Decorticate and Decerebrate Rigidity

Definition

Historical Background

1. Decorticate Rigidity (Abnormal Flexion Posturing)

• Upper extremities: flexion of arm, wrist, and fingers + adduction at shoulder
• Lower extremities: extension, internal rotation, and plantar flexion
• Head may be extended

2. Decerebrate Rigidity (Abnormal Extension Posturing)

• Upper extremities: extension, pronation of forearms, fingers flexed
• Lower extremities: extension, internal rotation, plantar flexion (toes pointed inward)
• Opisthotonus (neck and back extended), jaw clenching

Key Differences at a Glance

Diagram (Ganong's Physiology)

Etiology (Common Causes)

• Traumatic brain injury (TBI) - most common
• Cerebral hemorrhage or infarct
• Uncal herniation from supratentorial mass (tumor, hematoma)
• Anoxic brain injury / hypoglycemia
• Hepatic coma (rare)
• Severe drug/alcohol intoxication (rare)

Clinical Significance

1. Rostrocaudal deterioration: Progression from decorticate -> decerebrate posturing indicates downward herniation and worsening brainstem compromise.
2. Decerebrate -> flaccidity: If posturing gives way to complete flaccidity, the lesion has descended below the vestibular nuclei, indicating impending brain death.
3. Both responses are ominous in the setting of head injury, carrying high mortality.
4. GCS scoring: Decorticate = M3 (abnormal flexion); Decerebrate = M2 (extension) on the motor component of the Glasgow Coma Scale.
5. Metabolic causes (anoxia, hypoglycemia, hepatic coma) can produce either pattern and may be reversible.

Stages of Spinal Shock

Definition

Classical Description: Two Stages (Adams & Victor)

Stage 1 - Stage of Spinal Shock (Areflexia)

• Flaccid paralysis below the level of lesion
• Complete loss of all deep tendon reflexes (areflexia)
• Loss of all sensation below the lesion
• Bladder: atonic detrusor, contracted sphincter → overflow incontinence
• Bowel: paralytic ileus, fecal retention
• Autonomic: hypotension (BP may drop to 40 mmHg), loss of vasomotor tone, loss of sweating and piloerection below lesion
• Genital reflexes abolished (bulbocavernosus, cremasteric)
• Priapism may occur

Stage 2 - Stage of Heightened Reflex Activity (Spasticity)

• Spasticity gradually replaces flaccidity
• Deep tendon reflexes return and become hyperactive (hyperreflexia)
• Extensor plantar response (Babinski sign)
• Mass reflex (flexor spasms in response to cutaneous stimuli)
• Bladder and bowel become spastic (automatic/reflex bladder)
• Autonomic dysreflexia may develop (in lesions above T6)

Modern 4-Phase Model (Ditunno et al., 2004)

Phase 1 - Areflexia (0-1 day)

• All reflexes below SCI are absent or markedly reduced
• Neurons lose supraspinal excitatory input → hyperpolarization → unresponsive to stimuli
• Flaccid paralysis, sensory loss, autonomic dysfunction

Phase 2 - Return of Polysynaptic Reflexes (1-3 days)

• Polysynaptic reflexes return first (e.g., bulbocavernosus reflex)
• Monosynaptic DTRs not yet restored
• Mechanism: denervation supersensitivity - upregulation of neurotransmitter receptors on post-synaptic neurons
• Recovery is polysynaptic → monosynaptic (NOT rostral to caudal as previously believed)

Phase 3 - Hyperreflexia Begins (1-4 weeks)

• Monosynaptic DTRs return and become exaggerated
• Interneuron axon sprouting creates new synapses below the injury
• Early spasticity appears

Phase 4 - Established Spasticity (1-12 months)

• Full hyperreflexia and spasticity
• Soma-mediated sprouting: longer axons with soma-transported growth factors form new synaptic connections
• Autonomic dysreflexia may appear in high thoracic/cervical lesions

Order of Reflex Return (Guyton & Hall)

1. Stretch reflexes (DTRs) - first monosynaptic reflexes
2. Flexor reflexes
3. Postural antigravity reflexes
4. Rudimentary stepping reflexes

Key Points for Exam

• Spinal shock is NOT neurogenic shock (do not confuse)
• Duration is longer in humans and higher primates than in lower animals
• The end of spinal shock is marked by return of the bulbocavernosus reflex
• Incomplete or slow-developing lesions produce little or no spinal shock
• Permanent spinal shock (no reflex recovery) occurs in ~5/29 cases (Kuhn) - suggests secondary vascular injury to cord segments below the lesion
• Above T6 injuries: neurogenic shock + spinal shock can coexist acutely; autonomic dysreflexia in the chronic phase

Classical Decerebrate Rigidity vs. Ischemic (Alpha) Rigidity

Background: Normal Motor Control

Classical Decerebrate Rigidity (Gamma Rigidity)

Experimental Basis

Mechanism

• Corticospinal tract
• Corticobulbar tract
• Rubrospinal tract
• Corticoreticular fibers to medullary inhibitory RF

• Pontine excitatory reticulospinal tract
• Lateral vestibulospinal tract (Deiters' nucleus)

The Gamma Loop (Key Mechanism)

• Cutting the dorsal roots (section B in diagram) of a limb in a midcollicular decerebrate animal immediately abolishes the rigidity in that limb
• This is because dorsal root section interrupts the Ia afferent spindle feedback, breaking the gamma loop
• Therefore classical decerebrate rigidity is GAMMA rigidity - it depends on the intact gamma loop

Features of Classical Decerebrate Rigidity

Ischemic (Alpha) Rigidity - Decerebellate Rigidity

Experimental Basis

Mechanism

• Purkinje cell inhibitory output to the fastigial nucleus
• This disinhibits the fastigial nucleus → increased excitatory output → vestibular nuclei (Deiters') become hyperexcited
• This enormously enhances excitation of α-motor neurons directly (not via gamma loop)

• Subsequent dorsal root section (B after A+C) does NOT reverse the rigidity
• This proves it is independent of the gamma loop - alpha motor neurons are being activated directly
• Therefore ischemic/decerebellate rigidity is ALPHA rigidity

Features of Ischemic (Alpha) Rigidity

Key Comparison Table

Summary Mnemonic

"Gamma - Gone with dorsal root section" (classical decerebrate - gamma rigidity is abolished by cutting dorsal roots) "Alpha - Always stays" (ischemic/alpha rigidity persists even after dorsal root section)

Clinical Points

1. Both types produce the same posture: neck extended (opisthotonus), jaws clenched, arms and legs extended, forearms pronated, feet plantar flexed
2. Classical decerebrate rigidity clinically correlates with midbrain/upper pontine lesions, herniation, or metabolic causes
3. Ischemic/alpha rigidity is seen after cardiac arrest, severe hypoxia/anoxia and carries an extremely poor prognosis
4. The distinction is experimentally important for understanding stretch reflex physiology and the role of the gamma loop

Professional Qualities and Roles of a Physician; Empathy in Patient Encounters

I. Professional Qualities of a Physician

1. Knowledge and Competence

• Thorough grounding in medical science - anatomy, physiology, pathology, pharmacology, and clinical medicine
• Commitment to lifelong learning and updating knowledge
• Clinical skills: accurate history-taking, physical examination, investigation, and management

2. Communication Skills

• Ability to communicate clearly, respectfully, and empathetically with patients, families, and colleagues
• Use of simple language - avoiding jargon when speaking to patients
• Active listening - allowing the patient to express themselves fully

3. Ethical Integrity

• Honesty and transparency in clinical practice
• Maintaining confidentiality of patient information
• Obtaining informed consent before procedures
• Avoiding conflicts of interest

4. Empathy and Compassion

• Understanding the patient's emotional and physical suffering
• Responding with compassion without losing clinical objectivity
• Treating all patients with dignity regardless of background

5. Responsibility and Accountability

• Being reliable, punctual, and thorough
• Acknowledging errors and working to correct them
• Accepting scrutiny and participating in self-regulation

6. Respect for Diversity

• Non-judgmental attitude toward patients of all races, religions, genders, and socioeconomic backgrounds
• Commitment to social justice and equitable healthcare

7. Teamwork and Collaboration

• Working effectively with nurses, paramedics, specialists, and allied health professionals
• Placing patient welfare above personal or institutional interests

II. Roles of a Physician

III. Empathy in Patient Encounters

Definition

Empathy is NOT the same as sympathy.

• Sympathy = sharing the feeling ("I feel sad too")
• Empathy = understanding the feeling ("I understand how difficult this must be for you")

Why Empathy Matters

• Builds trust in the doctor-patient relationship
• Improves patient satisfaction and treatment adherence
• Leads to better clinical outcomes - patients share more information, leading to accurate diagnosis
• Reduces patient anxiety and distress

How to Demonstrate Empathy in Clinical Encounters

• Maintain eye contact; do not interrupt
• Use open-ended questions: "Tell me how you have been feeling"

• Verbal acknowledgment: "I can see this has been very worrying for you"
• Normalize emotions: "It is understandable to feel scared about this diagnosis"

• Appropriate facial expression, nodding
• Sitting at the same level as the patient (not standing over them)
• Appropriate gentle touch when culturally appropriate

• Ask about the patient's beliefs and concerns: "What do you think is causing this?"
• Involve the patient in decision-making

• Avoid dismissing concerns
• Avoid rushing consultations
• Avoid using phones or computers during the encounter without explanation

Empathy vs. Professional Boundaries

• While empathy is essential, a physician must maintain professional detachment - over-involvement can impair clinical judgment
• The balance is called "detached concern" - caring for the patient without being emotionally overwhelmed

Key Points (for exam recall)

1. Medical professionalism = knowledge + ethics + communication + empathy + accountability
2. Empathy improves patient satisfaction, adherence, and outcomes
3. Empathy ≠ sympathy - it is cognitive + emotional understanding
4. The CanMEDS model defines 7 physician roles
5. Demonstrated through active listening, verbal acknowledgment, and appropriate non-verbal cues

Molecular Motors

Definition

Classification

1. Kinesin

• Double-headed (two globular heads, or motor domains)
• Long coiled-coil tail that attaches to cargo (vesicles, organelles)
• Associated light chains help bind cargo

• One head binds the microtubule and bends its neck region (power stroke)
• The other head swings forward and binds the next tubulin dimer
• Produces nearly continuous, hand-over-hand "walking" powered by ATP hydrolysis at each head
• Moves toward the plus (+) end of microtubules (cell periphery / axon tips)

• Anterograde fast axonal transport in neurons: moves vesicles from cell body centrosome (minus end) to axon terminal (plus end) - e.g., neurotransmitter vesicles, synaptic proteins
• Mitosis and meiosis: spindle formation, chromosome segregation
• Transport of organelles (endosomes, lysosomes, Golgi-derived vesicles)
• Some kinesins (minus-end directed) move in the opposite direction

2. Dynein

• Axonemal (ciliary) dynein - found in cilia and flagella
• Cytoplasmic dynein - found in the cell cytoplasm

• Two heads with neck pieces embedded in a complex multi-subunit protein structure
• Large and complex compared to kinesin (~4 nm stalks connecting to microtubule-binding domain)

• ATP hydrolysis causes conformational change (bending motion) in the dynein molecule
• In cilia: dynein arms connect adjacent outer tubules of the 9+2 axoneme; when dynein on one outer tubule pulls on the adjacent tubule, the entire axoneme bends → ciliary beating motion
• Nexin links restrict excessive sliding, converting the sliding force into a coordinated bending wave

• Cytoplasmic dynein: retrograde transport (plus → minus direction) - brings endosomes, autophagosomes, and signaling molecules back toward the cell body/nucleus
• Axonemal dynein: powers beating of cilia (respiratory epithelium, fallopian tube) and flagella (sperm motility)
• Chromosome movement during cell division

3. Myosin

• Globular heads (motor domain) that bind actin + hydrolyze ATP
• Neck region (lever arm / hinge region) amplifies conformational change
• Tail region for cargo binding or thick filament formation
• 18 classes - most important are:
  • Myosin II (conventional muscle myosin) - forms thick filaments, responsible for muscle contraction
  • Myosin V - "walks" along actin filaments carrying organelles; vesicle and melanosome transport

1. ATP binds to myosin head → myosin detaches from actin
2. ATP hydrolysis (ADP + Pi) → myosin head cocks into high-energy "cocked" position
3. Myosin head binds actin (cross-bridge formation)
4. Pi release → power stroke - myosin head pivots 45° at hinge → actin filament slides
5. ADP released → rigor state (tight binding)
6. New ATP binds → cycle repeats

• Myosin II: skeletal, cardiac, and smooth muscle contraction; cytokinesis (contractile ring)
• Myosin V: transports organelles, vesicles, and melanosomes along actin filaments (hand-over-hand walking, toward barbed + end)
• Cell motility, lamellipodia formation, phagocytosis

Comparison Summary

Clinical Relevance

Key Points

1. All three superfamilies are ATPases - they use ATP hydrolysis to generate movement
2. Kinesin = anterograde (cell periphery / axon tip); Dynein = retrograde (cell centre / cell body)
3. Myosin = actin-based; Kinesin and Dynein = microtubule-based
4. The "head" domain binds the cytoskeletal track and contains the ATPase site
5. The "tail" domain binds the cargo
6. Dynein arms in cilia cause microtubule sliding → converted to bending by nexin cross-links

Gibbs-Donnan Equilibrium

Definition

Prerequisites / Conditions

1. A semipermeable membrane must separate two compartments
2. One side must contain a non-diffusible charged ion (impermeant ion - usually a large negatively charged protein)
3. The diffusible ions must be free to move across the membrane
4. Electroneutrality must be maintained in each compartment at all times

Basic Example / Setup

The Gibbs-Donnan Equation

• This is the product rule: the product of diffusible cation and anion concentrations is equal on both sides
• This holds for any pair of monovalent cation and anion
• The ratio r = [Na⁺]outside / [Na⁺]inside = [Cl⁻]inside / [Cl⁻]outside is called the Donnan ratio
• In plasma vs. interstitial fluid, the Gibbs-Donnan ratio is approximately 0.95 for both Na⁺ and Cl⁻

Three Key Consequences

1. Asymmetric Distribution of Diffusible Ions

• Cations (Na⁺, K⁺) are slightly higher on the protein-containing side (X)
• Anions (Cl⁻, HCO₃⁻) are slightly lower on the protein-containing side (X)
• Electrical neutrality is maintained in each compartment individually

• Plasma has impermeant proteins (albumin, globulins - negatively charged)
• Result: [Na⁺]plasma slightly > [Na⁺]interstitial fluid
• Result: [Cl⁻]plasma slightly < [Cl⁻]interstitial fluid
• Example: Cl⁻ in CSF is ~15% higher than plasma (blood-brain barrier excludes proteins, so CSF side must have higher Cl⁻ to balance)

2. Osmotic Pressure Difference (Oncotic Pressure)

• The protein-containing side (X) has more total osmotically active particles than side Y
• This is because cations are attracted in, adding to the particles already present
• This contributes to the colloid osmotic pressure (oncotic pressure) of plasma
• The Gibbs-Donnan effect adds approximately 1 mOsm/L extra to plasma oncotic pressure beyond just the protein molecules themselves - this is the Donnan osmotic effect

[K⁺_X] + [Cl⁻_X] + [Prot⁻_X] > [K⁺_Y] + [Cl⁻_Y] Side X has more osmotically active particles

3. Electrical Potential Difference Across the Membrane

• Because diffusible ions are asymmetrically distributed, an electrical potential difference develops across the membrane
• Side X (protein-containing) becomes electrically negative relative to side Y
• The charges line up along the membrane - the electrical gradient exactly balances the concentration gradient for each ion (satisfying the Nernst equation for each diffusible ion)
• This Donnan potential contributes to the resting membrane potential of cells

Gibbs-Donnan Effect and Cell Volume (Critical Concept)

• These intracellular anions attract cations (Na⁺, K⁺) inward
• More osmotically active particles accumulate inside the cell
• Water enters osmotically → cell swells → eventually bursts (osmotic lysis)

• The Na-K pump continuously pumps 3 Na⁺ out and 2 K⁺ in per cycle
• This actively excludes NaCl from the intracellular space, counteracting Donnan-driven swelling
• The cell exists in a steady state, NOT true equilibrium - it requires constant energy expenditure
• If the Na-K pump is inhibited (e.g., hypoxia, ouabain):
  • Na⁺ enters, Cl⁻ follows (to maintain electroneutrality)
  • Intracellular osmolarity rises → water enters → cell swells and may rupture

Key concept: Normal cell volume depends on the Na⁺/K⁺-ATPase doing "osmotic work" to counteract Donnan forces. NaCl acts as a functionally impermeant extracellular solute that offsets intracellular negative charges.

Physiological Applications

Key Points for Exam

1. Gibbs-Donnan equilibrium: unequal distribution of diffusible ions due to impermeant charged ion on one side
2. Equation: [cation_X × anion_X] = [cation_Y × anion_Y]
3. Side with impermeant anion: more cations, fewer anions, more total osmotic particles, electrically negative
4. Three effects: asymmetric ion distribution, osmotic pressure difference, electrical potential
5. Animal cells must use Na-K pump to prevent Donnan-driven swelling - it is a steady state, not true equilibrium
6. Donnan ratio (r) between plasma and ISF ≈ 0.95 for Na⁺ and Cl⁻

Differences Between Voltage-Gated Na⁺ and K⁺ Channels

1. Structure

2. Gating States

Na⁺ Channel - THREE States

1. Closed (Resting) - at resting membrane potential (-70 mV)
   • Activation gate (m gate) = CLOSED
   • Inactivation gate (h gate) = OPEN
   • Channel is available to open
2. Open (Activated) - at threshold/during depolarization
   • Activation gate (m gate) = OPEN
   • Inactivation gate (h gate) = OPEN
   • Na⁺ rushes in (upstroke of AP)
   • Duration: only ~1 ms (extremely brief)
3. Inactivated - rapidly after opening
   • Activation gate (m gate) = OPEN
   • Inactivation gate (h gate) = CLOSED (III-IV linker "plugs" the pore)
   • Channel cannot re-open → absolute refractory period
   • Returns to closed (resting) state only after repolarization

K⁺ Channel (Delayed Rectifier) - TWO States

1. Closed - at resting potential
   • Activation gate (n gate) = CLOSED
   • No separate inactivation gate in most delayed rectifier Kv channels
2. Open - after delayed activation during depolarization
   • Activation gate (n gate) = OPEN
   • K⁺ flows out (repolarization)
   • Returns to closed upon repolarization - does NOT inactivate (in most delayed rectifier types)

Key difference: Na⁺ channels have a fast inactivation mechanism; delayed rectifier K⁺ channels do not inactivate (or inactivate very slowly).

3. Kinetics (Speed)

• Na⁺ channel opens fast → rapid depolarization (upstroke)
• Na⁺ channel inactivates fast → AP cannot sustain
• K⁺ channel opens slowly → repolarization (falling phase)
• K⁺ channel does not inactivate → may cause brief hyperpolarization (after-hyperpolarization)

4. Role in the Action Potential

5. Pharmacology and Blockers

6. Summary Comparison Table

Clinical Relevance

• Mutations in Nav1.4 (SCN4A): Hyperkalemic periodic paralysis, paramyotonia congenita (impaired inactivation → sustained Na⁺ influx → membrane depolarization)
• Mutations in Nav1.1 (SCN1A): Dravet syndrome (epilepsy)
• Mutations in Kv1.1 (KCNA1): Episodic ataxia type 1
• Long QT syndrome: Mutations in cardiac K⁺ channels (KCNQ1, KCNH2) or Na⁺ channels (SCN5A) - impaired repolarization → prolonged AP → arrhythmia
• Local anesthetics: Block Na⁺ channels in their inactivated state (use-dependent block) → prevent nerve conduction

Physiological Basis of ST Elevation

What is the ST Segment?

Core Concept: The "Current of Injury"

"Severe, acute ischemia lowers the resting membrane potential and shortens the duration of the action potential. Such changes cause a voltage gradient between normal and ischemic zones. As a consequence, current flows between those regions. These currents of injury are represented on the surface ECG by deviation of the ST segment." — Harrison's Principles of Internal Medicine 22e

Cellular Effects of Ischemia on the Action Potential

Two Mechanisms of ST Elevation

1. Diastolic Current of Injury (TQ Depression)

• Ischemic cells are partially depolarized (resting Vm less negative, e.g., -60 mV instead of -90 mV) → relatively positive compared to normal
• Normal cells are fully repolarized (-90 mV) → relatively negative

• This depresses the TQ baseline (the true zero reference) in leads facing the ischemic zone
• Because ECG machines are AC-coupled and use the TP segment as their baseline reference, this TQ depression is interpreted as apparent ST elevation

2. Systolic Current of Injury (True ST Elevation)

• Normal cells are fully depolarized and at plateau potential → relatively positive
• Ischemic cells have an abbreviated/shortened action potential (early repolarization, shortened plateau) → repolarize earlier → relatively negative during systole

• The ischemic zone is relatively negative during systole → the ST vector points away from the ischemic zone in normal leads, but the epicardial ischemia creates a net outward ST vector pointing toward overlying leads
• This produces true ST elevation in leads overlying the transmural/epicardial ischemia

Vector Basis: Transmural vs. Subendocardial Ischemia

Additional Ionic Mechanisms

1. ATP-sensitive K⁺ channels (I_KATP) open - ischemia depletes ATP → I_KATP channels activate → K⁺ efflux → shortens AP plateau → creates transmural voltage gradient
2. Accumulation of extracellular K⁺ - K⁺ exits ischemic cells → [K⁺]outside rises → depolarizes resting Vm of ischemic cells → potentiates the diastolic injury current
3. Loss of epicardial AP dome - Ischemia predominantly affects the epicardial cells (shorter AP plateau) while endocardial cells retain their dome → this transmural gradient directly generates the systolic current of injury producing ST elevation
4. Na⁺ channel inactivation - Partial depolarization of ischemic cells inactivates fast Na⁺ channels → reduced AP amplitude → reduced excitability in epicardium → systolic transmural gradient

ECG Evolution in STEMI (Time Course)

Localization of ST Elevation

Other Causes of ST Elevation (Non-Ischemic)

1. Acute pericarditis - diffuse, saddle-shaped ST elevation in multiple leads + PR depression
2. Vasospastic (Prinzmetal's) angina - transient, reversible ST elevation without infarction
3. Benign early repolarization - concave upward ST elevation in young individuals, notching at J-point
4. Left ventricular aneurysm - persistent ST elevation after old MI
5. Brugada syndrome - coved-type ST elevation in V1-V3
6. Hyperkalemia - may cause ST changes
7. Takotsubo syndrome - transient ST elevation mimicking STEMI

Summary

• Diastolic: Partially depolarized ischemic cells are relatively positive → current flows toward normal cells → true TQ baseline depression (appears as ST elevation on AC-coupled ECG)
• Systolic: Ischemic cells have shortened APs and repolarize early → are relatively negative during systole → current flows from normal to ischemic zone → true ST elevation

Clinical Case: 60-year-old Male, Left Hemiplegia + MCA Blockage

a) Probable Diagnosis (1 mark)

• Left-sided weakness (upper and lower limb) → contralateral to lesion → right hemisphere
• Drowsiness → cortical involvement
• Difficulty speaking (dysphasia/aphasia) → though patient is 60M, if dominant hemisphere (usually left) were involved this would be classic Broca's aphasia; here the "uncommunicative behaviour / difficulty speaking" with LEFT hemiplegia suggests right MCA, though dysarthria is also possible
• Left facial paralysis → upper motor neuron type (central), right hemisphere corticobulbar tract involvement
• CT scan confirms blockage of MCA
• Increased tone in left limbs → UMN lesion pattern

b) Pathophysiology of Ischemic Stroke (2 marks)

Step 1: Occlusion

Step 2: Energy Failure

• Normal cerebral blood flow (CBF) = 50-55 mL/100g/min
• CBF < 20 mL/100g/min → neuronal dysfunction (electrical failure) → symptoms begin
• CBF < 10 mL/100g/min → neuronal death (infarction core) within minutes

Step 3: Ionic Cascade

• Na⁺ accumulates inside neurons → osmotic water entry → cytotoxic edema (cell swelling)
• Membrane depolarization → voltage-gated Ca²⁺ channels open → massive Ca²⁺ influx (most damaging step)

Step 4: Excitotoxicity

• Ischemic neurons release excessive glutamate
• Glutamate binds NMDA and AMPA receptors → further Ca²⁺ influx → excitotoxic neuronal death

Step 5: Downstream Damage

• Ca²⁺ overload activates:
  • Phospholipases → membrane breakdown → free fatty acids + arachidonic acid
  • Proteases (calpain) → cytoskeletal destruction
  • Endonucleases → DNA fragmentation
  • Nitric oxide synthase (NOS) → free radical (ROS) generation → oxidative stress
• Mitochondrial dysfunction → cytochrome C release → apoptosis

Step 6: Ischemic Penumbra

• Surrounding the infarct core is the ischemic penumbra - a zone of functionally impaired but structurally viable tissue that can be salvaged if reperfusion occurs within the therapeutic window (4.5 hours for IV tPA)

Step 7: Secondary Injury

• Vasogenic edema (blood-brain barrier breakdown, hours to days)
• Inflammatory cell infiltration
• If large infarct: cerebral herniation

c) Hemiplegia and Paraplegia (2 marks)

Hemiplegia

• Definition: Complete paralysis of one side of the body (upper AND lower limb on the same side), often with facial palsy on the same side
• Cause: Unilateral lesion of the corticospinal/corticobulbar tract above the pyramidal decussation (i.e., in cerebral hemisphere, internal capsule, or upper brainstem)
• Side: Contralateral to the lesion (because the corticospinal tract crosses at the pyramidal decussation in the medulla)
• Features (UMN type):
  • Increased tone (spasticity) - clasp-knife rigidity
  • Hyperreflexia (exaggerated deep tendon reflexes)
  • Extensor plantar response (Babinski sign)
  • Initial flaccidity → later spasticity
  • No significant muscle wasting
• Example: Right MCA stroke → Left hemiplegia (as in this case)

Paraplegia

• Definition: Paralysis of both lower limbs (legs) only - upper limbs are spared
• Cause: Lesion of the spinal cord at thoracic level (T1-L1), affecting both corticospinal tracts bilaterally; or bilateral lesion affecting both lower limb areas of the motor cortex (parasagittal meningioma, superior sagittal sinus thrombosis)
• Features (UMN type - if spinal cord lesion):
  • Spastic paraplegia (increased tone, brisk reflexes)
  • If below conus medullaris: LMN features (flaccid paraplegia)
  • Bladder and bowel involvement common
  • Sensory level may be present
• Examples: Traumatic spinal cord injury, multiple sclerosis, spinal cord tumor, transverse myelitis

d) Origin, Course, and Termination of Corticospinal Tract (4 marks)

Origin

• ~3% are Betz cells (giant pyramidal neurons, layer V) - the largest neurons in the human nervous system
• Somatotopic arrangement: face (medial) → arm → leg (lateral, near longitudinal fissure)

Course

• Axons descend from cortex into the corona radiata (fan-shaped white matter above the internal capsule)

• Fibers converge into the posterior limb of the internal capsule
• Somatotopic order: face fibers most anterior (near genu), arm fibers intermediate, leg fibers most posterior
• Compact arrangement here - a small lesion (lacunar infarct) can cause complete contralateral hemiplegia

• Pass through the middle one-third of the basis pedunculi (cerebral peduncles)
• Arrangement: face (medial) → arm → leg (lateral)
• Corticopontine fibers occupy the medial and lateral thirds

• Fibers become scattered as fascicles (separated by transverse pontine fibers and pontine nuclei)
• Corticobulbar fibers leave here to synapse on cranial nerve motor nuclei

• Fibers re-converge on the ventral surface of the medulla to form the medullary pyramids
• This is why the corticospinal tract is also called the pyramidal tract

• At the junction of medulla and spinal cord (foramen magnum level), ~85% of fibers cross to the opposite side → pyramidal decussation (decussation of the pyramids)
• ~15% do NOT cross → continue as anterior (ventral) corticospinal tract

After Decussation

• Crossed fibers form the lateral corticospinal tract in the dorsolateral white matter of the lateral funiculus
• Present throughout the length of the spinal cord
• Somatotopic: upper limb fibers medial, lower limb fibers lateral within the tract

• Uncrossed 15% form the anterior (ventral) corticospinal tract in the anterior funiculus
• Most of these cross at the spinal cord segmental level before terminating

Termination

• Corticospinal fibers synapse (directly or via interneurons) on lower motor neurons (LMN) in the anterior (ventral) horn of the spinal cord gray matter (Rexed laminae VI, VII, IX)
• Direct monosynaptic connections are most important for fine, skilled movements (especially hand and finger movements)
• Corticobulbar fibers terminate on cranial nerve motor nuclei in the brainstem (III, IV, V, VI, VII, IX, X, XI, XII)

Key Rule - Laterality

• Lesion above pyramidal decussation (cortex, IC, midbrain, pons, medulla above decussation) → contralateral weakness
• Lesion below pyramidal decussation (spinal cord) → ipsilateral weakness

e) Line of Treatment (1 mark)

Acute Management (within 4.5 hours = "Golden Window")

1. IV Alteplase (tPA) 0.9 mg/kg - if within 4.5 hours of symptom onset, no contraindications (standard of care for ischemic stroke)
2. Mechanical thrombectomy - if large vessel occlusion (MCA), within 6-24 hours

Immediate Supportive Care

• ABC - Airway, Breathing, Circulation
• Aspirin 300 mg (if tPA not given) - antiplatelet
• Oxygen if SpO₂ < 94%
• IV fluids (Normal saline) - maintain euvolemia
• Blood pressure control - allow permissive hypertension up to 220/120 mmHg acutely (unless thrombolysis given, then < 180/105)
• Blood glucose control - target 140-180 mg/dL
• Statin therapy - atorvastatin 40-80 mg
• DVT prophylaxis - heparin/LMWH after 24-48 hours

Rehabilitation

• Physiotherapy - limb strengthening, gait training
• Speech therapy - for aphasia/dysarthria
• Occupational therapy

Secondary Prevention

• Antiplatelet therapy (aspirin + clopidogrel or clopidogrel alone long-term)
• Statin (atorvastatin)
• Antihypertensives (if hypertensive - ACE inhibitor + diuretic preferred)
• Anticoagulation if atrial fibrillation is the cause (warfarin / NOAC)
• Carotid endarterectomy if significant carotid stenosis (>70%) identified

Wallerian Degeneration

Definition

Prerequisites

• Requires axonotmesis (grade II) or higher injury - simple neurapraxia (conduction block) does NOT cause Wallerian degeneration
• The cell body (perikaryon) must remain intact for regeneration to occur
• The endoneurial tubes (Schwann cell basement membrane) must ideally be preserved for guided regeneration

Diagram

Flowchart

NERVE INJURY (axonotmesis / neurotmesis)
               │
               ▼
    ┌──────────────────────────────────────────┐
    │           IMMEDIATE (0-24 hrs)            │
    │  - Axoplasm leaks at injury site          │
    │  - Ca²⁺ and Na⁺ influx through            │
    │    disrupted axonal membrane              │
    │  - Axoplasmic flow interrupted            │
    └──────────────┬───────────────────────────┘
                   │
         ┌─────────┴──────────┐
         ▼                    ▼
  DISTAL TO INJURY        PROXIMAL TO INJURY
  (Wallerian /            (Retrograde changes)
   Anterograde            
   degeneration)          
         │                    │
         ▼                    ▼
  ┌─────────────────┐   ┌────────────────────┐
  │ 8-24 hrs:       │   │ CELL BODY:          │
  │ Axonal swelling │   │ CHROMATOLYSIS       │
  │                 │   │ - Nissl bodies      │
  │                 │   │   disperse/dissolve │
  │                 │   │ - Nucleus moves to  │
  │                 │   │   cell periphery    │
  │                 │   │ - Cell swells        │
  │                 │   │ - Switch from        │
  │                 │   │   maintenance to     │
  │                 │   │   regeneration mode  │
  └────────┬────────┘   └────────────────────┘
           │
           ▼
  ┌─────────────────────┐
  │ DAY 1-3:             │
  │ Granular             │
  │ disintegration of    │
  │ axonal cytoskeleton  │
  │ - Microtubules       │
  │   disassemble        │
  │ - Neurofilaments     │
  │   break down         │
  │ - Axon fragments     │
  └────────┬────────────┘
           │
           ▼
  ┌─────────────────────┐
  │ DAY 3-7:             │
  │ SCHWANN CELL         │
  │ CHANGES              │
  │ - Retract from       │
  │   nodes of Ranvier   │
  │ - Dedifferentiate    │
  │   → Repair Schwann   │
  │   cells              │
  │ - Downregulate       │
  │   myelin proteins    │
  │ - Upregulate c-Jun   │
  │ - Myelin autophagy   │
  │   (myelin breakdown) │
  └────────┬────────────┘
           │
           ▼
  ┌─────────────────────┐
  │ DAY 3-14:            │
  │ MACROPHAGE           │
  │ INFILTRATION         │
  │ - Schwann cells      │
  │   secrete cytokines  │
  │ - Macrophages        │
  │   recruited          │
  │ - Phagocytosis of    │
  │   axon debris +      │
  │   myelin fragments   │
  │ (myelin = "debris")  │
  └────────┬────────────┘
           │
           ▼
  ┌─────────────────────┐
  │ ~1 WEEK:             │
  │ BANDS OF BÜNGNER     │
  │ - Repair Schwann     │
  │   cells proliferate  │
  │ - Align along empty  │
  │   endoneurial tubes  │
  │ - Form hollow        │
  │   cellular "tubes"   │
  │ - Secrete NGF, BDNF, │
  │   GGFs (neurotrophins│
  │   guide regeneration)│
  └────────┬────────────┘
           │
           ▼
  ┌─────────────────────────────────────────────┐
  │           REGENERATION PHASE                 │
  │                                              │
  │ Day 4 onwards: Proximal stump sends sprouts  │
  │ Growing axon cone penetrates Bands of Büngner│
  │ Rate: 0.5-3 mm/day (avg ~1 mm/day)           │
  │ Target organ reinnervated                    │
  │ Schwann cells redifferentiate → remyelinate  │
  │ New myelin = thinner, shorter internodes     │
  └─────────────────────────────────────────────┘

Detailed Steps (Guyton-style)

A. Distal Changes - Wallerian (Anterograde) Degeneration

B. Proximal Changes - Traumatic (Retrograde) Degeneration

• Limited degeneration proximal to injury - up to the first node of Ranvier
• More extensive with proximal injuries

C. Cell Body Changes - Chromatolysis

• Chromatolysis = dissolution of Nissl bodies (rough ER - ribosomes)
• Nucleus moves to cell periphery (eccentric displacement)
• Cell body swells
• Switch from neurotransmitter synthesis → structural protein synthesis (actin, tubulin for regeneration)
• Transcription factors upregulated (c-Jun, ATF3, Sox2)
• If injury is very proximal → cell body may undergo apoptosis (cell death, no regeneration)

D. Nerve Regeneration

• Day 4: Proximal stump sends multiple axonal sprouts (growth cones) into the endoneurial tube
• Sprouts attracted by neurotrophins (NGF, BDNF, GDNF) secreted by repair Schwann cells
• Growth cones penetrate Bands of Büngner and advance at 0.5-3 mm/day
• On reaching target organ: new neuromuscular junctions form
• Schwann cells redifferentiate → remyelinate regenerated axon
• New myelin is thinner with shorter internodes than original

PNS vs CNS - Why PNS Regenerates But CNS Does Not

Clinical Significance

Key Points (Exam Summary)

1. Wallerian degeneration = anterograde (distal) degeneration after axon injury
2. First sign: axonal swelling at 8-24 hours
3. Complete degeneration: ~1 week
4. Cell body shows chromatolysis (retrograde reaction)
5. Schwann cells → Bands of Büngner (guide regeneration)
6. Regeneration rate: 1 mm/day
7. New myelin is thinner with shorter internodes
8. PNS regenerates; CNS does not (due to Nogo, MAG inhibitors + no Schwann cells)