NEW IN 2026 ACC/AHA vs 2018

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16. KEY EXAM FACTS AT A GLANCE

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STROKE (CEREBROVASCULAR ACCIDENT)

PG Exam Long Answer — Based on 2026 AHA/ASA Acute Ischemic Stroke Guidelines (PMID: 41582814) + Harrison's Principles of Internal Medicine, 22nd Edition (Chapters 437-439)

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1. DEFINITION AND CLASSIFICATION

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2. PATHOPHYSIOLOGY OF ISCHAEMIC STROKE (Harrison's)

Ischaemic Cascade

The Ischaemic Penumbra

• Core = dead tissue; penumbra = at-risk but salvageable tissue surrounding the core
• Reperfusion of penumbra within the therapeutic window = basis of thrombolysis and thrombectomy
• The penumbra is detected on perfusion imaging (CT perfusion or MRI DWI/PWI mismatch)

Cellular Injury Mechanisms

1. Energy failure → failure of Na-K ATPase → cell swelling
2. Glutamate excitotoxicity → NMDA receptor activation → Ca²⁺ influx → cell death
3. Free radical generation → lipid peroxidation
4. Nitric oxide (iNOS) → cytotoxicity
5. Apoptosis (caspase activation)
6. Reperfusion injury → paradoxically more damage on restoring blood flow

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3. AETIOLOGY OF ISCHAEMIC STROKE (TOAST Classification)

Cardioembolism — Details (Harrison's)

• Non-rheumatic AF = most common cause of cerebral embolism overall
• Average annual stroke risk with AF = ~5%
• Risk stratified by CHA₂DS₂-VASc score (see below)
• Emboli lodge most often in: ICA, MCA, PCA, or their branches
• Other sources: MI (antero-apical wall), prosthetic valves, rheumatic MS, ischaemic cardiomyopathy, PFO (paradoxical embolism — present in ~15% of general population)

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4. RISK FACTORS

Non-Modifiable

• Age (risk doubles each decade after 55)
• Male sex (younger), female sex (higher lifetime risk due to longevity)
• Race/ethnicity (Black, Hispanic higher risk)
• Family history
• Prior stroke/TIA

Modifiable (ABCDEF mnemonic)

• Atrial fibrillation — single biggest modifiable risk
• Blood pressure — hypertension is the most important overall risk factor
• Cholesterol — dyslipidaemia (↑ LDL, ↓ HDL)
• Diabetes mellitus
• Exercise (lack of)
• Fibromuscular dysplasia, Smoking, Obesity, Alcohol excess, Oral contraceptives, Homocysteinaemia

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5. CLINICAL FEATURES

Vascular Territory Syndromes (Harrison's)

Anterior Circulation (Internal Carotid Artery territory)

Posterior Circulation (Vertebrobasilar territory)

Lacunar (Small Vessel) Syndromes (Harrison's)

1. Pure motor hemiparesis — posterior limb internal capsule or pons; face + arm + leg all involved
2. Pure sensory stroke — ventral thalamus
3. Ataxic hemiparesis — ventral pons or internal capsule
4. Dysarthria-clumsy hand syndrome — ventral pons or genu of internal capsule

• Small vessels: prone to lipohyalinosis (hypertension, diabetes)
• Risk factors: Hypertension and age (principal risk factors)

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6. INVESTIGATIONS

Immediate (Target: door-to-imaging <25 minutes; door-to-needle <60 minutes)

1. Non-contrast CT brain — FIRST investigation; excludes haemorrhage (thrombolysis decision); detects early ischaemic signs (loss of grey-white differentiation, hyperdense MCA sign)
2. CT Angiography (CTA) — identifies large vessel occlusion (LVO) — essential for thrombectomy decision; done simultaneously with NCCT
3. CT Perfusion (CTP) — identifies core infarct vs salvageable penumbra; particularly important for extended time window decisions (4.5-24h)
4. Blood glucose (finger stick) — exclude hypoglycaemia mimicking stroke; treat immediately if abnormal
5. ECG — detect AF
6. 12-lead ECG, cardiac monitoring (24-48h) — detect paroxysmal AF

Urgent Labs

• CBC, coagulation (PT, APTT, INR), platelets
• RFTs, electrolytes
• Cardiac biomarkers (troponin)
• Blood glucose

MRI (when available / if CT equivocal)

• DWI (Diffusion-Weighted Imaging) — most sensitive for acute ischaemia within minutes
• FLAIR — older infarct; wake-up stroke timing (DWI+/FLAIR- = within 4.5h)
• SWI/GRE — haemorrhage, microbleeds

Workup for Aetiology (after stabilisation)

• Echocardiography (TTE/TOE) — cardiac source, PFO, vegetation
• Carotid Doppler/CTA — carotid stenosis
• Prolonged cardiac monitoring (Holter, implantable loop recorder) — occult AF
• MRA/CTA of intracranial vessels
• Lipid profile, HbA1c, homocysteine
• Hypercoagulable screen (protein C, protein S, antithrombin III, antiphospholipid antibodies) — young stroke, no other cause

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7. ASSESSMENT TOOLS

NIHSS (NIH Stroke Scale)

• 15-item neurological exam; scores 0-42
• 0-4: Minor stroke
• 5-15: Moderate stroke
• 16-20: Moderate-severe
• >20: Severe stroke
• Used to guide treatment decisions (EVT requires NIHSS ≥6)

ASPECTS (Alberta Stroke Programme Early CT Score)

• Assesses early ischaemic changes on NCCT of MCA territory
• Score 0-10 (10 = normal; 0 = all 10 regions infarcted)
• ASPECTS ≥6: Typically considered for thrombolysis
• ASPECTS 3-10: EVT eligibility (within 6h — 2026 guideline)
• ASPECTS 3-5: EVT may still be considered 6-24h (selected patients — 2026 guideline)

CHA₂DS₂-VASc Score (for AF stroke risk)

• Score 0 (male) or 1 (female): No anticoagulation (annual stroke risk <1%)
• Score 1 (male): Consider anticoagulation
• Score ≥2: Anticoagulate (annual stroke risk increases significantly)

ABCD² Score (TIA risk stratification — 2-day stroke risk)

• Score ≥4: High risk → urgent hospital admission and workup

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8. MANAGEMENT OF ACUTE ISCHAEMIC STROKE

2026 AHA/ASA GUIDELINE — ACUTE MANAGEMENT

A. PREHOSPITAL AND SYSTEMS OF CARE

• ASC (Acute Stroke-Ready) → PSC (Primary Stroke Centre) → TSC (Thrombectomy-Capable Stroke Centre) → CSC (Comprehensive Stroke Centre)

B. INITIAL MEDICAL SUPPORT

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C. INTRAVENOUS THROMBOLYSIS (IVT) — 2026 AHA/ASA MAJOR UPDATES

Drug Choice — MAJOR 2026 CHANGE

KEY 2026 CHANGE: Tenecteplase is now a Class I, equal recommendation to alteplase (previously only a COR 2a "reasonable alternative"). Tenecteplase advantage: single IV bolus (simpler; no infusion pump needed; practical in pre-hospital and EVT bridge settings)

Standard Time Window (Well-Established)

• Within 4.5 hours of symptom onset or last known well
• Benefits documented extensively from NINDS, ECASS III, IST-3 trials

Extended Time Window — NEW 2026 (COR 2a)

• (a) Wake up with stroke symptoms within 9 hours from the midpoint of sleep, OR
• (b) 4.5-9 hours from last known well

Penumbra detected by CT perfusion or MRI DWI/FLAIR mismatch (FLAIR-negative, DWI-positive = within 4.5h of onset)

IVT Eligibility — Standard Inclusion Criteria

• AIS with measurable neurological deficit
• Age ≥18 years (also consider in ≥80 years — benefit established)
• Within 4.5h of onset (or extended window as above)
• BP controlled to <185/110 mmHg before administration

IVT Absolute Contraindications (2026 — Modified from 2018)

• Active intracranial haemorrhage on CT
• Prior intracranial haemorrhage
• Ischaemic stroke within 3 months
• Suspected or confirmed aortic dissection
• Active internal bleeding (excluding menstruation)
• Significant head trauma within 3 months
• Infective endocarditis (risk of mycotic aneurysm haemorrhage)
• Intra-axial intracranial neoplasm
• BP not controllable to <185/110 mmHg

2026 UPDATE on contraindications: Multiple prior "relative contraindications" have been reclassified or removed based on new evidence. The 2026 guideline streamlines the contraindication list, enabling more patients to receive IVT.

IVT in Specific Situations (Selected 2026 Recommendations)

Symptomatic Intracranial Haemorrhage (sICH) after IVT

• Occurs in ~6% of patients (6.4% in NINDS trial)
• Management: Stop tPA infusion; check coagulation; cryoprecipitate (for fibrinogen) ± platelets; urgent neurosurgical consultation

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D. ENDOVASCULAR THROMBECTOMY (EVT / Mechanical Thrombectomy) — 2026 UPDATES

Standard Window: Within 6 hours

• AIS from anterior circulation proximal LVO (ICA or M1 segment of MCA)
• NIHSS ≥6
• Prestroke mRS 0-1 (functionally independent)
• ASPECTS 3-10
• Within 6 hours from symptom onset

Extended Window: 6-24 hours — 2026 GUIDELINE

• AIS from anterior circulation proximal LVO (ICA or M1)
• Age <80 years
• NIHSS ≥6
• Prestroke mRS 0-1
• ASPECTS 3-5 (moderate infarct core acceptable in extended window)
• No significant mass effect on imaging

Additional EVT Considerations (2026)

IVT Bridge before EVT

• For eligible patients undergoing EVT who are also IVT-eligible: Give IVT first (bridge therapy), then proceed to EVT — do not delay EVT for IVT to complete

Door-to-Reperfusion Time Goals

• Door-to-needle (IVT): ≤60 minutes (target ≤45 minutes in high-performing centres)
• Door-to-puncture (EVT): ≤90 minutes
• Door-to-recanalization: ≤120 minutes

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E. ANTITHROMBOTIC THERAPY (ACUTE PHASE)

CYP2C19 polymorphism: Clopidogrel poor metabolisers (loss-of-function allele) have reduced antiplatelet effect — consider ticagrelor in these patients (CHANCE-2 trial)

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F. HYPERGLYCAEMIA MANAGEMENT (NEW 2026)

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G. DYSPHAGIA SCREENING (2026 — Strengthened Recommendation)

• Screen for dysphagia BEFORE oral feeding, medications, or fluids in all AIS patients — COR 1
• Use validated bedside swallowing screen (e.g., 3-oz water test, GUSS)
• If fails: NPO, NG tube feeding; formal SLT evaluation
• Aspiration pneumonia is a leading cause of post-stroke death

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H. PAEDIATRIC STROKE (NEW — First Time in 2026 Guidelines)

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9. IN-HOSPITAL COMPLICATIONS MANAGEMENT

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10. STROKE UNIT CARE (COR 1)

• Dedicated stroke unit care reduces mortality and disability vs general ward care (absolute benefit ~5% reduction in death, ~5% reduction in dependency)
• Components: Dedicated nurses + physicians + therapists; standardised order sets; monitoring
• Telemedicine/Telestroke: Extends expert stroke care to remote/rural hospitals (COR 1)

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11. REHABILITATION (COR 1)

• Begin as soon as patient is medically stable (early mobilisation within 24-48h if stable)
• Multidisciplinary team: Physical therapy + occupational therapy + speech/language therapy
• Constraint-induced movement therapy (CIMT): Immobilise unaffected limb to force use of affected limb — improves hemiparesis even years after stroke
• Goal: Return patient to home; prevent complications (contractures, pneumonia, DVT)
• SSRIs may help prevent post-stroke depression; controversial for motor recovery
• Newer approaches: Robotic therapy, rTMS, tDCS — under investigation

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12. SECONDARY PREVENTION OF STROKE

A. Antiplatelet Therapy (Non-Cardioembolic Stroke)

B. Anticoagulation (Cardioembolic Stroke — AF)

When to start anticoagulation after AIS (Harrison's): Generally wait 2-14 days depending on infarct size (to avoid haemorrhagic transformation). Small infarct → start early (~2-3 days); large infarct or haemorrhagic transformation → wait up to 14 days.

• Dabigatran → Idarucizumab (Praxbind)
• Apixaban/Rivaroxaban → Andexanet alfa (Ondexxya) — FDA approved

• Left atrial appendage occlusion (LAAO/Watchman device): Non-inferior to warfarin for stroke prevention; for patients who cannot take anticoagulants (COR 2a; 2023 ACC/AHA AF guidelines)

C. PFO-Related Stroke (Cryptogenic Stroke in Young Patients)

• If cryptogenic stroke with PFO + atrial septal aneurysm (ASA) + significant right-to-left shunt → PFO closure + antiplatelet therapy superior to antiplatelet alone (CLOSE, RESPECT, REDUCE trials)
• Age <60, no other cause found: Consider PFO closure after multidisciplinary discussion

D. Carotid Artery Disease

CEA must be done within 2 weeks for maximum benefit in symptomatic high-grade stenosis — this is a time-critical intervention.

E. Risk Factor Modification

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13. TIA MANAGEMENT (URGENT)

• TIA = neurological emergency — 10% risk of stroke within 2 days; 5% in first 48h
• ABCD² score ≥4 → urgent hospital admission
• Management ("Time is Brain"):
  1. Urgent brain imaging (MRI DWI preferred; NCCT if MRI unavailable)
  2. Urgent carotid imaging (duplex/CTA) if anterior circulation TIA
  3. Start DAPT immediately (aspirin + clopidogrel for 21 days) — COR 1
  4. Cardiac monitoring (48h minimum) for AF detection
  5. Statin and antihypertensive (start in hospital)
  6. Urgent carotid endarterectomy if ≥50% symptomatic carotid stenosis (within 2 weeks)
  7. Anticoagulate if AF detected

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14. HAEMORRHAGIC STROKE

Intracerebral Haemorrhage (ICH)

• Hypertension (most common) — basal ganglia, thalamus, pons, cerebellum
• Cerebral amyloid angiopathy (CAA) — lobar haemorrhage in elderly; recurrent
• Anticoagulation, thrombolytics
• AVM, cavernous malformation, tumour, vasculitis

• Sudden onset headache + focal deficit + declining consciousness
• Vomiting common (↑ICP)
• Haematoma may expand in first 24h → clinical deterioration

• Reverse anticoagulation urgently (vitamin K + PCC/FFP; idarucizumab for dabigatran)
• Blood pressure: Target SBP <140 mmHg acutely (INTERACT2, ATACH-2 trials)
• Neurosurgical consultation: Evacuation for accessible lobar haematoma / cerebellar haematoma >3cm with deterioration / hydrocephalus
• Stop antiplatelet/anticoagulants acutely

Subarachnoid Haemorrhage (SAH)

• NCCT brain (95% sensitive within 12h; sensitivity decreases after)
• Lumbar puncture if CT negative and high clinical suspicion — xanthochromia (12h-2 weeks post SAH)
• CTA/DSA for aneurysm detection

• Secure aneurysm: Endovascular coiling preferred over surgical clipping in most cases (ISAT trial)
• Nimodipine 60 mg every 4 hours for 21 days — reduces vasospasm-related morbidity (NOT blood pressure management)
• Monitor for and treat vasospasm (TCD monitoring; triple-H therapy or endovascular rescue)
• EVD for hydrocephalus

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15. WHAT'S NEW IN 2026 AHA/ASA vs 2018 GUIDELINES

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16. KEY EXAM FACTS AT A GLANCE

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