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🧠 NEUROLOGY PATHOLOGY - COMPLETE LECTURE NOTES

Pages 531-539 | First Aid USMLE

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PAGE 531 - SEIZURES

What is a Seizure?

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LINE 1: "Characterized by synchronized, high-frequency neuronal firing"

• Synchronized = all happening at the same time, together
• High-frequency = very rapid, fast firing
• Neuronal firing = nerve cells sending electrical signals

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THE 3 PHASES OF A SEIZURE

"Aura - early part of a seizure, may include odd smells or tastes"

• Aura = a warning sign that comes BEFORE the main seizure
• The word "aura" comes from Greek meaning "breeze" or a feeling that something is about to happen
• It represents the BEGINNING of abnormal electrical activity, but only in a small, localized area of the brain

• If it starts in the area that processes smell (olfactory cortex) → you smell something that isn't there (often burning rubber, rotten eggs)
• If it starts near taste centers → odd tastes
• If it starts in vision areas → flashing lights
• If emotional/memory areas → intense fear, deja vu

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"Ictal - time from first symptom to end of seizure activity"

• Ictal comes from Latin "ictus" meaning "stroke" or "blow"
• This is the ACTUAL seizure itself - the main event
• During the ictal phase, the electrical storm is at its peak
• The patient may be shaking, unconscious, staring blankly - depending on the seizure type

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"Postictal - period of gradual recovery back to preseizure baseline level of function/awareness"

• Post = after, ictal = seizure
• This is the RECOVERY phase after the seizure ends
• The brain has just fired so many neurons so rapidly that it's exhausted - like a muscle after maximum exercise
• The patient feels confused, disoriented, sleepy, or has a headache
• Can last minutes to hours

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TYPES OF SEIZURES

1. Focal (Partial) - starts in one area of the brain
2. Generalized (Diffuse) - involves the whole brain at once

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FOCAL SEIZURES

• Medial temporal lobe = inner part of the temporal lobe (the side of your brain, near your ears)
• This area contains the hippocampus (memory center) and amygdala (emotion center)
• This is the most common starting point for focal seizures

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"Focal aware (formerly called simple partial) - consciousness intact; motor, sensory, autonomic, psychic symptoms"

• Focal aware = the patient is AWAKE and AWARE during the seizure
• Old name was "simple partial" - they changed it because "simple" was confusing
• Consciousness intact = the person knows what's happening to them

• Motor = jerking of one hand or arm (if it starts in the motor cortex)
• Sensory = tingling, numbness in one body part (if sensory cortex)
• Autonomic = changes in heart rate, sweating, stomach feelings (if autonomic areas)
• Psychic = déjà vu, strange feelings, fear (if limbic/emotional areas)

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"Focal impaired awareness (formerly called complex partial) - impaired consciousness, automatisms"

• Focal impaired awareness = seizure starts in one area BUT consciousness is affected
• Old name: "complex partial"
• Automatisms = automatic, repetitive, purposeless movements the patient does WITHOUT being aware

• Lip smacking
• Chewing movements
• Hand rubbing or fumbling
• Picking at clothes
• Repeating words or phrases

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GENERALIZED SEIZURES (DIFFUSE)

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"Absence (petit mal) - 3 Hz spike-and-wave discharges on EEG; short (usually 10 seconds), frequent episodes of blank stare, possible automatisms; no postictal confusion. Can be triggered by hyperventilation"

• Absence seizure = the name comes from the patient being "absent" - they suddenly stare blankly into space
• Petit mal = French for "small illness/bad" (as opposed to grand mal = "big bad")
• These are VERY common in children

• EEG = Electroencephalogram = a machine that measures the brain's electrical activity (like an ECG for the heart)
• Spike-and-wave = a characteristic pattern on EEG - a sharp spike followed by a slow wave, repeating exactly 3 times per second
• This is the DIAGNOSTIC signature of absence seizures

• These seizures are BRIEF - just a few seconds
• The child just stares blankly, stops what they're doing, then resumes as if nothing happened

• A child can have 50-100 absence seizures per DAY without knowing it
• They often go undiagnosed - teachers think the child is "daydreaming" or "not paying attention"

• Unlike other seizures, after an absence seizure the child immediately returns to normal
• No sleepiness, no confusion - they just continue their sentence mid-word!

• Hyperventilation = breathing very fast and deep
• This lowers carbon dioxide in blood, making the blood more alkaline (basic)
• Alkaline blood causes neurons to become more excitable = can trigger absence seizure
• Doctors actually use this in their office to trigger an absence seizure for diagnosis!

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"Myoclonic - quick, repetitive jerks; no loss of consciousness or postictal confusion"

• Myo = muscle, clonic = jerking
• Myoclonic seizures = sudden, brief, shock-like muscle jerks

• Like you're being zapped by electricity - a sudden jerk
• Affects both sides of body (generalized)
• Person stays conscious (no loss of awareness)
• No postictal confusion

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"Tonic-clonic (grand mal) - alternating stiffening and movement, postictal confusion, urinary incontinence, tongue biting"

1. Tonic phase (stiffening):

• All muscles contract/stiffen simultaneously
• Person falls to the ground (can't support themselves)
• May cry out (air forced through vocal cords by muscle contraction)
• Lasts about 10-30 seconds
• Breathing may stop briefly

1. Clonic phase (jerking):

• Rhythmic, alternating contraction and relaxation of muscles
• Arms and legs shake/jerk rhythmically
• Lasts 1-3 minutes

• Why? Because during the tonic phase, ALL muscles contract, including the bladder's detrusor muscle, which forces urine out
• The sphincter (the muscle that holds urine in) also loses voluntary control

• This is why you should NEVER put anything in a seizing person's mouth (they will bite you)
• If they've bitten their tongue, you'll see blood in the mouth - this is a clue that a tonic-clonic seizure occurred

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"Tonic - stiffening"

• A tonic seizure is ONLY the stiffening phase, without the clonic (jerking) component
• The person suddenly stiffens and falls - can be very dangerous because they fall like a plank of wood
• Common in children with severe epilepsy syndromes

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"Atonic - 'drop' seizures (falls to floor); commonly mistaken for fainting"

• A = without, tonic = muscle tone
• Atonic seizure = sudden complete LOSS of muscle tone
• The person just drops - like a puppet with its strings cut
• Very dangerous - serious head injuries from falls
• Also called "drop attacks"

• Fainting (syncope) = gradual: person feels dizzy, turns pale, slowly slides down
• Atonic seizure = instantaneous, no warning, drops like a stone
• And fainting has a clear cause (standing up too fast, heat, emotional stress); atonic doesn't

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EPILEPSY

• Recurrent = happening more than once (you need at least 2 seizures to diagnose epilepsy, OR 1 seizure with high risk of recurrence)
• Unprovoked = no clear immediate cause (not due to fever, low blood sugar, drug withdrawal, etc.)

• Febrile = related to fever
• Children aged 6 months - 5 years can have seizures when they get a high fever
• This is a NORMAL response to fever in young children (their brains are more excitable and sensitive to temperature)
• Febrile seizures do NOT mean the child has epilepsy
• Most children outgrow them and are completely normal

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CONVULSIVE STATUS EPILEPTICUS

• Status epilepticus = a seizure emergency
• Convulsive = with physical shaking/convulsions
• Interictal = between seizures

• A seizure lasting ≥5 minutes (used to be 30 min, lowered to 5 min because the longer a seizure goes, the harder it is to stop)
• OR multiple seizures without regaining consciousness in between

• During prolonged seizures, neurons fire so rapidly they exhaust their energy supply
• This causes EXCITOTOXICITY - neurons are "excited to death" by excessive glutamate
• Brain temperature rises
• Oxygen delivery can't keep up with demand
• Result: permanent brain damage or death

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CAUSES OF SEIZURES BY AGE

• Genetic = inherited epilepsy syndromes
• Infection (febrile) = fever-induced seizures
• Trauma = head injury
• Congenital = brain abnormalities from birth
• Metabolic = low blood sugar, low sodium

• Tumor = brain tumors irritate nearby neurons
• Trauma = head injury (scar tissue from old injuries can become seizure foci)
• Stroke = damaged brain area becomes electrically unstable
• Infection = meningitis, encephalitis, brain abscess

• Stroke (most common)
• Tumor
• Trauma
• Metabolic = low sodium, low glucose (very common in elderly)
• Infection

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PSYCHOGENIC NONEPILEPTIC EVENTS (PNEE)

• Last > 1 minute (real tonic-clonic usually < 3 min)
• No postictal confusion (patient returns to normal immediately)
• No autonomic disturbances (no elevated heart rate, no elevated blood pressure)
• No tongue biting
• Normal EEG during the event - this is the KEY diagnostic test. If the brain isn't having electrical activity but the person is "seizing" → psychogenic

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PAGE 532 - HEADACHES

Introduction

• Meninges = the three membranes covering the brain (like a tight, sensitive wrapping)
• Blood vessels = the arteries and veins feeding the brain are very pain-sensitive
• Muscles of the scalp and neck
• Sinuses

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THE HEADACHE TABLE

TENSION-TYPE HEADACHE

• Photophobia = sensitivity to light (light makes it worse)
• Phonophobia = sensitivity to sound (noise makes it worse)
• Tension headaches may have ONE of these but not both (migraine has both)

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MIGRAINE

• P = Pulsatile (throbbing, beating pain - you can feel your heartbeat in your head)
• O = One-day duration (4-72 hours)
• U = Unilateral
• N = Nausea
• D = Disabling (severe enough to stop normal activities)

• CN V = Cranial Nerve 5 (Trigeminal nerve) - the main pain nerve of the face and meninges
• When triggered, the trigeminal nerve releases inflammatory substances (especially CGRP = Calcitonin Gene-Related Peptide) around blood vessels
• These substances cause blood vessels to dilate and become inflamed = PAIN
• The meninges (brain covering) become inflamed and irritated = more PAIN

• Zigzag lines (fortification spectra)
• Blind spots
• Flashing lights
• Spreading across visual field over 20-30 minutes, then fading
• Some patients get aura without headache

• Acute (attack): NSAIDs, Triptans (like sumatriptan - they work by constricting blood vessels and blocking pain pathways)
• Prophylaxis: Beta-blockers (propranolol), tricyclic antidepressants (amitriptyline), valproate, topiramate, lifestyle changes (sleep, diet, exercise), anti-CGRP monoclonal antibodies

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CLUSTER HEADACHE

• Periorbital = around the eye
• This is considered one of the most painful conditions known to medicine
• Patients describe it as a "hot poker" or "ice pick" being driven through the eye
• The pain is so severe that patients are often found rocking, pacing, or banging their head - they CANNOT lie still (opposite of migraine patients who lie quietly in dark rooms)

• Lacrimation = eye watering/tearing (Latin: lacrima = tear)
• Rhinorrhea = runny nose (rhino = nose, rhea = flow)
• Conjunctival injection = red eye (blood vessels in white of eye dilate and become visible)
• These are from activation of the parasympathetic nervous system

• Ptosis = drooping of the upper eyelid
• Miosis = small/constricted pupil
• Anhidrosis = no sweating on that side of face
• This happens because the sympathetic nerve supply to the eye is disrupted during cluster attacks

• Acute: Sumatriptan injection, 100% oxygen (breathing pure oxygen through a mask for 15 minutes often aborts the attack - very effective)
• Prophylaxis: Verapamil (calcium channel blocker - the MAIN preventive drug)

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TRIGEMINAL NEURALGIA

• The main sensory nerve of the face
• Divided into 3 branches:
• V₁ (Ophthalmic) = forehead, top of nose, eye
• V₂ (Maxillary) = cheek, upper lip, upper teeth
• V₃ (Mandibular) = jaw, lower lip, lower teeth, chin

• Brief episodes = lasts only SECONDS but feels like a lightning bolt
• Unilateral = one side of face only
• Electric shock-like, stabbing = most people describe it as the most intense pain of their life, like electricity or a hot knife

• Washing face
• Brushing teeth
• Talking
• Chewing
• Gentle breeze on face
• This is remarkable - a very light touch triggers EXCRUCIATING pain

• Usually a blood vessel (often the superior cerebellar artery) is touching/compressing the trigeminal nerve root
• This compression damages the myelin sheath (insulation) of the nerve
• Without insulation, signals "cross-talk" and light touch signals trigger pain signals

• Carbamazepine / Oxcarbazepine = anti-seizure medications that reduce nerve excitability
• If medication fails: surgical separation of the blood vessel from the nerve (microvascular decompression = Jannetta procedure)

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PAGE 533 - DYSKINESIAS (MOVEMENT DISORDERS)

What is a Dyskinesia?

• Substantia nigra = produces dopamine, crucial for smooth movement
• Basal ganglia (caudate, putamen, globus pallidus) = coordinate movement
• Cerebellum = coordinates balance and fine movement
• Thalamus = relay station

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AKATHISIA

• A = without, kathisis = sitting = can't sit still
• Patient feels an intense inner restlessness, MUST keep moving - rocking, shifting, pacing
• It's a SUBJECTIVE feeling of inner motor restlessness, not just visible movement

• Neuroleptics = antipsychotic drugs (haloperidol, chlorpromazine) - they block dopamine receptors
• Dopamine blockade in certain brain areas causes akathisia
• Also seen with some Parkinson's medications

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ATHETOSIS

• Athetosis = from Greek "without position" - the hand/fingers can never stay in one place
• Slow, continuous, flowing, writhing movements
• Like fingers and wrists slowly twisting and untwisting in a snake-like fashion
• Most prominent in hands and fingers

• Hepatic encephalopathy = liver failure causes toxins (ammonia) to accumulate in blood → damages brain, especially basal ganglia
• Wilson disease = genetic condition where copper accumulates in liver and brain → damages basal ganglia

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ASTERIXIS

• Ask the patient to hold their arms outstretched with wrists bent back (like stopping traffic)
• Instead of holding still, the wrists suddenly FLAP down and back up
• Like a bird flapping its wings, or a person waving slowly

• Also called negative myoclonus = it's caused by brief lapses in muscle tone (NOT muscle jerks)

• Liver failure (hepatic encephalopathy) = most classic
• Renal failure
• CO₂ retention (respiratory failure)
• Remember: any METABOLIC ENCEPHALOPATHY can cause asterixis

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CHOREA

• Chorea = Greek word for "dance" (Chorea = dancing)
• Quick, random, involuntary, dance-like movements
• Can affect face, arms, legs, trunk
• Patient can't predict or control them
• Movements flow from one body part to another

• Huntington disease = genetic disorder causing degeneration of the caudate nucleus (part of basal ganglia) → chorea is the hallmark movement disorder
• Sydenham's chorea = occurs after streptococcal throat infection (part of acute rheumatic fever) → antibodies against strep bacteria accidentally attack basal ganglia
• Think: "Chorea = Basal Ganglia problem"

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DYSTONIA

• Dystonia = abnormal, sustained muscle contractions that cause twisting, repetitive movements or abnormal postures
• Unlike chorea (which is fleeting), dystonia HOLDS the body part in an abnormal position

• Torticollis = neck twists to one side and stays there (wry neck)
• Writer's cramp = hand/fingers go into painful cramped position when writing
• Blepharospasm = eyelids clamp shut involuntarily

• Botulinum toxin (Botox) = blocks acetylcholine release at neuromuscular junction → temporarily paralyzes the overactive muscle → relieves the dystonic posture
• Injected directly into the affected muscle every 3-4 months

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ESSENTIAL TREMOR

• Tremor = rhythmic, oscillating movement
• Essential tremor = the most COMMON movement disorder (far more common than Parkinson's)
• High-frequency = fast tremor (6-12 Hz)
• Action/postural tremor = occurs when the person HOLDS a position (like arms outstretched) or is DOING something (like drinking a cup of coffee)

• Essential tremor = tremor when MOVING or HOLDING position (action tremor)
• Parkinson's tremor = tremor at REST (resting tremor) - goes away when moving
• This is the KEY clinical distinction!

• Familial = runs in families (autosomal dominant)
• "Patients self-medicate with alcohol" = alcohol reduces essential tremor dramatically. This is why some people say "I need a drink to function." Very important clinically - suggests essential tremor when patient says alcohol helps their tremor.
• Treatment: Propranolol (beta-blocker) is first line

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INTENTION TREMOR

• This tremor gets WORSE as the hand approaches its target
• Ask patient to touch their nose, then touch your finger - as they get closer to target, the tremor gets bigger and more wild
• Like a guided missile that keeps wobbling more and more as it approaches the target

• The cerebellum is responsible for fine-tuning movements and correcting errors
• When the cerebellum is damaged, it can't send corrective signals fast enough → overshoot → overcorrect → overshoot again = zigzag/intention tremor
• Causes of cerebellar damage: MS, stroke, alcohol, tumors

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RESTING TREMOR

• Resting tremor = occurs when the body part is at REST, supported against gravity
• Disappears or decreases when you MOVE intentionally
• Classic description: "pill-rolling tremor" = looks like you're rolling a small pill between your thumb and index finger

• The memory trick: when you PARK your car → it is at REST → PARK = PARKinson's = resting tremor!
• Substantia nigra = the area in the midbrain that makes dopamine. In Parkinson's, these neurons die → loss of dopamine → abnormal basal ganglia activity → resting tremor

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HEMIBALLISMUS

• Hemi = half/one side, ballismus = throwing/flailing (ballistic)
• Large-amplitude, violent, flinging movements of one arm and/or leg
• Movements are SO violent they can cause exhaustion and injury

• Subthalamic nucleus = a structure in the basal ganglia circuit that normally SUPPRESSES unwanted movements
• When this is destroyed (usually by a small stroke = lacunar stroke), the brake is removed → wild, uncontrolled movements
• Contralateral = the subthalamic nucleus is on the OPPOSITE side from the movements (right STN lesion = left-sided hemiballismus)

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MYOCLONUS

• Quick, shock-like muscle jerks
• Can be normal (hiccups = myoclonus of the diaphragm! Falling-asleep jerks = benign sleep myoclonus)
• Pathological: repetitive, multiple body parts

• Creutzfeldt-Jakob disease (CJD) = rapidly fatal prion disease - startle myoclonus is a hallmark finding
• Metabolic encephalopathy (liver failure, kidney failure, low oxygen) = causes myoclonus throughout the body

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RESTLESS LEGS SYNDROME

• Restless Legs Syndrome (RLS) = the patient KNOWS their legs, not any visible movement disorder - it's a SENSATION problem
• Uncomfortable sensations = creeping, crawling, itching, burning, aching DEEP inside the legs - hard to describe
• "Irresistible urge to move" = patients MUST move to relieve the sensation
• "Most prominent in evening/night" = circadian pattern - worse at night when trying to sleep = major cause of insomnia
• "Relieved by movement" = walking, stretching the leg relieves it temporarily

• Iron deficiency = iron is needed for dopamine synthesis; low iron = low dopamine in brain pathways controlling movement sensation
• CKD (Chronic Kidney Disease) = kidney failure causes uremic toxins to affect nerve function
• Diabetes = diabetic neuropathy can trigger RLS

• Gabapentinoids (gabapentin, pregabalin) = reduce nerve excitability
• Dopamine agonists (pramipexole, ropinirole) = stimulate dopamine receptors in the brain circuits controlling this sensation

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PAGE 534 - NEURODEGENERATIVE MOVEMENT DISORDERS + DEMENTIA

First: What is DEMENTIA?

• Dementia = progressive loss of brain function - especially memory, thinking, behavior, and ability to perform daily activities
• Cognitive ability = the ability to think, remember, reason, plan, and understand
• Executive function = higher-level thinking: planning, decision-making, organizing, problem-solving (like the "CEO" functions of your brain)
• Intact consciousness = the person is awake and alert (unlike delirium where consciousness fluctuates)

• Depression = can mimic dementia ("pseudodementia") - treat the depression and cognition improves
• Hypothyroidism = low thyroid hormone slows everything down, including brain function
• Vitamin B₁₂ deficiency = B₁₂ is essential for myelin (brain cell insulation); deficiency = brain damage
• Normal pressure hydrocephalus = too much fluid in the brain (covered later)
• Neurosyphilis = syphilis bacteria infecting the brain

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NEURODEGENERATIVE MOVEMENT DISORDERS

PARKINSON DISEASE

• Abnormal protein (alpha-synuclein) misfolds and accumulates inside neurons
• These clumps are called Lewy bodies (named after Dr. Frederic Lewy)
• Lewy bodies = round, pink inclusions inside the neuron (visible under microscope)
• They're toxic - they kill the neuron

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"Symptoms typically manifest after age 60 ('body' depigmentation in A)"

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"TRAP" mnemonic:

• As discussed - "pill-rolling" tremor at REST
• 4-6 Hz frequency
• Disappears when moving intentionally

• Muscles are stiff and resistant to passive movement
• Two types:
• Cogwheel rigidity = when you try to move someone's arm at the elbow, it moves in a ratcheting, jerky fashion - like moving a gear wheel (click-click-click) - because tremor is superimposed on rigidity
• Lead pipe rigidity = smooth, constant resistance throughout the range of motion - like bending a lead pipe

• Akinesia = no movement (complete inability to initiate movement)
• Bradykinesia = slow movement (slowed initiation and execution of movement)
• THIS is the most disabling symptom in daily life
• The patient thinks "move your hand" but there's a long delay before the hand moves
• Manifestations:
• Masked face = reduced facial expressions (face like a mask, reduced blinking)
• Small handwriting = micrographia (writing starts normal size then gets smaller)
• Shuffling gait = small steps, feet barely leave the floor
• Festination = patient walks with progressively faster small steps, like they're about to fall forward - they can't stop easily
• Hypophonia = soft, monotone voice
• Drooling = reduced swallowing frequency

• Patient can't maintain balance
• Falls backward easily (retropulsion) - when pushed, they keep stepping backward
• This leads to serious falls and fractures

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"Akineseia/Bradykinesia → shuffling gait, small handwriting (micrographia)"

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"Rigidity (cogwheel or leadpipe)"

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"Tremor (pill-rolling tremor at rest)"

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Clinical presentations:

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Treatment of Parkinson Disease:

1. Levodopa/Carbidopa (most effective)

• Levodopa = precursor to dopamine that can cross the blood-brain barrier (dopamine itself cannot cross)
• Once in the brain → converted to dopamine
• Carbidopa = inhibits peripheral conversion of levodopa before it reaches the brain (so more reaches the brain, and you avoid systemic side effects like nausea)
• This is the GOLD STANDARD treatment

1. Dopamine agonists (ropinirole, pramipexole) = directly stimulate dopamine receptors
2. MAO-B inhibitors (selegiline) = prevent breakdown of dopamine in the brain
3. COMT inhibitors (entacapone) = prevent breakdown of levodopa
4. Anticholinergics (benztropine) = help with tremor

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"Dementia is usually a late finding"

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Pathology: Lewy bodies

• Intracellular = inside the neuron
• Eosinophilic = stains pink/red with standard H&E stain under microscope (eosin = pink dye)
• Alpha-synuclein = the protein that misfolds and aggregates to form Lewy bodies
• They look like round pink blobs with a pale halo inside the neuron

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PROGRESSIVE SUPRANUCLEAR PALSY (PSP)

• "Plus syndrome" = has all Parkinson features PLUS additional features that Parkinson's doesn't have
• Supranuclear = above the nucleus (of CN III which controls eye movement) - meaning the control CENTERS for eye movement are damaged, not the eye muscles themselves

• The patient CANNOT look UP or DOWN voluntarily
• They can still look side to side (horizontal gaze preserved)
• This is the MAIN feature that distinguishes PSP from Parkinson's

• Falls BACKWARD (unlike Parkinson's falls)
• Dysarthria (slurred speech)
• Dysphagia (difficulty swallowing)
• Cognitive decline (early, unlike Parkinson's)

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HUNTINGTON DISEASE

Genetics:

• Normal people have the CAG sequence repeated 10-35 times in the HTT gene
• Huntington patients have it repeated 36+ times (often 40-80+ times)
• The more repeats, the earlier and more severe the disease = anticipation (each generation tends to have more repeats and earlier onset)

• GABA = the main INHIBITORY neurotransmitter in the brain (calms things down)
• GABAergic neurons = neurons that use GABA
• Striatum = the caudate nucleus + putamen (parts of basal ganglia)
• When GABA neurons in the striatum die, the inhibitory brakes on movement are lost → CHOREA (random, uncontrolled movements)

• The caudate nucleus and putamen shrink as neurons die
• The space left behind is filled by the adjacent ventricles (fluid-filled spaces expanding into the empty space = "ex vacuo" = because of the vacuum/empty space)
• On MRI: ventricles look enlarged with loss of the normal caudate "bulge" into the ventricle

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Neurotransmitter changes in Huntington:

• ↓ dopamine (loss of dopaminergic input to striatum)
• ↓ GABA (GABAergic striatal neurons are dying)
• ↑ ACh (relative increase as other neurotransmitters fall)
• Caudate loses ACh and GABA - the mnemonic is: Caudate loses "ACh and GABA" (think: A-C-G-B... Anticipation, Caudate, GABAergic, B-reak)

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Symptoms:

• Age 30-50 = onset in MIDDLE age (not old age like Parkinson's and Alzheimer's)
• Chorea = the hallmark movement symptom - random, dance-like jerking
• Athetosis = slower writhing movements (may combine with chorea = "choreoathetosis")
• Psychiatric symptoms = depression, aggression, irritability, psychosis can appear BEFORE the movement disorder
• Dementia = cognitive decline is progressive and inevitable
• "Mistaken for substance use" = the bizarre movements and behavior changes in early Huntington's can look like someone who is drunk or high

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ALZHEIMER DISEASE

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"Down syndrome patients have ↑ risk of developing early-onset Alzheimer disease, as amyloid precursor protein (APP) is located on chromosome 21."

• Down syndrome = trisomy 21 (three copies of chromosome 21 instead of two)
• APP = Amyloid Precursor Protein - normally lives on chromosome 21
• With THREE copies of chromosome 21, Down syndrome patients have extra APP gene copies → produce MORE APP → more amyloid → Alzheimer's earlier (often by age 40-50)

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"ApoE-4: 1 risk of sporadic form. ApoE-2: ↓ risk of sporadic form. ApoE-2 is 'protwoctive.' ApoE-4 is 'four' forms (10%) with earlier onset."

• ApoE-4 allele = INCREASES risk of sporadic (late-onset) Alzheimer's
• ApoE-2 allele = PROTECTIVE ("protwoctive" - two/protective - clever memory trick)
• ApoE-3 = neutral (most common allele)

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"Familial forms (10%) with earlier onset - APP, presenilin-1, presenilin-2 mutations"

• APP = Amyloid Precursor Protein gene (chromosome 21)
• Presenilin-1 (PSEN1, chromosome 14) = most common cause of familial early-onset
• Presenilin-2 (PSEN2, chromosome 1) = rare

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Pathology:

• Cortical atrophy = the outer layer of the brain (cortex) shrinks as neurons die
• Hippocampi = the memory centers - first and most severely affected
• Gyri (ridges of the brain) become narrower
• Sulci (grooves between gyri) become wider
• Think of the brain like a walnut - in Alzheimer's, the walnut meat shrinks and the grooves get bigger

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• Senile plaques = one of the two hallmark pathological findings
• Extracellular = outside the neurons (in the space between cells)
• Amyloid-beta (Aβ) = the toxic protein that forms these plaques
• How does it form? APP (normal protein on neuron surface) is cut by enzymes:
• Normal cutting (alpha-secretase pathway): produces harmless fragments
• Abnormal cutting (beta + gamma-secretase pathway): produces Aβ-42 = sticky, toxic, aggregates into plaques
• Amyloid angiopathy = amyloid also deposits in blood vessel walls → weakens them → can rupture = brain hemorrhage

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• Neurofibrillary tangles = second hallmark pathological finding
• Intracellular = INSIDE the neurons (contrast with plaques which are extracellular)
• Tau protein = normally helps stabilize microtubules (the skeleton of the neuron - like the railway tracks that transport things along the neuron's axon)
• In Alzheimer's, tau gets hyperphosphorylated (too many phosphate groups attached) → tau detaches from microtubules → microtubules collapse → tau tangles form inside the neuron → neuron dies
• "Number of tangles correlates with degree of dementia" = important clinical correlation - the more tangles you have, the worse the cognitive decline

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• Hirano bodies = rod-shaped eosinophilic (pink) inclusions found in hippocampal neurons
• Another microscopic finding of Alzheimer's
• Less emphasized than plaques and tangles but still a pathological feature

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PAGE 535 - DEMENTIAS (CONTINUED)

FRONTOTEMPORAL DEMENTIA (FTD)

• The brain's frontal lobe = personality, social behavior, impulse control, decision-making
• The temporal lobe = language, memory, emotion
• In FTD, these areas degenerate FIRST (unlike Alzheimer's which starts in hippocampus)

• Personality change is the FIRST symptom - patient becomes disinhibited (says inappropriate things), lacks empathy, impulsive, socially inappropriate
• This is often mistaken for a psychiatric disorder (depression, mania, personality disorder) - but it's actually neurodegeneration
• Family members often say "they're a completely different person"

• Aphasia = inability to use/understand language (from brain damage to language areas)
• Patient progressively loses the ability to speak, find words, or understand language
• Their memory may be relatively preserved initially (unlike Alzheimer's)

• Pick bodies = round inclusions of hyperphosphorylated tau (like Alzheimer's tangles but round and in different location)
• TDP-43 inclusions = another protein that aggregates in FTD (ubiquitinated TDP-43)
• Both are types of tauopathies (diseases of abnormal tau protein)

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LEWY BODY DEMENTIA

• "haLEWYcinations" = brilliant memory trick! Visual hallucinations are the HALLMARK of Lewy body dementia - very vivid, detailed (often small people or animals that the patient describes in detail)
• Fluctuating cognition = the patient has good days and bad days - cognition varies dramatically, even hour to hour
• REM sleep behavior disorder = during REM sleep (dreaming), normal people have muscle paralysis. In Lewy body dementia, this paralysis FAILS → patient acts out their dreams, punching, kicking, screaming → can injure themselves or bed partner. This can precede dementia by YEARS.
• Parkinsonism = they also have Parkinson-like features (shuffling, rigidity, etc.)

• If you already have Parkinson's disease for years and THEN develop dementia → "Parkinson's Disease Dementia"
• If cognitive and motor symptoms start together (within 1 year) → "Lewy Body Dementia"
• Same pathology, different clinical timing = different diagnosis

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VASCULAR DEMENTIA

• Alzheimer's = GRADUAL, continuous, progressive decline (like a gentle slope)
• Vascular dementia = STEP-WISE decline (sudden drop in function with each mini-stroke, then plateaus, then another sudden drop = like going down stairs)

• Small vessel disease
• Multiple small strokes (lacunar infarcts)
• Or diffuse white matter damage from chronic reduced blood flow

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CREUTZFELDT-JAKOB DISEASE (CJD)

• NOT bacteria, NOT viruses, NOT fungi
• They are simply misfolded proteins - no DNA, no RNA, nothing alive
• Yet they are INFECTIOUS
• They spread from cell to cell by CONVERTING normal proteins into misfolded ones
• Like a chain reaction - one misfolded protein makes neighboring normal proteins misfold too
• They CANNOT be killed by standard sterilization, antibiotics, antiviral drugs, or even autoclaving easily

• PrPC = normal prion protein (everyone has this - normal function unclear)
• PrPSc = misfolded, disease-causing form (Sc = Scrapie, the animal form)
• The misfolded PrPSc converts normal PrPC into more PrPSc = exponential spread

• Normal proteins can be broken down (digested) by proteases (enzymes that chew up proteins)
• PrPSc forms a β-pleated sheet structure that is RESISTANT to these enzymes
• This is why prions accumulate - they can't be cleared

• Rapidly progressive dementia = weeks to months (compared to years for Alzheimer's)
• Myoclonus = startle myoclonus - the patient jerks violently in response to sudden sounds or touches
• Ataxia = loss of coordination
• Fatal = always fatal, no treatment exists

• Under microscope, the brain looks like a SPONGE - full of holes (vacuoles)
• But NO inflammation (unlike encephalitis)
• This is the pathological hallmark: spongiform encephalopathy

• EEG shows characteristic 1 Hz periodic sharp waves (triphasic waves)
• 14-3-3 protein in CSF = marker of rapid neuronal destruction - elevated in CJD

• Sporadic (most common, 85%) = spontaneous misfolding, no known exposure
• Iatrogenic = through contaminated medical/surgical instruments, corneal transplants, dura mater grafts
• Variant CJD = from eating BSE-infected beef ("mad cow disease")
• Familial = inherited mutation in prion protein gene

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HIV-ASSOCIATED DEMENTIA

• This produces a different cognitive profile from Alzheimer's (which is cortical)
• Subcortical dementia = slowed thinking, attention/concentration problems, mood disturbance, BUT relatively preserved language and memory (initially)

• HIV infects microglia (brain's immune cells) and macrophages
• These release inflammatory mediators that damage surrounding neurons
• HIV envelope protein (gp41) is directly neurotoxic
• Also causes opportunistic infections of the brain

• Multinucleated giant cells = HIV-infected macrophages fuse together = hallmark of HIV encephalitis
• Microglial nodules = clusters of activated brain immune cells

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PAGE 536 - HYDROCEPHALUS + IDIOPATHIC INTRACRANIAL HYPERTENSION

Understanding CSF First

• Produced by the choroid plexus (specialized cells in the ventricles) at ~500 mL/day
• Flows through the ventricles (4 fluid-filled chambers in the brain) → out to the subarachnoid space (the space between the brain's coverings) → absorbed back into blood through arachnoid granulations

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HYDROCEPHALUS

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COMMUNICATING HYDROCEPHALUS

• CSF accumulates
• ↑ ICP (increased intracranial pressure)
• ALL ventricles are dilated (because fluid can't drain anywhere)
• Papilledema = the increased pressure is transmitted along the optic nerve sheath → optic disc swells → seen on eye exam as blurring of optic disc margins

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NORMAL PRESSURE HYDROCEPHALUS (NPH)

• Wobbly = Gait ataxia (unsteady, wide-based, magnetic gait - feet seem stuck to floor, small shuffling steps)
• Wacky = Cognitive dysfunction (dementia - often confused, forgetful)
• Wet = Urinary incontinence (can't control bladder)

• LP (Lumbar Puncture/spinal tap) = temporary relief - symptoms dramatically improve after removing CSF (diagnostic AND therapeutic)
• Shunt placement = a tube inserted surgically that drains CSF continuously from ventricles to the abdomen (peritoneum) = ventriculoperitoneal (VP) shunt

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NONCOMMUNICATING (OBSTRUCTIVE) HYDROCEPHALUS

• Aqueduct of Sylvius = narrow passage connecting the 3rd and 4th ventricles - most common site of obstruction
• Congenital stenosis (narrow from birth)
• Tumor
• Foramen of Monro = openings connecting the lateral ventricles to the 3rd ventricle
• Colloid cyst = a benign cyst that floats and can suddenly block this opening → acute, life-threatening rise in ICP
• Tumors anywhere in the ventricular system

• Like a blocked pipe - water backs up only on the INLET side of the blockage
• If the aqueduct is blocked: both lateral ventricles and the 3rd ventricle dilate, but the 4th ventricle stays normal

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EX VACUO VENTRICULOMEGALY

• Think of it like: if the brain is a sponge that shrinks, the surrounding spaces (ventricles) fill the extra space
• ICP is NORMAL (unlike true hydrocephalus)
• This is seen in any condition with widespread brain atrophy

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IDIOPATHIC INTRACRANIAL HYPERTENSION

• ICP is elevated (often > 25 cmH₂O)
• Brain appears NORMAL on MRI/CT

• T = Tetracyclines (antibiotics)
• O = Obesity (increased abdominal pressure transmits to intracranial space)
• A = vitamin A excess (high-dose vitamin A supplements or isotretinoin for acne)
• d = Danazol (a hormonal drug)
• Female sex = strongly associated with women of childbearing age

• Headache (worse when lying down, in the morning)
• Visual problems (blurred vision from papilledema, double vision from CN VI palsy)
• Pulsatile tinnitus (whooshing sound in the ear)
• No change in mental status (this distinguishes it from other raised ICP causes)

• Visual field testing = enlarged blind spot, peripheral constriction
• Optic nerve sheath dilation on MRI

• Weight loss (most important for obese patients)
• Acetazolamide (reduces CSF production by inhibiting carbonic anhydrase)
• Invasive: LP shunting, optic nerve sheath fenestration surgery (to save vision)

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PAGE 537 - MULTIPLE SCLEROSIS (MS)

What is MS?

• Electrical signals leak out
• Transmission slows dramatically
• Eventually the wire itself (the axon) can get damaged

• Autoimmune = your own immune system attacks your own tissue (self vs self)
• Demyelination = destruction of myelin
• Axonal damage = eventually the nerve fiber itself is damaged (this causes PERMANENT disability)
• The inflammation comes in ATTACKS (flares/relapses), and between attacks there's recovery (remissions)

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"Most often affects females aged 20-40, higher prevalence in individuals who grew up farther from equator and have ↑ serum vitamin D levels."

• Vitamin D hypothesis: Sunlight produces vitamin D in skin. Near the equator = more sun = more vitamin D = more immune regulation. Far from equator = less sun = less vitamin D = more autoimmune risk.
• People who MIGRATE from high-risk to low-risk areas BEFORE puberty take on the lower risk of their new home. After puberty, they keep the risk of their birthplace.

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Symptoms (multiple areas of CNS affected)

• Different neurological symptoms at different times (time)
• Affecting different parts of the nervous system (space)

• Optic neuritis = inflammation of the optic nerve (CN II)
• Presents as sudden, PAINFUL loss of vision in ONE eye (monocular)
• Pain is worse with eye movement
• Often the FIRST symptom of MS
• Marcus Gunn pupil (RAPD) = Relative Afferent Pupillary Defect - when you shine a light from the normal eye to the affected eye, the affected eye's pupil DILATES instead of constricting (paradoxical response because the optic nerve is damaged and can't relay the light signal properly)

• INO = one of the most SPECIFIC signs of MS
• When looking to the side, the INNER eye (the eye moving toward the nose) cannot cross the midline fully
• The outer eye develops nystagmus (rhythmic beating movements)
• Caused by demyelination of the medial longitudinal fasciculus (MLF) - a tract that coordinates eye movements
• Memory: bilateral INO in a young person = MS until proven otherwise

• Diplopia = double vision
• Ataxia = unsteady gait, like walking drunk
• Vertigo = spinning sensation
• Scanning speech = slow, robotic, word-by-word speech (characteristic of cerebellar involvement)
• Dysarthria = slurred/difficult speech
• Intention tremor = worsens as hand approaches target (cerebellar)

• Pyramidal tract = the main motor pathway from brain to spinal cord (corticospinal tract)
• Demyelination here causes: weakness, spasticity (stiff, jerky muscles), hyperreflexia (overactive reflexes)
• Spasticity = muscles are stiff and resist passive movement, especially worse when movement is fast

• Lhermitte sign = when the patient bends their neck forward, they feel an electric shock sensation running DOWN the spine and into the arms and legs - like electricity running down your back. Caused by demyelination in the cervical (neck) spinal cord.
• Neurogenic bladder = damage to spinal cord autonomic fibers causes urinary frequency, urgency, incontinence - very common and disabling in MS
• Paraparesis = weakness of both legs

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Important Principle: Uhthoff Phenomenon

• Uhthoff phenomenon = symptoms WORSEN with heat (hot bath, exercise, fever)
• Why? Heat slows conduction in already-damaged (demyelinated) nerves. Even a 1°C increase in body temperature can block nerve conduction in a demyelinated nerve.
• Classic history: patient's MS symptoms worsen when they take a hot bath, or in summer heat
• The symptoms come back when they cool down - this is NOT a relapse (no new damage), just temporary functional worsening

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Diagnosis

• Lumbar puncture (spinal tap) reveals:
• ↑ IgG = elevated antibodies in CSF (immune cells have crossed into CNS)
• Oligoclonal bands = a pattern on CSF protein analysis showing several distinct bands of IgG produced by different clones of B cells in the CNS. This is the DIAGNOSTIC hallmark of MS in CSF.
• Myelin basic protein = released when myelin is destroyed

• MRI is the most important diagnostic test
• Shows plaques = areas of demyelination
• Periventricular = around the ventricles (classically described as "Dawson fingers" - plaques perpendicular to ventricles on sagittal MRI, looking like fingers)
• Oligodendrocytes = the cells that MAKE myelin in the CNS. When attacked and killed → demyelination
• Reactive gliosis = scar tissue formation (astrocytes multiply to fill the space) = "sclerosis" = hence "multiple sclerosis" (multiple scars)

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Treatment

• β-interferon (beta-interferon) = modulates immune response, reduces inflammation
• Glatiramer acetate = synthetic protein that competes with myelin for T-cell attack
• Natalizumab = monoclonal antibody that blocks immune cells from entering the CNS (blocks alpha-4 integrin)

• Spasticity → Baclofen (GABA-B agonist = muscle relaxant)
• Bladder → Antimuscarinics (oxybutynin), botulinum toxin
• Pain → TCAs, anticonvulsants (gabapentin)
• Fatigue → Amantadine, modafinil

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PAGE 538 - OTHER DEMYELINATING AND DYSMYELINATING DISORDERS

OSMOTIC DEMYELINATION SYNDROME

• Locked-in syndrome (paralyzed but conscious)
• Dysarthria (slurred speech)
• Dysphagia (difficulty swallowing)
• Diplopia (double vision)
• Loss of consciousness
• Quadriplegia

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GUILLAIN-BARRÉ SYNDROME (GBS)

• An infection comes (most commonly Campylobacter jejuni gut infection, or viruses like Zika, CMV, EBV)
• Your immune system makes antibodies against the bacteria/virus
• BUT the bacteria's surface molecules LOOK SIMILAR to molecules on your own peripheral nerve myelin
• Your immune system gets confused and ALSO attacks your own nerve myelin
• Like friendly fire - your immune system attacks the wrong target

1. Patient has diarrhea (Campylobacter) or respiratory infection 2-4 weeks earlier
2. Then develops tingling/numbness in toes and fingers
3. Then ASCENDING weakness starts in the LEGS and moves UPWARD
4. Weakness can progress to respiratory muscles → respiratory failure → need ventilator
5. Facial paralysis (bilateral) = CN VII involvement
6. Autonomic dysfunction = dangerous cardiac arrhythmias, blood pressure swings

• "Most patients survive with good functional recovery" - most recover fully over weeks to months
• Respiratory support may be needed

• Albuminocytologic dissociation = protein is HIGH but cell count is NORMAL
• Normal CSF has low protein AND low cells
• Infections: high protein AND high cells
• GBS: HIGH protein but NORMAL cells = very characteristic
• Why high protein? The inflamed nerve roots leak protein into CSF

• IV immunoglobulins (IVIG) = flood the blood with normal antibodies to "dilute" and block the abnormal antibodies
• Plasma exchange = remove the patient's plasma (which contains the harmful antibodies) and replace it with fresh plasma
• NO role for steroids (steroids actually don't work in GBS - important exam point)
• Respiratory support = critical

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ACUTE DISSEMINATED ENCEPHALOMYELITIS (ADEM)

• Acute = sudden onset
• Disseminated = widespread, multiple areas
• Encephalomyelitis = encephalitis (brain inflammation) + myelitis (spinal cord inflammation)

• ADEM = single episode, usually after infection/vaccination, mainly in children
• MS = recurrent, unprovoked, usually in adults

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CHARCOT-MARIE-TOOTH DISEASE

• Pes cavus = high-arched foot (opposite of flat foot) - from muscle imbalance
• Hammer toe = the middle joints of the toes bend downward, looking like a hammer
• Foot drop = patient can't lift the front of the foot → they walk with a high-stepping gait to avoid dragging the toes

• PMP22 = Peripheral Myelin Protein 22 - a structural component of peripheral nerve myelin
• With too much PMP22 (duplication = extra copy) → abnormal myelin formation → progressive nerve dysfunction

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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)

• A very common virus (most adults have been infected in childhood - it's usually harmless)
• Lies dormant in the kidneys
• If the immune system becomes severely weakened → virus reactivates → travels to brain → infects and kills oligodendrocytes (myelin-making cells in CNS)
• Loss of oligodendrocytes → demyelination of white matter in multiple places

• Visual disturbances (parietal and occipital areas first - these process vision)
• Weakness
• Speech problems
• Cognitive decline
• Rapidly progressive → usually fatal if untreated

• AIDS patients (CD4 count < 200) = most common
• Organ transplant recipients on immunosuppressants
• MS patients on natalizumab (natalizumab blocks immune cells from entering the CNS = JC virus also gets free access; this is a serious side effect of the drug)

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CRITICAL ILLNESS POLYNEUROPATHY

• Occurs in patients who are seriously ill in the ICU for a prolonged time (severe sepsis, multi-organ failure)
• Inflammation and poor circulation damage peripheral nerves
• Results in profound weakness
• Makes it very hard to wean the patient off the ventilator (breathing machine) - because the diaphragm muscle is weakened too
• Distinguish from GBS by context (ICU patient) and nerve conduction studies

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PAGE 539 - NEUROCUTANEOUS DISORDERS

What are Neurocutaneous Disorders?

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STURGE-WEBER SYNDROME

• NOT hereditary = it's a somatic mutation (happens in a single cell during early embryonic development, not inherited from parents)
• Mosaicism = only SOME cells in the body carry the mutation (the cells descended from that one mutated cell)
• GNAQ gene = regulates cell growth; activating mutation = cells grow uncontrollably → abnormal blood vessels form

• Encephalo = brain, trigeminal = CN V (trigeminal nerve), angioma = abnormal blood vessel growth
• = abnormal blood vessels on the face (in trigeminal nerve distribution) AND the brain

• "Port-wine stain (nevus flammeus or non-neoplastic birthmark) in CN V₁/V₂ distribution" = the HALLMARK
• A flat, pink-red to deep purple skin discoloration on the face
• Follows the distribution of V₁ (forehead/eye area) or V₂ (cheek/nose)
• Present from birth, doesn't fade
• "Port wine" = the color resembles red port wine
• It's a capillary vascular malformation (abnormally dilated capillaries in skin)
• "Ipsilateral leptomeningeal angioma with calcifications → seizures/epilepsy"
• On the SAME side as the port-wine stain, there is an abnormal collection of blood vessels on the surface of the brain (leptomeninges = pia + arachnoid)
• These calcify (calcium deposits form) over time → look like "tram track" calcifications on CT/X-ray
• The abnormal vasculature causes ischemia (poor oxygen) and seizures are VERY common
• "Intellectual disability" = from seizures and brain ischemia
• "Episcleral hemangioma → ↑ IOP → early-onset glaucoma"
• Hemangioma in the eye (episclera = outer layer of eyeball) → blocks fluid drainage → raises intraocular pressure (IOP) → glaucoma = damage to the optic nerve from high eye pressure → vision loss

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TUBEROUS SCLEROSIS COMPLEX (TSC)

• AD = Autosomal Dominant (one mutant copy enough to cause disease)
• Variable expression = different patients with the same mutation can have very different severity
• Two genes can be affected:
• TSC1 = chromosome 9 = hamartin
• TSC2 = chromosome 16 = tuberin (memory trick: "two" sounds like "tuBERin" → chromosome 16 has "two" × 8 letters = 16... okay the actual trick is: "tWOberin" → chromosome 16)

• "Hamartomas in CNS and skin"
• "Angiofibromas" = small red-pink bumps on the face (especially nose and cheeks) - look like acne but aren't. Present after age 3.
• "Ash-leaf spots" = hypopigmented (pale white) leaf-shaped patches on the skin. Often the FIRST sign, visible even at birth. Diagnosed with Wood's lamp (UV light makes them fluoresce).
• "Cardiac rhabdomyoma" = benign heart muscle tumor. Can cause arrhythmias or heart failure in newborns. Often detected on prenatal ultrasound.
• "Intellectual disability"
• "Renal angiomyolipoma" = benign kidney tumor (angio = blood vessel, myo = muscle, lipo = fat) - can bleed
• "Seizures" = from cortical tubers (potato-like benign brain growths)
• "Shagreen patches" = rough, leathery, orange-peel textured skin patches on the lower back (connective tissue hamartoma)

• Subependymal giant cell astrocytoma (SEGA) = a benign brain tumor near the ventricles that can block CSF flow → hydrocephalus. Treated with mTOR inhibitor (everolimus) or surgery.
• Ungual fibromas = fibrous growths under or around the nails (fingernails/toenails)

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NEUROFIBROMATOSIS TYPE 1 (NF1)

• AD = Autosomal Dominant
• 100% penetrance = if you have the mutation, you WILL have the disease (some manifestation)
• Chromosome 17 = key fact (17 letters in "von Recklinghausen" - the old name for NF1)
• Neurofibromin = normally SUPPRESSES RAS (a signaling protein that promotes cell growth). Without neurofibromin → RAS is always ON → uncontrolled cell growth → tumors

• C = Café-au-lait spots = light brown, flat skin patches (color of coffee with milk). 6 or more spots, each >1.5 cm diameter = diagnostic criterion.
• I = Intellectual disability (mild)
• C = Cutaneous neurofibromas = soft, flesh-colored skin bumps caused by benign nerve sheath tumors. Can be thousands covering the body.
• L = Lisch nodules = pigmented hamartomas of the IRIS (colored part of the eye). Look like tiny brown bumps in the iris under a slit lamp. Almost always present in adults with NF1. Harmless but diagnostic.
• O = Optic gliomas = benign tumors of the optic nerve. Can cause vision loss. Very common in children with NF1.
• P = Pheochromocytomas = tumors of the adrenal gland medulla that secrete adrenaline → episodes of severe hypertension, sweating, palpitations
• S = Seizures/focal neurologic Signs (often from meningioma)
• S = Sphenoid dysplasia = abnormal development of the sphenoid bone (part of skull base)

• Bone lesions = thinning of long bones, scoliosis

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NEUROFIBROMATOSIS TYPE 2 (NF2)

• Different gene, different chromosome from NF1
• NF2 = chromosome 22 (memory: NF2 affects 2 ears, 2 eyes, chromosome 2×2=? no... just remember: NF2 = 2 ears, 2 eyes, chromosome 22)
• Merlin = the protein product of NF2. It regulates cell shape and contact inhibition of growth.

• Bilateral vestibular schwannomas = the HALLMARK and DEFINING feature
• Vestibular schwannoma (acoustic neuroma) = benign tumor of the Schwann cells of the vestibular branch of CN VIII (hearing/balance nerve)
• BILATERAL = both sides - this is pathognomonic (specific to NF2). Unilateral acoustic neuroma is common in the general population, but bilateral is essentially exclusive to NF2.
• Presents with progressive hearing loss, tinnitus (ringing), balance problems
• Juvenile cataracts = clouding of the eye lens at a young age
• Meningiomas = benign tumors of the meninges (brain coverings) - multiple
• Ependymomas = tumors of the ependymal cells lining the ventricles and spinal cord

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VON HIPPEL-LINDAU (VHL) DISEASE

• AD = Autosomal Dominant
• Chromosome 3 (VHL = 3 letters → chromosome 3)
• pVHL = the Von Hippel-Lindau protein. Normally it marks HIF-1α (Hypoxia Inducible Factor 1-alpha) for destruction via ubiquitination.

• In LOW OXYGEN conditions, HIF-1α is normally stabilized → tells cells to make new blood vessels (VEGF) to bring more oxygen
• pVHL normally DESTROYS HIF-1α when oxygen is adequate (by tagging it with ubiquitin = a "destroy me" tag)
• In VHL disease: pVHL is dysfunctional → HIF-1α is NEVER destroyed → cells act as if permanently oxygen-deprived → CONSTANTLY make new blood vessels → highly vascular tumors everywhere

• H = Hemangioblastomas (high-vascularity tumors with hyperchromatic nuclei) in:
• Retina (visual symptoms)
• Brainstem, cerebellum, spine
• Can cause angiomatosis (abnormal blood vessel growth)
• A = Angiomatosis (abnormal blood vessels)
• R = bilateral Renal cell carcinomas (RCC) - clear cell type. This is the most life-threatening manifestation. VHL gene is also mutated in MOST sporadic (non-familial) RCC cases.
• P = Pheochromocytoma (adrenal gland tumor)

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MASTER SUMMARY TABLE - All 9 Pages at a Glance

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🧠 SEIZURES QUICK REFERENCE

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🤕 HEADACHES QUICK REFERENCE

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🕺 MOVEMENT DISORDERS QUICK REFERENCE

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🧓 DEMENTIAS QUICK REFERENCE

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🧬 NEUROCUTANEOUS DISORDERS QUICK REFERENCE

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💡 TOP EXAM MNEMONICS

1. TRAP = Tremor, Rigidity, Akinesia, Postural instability (Parkinson's)
2. POUND = Pulsatile, One-day, Unilateral, Nausea, Disabling (Migraine)
3. WWW = Wobbly, Wacky, Wet (Normal Pressure Hydrocephalus)
4. CICLOPSS = Café-au-lait, Intellectual disability, Cutaneous neurofibromas, Lisch nodules, Optic glioma, Pheochromocytoma, Seizures, Sphenoid dysplasia (NF1)
5. HARP = Hemangioblastomas, Angiomatosis, Renal cell carcinoma, Pheochromocytoma (VHL)
6. PARK = at REST (resting tremor = Parkinson's)
7. haLEWYcinations = Lewy body dementia
8. 4 letters in "hunt" = chromosome 4 = Huntington's
9. VHL = 3 letters = chromosome 3 = RCC (3 letters)
10. NF1 on chromosome 17 = 17 letters in "von Recklinghausen"
11. "Female TOAd" = risk factors for idiopathic intracranial hypertension

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