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ANCA-Associated Vasculitis (AAV): Treatment Protocol per Current Guidelines

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1. Classification and Initial Diagnosis

• GPA (Granulomatosis with Polyangiitis) - predominantly PR3-ANCA
• MPA (Microscopic Polyangiitis) - predominantly MPO-ANCA
• EGPA (Eosinophilic Granulomatosis with Polyangiitis) - variable ANCA

• ANCA testing (PR3-ANCA / MPO-ANCA) by ELISA
• Kidney biopsy to confirm pauci-immune crescentic GN when feasible
• Do NOT delay treatment while awaiting biopsy if the patient has positive ANCA serology + compatible clinical picture and is rapidly deteriorating (KDIGO 2024, Practice Point 9.1.1)
• Treat at centers with experience in AAV management

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2. Disease Severity Classification (drives treatment decisions)

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3. INDUCTION THERAPY (Phase 1)

3.1 Standard Induction - Life-threatening or Organ-threatening AAV

Glucocorticoids + Rituximab OR Cyclophosphamide

Glucocorticoids

• IV methylprednisolone 500 mg-1 g/day x 3 days (pulse), then
• Oral prednisolone 1 mg/kg/day (max 60-80 mg), tapered to 5 mg/day within 4-5 months (EULAR 2022 target)
• Reduced-dose GC protocol (from PEXIVAS trial): ~60% less exposure than standard, with non-inferior outcomes in ESKD/death - now preferred to limit toxicity
• Target: discontinue or reach ≤5 mg/day prednisolone by ~4-5 months

Option A - Rituximab (PREFERRED in most patients)

• 375 mg/m² IV x 4 weekly doses (RAVE/RITUXVAS dosing), OR
• 1000 mg IV x 2 doses separated by 2 weeks (ANCA-GN)
• Preferred over cyclophosphamide in:
  • Children/adolescents
  • Pre-menopausal women / men with fertility concerns
  • Frail older adults (glucocorticoid-sparing important)
  • Relapsing disease
  • PR3-ANCA positive disease

Option B - Cyclophosphamide (alternative)

• IV pulsed: 0.35-0.5 g/m² IV q3 weeks (CYCLOPS protocol), titrating up to 1 g/m² based on leukocyte nadir (target nadir 3,000 cells/mm³); preferred over daily oral in most cases (similar remission, lower cumulative dose)
• Oral: 2 mg/kg/day (reduce by 25 mg in patients >60 years)
• Preferred when rituximab is difficult to access, or for severe GN (SCr >4 mg/dL / 354 µmol/L)
• Duration: 3-6 months, then switch to maintenance agent

Combination (CYC + RTX): A combination of 2 IV pulses of cyclophosphamide with rituximab can be considered for severe GN.

3.2 Non-severe / Limited Disease

• Methotrexate 20-25 mg/week (PO or SC) + glucocorticoids: appropriate for early limited GPA without significant renal impairment
  • Avoid if creatinine clearance <80 mL/min; contraindicated <10 mL/min
  • Higher relapse rate than CYC (69.5% vs 46.5%) - use only in truly limited disease
• Mycophenolate mofetil (MMF): alternative for non-severe disease, especially MPO-ANCA

3.3 Avacopan (Complement C5a Receptor Inhibitor)

• Avacopan 30 mg PO twice daily - approved adjunct to reduce glucocorticoid exposure
• Used as part of a glucocorticoid-sparing strategy in GPA/MPA (EULAR 2022; KDIGO 2024)
• In the ADVOCATE trial: 72.3% remission at week 26 (vs 70.1% with prednisone), with superior sustained remission at week 52 (65.7% vs 54.9%)
• Start as early as possible; continue for 12 months
• Does NOT fully replace glucocorticoids; reduces overall exposure
• Consider especially in: frail elderly, diabetes, obesity, high infection risk

3.4 Plasma Exchange (PLEX)

• SCr >3.4 mg/dL (300 µmol/L)
• Dialysis-dependent at presentation or rapidly rising SCr
• Diffuse alveolar hemorrhage (DAH) with hypoxemia
• Mandatory: overlap of ANCA vasculitis + anti-GBM disease

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4. MAINTENANCE THERAPY (Phase 2)

4.1 Rituximab (PREFERRED maintenance)

• 500 mg IV every 6 months, OR 1000 mg every 6 months (fixed-interval dosing)
• Preferred in:
  • Relapsing disease
  • PR3-ANCA positive disease
  • Frail older adults
  • When glucocorticoid-sparing is critical
  • Azathioprine allergy
  • Low baseline IgG (<300 mg/dL - though monitor for hypogammaglobulinemia with repeated doses)

4.2 Azathioprine (alternative)

• 2 mg/kg/day PO (after switch from cyclophosphamide at remission)
• Check TPMT/NUDT15 genotype before starting
• Preferred when: rituximab difficult to access, or MPO-ANCA with low relapse risk
• Combined with low-dose prednisolone (≤5-7.5 mg/day)

4.3 Other maintenance alternatives

• Methotrexate 20-25 mg/week: for patients in remission who cannot tolerate azathioprine; avoid if GFR reduced
• Mycophenolate mofetil (MMF) 1500-2000 mg/day: less preferred (inferior to azathioprine in IMPROVE trial)
• Leflunomide 20-30 mg/day: used in some centers for GPA maintenance

4.4 Duration of Maintenance

• Optimal duration: 18 months to 4 years after induction (KDIGO 2024)
• When withdrawing: assess relapse risk factors (PR3-ANCA, prior relapse, persistent ANCA positivity), and counsel patients to return promptly if symptoms recur
• Higher relapse risk: PR3-ANCA, GPA phenotype, respiratory tract disease, persistent ANCA positivity at 12 months
• Lower relapse risk: MPO-ANCA, MPA phenotype - may sometimes avoid prolonged maintenance

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5. RELAPSING DISEASE

• Major/organ-threatening relapse: Re-induce with full induction protocol (rituximab preferred) - KDIGO 2024, Practice Point 9.3.3.1
• Minor relapse: Increase glucocorticoid dose +/- adjust immunosuppressive maintenance
• Remission rates for relapsing disease are similar to new-onset disease
• After re-induction, continue maintenance (rituximab preferred for relapsing disease)

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6. REFRACTORY DISEASE

• Increase glucocorticoids (IV or oral)
• If CYC-induced induction: add rituximab; if RTX-induced induction: add CYC pulses
• Plasma exchange can be considered
• Referral to specialist vasculitis center
• Consider clinical trial enrollment

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7. EGPA-SPECIFIC TREATMENT

• Induction: Glucocorticoids + Cyclophosphamide (for severe disease with cardiac, renal, peripheral nerve involvement)
• Mepolizumab 300 mg SC every 4 weeks (anti-IL-5): recommended for relapsing or refractory EGPA (EULAR 2022 - strong recommendation); reduces relapse rates and glucocorticoid requirements significantly
• For mild EGPA: glucocorticoids alone may suffice
• Rituximab: used in ANCA-positive or refractory EGPA (BSR 2025)

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8. SUPPORTIVE CARE AND MONITORING

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9. SPECIAL POPULATIONS

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10. Summary Treatment Algorithm

SUSPECTED AAV
    |
    ├─ ANCA+ & compatible clinical → START TREATMENT (biopsy when feasible, don't delay)
    |
    ├─ ORGAN-/LIFE-THREATENING?
    |      YES → Pulse methylprednisolone → Oral GC taper (reduced-dose protocol)
    |              + Rituximab (preferred) OR Cyclophosphamide
    |              ± Avacopan (GC-sparing)
    |              ± Plasma exchange (if SCr >3.4, dialysis, DAH, anti-GBM overlap)
    |
    ├─ LIMITED/NON-SEVERE?
    |      → GC + Methotrexate (or MMF)
    |
    ├─ EGPA?
    |      → GC ± CYC (severe); Mepolizumab (relapsing/refractory)
    |
    REMISSION ACHIEVED (~3-6 months)
    |
    └─ MAINTENANCE THERAPY (18 months to 4 years)
           Rituximab (preferred) OR Azathioprine + low-dose GC
           ± Avacopan (complete 12-month course)
           Monitor: ANCA, renal function, IgG, infections

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Key Guideline Sources

• KDIGO 2024 Clinical Practice Guideline for AAV - Kidney Int. 2024;105(Suppl 3S):S71-S116 [PMID: 38388102]
• EULAR 2022 Recommendations for AAV Management - Ann Rheum Dis 2024 [PMID: 36927642]
• BSR 2025 Management Recommendations for AAV - Rheumatology (Oxford) 2025 [PMID: 40499922]
• Comprehensive Clinical Nephrology, 7th Ed. (Elsevier)
• Brenner & Rector's The Kidney, 9th Ed. (Elsevier)

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• Rituximab has largely replaced cyclophosphamide as the preferred induction and maintenance agent in most patients
• Glucocorticoid dose should be minimized - target ≤5 mg/day by 4-5 months (EULAR) or use reduced-dose protocol (PEXIVAS)
• Avacopan is a new approved option to reduce steroid exposure in GPA/MPA
• Plasma exchange is no longer routine - reserve for selected severe cases
• Mepolizumab is the key biologic for relapsing/refractory EGPA
• Maintenance duration: 18 months to 4 years depending on relapse risk profile

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Approach to Thrombocytopenia

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1. Definition

• Platelet count < 150,000/µL (traditionally)
• Counts 100,000-150,000/µL stable for >6 months may be considered normal variants
• Clinically significant threshold: < 100,000/µL warrants active investigation
• Critical: < 10,000-20,000/µL carries risk of spontaneous life-threatening hemorrhage

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2. FIRST STEP: Rule Out Pseudothrombocytopenia

• Cause: EDTA-dependent antiplatelet antibodies cause in vitro platelet clumping (~0.1% of population); the automated counter reads clumped platelets as one
• Clue: Low platelet count with NO clinical bleeding in an otherwise well patient
• Action:
  • Review the peripheral blood smear for platelet clumps
  • Repeat CBC in sodium citrate (blue top) or heparin (green top) tube
  • Or examine a finger-stick smear without anticoagulant

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3. Clinical Assessment

History

• Bleeding symptoms: petechiae, purpura, ecchymoses, epistaxis, gingival bleeding, menorrhagia, GI bleed, hematuria, intracranial bleed
• Drug history (most common cause - ask about ALL drugs, herbals, OTC, quinine, heparin, NSAIDs, antibiotics, chemotherapy)
• Infections: recent viral illness (children), HIV, hepatitis B/C, EBV, CMV, COVID-19
• Systemic illness: liver disease, autoimmune disease (SLE, APS), malignancy
• Family history (inherited thrombocytopenia)
• Pregnancy (gestational thrombocytopenia is most common cause in pregnancy)
• Prior platelet counts (chronicity matters)
• Transfusions, ECMO, recent surgery (dilution, mechanical destruction)

Physical Examination

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4. Pathophysiologic Classification (The Core Framework)

THROMBOCYTOPENIA
        |
        ├── DECREASED PRODUCTION (bone marrow problem)
        |        → Peripheral smear: normal or small platelets
        |        → Immature Platelet Fraction (IPF): LOW or normal
        |        → Bone marrow: ↓ megakaryocytes or infiltration
        |
        ├── INCREASED DESTRUCTION / CONSUMPTION
        |        → Peripheral smear: large platelets (megakaryocytes working harder)
        |        → IPF: HIGH (elevated reticulated platelets)
        |        → Bone marrow: normal or ↑ megakaryocytes
        |
        └── SEQUESTRATION
                 → Splenomegaly traps up to 90% of platelet pool
                 → Production normal; distribution problem

Immature Platelet Fraction (IPF) / Reticulated Platelets

• High IPF = peripheral destruction/consumption (bone marrow compensating)
• Low/normal IPF = decreased production (marrow not responding)
• Available on modern hematology analyzers - a useful, underused test

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5. Diagnostic Algorithm

1. Confirm true thrombocytopenia (rule out pseudothrombocytopenia)
2. Check full CBC - is thrombocytopenia isolated or part of pancytopenia?
3. Peripheral blood smear - this is the single most important next test:
   • Platelet size (large = destruction; small = production defect/congenital)
   • Schistocytes/fragmented RBCs → microangiopathic process (TTP, HUS, DIC, HELLP)
   • Platelet clumps → pseudothrombocytopenia
   • Blasts → leukemia
   • Hypersegmented neutrophils → B12/folate deficiency
   • Teardrop cells (dacrocytes) → myelofibrosis
4. Check coagulation (PT, aPTT, fibrinogen, D-dimer) → if abnormal, consider DIC
5. If cause unclear → bone marrow examination (especially age >60 or no response to treatment)

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6. Differential Diagnosis by Mechanism

A. Decreased Production

B. Increased Destruction / Consumption

Immune-mediated

Consumptive (non-immune)

C. Sequestration

D. Dilutional

• Massive transfusion / fluid resuscitation
• ECMO, cardiopulmonary bypass, hemodialysis

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7. Key Specific Conditions

Immune Thrombocytopenic Purpura (ITP)

• CBC, peripheral smear (large platelets, otherwise normal)
• HIV, HCV, HBV serology
• ANA, anti-dsDNA (screen for SLE)
• H. pylori testing
• Serum immunoglobulins (IgG, IgA, IgM)
• Direct Coombs test (rule out Evans syndrome)
• Bone marrow biopsy NOT required routinely (reserve for age >60 or treatment failure)

• TPO receptor agonists: romiplostim (SC weekly), eltrombopag (oral daily), avatrombopag (oral)
• Rituximab (anti-CD20): ~30% long-term remission
• Splenectomy: now less common; give pneumococcal, meningococcal, Hib vaccines 2 weeks before
• Fostamatinib (spleen tyrosine kinase inhibitor): newer option

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Heparin-Induced Thrombocytopenia (HIT)

• Type 1 HIT: Non-immune, mild drop (>100,000), onset within 1-2 days, self-limiting - continue heparin
• Type 2 HIT (TRUE HIT): Immune-mediated (anti-PF4/heparin antibodies), onset 5-10 days after heparin exposure (sooner if recent prior exposure), platelet drop typically >50% from baseline, paradoxically thrombotic (HITT)

• Score 6-8 = High pre-test probability
• Score 4-5 = Intermediate
• Score 0-3 = Low

1. Stop ALL heparin immediately (including flushes, LMWH)
2. Start non-heparin anticoagulation immediately: argatroban, bivalirudin, fondaparinux, or DOAC
3. DO NOT give platelet transfusions (can worsen thrombosis - "feed the clot")
4. DO NOT start warfarin until platelet count recovers (risk of limb gangrene)
5. Confirm with anti-PF4/heparin antibody ELISA (high sensitivity) + serotonin release assay (gold standard)

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Thrombotic Thrombocytopenic Purpura (TTP)

• Mnemonic (classic pentad): Fever + microAngiopathic hemolytic Anemia + Thrombocytopenia + Renal dysfunction + Neurological symptoms (FAT RN)
• Actually, the full pentad is rare; MAHA + thrombocytopenia is sufficient to initiate treatment
• Mechanism: ADAMTS13 deficiency (congenital or acquired) → accumulation of ultra-large von Willebrand factor multimers → platelet thrombi in microvasculature
• Smear: Schistocytes (fragmented RBCs) + ↓ platelets
• Labs: ↓ADAMTS13 activity (<10% confirms diagnosis), anti-ADAMTS13 antibodies

1. Plasma exchange (PLEX) - EMERGENCY, start immediately
2. Steroids (methylprednisolone or prednisone)
3. Caplacizumab (anti-VWF nanobody) - add to PLEX + steroids for faster platelet recovery
4. Rituximab for acquired TTP (to reduce anti-ADAMTS13 antibodies)
5. Avoid platelet transfusions (worsens microvascular thrombosis)

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DIC (Disseminated Intravascular Coagulation)

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8. Bleeding Risk by Platelet Count

• Non-bleeding: transfuse if <10,000/µL (prophylactic)
• Pre-procedure: >50,000/µL for most; >100,000/µL for neurosurgery/ophthalmology
• Active major bleeding: >50,000-100,000/µL target
• NEVER transfuse in TTP or HIT (worsens outcome)

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9. Investigations Summary

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10. Quick Summary Mnemonic

• D - Decreased production (aplastic anemia, MDS, B12/folate, drugs, alcohol, viruses)
• I - Increased destruction (ITP, HIT, TTP/HUS, DIC, drugs, infections)
• P - Pooling/sequestration (hypersplenism)
• S - Spurious/dilutional (pseudothrombocytopenia, massive transfusion)

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Basics of Neurology for the MD Medicine Resident

Neurological Examination & Localization

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THE FUNDAMENTAL PRINCIPLE: Think in Anatomy First

The #1 skill in neurology is localization - "Where is the lesion?" always before "What is the lesion?"

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PART 1: THE NEUROLOGICAL EXAMINATION - Overview

1. Mental Status
2. Cranial Nerves (I–XII)
3. Motor System
4. Reflexes
5. Coordination & Cerebellar
6. Gait & Balance
7. Sensory System

• Facial expression: flat (parkinsonism), worried/surprised (progressive supranuclear palsy)
• Ptosis: myasthenia gravis, Horner's syndrome, CN III palsy
• Speech: dysarthria vs. aphasia vs. dysphonia
• Posture and involuntary movements: tremor, chorea, dystonia

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PART 2: MENTAL STATUS EXAMINATION

The 6 Core Domains to Test

Language - Critically Important (localizes to dominant hemisphere)

Clinical Pearl: In right-handed people (and ~70% of left-handed), language is in the LEFT hemisphere. A fluent patient with poor comprehension = Wernicke's = posterior. A non-fluent patient who understands well = Broca's = anterior.

Additional Cortical Functions

• Neglect: Ask patient to bisect a line; hemi-neglect = non-dominant (right) parietal lesion
• Apraxia: Inability to perform learned motor tasks despite intact motor/sensory function (dominant parietal)
• Agnosia: Inability to recognize despite intact perception
• Right-left disorientation + acalculia + agraphia + finger agnosia = Gerstmann syndrome (dominant angular gyrus)

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PART 3: CRANIAL NERVE EXAMINATION

Quick Reference: All 12 Cranial Nerves

Critical CN Pearls for Medicine Residents

• Dilated, fixed pupil (mydriasis) = CN III palsy - surgical emergency (aneurysm or herniation)
• Small, reactive pupil (miosis) + ptosis + anhidrosis = Horner syndrome (sympathetic chain disruption - think lung apex, carotid dissection, brainstem)
• RAPD (Relative Afferent Pupillary Defect / Marcus Gunn pupil): When you swing light from normal to affected eye, the affected eye appears to dilate - indicates optic nerve or extensive retinal disease

• UMN lesion (e.g., stroke in internal capsule): lower face weakness only (forehead SPARED because forehead has bilateral cortical representation)
• LMN lesion (e.g., Bell's palsy): ENTIRE face on one side, including forehead - cannot close eye, cannot raise eyebrow

1. Is it monocular (one eye closed, still diploid) → ophthalmological (lens/cornea)
2. Is it binocular → CN III, IV, VI palsy or internuclear ophthalmoplegia (INO)
3. INO = medial longitudinal fasciculus (MLF) lesion → failure of adduction on the side of the lesion + nystagmus in the abducting eye → bilateral INO in young patient = multiple sclerosis

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PART 4: MOTOR SYSTEM EXAMINATION

The Motor Pathway - From Cortex to Muscle

Motor Cortex (precentral gyrus)
    ↓ Corticospinal (pyramidal) tract
Internal Capsule (posterior limb)
    ↓
Brainstem (crosses at pyramidal decussation in medulla)
    ↓
Lateral corticospinal tract in CONTRALATERAL spinal cord
    ↓
Anterior Horn Cell (lower motor neuron)
    ↓
Peripheral nerve → Neuromuscular junction → Muscle

UMN vs LMN - The Most Important Table in Neurology

Important caveat: In acute UMN lesions (e.g., acute stroke, acute spinal cord injury), you may see flaccidity and hyporeflexia initially (spinal shock / diaschisis). Spasticity and hyperreflexia develop over days to weeks.

Muscle Strength Grading (MRC Scale)

Motor Exam Steps

1. Observation: Posture, involuntary movements, wasting
2. Inspection: Fasciculations (best seen with tangential light), atrophy
3. Tone: Roll the limb passively; spasticity = velocity-dependent resistance; rigidity = lead-pipe/cogwheel (Parkinson's)
4. Functional testing: Pronator drift (extend arms, supinate, close eyes - weak arm pronates and drifts down); heel-toe walking; push-up, rising from floor
5. Individual muscle group strength: Proximal vs. distal pattern
6. Key pattern:
   • Proximal > distal weakness → myopathy
   • Distal > proximal weakness → neuropathy
   • Pure motor with UMN + LMN signs → ALS

Pronator Drift Test

• Downward + pronation drift = UMN weakness (corticospinal)
• Upward drift = proprioceptive loss (sensory ataxia)
• Tremor = essential tremor or Parkinson's
• Pseudoathetosis = proprioceptive loss

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PART 5: REFLEXES

Deep Tendon Reflexes (DTRs)

• 0 = Absent; 1 = Diminished; 2 = Normal; 3 = Brisk (spread); 4 = Clonus

Pathological Reflexes

• Hoffman's sign (hand): Flick the middle fingernail; thumb and index flex = UMN in cervical cord or cortex
• Clonus: Rapid dorsiflexion of ankle held; sustained rhythmic beats = UMN (>5 beats = significant)

• Grasp reflex, rooting reflex, palmomental reflex, snout reflex

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PART 6: COORDINATION & CEREBELLAR EXAMINATION

Cerebellar Tests

DASHING - Cerebellar Signs Mnemonic

• D - Dysdiadochokinesia (rapid alternating)
• A - Ataxia (gait)
• S - Slurred speech (dysarthria - "scanning speech")
• H - Hypotonia
• I - Intention tremor (worsens near target; resting tremor is Parkinson's)
• N - Nystagmus (fast phase toward lesion)
• G - Gaze palsy / past-pointing

Localization within the Cerebellum

Key rule: Cerebellar signs are ipsilateral to the lesion (cerebellum does NOT cross). Motor cortex signs are contralateral.

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PART 7: GAIT EXAMINATION

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PART 8: SENSORY EXAMINATION

Two Major Sensory Pathways

• First-order neuron enters ipsilateral dorsal column → ascends to medulla → crosses in medulla → reaches thalamus → parietal cortex
• Carries: Vibration, joint position sense (proprioception), fine/discriminative touch, 2-point discrimination

• First-order neuron enters spinal cord → crosses within 1-2 segments in anterior commissure → ascends in contralateral spinothalamic tract → thalamus → parietal cortex
• Carries: Pain, temperature, crude touch

This is why Brown-Séquard syndrome (spinal cord hemisection) is so elegant: ipsilateral motor + proprioception loss, contralateral pain + temperature loss - because the two pathways cross at different levels.

What to Test

Sensory Patterns and Localization

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PART 9: LOCALIZATION FRAMEWORK - The Core Skill

"Where is the lesion?" - 8 Key Levels

1. CORTEX (cerebral cortex)
2. SUBCORTEX (white matter, basal ganglia, thalamus, internal capsule)
3. BRAINSTEM (midbrain, pons, medulla)
4. CEREBELLUM
5. SPINAL CORD
6. ANTERIOR HORN CELL
7. PERIPHERAL NERVE / NERVE ROOT
8. NEUROMUSCULAR JUNCTION / MUSCLE

Localization at Each Level - Key Features

1. Cortex

• Focal deficits reflecting the homunculus (monoparesis, or face + arm > leg)
• PLUS cortical signs: aphasia, neglect, apraxia, visual field defects, seizures
• Contralateral findings

2. Internal Capsule / Subcortical

• Dense hemiplegia = face, arm, leg affected equally (because all fibers converge in the capsule)
• NO cortical signs (aphasia, neglect)
• Thalamic lesion: hemisensory loss with little/no weakness

3. Brainstem

• "Crossed signs" = the hallmark:
  • Ipsilateral cranial nerve palsy + contralateral hemiplegia
  • Or: ipsilateral face sensory loss + contralateral body sensory loss
• Diplopia, dysarthria, dysphagia, vertigo accompanying motor signs

4. Cerebellum

• Ipsilateral limb ataxia (hemispheric)
• Truncal/gait ataxia (vermis)
• NO weakness, NO sensory loss, NO cortical signs

5. Spinal Cord

• Sensory level (all modalities below a segmental line)
• UMN signs below the level
• LMN signs AT the level
• Bladder/bowel dysfunction
• Brown-Séquard (hemisection): Ipsilateral UMN + dorsal column loss; contralateral pain/temp loss

6. Anterior Horn Cell

• Pure LMN (weakness, atrophy, fasciculations, no sensory loss)
• Multiple levels simultaneously
• Causes: ALS (also has UMN), polio, spinal muscular atrophy

7. Peripheral Nerve / Nerve Root

• Radiculopathy: dermatomal sensory + myotomal weakness; pain radiating in dermatomal pattern
• Mononeuropathy: single nerve territory
• Polyneuropathy: glove-and-stocking; length-dependent; distal > proximal
• Plexopathy: brachial or lumbosacral plexus

8. Neuromuscular Junction (NMJ)

• Fatigable weakness - worsens with activity, improves with rest
• NO sensory involvement
• NO reflex change (usually)
• Myasthenia Gravis: ptosis, diplopia, dysarthria, dysphagia; anti-AChR antibodies; edrophonium test; decrement on repetitive stimulation
• Lambert-Eaton: proximal weakness; improves briefly with activity; facilitation on repetitive stimulation; paraneoplastic (SCLC)

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PART 10: THE CLINICAL LOCALIZATION APPROACH - A Practical Template

Step-by-Step When You See a Neurology Patient

• Focal (one side, one limb, one function) = structural lesion
• Diffuse/symmetric = metabolic, toxic, polyneuropathy, or systemic disease

• Positive symptoms (new things happening: pain, tingling, spasms, jerks) vs. negative symptoms (things lost: weakness, numbness)
• Acute (<24h) = vascular (stroke) until proven otherwise
• Subacute (days-weeks) = inflammatory, infectious, neoplastic
• Chronic/progressive = degenerative, hereditary, metabolic

• UMN + cortical signs = cortex
• UMN + cranial nerve palsy = brainstem
• UMN + sensory level = spinal cord
• LMN only, multiple levels = anterior horn cell
• LMN + sensory in nerve territory = peripheral nerve
• Fatigable weakness, no sensory = NMJ
• Proximal weakness, no sensory = muscle

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Quick Summary Diagram

Cortex ──────────────────── Contralateral hemiparesis
                             + Aphasia / neglect / seizures
                             FACE & ARM > LEG (MCA)
                             LEG > FACE & ARM (ACA)

Internal Capsule ─────────── Contralateral dense hemiplegia
                             (face = arm = leg)
                             NO cortical signs

Brainstem ────────────────── CROSSED signs:
                             Ipsilateral CN palsy
                             + Contralateral hemiplegia/sensory

Cerebellum ───────────────── Ipsilateral limb ataxia
                             Gait ataxia (midline)
                             NO weakness or sensory loss

Spinal Cord ──────────────── Sensory level
                             UMN below, LMN at level
                             Bladder/bowel dysfunction

Anterior Horn Cell ──────── Pure LMN, no sensory loss
                             Fasciculations prominent

Peripheral Nerve ─────────── LMN + sensory loss
                             In nerve/dermatomal territory

NMJ ─────────────────────── Fatigable weakness
                             No sensory, no reflex change

Muscle ──────────────────── Proximal symmetric weakness
                             No sensory loss
                             Elevated CK

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Clinical Pearls to Remember

1. Always rule out pseudothrombocytopenia in thrombocytopenia - analogously, always rule out pseudo-neurological signs (functional/conversion disorder) - look for inconsistency, Hoover's sign, collapsing weakness
2. Babinski is always abnormal in adults - never dismiss it
3. Forehead sparing = UMN facial palsy (stroke); entire face = Bell's palsy or other LMN cause
4. A fixed dilated pupil is CN III until proven otherwise - think PCA aneurysm or uncal herniation
5. Tandem gait is the most sensitive test for subtle cerebellar disease
6. Crossed findings (face one side, body other) = brainstem - this is pathognomonic
7. INO in young patient = MS; in older patient = brainstem stroke
8. Vibration and proprioception travel together (dorsal column); pain and temperature travel together (spinothalamic)
9. The cerebellum is always ipsilateral - left cerebellar lesion = left limb ataxia
10. Gait examination is often the most informative single test - never skip it

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General Physical Examination - Detailed Guide for MD Medicine Practical

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THE FUNDAMENTAL PRINCIPLE

The examiner is watching HOW you examine, not just WHAT you find.

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THE STRUCTURE OF GENERAL EXAMINATION

1. GENERAL SURVEY (First Impression / On Inspection)
2. VITAL SIGNS
3. ANTHROPOMETRY
4. THE "BIG 8" CLINICAL SIGNS
   - Pallor
   - Icterus (Jaundice)
   - Cyanosis
   - Clubbing
   - Lymphadenopathy
   - Edema
   - Koilonychia / other nail changes
   - Dehydration
5. SPECIFIC FACIES
6. SKIN & HAIR
7. HANDS (a complete story in themselves)

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PART 1: GENERAL SURVEY (First Look)

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PART 2: VITAL SIGNS

1. Temperature

• Normal: 36.5°C - 37.5°C (oral); rectal is 0.5°C higher
• Pyrexia: >38°C; Hyperpyrexia: >41°C
• Hypothermia: <35°C (septic shock, hypothyroidism, exposure)

2. Pulse

• Rate: Bradycardia <60 bpm; Tachycardia >100 bpm
• Rhythm: Regular / irregular / irregularly irregular
• Volume: Full, normal, low, collapsing
• Character:

• Compare both radials simultaneously: Delay or absent pulse = aortic dissection, Takayasu's, subclavian steal
• Radio-femoral delay: Coarctation of aorta

3. Blood Pressure

• Normal: <120/80 mmHg
• Check in BOTH arms (>10 mmHg difference = aortic dissection, subclavian stenosis)
• Postural BP: Supine → standing; fall >20 mmHg systolic or >10 mmHg diastolic = orthostatic hypotension
• PP (Pulse Pressure) = Systolic - Diastolic: Wide PP (>60) = AR, PDA, hyperthyroidism, anemia, AV fistula; Narrow PP = tamponade, severe AS, cardiogenic shock

4. Respiratory Rate

• Normal: 12-20 breaths/min
• Tachypnea (>20): pneumonia, PE, metabolic acidosis, anxiety, heart failure
• Bradypnea (<12): opioids, raised ICP, hypothyroidism
• Cheyne-Stokes: Crescendo-decrescendo with apnea → HF, stroke, uraemia, high altitude
• Kussmaul: Deep, sighing, regular → metabolic acidosis (DKA)
• Biot's: Irregular with sudden apnea → brainstem lesion (pontine)
• Apneustic: Prolonged inspiration → pontine lesion

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PART 3: ANTHROPOMETRY

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PART 4: THE "BIG 8" CLINICAL SIGNS

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1. PALLOR

1. Lower palpebral conjunctiva - most reliable site; pull down lower lid, look at inner pink surface - pale = pallor
2. Palmar creases - if creases are pale = Hb usually <7 g/dL
3. Nail beds - press to blanch, release; slow return + pale = pallor
4. Oral mucosa (inner lips, buccal mucosa)
5. Tongue

Exam Tip: Always look at the conjunctiva first. Say: "I am looking for pallor in the lower palpebral conjunctiva, palmar creases, nail beds, and oral mucosa."

• Mild: only detectable in conjunctiva
• Moderate: conjunctiva + palmar creases pale
• Severe: all sites pale, including nail beds and tongue

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2. ICTERUS (JAUNDICE)

1. Sclerae (icterus) - most sensitive; look in natural light; roll eyes upward
2. Under the tongue / oral mucosa (early jaundice)
3. Skin (usually visible when bilirubin >5-7 mg/dL)
4. Palms (deep jaundice)

"I am examining for icterus in the sclerae under natural light." Turn patient toward the window.

• Grade I: Icterus only in sclerae
• Grade II: Sclerae + skin (face/trunk)
• Grade III: Generalized deep icterus; skin bright yellow/green
• Grade IV: Extreme deep jaundice with greenish hue (biliary obstruction)

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3. CYANOSIS

Key Point: Cyanosis is NOT detectable in severe anemia (even if O₂ saturation is very low, not enough Hb to reach 5 g/dL of deoxygenated form). Conversely, polycythemia patients may appear cyanotic at relatively higher O₂ saturations.

1. Look at tongue in natural light first (central)
2. Then nail beds and periphery (peripheral)
3. If central cyanosis: check SpO₂, look for clubbing (chronic hypoxia), assess respiratory/cardiac system

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4. CLUBBING

1. Schamroth's window test: Place dorsal surfaces of both index fingers together. Normally, a diamond-shaped window is visible at the nail bases. In clubbing, the window is obliterated (most sensitive bedside test).
2. Look at nail from the side: Hyponychial angle >180° (normally <160°)
3. Fluctuation test (Lovibond angle): Normally the angle between nail plate and proximal nail fold is <160°; >180° = clubbing
4. Look for periungual erythema, shiny nails
5. Check toes (toe clubbing confirms it is true clubbing, not pseudo-clubbing)

Exam Trick: Unilateral clubbing = vascular cause (AV fistula, Pancoast tumor affecting one side). Bilateral = systemic cause.

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5. LYMPHADENOPATHY

• Use pulp of 2-4 fingers; gentle circular palpation
• For cervical: stand behind the patient; systematically palpate all groups
• Always compare both sides

1. Submental (under chin)
2. Submandibular
3. Pre-auricular
4. Post-auricular (mastoid)
5. Occipital
6. Anterior cervical chain (along anterior border of SCM)
7. Posterior cervical chain (along posterior border of SCM)
8. Supraclavicular (Virchow's node on left = gastric/abdominal malignancy)
9. Deep cervical chain

• Axillary (examine with arm relaxed at side; palpate apex, anterior, posterior, medial, lateral)
• Epitrochlear (medial side of elbow - sarcoid, secondary syphilis, lymphoma, infections)
• Inguinal (horizontal and vertical chains; common = lower limb/genital infections, STIs)
• Para-aortic (not palpable unless massively enlarged)

• Infections: EBV (glandular fever), HIV, TB, CMV, toxoplasmosis, brucellosis
• Hematological malignancies: lymphoma, CLL, ALL
• Autoimmune: SLE, RA, sarcoidosis
• Drugs: phenytoin, isoniazid

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6. EDEMA

1. Press firmly with thumb over bony prominence (tibia, dorsum of foot, sacrum) for 5 seconds
2. Pitting edema: Pit remains after releasing pressure
3. Grade by height it extends: ankle, shin, knee, thigh, scrotal/labial, sacral, ascites → anasarca

Always examine both: ankles in ambulatory patients + sacrum in bedridden patients

1. ↑Hydrostatic pressure (CCF, venous obstruction)
2. ↓Oncotic pressure (hypoproteinemia: nephrotic, cirrhosis, malnutrition)
3. ↑Capillary permeability (sepsis, burns, anaphylaxis, angioedema)
4. Lymphatic obstruction (filariasis, post-surgical, malignancy)

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7. KOILONYCHIA & OTHER NAIL SIGNS

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8. DEHYDRATION

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PART 5: FACIES - Diagnostic at a Glance

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PART 6: HANDS - A Complete Clinical Examination Tool

Routine Hand Examination Sequence:

1. Nails: Clubbing, koilonychia, leuconychia, pitting, splinter hemorrhages, onycholysis
2. Palmar skin: Palmar erythema (liver disease, RA, pregnancy, polycythemia), Dupuytren's contracture (alcoholic liver disease, diabetes)
3. Palmar creases: Pale = anemia; extra palmar crease (single transverse/simian crease) = Down syndrome
4. Thenar wasting: Carpal tunnel syndrome, T1 lesion
5. Hypothenar wasting: Ulnar nerve palsy
6. Interosseous wasting: Ulnar nerve, RA, cord lesion
7. Joints: Deformity, swelling, boggy synovium (RA), DIP involvement (psoriatic/OA), tophi (gout)
8. Skin: Janeway lesions (non-tender hemorrhagic maculopapular on palms/soles = infective endocarditis), Osler's nodes (tender on pulp of fingers = IE), nodules
9. Tremor: Rest tremor (Parkinson's), postural tremor (essential/thyrotoxic), intention tremor (cerebellar)
10. Temperature: Hot, sweaty palms = thyrotoxicosis, anxiety; cold = hypothyroidism, Raynaud's, shock

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PART 7: SUMMARY CHECKLIST FOR MD MEDICINE EXAM

"On general examination, the patient is:

1. Conscious / Oriented / Cooperative
2. Built and nourished: Well built & nourished / Moderately / Poorly
3. Vital Signs:
   - Temperature: ___°C
   - Pulse: ___ bpm, regular/irregular, volume, character
   - BP: ___/___ mmHg (both arms if relevant)
   - RR: ___ breaths/min
   - SpO2: ___%
   - BMI: ___

4. General signs:
   - Pallor: Present (mild/moderate/severe) / Absent
   - Icterus: Present (mild/moderate/deep) / Absent
   - Cyanosis: Present (central/peripheral/differential) / Absent
   - Clubbing: Present (Grade ___) / Absent
   - Lymphadenopathy: Present (location, characteristics) / Absent
   - Edema: Present (pitting, Grade ___, location) / Absent
   - Dehydration: Present (mild/moderate/severe) / Absent

5. Facies: Normal / (Specific facies noted)
6. Hands: Relevant nail signs, palmar changes, joint deformity
7. Skin: Rashes, pigmentation, jaundice, purpura, petechiae"

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CLINICAL EXAM PEARLS FOR MD VIVA

• Never say "no pallor" without actually looking at the conjunctiva - examiners watch this
• For jaundice: Always examine in natural light (artificial light hides early jaundice); the sclerae are the most sensitive site
• Schamroth's window test is the simplest, most elegant test for clubbing - always demonstrate it
• Sacral edema must be checked in every bedridden patient - this is frequently missed
• Lymph nodes: Always mention if you are palpating BOTH sides; describe all features; never omit the supraclavicular fossa (Virchow's node = carcinoma of stomach/GI tract)
• Cyanosis: The tongue is the key - if the tongue is blue, it is central cyanosis; peripheral cyanosis never affects the tongue
• Pulse: Always palpate both radials simultaneously first (for asymmetry); then describe rate, rhythm, volume, character
• Edema: Specify location and grade; always check sacrum and say "bilateral pitting pedal edema up to the level of..."
• Dehydration: Combine skin turgor + mucous membranes + pulse + BP for the clinical picture
• Facies: Comment on it even if normal: "Facies is unremarkable / normal"

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• Colour-coded by section (navy/teal/accent headers)
• Alternating row shading for easy reading
• Red warning boxes for critical exam mistakes
• Star-marked clinical pearls throughout
• Compact but readable font (7.5–9 pt) for maximum density on A4