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MD MEDICINE EXAMINATION NOTES — NEUROLOGY

References: Harrison's Principles of Internal Medicine 22E, Bradley & Daroff's Neurology in Clinical Practice, Adams & Victor's Principles of Neurology 12E, Costanzo Physiology 7E

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QUESTION 1 (Long Answer - 20 Marks)

RECENT ADVANCES IN ACUTE STROKE MANAGEMENT

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DEFINITION & OVERVIEW

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CLASSIFICATION OF ACUTE ISCHEMIC STROKE (TOAST)

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PATHOPHYSIOLOGY - ISCHEMIC PENUMBRA

CORE INFARCT (CBF <10 mL/100g/min)
    - Irreversible injury, necrosis
    - Cannot be saved

ISCHEMIC PENUMBRA (CBF 10-20 mL/100g/min)
    - Electrically silent but metabolically active
    - SALVAGEABLE with timely reperfusion
    - Basis of thrombolysis & thrombectomy

OLIGEMIC ZONE (CBF 20-50 mL/100g/min)
    - At risk if BP drops
    - "Tissue at risk"

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A. INITIAL ASSESSMENT & STABILIZATION

ABC Protocol

• Airway: Secure if GCS ≤8 or bulbar dysfunction
• Breathing: Supplemental O₂ only if SpO₂ <94%
• Circulation: IV access, cardiac monitoring, ECG

Emergency Investigations

• Non-contrast CT head (within 25 minutes of arrival)
• CT angiography (CTA) and CT perfusion (CTP)
• Blood glucose, CBC, coagulation (PT/aPTT), electrolytes
• Troponin, ECG (for AF/MI)

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B. BLOOD PRESSURE MANAGEMENT

BLOOD PRESSURE IN ACUTE ISCHEMIC STROKE
        |
        v
Is patient a thrombolysis candidate?
    |                           |
   YES                         NO
    |                           |
Bring BP to                 Allow permissive
<185/110 before tPA         hypertension up to
(use labetalol or           220/120 mmHg
nicardipine)                (autoregulatory reserve)
    |
After tPA: maintain <180/105

• Avoid aggressive BP lowering (collateral flow dependent on MAP)
• Target <220/120 in non-thrombolysis candidates
• Target <185/110 BEFORE tPA; <180/105 AFTER tPA

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C. INTRAVENOUS THROMBOLYSIS (IVT) — THE CORNERSTONE

Alteplase (rt-PA)

• Dose: 0.9 mg/kg IV (max 90 mg), 10% as bolus, rest over 60 min
• Time window: ≤4.5 hours from symptom onset (NINDS, ECASS-III criteria)
• Mechanism: Converts plasminogen → plasmin → fibrin degradation

Tenecteplase (TNK-tPA) — NEWER ADVANCE

• Dose: 0.25 mg/kg IV (max 25 mg) as single bolus
• More fibrin-specific, longer half-life, easier to administer
• Non-inferior to alteplase in several trials (NOR-TEST, EXTEND-IA TNK)
• AHA/ASA 2019: TNK may be preferred for large vessel occlusion going for thrombectomy

Inclusion/Exclusion Criteria for IVT

WAKE-UP STROKE — MRI-GUIDED THROMBOLYSIS (Recent Advance)

• WAKE-UP Trial (2018): Alteplase beneficial in unknown onset stroke with MRI DWI-FLAIR mismatch
• DWI positive + FLAIR negative = onset likely <4.5 hours

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D. MECHANICAL THROMBECTOMY (MT) — REVOLUTION IN STROKE CARE

The "DAWN & DEFUSE-3 Era" — Extended Window

Eligibility for MT (2023 Guidelines)

• Large vessel occlusion (ICA, M1, M2, basilar)
• NIHSS ≥6
• ASPECTS ≥6 on CT (viable tissue)
• Premorbid mRS 0-2
• Time window: 0-24 hours with mismatch (DAWN/DEFUSE criteria)

FLOWCHART — Acute Ischemic Stroke Management

ACUTE STROKE ONSET
        |
        v
Emergency CT Head (< 25 min)
        |
   _____|_____
  |           |
BLEED      NO BLEED
  |           |
  v           v
See       Is LVO present? (CTA)
ICH Mgmt      |
         _____|_____
        |           |
       YES          NO
        |           |
        v           v
Is within     IV Alteplase/TNK
6-24 hr?      if ≤4.5 hrs
        |
   _____|_____
  |           |
 YES         NO
  |           |
 DAWN/    IV tPA
DEFUSE-3     only
 criteria
   met?
        |
        v
MECHANICAL THROMBECTOMY
(Stent retriever / aspiration catheter)
        |
        v
TICI 2b/3 reperfusion goal
        |
        v
Post-procedure: BP <180/105,
Antiplatelet 24 hrs later,
Neurological monitoring ICU

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E. NEWER IMAGING ADVANCES

CT Perfusion (CTP)

• Identifies penumbra vs infarct core
• Core: rCBF <30%, Tmax >6s = penumbra
• Software: RAPID (automated, FDA-approved)
• Used to select patients for extended window thrombectomy

MRI - DWI/FLAIR Mismatch

• DWI shows infarction within minutes
• FLAIR changes appear after ~4.5-6 hours
• DWI+/FLAIR- = acute stroke, likely within window

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F. ANTIPLATELET THERAPY

Dual Antiplatelet Therapy (DAPT) — Recent Evidence

• CHANCE Trial (China): Aspirin + Clopidogrel for 21 days for minor stroke/TIA (NIHSS ≤3, ABCD2 ≥4) - 32% RRR in 90-day stroke
• POINT Trial (USA): Confirmed benefit of DAPT for 21 days
• THALES Trial (2020): Aspirin + Ticagrelor (90 mg BD for 30 days) reduced 30-day stroke/death in minor ischemic stroke/TIA

Standard Antiplatelet

• Aspirin 325 mg stat within 24-48 hrs (if no tPA in last 24 hrs)
• Clopidogrel 75 mg OD as alternative

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G. NEUROPROTECTION & OTHER ADVANCES

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H. HEMORRHAGIC TRANSFORMATION & MONITORING

• Symptomatic ICH (sICH) occurs in ~6% after alteplase
• Risk factors: large infarct, hyperglycemia, high BP after tPA
• NIHSS monitoring every 15 min during infusion, hourly × 6 hrs

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I. SECONDARY PREVENTION (Recent Advances)

Atrial Fibrillation

• DOACs (rivaroxaban, apixaban, dabigatran) preferred over warfarin
• ESUS (Embolic Stroke of Undetermined Source): NAVIGATE ESUS, RESPECT ESUS trials - DOACs not superior for ESUS without AF

Carotid Artery Disease

• CEA (carotid endarterectomy) within 2 weeks for symptomatic >70% stenosis
• CAS (carotid artery stenting) for high surgical risk patients

PFO Closure

• PFO closure + antiplatelet > antiplatelet alone for cryptogenic stroke in young patients (CLOSE, REDUCE, RESPECT trials)

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J. STROKE UNIT CARE — PROVEN TO REDUCE MORTALITY

• Dedicated stroke unit reduces mortality by 18% and dependency by 20%
• Early mobilization (within 24-48 hrs if clinically stable)
• Dysphagia screening before oral intake
• DVT prophylaxis with LMWH + compression stockings

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QUESTION 2 (Short Answer - 6 Marks)

RECENT ADVANCES IN MANAGEMENT OF EPILEPSY

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DEFINITION

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ADVANCES IN CLASSIFICATION (ILAE 2017)

SEIZURE TYPE
    |
    |--- FOCAL (awareness preserved/impaired)
    |        |-- With motor (automatisms, tonic, clonic)
    |        |-- Without motor (sensory, autonomic)
    |        |-- Focal to bilateral tonic-clonic
    |
    |--- GENERALIZED
    |        |-- Motor (tonic-clonic, tonic, atonic, myoclonic)
    |        |-- Non-motor (absence, typical, atypical, myoclonic)
    |
    |--- UNKNOWN ONSET

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RECENT PHARMACOLOGICAL ADVANCES

1. Precision/Targeted Therapy

• Fenfluramine (2020): Approved for Dravet syndrome - reduces seizures by ~63%
• Cannabidiol (Epidiolex): FDA approved for Dravet, Lennox-Gastaut syndrome (2018)
• Vigabatrin: Infantile spasms (West syndrome)
• Everolimus: TSC-associated epilepsy (mTOR pathway inhibitor)

2. Status Epilepticus (SE) - Updated Protocol (Established SE)

0-5 min: Lorazepam 0.1 mg/kg IV (or midazolam IM)
5-20 min: Levetiracetam 60 mg/kg IV OR Valproate 40 mg/kg IV OR Fosphenytoin 20 mg PE/kg
20-40 min: If refractory → Lacosamide 200-400 mg IV
>40 min: RSE → Propofol, Midazolam, Ketamine infusion (ICU)

3. Biomarker-Guided Therapy

• Genetic testing: SCN1A (Dravet), KCNQ2, CDKL5 - guides medication choice
• Avoid sodium channel blockers (phenytoin, carbamazepine) in SCN1A mutations

4. Neuromodulation — Non-Pharmacological

5. Surgical Advances

• Stereo-EEG (SEEG) for precise seizure focus localization
• Laser interstitial thermal therapy (LITT) - minimally invasive
• MRI-guided focused ultrasound for hippocampal sclerosis

6. Diet Therapy

• Ketogenic diet: Proven for Dravet, Doose, GLUT-1 deficiency
• Modified Atkins diet: More tolerable alternative

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QUESTION 3 (Short Answer - 6 Marks)

NEWER ANTIEPILEPTIC DRUGS

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CLASSIFICATION OF AEDs BY GENERATION

1st Generation (Traditional)

2nd Generation

3rd Generation (Newest)

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NEWER AEDs — DETAILED TABLE

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KEY PHARMACOKINETIC FEATURES

DRUG INTERACTIONS:
- Enzyme INDUCERS: Phenytoin, Carbamazepine, Phenobarbitone
  → Reduce levels of: OCP, warfarin, immunosuppressants

- Enzyme INHIBITORS: Valproate
  → Increase: Lamotrigine (double LTG half-life)

- NEWER drugs (LEV, LAC, BRV): Minimal P450 interactions - SAFER in polypharmacy

MONITORING:
- Valproate: LFT, ammonia, CBC
- Phenytoin: levels (narrow therapeutic index)
- Carbamazepine: Na+, CBC (agranulocytosis)
- Lamotrigine: SJS risk, especially with VPA
- Lacosamide: PR interval (avoid in 2nd degree AV block)

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AED SELECTION GUIDE

FOCAL SEIZURES:
1st: Lamotrigine / Levetiracetam / Carbamazepine
Refractory: Add Lacosamide / Perampanel / Brivaracetam

GENERALIZED (TONIC-CLONIC):
1st: Valproate (males) / Lamotrigine (females of childbearing age)
2nd: Levetiracetam / Topiramate

ABSENCE:
Ethosuximide (first choice) / Valproate / Lamotrigine
Avoid: Carbamazepine, Phenytoin (worsen absence)

MYOCLONIC:
Valproate / Levetiracetam / Clonazepam
Avoid: Carbamazepine, Phenytoin, Oxcarbazepine

DRAVET SYNDROME:
Valproate + Clobazam → Add Cannabidiol / Fenfluramine
AVOID: Sodium channel blockers (SCN1A mutation)

LENNOX-GASTAUT SYNDROME:
Valproate + Rufinamide + Clobazam
Add: Cannabidiol / Lamotrigine / Topiramate

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QUESTION 4 (Long Answer - 20 Marks)

LABELLED DIAGRAM OF BRAINSTEM AND APPLIED ANATOMY OF BRAINSTEM SYNDROMES

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ANATOMY OF BRAINSTEM — OVERVIEW

1. Midbrain (mesencephalon)
2. Pons (metencephalon)
3. Medulla oblongata (myelencephalon)

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DIAGRAM 1: EXTERNAL FEATURES OF BRAINSTEM (Anterior View)

                    MIDBRAIN
          ___________________________
         |    Cerebral peduncles     |
         |  CN III exits here        |
         |  (interpeduncular fossa)  |
         |___________________________|
                     |
                    PONS
          ___________________________
         |  Basilar sulcus (groove)  |
         |  CN V (lateral pons)      |
         |  CN VI (pontomedullary)   |
         |  CN VII, VIII (CPA angle) |
         |___________________________|
                     |
                  MEDULLA
          ___________________________
         | Pyramids (anterior)       |
         | Olives (lateral)          |
         | CN IX, X, XI, XII         |
         | Pyramidal decussation     |
         |___________________________|
                     |
                 SPINAL CORD

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DIAGRAM 2: CROSS-SECTION OF MIDBRAIN (At level of Superior Colliculus)

           DORSAL (TECTUM)
    ___________________________________
   |    Superior Colliculus (roof)     |
   |  Cerebral Aqueduct (center)       |
   |    PAG (periaqueductal grey)      |
   |  CN III nucleus (medial)          |
   |  MLF (medial longitudinal fascic) |
   |    Red nucleus (tegmentum)        |
   |  Corticospinal tract              |
   |  CN III nerve exits               |
   |___________________________________|
           VENTRAL (BASIS PEDUNCULI)

Structures:
- Tectum: Superior & inferior colliculi
- Tegmentum: CN III, IV nuclei, red nucleus, PAG, MLF, decussation of rubrospinal
- Basis pedunculi: Corticospinal, corticobulbar, corticopontine tracts

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DIAGRAM 3: CROSS-SECTION OF PONS (Mid-Pons)

          DORSAL
    ________________________________
   | 4th Ventricle (floor)          |
   | CN VI nucleus (floor of 4th V) |
   | PPRF (horizontal gaze center)  |
   | CN VII nucleus (loops CN VI)   |
   | MLF                            |
   | Medial lemniscus (VC touch)    |
   | Spinothalamic tract (pain/temp) |
   | CN V nucleus & tract           |
   | Lateral: AICA territory        |
   | Corticospinal (pontine basis)  |
   |________________________________|
          VENTRAL

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DIAGRAM 4: CROSS-SECTION OF MEDULLA (At level of Olives)

          DORSAL
    ________________________________
   | 4th Ventricle / Central canal  |
   | CN XII nucleus (medial)        |
   | CN X dorsal motor nucleus      |
   | Nucleus tractus solitarius     |
   | MLF                            |
   | Medial lemniscus               |
   | Nucleus Ambiguus (CN IX,X,XI)  |
   | PICA territory (lateral)       |
   | Spinothalamic tract            |
   | Inferior olivary nucleus       |
   | Pyramids (corticospinal)       |
   |________________________________|
          VENTRAL

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APPLIED ANATOMY: BRAINSTEM SYNDROMES

MIDBRAIN SYNDROMES

1. Weber's Syndrome (Medial Midbrain - Cerebral Peduncle)

• Lesion: Infarction of anteromedial midbrain (PCA territory)
• CN III palsy (ipsilateral): Complete ptosis, mydriasis, "down and out" eye
• Contralateral hemiplegia: Corticospinal tract below decussation
• Mnemonic: Weber = White matter (cerebral peduncle) + III

WEBER'S SYNDROME:
Site: Anteromedial midbrain
┌─────────────────────┐
│ Ipsilateral:        │
│  - CN III palsy     │
│  - Complete ptosis  │
│  - Dilated pupil    │
│  - "Down & Out" gaze│
│ Contralateral:      │
│  - Hemiplegia       │
│  - UMN type         │
└─────────────────────┘
Cause: PCA branch occlusion

2. Benedikt's Syndrome (Tegmentum of Midbrain)

• Lesion: Posterior to CN III, involving red nucleus
• CN III palsy (ipsilateral)
• Contralateral tremor, ataxia (red nucleus/rubrospinal tract)
• Contralateral hemianesthesia (medial lemniscus)

3. Parinaud's Syndrome (Dorsal Midbrain / Tectum)

• Lesion: Dorsal midbrain (pinealoma, hydrocephalus, MS)
• Upgaze palsy (paralysis of upward gaze)
• Convergence-retraction nystagmus on attempted upgaze
• Light-near dissociation (Argyll Robertson-like pupils)
• Collier's sign: Lid retraction (sunset sign in children)

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PONTINE SYNDROMES

4. Millard-Gubler Syndrome (Ventral Pons)

• Lesion: Ventral pons (basilar artery branch)
• Ipsilateral CN VI palsy (lateral rectus - convergent squint)
• Ipsilateral CN VII palsy (peripheral type - all facial muscles)
• Contralateral hemiplegia (corticospinal)

MILLARD-GUBLER:
Ipsilateral:
  - CN VI palsy (esotropia)
  - CN VII palsy (ALL facial muscles)
Contralateral:
  - Hemiplegia/hemiparesis
Cause: Ventral pontine infarct

5. Foville's Syndrome (Dorsal Pons)

• Ipsilateral conjugate gaze palsy (PPRF + CN VI nucleus)
• Ipsilateral CN VII palsy
• Contralateral hemiplegia
• • Ipsilateral Horner's syndrome (descending sympathetic)

6. Raymond's Syndrome

• Ipsilateral CN VI palsy + Contralateral hemiplegia (no VII palsy)
• More medial lesion than Millard-Gubler

7. One-and-a-Half Syndrome (Fisher)

• MLF (internuclear ophthalmoplegia) + ipsilateral CN VI/PPRF lesion
• Ipsilateral eye: Cannot adduct OR abduct
• Contralateral eye: Can only abduct with nystagmus
• Only one movement remains: contralateral eye abduction

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MEDULLARY SYNDROMES

8. Lateral Medullary Syndrome — Wallenberg's Syndrome (MOST IMPORTANT)

• Lesion: PICA (posterior inferior cerebellar artery) or vertebral artery occlusion
• Involves lateral medullary tegmentum

WALLENBERG'S SYNDROME — Memory Aid: "PICA"
P - Pain & temperature loss: Ipsilateral face (CN V tract)
                             Contralateral body (STT)
I - Ipsilateral Horner's syndrome (descending sympathetics)
C - Cerebellar signs: Ipsilateral ataxia, dysmetria (ICP + restiform body)
A - Autonomic/Dysphagia: Nausea, vomiting, hiccups, dysphagia (CN IX, X)

Additional:
  - Ipsilateral palatal weakness (CN IX, X - nucleus ambiguus)
  - Ipsilateral vocal cord paralysis (hoarseness)
  - Ipsilateral reduced corneal reflex (CN V spinal nucleus)
  - Vertigo, nystagmus (vestibular nuclei)

KEY: NO motor hemiplegia (pyramids spared - medial structure)
KEY: Dissociated sensory loss (pain/temp crossed, proprioception spared)

9. Medial Medullary Syndrome (Déjerine's Syndrome)

• Lesion: Anterior spinal artery occlusion (medial medulla)
• Ipsilateral CN XII palsy (tongue deviates to side of lesion)
• Contralateral hemiplegia (pyramidal tract)
• Contralateral loss of touch, vibration, proprioception (medial lemniscus)
• Pain/temperature sensation SPARED (STT is lateral - not affected)

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SUMMARY TABLE OF BRAINSTEM SYNDROMES

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QUESTION 5 (Short Answer - 6 Marks)

FORMATION AND CIRCULATION OF CSF AND CLINICAL APPLICATIONS

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FORMATION OF CSF

Site of Production

• Primary site: Choroid plexus (lateral, 3rd, and 4th ventricles)
• Minor contribution: Ependymal cells, brain parenchyma

Volume & Rate

• Total CSF volume: 150 mL (50 mL spinal, 100 mL intracranial)
• Rate of formation: 500 mL/day (20 mL/hour)
• Complete turnover: ~3-4 times/day

Mechanism of Formation

CEREBRAL CAPILLARY BLOOD
        |
        | Pressure-dependent ultrafiltration
        v
INTERSTITIAL FLUID (bathing brain cells)
        |
        | Active transport through choroid plexus epithelium
        v
CSF IN VENTRICLES
        |
   Active secretion:
   Na+ (Na-K ATPase), Cl-, HCO3-, H2O
   Excluded: Protein, cholesterol (large molecules)

Composition of Normal CSF

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CIRCULATION OF CSF

CHOROID PLEXUS
(Lateral ventricles)
        |
        v [via Foramen of Monro]
3rd VENTRICLE
        |
        v [via Cerebral Aqueduct of Sylvius]
4th VENTRICLE
        |
        |---→ [Foramen of Luschka - lateral] → Lateral cisterns
        |
        v [Foramen of Magendie - median]
CISTERNA MAGNA
        |
        v
SUBARACHNOID SPACE
(over brain and spinal cord)
        |
        v [Arachnoid granulations / Pacchionian bodies]
SUPERIOR SAGITTAL SINUS
        |
        v
VENOUS BLOOD (CIRCULATION)

Additional CSF Drainage Pathways (Recent discoveries)

• Glymphatic system (Nedergaard, 2013): Paravascular drainage along arterial walls; most active during sleep
• Lymphatic drainage: Via cribriform plate to nasal lymphatics; also cranial nerve sheaths
• Arachnoid villi: Pressure-dependent, one-way valves

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CLINICAL APPLICATIONS OF CSF

1. Lumbar Puncture (LP) - Indications

• Meningitis/encephalitis (CSF culture, cell count)
• Subarachnoid hemorrhage (xanthochromia when CT negative)
• Intracranial pressure measurement
• MS (oligoclonal bands, IgG index)
• GBS (albuminocytologic dissociation)
• Neurosyphilis, neuroborreliosis

2. CSF Analysis in Disease — Diagnostic Patterns

3. Hydrocephalus — Clinical Application

TYPES:
Non-communicating (Obstructive): Blockage within ventricular system
  - Aqueductal stenosis, colloid cyst
  → Treatment: VP shunt or ETV (endoscopic third ventriculostomy)

Communicating: Block at arachnoid granulations
  - Post-meningitic, post-SAH
  → Treatment: LP, acetazolamide, VP shunt

Normal Pressure Hydrocephalus (NPH):
  - Classic triad: Dementia + Gait ataxia + Urinary incontinence
  - Large ventricles with normal opening pressure on LP
  - Treatment: VP shunt (dramatic improvement in gait)

4. Intracranial Hypertension

• Idiopathic intracranial hypertension (pseudotumor cerebri): LP opening pressure >25 cm H₂O, normal CSF
• Treatment: Weight loss, acetazolamide, serial LP, optic nerve sheath fenestration if vision threatened

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QUESTION 6 (Long Answer - 20 Marks)

APPROACH TO ACUTE FLACCID QUADRIPARESIS + MANAGEMENT OF GBS

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PART A: APPROACH TO ACUTE FLACCID QUADRIPARESIS

Definition

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ANATOMICAL LOCALIZATION — KEY STEP

ACUTE FLACCID QUADRIPARESIS
            |
    _________|_________
    |                  |
 Is there:        Upper motor features?
 - Hyperreflexia?      → UMN (spinal cord)
 - Plantar extensor?   → NOT true flaccid
    |
 Hypotonia + Areflexia = LMN lesion
    |
    |--→ Anterior horn cell (AHC)
    |--→ Nerve root / Plexus
    |--→ Peripheral nerve (Neuropathy)
    |--→ Neuromuscular junction (NMJ)
    |--→ Muscle (Myopathy)

DIFFERENTIAL DIAGNOSIS BY SITE

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HISTORY — KEY POINTS

HISTORY CHECKLIST:
□ Onset: Hours vs Days (GBS over days; periodic paralysis hours)
□ Progression: Ascending (GBS) vs Descending (botulism)
□ Preceding illness: URTI/diarrhea 2-4 weeks before (GBS - C. jejuni, CMV)
□ Sensory symptoms: Tingling, numbness (neuropathy) vs no sensory (NMJ, muscle)
□ Autonomic: BP fluctuations, constipation, urinary retention (GBS)
□ Bulbar: Diplopia, dysarthria, dysphagia (MG, botulism, GBS)
□ Respiratory: Dyspnea (vital capacity assessment critical)
□ Drug history: Aminoglycosides, organophosphates, neuromuscular blockers
□ Diet: Canned food (botulism), alcohol (neuropathy)
□ Family history: Periodic paralysis, myopathy

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EXAMINATION — NEUROLOGICAL LOCALIZATION

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INVESTIGATIONS — STRUCTURED APPROACH

Bedside

• SpO₂ monitoring, spirometry (FVC - respiratory compromise)
• FVC < 20 mL/kg = consider intubation
• Negative inspiratory force (NIF) < -25 cmH₂O = intubation

Bloods

• CBC, electrolytes (K+ for periodic paralysis), Ca²⁺, Mg²⁺
• CK (markedly elevated in myositis, rhabdomyolysis)
• Thyroid function (thyrotoxic periodic paralysis)
• LDH, aldolase
• Serology: Anti-GQ1b (MFS/GBS), Anti-AchR (MG), Anti-MuSK (MG)
• Blood cultures, CSF if infection suspected

CSF Analysis

• GBS: High protein, normal cells (albuminocytologic dissociation)
• Viral myelitis: Lymphocytic pleocytosis

Nerve Conduction Studies (NCS) + EMG

• Demyelinating: Slow conduction velocity, prolonged F-waves, conduction block (GBS-AIDP)
• Axonal: Reduced amplitude, normal velocity (AMAN, AMSAN subtypes of GBS)
• NMJ: Repetitive nerve stimulation - decremental response (MG), incremental (Lambert-Eaton, botulism)
• Myopathy: Short-duration, low-amplitude polyphasic potentials; early recruitment

Imaging

• MRI spine with contrast: Transverse myelitis, cord compression
• MRI brain: Encephalitis, brainstem involvement
• CT chest: Thymoma (MG)

Neuroimaging Flowchart

Suspected spinal cord lesion?
→ MRI SPINE STAT (rule out compressive myelopathy)

Ascending flaccid paralysis + areflexia?
→ LP (GBS pattern) + NCS/EMG

Fatigable weakness + ptosis?
→ Tensilon test, Anti-AchR antibodies, NCS (decremental)

Preserved reflexes + proximal weakness?
→ CK, EMG, muscle biopsy

Low potassium + episodic paralysis?
→ Potassium replacement (may be diagnostic and therapeutic)

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PART B: MANAGEMENT OF GBS (AIDP)

Definition & Pathophysiology

• Campylobacter jejuni (most common - AMAN subtype), CMV, EBV, Mycoplasma, COVID-19, influenza vaccine (rare)

Subtypes of GBS

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DIAGNOSTIC CRITERIA (Brighton Collaboration)

1. Bilateral limb weakness
2. Decreased or absent deep tendon reflexes in weak limbs
3. Monophasic course, nadir 12 hrs - 28 days, then plateau
4. CSF: Cytoalbuminous dissociation (protein ↑, cells <10)
5. NCS: Features of polyneuropathy

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MANAGEMENT FLOWCHART

CONFIRMED GBS
      |
      v
EMERGENCY ASSESSMENT
  - Respiratory: FVC, NIF, SpO₂
  - Cardiac: ECG, BP monitoring
  - Bulbar: Swallowing assessment
      |
      v
ADMISSION ICU/HDU
      |
      |
  FVC < 20 mL/kg  OR  NIF < -25 cmH₂O
  OR SpO₂ falling, dysphagia, rapid progression?
      |                               |
     YES                             NO
      |                               |
  Elective INTUBATION              HDU monitoring
  (before crisis!)                 (4-6 hourly FVC)
      |
      v
SPECIFIC TREATMENT
(Equally effective, do NOT combine)
      |
      |--- IVIg: 0.4 g/kg/day × 5 days
      |          OR 1 g/kg/day × 2 days
      |
      |--- Plasmapheresis: 4-5 exchanges (40-50 mL/kg)
                           over 2 weeks
                           (best if started within 14 days)

(STEROIDS = NOT beneficial; may be HARMFUL in GBS)
      |
      v
SUPPORTIVE CARE
  - DVT prophylaxis: LMWH + compression stockings
  - Autonomic monitoring: BP lability (may need dopamine/atropine)
  - Pain management: Gabapentin, pregabalin, opioids (severe pain in 50%)
  - Nutrition: NG tube if dysphagia; high calorie
  - Bowel/bladder care (constipation, urinary retention)
  - Pressure ulcer prevention
  - Psychological support
  - Chest PT, suctioning
      |
      v
REHABILITATION
  - Early physiotherapy
  - Ankle-foot orthoses (foot drop)
  - OT, speech therapy
  - Target: Ambulation, ADLs

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MONITORING PARAMETERS IN GBS

"20-30-40 Rule" for Intubation in GBS

• FVC < 20 mL/kg
• NIF < -30 cmH₂O
• MIP < -40 cmH₂O

---

PROGNOSIS

• 85% recover to ambulate independently within 6 months
• 3-5% mortality (respiratory failure, autonomic dysfunction, PE)
• 10-20% have persistent disability
• Poor prognosis: Older age, rapid onset (<7 days to nadir), axonal variant, preceding C. jejuni, requiring ventilation

---

---

QUESTION 7 (Short Answer - 6 Marks)

MYASTHENIA GRAVIS

---

DEFINITION

---

PATHOPHYSIOLOGY

NORMAL NMJ:
Motor nerve terminal → ACh release → binds AChR → End-plate potential → Muscle contraction

MYASTHENIA GRAVIS:
Autoantibodies (IgG) → Attack postsynaptic AChR
        |
        v
Complement-mediated destruction of AChR
+ Blockade of ACh binding sites
+ Simplification of postsynaptic folds
        |
        v
Reduced AChR → Reduced end-plate potential
        |
        v
FATIGABLE WEAKNESS (worsens with use, improves with rest)

ANTIBODIES (% of patients):
- Anti-AChR: 85% of generalized MG
- Anti-MuSK: 5-8% (seronegative AChR; bulbar, respiratory)
- Anti-LRP4: 1-5%
- Seronegative: ~10%

---

CLINICAL FEATURES

Pattern of Weakness

• Ocular (first symptom in 50%): Ptosis, diplopia (asymmetric)
• Bulbar: Dysarthria (nasal voice), dysphagia, chewing fatigue
• Limb: Proximal > distal; arms > legs
• Respiratory: Life-threatening (myasthenic crisis)
• Key: Worsens with sustained effort; improves with rest/sleep
• Pupil: NORMAL (distinguishes from CN III palsy of Weber's syndrome)

Clinical Classification (Osserman / MGFA)

---

DIAGNOSIS

1. Bedside Tests

• Ice pack test: Apply ice to closed eyelid for 2 min; ptosis improves = POSITIVE (93% sensitivity for ocular MG)
• Edrophonium (Tensilon) test: IV edrophonium 2 mg → 8 mg; ptosis improves within 30 sec (have atropine ready for bradycardia)
• Sleep test: Ptosis improves after 30 min of sleep

2. Serology

• Anti-AchR antibodies (85% sensitivity for generalized MG)
• Anti-MuSK antibodies (in AChR-negative cases)
• Anti-striated muscle antibodies (suggests thymoma)

3. Electrodiagnostic Studies

• Repetitive nerve stimulation (3 Hz): >10% decremental response = positive
• Single fiber EMG (SFEMG): Increased "jitter" - most sensitive test (95%+)

4. Imaging

• CT chest: Thymoma in 10-15% of MG patients (must screen all MG patients)

5. Additional

• Thyroid function (associated autoimmune diseases)
• ANA, RF (associated autoimmune disorders)

---

TREATMENT

Symptomatic Treatment

• Dose: 30-60 mg every 4-6 hrs (max 600 mg/day)
• Mechanism: Inhibits acetylcholinesterase → more ACh available
• SE: Muscarinic effects (diarrhea, bradycardia, salivation, sweating) - treat with glycopyrrolate

Immunosuppression (Disease-modifying)

Rapid Immunotherapy (for Crisis)

• IVIg: 1-2 g/kg over 2-5 days
• Plasmapheresis: 5 exchanges over 10 days (faster onset)

Newer/Biological Therapies (Recent Advances)

Thymectomy

• Indication: All MG patients with thymoma (mandatory)
• Generalized AChR+ MG patients aged 18-65 years (MGTX trial: thymectomy + prednisone > prednisone alone; NNT=5 for sustained remission)
• Extended transsternal thymectomy preferred
• Robotic/VATS thymectomy increasingly used

---

MYASTHENIC CRISIS

Precipitating Factors ("AMPS")

• A: Aspiration/infection, Antibiotics (aminoglycosides, fluoroquinolones)
• M: Medications (beta-blockers, magnesium, muscle relaxants, phenytoin)
• P: Physiological stress (surgery, pregnancy)
• S: Stopping medications, Sleep deprivation

Management of Myasthenic Crisis

MYASTHENIC CRISIS
        |
        v
1. AIRWAY: Intubate early (don't wait for complete failure)
   FVC < 20 mL/kg OR NIF < -25 cmH₂O → Intubate
        |
        v
2. HOLD PYRIDOSTIGMINE (may worsen secretions when intubated)
        |
        v
3. SPECIFIC TREATMENT (choose one):
   - Plasmapheresis: 5 exchanges (faster, preferred)
     OR
   - IVIg: 1-2 g/kg over 2-5 days
        |
        v
4. Identify and treat PRECIPITANT
        |
        v
5. Resume PYRIDOSTIGMINE after extubation
6. Optimize IMMUNOSUPPRESSION

Cholinergic Crisis vs Myasthenic Crisis

---

DIFFERENTIAL DIAGNOSIS OF MG

• Lambert-Eaton Myasthenic Syndrome (LEMS): Proximal limb > ocular; INCREMENTAL on RNS; paraneoplastic (SCLC); Anti-VGCC antibodies
• Botulism: Descending paralysis, fixed dilated pupils, autonomic dysfunction, food exposure
• Congenital myasthenic syndromes: No antibodies, childhood onset, genetic
• Graves' ophthalmopathy: Proptosis, lid lag, painful eye movements

---

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Exam Tip for MD Medicine: For 20-mark questions, structure as: Definition → Classification → Pathophysiology (with diagram) → Clinical features → Investigations → Management (with flowchart) → Prognosis. For 6-mark questions: Definition → Key pathophysiology → Diagnostic criteria/types → Management highlights → One table or flowchart. Always include at least ONE diagram/flowchart per answer - examiners specifically reward visual organization.

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MD MEDICINE EXAMINATION NOTES — NEUROLOGY & PSYCHIATRY (PART 2)

References: Harrison's Principles of Internal Medicine 22E, Bradley & Daroff's Neurology, Adams & Victor's Neurology 12E, Goldman-Cecil Medicine, Robbins Pathology, Kaplan & Sadock's Psychiatry

---

---

QUESTION 8 (Short Answer - 6 Marks)

CHRONIC FATIGUE SYNDROME (CFS / ME-CFS)

---

DEFINITION

• Not explained by another medical condition
• Not relieved by rest
• Worsened by physical or mental exertion (Post-Exertional Malaise - PEM)

---

DIAGNOSTIC CRITERIA (Institute of Medicine, 2015 — "SEID")

1. Substantial reduction in function (>6 months) with post-exertional malaise
2. Unrefreshing sleep
3. Cognitive impairment OR Orthostatic intolerance

---

PATHOPHYSIOLOGY (Current Understanding)

TRIGGER (Viral infection, physical/emotional stress)
        |
        v
IMMUNE DYSREGULATION
  - Elevated pro-inflammatory cytokines (IL-1β, IL-6, TNF-α)
  - NK cell dysfunction
  - T-cell activation abnormalities
        |
        v
NEUROENDOCRINE AXIS ABNORMALITIES
  - HPA axis hypoactivity (low cortisol)
  - Hypothalamic dysfunction
        |
        v
AUTONOMIC NERVOUS SYSTEM DYSFUNCTION
  - Orthostatic hypotension / POTS
  - Small fiber neuropathy
        |
        v
MITOCHONDRIAL/ENERGY DYSFUNCTION
  - Ion channel dysfunction (Na+/K+ ATPase)
  - Impaired oxidative phosphorylation
        |
        v
SYMPTOMS: Fatigue, pain, cognitive fog, PEM

---

CLINICAL FEATURES

---

INVESTIGATIONS (to exclude other causes)

MANDATORY:
- CBC, ESR, CRP (infection, inflammation)
- TFT (hypothyroidism - most common mimic)
- Blood glucose, HbA1c (diabetes)
- Liver function tests, renal function
- Serum calcium, phosphate
- Urinalysis
- Sleep study (if sleep apnea suspected)

SELECTED:
- ANA, anti-dsDNA (connective tissue disease)
- Viral serology: EBV, CMV, Parvovirus B19
- Ferritin, B12, folate (deficiency states)
- Cortisol, ACTH stimulation test (adrenal insufficiency)
- Tilt-table test (autonomic dysfunction/POTS)
- Neuropsychological testing

Diagnosis is CLINICAL - no definitive biomarker

---

MANAGEMENT

Non-Pharmacological (First Line)

1. Pacing / Energy management: Activity within "energy envelope" — avoid boom-bust cycles
2. Graded Exercise Therapy (GET): Controversial; NOT recommended for PEM-predominant ME/CFS (NICE 2021 guidelines reversed earlier recommendation)
3. Cognitive Behavioral Therapy (CBT): Helpful for coping, depression; NOT curative
4. Sleep hygiene: Regular schedule, no caffeine; treat sleep disorders
5. Orthostatic intolerance: Increased fluid/salt, compression stockings, tilt training

Pharmacological (Symptomatic)

Emerging Therapies

• Rintatolimod (Ampligen): Immunomodulator; limited FDA approval
• Low-dose naltrexone: Microglial modulation; promising trials
• Rituximab: RCT showed NO benefit (2019 Norway trial)
• BC007: Anti-autoantibody therapy (under investigation)

---

---

QUESTION 9 (Long Answer - 20 Marks)

SEIZURE DISORDERS — PATHOPHYSIOLOGY, CLASSIFICATION, CLINICAL FEATURES, INVESTIGATIONS, MANAGEMENT

---

DEFINITION

---

EPIDEMIOLOGY

• Prevalence: ~50 million worldwide; ~1% of population
• Lifetime risk of single seizure: ~10%
• Incidence peaks: <1 year and >60 years (bimodal)

---

PATHOPHYSIOLOGY

Cellular Mechanisms of Seizure Generation

NORMAL NEURON:
Balanced excitation (Glutamate/NMDA/AMPA) 
    vs 
Inhibition (GABA/GABA-A/Cl-)
        |
        v
SEIZURE INITIATION requires:
1. Excessive neuronal excitability (↑ Na+, Ca2+ influx)
2. Failure of inhibitory mechanisms (↓ GABAergic)
3. Synchronization of neuronal firing
4. Spread of abnormal activity

Paroxysmal Depolarization Shift (PDS)

• Key cellular event in focal seizure initiation
• Prolonged depolarization with burst firing of action potentials
• Sustained by: NMDA receptor activation, Ca2+ influx, reduced K+ conductance

SEIZURE PATHOPHYSIOLOGY MAP:

ION CHANNEL DYSFUNCTION
(Na+, K+, Ca2+, Cl- channels)
        |
        v
↑ GLUTAMATE (excitatory) OR ↓ GABA (inhibitory)
        |
        v
PAROXYSMAL DEPOLARIZATION SHIFT
        |
        |--→ Focal seizure (localized PDS)
        |
        |--→ Recruitment of surrounding neurons
        |
        v
SPREAD via:
  - Cortico-cortical connections
  - Thalamo-cortical loops (generalization)
        |
        v
GENERALIZED SEIZURE (bilateral cerebral involvement)
        |
        v
POSTICTAL STATE: Depression of neuronal activity
  (Todd's paralysis, confusion, headache)

Why Does a Seizure Stop?

• Sodium pump (Na+/K+ ATPase) fatigue
• Endogenous adenosine release (inhibitory)
• GABA-B receptor activation (late inhibition)
• Hyperpolarization after burst firing
• Metabolic failure (glucose, oxygen depletion in seizure focus)

---

CLASSIFICATION (ILAE 2017)

Level 1: Onset Type

SEIZURE ONSET
      |
   ___|___________
   |              |              |
FOCAL         GENERALIZED    UNKNOWN ONSET
(one hemisphere) (both hemispheres)
   |              |
Aware/          Motor:
Impaired         - Tonic-clonic
awareness        - Tonic
                 - Clonic
Focal onset →   - Myoclonic
Motor or non-   - Atonic
motor           - Myoclonic-tonic-clonic
                Non-motor:
                - Absence (typical/atypical)
                - Myoclonic absence
                - Eyelid myoclonia

FOCAL SEIZURE SUBTYPES

GENERALIZED SEIZURE SUBTYPES

Level 2: Epilepsy Type

• Focal epilepsy
• Generalized epilepsy
• Combined generalized and focal epilepsy
• Unknown epilepsy type

Level 3: Epilepsy Syndrome

---

CLINICAL FEATURES

Phases of a GTCS (Grand Mal Seizure)

PRODROME (hours-days before):
  Irritability, mood change, headache (30% of patients)
        |
        v
AURA (seconds, if focal onset):
  Olfactory (uncinate - TL), Gustatory, Visual (occipital),
  Rising epigastric sensation (temporal), Déjà vu
        |
        v
TONIC PHASE (10-30 seconds):
  Generalized muscle stiffening
  Cry/grunt (forced expiration through closed glottis)
  Cyanosis, apnea
  Jaw clenching (may bite tongue)
        |
        v
CLONIC PHASE (1-3 minutes):
  Rhythmic jerking → gradually slowing
  Bowel/bladder incontinence
  Diaphoresis
        |
        v
POSTICTAL PHASE (minutes to hours):
  Deep sleep/unconsciousness
  Confusion, disorientation
  Headache, myalgia
  Todd's paralysis (focal weakness, minutes to hours)
  Amnesia for event

Specific Syndrome Features

• Most common focal epilepsy
• Aura: Rising epigastric sensation, déjà vu, fear, olfactory
• Automatisms: Lip smacking, chewing, hand fumbling, picking
• Post-ictal confusion/aphasia (dominant TL)
• Associated with hippocampal sclerosis (80%)

• Onset 12-18 years
• Morning myoclonic jerks (especially on awakening)
• GTCS (triggered by sleep deprivation, alcohol, stress)
• Absence in 30%
• Lifelong condition; responds well to valproate

---

STATUS EPILEPTICUS

STATUS EPILEPTICUS MANAGEMENT PROTOCOL:

TIME 0-5 min:
  ABCDE, IV access, oxygen
  Glucose check → treat hypoglycemia (50 mL 50% dextrose + thiamine 100 mg IV)
  Send: CBC, electrolytes, AED levels, toxicology

TIME 0-5 min (1st line BENZODIAZEPINE):
  - Lorazepam 0.1 mg/kg IV (max 4 mg) - PREFERRED
  - OR Diazepam 0.2 mg/kg IV (max 10 mg)
  - OR Midazolam 10 mg IM (if no IV access) - FIRST CHOICE prehospital

TIME 5-20 min (2nd line if still seizing - CHOOSE ONE):
  - Levetiracetam 60 mg/kg IV (max 4500 mg) over 10 min
  - OR Valproate 40 mg/kg IV (max 3000 mg) over 10 min
  - OR Fosphenytoin 20 PE/kg IV at 150 PE/min

TIME 20-40 min (3rd line - REFRACTORY SE):
  - Lacosamide 200-400 mg IV over 15 min
  - OR repeat 2nd line agent

TIME >40 min (SUPER-REFRACTORY SE):
  - ICU intubation + EEG monitoring
  - Propofol infusion (1-2 mg/kg bolus then 2-10 mg/kg/hr)
  - OR Midazolam infusion (0.2 mg/kg bolus then 0.1-2 mg/kg/hr)
  - OR Pentobarbital (burst suppression target on EEG)
  - Ketamine as adjunct (NMDA receptor blockade)

---

INVESTIGATIONS

EEG — The Key Investigation

Neuroimaging

WHEN TO IMAGE:
All new-onset seizures → MRI brain preferred
CT: Acute setting (emergency), metallic implant, unavailability of MRI

MRI PROTOCOL FOR EPILEPSY:
- 3 Tesla if available
- Coronal FLAIR (hippocampal sclerosis)
- Coronal T2 (mesial temporal)
- Axial T2/FLAIR (cortical dysplasia, tumor)
- DWI (acute)
- Gadolinium for suspected encephalitis, tumor

Common MRI Findings:
- Hippocampal sclerosis (most common - TLE)
- Cortical dysplasia (FCD Type I, II)
- Tuberous sclerosis (tubers, sub-ependymal nodules)
- Cavernous malformation
- Low-grade glioma
- Encephalitis (limbic - NMDAR, LGI1)

Other Investigations

• Blood: CBC, electrolytes (Na+, Ca2+, Mg2+), glucose, BUN/Cr, LFT, TFT
• AED levels: Phenytoin, valproate, carbamazepine (therapeutic drug monitoring)
• Lumbar puncture: If encephalitis/meningitis suspected
• ECG: To rule out Stokes-Adams (cardiac syncope mimicking seizure)
• Autoimmune antibody panel: Anti-NMDAR, LGI1, CASPR2, GABA-B (if autoimmune encephalitis)
• Genetic testing: Dravet (SCN1A), KCNQ2, CDKL5, PRRT2 (for appropriate syndromes)

---

MANAGEMENT

Treatment Decision

FIRST UNPROVOKED SEIZURE:
  |
  v
Recurrence risk assessment:
  - EEG abnormality → ↑ risk
  - Structural lesion on MRI → ↑ risk
  - Abnormal neurological exam → ↑ risk
  - Family history → ↑ risk
  |
  v
High risk (>60%): START AED
Low risk (<30%): Observe + counseling
  |
  v
SECOND UNPROVOKED SEIZURE:
START AED (diagnosis of epilepsy established)

AED Selection (2024 Guidelines)

Monitoring on AEDs

• Valproate: LFT, ammonia, CBC (thrombocytopenia), weight
• Phenytoin: Levels (narrow TI), gums, CBC, folate
• Carbamazepine: Na+ (SIADH), CBC (agranulocytosis - rare), rash (HLA-B*1502 - Asians)
• Lamotrigine: Rash (SJS) - slow titration, especially with VPA
• Levetiracetam: Mood/behavioural (depression, irritability) — add B6

When to Consider Epilepsy Surgery

• Drug-resistant epilepsy (failed ≥2 appropriate AEDs)
• Identifiable surgical lesion (hippocampal sclerosis, cortical dysplasia, tumor)
• Seizure-free rate: 60-80% after temporal lobectomy for TLE

Lifestyle & Special Situations

• Driving: Seizure-free for 1 year (India: 2 years) before driving
• Pregnancy: Folic acid 5 mg/day pre-conceptually; VPA contraindicated; lowest effective dose of AED; vitamin K for neonate
• Contraception: Enzyme-inducing AEDs reduce OCP efficacy → use higher dose OCP or alternative
• Women: LTG levels fall in pregnancy (requires dose increase); VPA - neural tube defects, cognitive effects on child

---

---

QUESTION 10 (Long Answer - 20 Marks)

INFLAMMATORY MYOPATHIES — TYPES, DIAGNOSTIC APPROACH, DIFFERENTIAL DIAGNOSIS, TREATMENT

---

DEFINITION

---

CLASSIFICATION (Bohan & Peter, Modified by Lundberg 2021)

INFLAMMATORY MYOPATHIES
        |
   _____|_____________________________
   |           |           |         |
DERMATO-   IMMUNE-     ANTI-     INCLUSION
MYOSITIS   MEDIATED    SYNTHETASE  BODY
(DM)       NECROTIZING  SYNDROME  MYOSITIS
           MYOPATHY    (ASS)      (IBM)
           (IMNM)

1. Dermatomyositis (DM)

• Most common IIM
• Age: Bimodal - children and adults (40-60 yrs)
• Pathology: Perifascicular atrophy, complement (MAC) deposition in capillaries, B-cell/CD4+ T-cell predominant inflammation
• Key: Skin + muscle inflammation (sometimes amyopathic DM - skin only)

2. Polymyositis (PM)

• IMPORTANT UPDATE: Classic PM is now largely reclassified as:
  • Immune-mediated necrotizing myopathy (IMNM)
  • Antisynthetase syndrome
  • Overlap myositis (Robbins Pathology 10E)
• True PM (endomysial CD8+ T-cell infiltration) is rare

3. Immune-Mediated Necrotizing Myopathy (IMNM)

• Associated with: Anti-SRP or Anti-HMGCR antibodies
• Statin-induced (anti-HMGCR) — continues after statin cessation
• Pathology: Muscle fiber necrosis with MINIMAL inflammation
• Severe weakness, very high CK (>10,000)

4. Antisynthetase Syndrome (ASS)

• Classic triad: Myositis + Interstitial lung disease (ILD) + Arthritis
• Plus: Mechanic's hands, Raynaud's, fever
• Antibodies: Anti-Jo-1 (most common), anti-PL-7, anti-PL-12, anti-EJ, anti-OJ
• ILD is major cause of morbidity/mortality

5. Inclusion Body Myositis (IBM)

• Most common IIM in patients >50 years
• Men > Women (2:1)
• Distinctive feature: Distal + proximal weakness; early finger flexor and quadriceps involvement
• Pathology: Rimmed vacuoles, protein aggregates (TDP-43), tubulofilamentous inclusions on EM
• DOES NOT respond to immunosuppression (unlike other IIM)
• Slow progression over years; supportive treatment only

---

CLINICAL FEATURES

Muscle Features (Common to All Except IBM)

TYPICAL PRESENTATION:
  - Insidious onset (weeks to months) of proximal weakness
  - Hip flexors: Difficulty rising from chair, climbing stairs
  - Shoulder girdle: Difficulty lifting arms overhead
  - Neck flexors: Head drop (severe DM/PM)
  - Pharyngeal: Dysphagia (bulbar involvement)
  - Respiratory: Diaphragm weakness → respiratory failure
  - Pain: Variable (myalgia in 50%; usually NOT prominent)
  - CK: Markedly elevated (10-50× normal)

Skin Features (Dermatomyositis)

Extra-Muscular Manifestations

• CT chest/abdomen/pelvis
• Mammography, cervical smear, PSA
• Colonoscopy (if >50)
• PET-CT for high-risk patients

---

DIAGNOSTIC APPROACH

Bohan & Peter Criteria (Modified)

DEFINITE INFLAMMATORY MYOPATHY requires:
  ✓ Proximal symmetrical weakness
  ✓ ↑ CK (or LDH, aldolase, AST, ALT)
  ✓ EMG: Myopathic changes
  ✓ Muscle biopsy: Characteristic changes
  ✓ (DM only): Typical skin rash

Investigations Flowchart

SUSPECTED INFLAMMATORY MYOPATHY
        |
        v
STEP 1: SEROLOGY
  - CK, LDH, aldolase (CK most sensitive)
  - CBC, ESR, CRP
  - Creatinine (myoglobinuria → renal failure)
  - LFT (CK isoforms: MM vs MB)
        |
        v
STEP 2: MYOSITIS ANTIBODIES (MSA)
  - Anti-Jo-1 (ASS - ILD, arthritis)
  - Anti-Mi-2 (DM - good prognosis)
  - Anti-MDA5 (amyopathic DM - severe ILD, rapidly progressive)
  - Anti-TIF1-γ (cancer-associated DM)
  - Anti-NXP2 (juvenile DM, calcinosis)
  - Anti-SRP (IMNM - severe weakness)
  - Anti-HMGCR (statin-induced IMNM)
  - Anti-PM/Scl (overlap with SSc)
        |
        v
STEP 3: EMG
  - Myopathic: Short, small amplitude MUAP, polyphasic
  - Spontaneous activity: Fibrillations, positive sharp waves
  - EXCLUDE: Neuropathy (elongated MUAP)
        |
        v
STEP 4: IMAGING
  - MRI muscle (STIR sequence): Areas of edema/inflammation
  - Guides biopsy site
  - Monitors treatment response
        |
        v
STEP 5: MUSCLE BIOPSY (GOLD STANDARD)
  - Open or needle biopsy of affected muscle
  - Histopathology distinguishes IIM subtypes
        |
        v
STEP 6: ORGAN ASSESSMENT
  - HRCT chest (ILD)
  - Echo, ECG (cardiac involvement)
  - Swallowing study (dysphagia)
  - Pulmonary function tests (FVC, DLCO)

Histopathology Comparison

---

DIFFERENTIAL DIAGNOSIS

PROXIMAL MYOPATHY DIFFERENTIAL:

INFLAMMATORY:
  DM, IMNM, ASS, IBM, Overlap myositis
  Infectious myositis (viral, bacterial, parasitic)

METABOLIC:
  Hypothyroid myopathy (very common mimic - check TFT)
  Cushing's (steroid myopathy - normal CK)
  Hypokalemic myopathy
  Hypocalcemia
  Glycogen storage diseases (Pompe, McArdle)
  Lipid storage myopathy

TOXIC:
  Statin myopathy (IMNM vs statin-induced CK rise)
  Alcohol myopathy
  Drug-induced: Hydroxychloroquine, colchicine, AZT

DYSTROPHIES:
  LGMD (limb-girdle muscular dystrophy)
  FSHD (Facioscapulohumeral)
  Becker muscular dystrophy (adults)
  Emery-Dreifuss

NEUROMUSCULAR:
  MG (fatigable, NMJ)
  Lambert-Eaton (NMJ)
  Motor neuron disease (ALS - UMN+LMN)
  Spinal muscular atrophy

KEY DIFFERENTIATING POINTS:
  - CK very high (>10,000) → IMNM or rhabdomyolysis
  - Normal CK → steroid myopathy, MG, endocrine
  - Distal + proximal + finger flexors → IBM
  - Fatigable → NMJ disorder
  - No sensory loss → pure myopathy (vs neuropathy)

---

TREATMENT

General Principles

1. Corticosteroids: First-line for all IIM (except IBM)
2. Steroid-sparing agents: Added early to reduce steroid toxicity
3. Treat underlying malignancy (cancer-associated DM)
4. ILD management: Critical in ASS and anti-MDA5 DM

Treatment Algorithm

NEWLY DIAGNOSED DM/IMNM/ASS
        |
        v
STEP 1: INDUCTION
  Prednisolone 1 mg/kg/day (max 60-80 mg/day)
  + Methylprednisolone IV pulse 500-1000 mg/day × 3 days (severe disease)
        |
        v
STEP 2: STEROID-SPARING AGENT (start simultaneously)
  Choose one:
  - Methotrexate 15-25 mg/week + Folic acid
  - Azathioprine 2-3 mg/kg/day
  - Mycophenolate mofetil 1-1.5 g BD (preferred if ILD)
        |
        v
STEP 3: TAPER PREDNISOLONE
  Slowly over 12-24 months guided by clinical response + CK
        |
        v
REFRACTORY DISEASE (failed above):
  - IVIG 2 g/kg over 2-5 days monthly × 3-6 months
  - Rituximab 1000 mg × 2 doses 2 weeks apart (anti-CD20; good for ASS, anti-Jo-1+)
  - Tacrolimus 3 mg/day (ILD in ASS)
  - Cyclophosphamide (severe rapidly progressive ILD in anti-MDA5)
  - JAK inhibitors (tofacitinib - for refractory DM/ILD - emerging evidence)
        |
        v
IBM: NO immunosuppression (does not help)
  - Physiotherapy, occupational therapy
  - Dysphagia management
  - Ankle-foot orthoses
  - Possible future: Bimagrumab (anti-ActRII antibody - trials ongoing)

Monitoring Treatment Response

• CK: Correlates with disease activity (except IBM)
• Manual muscle testing (MMT-8): Standardized outcome measure
• MRI muscle: Serial STIR imaging
• PFT/HRCT: ILD monitoring
• Myositis disease activity assessment (MDAA): Physician global activity score

Management of Specific Complications

---

---

QUESTION 11 (Short Answer - 6 Marks)

DEEP BRAIN STIMULATION (DBS)

---

DEFINITION

---

COMPONENTS OF DBS SYSTEM

DBS SYSTEM:
        ┌──────────────────────────────────┐
        │  BRAIN LEAD (electrode array)    │
        │  (4 contact points, 1.5 mm apart)│
        └────────────┬─────────────────────┘
                     │ (subcutaneous extension cable)
        ┌────────────┴─────────────────────┐
        │  IMPLANTABLE PULSE GENERATOR     │
        │  (IPG) - "Brain Pacemaker"       │
        │  (subclavicular, battery-powered) │
        └──────────────────────────────────┘
                Controlled by:
        External programmer (physician)
        + Patient handheld controller

---

MECHANISM OF ACTION

• High-frequency stimulation (>100 Hz) → functional inactivation of target (similar to ablation but reversible)
• Disrupts pathological oscillations (beta band 12-30 Hz in Parkinson's disease)
• Modulates the basal ganglia-thalamocortical circuits
• NOT simply inhibitory; complex effects on output

---

DBS TARGETS AND INDICATIONS

---

PARKINSON'S DISEASE DBS — MOST ESTABLISHED INDICATION

Ideal Candidate

• Diagnosis of idiopathic PD (not atypical parkinsonism)
• Age typically <70 years
• Disabling motor fluctuations (on-off) despite optimal medications
• L-DOPA responsive (DBS effects mirror best levodopa response)
• Good cognition (MoCA >24)
• No major depression, dementia, or psychiatric comorbidity
• Adequate surgical risk

Benefits

• Dramatic reduction in motor fluctuations
• Reduces dyskinesia (GPi target)
• Reduces "off" time
• Improves quality of life
• Allows reduction of levodopa dose

Limitations

• Does NOT improve: axial symptoms (gait, balance, speech, swallowing), non-motor symptoms, dementia
• Requires regular programming
• Battery replacement every 5-10 years (or rechargeable)

---

COMPLICATIONS OF DBS

SURGICAL:
  - Hemorrhage (1-2%): Intracerebral, subdural
  - Infection (2-4%): Lead/IPG site
  - Lead misplacement

HARDWARE:
  - Lead fracture or migration
  - IPG malfunction/battery failure
  - Impedance changes

STIMULATION-INDUCED:
  - PD: Dysarthria, dysphagia (GPI), cognitive decline
  - Depression, mood changes
  - Impulse control disorders (STN - dopaminergic modulation)
  - Visual disturbance (optic tract spread)
  - Paresthesia, involuntary movements

LATE:
  - Disease progression (DBS controls symptoms, not disease)
  - Tolerance over years

---

EMERGING DBS APPLICATIONS

• Adaptive/Closed-loop DBS: Senses brain signals (LFP beta band) and automatically adjusts stimulation
• Focused ultrasound (FUS): Non-invasive, ablative alternative to DBS for essential tremor (incisionless thalamotomy)
• Alzheimer's disease: Fornix DBS - ADVANCE trial; mixed results
• Obesity: Lateral hypothalamus DBS (investigational)
• Chronic pain: PAG/PVG targets

---

---

QUESTION 12 (Long Answer - 20 Marks)

CLINICAL ANATOMY AND CORRELATION OF CEREBELLAR DYSFUNCTION

---

ANATOMY OF THE CEREBELLUM

External Anatomy

CEREBELLUM - LOBES:
        ___________________
       /                   \
      /    ANTERIOR LOBE    \   (Paleocerebellum - spinocerebellum)
     /___________________/
    /                      \
   /    POSTERIOR LOBE      \  (Neocerebellum - cerebrocerebellum)
  /_______________________ /
 /                         \
/     FLOCCULONODULAR LOBE  \ (Archicerebellum - vestibulocerebellum)
\___________________________/
        |          |
   Flocculus    Nodulus (part of vermis)

FUNCTIONAL DIVISIONS:
                |
       _________|_________
       |                  |
    VERMIS           HEMISPHERES
  (midline)          (bilateral)
    |                    |
Spinocerebellum     Cerebrocerebellum
(axial/proximal     (distal limb
 coordination)       coordination)

Functional Anatomy

---

CEREBELLAR CIRCUITRY

INPUT TO CEREBELLUM:
  Cerebral cortex → Pons (pontine nuclei) → Middle cerebellar peduncle (MCP) → Purkinje cells
  Spinal cord → Dorsal/ventral spinocerebellar tract → Inferior cerebellar peduncle (ICP)
  Vestibular nuclei → ICP
  Inferior olive → Climbing fibers → ICP (error signals)

INTERNAL CIRCUIT:
  Mossy fibers (all inputs except olive) → Granule cells → Parallel fibers →
  Purkinje cells (GABA - inhibitory) → Deep cerebellar nuclei

  Climbing fibers (from inferior olive) → Direct monosynaptic to Purkinje cells
  (motor error signals - "teaching function")

  Deep Cerebellar Nuclei:
  - Dentate (lateral - cerebrocerebellum)
  - Emboliform + Globose (= Interposed nuclei - spinocerebellum)
  - Fastigial (medial - vestibulocerebellum)

OUTPUT FROM CEREBELLUM:
  Deep nuclei → Superior cerebellar peduncle (SCP) → decussation in midbrain →
  Red nucleus + VL thalamus → Motor cortex (dentate-thalamo-cortical loop)
  Fastigial → Vestibular nuclei + reticular formation → Spinal cord

---

CLINICAL FEATURES OF CEREBELLAR DYSFUNCTION

The "DANISH" Mnemonic

D - Dysdiadochokinesia: Impaired rapid alternating movements
    (pronation-supination; "wiping a table")
    → Assess: Alternating hands on knee, finger-nose-finger

A - Ataxia (Gait): Wide-based, staggering, unsteady gait
    Truncal ataxia (vermis) vs Limb ataxia (hemisphere)
    Romberg: Negative (vestibular normal → falls with open eyes too)

N - Nystagmus: Horizontal gaze-evoked; fast component toward lesion side
    Pendular nystagmus (acquired cerebellar)
    Downbeat nystagmus (cervicomedullary junction)

I - Intention tremor: Tremor that INCREASES near target (4-6 Hz)
    Finger-nose test: Tremor worst at target
    (vs Resting tremor in PD - disappears with action)

S - Slurred speech (Dysarthria / Scanning speech):
    "Explosive" or "scanning" character
    Irregular volume and rate (cerebellar dysarthria)

H - Hypotonia + Hyporeflexia:
    Pendular reflexes (ipsilateral)
    Reduced muscle tone (ipsilateral limbs)

ADDITIONAL SIGNS:
- Decomposition of movement: Multi-joint movements broken into component parts
- Dysmetria: Inability to judge distance; past-pointing (overshoot/undershoot)
- Rebound phenomenon: Lack of check reflex when resistance suddenly released
- Titubation: Rhythmic head/body tremor (truncal - vermis/vestibular)
- Ocular dysmotility: Saccadic pursuit, square-wave jerks
- Heel-shin test: Abnormal (limb ataxia)

---

LOCALIZATION OF CEREBELLAR SIGNS

MIDLINE (VERMIS) LESION:
  - Truncal ataxia (prominent)
  - Gait ataxia (wide-based, cannot tandem walk)
  - Titubation (head bobbing)
  - Eye movement abnormalities
  - Relatively PRESERVED limb coordination initially
  Causes: Medulloblastoma (children), alcoholic cerebellar degeneration,
          paraneoplastic (vermis), MS

HEMISPHERIC LESION:
  - IPSILATERAL limb ataxia
  - Dysmetria, dysdiadochokinesia
  - Intention tremor
  - Scanning dysarthria
  - Ipsilateral hypotonia, pendular reflexes
  - Gait deviation to IPSILATERAL side
  Causes: Stroke (PICA - inferior; AICA - middle; SCA - superior)
          Tumor, MS, Abscess

CEREBELLAR PEDUNCLE LESION:
  - ICP (inferior): Ipsilateral cerebellar signs + sometimes CN IX/X
  - MCP (middle): Ipsilateral cerebellar signs + possible facial palsy
  - SCP (superior): Ipsilateral cerebellar signs + CN III palsy (midbrain)

---

DIAGRAM: CEREBELLAR BLOOD SUPPLY

ARTERIAL SUPPLY:
        |
   _____|_____________________
   |           |              |
 PICA        AICA            SCA
(posterior  (anterior       (superior
inferior    inferior        cerebellar
cerebellar) cerebellar)     artery)
   |           |              |
Inferior    Middle           Superior
cerebellum  cerebellum +     cerebellum +
+ lateral   flocculus +      superior vermis
medulla     CN VII/VIII area

PICA occlusion → LATERAL MEDULLARY SYNDROME (Wallenberg's)
AICA occlusion → Ipsilateral deafness, CN VII palsy, cerebellar signs
SCA occlusion → Contralateral pain/temp loss (trigeminothalamic/STT),
                Ipsilateral cerebellar signs, CN V involvement

---

CEREBELLAR DISORDERS — CLINICAL CLASSIFICATION

ACUTE ONSET (<72 hours)

SUBACUTE ONSET (weeks to months)

CHRONIC/PROGRESSIVE ONSET (months to years)

HEREDITARY ATAXIAS:
        |
   _____|_______________________
   |                            |
AUTOSOMAL DOMINANT          AUTOSOMAL RECESSIVE
   |                            |
Spinocerebellar Ataxia (SCA)  Friedreich's Ataxia (most common)
  - SCA1: ATXN1 (polyQ)       X-linked: Fragile X tremor-ataxia
  - SCA2: ATXN2
  - SCA3: MJD (Machado-Joseph)
  - SCA6: CACNA1A (Ca channel)
  - SCA17: TBP

SPORADIC DEGENERATIVE:
  - Multiple System Atrophy-Cerebellar (MSA-C)
  - Idiopathic late-onset cerebellar ataxia (ILOCA)

TOXIC:
  - Alcoholic cerebellar degeneration (vermis, gait)

METABOLIC:
  - Wilson's disease (KF rings, liver disease)
  - Mitochondrial (MELAS, MERRF)
  - Vitamin E deficiency (AVED)
  - Vitamin B12 deficiency
  - Refsum disease

IMMUNE:
  - Gluten ataxia (anti-gliadin antibodies, responds to gluten-free diet)
  - Anti-GAD65 ataxia (responds to immunosuppression)

---

FRIEDREICH'S ATAXIA — HIGH-YIELD

Genetics

• Autosomal recessive - chromosome 9q
• GAA trinucleotide repeat expansion in FXN gene (frataxin)
• Frataxin = mitochondrial iron-chaperone; deficiency → iron accumulation → oxidative stress

Clinical Features (Triad + more)

TYPICAL FRIEDREICH'S (onset <25 yrs):
  1. Progressive ATAXIA of gait and limbs
  2. AREFLEXIA (absent deep tendon reflexes - peripheral neuropathy)
  3. EXTENSOR PLANTAR responses (corticospinal involvement)
  + Dysarthria, dysphagia
  + Cardiomyopathy (hypertrophic - cause of death in 50%)
  + Diabetes mellitus (10-20%)
  + Pes cavus, kyphoscoliosis (skeletal deformities)
  + Loss of vibration sense, proprioception (dorsal columns)
  + Optic atrophy (late)

Management

• Omaveloxolone (Skyclarys): First FDA-approved therapy for Friedreich's ataxia (2023) - Nrf2 activator, reduces oxidative damage
• Idebenone: Cardioprotective (limited evidence)
• Physiotherapy, cardiac monitoring, ECHO annually
• Treat diabetes, scoliosis

---

INVESTIGATIONS FOR CEREBELLAR DYSFUNCTION

ACUTE ONSET:
  MRI brain (DWI + FLAIR) → Stroke, demyelination, hemorrhage
  CT head → If MRI unavailable
  Glucose, thiamine level, TFT, alcohol level
  ECG + Echo (cardiac source for cerebellar stroke)

SUBACUTE:
  Anti-cerebellar antibodies: Anti-Yo, Anti-Hu, Anti-Ri, Anti-CV2, Anti-Ma2
  CSF: Cells, protein, cytology, 14-3-3 (CJD)
  PET-CT whole body (paraneoplastic workup)
  Anti-GAD antibodies, anti-gliadin (IgA/IgG)
  TFT, B12, Vit E, ceruloplasmin/Cu (Wilson's)

HEREDITARY:
  Genetic panel: SCA 1,2,3,6,7,17; Friedreich's (GAA repeat)
  EMG/NCS (Friedreich's - sensory neuropathy)
  ECHO (Friedreich's - cardiomyopathy)
  OGTT (Friedreich's - DM)

---

---

QUESTION 13 (Short Answer - 6 Marks)

CHANNELOPATHIES IN NEUROLOGY

---

DEFINITION

---

CLASSIFICATION

CHANNELOPATHIES IN NEUROLOGY
        |
   _____|_________________________
   |             |               |
NEURONAL      MUSCLE          NMJ /
CHANNELOPATHIES CHANNELOPATHIES  ANTIBODY
   |             |              |
Epilepsies    Periodic       Myasthenia
Migraine      Paralysis      Gravis
Episodic      Myotonias      Lambert-Eaton
Ataxias       Malignant hyp  Neuromyotonia
Pain syndromes

---

MAJOR NEUROLOGICAL CHANNELOPATHIES

1. SODIUM CHANNEL (SCN) Disorders

2. POTASSIUM CHANNEL (KCNQ/KCNA) Disorders

3. CALCIUM CHANNEL (CACNA) Disorders

4. CHLORIDE CHANNEL (CLC) Disorders

5. ACQUIRED CHANNELOPATHIES (Autoimmune)

---

PERIODIC PARALYSIS — HIGH YIELD

HYPOKALEMIC PP (type 1 - CACNA1S; type 2 - SCN4A):
  Trigger: Carbohydrate meal, rest after exercise, cold
  K+ during attack: LOW (<3.5 mEq/L)
  Treatment: KCl replacement, acetazolamide (prevention)
  Avoid: Glucose/insulin during attacks

HYPERKALEMIC PP (SCN4A):
  Trigger: Fasting, cold, rest after exercise, K+ foods
  K+ during attack: HIGH (>5.5 mEq/L) or normal
  Treatment: Carbohydrate-rich food, calcium gluconate, thiazide diuretics
  Acetazolamide, mexiletine for prevention

NORMOKALEMIC PP (SCN4A variant):
  Normal K+ during attacks
  Treatment: Na+ restriction, acetazolamide

---

---

QUESTION 14 (Short Answer - 6 Marks)

ATAXIC PARAPARESIS

---

DEFINITION

• Paraparesis: Weakness of both lower limbs
• Ataxia: Sensory (proprioceptive) ataxia due to posterior column dysfunction OR cerebellar ataxia

---

ANATOMICAL BASIS

SPINAL CORD CROSS-SECTION:

       DORSAL COLUMNS (Proprioception, vibration, fine touch)
    ____________________________________________
   |  Gracilis      Cuneatus                   |
   |  (lower limb)  (upper limb)               |
   |                                            |
   |   LATERAL CORTICOSPINAL TRACT (ipsilateral)|← (UMN - crossed above)
   |                                            |
   |   LATERAL SPINOTHALAMIC TRACT (contralateral)
   |   (pain/temp)                              |
   |____________________________________________|

ATAXIC PARAPARESIS:
Dorsal column dysfunction → Proprioceptive loss → SENSORY ATAXIA
+ Corticospinal tract involvement → UMN WEAKNESS = Paraparesis
(± additional cerebellar dysfunction)

---

CAUSES OF ATAXIC PARAPARESIS

MNEMONIC: "DIVERT MS"

---

SUBACUTE COMBINED DEGENERATION (SCD) — MOST IMPORTANT

Cause

• Vitamin B12 deficiency (most common)
• Also: Copper deficiency, NOS exposure (inactivates B12)

Pathology

• Posterior columns (earliest - proprioception, vibration)
• Lateral corticospinal tracts (upper motor neuron signs)
• Peripheral nerves (lower motor neuron + sensory features)

Clinical Features

EARLY:
  - Paresthesia (hands and feet) - pins and needles
  - Loss of vibration sense (tuning fork) - feet first
  - Loss of proprioception (joint position sense)
  - Positive Romberg sign
  - Lhermitte's sign (electric shock on neck flexion)

LATE:
  - Spastic paraparesis (corticospinal tract)
  - Extensor plantar response
  - Bladder/bowel dysfunction
  - Cognitive decline, memory impairment
  - Optic atrophy (late)
  - COMBINED UMN + LMN signs (peripheral neuropathy also)

Investigations

• Serum B12 <200 pg/mL (may be normal in 30% - check methylmalonic acid + homocysteine)
• Methylmalonic acid (MMA) ↑, Homocysteine ↑ (more sensitive)
• CBC: Megaloblastic anemia (macrocytosis, hypersegmented PMN)
• MRI spine: T2 hyperintensity in posterior columns ("inverted V sign" on axial)
• Anti-intrinsic factor antibodies (pernicious anemia)

Treatment

• IM cyanocobalamin or hydroxocobalamin 1000 mcg daily × 7 days → weekly × 4 weeks → monthly (for life if PA)
• Neurological improvement begins in weeks; complete recovery in mild cases

---

INVESTIGATION APPROACH TO ATAXIC PARAPARESIS

ATAXIC PARAPARESIS
      |
      v
MRI SPINE (T2, STIR, contrast) - FIRST INVESTIGATION
  - Cervical + thoracic + lumbar
  - Posterior column T2 changes (SCD, MS, tabes)
  - Lateral column changes (MS)
  - Cord compression (spondylosis, tumor)
      |
      v
BLOOD:
  B12, folate, MMA, homocysteine
  Copper, ceruloplasmin
  Vitamin E
  HIV, HTLV-1 serology
  ANA, anti-dsDNA, ANCA (vasculitis)
  Anti-AQP4 (NMO), anti-MOG (MOGAD)
  RPR/VDRL + TPHA (syphilis)
      |
      v
CSF:
  Oligoclonal bands (MS)
  HIV, HTLV viral load
  VDRL (tabes)
  Cytology (lymphoma, carcinomatosis)
      |
      v
NEUROPHYSIOLOGY:
  NCS/EMG (peripheral neuropathy in SCD, CIDP)
  Visual evoked potentials (MS - optic pathway)
  Somatosensory evoked potentials (posterior column)

---

---

QUESTION 15 (Short Answer - 6 Marks)

EATING DISORDERS

---

CLASSIFICATION (DSM-5)

1. Anorexia Nervosa (AN)
2. Bulimia Nervosa (BN)
3. Binge Eating Disorder (BED)
4. ARFID (Avoidant/Restrictive Food Intake Disorder)
5. Other Specified Feeding/Eating Disorder (OSFED)

---

ANOREXIA NERVOSA

Diagnostic Criteria (DSM-5)

1. Restriction of energy intake → Significantly low body weight
2. Intense fear of gaining weight (even when underweight)
3. Disturbed body image OR denial of seriousness of low weight

Clinical Features & Complications

ANOREXIA NERVOSA — SYSTEM-WISE:

METABOLIC:
  - Hypothermia, bradycardia, hypotension
  - Electrolyte abnormalities (hypokalemia, hypomagnesemia, hypophosphatemia)
  - Hypoglycemia, elevated LFTs
  - Osteoporosis (estrogen deficiency, low IGF-1)
  - Refeeding syndrome (hypophosphatemia on refeeding)

ENDOCRINE:
  - Amenorrhea (hypothalamic hypogonadism)
  - Low T3 syndrome (euthyroid sick)
  - Elevated cortisol, GH resistance

CARDIOVASCULAR:
  - Bradycardia, prolonged QTc
  - Orthostatic hypotension
  - Mitral valve prolapse

GASTROINTESTINAL:
  - Gastroparesis, constipation, fullness
  - Esophageal tears (if purging)

HEMATOLOGICAL:
  - Pancytopenia (bone marrow suppression)
  - Low ESR

NEUROLOGICAL:
  - Cognitive impairment, brain atrophy (gray matter loss)
  - Peripheral neuropathy

DERMATOLOGICAL:
  - Lanugo hair (fine downy hair on body)
  - Hair loss, dry skin
  - Hypercarotenemia (orange skin)

---

BULIMIA NERVOSA

Diagnostic Criteria (DSM-5)

1. Recurrent binge eating (large amounts, loss of control) ≥1×/week × 3 months
2. Recurrent compensatory behaviors: Purging (vomiting, laxatives), fasting, over-exercise
3. Self-evaluation unduly influenced by shape/weight
4. Not occurring exclusively during AN

Clinical Features

• Usually normal weight (vs AN - underweight)
• Russell's sign: Calluses on dorsum of hand from self-induced vomiting
• Parotid hypertrophy (bilateral, painless)
• Dental erosion (acid from vomiting)
• Esophagitis, Mallory-Weiss tears
• Metabolic alkalosis + hypokalemia (from purging)

---

BINGE EATING DISORDER (BED)

• Binge eating WITHOUT compensatory behaviors
• Most common eating disorder
• Associated with obesity, type 2 DM, depression
• Lisdexamfetamine (Vyvanse): FDA-approved for BED

---

MANAGEMENT OF EATING DISORDERS

MANAGEMENT ALGORITHM:

ALL EATING DISORDERS:
  1. Multidisciplinary team (psychiatrist, dietitian, physician, therapist)
  2. Medical stabilization first (if life-threatening)
  3. Nutritional rehabilitation
  4. Psychotherapy
  5. Pharmacotherapy (adjunct)

Anorexia Nervosa Treatment

Bulimia Nervosa Treatment

• CBT-BN: Gold standard (50-60% remission)
• Fluoxetine 60 mg/day: Only FDA-approved medication for BN (higher dose than depression)
• TCAs (imipramine), MAOIs: Less preferred
• Avoid: Bupropion (increased seizure risk in BN due to electrolytes)

---

---

QUESTION 16 (Long Answer - 20 Marks)

ATAXIA — DEFINITION, CLASSIFICATION, CLINICAL FEATURES, DIAGNOSIS, MANAGEMENT

---

DEFINITION

---

CLASSIFICATION OF ATAXIA

ATAXIA
   |
   |── CEREBELLAR ATAXIA (most common)
   |       |── Anterior lobe: Gait > limb ataxia
   |       |── Posterior lobe: Limb ataxia > gait
   |       |── Panhemispheric/Diffuse
   |
   |── SENSORY ATAXIA (posterior column / peripheral nerve)
   |       - Worsens in dark (Romberg positive)
   |       - Vibration/proprioception lost
   |
   |── VESTIBULAR ATAXIA
   |       - Falls to affected side
   |       - Nystagmus, vertigo, hearing symptoms
   |
   |── FRONTAL ATAXIA (frontal lobe, "gait apraxia")
           - Magnetic gait (feet stuck to floor)
           - NPH, bilateral frontal lesions

---

ETIOLOGICAL CLASSIFICATION

A. HEREDITARY ATAXIAS

1. Autosomal Dominant Cerebellar Ataxias (ADCA) = Spinocerebellar Ataxias (SCAs)

2. Autosomal Recessive Ataxias

3. X-Linked

• Fragile X Tremor-Ataxia Syndrome (FXTAS): Males >50 yrs; premutation (55-200 CGG) in FMR1; ataxia + tremor + parkinsonism + cognitive decline

---

B. ACQUIRED ATAXIAS

ACUTE ONSET

ACUTE ATAXIA DIFFERENTIAL:
  VASCULAR:
    - Cerebellar stroke (PICA, AICA, SCA occlusion)
    - Cerebellar hemorrhage
    - Basilar artery thrombosis
    [Key: Sudden onset, vascular risk factors]

  DEMYELINATING:
    - Multiple sclerosis (relapse)
    - ADEM (acute disseminated encephalomyelitis)

  INFECTIOUS:
    - Acute viral cerebellitis (post-VZV, EBV, enterovirus)
    - Bacterial abscess
    - Listeria (immunocompromised)

  TOXIC/METABOLIC:
    - Phenytoin toxicity (ataxia + nystagmus at toxic levels)
    - Alcohol intoxication/Wernicke's
    - Lithium, amiodarone toxicity
    - Sedative/benzodiazepine overdose

  INFECTIOUS ENCEPHALITIS:
    - NMDAR encephalitis (cerebellar ataxia in early phase)

SUBACUTE ONSET

PARANEOPLASTIC CEREBELLAR DEGENERATION (PCD):
  - Rapid (weeks-months) severe pancerebellar syndrome
  - Women >50 years (ovarian, breast cancer)
  - Antibodies: Anti-Yo (most common - gynecological tumors)
                Anti-Hu (SCLC)
                Anti-Ri (breast cancer, SCLC)
                Anti-CV2 (SCLC, thymoma)
  - Precedes or follows cancer diagnosis
  - Poor response to treatment (often irreversible)
  - Management: Tumor treatment + immunotherapy

IMMUNE-MEDIATED ATAXIA:
  - Anti-GAD65 ataxia: Pure cerebellar; isolated; responds to IVIG/steroids
  - Gluten ataxia: Anti-gliadin, anti-TG6; responds to gluten-free diet
  - Anti-NMDAR (early cerebellar features)
  - Post-infectious (Miller Fisher syndrome, ADEM)

CJD/PRION:
  - Subacute ataxia + myoclonus + rapidly progressive dementia
  - EEG: Periodic sharp complexes (1/sec)
  - MRI: DWI cortical ribboning + basal ganglia, thalamic (pulvinar) hyperintensity
  - CSF 14-3-3 protein (positive)
  - RT-QuIC (highly specific, 85-95% sensitivity)

CHRONIC PROGRESSIVE ONSET

DEGENERATIVE:
  - MSA-C (Multiple System Atrophy - Cerebellar type)
  - Fragile X tremor-ataxia syndrome (FXTAS)

METABOLIC:
  - Wilson's disease: KF rings, liver disease, copper/ceruloplasmin
  - Hypothyroid cerebellar syndrome (reversible)
  - Vitamin E deficiency (AVED)
  - Vitamin B12 deficiency (sensory ataxia)
  - Celiac/gluten ataxia

STRUCTURAL:
  - Chiari malformation Type I (downbeat nystagmus, syringomyelia)
  - Posterior fossa tumor (medulloblastoma in children, metastasis in adults)
  - Normal pressure hydrocephalus (gait apraxia - "frontal ataxia")

---

CLINICAL FEATURES — COMPREHENSIVE

Cerebellar vs Sensory Ataxia

---

INVESTIGATIONS ALGORITHM

ATAXIA
  |
  v
STEP 1: NEUROIMAGING
  MRI brain + spine (T2, FLAIR, DWI, Gadolinium, MR angiography)
  CT brain if acute (hemorrhage exclusion)
  → Cerebellar infarct, hemorrhage, atrophy, demyelination, tumor, Chiari

  |
  v
STEP 2: BLOOD WORK
  - Electrolytes, glucose, renal, hepatic function
  - TFT (hypothyroid ataxia - reversible)
  - B12, folate
  - Vit E level
  - Copper, ceruloplasmin (Wilson's)
  - Ceruloplasmin + 24hr urine copper
  - Anti-gliadin IgA/IgG, tissue transglutaminase (gluten ataxia)
  - Anti-cerebellar antibodies (paraneoplastic): Yo, Hu, Ri, CV2, Ma2
  - Anti-GAD65 (autoimmune ataxia)
  - Lipid profile (abetalipoproteinemia if very low cholesterol)
  - AFP (ataxia-telangiectasia, hepatocellular)

  |
  v
STEP 3: CSF ANALYSIS
  - Oligoclonal bands (MS)
  - 14-3-3, tau (CJD)
  - RT-QuIC (CJD - high specificity)
  - Cytology (leptomeningeal carcinomatosis)
  - Paraneoplastic antibodies in CSF

  |
  v
STEP 4: NEUROPHYSIOLOGY
  - NCS/EMG (sensory neuropathy - Friedreich's, SCA)
  - VEP (optic atrophy in SCA7, Friedreich's)
  - SSEP (posterior column dysfunction)
  - EEG (CJD - periodic sharp complexes)

  |
  v
STEP 5: GENETIC TESTING
  If hereditary suspected:
  - SCA 1, 2, 3, 6, 7, 17 (CAG repeat PCR)
  - Friedreich's (GAA repeat analysis)
  - FMR1 (FXTAS - CGG repeat)
  - Mitochondrial panel (MELAS, MERRF, NARP)
  - Whole exome/genome sequencing (complex/undiagnosed cases)

---

MANAGEMENT

Specific Treatments

Symptomatic Treatment

Rehabilitation (Cornerstone of Management)

• Physiotherapy: Balance retraining (Frenkel's exercises), gait training, fall prevention
• Occupational therapy: Adaptive equipment, activities of daily living
• Speech therapy: Dysarthria management, dysphagia management
• Assistive devices: Walking frame, wheelchair planning
• Genetic counseling: For hereditary ataxias

---

---

QUESTION 17 (Short Answer - 6 Marks)

PRIMARY HEADACHE DISORDERS

---

CLASSIFICATION (ICHD-3, 2018)

PRIMARY HEADACHE DISORDERS
(No underlying structural cause)
        |
   _____|___________________
   |         |         |        |
MIGRAINE  TENSION   CLUSTER  OTHERS
          TYPE      + TACs    (cough, exertional,
                              thunderclap, hypnic)

---

1. MIGRAINE

Diagnostic Criteria (ICHD-3) — "POUND"

• Pulsatile quality
• One day (4-72 hours)
• Unilateral
• Nausea/vomiting
• Disabling (moderate-severe intensity)
• Associated with photophobia AND phonophobia

Pathophysiology

CORTICAL SPREADING DEPRESSION (CSD)
        |
        v
Depolarization wave at 3-5 mm/min across cortex
  (basis of migraine aura)
        |
        v
Trigeminovascular activation
(CN V ophthalmic branch → CGRP release)
        |
        v
Neurogenic inflammation (CGRP, substance P, VIP)
at meningeal vessels
        |
        v
Central sensitization → Throbbing pain
Brainstem (PAG, NRM) modulation

Treatment

---

2. TENSION-TYPE HEADACHE (TTH)

Diagnostic Criteria (ICHD-3)

• Bilateral pressing/tightening (band-like)
• Mild to moderate intensity
• Does NOT worsen with routine activity
• NO nausea/vomiting; photophobia OR phonophobia (not both)
• Duration: 30 min - 7 days (episodic); >15 days/month × 3 months (chronic)

Treatment

• Acute: Paracetamol 1g, Ibuprofen 400 mg, Aspirin 500-1g
• Prophylaxis (chronic TTH): Amitriptyline 10-75 mg nocte (first choice)
• Non-pharmacological: Stress management, biofeedback, relaxation therapy

---

3. CLUSTER HEADACHE

Diagnostic Criteria (ICHD-3)

• Severe/excruciating unilateral (orbital/periorbital/temporal)
• 15-180 minutes
• At least 1 ipsilateral autonomic feature:
  • Lacrimation, rhinorrhea, ptosis, miosis, eyelid edema, facial flushing
• Frequency: 1 every other day to 8/day
• "Alarm clock headache" (nocturnal, same time)
• "Cluster periods" lasting weeks-months; then remission

Treatment

---

COMPARISON TABLE

---

---

QUESTION 18 (Short Answer - 6 Marks)

CIRCLE OF WILLIS

---

DEFINITION

---

DIAGRAM OF CIRCLE OF WILLIS

                        ANTERIOR
                            |
              ACA    ←─── ACoA ───→    ACA
           (Left)     (Ant. Comm.)    (Right)
              ↑                           ↑
           MCA ←── ICA ←←     →→ ICA ──→ MCA
         (Left)  (Left)         (Right)  (Right)
              ↑                           ↑
           PCoA                         PCoA
        (Posterior                  (Posterior
        Comm. L)                     Comm. R)
              ↑                           ↑
           PCA ←───── Basilar ──────→ PCA
         (Left)       Artery          (Right)
                          ↑
               ┌──────────┴──────────┐
          PICA/VA                 PICA/VA
          (Left)                  (Right)

COMPONENTS:
Anterior part:
  - 2 × Anterior Cerebral Arteries (ACA) - from ICA
  - 1 × Anterior Communicating Artery (ACoA) - connects both ACAs

Posterior part:
  - 2 × Posterior Communicating Arteries (PCoA) - connects ICA to PCA
  - 2 × Posterior Cerebral Arteries (PCA) - from basilar artery

Lateral connections:
  - 2 × Internal Carotid Arteries (ICA) contributing to circle

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ARTERIAL TERRITORIES

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VARIATIONS (CLINICALLY IMPORTANT)

• Complete Circle of Willis: Present in only ~20-35% of population
• Common variations:
  • Hypoplastic or absent PCoA (most common)
  • Absent ACoA
  • Fetal PCA (PCA arising from ICA rather than basilar - 20-25%)
  • Hypoplastic A1 segment of ACA
• Clinical implication: Incomplete circle → Poor collateral flow during ICA occlusion → Larger infarct

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CLINICAL IMPORTANCE

1. Collateral Circulation

• When ICA is occluded: ACoA diverts flow from contralateral ICA
• When basilar is occluded: PCoA can provide posterior fossa supply
• Allows carotid endarterectomy to be performed safely in complete circle

2. Saccular (Berry) Aneurysms

• Most common at branch points of circle of Willis (wall stress highest)
• Locations (in order of frequency):
  1. ACoA (most common - 35%): Rupture → SAH, bifrontal vasospasm
  2. ICA-PCoA junction (30%): CN III palsy (first sign of expanding aneurysm)
  3. MCA bifurcation (20%)
  4. Basilar tip (10%)
• Risk: Hypertension, smoking, polycystic kidney disease, connective tissue disorders (EDS, Marfan's)
• Unruptured aneurysm >7 mm or symptomatic: Surgical clipping or endovascular coiling

3. "Posterior Communicating Artery Aneurysm" - High Yield

• Expands → compresses CN III (oculomotor nerve)
• Presents as: Painful third nerve palsy with pupil involvement (mydriasis)
• This is a surgical emergency — distinguish from diabetic CN III palsy (pupil spared)

ANEURYSMAL CN III PALSY (PCoA):         ISCHEMIC/DIABETIC CN III:
  - Pupil DILATED (mydriasis)            - Pupil SPARED (miosis or normal)
  - Painful (headache)                   - May have pain but less severe
  - Complete ptosis                      - Often pupil-sparing
  - "Worst headache of life" if SAH      - No sudden onset "sentinel" headache
  - EMERGENCY                            - Watch & wait (resolves 3-6 months)

4. ACoA Aneurysm Rupture

• Massive SAH (most common cause of non-traumatic SAH)
• "Thunderclap headache" - instantaneous, worst of life
• Signs: Neck stiffness, photophobia, confusion
• Investigation: CT (non-contrast) → LP (xanthochromia) → CTA/DSA (aneurysm)

5. Arteriovenous Malformations (AVM)

• Congenital tangle of arteries and veins without capillaries (direct A-V shunting)
• Present with: Hemorrhage (50%), seizures (30%), headache
• Diagnosis: CTA, MR angiography, catheter DSA (gold standard)
• Treatment: Microsurgical resection, Gamma knife radiosurgery, endovascular embolization, or combination

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MD Medicine Exam Strategy: For 20-mark questions, target ~500-600 words minimum with mandatory diagrams/flowcharts. For 6-mark questions, aim for ~150-200 words with a key table or mnemonic. Always mention recent advances (CGRP inhibitors for migraine, omaveloxolone for Friedreich's, cenobamate for epilepsy, efgartigimod for MG). Examiners at MD level expect you to cite trial names (DAWN, SANTE, MGTX) and current guidelines (ILAE, ICHD-3, IOM criteria for CFS). Good luck!

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MD MEDICINE EXAMINATION NOTES — NEUROLOGY & MEDICINE (PART 3)

References: Harrison's Principles of Internal Medicine 22E, Bradley & Daroff's Neurology in Clinical Practice, Adams & Victor's Principles of Neurology 12E, Murray & Nadel's Respiratory Medicine, Fuster & Hurst's The Heart 15E, Kaplan & Sadock's Psychiatry, Sleisenger & Fordtran's GI & Liver Disease

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QUESTION 20 (Long Answer - 20 Marks)

PATHOPHYSIOLOGY OF SLEEP AND SLEEP DISORDERS

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PART A: NORMAL SLEEP — PHYSIOLOGY & ARCHITECTURE

Definition of Sleep

• Perceptual disengagement from the environment
• Reduced responsiveness to external stimuli
• Characteristic EEG, EMG, and EOG patterns
• Active regulation by the brain (NOT passive absence of wakefulness)

---

NEURAL CONTROL OF SLEEP-WAKE CYCLES

WAKEFULNESS PROMOTION SYSTEM (Ascending Arousal System):

BRAINSTEM/HYPOTHALAMUS
        |
   _____|_________________________________________________
   |          |          |          |           |         |
Locus       Dorsal    Tuber-    Lateral      Basal    TMN
Coeruleus   Raphe    omammillary Hypothal.   Forebrain (Histamine)
(NE)        (5-HT)   Nucleus    (Orexin/    (ACh)
                     (Histamine) Hypocretin)
        |
        v
Thalamus → Cortex → WAKEFULNESS

SLEEP PROMOTION:
Ventrolateral preoptic nucleus (VLPO) - "sleep switch"
  → Inhibits arousal systems via GABA and Galanin
  → Promotes NREM sleep

Median Preoptic Nucleus → Sleep onset facilitation

FLIP-FLOP MODEL (Saper, Harrison's 22E)

WAKEFULNESS                         SLEEP
   ↑                                   ↑
   |                                   |
Arousal systems ←─── mutual ───→ VLPO nucleus
(LC, DR, TMN,         inhibition
 Orexin)

→ Two stable states (like a light switch)
→ Orexin/Hypocretin stabilizes the switch toward WAKEFULNESS
→ Loss of orexin (narcolepsy) = unstable switching (sudden sleep attacks)

CIRCADIAN RHYTHM

SUPRACHIASMATIC NUCLEUS (SCN) - "Master Circadian Clock"
  Location: Anterior hypothalamus (above optic chiasm)
        |
        | Light → retina → retinohypothalamic tract
        v
SCN CLOCK GENES (CLOCK, BMAL1, PER1/2/3, CRY1/2)
  24-hour transcription-translation feedback loop
        |
        v
MELATONIN (Pineal gland):
  - Secreted in darkness
  - Peak: 2-4 AM
  - Inhibited by light (via SCN)
  - "Chemical signal of darkness"
        |
        v
SLEEP TIMING REGULATION
  Core body temperature ↓ 1-2°C at sleep onset

---

PART B: STAGES OF SLEEP

Architecture of Normal Sleep

HYPNOGRAM - NORMAL YOUNG ADULT (8 hours):

Time →  0h    1h    2h    3h    4h    5h    6h    7h    8h
        ──────────────────────────────────────────────────
Wake    ████
N1          █░░█░░░░░░░░░░░░░░░░░░░░░░░░░░░░░░░░░░░░░░
N2              ████████████████████████████████████████
N3                  ████████░░░░░░░░░░░░░░░░░░░░░░░░░░░
REM                     ████████████████████████████████
                        |→ Short  |→ Longer REM periods

DISTRIBUTION:
  - N1: 2-5% of total sleep
  - N2: 45-55% of total sleep  ← Most of the night
  - N3 (slow-wave): 15-20% - Predominates in FIRST half
  - REM: 20-25% - Predominates in SECOND half
  - Cycle length: ~90 minutes, 4-6 cycles/night

EEG Characteristics by Stage

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FUNCTIONS OF SLEEP

NREM (especially N3 - Slow Wave Sleep):
  - Physical restoration (GH secretion peak)
  - Memory consolidation (declarative/hippocampal)
  - Immune system restoration (IL-1, TNF release)
  - Glymphatic system activation (waste clearance: Aβ, tau)
  - Metabolic restoration

REM:
  - Emotional memory processing
  - Procedural memory consolidation
  - Creativity and problem solving
  - Dreaming (vivid, narrative)
  - Sympathetic surge (BP, HR increase)
  - Penile/clitoral tumescence
  - Thermoregulation OFF (poikilothermic)

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PART C: CLASSIFICATION OF SLEEP DISORDERS (ICSD-3)

SLEEP DISORDERS (ICSD-3):
        |
   _____|______________________________________
   |         |         |       |      |       |
INSOMNIA  SLEEP-    HYPER-   CIRCA- PARA-   SLEEP-
DISORDER  RELATED   SOMNIAS  DIAN   SOMNIAS RELATED
          BREATHING (Narco-   RHYTHM         MOVEMENT
          DISORDERS  lepsy)  DISORDERS       DISORDERS
          (OSA, CSA) Hyper-  (DSWPD,  (REM  (RLS,
                     somnia   ASWPD,  behavior PLMD)
                     IH)      ISWRD)  disorder,
                                     Sleepwalk,
                                     Sleep terror)

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PART D: MAJOR SLEEP DISORDERS — DETAILED

1. INSOMNIA DISORDER

HYPERAROUSAL MODEL:
  Predisposing factors (genetics, anxiety trait)
    + Precipitating factors (stress, illness)
      + Perpetuating factors (poor sleep hygiene, conditioned arousal)
              ↓
  Chronic Insomnia (3-P Model)

STEP 1: CBT-I (Cognitive Behavioral Therapy for Insomnia) - FIRST LINE
  Components:
  - Sleep restriction therapy (limit time in bed to actual sleep time)
  - Stimulus control (use bed for sleep only)
  - Sleep hygiene education
  - Cognitive restructuring (catastrophic thoughts)
  - Relaxation training

STEP 2: PHARMACOTHERAPY (2nd line, short-term)
  Benzodiazepines: Temazepam (avoid dependence)
  Non-benzodiazepine "Z-drugs": Zolpidem 5-10 mg, Zaleplon, Eszopiclone
  Melatonin receptor agonist: Ramelteon 8 mg (onset insomnia; no dependence)
  Orexin receptor antagonist: Suvorexant 10-20 mg, Lemborexant (NEWER - FDA 2019/2020)
  Low-dose sedating antidepressants: Doxepin 3-6 mg (sleep maintenance)
  Antihistamines: Diphenhydramine (limited use; tolerance rapidly)

---

2. OBSTRUCTIVE SLEEP APNEA (OSA)

• Most common sleep-related breathing disorder
• AHI ≥5/hr with symptoms or ≥15/hr regardless
• Treatment: CPAP, weight loss, positional therapy

---

3. NARCOLEPSY

LOSS OF HYPOCRETIN (OREXIN) NEURONS in lateral hypothalamus
  |
  (Autoimmune destruction - HLA-DQB1*0602 association in >90%)
  (Often triggered by H1N1 infection or Pandemrix vaccine)
  |
  v
Loss of stabilization of wake state
  |
  v
FOUR CLASSIC FEATURES ("CHESS"):
C - Cataplexy: Sudden bilateral muscle weakness triggered by strong emotions (laughing, anger)
     Consciousness preserved; pathognomonic for Type 1
     Caused by: REM atonia "leaking" into wakefulness
H - Hypnagogic hallucinations: Vivid dreams at sleep onset (REM intrusion)
E - Excessive Daytime Sleepiness (EDS): Irresistible sleep attacks; refreshing naps
S - Sleep paralysis: Unable to move at sleep onset/offset (REM atonia)
S - Sleep fragmentation: Disrupted nocturnal sleep

• PSG followed by MSLT (Multiple Sleep Latency Test)
• MSLT criteria: Mean sleep latency <8 min + ≥2 sleep-onset REM periods (SOREMPs)
• CSF hypocretin-1 <110 pg/mL (in Type 1 narcolepsy)
• HLA-DQB1*0602 (present in 95% but nonspecific)

---

4. RESTLESS LEGS SYNDROME (RLS) / WILLIS-EKBOM DISEASE

1. Urge to move legs (usually with uncomfortable sensations)
2. Worsens at rest
3. Relieved by movement
4. Worse in evening/night
5. Not due to other medical/behavioral condition

• CNS dopaminergic hypofunction (especially spinal cord)
• Iron deficiency (low brain iron → ↓ dopamine synthesis)
• Genetic: BTBD9, MEIS1, MAP2K5 gene variants

1st: Correct iron deficiency (ferritin <75 ng/mL → oral iron; <50 → IV iron)
2nd: Dopamine agonists: Pramipexole 0.125-0.5 mg, Ropinirole 0.25-4 mg, Rotigotine patch
     Beware: Augmentation (worsening over time, earlier onset, spread to arms)
3rd: Alpha-2-delta ligands: Pregabalin 150-300 mg, Gabapentin enacarbil (FDA approved)
     Preferred if pain co-morbidity; less augmentation
4th: Opioids (oxycodone-naloxone, methadone) for refractory RLS

---

5. REM SLEEP BEHAVIOR DISORDER (RBD)

• RBD is a BIOMARKER and PRODROMAL STATE of Parkinson's

• Clonazepam 0.5-2 mg at bedtime (most effective)
• Melatonin 3-12 mg at bedtime (safer in elderly/PD)
• Bedroom safety (padding, mattress on floor)

---

6. PARASOMNIAS (NREM)

---

7. CIRCADIAN RHYTHM DISORDERS

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PART E: SLEEP AND CARDIOVASCULAR SYSTEM

• NREM sleep: Sympathetic activity ↓, parasympathetic ↑ → BP ↓ 10-20% ("dipping"), HR ↓, CO ↓ (Fuster & Hurst 15E)
• REM sleep: Sympathetic surges → BP/HR variability → vulnerable period for cardiac events (MI, arrhythmias)
• OSA → Non-dipping BP pattern → cardiovascular risk

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QUESTION 21 (Short Answer - 6 Marks)

BELL'S PALSY

---

DEFINITION

---

ETIOLOGY & PATHOGENESIS

MOST LIKELY CAUSE:
Herpes Simplex Virus type 1 (HSV-1) reactivation in geniculate ganglion
(Bradley & Daroff; HSV-1 DNA found in endoneural fluid)

Mechanism:
  HSV-1 reactivation → Viral inflammation → Edema of CN VII
  → Compression in narrow bony facial canal → Ischemia/demyelination
  → LMN facial weakness

Other associations:
  - Herpes zoster (Ramsay Hunt syndrome - severe form with vesicles)
  - VZV reactivation in geniculate ganglion

---

CLINICAL FEATURES

LMN vs UMN Facial Palsy — Crucial Distinction

LMN FACIAL PALSY (Bell's Palsy):         UMN FACIAL PALSY (Stroke):
  - FOREHEAD INVOLVED                      - FOREHEAD SPARED
  (ipsilateral brow cannot be raised)      (bilateral cortical representation)
  - Complete facial muscle weakness        - Only lower face weakness
  - Ipsilateral (same side as lesion)      - Contralateral (opposite to lesion)

Full Feature Set of Bell's Palsy

FACIAL SYMPTOMS:
  □ Sudden onset (hours to 2-3 days)
  □ Unilateral facial droop
  □ Inability to close eye (lagophthalmos) → exposure keratitis risk
  □ Cannot raise eyebrow (forehead spared in UMN)
  □ Bell's phenomenon: Eye rolls upward on attempted closure
  □ Flattening of nasolabial fold
  □ Mouth droops, food/fluid collection

ASSOCIATED SYMPTOMS (based on level of CN VII involvement):
  □ Retroauricular pain (pre-paralysis - geniculate ganglion)
  □ Hyperacusis (nerve to stapedius, above geniculate ganglion)
  □ Loss of taste on anterior 2/3 tongue (chorda tympani)
  □ Reduced lacrimation (greater superficial petrosal nerve - proximal)
  □ Reduced salivation (chorda tympani)

Grading (House-Brackmann Scale)

---

DIAGNOSIS

• Ramsay Hunt syndrome (VZV): Vesicles in EAC/pinna + facial palsy + sensorineural deafness
• Lyme disease (bilateral facial palsy possible)
• Parotid tumor (gradual onset, mass)
• Stroke (UMN pattern - forehead spared)
• Sarcoidosis (bilateral facial palsy - Heerfordt syndrome)
• GBS (bilateral - Miller Fisher variant)
• Skull base tumor

• No routine testing for typical Bell's palsy
• If atypical: MRI (with gadolinium), CSF, Lyme serology, glucose
• NCS/EMG at 14 days (prognostic - denervation = poor prognosis)

---

MANAGEMENT

Treatment Protocol

BELL'S PALSY TREATMENT:

WITHIN 72 HOURS (best results):
1. PREDNISOLONE 60-80 mg/day × 5-7 days, then taper over 5 days
   (Kanski's Ophthalmology: 60-80 mg × 1 week, then taper)
   Evidence: BELLS study (2007) - steroids improve recovery rate

2. ANTIVIRAL (add to steroids for severe palsy HB Grade IV-VI):
   Valaciclovir 1000 mg TID × 7 days OR Acyclovir 400 mg 5×/day × 7 days
   (Evidence controversial - some benefit when combined with steroids)
   Note: Antivirals alone are INSUFFICIENT

EYE PROTECTION (critical - exposure keratitis prevention):
  - Artificial tears every 2 hours during waking
  - Lubricating eye ointment at night (Lacrilube)
  - Tape eyelid closed at night
  - Moisture chamber/eyeglass side shield
  - Ophthalmology referral if corneal signs

PHYSIOTHERAPY:
  - Facial exercises (after 3-4 weeks)
  - Neuromuscular rehabilitation
  - Mirror feedback therapy

LATER:
  - Botulinum toxin for synkinesis or spasm (after 3-6 months)
  - Surgical decompression (controversial; rarely used)

Prognosis

PROGNOSIS OF BELL'S PALSY:
  - 85% COMPLETE recovery within 3-6 months
  - 10-15% have incomplete recovery (synkinesis, contracture, crocodile tears)
  - <5% severe permanent deficit

POOR PROGNOSIS:
  - Complete paralysis at onset (HB Grade VI)
  - Age >60
  - Hypertension, diabetes
  - No recovery by 3-4 weeks
  - Absent CMAP on EMG at 14 days
  - Ramsay Hunt (worse prognosis than Bell's)

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QUESTION 22 (Short Answer - 6 Marks)

ABERNETHY SYNDROME (ABERNETHY MALFORMATION)

---

DEFINITION

---

CLASSIFICATION (Morgan & Superina, 1994)

ABERNETHY MALFORMATION
        |
   _____|___________
   |                |
TYPE 1            TYPE 2
(Extrahepatic)    (Side-to-side extrahepatic)
   |                |
Portal vein       Portal vein
COMPLETELY        PARTIALLY
diverted to IVC   diverted to IVC
(Absent/absent    (Portal vein present
portal flow       but large side-to-side
to liver)         shunt to IVC/renal/
   |               iliac vein)
TYPE 1a: SMA + SMV →IVC
TYPE 1b: Confluence (portal)→IVC

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PATHOPHYSIOLOGY

CONGENITAL SHUNT FORMATION
        |
        v
Portal blood bypasses hepatic sinusoids
        |
   _____|____________________
   |                        |
LIVER:                  SYSTEMIC CIRCULATION:
  - Reduced portal        - Elevated ammonia
    flow → atrophy          (portosystemic
  - Hepatic nodules          encephalopathy)
  - NRH (nodular           - Elevated bile acids
    regenerative           - Gut-derived hormones
    hyperplasia)             unmetabolized
  - Hepatocellular         - Vasoactive peptides
    carcinoma risk            → Hyperdynamic
  - Risk of malignant        circulation
    transformation         - Hepatopulmonary
    in nodules               syndrome (HPS)

---

CLINICAL FEATURES

Presentation (Variable — Often Diagnosed Incidentally)

AGE OF PRESENTATION:
  Neonates/Infants: Cholestatic jaundice, liver failure, hypoglycemia
  Children: Hepatic encephalopathy, abnormal LFTs
  Adults: Incidental finding on imaging; complications

MANIFESTATIONS BY SYSTEM:

NEUROLOGICAL:
  - Hepatic encephalopathy (asterixis, confusion, altered consciousness)
  - Portosystemic myelopathy (spastic paraparesis - rare)

PULMONARY:
  - Hepatopulmonary syndrome (HPS): Intrapulmonary vascular dilatation
    → Hypoxemia, platypnea (dyspnea worsening upright) + orthodexia
  - Portopulmonary hypertension (rare)

HEPATIC:
  - Hepatic nodules (NRH, HCC, FNH, adenoma)
  - Liver atrophy and hypertrophy (Type 1)
  - Biliary atresia (associated)

CARDIAC:
  - Congenital heart defects (ASD, VSD, PDA) - especially Type 1
  - Hyperdynamic circulation

ENDOCRINE:
  - Hyperinsulinemic hypoglycemia
  - Galactosemia-like picture

GASTROINTESTINAL:
  - Splenomegaly (variable)
  - May have NO portal hypertension (portal blood never reaches liver)

---

INVESTIGATIONS

---

MANAGEMENT

TREATMENT DECISION TREE:

TYPE 1 (NO portal flow to liver):
        |
        v
Liver function adequate?
  NO → Liver transplantation (with shunt ligation)
  YES → Symptomatic management only (no curative option)
         (Lactulose for HE; screen for HCC)

TYPE 2 (partial portal flow preserved):
        |
        v
Test portal vein patency and liver reserve
        |
        v
Balloon occlusion test of shunt → Does portal pressure rise <40 mmHg?
        |
   YES (liver can handle)    NO (portal hypertension develops)
        |                         |
   SHUNT CLOSURE              Conservative
   (surgical ligation or      OR liver transplant if severe
   endovascular coiling)

SPECIFIC COMPLICATIONS:
  HE: Lactulose, rifaximin, low-protein diet (avoid)
  HPS: O₂ supplementation; liver transplant (HPS resolves post-transplant)
  Nodules: Serial surveillance; resect if HCC suspected
  Hypoglycemia: Continuous glucose infusion, cornstarch

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QUESTION 23 (Long Answer - 20 Marks)

CLINICAL FEATURES OF GBS + NEWER MODALITIES OF TREATMENT

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PART A: CLINICAL FEATURES OF GBS

Definition & Overview

• Most common cause of acute flaccid paralysis worldwide after polio eradication
• Incidence: 1-2/100,000/year; slight male predominance
• Peak ages: 15-35 years and >55 years (bimodal)

Antecedent Illness (Trigger)

• 2/3 patients have infection 1-4 weeks before onset
• Campylobacter jejuni (most common; 30%; AMAN subtype)
• CMV, EBV, Mycoplasma pneumoniae, Zika virus
• SARS-CoV-2 (COVID-19 association documented)
• Surgery, trauma, vaccination (very rare)

---

SUBTYPES AND CLINICAL PATTERNS

---

CLINICAL FEATURES — DETAILED

PRODROMAL PHASE (1-4 weeks before):
  Upper respiratory infection (sore throat, runny nose)
  OR Gastrointestinal illness (diarrhea - C. jejuni)

ONSET PHASE (hours to days):
  - Paresthesia in feet/toes (tingling, "pins and needles")
  - Pain in lower back, thighs (radicular pain in ~50%)
  - Pain is often the FIRST symptom (missed/overlooked)
  - Mild weakness begins distally

Motor Features

ASCENDING PARALYSIS (centripetal spread):
  Toes → Feet → Legs → Hips → Trunk → Arms → Hands
                                → Neck → CN (bulbar)
                                → Respiratory muscles

CHARACTERISTICS:
  ✓ Bilateral (usually symmetric)
  ✓ FLACCID (hypotonia)
  ✓ AREFLEXIA (absent deep tendon reflexes - hallmark)
    - First to disappear: Ankle jerks
    - Then: Knee jerks, biceps, triceps
  ✓ Relatively rapid progression (days to weeks)
  ✓ NADIR reached by 4 weeks (by definition)

Sensory Features

• Paresthesia (tingling, numbness) in glove-stocking distribution
• Large fiber modalities affected: Vibration, proprioception
• Pain: Present in >50% (radicular, myalgic, dysesthetic)
• Sensory loss usually LESS severe than motor loss
• Pure sensory GBS: Rare variant

Cranial Nerve Involvement (50% of patients)

• Bilateral facial palsy (CN VII): Most common CN involvement (bilateral = clue to GBS)
• Oculomotor palsy (CN III, IV, VI): MFS variant especially
• Bulbar palsy: Dysarthria, dysphagia, nasal voice (CN IX, X)
• Neck flexor weakness (head drop)

Respiratory Involvement — CRITICAL

RESPIRATORY COMPROMISE:
  - Occurs in 25-30% of GBS patients requiring ICU admission
  - Due to: Intercostal + diaphragm paralysis

  PREDICTORS ("20-30-40 RULE"):
  FVC < 20 mL/kg → Consider intubation
  NIF < -30 cmH₂O → Consider intubation
  MIP < -40 cmH₂O → Consider intubation

  EARLY SIGNS:
  □ Dyspnea on exertion then at rest
  □ Orthopnea (diaphragm - worse when lying flat)
  □ Inability to count to 20 in one breath
  □ Paradoxical abdominal movement
  □ Accessory muscle use

  "FVC monitors should be done every 4-6 hours in ICU"

Autonomic Features (Life-Threatening)

• Present in 50-75% of hospitalized GBS patients
• Cardiac: Tachycardia, bradycardia, cardiac arrhythmias (most dangerous)
• Blood pressure: Labile hypertension/hypotension (dysautonomia)
• GI: Ileus, constipation, diarrhea
• Urinary: Retention, incontinence
• Sweating abnormalities
• Pupillary dysfunction
• Sinus arrest/asystole (rare but fatal) → Cardiac monitoring MANDATORY

---

DIAGNOSTIC CRITERIA (Brighton Collaboration 2011)

CSF Findings

• Albuminocytologic dissociation = Elevated protein + normal cells
• Protein: 100-1000 mg/dL (elevated in >80% at 2-4 weeks)
• Cells: <10 WBC/μL (if >50 → consider other diagnoses: HIV, Lyme, CMV)
• May be normal in FIRST week (repeat LP if strong clinical suspicion)

NCS/EMG Pattern

AIDP (demyelinating):
  - Prolonged distal latencies
  - Slowed conduction velocity (<60% LLN)
  - Conduction block (diagnostic of demyelination)
  - Prolonged/absent F-waves (early, sensitive)
  - Abnormal H-reflex

AMAN/AMSAN (axonal):
  - Reduced CMAP/SNAP amplitude (early)
  - Normal or mildly reduced conduction velocity
  - May show reversible conduction failure (early motor recovery)

---

DIFFERENTIAL DIAGNOSIS OF GBS

MIMICS OF GBS:
  ├── Transverse Myelitis (sensory level + bladder)
  ├── Spinal cord compression (UMN signs, sensory level)
  ├── Hypokalemic periodic paralysis (K+ level, no sensory loss)
  ├── Myasthenia Gravis crisis (fatigable, normal CSF, decremental EMG)
  ├── Botulism (descending, dilated fixed pupils, autonomic)
  ├── West Nile Virus myelitis (fever, asymmetric, CSF pleocytosis)
  ├── Critical illness polyneuropathy (ICU setting, gradual)
  ├── Vasculitic neuropathy (multifocal, painful, asymmetric)
  └── Porphyric neuropathy (abdominal pain, urine ALA/PBG)

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PART B: NEWER MODALITIES OF TREATMENT OF GBS

Standard Disease-Modifying Therapy (Established)

STANDARD TREATMENT (Choose ONE):

IVIG:
  Dose: 0.4 g/kg/day × 5 days (total 2 g/kg)
  OR 1 g/kg/day × 2 days
  MUST be within 4 weeks of onset (best if within 2 weeks)
  Mechanism: Anti-idiotype antibodies neutralizing pathogenic Ab

PLASMAPHERESIS:
  5 exchanges (40-50 mL/kg) over 10-14 days
  Best if within 2 weeks of onset
  Removes pathogenic antibodies/complement

(DO NOT COMBINE — no additional benefit, increased complications)
(STEROIDS ALONE: NOT beneficial; may delay recovery)

NEWER MODALITIES

1. Second Course of IVIg (SID-GBS Trial, 2023)

• Rationale: Poor responders to initial IVIg had low IgG levels → need higher dose
• ICE score / SID-GBS criteria: Identifies non-responders after first IVIg course
• Approach: Second 2 g/kg IVIg course in patients with low IgG increase after 1st course
• IGOS Trial ongoing: International GBS Outcome Study — largest prospective cohort

2. Eculizumab (Terminal Complement Inhibitor)

• Mechanism: Blocks C5 cleavage → prevents MAC (C5b-9) formation on peripheral nerve myelin/axon
• Evidence: PREVENT-GBS phase 2/3 trial — small pilot showed faster improvement in severe GBS
• Anti-GQ1b positive MFS: May be especially effective
• Ongoing trials: Phase 3 CARES-GBS trial

3. Imlifidase (IgG-degrading enzyme)

• Mechanism: Cysteine protease from Streptococcus pyogenes that cleaves ALL IgG including anti-ganglioside antibodies
• Advantage: Rapid (hours) clearance of IgG (vs days for PE/IVIg)
• Evidence: Phase 2 ImGUARD trial ongoing
• Could be used as rapid "induction" before IVIg

4. Inhibitors of Neonatal Fc Receptor (FcRn antagonists)

• Efgartigimod, Rozanolixizumab: Block FcRn → accelerate catabolism of all IgG
• Already approved for MG — trials in GBS underway

5. Anti-Ganglioside Monoclonal Antibodies

• Blocking anti-GM1/GD1a antibodies before they bind peripheral nerve
• Preclinical stage

6. Neurofilament Light Chain (NfL) as Biomarker

• Serum NfL correlates with axonal injury severity
• Predicts functional outcome at 6 months
• Guides treatment decisions (not a treatment itself, but precision medicine tool)

7. Neuroregeneration / Remyelination Strategies

• GDNF, CNTF: Neurotrophic factors promoting remyelination — preclinical
• Etanercept (anti-TNF): Reduces neuroinflammation — small studies

8. Targeted Physiotherapy (newer protocols)

• High-intensity physiotherapy during plateau/recovery phase
• Body weight-supported treadmill training
• Neuromuscular electrical stimulation (NMES) for severe weakness
• Intensive dysphagia rehabilitation

SUMMARY — NEWER GBS TREATMENTS:
        |
   _____|_______________________________________
   |              |              |             |
COMPLEMENT    FcRn           IgG            AXONAL
INHIBITION    INHIBITION     DEGRADATION    PROTECTION
(Eculizumab)  (Efgartigimod) (Imlifidase)   (NfL biomarker
              (Rozanolixizumab)              guided therapy)
   |              |              |
Phase 2/3     Trials         Phase 2
ongoing       ongoing        ongoing

MONITORING & SUPPORTIVE CARE (Essential)

---

---

QUESTION 24 (Long Answer - 20 Marks)

APHASIAS — TYPES, DEVELOPMENT, STRUCTURE-PHYSIOLOGY, AND CONDUCTION APHASIA

---

DEFINITION

---

ANATOMY OF LANGUAGE — THE PERISYLVIAN NETWORK

Key Structures

LEFT LATERAL HEMISPHERE — LANGUAGE CIRCUIT:

BROCA'S AREA (Inferior Frontal Gyrus - BA 44, 45):
  - Motor programming of speech
  - Syntactic processing
  - Expressive/productive speech
  - "Speech output area"
  - Blood supply: ANTERIOR division of Left MCA
        |
        | [Arcuate Fasciculus + Superior Longitudinal Fasciculus]
        | (subcortical white matter connection)
        |
WERNICKE'S AREA (Posterior Superior Temporal Gyrus - BA 22):
  - Auditory processing and comprehension of spoken language
  - Phonological decoding
  - "Receptive/comprehension area"
  - Blood supply: POSTERIOR division of Left MCA

ANGULAR GYRUS (BA 39) - inferior parietal lobule:
  - Reading and writing
  - Cross-modal integration (visual-auditory-verbal)
  - Alexia/agraphia when damaged

SUPRAMARGINAL GYRUS (BA 40):
  - Phonological working memory
  - Repetition (part of arcuate fasciculus relay)

ARCUATE FASCICULUS:
  - White matter bundle connecting Wernicke → Broca
  - Damage → Conduction aphasia

Diagram of Language Areas

SUPERIOR VIEW OF LEFT LATERAL HEMISPHERE:

     FRONTAL LOBE          |    PARIETAL LOBE
                           |
  ┌────────────┐           |  ┌──────────────────┐
  │ BROCA'S   │           |  │  SUPRAMARGINAL   │
  │ AREA      │           |  │  GYRUS (BA40)    │
  │ BA 44/45  │           |  │  [repetition]    │
  └────┬───────┘           |  └─────────────────┬┘
       │     Arcuate fasciculus (subcortical)   │
       │◄──────────────────────────────────────│
       │                   |                   │
       │                   |  ┌────────────────┐│
       │                   |  │ ANGULAR GYRUS  ││
       │                   |  │ BA39 [reading/ ││
       │                   |  │ writing]       ││
       │                   |  └────────────────┘│
                SYLVIAN FISSURE
     TEMPORAL LOBE         |
  ┌────────────────────────┘
  │ WERNICKE'S AREA
  │ BA 22 (Post. Sup. Temporal Gyrus)
  │ [comprehension, decoding]
  └──────────────────────────

ALSO: Insula, Basal Ganglia, Thalamus = "Deep language structures"

---

CLASSIFICATION OF APHASIAS

Major Aphasias — Perisylvian (Repetition IMPAIRED)

Minor Aphasias — Transcortical (Repetition PRESERVED)

Other Specific Aphasias

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DETAILED CLINICAL FEATURES

BROCA'S APHASIA (Expressive/Motor Aphasia)

"BROKEN SPEECH":
  - NON-FLUENT: Few words, long pauses, effortful
  - Telegraphic (agrammatic) speech - omits function words
    ("want...water...drink" instead of "I want to drink water")
  - Phonemic/literal paraphasia (sound substitutions: "spoon" → "fpoon")
  - Comprehension: Relatively PRESERVED for simple speech
    (impaired for complex syntax)
  - Repetition: IMPAIRED
  - Reading: Usually impaired (alexia)
  - Writing: Agraphia (parallels speech)
  - Awareness: PRESERVED (frustrated, depressed)
  - Associated right hemiplegia (Broca's area adjacent to motor cortex)
  - Buccofacial apraxia (cannot perform oral movements on command)
  
Lesion: Inferior frontal gyrus (BA 44/45) ± insula
Cause: Left MCA anterior division infarct

WERNICKE'S APHASIA (Receptive/Sensory Aphasia)

"WORD SALAD":
  - FLUENT: Normal rate and rhythm, normal prosody
  - Paraphasias:
    * Literal (phonemic): "pat" → "bat"
    * Verbal (semantic): "dog" → "animal"
    * Neologisms: Made-up words ("brakish")
    * Jargon aphasia: String of paraphasic errors, unintelligible
  - Comprehension: SEVERELY IMPAIRED
    (cannot understand spoken OR written language)
  - Repetition: IMPAIRED
  - Naming: IMPAIRED (paraphasic substitutions)
  - Awareness: Often ABSENT → patient unaware of errors
    (important clinically - denial, no frustration)
  - NO associated hemiplegia (usually; motor cortex spared)
  - May have superior quadrantanopia (optic radiation)
  
Lesion: Posterior superior temporal gyrus (BA 22)
Cause: Left MCA posterior division infarct

---

CONDUCTION APHASIA

CONDUCTION APHASIA — KEY FEATURES:
  
  Fluency: FLUENT (well-formed sentences, good prosody)
  Comprehension: RELATIVELY INTACT
  Repetition: SEVERELY IMPAIRED ← HALLMARK
  Naming: Impaired (literal paraphasia)
  
CHARACTERISTIC FINDING:
  Patient can understand what you say
  Patient can speak fluently on their own
  BUT when asked to REPEAT a phrase:
  → Cannot do it exactly
  → Makes substitutions (literal/phonemic paraphasias)
  → Makes multiple attempts to correct errors ("conduite d'approche")
    e.g., Examiner: "Say hippopotamus"
          Patient: "hippopota... no... hipp... hippotamus... hippopotamus" 
  
ANATOMY:
  Lesion in ARCUATE FASCICULUS
  (connecting Wernicke's area in temporal lobe to Broca's area in frontal lobe)
  OR Supramarginal gyrus (BA 40) - insular cortex

  The repetition circuit is DISCONNECTED:
  Wernicke's (intact comprehension) → Arcuate fasciculus (damaged)
  → Cannot transmit to Broca's area for repetition

  → This is a DISCONNECTION SYNDROME
  (Adams & Victor 12E: "central aphasia" — Wernicke area separated from Broca area)

---

ASSESSMENT OF APHASIA

Bedside Testing Protocol

LANGUAGE EXAMINATION:
  1. SPONTANEOUS SPEECH:
     - Fluent or Non-fluent?
     - Paraphasias? (semantic/phonemic/neologisms)
     - Prosody, grammar, word finding

  2. COMPREHENSION (simple → complex):
     - "Close your eyes" (1-step)
     - "Point to the window then the door" (2-step)
     - Yes/No questions
     - Token test (follow written instructions)

  3. REPETITION:
     - Single words → phrases → sentences
     - Key test: "No ifs, ands, or buts"
     - "The spy fled to Greece" (syntax-heavy)

  4. NAMING:
     - Confrontation naming (show objects: pen, watch, coin)
     - Category fluency ("Name 10 animals in 1 minute")
     - Phonemic fluency ("Words beginning with F")

  5. READING:
     - Read aloud vs silent reading comprehension
     - Simple text to complex

  6. WRITING:
     - Spontaneous writing
     - Writing to dictation
     - Copying

FORMAL: WAB (Western Aphasia Battery), Boston Diagnostic Aphasia Examination

---

MANAGEMENT OF APHASIA

Speech-Language Therapy (Core)

• Constraint-induced aphasia therapy (CIAT/CILT): Intensive, massed practice
• Supported conversation techniques
• Augmentative and Alternative Communication (AAC) devices
• Melodic intonation therapy (MIT): Using melody/rhythm to improve expression in Broca's aphasia

Pharmacological (Adjunct)

• Amphetamine + speech therapy: Some RCT evidence for speed of recovery
• Donepezil (cholinesterase inhibitor): Modest evidence for improvement
• Bromocriptine: Tried for transcortical motor aphasia (limited evidence)
• Memantine: Being investigated

Neuroimaging-Guided Treatment

• TMS (Transcranial Magnetic Stimulation):
  • Inhibitory TMS to right hemisphere (silences competitive right-sided language areas)
  • Allows left hemisphere to reactivate
  • Some benefit in chronic aphasia
• tDCS (Transcranial Direct Current Stimulation):
  • Anodal over left Broca's → facilitates left hemisphere re-recruitment

---

---

QUESTION 25 (Long Answer - 20 Marks)

STAGES OF SLEEP + PATHOPHYSIOLOGY & MANAGEMENT OF OSA

---

PART A: STAGES OF SLEEP (Detailed)

POLYSOMNOGRAPHY (PSG) — THE GOLD STANDARD

• EEG (brain electrical activity — sleep staging)
• EOG (electro-oculogram — eye movements)
• EMG (submental — muscle tone; limb — movements)
• Airflow (nasal/oral thermistor + pressure transducer)
• Respiratory effort (chest + abdominal belts)
• SpO₂ (pulse oximetry)
• ECG
• Body position sensor
• Audio/video recording

---

DETAILED SLEEP STAGES

STAGE N1 (NREM 1 — Drowsiness, Transition)

EEG: Alpha (8-12 Hz) disappears → Theta (4-7 Hz) appears
EOG: Slow rolling eye movements (SEM)
EMG: Reduced (slight reduction in muscle tone)
Duration: 1-7 minutes per epoch
Features:
  - Hypnic jerks (sleep starts) — sudden myoclonic jerks
  - Vertex sharp waves
  - Hypnagogic hallucinations (vivid images at sleep onset - especially narcolepsy)
  - Easily awakened; may not feel they were asleep
% of night: 2-5%

STAGE N2 (NREM 2 — Light Sleep)

EEG: Background theta + TWO DISTINCTIVE FEATURES:
  1. SLEEP SPINDLES (sigma waves, 12-16 Hz, 0.5-2 sec duration, waxing-waning)
     - Generated by thalamocortical circuits
     - Thalamic reticular nucleus acts as "pacemaker"
     - Function: Memory consolidation + protection from external stimuli
  2. K-COMPLEXES (large negative-positive biphasic waves, max amplitude >75μV)
     - Can be evoked by external stimuli
     - Function: Suppress cortical arousal + initiate sleep spindles

EOG: No eye movements
EMG: Further reduced
% of night: 45-55%
Features:
  - Bruxism (teeth grinding) can begin here
  - Blood pressure and heart rate decline

STAGE N3 (NREM 3 — Slow Wave Sleep / Deep Sleep)

EEG: Delta waves (0.5-4 Hz, >75μV amplitude) comprising >20% of epoch
   "High-amplitude slow wave activity"
EOG: No eye movements
EMG: Very low (most relaxed)
% of night: 15-20% (predominantly in FIRST HALF of night)
Features:
  - MOST DIFFICULT to arouse ("deep sleep")
  - Night terrors, sleepwalking, confusional arousal occur here
  - GROWTH HORMONE secretion peaks (GH surge in first SWS period)
  - Glymphatic system most active (brain waste clearance)
  - Immune restoration
  - Declarative memory consolidation
  - Decreases with age (elderly have very little N3)

REM SLEEP (Rapid Eye Movement)

EEG: Low voltage, mixed frequency (similar to wakefulness - "activated")
     Sawtooth waves (2-6 Hz theta, serrated appearance) = CHARACTERISTIC
EOG: Bursts of rapid, conjugate eye movements (REMs)
EMG: MUSCLE ATONIA (virtually flat EMG - active inhibition via glycine/GABA)
     Exception: Respiratory muscles, extra-ocular muscles

% of night: 20-25% (predominantly in SECOND HALF of night)
Features:
  ✓ Vivid, narrative dreaming
  ✓ Autonomic variability (heart rate, blood pressure fluctuations)
  ✓ Thermoregulation suspended (poikilothermic)
  ✓ Penile/clitoral tumescence
  ✓ Increased cerebral blood flow
  ✓ Emotional memory processing
  ✓ Acetylcholine-driven (ACh promotes REM from LDT/PPT nuclei)
  ✓ Norepinephrine and serotonin LOWEST during REM
     (NE from LC; 5-HT from DR — minimal during REM)

REM CYCLES: First 90 min, gradually LENGTHEN → 
  Last REM period: 45-60 min

---

SLEEP CYCLE DIAGRAM

NORMAL SLEEP ARCHITECTURE (HYPNOGRAM):

           Awake ─┐
                  │
           N1 ────┤    ┌─────────────────────────────────┐
                  │    │                                  │
           N2 ────┤────┤    ┌──────────┐    ┌────────────┤
                  │    │    │          │    │             │
           N3 ────┤────┘    │          └────┘             │
                  │         │                              │
           REM ───┤─────────┘──────────────────────────────┘
                  └───────────────────────────────────────────►
                  11PM   12AM    1AM    2AM    3AM    4AM    5AM    6AM

NREM-REM Cycle = ~90 minutes
N3 (deep sleep) = FIRST 2 cycles
REM (dreaming) = LAST 2-3 cycles (lengthens through night)

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PART B: OBSTRUCTIVE SLEEP APNEA (OSA)

Definition

• Sleep fragmentation
• Hypoxemia and hypercapnia
• Daytime symptoms

• Apnea: Cessation of airflow ≥10 seconds
• Hypopnea: ≥30% reduction in airflow + ≥3% SpO₂ drop OR arousal
• AHI (Apnea-Hypopnea Index): Number of events per hour of sleep

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PATHOPHYSIOLOGY OF OSA

PATHOPHYSIOLOGY — MULTILEVEL MODEL:

1. ANATOMICAL PREDISPOSITION:
   - Narrow oropharynx (large tongue, tonsils, low soft palate)
   - Reduced upper airway size (retrognathia, maxillary hypoplasia)
   - Fat deposition in parapharyngeal fat pads (obesity)
   - Increased airway length (males > females; risk factor)

2. REDUCED UPPER AIRWAY MUSCLE ACTIVITY DURING SLEEP:
   - Genioglossus and tensor palatini normally stiffen airway
   - Sleep → NE and 5-HT withdrawal → Reduced muscle tone
   - Critical closing pressure (Pcrit) becomes positive → airway collapses

3. IMPAIRED AROUSAL THRESHOLD (HIGH arousal threshold in some):
   - Delayed awakening from apneic events
   - Prolonged hypoxia before arousal

4. UNSTABLE VENTILATORY CONTROL (High loop gain):
   - Excessive ventilatory response to CO₂ changes
   - Leads to cycling of apnea-hyperpnea (Cheyne-Stokes-like)

5. THE APNEA CYCLE:
   
   SLEEP ONSET
       |
       v
   Upper airway muscle tone ↓
       |
       v
   AIRWAY COLLAPSE (Obstructed)
       |
       v
   Airflow ↓ or ↑ → APNEA / HYPOPNEA
       |
       v
   PCO₂ rises, PO₂ falls
       |
       v
   Chemoreceptors activated → Drive ↑
       |
       v
   AROUSAL (micro or full)
       |
       v
   Airway reopens → Airflow restored → SNORT
       |
       v
   Returns to sleep → CYCLE REPEATS
   (Often 30-50 times/hour in severe OSA)

CONSEQUENCES OF OSA

ACUTE (each apnea event):
  - Hypoxemia (SpO₂ drops; < 80% in severe)
  - Hypercapnia
  - Negative intrathoracic pressure (attempts against closed airway)
  - Sympathetic surges (catecholamine release)
  - Cortisol elevation
  - Increased platelet aggregation

CHRONIC:
  CARDIOVASCULAR:
    - Systemic hypertension (present in 50% OSA; non-dipping BP pattern)
    - Pulmonary hypertension (from hypoxia)
    - Coronary artery disease (2-3× risk)
    - Atrial fibrillation (1.5-4× risk)
    - Heart failure (exacerbation)
    - Stroke (2-3× risk)
  
  METABOLIC:
    - Insulin resistance / Type 2 DM
    - Dyslipidemia
    - NAFLD/NASH
    - Metabolic syndrome
  
  NEUROLOGICAL/COGNITIVE:
    - Excessive daytime sleepiness (EDS)
    - Cognitive impairment (memory, executive function)
    - Depression, anxiety
    - Increased motor vehicle accidents (7× risk)
  
  ENDOCRINE:
    - GH secretion blunted (N3 disrupted)
    - Testosterone ↓ in males
    - Erythrocytosis (polycythemia from hypoxia)

---

CLINICAL FEATURES

NOCTURNAL:
  ✓ Loud, habitual snoring (prominent; sleeping partner reports)
  ✓ Witnessed apneas (breathing stops; partner observes)
  ✓ Gasping/choking/snorting arousals
  ✓ Nocturia (atrial natriuretic peptide from cardiac distension)
  ✓ Diaphoresis (from sympathetic surges)
  ✓ Bruxism, restless sleep
  ✓ Unrefreshing sleep despite adequate hours

DAYTIME:
  ✓ Excessive daytime sleepiness (Epworth Sleepiness Scale >10 = abnormal)
  ✓ Non-restorative sleep
  ✓ Morning headache (CO₂ retention)
  ✓ Cognitive impairment: Concentration, memory
  ✓ Irritability, mood disturbance
  ✓ Sexual dysfunction, erectile dysfunction

PHYSICAL EXAMINATION:
  ✓ Obesity (BMI >30 in 60-70%; but 30% of OSA is non-obese)
  ✓ Neck circumference: Men >43 cm, Women >38 cm
  ✓ Mallampati class III/IV (tongue relative to oropharynx)
  ✓ Tonsillar hypertrophy, low-hanging soft palate, small mandible
  ✓ Crowded oropharynx
  ✓ Hypertension, arrhythmia, signs of right heart failure

MODIFIED MALLAMPATI CLASSIFICATION

Class I: Full visibility of tonsils, uvula, soft palate
Class II: Visibility of hard and soft palate, upper portion of tonsils and uvula
Class III: Soft and hard palate visible; base of uvula visible
Class IV: Only hard palate visible
→ Class III/IV correlates with difficult intubation AND OSA risk

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DIAGNOSIS

Screening Tools

S - Snoring: Do you snore loudly?
T - Tired: Often tired/sleepy during daytime?
O - Observed: Observed to stop breathing during sleep?
P - Pressure: Treated or have high blood pressure?
B - BMI: >35?
A - Age: >50 years?
N - Neck: Circumference >40 cm?
G - Gender: Male?
Score: 0-2 (low), 3-4 (intermediate), 5-8 (high risk)

Diagnostic Testing

SUSPECTED OSA
      |
      v
Level 3 Home Sleep Apnea Test (HSAT):
  - Portable monitor (airflow, SpO₂, effort, HR, position)
  - Used for uncomplicated OSA (no other sleep disorders)
  - Cost-effective, convenient
      |
      v
OR Level 1/2 In-Lab PSG (Polysomnography):
  - Gold standard
  - Required if: HSAT inconclusive, suspected non-OSA disorders,
    significant comorbidities, respiratory disease, neuromuscular disease
      |
      v
AHI interpretation:
  <5 = Normal; 5-15 = Mild; 15-30 = Moderate; >30 = Severe

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MANAGEMENT OF OSA

FLOWCHART

CONFIRMED OSA
      |
      v
ASSESS: Severity (AHI), Symptoms (ESS), Comorbidities
      |
      v
ALL PATIENTS: GENERAL MEASURES
  - Weight loss (10% weight loss → 26% AHI reduction)
  - Sleep position (lateral/avoidance of supine)
  - Avoid alcohol, sedatives, smoking cessation
  - Treat nasal congestion
      |
      v
      |
MILD OSA (AHI 5-15):                   MODERATE-SEVERE (AHI >15):
  First: Positional therapy +            CPAP THERAPY (First Line)
  Weight loss + Oral appliance           (even if asymptomatic if AHI >30
      |                                   or significant comorbidities)
If fails → CPAP

1. CPAP (Continuous Positive Airway Pressure) — GOLD STANDARD

MECHANISM:
  Delivers continuous positive pressure (4-20 cmH₂O)
  Acts as "pneumatic splint" to keep upper airway open
  → Prevents pharyngeal collapse

TYPES:
  Fixed CPAP: Single preset pressure
  Auto-CPAP (APAP): Automatically adjusts 4-20 cmH₂O
  BiPAP (Bilevel): Higher pressure on inspiration, lower on expiration
    (for OSA with hypoventilation, CO₂ retention, obesity hypoventilation)

BENEFITS:
  - Eliminates apneas/hypopneas
  - Normalizes SpO₂
  - Reduces daytime sleepiness (ESS improves)
  - Reduces blood pressure (~3-4 mmHg systolic)
  - Reduces atrial fibrillation recurrence after cardioversion
  - Improves cognitive function
  - May reduce HbA1c (modest)

ADHERENCE ISSUES:
  - 50% of patients non-adherent (use <4 hrs/night)
  - Barriers: Discomfort, claustrophobia, mask leak
  - Improve adherence: Heated humidifier, pressure ramp, mask refitting

2. Mandibular Advancement Device (MAD) / Oral Appliance

• Moves mandible 50-75% of maximum protrusion
• Enlarges oropharyngeal airspace
• Efficacy: 50-65% of CPAP in mild-moderate OSA
• Preferred when CPAP-intolerant, mild-moderate OSA
• SE: Jaw discomfort, TMJ issues, tooth movement

3. Positional Therapy

• 30-50% of OSA is "positional" (AHI doubles in supine vs lateral)
• Positional devices: Tennis ball shirt, vibrating positional alarm
• Appropriate for mild-moderate positional OSA

4. Weight Loss / Bariatric Surgery

• Every 1 kg/m² BMI reduction → ~3 events/hr AHI reduction
• Bariatric surgery (Roux-en-Y, sleeve gastrectomy): 80-85% reduction in AHI
• Weight loss alone: Rarely curates OSA (but dramatically reduces severity)

5. Surgical Options

• UPPP (Uvulopalatopharyngoplasty): Removes excess tissue; 50% cure rate; last resort
• Tonsillectomy/Adenoidectomy: Children (first line; 70-80% cure)
• Maxillomandibular advancement (MMA): Most effective surgery; 87% success
• Inspire Hypoglossal Nerve Stimulator:
  • Implantable device stimulates hypoglossal nerve (CN XII) during inspiration
  • Moves tongue forward, opens airway
  • For CPAP-intolerant moderate-severe OSA, AHI 15-65
  • FDA approved 2014; recent STAR trial confirms 68% reduction in AHI
  • NEWER and highly effective

6. Pharmacological (Emerging)

• Combination low-dose oxybutynin + atomoxetine: Reduces genioglossus activity degradation; Phase 2 trials showing promising AHI reduction
• AD109 (aroxybutinin + atomoxetine): FDA breakthrough designation
• Solriamfetol: For residual daytime sleepiness in OSA despite CPAP
• Tirzepatide/Semaglutide: Weight loss drugs → significant OSA improvement in obese patients (SURMOUNT-OSA trial, 2024: 50-60% AHI reduction)

---

OBESITY HYPOVENTILATION SYNDROME (OHS) — SPECIAL SUBSET

DEFINITION:
  BMI >30 + Daytime hypercapnia (PaCO₂ >45 mmHg) + No other cause
  (90% have concurrent OSA)

PATHOPHYSIOLOGY:
  Obesity → ↓ Chest wall compliance → ↑ Work of breathing
  → Central respiratory depression (leptin resistance)
  → Ventilatory failure → Hypercapnia

TREATMENT:
  BiPAP-ST (Bilevel PAP with backup rate) or AVAPS
  (Average Volume Assured Pressure Support)
  + Weight loss + O₂ supplementation

---

---

QUESTION 26 (Short Answer - 6 Marks)

TUBERCULOSIS MENINGITIS — MANIFESTATIONS AND MANAGEMENT

---

DEFINITION

---

PATHOGENESIS

PRIMARY LUNG INFECTION (Mycobacterium tuberculosis)
        |
        v
HEMATOGENOUS DISSEMINATION
        |
        v
Seeding of meninges / subpial brain (Rich focus)
(Formation of small subpial/meningeal tubercles)
        |
        v
RUPTURE of Rich focus INTO subarachnoid space
        |
        v
TUBERCULOUS MENINGITIS
        |
        v
THREE MECHANISMS OF INJURY:

1. EXUDATE: Dense gelatinous exudate at base of brain (basal cisterns)
   → Cranial nerve palsies (CN II, III, VI, VII most common)
   → Hydrocephalus (communicating, from blocked arachnoid granulations)

2. VASCULITIS: Obliterative endarteritis of small/medium vessels
   → Infarcts (basal ganglia, internal capsule, thalamus most common)
   → Hemiplegia, hemichorea

3. DIRECT PARENCHYMAL INVASION:
   → Tuberculoma (granuloma - mass lesion)
   → Tuberculous encephalitis
   → Myelopathy
(Adams & Victor 12E)

---

CLINICAL MANIFESTATIONS

Stages (British Medical Research Council Staging)

Symptoms

PRODROMAL (2-4 weeks):
  - Malaise, fever, night sweats, weight loss
  - Headache (gradually worsening)
  - Personality change, irritability
  - Children: Loss of milestones, altered play

MENINGITIC (established TBM):
  - Severe persistent headache
  - Fever (LOW-GRADE, intermittent - unlike bacterial meningitis)
  - Neck stiffness (Kernig's, Brudzinski's signs)
  - Photophobia, phonophobia
  - Vomiting

ENCEPHALITIC/COMPLICATED:
  - Altered consciousness → Coma
  - Seizures (focal or generalized)
  - Cranial nerve palsies (CN VI most common → diplopia)
  - Hemiplegia, monoplegia (vascular infarct)
  - Papilledema (hydrocephalus, raised ICP)
  - Chorea (striatal infarct)
  - SIADH → Hyponatremia (worsens brain edema)

Cranial Nerve Involvement

• CN VI (abducens): Most commonly affected (traction on long intracranial course)
• CN III (oculomotor): From basal exudate
• CN VII (facial): Facial palsy
• CN II (optic): Optic neuritis, papilledema, visual loss

---

INVESTIGATIONS

CSF Analysis (Key Diagnostic Tool)

Other Investigations

• CXR / CT chest: Pulmonary TB in 50% (miliary pattern, consolidation)
• Tuberculin test (Mantoux): May be negative in immunosuppressed/miliary
• IGRA (QuantiFERON-TB Gold): Positive but doesn't distinguish latent vs active
• MRI brain with gadolinium:
  • Basal meningeal enhancement (most common and characteristic)
  • Hydrocephalus (communicating)
  • Infarcts (basal ganglia, thalamus)
  • Tuberculomas (ring-enhancing lesions)
• CSF Xpert MTB/RIF: First-line rapid molecular test (WHO recommended)
• NAAT (Nucleic Acid Amplification Test): Best sensitivity in new tests

---

MANAGEMENT

Antituberculous Therapy (ATT)

INTENSIVE PHASE (first 2 months):
  HRZE:
  H - Isoniazid (INH)    5 mg/kg/day (max 300 mg)
  R - Rifampicin         10 mg/kg/day (max 600 mg)
  Z - Pyrazinamide       25 mg/kg/day (max 2000 mg)
  E - Ethambutol         15-20 mg/kg/day (max 1600 mg)
  
CONTINUATION PHASE (months 3-12):
  HR (Isoniazid + Rifampicin) × 10 months
  Total duration: 12 months for TBM
  (vs 6 months for pulmonary TB)
  
  NOTE: Some experts recommend 18-24 months in severe cases
  ADD: Pyridoxine (Vit B6) 25-50 mg/day with INH (prevents neuropathy)

Corticosteroids (MANDATORY Adjunct)

DEXAMETHASONE:
  Adults: 0.4 mg/kg/day IV for 2 weeks → 0.3 mg/kg/day × 1 wk → 0.2 mg/kg × 1 wk → taper
  OR Prednisolone 60 mg/day × 4 weeks → taper over 4 weeks

EVIDENCE: UKMED trial (2004, Thwaites et al.):
  Dexamethasone significantly reduces:
  - 9-month mortality (31% → 22%)
  - Severe disability
  - Applies to ALL STAGES (but especially Stage I and II)
  
MECHANISM:
  - Reduces cerebral edema
  - Reduces vasculitis
  - Reduces exudate formation
  - Reduces intracranial pressure
  
Contraindications: None if TBM is suspected

Management of Complications

HYDROCEPHALUS:
  - Communicating (most common): Trial of acetazolamide/serial LP
  - Obstructive: External ventricular drain (EVD) → VP shunt
  - Ventriculoperitoneal shunt required in 20-30%

RAISED ICP:
  - Head elevation 30°
  - Mannitol 20% 1 g/kg IV
  - Hyperventilation (acute)
  - Corticosteroids

SEIZURES:
  - Phenytoin/Levetiracetam
  - If SE → Benzodiazepines → IV AED

HYPONATREMIA (SIADH):
  - Fluid restriction
  - Hypertonic saline if Na <125 mEq/L

TUBERCULOMAS:
  - Paradoxical reaction (enlargement during therapy) — continue ATT + add steroids
  - Surgical if >3 cm, causing severe mass effect

STROKE/INFARCTS:
  - Supportive care
  - Antiplatelet (aspirin 300 mg) if large vessel vasculitis

Drug-Resistant TBM

MDR-TBM (Rifampicin + INH resistant):
  - Fluoroquinolones (Moxifloxacin, Levofloxacin) — KEY agents, good CNS penetration
  - Second-line injectables (Amikacin, Kanamycin)
  - Linezolid (excellent CNS penetration)
  - Bedaquiline (newer — limited CNS penetration data)
  - Duration: 18-24 months (intensive 6-8 months + continuation)

Prognosis

MORTALITY:
  - Stage I: 5-10%
  - Stage II: 15-30%
  - Stage III: 50-70%
  
RISK FACTORS FOR POOR OUTCOME:
  - Delayed diagnosis (>2 weeks from symptom onset)
  - Advanced stage at presentation
  - Age <5 years or >50 years
  - HIV co-infection (CD4 <200)
  - Drug-resistant TB
  - Hydrocephalus requiring shunt
  - CSF protein >250 mg/dL

---

---

MD Medicine Exam Tips for This Set:

• Q20 (Sleep): Always draw the hypnogram with NREM/REM distribution. Examiners look for knowledge of the flip-flop model and orexin/hypocretin.
• Q23 (GBS): Emphasize the "20-30-40 rule" for intubation — this is a common MCQ and OSCE scenario. For newer treatments, mention Eculizumab and imlifidase by name.
• Q24 (Aphasia): MUST draw the perisylvian language circuit diagram. For conduction aphasia, demonstrate understanding that repetition tests the arcuate fasciculus specifically — this is the physiological basis examiners want.
• Q25 (OSA): STOP-BANG and Mallampati classifications are frequently asked. Include the Inspire (hypoglossal nerve stimulator) as a newer modality.
• Q26 (TBM): ADA level in CSF, Xpert MTB/RIF, and the Thwaites dexamethasone trial (2004) should be explicitly mentioned. Always state 12-month total ATT duration for TBM.

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MD MEDICINE EXAMINATION NOTES — NEUROLOGY, NEPHROLOGY & PHARMACOLOGY (PART 4)

References: Harrison's Principles of Internal Medicine 22E, Adams & Victor's Neurology 12E, Goldman-Cecil Medicine, Bradley & Daroff's Neurology, Goodman & Gilman's Pharmacology, Brenner & Rector's The Kidney, Comprehensive Clinical Nephrology 7E

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QUESTION 27 (Short Answer - 6 Marks)

INFLAMMATORY MUSCLE DISEASE

---

DEFINITION

---

CLASSIFICATION (Updated — Lundberg/EULAR 2018)

INFLAMMATORY MYOPATHIES
        |
   _____|____________________________________________
   |           |              |            |        |
DERMATO-   IMMUNE-        ANTI-        INCLUSION  OVERLAP
MYOSITIS   MEDIATED       SYNTHETASE   BODY       MYOSITIS
(DM)       NECROTIZING    SYNDROME     MYOSITIS   (with CTD:
           MYOPATHY       (ASS)        (IBM)      SSc, SLE,
           (IMNM)                                  Sjogren's)

---

KEY DISTINGUISHING FEATURES

---

KEY SKIN SIGNS IN DERMATOMYOSITIS

PATHOGNOMONIC:
  ✓ Gottron's papules: Violaceous flat papules over MCP/PIP joints
  ✓ Gottron's sign: Flat erythema over extensor surfaces

HIGHLY CHARACTERISTIC:
  ✓ Heliotrope rash: Periorbital violaceous discoloration ± edema
  ✓ Shawl sign: Erythema upper back, shoulders, posterior neck
  ✓ V-sign: Photosensitive erythema on anterior chest
  ✓ Mechanic's hands: Cracked lateral fingers (ASS overlap)
  ✓ Periungual telangiectasias + ragged cuticles
  ✓ Calcinosis cutis (especially juvenile DM)

---

SPECIFIC ANTIBODIES AND CLINICAL CORRELATIONS

---

INVESTIGATIONS

• CK (most sensitive): Elevated 10-100× normal (IBM may be lower)
• Anti-nuclear antibody (ANA): Positive in 20-30%
• Myositis-specific antibodies (MSA): Panel as above
• EMG: Myopathic (short MUAP, fibrillations, positive sharp waves)
• MRI muscle (STIR): Areas of edema, inflammation; guides biopsy
• Muscle biopsy: Gold standard — distinguishes subtypes
• HRCT chest: ILD screening
• Echo + ECG: Cardiac involvement
• Malignancy screen: CT CAP, PET-CT (high risk: DM >40 yrs, anti-TIF1γ+)

---

MANAGEMENT

STEP 1: INDUCTION (Moderate-Severe disease)
  Prednisolone 1 mg/kg/day (max 60-80 mg/day)
  ± Methylprednisolone IV 1 g/day × 3 days (severe/ILD)
  Start steroid-sparing agent SIMULTANEOUSLY

STEP 2: MAINTENANCE (Steroid-sparing)
  Methotrexate 15-25 mg/week + Folic acid 5 mg/week
  OR Azathioprine 2-3 mg/kg/day
  OR Mycophenolate mofetil 1.5 g BD (preferred if ILD)
  OR Tacrolimus 3 mg/day (ILD in ASS)

STEP 3: REFRACTORY DISEASE
  IVIG 2 g/kg monthly × 3-6 months
  Rituximab 1000 mg × 2 doses, 2 weeks apart
  Cyclophosphamide (rapidly progressive ILD, anti-MDA5)
  JAK inhibitors (tofacitinib, ruxolitinib): Emerging for refractory DM/ILD

STEP 4: IBM
  No immunosuppression (proven ineffective)
  Supportive: PT, OT, dysphagia management, AFOs
  Bimagrumab (anti-ActRIIA) trials ongoing

---

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QUESTION 28 (Short Answer - 6 Marks)

PARKINSONISM

---

DEFINITION

---

CARDINAL FEATURES (TRAP Mnemonic)

T - TREMOR (Resting tremor):
    "Pill-rolling" (4-6 Hz), worse at rest, better with movement
    Disappears during sleep
    Often asymmetric (starts unilateral)

R - RIGIDITY (Lead-pipe or Cogwheel):
    Uniform resistance throughout range of motion (lead-pipe)
    Ratchety quality when combined with tremor (cogwheel = rigidity + tremor)
    Tested: Passive flexion-extension of wrist/elbow

A - AKINESIA / BRADYKINESIA (most disabling):
    Slowness of movement initiation
    Reduced amplitude of repetitive movements (decrement)
    Micrographia, hypomimia (masked facies), hypophonia
    Festinating gait (short rapid shuffling steps)

P - POSTURAL INSTABILITY (late feature):
    Impaired righting reflexes
    Pull test (retropulsion)
    Falls (leading cause of morbidity)
    Flexed posture

---

CLASSIFICATION OF PARKINSONISM

PARKINSONISM
   |
   |── IDIOPATHIC (Primary)
   |      └── Parkinson's Disease (PD) [most common - 75%]
   |
   |── ATYPICAL PARKINSONISM (Parkinson-Plus Syndromes)
   |      ├── Progressive Supranuclear Palsy (PSP)
   |      ├── Multiple System Atrophy (MSA) - MSA-P, MSA-C
   |      ├── Corticobasal Degeneration (CBD)
   |      └── Dementia with Lewy Bodies (DLB)
   |
   |── SECONDARY PARKINSONISM
   |      ├── Drug-induced (dopamine blockers: haloperidol, metoclopramide)
   |      ├── Vascular (basal ganglia lacunar infarcts)
   |      ├── Toxic (MPTP, CO, Mn, pesticides)
   |      ├── Normal pressure hydrocephalus (gait apraxia)
   |      ├── Wilson's disease (young patient)
   |      └── Post-encephalitic (Von Economo's, rare now)
   |
   |── GENETIC PARKINSONISM
          ├── PARK1/4: SNCA (alpha-synuclein) mutations
          ├── PARK2: Parkin (AR, early onset)
          ├── PARK6: PINK1 (AR, early onset)
          ├── PARK7: DJ-1 (AR, early onset)
          └── PARK8: LRRK2 (AD, most common genetic PD)

---

PATHOPHYSIOLOGY OF PARKINSON'S DISEASE

NORMAL BASAL GANGLIA CIRCUIT:
  Striatum (Putamen/Caudate)
        |
   [D1 pathway]         [D2 pathway]
        |                      |
   DIRECT pathway        INDIRECT pathway
   (facilitates          (suppresses
    movement)             unwanted movement)
        |                      |
   GPi/SNr              GPe → STN → GPi/SNr
        |
        v
   THALAMUS (VL) → Motor Cortex → MOVEMENT

PD: Loss of dopaminergic neurons in SUBSTANTIA NIGRA pars compacta
        |
        v
  ↓ D1 (direct pathway underactive)
  ↓ D2 (indirect pathway overactive)
        |
        v
  Overactivation of STN → Excess GPi/SNr inhibition
        |
        v
  Thalamus suppressed → Reduced motor cortex output
        |
        v
  BRADYKINESIA, RIGIDITY

LEWY BODY PATHOLOGY:
  Alpha-synuclein misfolding → Lewy body formation
  Braak staging: Starts in DMV/olfactory bulb (Stage 1) → Substantia nigra (Stage 3-4) → Neocortex (Stage 5-6)

---

DIFFERENTIATING FEATURES: PD vs ATYPICAL PARKINSONISM

---

MANAGEMENT OF PARKINSON'S DISEASE

Pharmacological

MILD DISEASE (early):
  OPTION 1: Dopamine agonist (non-ergot preferred)
    Pramipexole 0.5-1.5 mg TID
    Ropinirole 3-24 mg/day
    Rotigotine patch 2-8 mg/day
    Advantage: Delays dyskinesia; good for younger patients (<65)
    SE: Hallucinations, impulse control disorders, edema, sleep attacks

  OPTION 2: MAO-B inhibitor (neuroprotective?)
    Rasagiline 1 mg/day or Selegiline 5 mg BD
    Safinamide 50-100 mg/day (3rd generation; also reduces glutamate)
    Advantage: Mild symptomatic + possible neuroprotection; well tolerated

  OPTION 3: Levodopa-Carbidopa (for elderly >70 or significant disability)
    Start: 100/25 mg TID; titrate every 1-2 weeks
    Gold standard — most effective; but causes dyskinesias long-term

MODERATE-SEVERE / ADVANCED:
  Levodopa-Carbidopa + Dopamine agonist + MAO-B inhibitor
  (Optimise levodopa: sustained-release, frequent dosing)
  
  COMT inhibitors (extend levodopa effect):
    Entacapone 200 mg with each L-DOPA dose
    Opicapone 50 mg OD (3rd generation; once-daily dosing, NEWER)
    Tolcapone (liver toxicity — restricted)

  Amantadine: For dyskinesias (NMDA antagonist)
  Anticholinergics (Trihexyphenidyl): For tremor-predominant (avoid elderly)

Advanced Therapies (Motor fluctuations/dyskinesias)

• DBS (STN or GPi): Gold standard for advanced PD with motor fluctuations
• Levodopa-carbidopa intestinal gel (LCIG/Duodopa): Continuous jejunal infusion via PEG-J
• Subcutaneous apomorphine pump: Continuous dopaminergic stimulation
• Focused ultrasound thalamotomy: Non-invasive, for tremor

Non-Motor Symptoms Treatment

---

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QUESTION 29 (Long Answer - 20 Marks)

MEMBRANOUS NEPHROPATHY / NEPHROTIC SYNDROME

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PART A: NEPHROTIC SYNDROME

Definition

• Proteinuria ≥3.5 g/day (or urine PCR >3500 mg/g)
• Hypoalbuminemia (serum albumin <3.5 g/dL)
• Edema (pitting, gravity-dependent; periorbital in children)
• Hyperlipidemia (total cholesterol often >300 mg/dL)
• Lipiduria (oval fat bodies, maltese cross on polarization)

---

PATHOPHYSIOLOGY OF NEPHROTIC SYNDROME

PODOCYTE INJURY (primary event in most causes)
        |
        v
DISRUPTION OF GLOMERULAR FILTRATION BARRIER:
  - Podocyte foot process effacement (fusion)
  - Loss of charge barrier (slit diaphragm proteins: nephrin, podocin)
  - Loss of size barrier (basement membrane)
        |
        v
MASSIVE PROTEINURIA (>3.5 g/day)
        |
        |─────────────────────────────────────────────────
        |                        |                        |
  ↓ SERUM ALBUMIN         HYPERLIPIDEMIA           LIPIDURIA
  (loss > hepatic         (↑ hepatic lipid          (Oval fat bodies
   synthesis)              synthesis, ↓LPL)          in urine)
        |
        v
EDEMA FORMATION — Two mechanisms:
  1. Underfill theory: ↓Albumin → ↓Plasma oncotic pressure
     → Fluid shifts to interstitium → ↓Plasma volume
     → ↑Renin-Angiotensin-Aldosterone → Na+H₂O retention
  
  2. Overfill theory (more common in adults):
     Primary renal Na+ retention → ↑Plasma volume
     → Despite full or high plasma volume, edema forms
     → ↓ANP response + ↑Na/K ATPase activity in collecting duct
        |
        v
  COMPLICATIONS:
    - Infections: Encapsulated organisms (Strep. pneumoniae, H. influenzae)
      ↓IgG (urinary loss), ↓complement factors
    - Thromboembolism: ↑pro-coagulants, ↓anti-thrombin III (urinary loss)
      DVT, renal vein thrombosis, PE (especially membranous nephropathy)
    - AKI: Hypovolemia, drug toxicity (NSAID, ACE inhibitors), RVT
    - Dyslipidemia → Accelerated atherosclerosis
    - Malnutrition

---

CAUSES OF NEPHROTIC SYNDROME

By Age Group

CHILDREN (primary):
  1. Minimal Change Disease (MCD) - 80% of nephrotic syndrome in children
  2. FSGS (10%)
  3. Membranous nephropathy (rare)

ADULTS (primary):
  1. Membranous Nephropathy (MN) - most common cause >40 years
  2. FSGS - most common in young adults, Black patients
  3. MCD - 20-25% of adult nephrotic syndrome
  4. MPGN (immune complex, C3G)
  5. Amyloidosis (older adults)

SECONDARY CAUSES:
  Infection: Hepatitis B (MN), Hepatitis C (MPGN, cryoglobulinemia),
             HIV (HIVAN - collapsing FSGS), Malaria (MN), Syphilis (MN)
  Drugs: NSAIDs (MCD), penicillamine (MN), gold, mercury, heroin (FSGS)
  Autoimmune: SLE (class V = MN; class III/IV = MPGN)
  Malignancy: Solid tumors (MN), lymphoma (MCD), multiple myeloma (amyloid)
  Diabetes: Diabetic nephropathy (most common cause globally)
  Amyloidosis: AA, AL
  Preeclampsia

---

PART B: MEMBRANOUS NEPHROPATHY (MN) — DETAILED

Definition

---

CLASSIFICATION

MEMBRANOUS NEPHROPATHY
        |
   _____|_____________
   |                  |
PRIMARY (70-80%)    SECONDARY (20-30%)
   |                  |
   Idiopathic         ├── Infections: HBV (most common), HCV, syphilis
   Anti-PLA2R Ab         malaria, schistosomiasis
   (70-80%)           ├── Autoimmune: SLE (Class V), RA, thyroiditis,
   Anti-THSD7A Ab         Sjogren's, IBD
   (2-5%)             ├── Malignancy: Lung, colon, breast, prostate, NHL
                      |   (10-25% of primary MN adults >60 yrs)
                      └── Drugs: NSAIDs, penicillamine, gold, captopril,
                          mercury compounds, bucillamine

---

PATHOGENESIS — MOLECULAR (Harrison's 22E)

PRIMARY MEMBRANOUS NEPHROPATHY:

Circulating IgG4 autoantibodies → Anti-PLA2R (Phospholipase A2 Receptor)
  (PLA2R expressed on podocyte foot processes)
        |
        v
In situ immune complex formation:
  Anti-PLA2R IgG + PLA2R antigen on podocyte foot processes
  → SUBEPITHELIAL IMMUNE DEPOSITS (in situ deposition)
        |
        v
Complement activation (C5b-9 MAC formation)
        |
        v
Podocyte injury → Foot process effacement
        |
        v
Loss of filtration barrier → PROTEINURIA
        |
        v
Progressive GBM thickening → "Spikes" (silver stain)

ANTI-PLA2R ANTIBODY:
  Present in 70-80% of primary MN
  Titre correlates with disease activity
  Useful for diagnosis, prognosis, and treatment monitoring
  Decreasing titres = remission
  
ANTI-THSD7A (Thrombospondin type-1 domain-containing 7A):
  Present in 2-5% of primary MN
  Strong association with malignancy (>20%)
  IHC for THSD7A on biopsy

---

HISTOPATHOLOGY

LIGHT MICROSCOPY:
  - Normal cellularity (no proliferation - "non-proliferative")
  - GBM thickening (may be subtle early)
  - "Spikes" on silver stain (Periodic acid-silver methenamine):
    GBM projections between subepithelial deposits
  - "Chain-link fence" pattern in advanced disease

IMMUNOFLUORESCENCE:
  - Granular deposits along GBM
  - IgG (predominantly IgG4) + C3 positive
  - "Tennis ball pattern" in subepithelial deposits

ELECTRON MICROSCOPY:
  - SUBEPITHELIAL immune complex deposits (key finding)
  - Foot process effacement
  
STAGING (Ehrenreich & Churg):
  Stage I: Small subepithelial deposits (GBM near-normal)
  Stage II: GBM spikes around deposits
  Stage III: Deposits incorporated into GBM (chain-link)
  Stage IV: Sclerotic, burned-out deposits

---

CLINICAL FEATURES

PRESENTATION:
  - Age: 40-60 years (most common); M > F (2:1)
  - Insidious onset of:
    ✓ Pitting edema (periorbital in morning, ankle in evening, ascites)
    ✓ Frothy urine (proteinuria)
    ✓ Weight gain (fluid retention)
    ✓ Fatigue, anorexia
    
COMPLICATIONS:
  ✓ Thromboembolism (HIGHEST RISK among all glomerular diseases):
    - Renal vein thrombosis (RVT) in 30-50%
    - DVT, PE
    - Anti-thrombin III lost in urine → thrombophilia
  ✓ Infections (IgG loss + complement loss)
  ✓ Accelerated atherosclerosis (hypercholesterolemia)
  ✓ AKI (hypovolemia, RVT, NSAID use)
  ✓ Hypothyroidism (loss of thyroid-binding globulin)
  
NATURAL HISTORY (Rule of Thirds — "Toronto criteria"):
  - 1/3: Spontaneous complete remission (especially low-risk)
  - 1/3: Partial remission (ongoing proteinuria)
  - 1/3: Progressive renal failure (within 10 years)

---

INVESTIGATIONS

URINE:
  - Spot urine PCR/ACR: >3500 mg/g creatinine (nephrotic range)
  - 24-hr urine protein: >3.5 g/day
  - Urine microscopy: Oval fat bodies, fatty casts (Maltese cross)
  - Urine ACR for monitoring

BLOOD:
  - Serum albumin: LOW (<3.5 g/dL)
  - Total protein: LOW
  - Lipid profile: Total cholesterol ↑, LDL ↑, TG ↑, HDL ↓
  - Serum creatinine, eGFR
  - CBC (thrombocytosis in hypoalbuminemia)
  - Coagulation: Anti-thrombin III, D-dimer, INR

SEROLOGY (secondary causes):
  - Anti-PLA2R antibody (ELISA): PRIMARY MN diagnosis (avoid biopsy if positive + clinical picture)
  - ANA, anti-dsDNA (SLE)
  - HBsAg, HBV DNA, HCV antibody
  - ANCA (if concurrent small vessel vasculitis)
  - SPEP, UPEP (myeloma), serum free light chains
  - Complement C3, C4 (low in SLE, MPGN)
  - Anti-phospholipase A2 receptor (anti-PLA2R): KEY BIOMARKER

IMAGING:
  - Renal ultrasound: Echogenicity, size (normal/increased in MN)
  - Doppler ultrasound: Renal vein thrombosis screening
  - CT abdomen: Malignancy screen (if anti-PLA2R negative, adult >60 yrs)

RENAL BIOPSY (Gold standard — when to do):
  - Anti-PLA2R negative + nephrotic syndrome in adult
  - Secondary cause needs confirmation (SLE-V)
  - Failure to respond to treatment
  - Atypical features (hematuria, impaired GFR, systemic features)

---

MANAGEMENT

General Measures (All Nephrotic Syndrome)

1. PROTEINURIA REDUCTION:
   ACE inhibitor (enalapril) or ARB (losartan): Even without hypertension
   Target: <500 mg/day proteinuria (if achievable)
   Combination ACEi + ARB: Avoid (hypotension, AKI, hyperkalemia risk)
   SGLT2 inhibitor (dapagliflozin/empagliflozin): Reduces proteinuria 30-40%
   (CREDENCE trial, DAPA-CKD): Now standard of care for proteinuric CKD

2. EDEMA MANAGEMENT:
   - Salt restriction (<2 g/day)
   - Diuretics: Furosemide (loop diuretic); resistance → combine with thiazide
   - IV albumin + furosemide: For severe hypoalbuminemia + diuretic resistance
   
3. HYPERLIPIDEMIA:
   Statin therapy: Atorvastatin 40-80 mg (REDUCE cardiac risk)
   
4. ANTICOAGULATION:
   - Full anticoagulation (warfarin target INR 2-3) if:
     * Serum albumin <2.5 g/dL + MN (high thromboembolism risk)
     * Confirmed DVT, PE, or RVT
     * Anti-thrombin III <70% + albumin <2.0 g/dL
   - DOACs: Increasing use (rivaroxaban, apixaban) — caution with GFR-based dosing

5. DIET:
   - Moderate protein: 0.8-1 g/kg/day (avoid high protein → increases proteinuria)
   - Low sodium: <2 g/day
   - Low saturated fat

6. INFECTION PROPHYLAXIS:
   - Pneumococcal vaccine
   - Influenza vaccine
   - Prophylactic penicillin in children on steroids (Strep. pneumoniae risk)

Disease-Specific Treatment of PRIMARY MEMBRANOUS NEPHROPATHY

RISK STRATIFICATION:
  LOW RISK (observe 6 months first):
    - Proteinuria <4 g/day + normal GFR + anti-PLA2R declining
    - 30-35% spontaneous remission in 1-2 years
  
  MODERATE RISK:
    - Proteinuria 4-8 g/day, or declining GFR
  
  HIGH RISK (treat promptly):
    - Proteinuria >8 g/day AND/OR GFR decline >30% AND/OR
      debilitating symptoms (severe edema, infections, thrombosis)

Treatment Regimens

KDIGO 2021 MEMBRANOUS NEPHROPATHY GUIDELINE:
  1st line: Rituximab (preferred) OR Cyclophosphamide-based (Ponticelli)
  2nd line (if 1st line fails): Switch to other option
  Calcineurin inhibitors: Alternative 2nd line
  
MONITORING RESPONSE:
  - Anti-PLA2R titre decline: Best predictor of immunological remission
  - 24-hr urine protein every 3 months
  - eGFR every 3 months
  - Complete remission: Protein <0.3 g/day
  - Partial remission: >50% reduction + protein <3.5 g/day

---

SECONDARY MEMBRANOUS NEPHROPATHY TREATMENT

• HBV-MN: Antiviral therapy (tenofovir/entecavir) — often induces remission without immunosuppression
• SLE Class V MN: Hydroxychloroquine + MMF ± low-dose steroids (per KDIGO lupus guidelines)
• Drug-induced: Withdraw offending drug
• Malignancy-associated: Treat underlying cancer → MN may resolve

---

NEPHROTIC SYNDROME vs NEPHRITIC SYNDROME — COMPARISON

---

---

QUESTION 30 (Long Answer - 20 Marks)

TREATMENT OF EPILEPSY WITH EMPHASIS ON NEWER THIRD-GENERATION ANTISEIZURE MEDICATIONS

---

OVERVIEW OF ANTISEIZURE MEDICATION (ASM) GENERATIONS

GENERATION 1 (Pre-1960):
  Phenobarbital (1912), Phenytoin (1938), Primidone, Ethosuximide
  "Older traditional AEDs"

GENERATION 2 (1960-1990):
  Carbamazepine, Valproate, Clonazepam
  "Modern traditional AEDs"

GENERATION 3 (1990-2010):
  Lamotrigine, Levetiracetam, Topiramate, Gabapentin, Oxcarbazepine
  Vigabatrin, Tiagabine, Zonisamide, Felbamate

GENERATION 4 (Third-generation, 2005-present):
  Lacosamide, Perampanel, Brivaracetam, Cenobamate, Eslicarbazepine
  Cannabidiol, Fenfluramine, Everolimus, Rufinamide, Stiripentol, Clobazam

---

PRINCIPLES OF EPILEPSY TREATMENT

WHEN TO START AED:
  ✓ After 2nd unprovoked seizure
  ✓ After 1st seizure IF: EEG epileptiform discharges + structural lesion
    + Nocturnal seizure + Epilepsy syndrome diagnosis
  ✗ After single provoked seizure (correct the provoking cause)

PRINCIPLES:
  - Start LOW, go SLOW
  - One drug at a time (monotherapy preferred)
  - Titrate to seizure freedom OR maximum tolerated dose
  - Drug-resistant epilepsy = failure of 2 appropriate AEDs
    → Consider referral for pre-surgical evaluation
  - Take AEDs REGULARLY (never miss dose)

WHEN TO STOP AED:
  - Seizure-free for 2 years + normal EEG + normal MRI
  - Reduce gradually over 3-6 months
  - Counsel about driving, swimming risks during withdrawal

---

MECHANISMS OF ACTION — CLASSIFICATION

MECHANISM CATEGORIES:
  1. Na+ channel blockade (fast inactivation)
  2. Na+ channel modulation (slow inactivation)  ← NEWER
  3. Ca2+ channel blockade (T-type, N-type, L-type)
  4. GABA enhancement (GABA-A or GABA-B)
  5. Glutamate blockade (AMPA, NMDA, kainate)  ← NEWEST
  6. SV2A (synaptic vesicle protein 2A) modulation
  7. HCN channel blockade (Ih current)
  8. Multiple/novel mechanisms

---

GENERATION 1 & 2 AEDs

GENERATION 3 AEDs

---

THIRD-GENERATION AEDs — DETAILED (Focus of Question)

1. LACOSAMIDE (Vimpat) — 2008

MECHANISM: DUAL, UNIQUE MECHANISM
  1. "Slow inactivation" of voltage-gated Na+ channels
     (Different from traditional Na+ channel blockers which enhance FAST inactivation)
     → Selectively stabilizes slowly-inactivated Na+ channel state
     → More selective inhibition of high-frequency firing
  
  2. CRMP-2 (Collapsin Response Mediator Protein-2) interaction
     (Role in neuronal plasticity — significance unclear clinically)

CLINICAL DETAILS:
  Indication: Focal seizures ± secondary generalization
  Dose: 50-400 mg/day (BD)
  IV formulation: Available (same dose as oral; great for SE/ICU)
  Half-life: 13 hours
  Bioavailability: ~100%
  Protein binding: <15% (minimal drug interactions)
  Renal excretion (dose reduce in severe renal impairment)

KEY ADVANTAGES:
  - IV form (only 3rd gen drug with IV available, besides LEV)
  - Minimal drug-drug interactions (no CYP induction/inhibition)
  - Safe in cardiovascular disease EXCEPT:
    - Caution: PR prolongation (avoid in 2nd/3rd degree AV block, severe cardiac disease)
  - Effective in refractory focal epilepsy

SIDE EFFECTS:
  - Dizziness, diplopia, nausea (dose-related, during titration)
  - PR interval prolongation (ECG monitoring recommended)
  - Rarely: SJS (very rare)

2. PERAMPANEL (Fycompa) — 2012

MECHANISM: FIRST-IN-CLASS AMPA RECEPTOR ANTAGONIST
  Selective, non-competitive antagonist of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) glutamate receptor
  
  AMPA receptors: Ionotropic glutamate receptors → fast excitatory transmission
  → Perampanel blocks excessive glutamate-mediated neuronal excitation
  → Unique mechanism: No other approved ASM targets AMPA receptors

  Action: Binds negative allosteric site on AMPA receptor (non-competitive)
  → Does not block glutamate binding but inhibits channel activity

CLINICAL DETAILS:
  Indications:
    - Focal seizures ± secondary generalization (≥4 yrs)
    - Primary GTCS (≥12 yrs) — FDA 2015
  Dose: 2-12 mg OD at bedtime (START 2 mg, increase by 2 mg/week)
  Half-life: 70-105 hours (ONCE DAILY dosing advantage)
  Metabolism: CYP3A4; enzyme inducers ↓ levels by 50%

KEY ADVANTAGES:
  - Unique mechanism (glutamate antagonism) → additive effect with other ASMs
  - Once-daily dosing (compliance benefit)
  - Active against focal AND generalized seizures

SIDE EFFECTS:
  - Neuropsychiatric (important): Aggression, hostility, irritability (up to 12%)
    "Boxed warning" in USA for serious psychiatric adverse reactions
  - Dizziness, somnolence, ataxia (especially dose escalation)
  - Weight gain
  - Drug interaction: Enzyme inducers (CBZ, PHT) reduce plasma levels by 50% → need higher doses

3. BRIVARACETAM (Briviact) — 2016

MECHANISM: SV2A MODULATOR (like Levetiracetam but SUPERIOR binding)
  - Binds SV2A (Synaptic Vesicle Glycoprotein 2A) with 10-30× higher affinity than LEV
  - SV2A regulates synaptic vesicle fusion and neurotransmitter release
  - ADDITIONAL mechanism: Na+ channel fast inactivation (minor, at high doses)
  
  SV2A is a transmembrane glycoprotein on synaptic vesicles
  → BRV binding → reduces calcium-dependent exocytosis of glutamate
  → Modulates high-frequency burst firing

CLINICAL DETAILS:
  Indication: Focal seizures ± secondary generalization (≥2 yrs)
  Dose: 50-200 mg/day (BD; or OD with food)
  IV formulation: Available
  Half-life: 9 hours
  Protein binding: <20%
  Metabolism: Hepatic (hydrolysis, not CYP major)
  Renal excretion: Metabolites

KEY ADVANTAGES OVER LEVETIRACETAM:
  - Fewer behavioral side effects (less irritability, aggression, depression)
  - Better tolerability profile
  - More potent SV2A binding
  - IV formulation
  - Effective in patients who failed LEV (different binding profile)
  - Faster onset of action
  
SIDE EFFECTS:
  - Dizziness, somnolence, fatigue (mild)
  - Nausea (less than LEV)
  - Nasopharyngitis
  - Behavioral issues: LESS than LEV but possible

4. CENOBAMATE (Xcopri) — 2019

MECHANISM: DUAL — NOVEL COMBINATION
  1. FAST Na+ channel inactivation (like PHT, CBZ) AND
     Preferential interaction with the persistent sodium current (INap)
     → Selectively blocks sustained repetitive firing at lower concentrations
  
  2. POSITIVE ALLOSTERIC MODULATION of GABA-A receptor
     (specifically at a NON-BENZODIAZEPINE site — different from BZD)
     → Enhances GABA-A receptor activity WITHOUT the tolerance typical of BZDs

CLINICAL DETAILS:
  Indication: Focal seizures in adults (FDA 2019)
  Dose: Start 12.5 mg → escalate SLOWLY over 20 weeks to 100-400 mg OD
  CRITICAL: Very slow titration (Q2 weeks) to reduce DRESS syndrome risk
  Half-life: 50-60 hours (once daily)
  Metabolism: CYP2E1 (mainly); minimal CYP induction

KEY CLINICAL DATA:
  - PHASE 3 TRIALS: 55% of patients achieved ≥50% seizure reduction
    21% of patients became SEIZURE-FREE (unprecedented in drug-resistant focal epilepsy)
  - More effective than most other ASMs in refractory focal epilepsy
  - DRESS syndrome risk: Drug Reaction with Eosinophilia and Systemic Symptoms
    (FATAL if rapid titration; hence ultra-slow dose escalation)

SIDE EFFECTS:
  - DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) — RAPID TITRATION RISK
    Monitor: CBC, LFT, CMP during first 16 weeks
  - Sedation, dizziness, fatigue, diplopia
  - Drug interactions: Increases levels of CYP2C19 substrates (PHT, clobazam)
    → Reduces levels of other drugs metabolized by CYP3A4

5. ESLICARBAZEPINE (Aptiom) — 2013

MECHANISM:
  Active metabolite of oxcarbazepine (similar to CBZ family)
  BUT selectively SLOW inactivation state blocker of Na+ channel
  (More selective than OXC or CBZ for slow inactivation)

CLINICAL:
  Indication: Focal seizures
  Dose: 400-1200 mg OD (once daily)
  Advantage: OD dosing; less hyponatremia than OXC; less diplopia than CBZ
  Interaction: Mild CYP3A4 inducer

6. CANNABIDIOL (Epidiolex) — 2018

MECHANISM: MULTIPLE (not fully elucidated):
  - TRPV1 (Transient Receptor Potential Vanilloid 1) activation → desensitizes neurons
  - Equilibrative nucleoside transporter inhibition → ↑adenosine (inhibitory)
  - GPR55 antagonism (reduces Ca2+ release)
  - Reduces intracellular Ca2+ (via VDAC1 modulation of mitochondria)
  - Does NOT act on CB1/CB2 cannabinoid receptors (non-psychoactive)

CLINICAL:
  Indications: Dravet syndrome, Lennox-Gastaut syndrome, TSC (≥1 yr)
  Dose: 5-20 mg/kg/day (BD)
  Interaction: Significant with clobazam (↑ active metabolite NCLB levels → sedation)
               Valproate → ↑ risk of LFT elevation
  KEY: Requires LFT monitoring (hepatotoxicity, especially with VPA)

7. FENFLURAMINE (Fintepla) — 2020

MECHANISM:
  - Stimulates serotonin release (+ blocks serotonin reuptake)
  - Sigma-1 receptor modulation
  - Serotonin receptor (5-HT2C, 5-HT1D) agonism
  → Anti-seizure effect via enhanced serotonergic tone

CLINICAL:
  Indication: Dravet syndrome (≥2 yrs) — also LGS (2022)
  Dose: 0.1-0.7 mg/kg/day (BD)
  Note: Low doses used (not anorectic doses — no cardiac valve issues at therapeutic doses)
  REMS program: Cardiac monitoring required (historical echocardiography concerns)
  Efficacy: 54-62% reduction in convulsive seizures (PHASE 3 STXBP1 studies)

8. EVEROLIMUS (Afinitor) — 2018 (for TSC-associated seizures)

MECHANISM: mTOR PATHWAY INHIBITOR
  - mTOR (mammalian target of rapamycin) pathway is hyperactivated in TSC
  - Everolimus blocks mTORC1 → Reduces abnormal neuronal growth (cortical tubers)
  - DISEASE-MODIFYING: Not just symptom control — reduces the epileptogenic substrate

CLINICAL:
  Indication: TSC-associated refractory focal seizures (EXIST-3 trial)
  Dose: 5-10 mg/day (target serum trough 5-15 ng/mL)
  Efficacy: 29.3% reduction in seizure frequency at lowest dose
  Serum monitoring required

---

MECHANISM COMPARISON TABLE — KEY FOR EXAM

MECHANISM            → DRUG(s)
─────────────────────────────────────────────────────
Na+ (fast inact.)   → PHT, CBZ, OXC, LTG, ZNS
Na+ (slow inact.)   → LACOSAMIDE, Cenobamate, ESL
GABA-A (BZD site)   → Benzodiazepines, Clobazam
GABA-A (barb site)  → Phenobarbital, Primidone
GABA-A (non-BZD)    → CENOBAMATE (novel)
GABA uptake block   → Tiagabine
GABA-T inhibition   → Vigabatrin
T-type Ca2+         → Ethosuximide, Valproate, ZNS
N/P/Q Ca2+          → Gabapentin, Pregabalin, LTG
HCN channel (Ih)    → Gabapentin, Pregabalin (partial)
α2δ Ca2+ subunit    → Gabapentin, Pregabalin
AMPA antagonist     → PERAMPANEL (unique)
NMDA antagonist     → Felbamate, Topiramate (partial)
SV2A modulation     → Levetiracetam, BRIVARACETAM
mTOR inhibition     → EVEROLIMUS
Serotonin release   → FENFLURAMINE
Multiple/unclear    → Topiramate, Valproate, CANNABIDIOL

---

DRUG-RESISTANT EPILEPSY APPROACH

DRUG-RESISTANT EPILEPSY (DRE):
  Definition: Failure of 2 adequate trials of tolerated, appropriately chosen
              and used ASM schedules (monotherapy or combination)

APPROACH:
  STEP 1: Verify diagnosis (is it really epilepsy?)
    - Video-EEG monitoring
    - Exclude PNES (psychogenic non-epileptic seizures)
  
  STEP 2: Verify seizure type and syndrome
    - Optimal ASM selection
  
  STEP 3: Add 3rd generation ASM
    (Lacosamide, Perampanel, Brivaracetam, Cenobamate)
  
  STEP 4: Pre-surgical evaluation
    - Phase 1: Non-invasive (MRI, PET, SPECT, video-EEG)
    - Phase 2: Invasive (SEEG, subdural grids)
    - Surgery: Resective, disconnective, LITT, RNS, VNS, DBS
  
  STEP 5: Non-pharmacological
    - Ketogenic diet, modified Atkins diet
    - VNS (vagus nerve stimulation)
    - RNS (responsive neurostimulation)
    - DBS (anterior nucleus of thalamus)

---

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QUESTION 31 (Short Answer - 6 Marks)

ANTIEPILEPTIC DRUGS

---

DEFINITION

---

CLASSIFICATION BY MECHANISM

1. SODIUM CHANNEL BLOCKERS:
   Fast inactivation: Phenytoin, Carbamazepine, Oxcarbazepine, Lamotrigine
   Slow inactivation: Lacosamide, Cenobamate, Eslicarbazepine

2. CALCIUM CHANNEL BLOCKERS:
   T-type (thalamic): Ethosuximide (absence epilepsy)
   α2δ subunit: Gabapentin, Pregabalin

3. GABA ENHANCERS:
   GABA-A (BZD site): Clonazepam, Clobazam
   GABA-A (barbiturate): Phenobarbital, Primidone
   GABA-T inhibitor: Vigabatrin (↑brain GABA)
   GABA uptake inhibitor: Tiagabine

4. GLUTAMATE INHIBITORS:
   AMPA antagonist: Perampanel (unique)
   NMDA (partial): Felbamate, Topiramate (partial)

5. SV2A MODULATORS:
   Levetiracetam, Brivaracetam

6. MULTIPLE/BROAD SPECTRUM:
   Valproate (Na+, GABA, Ca2+, NMDA)
   Topiramate (Na+, GABA, AMPA, CA inhibition)
   Zonisamide (Na+, T-type Ca2+, partial)

---

KEY CLINICAL DRUG TABLE

---

AED SELECTION BY SEIZURE TYPE

FOCAL SEIZURES: Lamotrigine / Levetiracetam / Carbamazepine
  Add-on: Lacosamide / Perampanel / Brivaracetam / Cenobamate

GENERALIZED TC: Valproate (M) / Lamotrigine (F) / Levetiracetam
ABSENCE: Ethosuximide / Valproate (AVOID CBZ, PHT)
MYOCLONIC: Valproate / Levetiracetam (AVOID CBZ, PHT, OXC)
DRAVET: Valproate + Clobazam → Add Cannabidiol / Fenfluramine
LENNOX-GASTAUT: Valproate + Rufinamide + Cannabidiol
INFANTILE SPASMS: ACTH / Vigabatrin (TSC) / Prednisolone

---

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QUESTION 32 (Long Answer - 20 Marks)

MOTOR NEURON DISEASE: GENETICS, CLINICAL FEATURES, AND DIAGNOSIS

---

DEFINITION

---

SPECTRUM OF MOTOR NEURON DISEASE

MOTOR NEURON DISEASES
        |
   _____|_______________________________
   |           |          |            |
  ALS          PLS        PMA          SBMA
(Combined    (Pure UMN)  (Pure LMN)   (Kennedy
 UMN+LMN)                              disease)
   |
   |── Classic ALS (limb-onset, 70%)
   |── Bulbar ALS (25%)
   |── Flail arm syndrome
   |── Flail leg syndrome
   |── ALS-FTD overlap (15%)
   |── Respiratory-onset ALS (rare, poor prognosis)

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EPIDEMIOLOGY

• Incidence: 2-3/100,000/year
• Prevalence: 5-7/100,000
• Male:Female = 1.5:1
• Mean age at onset: 55-65 years (earlier in familial)
• Mean survival: 2-5 years from symptom onset (median 30-36 months)
• 10% survive >10 years ("long survivors")

---

GENETICS OF ALS/MND

HEREDITARY ALS:
  Familial ALS (FALS): 5-10% of all ALS
  Sporadic ALS (SALS): 90-95% (but genetic variants in ~10%)

MAJOR GENES (in order of frequency):

1. C9orf72 (Chromosome 9q21) — MOST COMMON (40% FALS; 5-7% SALS)
   Mutation: GGGGCC hexanucleotide repeat expansion in intron 1
   Normal: <30 repeats; Pathological: Hundreds-thousands of repeats
   Mechanism:
     - RNA foci (toxic RNA aggregates)
     - Dipeptide repeat proteins (DPR): Poly-GA, poly-GR, poly-PR
     - Loss of C9orf72 protein function (autophagy impairment)
   Associated with: ALS + FTD (behavioral variant FTD)
   
2. SOD1 (Superoxide Dismutase 1, Ch. 21q22) — 15-20% FALS
   Mutation: >200 missense mutations (A4V most common in North America)
   Inheritance: AD (most), rare AR
   Mechanism:
     - Gain of toxic function (not loss of SOD1 activity)
     - Protein misfolding → Aggregation → ER stress, mitochondrial dysfunction
   Prognosis: A4V rapid (1 year); others variable
   THERAPEUTIC TARGET: SOD1-ASO (tofersen) — FDA approved 2023

3. FUS (FUsed in Sarcoma / TLS) — 5% FALS
   Mutation: Rare, but severe early-onset ALS (<40 yrs)
   Inheritance: AD (de novo mutations in young onset)
   Mechanism: Nuclear-cytoplasmic mislocalization, RNA binding dysfunction

4. TARDBP (TDP-43) — 4% FALS
   Mutation: Encoding TDP-43 protein
   TDP-43 pathology: Found in 97% of ALL ALS (sporadic + familial)
   → TDP-43 cytoplasmic aggregates (ubiquitinated inclusions) = hallmark of ALS
   THERAPEUTIC TARGET: TDP-43 pathology modulation (trials)

5. NEK1 — 3% FALS, 1.4% SALS (significant)
   Function: DNA damage repair kinase

6. UBQLN2 — X-linked
   Protein: Ubiquilin2 (ubiquitin-proteasome pathway)
   Feature: Males severely affected; females mild (X-linked dominant)

7. OPTN, TBK1, SQSTM1 — Autophagy/p62 pathway (2-3%)
   Mechanism: Defective autophagy → Protein aggregate accumulation

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PATHOPHYSIOLOGY OF ALS

GENETIC MUTATION / ENVIRONMENTAL TRIGGER
        |
        v
PROTEIN MISFOLDING + AGGREGATION
(SOD1, TDP-43, FUS, C9orf72 DPRs)
        |
   _____|__________________________________
   |          |           |              |
GLUTAMATE  ER STRESS  MITOCHONDRIAL  OXIDATIVE
EXCITOTOXICITY (UPR)   DYSFUNCTION    STRESS
   |          |           |              |
   └──────────┴───────────┴──────────────┘
                    |
                    v
          NEUROINFLAMMATION
          (Microglial activation, neuronal apoptosis)
                    |
                    v
          AXONAL TRANSPORT DEFECTS
          (Kinesin/dynein, neurofilament accumulation)
                    |
                    v
          MOTOR NEURON DEATH
          (UMN → corticospinal tract degeneration)
          (LMN → anterior horn cells of spinal cord)
                    |
                    v
          PROGRESSIVE MUSCLE DENERVATION → WASTING

---

CLINICAL FEATURES OF ALS

Upper vs Lower Motor Neuron Signs

UMN SIGNS:                          LMN SIGNS:
  ✓ Hyperreflexia                     ✓ Muscle wasting (atrophy)
  ✓ Spasticity                        ✓ Fasciculations (VISIBLE twitching)
  ✓ Extensor plantar (Babinski)       ✓ Hyporeflexia / Areflexia
  ✓ Pseudobulbar affect               ✓ Flaccidity
    (emotional incontinence)          ✓ Cramps
  ✓ Clonus                           ✓ Tongue fasciculations + wasting
  ✓ Jaw jerk brisk
  
KEY IN ALS: BOTH UMN AND LMN SIGNS IN SAME PATIENT
  = Hallmark of ALS (other MND syndromes have one or the other)

Regional Patterns

Limb-Onset ALS (70%)

ARMS:
  - Unilateral hand/arm weakness initially
  - "Split hand sign": Wasting of thenar + first dorsal interosseous
    with relative sparing of hypothenar — PATHOGNOMONIC for ALS
  - Weakness: Finger extension, wrist extension, grip
  - Fasciculations in biceps, triceps, deltoid
  - UMN: Brisk reflexes despite wasting (KEY)

LEGS:
  - Foot drop, tripping, difficulty with stairs
  - Leg wasting + hyperreflexia coexisting
  - Spastic-atrophic weakness

Bulbar-Onset ALS (25%)

DYSARTHRIA: Initially slurred speech → Progressive dysarthria
  LMN: Flaccid (nasal, breathy, hypophonic)
  UMN (pseudobulbar): Spastic (strained, strangled quality)
  MIXED: Both in ALS

DYSPHAGIA:
  - Difficulty with liquids first (aspiration)
  - Then solids
  - Sialorrhea (inability to swallow own saliva)
  - Weight loss, malnutrition

PSEUDOBULBAR AFFECT:
  - Pathological laughing and crying (UMN feature)
  - Emotional incontinence disproportionate to feelings

TONGUE: Atrophy + fasciculations (LMN)
JAW JERK: Brisk (UMN corticobulbar)

Respiratory Involvement

- Diaphragmatic weakness → Orthopnea
- Intercostal/accessory muscles → Dyspnea on exertion
- FVC <50% predicted = indication for NIV (BiPAP)
- Paradoxical abdominal movement (when supine)
- Signs of CO₂ retention: Morning headache, day somnolence

Cognitive Features (ALS-FTD Spectrum)

• ALS-FTD: 15% of ALS patients develop behavioral variant FTD
• Disinhibition, apathy, executive dysfunction, language impairment
• STRONGLY ASSOCIATED WITH C9orf72 mutations
• TDP-43 pathology links both conditions

---

WHAT IS SPARED IN ALS?

SPARED (Important for diagnosis):
  ✓ Sensation (NO sensory symptoms or signs)
  ✓ Eye movements (external ocular muscles - almost always spared until late)
  ✓ Sphincters (bowel and bladder — usually preserved until late)
  ✓ Cognitive function (mostly, except ALS-FTD overlap)
  
PRESENCE of sensory symptoms → NOT classical ALS
  → Consider: Kennedy disease, multifocal motor neuropathy, cervical myelopathy

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DIAGNOSIS OF ALS

Diagnostic Criteria — El Escorial Criteria (Revised Awaji 2012)

DIAGNOSIS REQUIRES:
  A. Evidence of LMN degeneration (clinical, EMG, or pathological)
  B. Evidence of UMN degeneration (clinical)
  C. Progression of signs/symptoms within a region or to other regions
  D. ABSENCE of:
     - Sensory disturbance
     - Sphincter dysfunction
     - Autonomic dysfunction
     - Visual disturbance
     - Parkinson features
     - Cognitive decline (excluding ALS-FTD)

CERTAINTY LEVELS:
  Definite ALS: UMN + LMN signs in ≥3 regions
  Probable ALS: UMN + LMN signs in ≥2 regions; some UMN rostral to LMN
  Possible ALS: UMN + LMN in 1 region (or UMN only in ≥2 regions)
  Probable ALS Lab-Supported: 1 region UMN + EMG LMN in 2+ regions

REGIONS: Bulbar, Cervical, Thoracic, Lumbosacral

Investigations — Structured Approach

CONFIRM DIAGNOSIS (exclude mimics):
  EMG/NCS:
    - Needle EMG: Fibrillations, positive sharp waves (active denervation)
    - Fasciculation potentials (chronic denervation)
    - Large, long-duration, polyphasic MUAPs (chronic reinnervation)
    - EMG should show acute and chronic changes in ≥3 regions
    - NCS: NORMAL (motor conduction normal until advanced disease)
      Sensory NCS: NORMAL (confirms pure motor)
    - "Awaji criteria": EMG fasciculations equivalent to clinical LMN signs

  BLOOD TESTS:
    - CK: Mild elevation (200-1000 U/L) — from muscle denervation (NOT diagnostic)
    - CBC, metabolic panel (rule out metabolic causes)
    - TFT, parathyroid (metabolic mimics)
    - Serology: Anti-GM1, anti-GD1a antibodies (MMN — treatable mimic!)
    - Serum protein electrophoresis (POEMS)
    - HIV, HTLV (infections)
    - Copper, zinc (deficiency — treatable UMN-LMN syndrome)
    - Hexosaminidase A (GM2 gangliosidosis — Tay-Sachs variant)

  CSF:
    - Usually normal
    - Protein slightly elevated in some (not routinely needed)
    - Cytology if malignancy concern

  NEUROIMAGING:
    - MRI brain + spine with contrast (MANDATORY to exclude structural disease)
    - Cervical myelopathy is most important mimic (spondylosis + radiculopathy)
    - MRI ALS features: T2/FLAIR hyperintensity along corticospinal tract
      (corticospinal tract sign — not specific but supportive)
    - MRI abnormal: Look for: Tumor, demyelination, syrinx, Chiari

  GENETIC TESTING:
    - C9orf72 repeat expansion (ALL ALS patients — if positive: FTD counseling, family)
    - SOD1 sequencing (familial ALS, especially with family history)
    - Full ALS gene panel (FALS: TBK1, NEK1, TARDBP, FUS, UBQLN2)
    - ALS-FTD overlap: C9orf72 most likely
    
  PULMONARY FUNCTION:
    - FVC (forced vital capacity) — baseline and every 3 months
    - SNIP (Sniff Nasal Inspiratory Pressure)
    - ABG (when FVC <50%)
    - Sleep study (nocturnal hypoventilation often precedes daytime symptoms)

---

DIFFERENTIAL DIAGNOSIS OF ALS

MULTIFOCAL MOTOR NEUROPATHY (MMN):
  - TREATABLE (IVIG)
  - LMN only, no UMN
  - Anti-GM1 antibodies
  - NCS: Conduction block on nerve conduction studies
  
KENNEDY DISEASE (SBMA):
  - X-linked; males; androgen receptor (AR) gene
  - LMN ONLY (no UMN signs)
  - Sensory neuropathy (asymptomatic usually)
  - Gynecomastia, testicular atrophy, diabetes
  - SLOW progression (survives decades)
  
CERVICAL MYELOPATHY:
  - Compressive myelopathy from spondylosis
  - Can have UMN legs + LMN arms (mimics ALS)
  - MRI shows cord compression
  - Sensory symptoms (distinguishing feature)
  
KENNEDY DISEASE vs ALS: DNA test differentiates
MMN vs ALS: Nerve conduction studies (conduction block in MMN)

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MANAGEMENT OF ALS

Disease-Modifying Therapy

1. RILUZOLE (1995) — FDA Approved
   Mechanism: Na+ channel + glutamate antagonist (reduces glutamate excitotoxicity)
   Dose: 50 mg BD
   Effect: Prolongs survival by 2-3 months (modest but statistically significant)
   Monitoring: LFT (hepatotoxicity)
   SE: Nausea, fatigue, liver enzymes rise

2. EDARAVONE (2017) — FDA Approved
   Mechanism: Free radical scavenger (antioxidant)
   Dose: IV 60 mg daily × 14 days every 28 days (IV formulation)
         OR Oral suspension 105 mg daily (2022)
   Effect: Slows functional decline in early ALS with normal FVC (ALSFRS-R slowing)
   Best for: Early ALS (<2 years, FVC >80%, rapid functional decline

3. TOFERSEN (Qalsody — 2023) — FDA Approved for SOD1-ALS
   Mechanism: Antisense oligonucleotide (ASO) → Degrades SOD1 mRNA
              → Reduces toxic mutant SOD1 protein
   Dose: Intrathecal injection 100 mg every 2 weeks × 3, then monthly
   Effect: Reduces SOD1 protein levels; slows functional decline in SOD1-ALS
   Significance: FIRST GENOTYPE-SPECIFIC TREATMENT for ALS

4. SODIUM PHENYLBUTYRATE-URSODOXICOLTAURINE (AMX0035 - Relyvrio) — 2022/Withdrawn 2024
   Mechanism: Targets ER stress + mitochondrial apoptosis
   Note: Initially FDA approved 2022; withdrawn 2024 after Phase 3 failed to confirm benefit
   
5. FUTURE: C9orf72 ASO (ongoing), TDP-43 targeting, CRISPR approaches

Symptomatic Management

Respiratory Support

NIV (BiPAP): Start when:
  - FVC <50% predicted OR
  - SNIP <40 cmH₂O OR
  - Orthopnea + nocturnal desaturation
  
Benefits: Prolongs survival 7-12 months + improves quality of life
Settings: IPAP 10-20, EPAP 4-6, backup rate 10-12/min

Tracheostomy ventilation: Decision at patient's discretion
(Maintains life but cannot speak or move — requires 24-hr care)

Nutrition

• Early dietitian involvement
• High-calorie diet (2× normal requirements — hypermetabolic)
• PEG tube: When dysphagia + weight loss >10% — place early when FVC >50%
• Nutritional status correlates with survival

Multidisciplinary Care (ALS Clinic)

• Neurologist, respiratory physician, dietitian, speech therapist
• PT, OT, social worker, palliative care, psychologist
• ALS specialist clinic reduces hospitalizations and prolongs survival

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QUESTION 33 (Short Answer - 6 Marks)

APPROACH TO REPERFUSION THERAPY FOR ACUTE ISCHEMIC STROKE

---

DEFINITION

---

TWO PILLARS OF REPERFUSION

REPERFUSION THERAPY
        |
   _____|_____________
   |                  |
IV THROMBOLYSIS    MECHANICAL
(Chemical)         THROMBECTOMY
                   (Endovascular)

---

FLOWCHART: APPROACH TO REPERFUSION THERAPY

ACUTE ISCHEMIC STROKE SUSPECTED
        |
        v
IMMEDIATE ASSESSMENT (Door-to-CT: <25 min)
  - NIHSS scoring
  - Blood glucose (hypoglycemia mimics stroke)
  - CT head (NON-CONTRAST) — exclude hemorrhage
  - CT angiography (CTA) — detect large vessel occlusion (LVO)
  - CT perfusion (CTP) — identify ischemic core vs penumbra
        |
        v
HEMORRHAGE?
  YES → Hemorrhagic stroke management (stop)
  NO  ↓
        |
        v
IV THROMBOLYSIS ELIGIBILITY CHECK:

TIME WINDOW:
  ≤4.5 hours from onset (known time) → ELIGIBLE for alteplase
  Unknown onset → MRI DWI/FLAIR mismatch → may be eligible (WAKE-UP trial)
  
BP CHECK:
  ≥185/110 → Treat with labetalol 10-20 mg IV or nicardipine infusion
              Until <185/110, then proceed
        |
        v
GIVE ALTEPLASE (if eligible):
  Dose: 0.9 mg/kg IV (MAX 90 mg)
  10% as IV bolus over 1 min → Rest over 60 min
  
  OR TENECTEPLASE (preferred if LVO and going for thrombectomy):
  Dose: 0.25 mg/kg IV single bolus (MAX 25 mg)
  (EXTEND-IA TNK, NOR-TEST: Non-inferior to alteplase; easier single bolus)
        |
        v
LVO IDENTIFIED ON CTA? (ICA, M1, M2, Basilar artery)
        |
   YES  |  NO
   ↓    |   → Continue IV thrombolysis + medical management
MECHANICAL THROMBECTOMY (MT)
  (Simultaneously with tPA if eligible for both — "drip and ship" or "mothership")
        |
        v
MT ELIGIBILITY (2023 AHA Guidelines):
  ✓ LVO on CTA (ICA, M1, M2 — now M2 included)
  ✓ NIHSS ≥6 (significant deficit)
  ✓ ASPECTS ≥6 on CT (viable tissue > infarct core)
  ✓ Premorbid mRS 0-2
  
  STANDARD WINDOW (0-6 hours): All above criteria
  EXTENDED WINDOW (6-24 hours):
    Apply DAWN criteria (Clinical-imaging mismatch):
      Age ≥80: Core <21 mL + NIHSS ≥10
      Age 18-79: Core <51 mL + NIHSS ≥10
    OR DEFUSE-3 criteria (Perfusion mismatch):
      Core <70 mL, Mismatch ratio >1.8, Mismatch volume >15 mL
        |
        v
MT PROCEDURE:
  Femoral/radial artery access → Catheter to occluded vessel
  Stent retriever (e.g., Solitaire, Trevo): FDA approved
  Direct aspiration (ADAPT technique): SOFIA catheter
  Combined approach: Aspiration + stent retriever
  
  GOAL: TICI 2b/3 reperfusion (>50% territory reperfusion)
  TARGET: Groin puncture to reperfusion <60 minutes
  DOOR-TO-GROIN: <90 minutes
        |
        v
POST-PROCEDURE CARE:
  - BP <180/105 after tPA/thrombectomy × 24 hours
  - No antiplatelet for 24 hours after tPA
  - ICU monitoring: Neurological obs Q1h × 24h
  - CT/MRI 24 hours post-procedure (detect hemorrhagic transformation)
  - Aspirin 325 mg at 24 hours (if no hemorrhage)

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KEY THROMBOLYSIS CONTRAINDICATIONS

ABSOLUTE CONTRAINDICATIONS:
  - Hemorrhage on CT
  - BP >185/110 (refractory to treatment)
  - INR >1.7 / Therapeutic anticoagulation
  - Platelet <100,000
  - Glucose <50 or >400
  - Major surgery/trauma <14 days
  - Active internal bleeding
  - Prior stroke + diabetes (ECASS-III)

RELATIVE (weigh risk-benefit):
  - Age >80 years (still benefit in most)
  - Minor or rapidly improving stroke
  - Seizure at onset (if residual deficit from stroke, can give)
  - Pregnancy
  - Recent LP or arterial puncture at non-compressible site

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KEY TRIALS — MUST KNOW

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METRICS (Door-to-Treatment Times)

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MD Medicine Exam Strategy for This Set:

• Q29 (Membranous Nephropathy): Always mention anti-PLA2R antibody as the diagnostic biomarker (can replace biopsy), MENTOR trial for Rituximab, and the "Rule of Thirds" natural history. Thromboembolism risk is highest in MN among all glomerulopathies — mention anti-thrombin III loss.
• Q30 (3rd Gen AEDs): Draw the mechanism table showing drug vs target. For cenobamate — emphasize DUAL mechanism (slow Na+ inactivation + NON-BZD GABA-A PAM) and the unprecedented seizure-free rates. For perampanel — emphasize it is the FIRST and ONLY AMPA receptor antagonist in clinical use.
• Q32 (MND): Always draw UMN vs LMN signs side by side. C9orf72 is the most common genetic cause. Tofersen is the first genotype-specific ALS treatment (SOD1-ALS) — extremely high-yield recent advance. The "split hand sign" is pathognomonic for ALS.
• Q33 (Reperfusion): The DAWN and DEFUSE-3 trials extended mechanical thrombectomy window to 24 hours — critical. Tenecteplase is increasingly preferred over alteplase (single bolus). Know the door-to-needle time targets by heart.