Movement Disorders 1 (Hyperkinetic)

Strictly from ICC3 Movement disorders

Etiology & Anatomy

Extrapyramidal system (Basal Ganglia) Dysfunction

Neurotransmitter Imbalance:

Dopamine and Acetylcholine imbalance.

Etiology (The Cause):

Primary: Idiopathic Neurodegenerative (Hereditary/Sporadic).
Secondary: Medication side effects, CVS, Metabolic, Space Occupying Lesion (SOL).
Psychogenic.

The 3 Patterns:

Hyperkinetic: Tremors, Chorea, Tics, Dystonia, Myoclonus, Ballism, Athetosis, Stereotypy, Hemifacial spasm, Myokymia, Restless legs.
Hypokinetic: Parkinson's disease.
Mixed: Parkinson's, Parkinsonism syndromes, Wilson's Disease.

Chorea, Athetosis & Ballism

The "Irregular Dance" Spectrum

Chorea: Irregular, purposeless, non-rhythmic, abrupt rapid, unpredictable, unsustained.
The Flow: Movements seem to flow from one body part to another.
Causes: Huntington Chorea, Parkinson's (L-dopa dyskinesia), Sydenham's chorea.
Athetosis: Slow, writhing movements.
Ballism: Violent, flinging movements.

Stereotypy & Tics

The "Driven" Repetitions & Stress Patterns

Stereotypy: Involuntary, rhythmic, repetitive, coordinated, patterned, nonreflexive, purposeless movement. Seems to be seemingly driven.
Tics: Common in head and neck area.
The Stress Rule: Worse during times that are stressful or exciting.
The Focus Rule: Improve when a person is calm or focused on an activity.

Dystonia & Myoclonus

Twisting Postures vs. Shock-like Jerks

Dystonia: Sustained muscle contractions causing twisting and abnormal postures (e.g., Oromandibular dystonia, oculogyric crisis).
Myoclonus: Sudden, brief, shock-like muscle jerks.
Management Rule: If a drug is suspected, cautiously decrease or discontinue the medication.

Drug-Induced Tardive

Orobuccal Dyskinesia

Context: Long term exposure to neuroleptics (antipsychotics).
Signs: Typically orobuccal dyskinesia (lip smacking, tongue movements).
Acute Reaction Tx: 1. ABCs. 2. IV Anticholinergics (e.g., procyclidine 5-10 mg).

Evaluation & Psychogenic Criteria

Distractibility and Stepwise Testing

Suspect Psychogenic if:

Abrupt onset.
Variable from time to time.
Distractible.
Bizarre gait.

Mandatory Testing:

Labs: Electrolytes, Glucose, Renal/Hepatic function, Calcium, Magnesium.
Paraneoplastic testing, Drug/Toxin screen.
Imaging: Brain imaging + EMG.

Movement Disorders 2 (Parkinson's)

Strictly from ICC3 (051) Movement disorders 2

The Pathology

Think: "Atrophy of Substantia Nigra + α-synuclein."

Core Defect: Loss of dopaminergic cells in SN (especially ventrolateral tier) and caudal putamen.
The 60% Rule: Symptoms only appear when 60% of neurons are already lost.
Biomarker: α-synuclein accumulation in Lewy bodies and neurites.
Risk Factors: Age (main), Genetics (AR: PRKN, PINK1, PARK; AD: SNCA, LRRK2, GBA, VPS35), Pesticides, Rural living, TBI.
Protective Factors: Physical activity, Coffee, Smoking, NSAIDs.

Cardinal Motor Symptoms

Think: "TRAP - Tremor, Rigidity, Akinesia/Bradykinesia, Postural instability."

Bradykinesia: Slowness + reduction in amplitude or speed of continuous movements.
Resting Tremor: Occurs in a fully resting limb; "Pill rolling."
Rigidity: Increased resistance to passive movement.
- Cogwheel: Lead-pipe + tremor.
- Lead-pipe: Hypertonic state throughout entire range of motion (co-contraction).
Postural Instability: Occurs in later stages of PD.

Exclude PD! (Red Flags)

Think: "If these exist, it's a Parkinson-Plus Syndrome, NOT Parkinson's Disease."

Supranuclear gaze palsy (Suggests PSP - Progressive Supranuclear Palsy).
Cerebellar symptoms (Suggests MSA or PSP).
Parkinsonism restricted to lower limbs > 3 years (Vascular parkinsonism / frontotemporal dementia).

Cortical sensory loss.
Absence of response to high-dose levodopa (>600 mg/d).
Recent treatment with dopamine receptor blockers or dopamine depletors.

Hoehn & Yahr Staging & Surgery

Scale of Severity

1: Unilateral involvement only.
2: Bilateral involvement; no balance impairment.
3: Mild to moderate bilateral disease, some postural instability, physically independent.
4: Severe disability; still able to walk/stand unassisted.
5: Uses wheelchair or bedridden unless assisted.
Surgery: Deep Brain Stimulation (DBS) or Magnetic resonance-guided focused ultrasound (targets basal ganglia without craniotomy).

Types of "OFF" States

When Levodopa stops working.

Morning Off: Symptoms experienced in the morning before the first dose.
Delayed On: Prolongation in time it takes for dose to alleviate symptoms (worse after eating).
Wearing Off: Decline in benefit at end-of-dose deterioration.
Sudden Off: Sudden and random transition from ON to OFF.
Dose Failure: When a therapeutic dose does not work.

PD Pharmacology Master

Strict mapping of neurotransmitter restoration and symptom management

1. Dopamine Precursor

Mechanism: DA cannot cross BBB. Levodopa (L-dopa) crosses via transport, then converted to DA by DOPA decarboxylase.

Levodopa / Carbidopa (Sinemet): Gold Standard.
Carbidopa's Role: Peripheral inhibitor. Prevents L-dopa converting to DA in the body. Reduces nausea, vomiting, and orthostatic hypotension.
Advanced Delivery: Duodopa (Intestinal gel pump). Bypasses stomach for steady plasma levels (16hrs/day). Used for severe fluctuations.
Complications: Dyskinesias (involuntary twisting) and Motor Fluctuations (On/Off periods).
Note: High protein diet and chronic constipation decrease absorption.

2. Dopamine Agonists

Mechanism: Synthetic compounds that mimic DA at D2 receptors directly.

Non-Ergot (Preferred): Pramipexole, Ropinirole, Rotigotine (Patch).
Ergot-Derived: Bromocriptine, Cabergoline, Pergolide, Lisuride.
Side Effects: Impulse Control Disorders (gambling/shopping), Sleep Attacks, leg edema, and hallucinations. DA withdrawal syndrome (agitation/anxiety).
Rescue Drug: Apomorphine (SubQ, Sublingual, or Inhaled). Provides rapid relief for Sudden Off states; short half-life.

3. DA Degradation Inhibitors

Mechanism: Block the enzymes that kill existing Dopamine.

MAO-B Inhibitors (Brain Protectors): Rasagiline, Selegiline, Safinamide.
Use: Early PD or add-on for "Off" episodes. Warning: Serotonin Syndrome risk with SSRIs.
COMT Inhibitors (Body Protectors): Entacapone, Opicapone, Tolcapone.
Rule: Used ONLY as an add-on to enhance L-dopa duration.
Side Effects: Orange Urine (Entacapone), Hepatotoxicity (Tolcapone).

4. Specialist Agents

NMDA Antagonist: Amantadine.
Primary use: Treating Levodopa-induced dyskinesia and resting tremor.
Side Effects: Livedo Reticularis (purple skin rash), ankle edema, confusion, hallucinations.
Anticholinergics: Benztropine, Trihexyphenidyl.
Use: Relieving motor symptoms, especially resting tremors.
The Age Rule: Only for YOUNG patients. Avoid in elderly due to Dementia risk, confusion, and urinary retention.

Clinical Strategy & Non-Motor Symptom Management

Patient Profile	First Choice Strategy
Mild Symptoms	Amantadine or Anticholinergic (Avoid anti-ACh in elderly)
Mild/Mod Disability	Dopamine Agonist (Less likely to cause fluctuation)
Mod/Severe Disability	Levodopa / Carbidopa (Sinemet)
Sudden "Off" State	Apomorphine (SubQ/Inhaled) or Inhaled L-dopa
Advanced Fluctuations	Duodopa Gel or DBS Surgery

Non-Motor Symptom	Treatment / Class
Psychosis / Hallucinations	Clozapine, Quetiapine
Cognitive / Dementia	Cholinesterase Inhibitors (Rivastigmine)
Depression & Anxiety	SSRIs
Orthostatic Hypotension	Pyridostigmine, Atomoxetine, Pseudoephedrine
Sleepiness / Fatigue	Modafinil (Sleep) / Rasagiline (Fatigue)
Urinary Dysfunction	Antimuscarinics (Solifenacin)
Constipation	Hydration, Probiotics, Fiber, Lactulose

Ataxia & Friedreich's

Strictly from ICC-3 Clinical approach to Ataxia

The 3 Anatomical Classes

Is it the Brain, the Nerves, or the Ears?

1. Cerebellar (Brain): Dysfunction assimilating sensory perception, coordination, and motor control.
2. Sensory (Nerves): Loss of proprioception.
- Unsteady, stomping gait (heel strikes hard).
- Instability worsens in poorly lit environments or if eyes closed + feet together.
3. Vestibular (Ears): Nerve damage in ear.
- Acute Unilateral: Vertigo, nausea, vomiting.
- Chronic Bilateral: Only unsteadiness.

The Reflex Rule (High Yield)

Look at Deep Tendon Reflexes to narrow the differential.

Reduced or Absent Reflexes:

Friedreich's Ataxia
Ataxia associated with Vitamin E deficiency

Present or Brisk Reflexes:

Most dominant SCAs (Spinocerebellar Ataxias)
Multiple Systems Atrophy (MSA) type C

Etiology & Cardinal Symptoms

Congenital: Cerebral palsy, Hydrocephalus, Tumors.
Hereditary: AD/AR SCAs, Friedreich's, Vit E deficiency.
Acquired: Immune (Paraneoplastic, Gluten ataxia), Degenerative (MSA type C), Deficiency (B12, Vit E), Toxicity (Alcohol, Phenytoin), Infection (HIV, CJD, PML).
Cardinal Symptoms: Gait ataxia/sitting balance (late), Gaze-evoked nystagmus (saccadic pursuit), Dysarthria, Intention tremor, Dysmetria, Dysdiadochokinesis.

Friedreich's Ataxia (FA)

Chromosome 9 GAA repeat causing a 'dying back' axon phenomena.

Genetics & Patho:

Autosomal Recessive. Chromosome 9. GAA repeat in 1st intron of the Frataxin gene.
Normal = up to 50 repeats. FA = 200 to 1000 repeats. Larger repeats = earlier onset, worse severity.
Pathophysiology ("Dying Back"): Begins in periphery, loss of large myelinated axons. Spares unmyelinated sensory fibers.
Spinal Cord: Becomes thin. Demyelination of posterior columns, corticospinal, spinocerebellar tracts.
Cranial Nerves: Loss of CN VII, X, XII cells (facial weakness, speech/swallow diff).

Clinical Features & Tx:

Progressive limb/gait ataxia, dysarthria, intention tremors, nystagmus.
Mixed Reflexes: Absent in Legs (neuropathy) BUT Exaggerated in Arms + Extensor plantars (UMNL).
Bony deformities: Pes cavus, Scoliosis.
Slide Note: "No sensory symptoms" (Meaning no superficial pain/temp complaints despite deep sensory loss).
Cardiomyopathy (chronic interstitial myocarditis + hypertrophy). Deafness, Diabetes Mellitus (~10%), Optic atrophy.
Imaging: MRI shows atrophy of the cervical spinal cord with minimal cerebellar atrophy.
Treatment: Omaveloxolone: Activator of Nrf2 (First FDA approved drug). Coenzyme Q.

Headache (Clinical & Pharma)

Strictly sourced from ICC-3 Headache

1. Migraine (The "Resting" Patient)

Goal: Kill attack. Prokinetics required. NO OPIATES.

SBA Buzzwords: 4-72 hours. Throbbing, unilateral (60%). Nausea, photophobia. Aggravated by movement. Aura (5-30m) in ~31%.
SBA Patient: 17yo girl. Hits on Saturday afternoons (relaxation after stress). Wants to lie down; better if she sleeps in a dark room.
Abortive: Non-specific (Paracetamol 1g, Aspirin 600-900mg, NSAIDs) + Domperidone 10mg / Metoclopramide 10mg. Specific: Triptans, Ergots. Opiates strictly avoided.
Preventive: Start if ≥5/month. Antidepressants (Amitriptyline, Duloxetine), Anticonvulsants (Topiramate, Valproate), Beta-blockers, CCBs. CGRP Mabs if failed 2 conventional trials.

2. Cluster (The "Restless" Patient)

Short, severe, autonomic. Oxygen required.

SBA Buzzwords: 15-180 mins. Unilateral (orbital/temporal). Strict Periodicity (circadian/circannual). Autonomic signs (red/watering eye, ptosis, miosis).
SBA Patient: 18yo male. Woken at 1:00 AM with severe left eye pain. Very restless and agitated (pacing). Triggered within 15 mins of alcohol.
Abortive (Good Efficacy): Subcutaneous Sumatriptan 6mg or 100% Oxygen (7-15 L/min).
Preventive: Verapamil, Lithium, Topiramate, Methysergide, Corticosteroids.

3. Tension-Type (The "Featureless")

SBA Buzzwords: 30 mins to 7 days. Bilateral, band-like/pressing. NO nausea or vomiting. Not aggravated by routine physical activity. Max 1 of photo/phonophobia.
Abortive: Simple analgesics (Paracetamol, Aspirin, NSAIDs).
ABSOLUTE RULE: Do NOT use Triptans, Opiates, Muscle relaxants, or combination analgesics.
Preventive: Amitriptyline, Mirtazapine, Topiramate.

4. Medication Overuse Headache (MOH)

Overuse triggers daily headaches. Detox AND Prevent.

SBA Patient: 40yo woman with pre-existing migraines. Now has a constant background daily mild headache. Takes Nurofen/Codeine daily.
Diagnostic Thresholds (≥ 3 months):
- ≥ 15 days/month: Simple analgesics.
- ≥ 10 days/month: Triptans, Ergots, Opiates, Combo drugs, Barbiturates.
Treatment Strategy: You must execute BOTH Detoxification (stopping the overused drug) AND start a Preventative therapy concurrently.

Focal / Cranial Neuralgias

SBA trigger: Sharp, shooting, or tender arteries.

Trigeminal Neuralgia:

SBA Buzzwords: Paroxysmal. Lasts a fraction of a second to 2 minutes. Intense, sharp, superficial, stabbing.
Triggers: Stereotyped attacks precipitated by touch, chewing, talking, cold wind.
First Line Tx: Carbamazepine, Oxcarbazepine.

Giant Cell Arteritis (GCA):

SBA Buzzwords: Age > 50. New onset continuous unilateral headache. Jaw claudication. Transient/permanent visual loss (optic neuropathy).
Exam / Systemic: Palpably thickened, tender temporal artery. 40% have Polymyalgia Rheumatica. Weight loss.
Tx: Long term oral Steroids (1 mg/kg). Monitor ESR.

Ultimate Clinical Comparison of All Headaches

Strictly sourced diagnostic differentiators from the lecture slides.

Headache Type	Duration	Pain Characteristics	Key Associated Symptoms	Specific Triggers / Timing	Primary Treatment
Migraine	4 - 72 hours	Unilateral (60%), Throbbing.	Nausea, Vomiting, Photophobia, Phonophobia.	Aggravated by movement. Aura (scintillations/numbness) in ~31%. Relaxation post-stress.	NSAIDs/Triptans (Abort), Beta-blockers/Anticonvulsants (Prevent).
Tension-Type	30 mins - 7 days	Bilateral, Non-throbbing (band-like), Mild to Moderate.	None of the migrainous features (No N/V, max 1 of photo/phonophobia).	Not aggravated by routine physical activity.	Simple analgesics. (Amitriptyline to prevent).
Cluster Headache	15 - 180 mins	Unilateral (orbital/temporal), Extremely Severe.	Restlessness/Agitation (pacing) + Autonomic signs (red/watering eye, ptosis, miosis, nasal congestion).	Alcohol trigger (within 15 mins). Highly periodic (REM sleep/1am, seasonal).	100% O2 / SubQ Sumatriptan (Abort), Verapamil (Prevent).
Trigeminal Neuralgia	Fraction of a sec to 2 mins	Unilateral (V nerve), Intense, Sharp, Stabbing, Superficial.	Stereotyped paroxysmal attacks.	Triggered by light touch, chewing, talking, cold wind.	Carbamazepine / Oxcarbazepine.
SAH / Thunderclap	Sudden onset (< 1 min)	"Worst headache of my life", hits max intensity instantly.	Retinal haemorrhage, vomiting, photophobia, neck stiffness (Kernig's), decreased GCS.	Often provoked by exercise/exertion (aneurysm rupture - "felt a pop").	Medical Emergency. BP control, Neurosurgery.
Raised ICP (e.g., IIH)	Continuous/ Fluctuating	Holocranial, dull.	Pulsatile tinnitus, transient visual obscurations (TVO), diplopia (VI palsy), papilloedema.	Worse lying down / on waking up. Worse with Valsalva (coughing).	Acetazolamide, Furosemide, Weight loss, LP drainage.
Intracranial Hypotension	Continuous/ Intermittent	Bilateral. Often a sudden/thunderclap onset.	Nausea, dizziness, tinnitus, neck stiffness, diplopia (VI palsy).	Orthostatic: Worse when upright, relieved by lying flat (recumbency).	Rest, Caffeine, Corticosteroids, Epidural blood patch.
Giant Cell Arteritis (GCA)	Continuous	New onset, usually unilateral.	Jaw claudication, visual loss, thickened/tender scalp artery, Polymyalgia Rheumatica.	Age > 50. Systemic symptoms (weight loss, myalgia).	Immediate high-dose Steroids to prevent blindness.
Bacterial Meningitis	Acute/Subacute	Severe headache, back/neck pain.	Fever, neck stiffness, rash, altered consciousness, seizures.	Signs of systemic infection.	IV Cefotaxime/Ceftriaxone (+ Ampicillin if >55yo).

Secondary Headache (Red Flags)

Strictly sourced from ICC-3 Secondary Headache

The Golden Rules of Diagnosis

When to suspect an ominous secondary cause.

The Age 50 Rule (Slide 9): New-onset headache after age 50 MUST be considered secondary until proven otherwise.
The Pattern Rule (Slide 18): If a patient with a known primary headache suddenly has a clear change in pattern or type, consider it a secondary headache.
The Childhood Rule (Slide 18): Headaches that have recurred reliably since childhood or young adulthood usually point to a benign primary disorder.

The SNOOP Mnemonic (All 10 Red Flags)

If any of these 10 components are positive, here is exactly what it indicates:

Mnemonic	Strict Definition / Features	If Positive, This Indicates...
1. Systemic	History of malignancy, HIV, or immunosuppression OR Fever, chills, night sweats, weight loss, jaw claudication.	Infection: Meningitis, Encephalitis, Brain Abscess. Giant Cell Arteritis (GCA): If jaw claudication/weight loss. Malignancy: Brain metastasis.
2. Neurologic	Focal/global symptoms (diplopia, weakness, sensory loss, ataxia) OR Abnormal neuro exam.	Space Occupying Lesion (SOL): Tumor, abscess, hematoma causing focal deficits. Raised ICP / IIH: If diplopia (6th nerve palsy) or TVO are present.
3. Onset (Sudden)	Thunderclap: reaches peak intensity in < 1 minute.	Vascular Emergency: Subarachnoid Haemorrhage (SAH), Artery Dissection, Venous Sinus Thrombosis.
4. Onset (Age)	New-onset headache < 5 years OR > 65 years.	High-Risk Secondary: Brain tumor, Giant Cell Arteritis (GCA if >50-65), or undetected stroke/bleed.
5. Pattern change	Progressive (evolution to daily headache) or a clear change in characteristics.	Medication Overuse Headache (MOH): If evolving into daily background pain. Expanding Mass: If getting progressively worse over time.
6. Precipitated by Valsalva	Provoked by coughing, sneezing, straining, lifting, laughing.	Raised Intracranial Pressure (ICP): A mass lesion, obstructive hydrocephalus, or Chiari malformation shifting with pressure changes.
7. Postural	Aggravated by posture.	Intracranial Hypotension (Low CSF): If worse when standing upright. Raised ICP: If worse when lying down flat.
8. Papilledema	Presence of papilledema on fundus examination.	Raised Intracranial Pressure (ICP): Idiopathic Intracranial Hypertension (IIH), Brain Tumor, Abscess, or severe venous thrombosis.
9. Pregnancy	New-onset headache or change in headache during pregnancy.	Vascular/Systemic: Cerebral Venous Sinus Thrombosis (CVST) due to hypercoagulable state, or Pre-eclampsia/Hypertensive crisis.
10. Phenotype of rare headache	Trigeminal autonomic cephalalgia (TAC); hypnic; exercise-, cough-, or sex-induced.	Underlying Structural/Vascular Issue: Mandates neuroimaging (MRI/MRA) to rule out aneurysms, dissections, or posterior fossa lesions.

Symptom & Physical Exam Mapping (SBA Cheat Sheet)

Review of Systems and Exam findings. Match the symptom to the secondary disease.

Visual, Eyes, & Pupils:

Red eye + Halos/Blurring = Acute angle-closure glaucoma.
Visual field deficit/Diplopia/Blurring = Mass lesion, IIH, or Ocular migraine.
Professor's Note (Slide 12): If Headache + Blurring of vision -> Do MRI, MRA, MRV.
Lacrimation + Facial flushing = Cluster headache.
Abnormal Pupils = Acute Glaucoma (red eye) or Tentorial Herniation (blown pupil).
EOM Deficits (Diplopia) = VI nerve palsy from Raised ICP, IIH, or CSF leak.

Systemic, Face, Neck & Ears:

Vomiting = Migraine OR Increased ICP.
Fever (Temp) = Infection (Encephalitis, meningitis, sinusitis).
Pulsatile Tinnitus = Idiopathic Intracranial Hypertension (IIH).
Myalgias + Vision changes (>50yrs) = Giant Cell Arteritis (GCA).
Scalp swelling/tenderness = Giant Cell Arteritis (GCA).
Nares purulence = Sinusitis.
Teeth tenderness / Oropharynx = Referred facial pain (Dental, TMJ, Sinus).
Neck Flexion stiffness (Meningismus) = Meningitis or Subarachnoid Haemorrhage (SAH).

Severe Neurological Symptoms:

Syncope at headache onset = Subarachnoid Hemorrhage (SAH).
Seizures = Encephalitis, tumor, or mass lesion.
Focal Neurologic Deficit = Encephalitis, meningitis, ICH, subdural hematoma, mass lesion.
Papilledema (Fundus) = Raised Intracranial Pressure (SOL, Bleed, IIH).

Master Investigations & Workup (Both Lectures)

The unvarnished truth of every test, scan, and biopsy mentioned across all headache slides.

1. Neuroimaging (Radiology)

Non-contrast CT Head: The immediate starting point. 90% sensitive for SAH in first 24hrs.
MRI Brain: Usually normal in primary headaches. Escalation step for red flags.
MRI (Dedicated Trigeminal & Brainstem cuts): To hunt for vascular compression or MS in Trigeminal Neuralgia.
MRI with Gadolinium: Diffuse meningeal enhancement (>80%) and tonsillar descent (40%) = Intracranial Hypotension (Low CSF).
MRV (Venography): Mandatory to exclude cerebral venous sinus thrombosis (CVST) when diagnosing IIH.
Spinal MRI / CT Myelography: CT Myelography (with water-soluble contrast) is the most reliable test to demonstrate the exact site of a CSF leak.
Angiography: For identifying aneurysms / AVMs in Subarachnoid Haemorrhage.

2. Lumbar Puncture (CSF)

Rule: You CAN perform an LP in raised ICP, but ONLY AFTER ruling out a focal mass, pressure gradient, or Septic Shock!

Opening Pressure > 25 cm H2O: Idiopathic Intracranial Hypertension (IIH). Note: CSF constituents will be completely normal.
Opening Pressure Very Low: Intracranial Hypotension.
Red Cells & Xanthochromia: Shows up 12 hours to 1 week after a SAH. Used if CT is negative.
Infectious Panel: Cells, chemistry, Culture & Sensitivity (C&S), PCR, Antibodies (Meningitis/Encephalitis workup).

3. Bloods, Biopsy & EEG

Bacterial Meningitis Labs: FBC, U&E, Gluc, LFT, CRP, clotting, ABG. Microbiology: Blood cultures, throat swabs, PCR.
Giant Cell Arteritis (GCA) Labs: ESR > 50 mm/h (used to diagnose AND monitor disease activity), CRP, Platelets.
The Gold Standard Biopsy: Temporal Arterial Biopsy is the ultimate confirmation for GCA.
Secondary Check (General): Hypercoagulable state labs, Tumor markers, Routine ABCDE.
Neurophysiology: EEG (Only indicated if seizures are present, pointing to Encephalitis or a Mass Lesion).

MS Differential Diagnosis

What to think when you see the phenocopies on the wards.

Likely MS Symptoms & Mimics

Before assuming MS, rule out these specific mimics.

Sensory (35%): Is it MS? Or Carpal Tunnel Syndrome, Spondylopathy (cervical/lumbar), Migraine, Epilepsy, or ARA?
Weakness (20%)
Optic neuritis (15%): Is it MS? Or Toxic-alcohol, nutritional (B12-functional deficiency), ON compression, Ischemic, Retinal?
Cerebellar (10%)

Warning Bells: This is NOT MS

If you see these, stop thinking MS immediately.

Symptoms: Dementia, Dysphasia, Seizures, Pain, Movement disorders.
Examination: Systemic features like skin lesions.
Imaging: MRI=normal.
CSF: Oligoclonal band negative OR CSF raised WCC>50;>100.
Treatment: Very steroid sensitive.

Transverse Myelitis (TM) Causes

If it's TM, it's not always MS. Look for the cause.

Para-infectious: Viral (herpes, flu, entero, HIV, hep A), Bact (mycoplasma, Lyme, syphilis, TB), Post-vaccine.
Systemic autoimmune: SLE, Sjögren's, Sarcoidosis.
Vascular: AVM, thrombotic, vasculitic.
Other: MS, Idiopathic, Paraneoplastic.

Neuromyelitis Optica (NMO / Devic's)

Common in Japan. Poor recovery between attacks.

The Rule: Optic neuritis + myelitis + 2 of 3 (Brain MRI normal, Longitudinally extensive cord lesion, NMO IgG/AQP4 positive).
Labs: CSF WCC > 50 +/- OCB positive. Pulse steroids +/- plasmapheresis.
MRI Red Flags: Normal cranial MRI, Abnormal cord MR (>3 segments), No occult changes in NAWM.

Acute Disseminated Encephalomyelitis (ADEM)

Post-infectious/vaccine. Monophasic and rapid recovery.

Clinical: Headache, seizures, meningism, altered conscious level/confusion, focal neuro signs (hemiplegia, hemianaesthesia).
Labs: CSF increased WCs and proteins.
MRI Red Flags: Symmetrically distributed, Poorly defined margins, Absent/rare Dawson fingers. Simultaneous enhancement of all lesions. Deep grey matter lesions.

Sarcoidosis

Afro-caribbean. Systemic rash, weight loss, BHL, uveitis.

Neurology (10% of cases): Meningeal infiltration (headache, fits, cranial neuropathies). 40% ON, 35% CN VII/VI/VIII.
MRI Red Flags: Meningeal enhancement, Hydrocephalus, Parenchymal deposits (SOL) in hypothalamus/pituitary. Punctiform parenchymal enhancement.

Behçet's Disease

Turkey > Asia > Western. Oral ulcers + 2 of: Genital ulcers/uveitis/skin lesions/Pathergy.

Clinical: Pathergy test positive. Increased inflammatory markers.
Neurology: CNS inflammation (Brainstem syndrome, myelitis, aseptic meningitis, headache) or Cerebral venous thrombosis (stroke-like, high ICP), Psychiatric.
MRI Red Flags: Large infiltrating brainstem/basal ganglia lesions, Cerebral venous sinus thrombosis, Regional brainstem atrophy.

Systemic Lupus Erythematosus (SLE)

Afro-caribbean. Malar rash, nephritis, arthritis, ANA/dsDNA.

Neurology (Neuro-lupus): Painless optic neuritis/neuropathy (subacute, progressive). Transverse myelopathy, headache, encephalopathy, chorea.
General MRI: Cerebral vasculitis, transverse myelitis.

Sjögren's Syndrome

90% female. Dry eyes, dry mouth, Anti-Ro/SSA, Anti-La/SSB or RF.

Neurology: Transverse myelitis, optic neuritis (overlap with NMO?), cerebral vasculitis, sensory (trigeminal/peripheral neuropathy), seizures, encephalopathy dementia.
MRI Red Flags: Large and swelling spinal cord lesions.

Cerebral Vasculitis

Acute/subacute. Headache, Seizures, Stroke-like, Chorea.

Systemic: Fever, night sweats, rash, weight loss, arthropathy. Increased inflammatory markers.
Primary CNS Vasculitis (PACNS) MRI: Large lesions with mass effect, Haemorrhages, Simultaneous enhancement, Punctiform enhancement, Dilation of VR spaces.

Giant Cell Arteritis (GCA)

Age > 50y. Systemic symptoms.

Clinical: Scalp tender, Visual loss, Jaw claudication.
Labs: Increased ESR, increased platelets, abnormal LFTs. Temporal artery biopsy.

CADASIL & Ischemic WMLs

Vascular mimics of MS.

CADASIL MRI Red Flags: T2-hyperintensity of temporal pole, U-fibres at vertex, external capsule, insula. Multiple bilateral microhaemorrhagic foci. Sparing of corpus callosum/cerebellum. Pontine lacunar infarcts.
Normal Aging MRI: Periventricular caps/bands, mild atrophy (widened sulci/ventricles), punctate/confluent deep white matter lesions (Fazekas I & II).

Infections (PML & Abscesses)

Look for atypical lesion borders and mass effect.

PML: Multifocal, asymmetrical starting juxtacortical and progressively enlarging. Large lesions with absent/rare mass effect. Absence of optic-nerve lesions.
Abscesses: Isolated lesions with ring enhancement (often complete). Infiltrating lesions that do not respect grey/white matter boundaries. Mass effect.

MS 2nd-Line Therapy Criteria

Based on NICE guidelines and clinical risk stratification

Scenario 1: Sub-optimal Response (Therapy Failure)

Switch to a second-line agent if the patient demonstrates high disease activity despite being on first-line DMT.

Must meet BOTH of the following:

Clinical: ≥ 1 relapse in the previous year while on therapy.
MRI: ≥ 9 T2 hyperintense lesions OR ≥ 1 Gadolinium-enhancing (Gd+) lesion.

*Alternative clinical criteria: Unchanged or increased relapse rate in the prior year compared with the previous 2 years.

Scenario 2: Rapidly Evolving Severe RRMS

Skip first-line agents entirely and initiate second-line therapy immediately if the patient presents with highly aggressive disease from the onset (no prior DMT required).

Must meet BOTH of the following:

Clinical: ≥ 2 disabling attacks in the previous year.
MRI: ≥ 1 Gadolinium-enhancing (Gd+) lesion at baseline MRI (or a significant increase in T2 load compared to previous MRI).

The Second-Line / Rescue Agents

If the above criteria are met, risk stratification and JC Virus (JCV) monitoring dictate the choice between:

Natalizumab (Tysabri) - Requires strict JCV monitoring protocol due to PML risk.
Fingolimod (Gilenya) - Specifically indicated for RRMS in two distinct cases:
- Insufficient response to existing immunomodulatory therapy (Matches Scenario 1).
- Non-pretreated high-risk patients: At least 2 relapses with disability progression in the last year AND detection of new disease activity by MRI (Matches Scenario 2).
Alemtuzumab (Lemtrada) - Intense/marked immunosuppression (pulsed therapy).

Neuromuscular Part 1 (Neuropathies)

Nerves, Roots, & Plexus

CNS vs PNS Lesion Rules

Think: "Are reflexes up (Brain/Cord) or down (Nerve/Muscle)?"

CNS (Upper Motor Neuron):

Spastic tone, normal bulk.
Hyperactive DTRs, Babinski sign present.
Sensory level on trunk, hemi-body symptoms.

PNS (Lower Motor Neuron):

Flaccid tone, atrophic bulk, fasciculations present.
Hypoactive DTRs, Babinski absent.
Sensory loss pattern: Hands and feet (Stocking & Glove).
Note: Neuropathic pain in a limb strongly suggests PNS.

Diagnostic Toolkit & Causes

Think: "Rule out systemic causes before blaming genetics."

Tools: 1. Labs (CK, Myositis Abs, ACh/MuSK Abs). 2. EMG & NC. 3. Radiology (Muscle/Spine MRI). 4. Biopsy (Muscle/Nerve). 5. Genetics.
Causes of Neuropathy:
- Toxins/Nutrition: DM, Uremia, Porphyria, Starvation, B12, Celiac, B6 in high doses.
- Infectious/Inflammatory: GBS, Lyme, Leprosy, HIV, Syphilis, SLE, Polyarteritis.
- Industrial: Arsenic, lead, mercury, thallium, N2O, n-hexane, toluene.

Guillain-Barré Syndrome (AIDP)

Acute post-infection ascending paralysis. Life threatening.

Presentation: Acroparesthesia -> symmetric ascending flaccid paresis and areflexia (over 1-2 weeks). Nadir by 4 weeks.
Severe Risks: Respiratory failure (phrenic nerve), Bulbar palsy. Bladder/Bowel function is preserved.
Labs: CSF shows albuminocytologic dissociation.
Tx: Plasmapheresis or IVIG. Steroids do NOT help.

Head-to-Head: GBS vs CMT

Acute Emergency vs. Lifelong Genetic Deformity.

Feature	Guillain-Barré Syndrome (GBS)	Charcot-Marie-Tooth (CMT)
Onset & Timeline	Acute/Rapid. Ascends over 1-2 weeks. Reaches nadir by 4 weeks.	Chronic/Lifelong. Starts in childhood/youth. Extremely slow progression.
Weakness Pattern	Proximal AND Distal. Ascending weakness hits both limb compartments, plus facial/respiratory muscles.	Strictly Distal. Symmetrical weakness of feet/hands (lower legs > upper). Core/proximal muscles spared.
Root Cause	Post-infectious (triggered by a recent virus/vaccine).	Genetic/Hereditary (PMP22, GJB1, MPZ mutations).
The "Look"	Ascending flaccid paralysis. High risk of hitting the lungs and face (bulbar palsy).	"Clumsy kid." Skeletal deformities (Pes cavus/high arches, hammertoes). Inverted champagne bottle legs.
Sensory Symptoms	Acroparesthesia (numbness and tingling in hands and feet).	Positive sensory symptoms are rare. Any pain is usually musculoskeletal from bad mechanics.

The Mononeuropathies & Multiplex

Nerve / Condition	Mechanism / Sign	Sensory / Motor Paresis
Median	Carpal Tunnel. Tinel sign / Phalen.	Thumb, 2nd, 3rd, lat 1/2 of 4th. Thenar atrophy. No reflex lost.
Ulnar	Cubital tunnel. Claw hand / Benediction.	5th finger, med 1/2 of 4th. Hand intrinsic muscles. No reflex lost.
Radial	Saturday night palsy. Wrist drop.	Dorsum of hand. Wrist/finger extensors. *Triceps reflex spared at spiral groove.
Lat. Fem. Cutaneous	Meralgia Paresthetica. Tight belts/Obesity.	Discrete oval patch on lateral thigh. Purely sensory.
Mononeuritis Multiplex	Random, stepwise multiple nerve failures.	Systemic illness: Vasculitis, Sarcoidosis, Lyme, SLE, Leprosy.

Neuromuscular Part 2 (Myopathies)

Strictly from ICC3 neuromuscular diseases part 2

The Base Rules: Terminology & General Myopathy

Where is the lesion?

Cell body/Root = Neuronopathy, Radiculopathy
Plexus = Plexopathy, Plexitis
Nerve = Neuropathy, Neuritis
NMJ = No term, just "dysfunction"
Muscle = Myopathy, Myositis
Spinal Cord = Myelopathy, Myelitis

General Myopathy Presentation (The Default)

Weakness: Proximal. Difficulty climbing stairs.
Weakness > Wasting.
Sensory & Reflexes: Normal.
Labs: CK Elevated. EMG Myopathic.

Myasthenia Gravis (NMJ)

Fatigable weakness. Droopy eyes worse in evening.

Clinical: Fatigable weakness. Proximal > distal. Ptosis, double vision, dysphagia, neck flexion weakness.
Key Negatives: Sensory and Reflexes are NORMAL.
Management: Pyridostigmine. CT chest to look for Thymoma. Immunosuppression.

Congenital Myopathy

The floppy infant with a completely normal CK.

Clinical: Neonatal onset. Severe hypotonia (frog-like posture), difficulty sucking. High arch palate, rigid spine.
Types: Nemaline, Central core, Centronuclear, Fiber-type disproportion, Myosin storage.
Labs: CK serum level is usually NORMAL. EMG is myopathic.

The Dystrophinopathies: Duchenne & Becker

Boys with huge calves using their hands to climb their own legs.

Duchenne (DMD)

Genetics: X-linked (1 in 3500 boys). Absolute absence of Dystrophin.
Signs: 3-6 yrs. Proximal weakness, Calf hypertrophy, Gowers' manoeuver.
Systemic: Low IQ, Autism, ADHD. Cardiomyopathy (start ACE-inhibitor + carvedilol at age 10).
Labs/Tx: CK massively raised (10,000). Tx: Deflazacort.

Becker (BMD)

Genetics: In-frame mutation causing a partially functional, short dystrophin protein.
Severity: Milder form of DMD. Onset later (age 6 to 30s).
Prognosis: May not need a wheelchair until their 20s or later.
Cause of death: Cardiomyopathy is a common cause of death.

Myotonic Dystrophy (DM1)

Hatchet face, frontal balding, cataracts, delayed grip relaxation.

Genetics: Expansion of CTG repeat in DMPK gene. Shows Anticipation.
The "Look": Frontal balding, Hatchet facies, Ptosis, SCM wasting. Myotonia.
Multisystem: Cataracts, Arrhythmias, Hypersomnia, Insulin resistance.

Facioscapulohumeral (FSHD)

Asymmetrical facial/shoulder weakness, winging, DELTOIDS PERFECT.

Genetics: Chromosome 4q35. DUX4 gene. Dominant. Onset by age 20.
Weakness: ASYMMETRICAL. Facial, Shoulder girdle (winging, SPARES the deltoid), Ankle dorsiflexion.
Labs: CK is only mildly elevated.

Limb Girdle Muscular Dystrophy (LGMD)

Shoulder and pelvic weakness requiring a biopsy to name the specific protein.

Clinical: >30 types. Weakness in proximal muscles (shoulders, upper arms, pelvic area, thighs). Can have cardiac/respiratory weakness.
Labs: High CK. Myopathic EMG.
Diagnosis: Fresh frozen muscle biopsy for Immunohistochemistry OR LGMD gene panel analysis.

Dermato & Polymyositis

Autoimmune attack on the muscles causing proximal weakness.

Dermatomyositis: Proximal weakness + Rash (Heliotrope rash, Gottron's papules). In adults, associated with malignancies. B-cell mediated (Vasculitis).
Polymyositis: Pure proximal weakness. CD8+ T-cell mediated attack on non-necrotic fibers in endomysium.

Inclusion Body Myositis (IBM)

The rule-breaker: Old patient (>50) with asymmetrical, DISTAL weakness.

Demographics: Age > 50 in 80% of cases.
Rule-Breaking Weakness: Distal > Proximal. May be asymmetric.
Specific Muscles: Long finger flexors (can't grip), Quadriceps (knees buckle), Ankle dorsiflexors (foot drop).

Glaucoma Treatments

Strictly sourced from ICC3 VM Glaucoma (2025-2026)

The Core Rule & Anatomical Mechanisms

The ONLY proven method of slowing optic nerve damage is by reducing Intraocular Pressure (IOP).

1. Decrease Aqueous Humor INFLOW (Production)

Fluid is produced by the nonpigmented epithelium on the ciliary body.
Drugs that stop production: β-blockers, α2-agonists, Carbonic Anhydrase Inhibitors (CAIs).

2. Increase Aqueous Humor OUTFLOW (Drainage)

Trabecular Outflow (90%): Through meshwork → Canal of Schlemm → episcleral vasculature. Increased by Muscarinic agonists.
Uveoscleral Outflow (10%): Drainage into uvea and sclera. Increased by Prostaglandin agonists.

Prostaglandin Analogues

The First-Line Treatment.

Drugs: Latanoprost, Bimatoprost.
Mechanism: Increases Uveoscleral outflow (the 10% pathway).
Side Effects: Pigmentation (darkening of iris/skin), increase in eyelash length, stinging sensation.

Beta-Blockers

The Production Stoppers. Watch out for systemic effects.

Drugs: Timolol.
Mechanism: Decreases aqueous humor production at the ciliary body.
Strict Contraindications (CI): Asthma, COPD, Heart block.

Carbonic Anhydrase Inhibitors (CAIs)

Usually used in combination therapies.

Drugs: Dorzolamide, Brinzolamide.
Mechanism: Decreases aqueous humor production at the ciliary body.
Usage Note: Usually prescribed in combination with a beta-blocker.

Selective α2 Receptor Agonists

Dual action: mostly decreases production.

Drugs: Brimonidine.
Mechanism: Decreases aqueous humor production.
Side Effects: Lethargy, dry mouth & eyes, allergy.

Acute Angle Closure Glaucoma Protocol

OCULAR EMERGENCY (IOP > 40mmHg, hazy cornea, fixed mid-dilated pupil, sudden pain).

Phase	Interventions Required
Step 1	Urgent referral to an Ophthalmologist.
Systemic (Oral/IV)	1. IV Acetazolamide (CAI) 500mgs. 2. PO Acetazolamide 500mgs. 3. Anti-emetics (for the intense nausea/vomiting). 4. IV Mannitol or Oral Glycerol (Osmotic agents to forcefully drag fluid out of the eye).
Topical (Eye Drops)	1. Beta-blockers. 2. Selective α2 agonists. 3. Pilocarpine 2% (Muscarinic agonist to constrict the pupil and pull the iris out of the angle). 4. Steroids (to reduce extreme inflammation).

Surgical & Laser Interventions

Used when medications fail, or as definitive treatment for closed angles.

Procedure	Indication & Mechanism
Trabeculoplasty (Laser to angle)	Open Angle Glaucoma. Uses laser to target the trabecular meshwork to alter the pores/spaces, increasing fluid outflow.
Trabeculectomy (Guarded Filtration)	Creates a new surgical passage between the anterior chamber and the conjunctival space. Fluid flows out into an artificial pocket called a "Bleb". (Definitive treatment for Angle Closure).
Tube Shunt Surgery	Used when meds/laser/trabeculectomy fail. Involves inserting a physical tube (e.g., Ahmed Valve, Baerveldt Shunt) to drain fluid.
Peripheral Laser Iridotomy	Definitive treatment for Angle Closure. Blasts a tiny hole in the iris to relieve the pupillary block and allow fluid to bypass the pupil.
Lens Extraction	Definitive treatment for Angle Closure. Removing the natural lens (especially if cataractous) deepens the anterior chamber and opens the angle.

Recognized Combination Therapies

Xalacom, Cosopt, and Combigan are specifically listed in the slides as common combination eye drops used to hit multiple mechanisms at once.