• Definition
• Aetiology
• Predisposing Factors
• Pathogenesis
• Clinical Features & Signs
• Diagnosis / Investigations
• Complications

Peripheral Neuropathy

1. Definition

• Large myelinated fibers (conduct ~50 m/s) - carry proprioception, vibration, and motor function
• Small myelinated fibers - carry pain and temperature
• Small unmyelinated (C) fibers - carry pain, temperature, and autonomic signals
• Harrison's Principles of Internal Medicine 22E, p. 3638

2. Aetiology

Metabolic / Systemic Diseases

• Diabetes mellitus (most common)
• Chronic kidney disease (uremic neuropathy)
• Hypothyroidism
• Acromegaly
• Chronic pulmonary disease
• Liver disease

Nutritional / Vitamin Deficiencies

• Thiamine (B1) deficiency - beriberi
• Vitamin B12 deficiency - subacute combined degeneration
• Pyridoxine (B6) deficiency
• Niacin deficiency (pellagra)

Drugs / Toxic

• Isoniazid, metronidazole, nitrofurantoin
• Vincristine, paclitaxel (chemotherapy)
• Thalidomide, phenytoin
• Statins (HMG-CoA reductase inhibitors)
• Heavy metals (lead, arsenic, mercury)
• Alcohol (likely via nutritional deficiency)

Infectious

• HIV (distal sensory polyneuropathy in up to 35% of HIV patients)
• Leprosy
• Lyme disease
• Hepatitis B, C, E
• CMV

Inflammatory / Immune-Mediated

• Guillain-Barré syndrome (GBS) - acute
• Chronic inflammatory demyelinating polyneuropathy (CIDP)
• Vasculitic neuropathy (polyarteritis nodosa, ANCA-associated vasculitis)
• Sjögren's syndrome
• Sarcoidosis

Hereditary

• Charcot-Marie-Tooth disease (CMT1, CMT2) - most common hereditary neuropathy
• Hereditary sensory and autonomic neuropathies (HSAN)
• Hereditary neuropathy with liability to pressure palsies (HNPP)

Paraproteinaemias / Malignancy

• Multiple myeloma
• Waldenström's macroglobulinaemia
• Monoclonal gammopathy of undetermined significance (MGUS)
• Amyloidosis (primary or familial)
• Paraneoplastic neuropathy

Porphyria

Idiopathic

• Harrison's Principles 22E, p. 3638; Rosen's Emergency Medicine, p. 1520; Textbook of Family Medicine 9e

3. Predisposing Factors

4. Pathogenesis

A. Axonal Degeneration (Axonopathy)

• The axon degenerates in a length-dependent (dying-back) fashion - distal axons are affected first
• Caused by: metabolic toxins, uremia, alcohol, drugs, diabetes
• Nerve conduction velocity (NCV) may be mildly reduced with reduced amplitude of compound muscle/sensory action potentials
• Most common pattern - accounts for toxic-metabolic polyneuropathies

B. Segmental Demyelination (Myelinopathy)

• Destruction of the myelin sheath with relative sparing of the axon
• Caused by: GBS, CIDP, CMT1, diphtheria
• Results in markedly slowed NCV (< half of normal indicates demyelination)
• Schwann cell proliferation around demyelinated fibers produces "onion bulb" formations (classic in CMT1)

C. Neuronopathy / Ganglionopathy

• Disease at the level of the nerve cell body (dorsal root ganglion or anterior horn cell)
• Causes: paraneoplastic, Sjögren's, cisplatin toxicity, vitamin B6 toxicity

Specific Mechanisms

• Diabetic neuropathy: polyol pathway activation, oxidative stress, reduced neurotrophic support, and microvascular ischaemia of vasa nervorum
• Uremic neuropathy: inhibition of Na-K-ATPase by uremic toxins; "middle molecule hypothesis" - accumulation of toxins 300-12,000 Da (peptide hormones, polyamines); hyperkalemia-induced axonal depolarization; elevated magnesium slows NCV
• Inflammatory neuropathies: T-cell mediated and humoral attack on myelin (GBS - anti-ganglioside antibodies; CIDP - IgG against paranodal proteins)
• Vasculitic neuropathy: ischaemia due to inflammation and occlusion of vasa nervorum - produces mononeuritis multiplex
• Comprehensive Clinical Nephrology 7E, p. 2610; Harrison's 22E, p. 3638

5. Clinical Features and Signs

Sensory Symptoms

• Positive symptoms: burning, tingling (paraesthesiae), allodynia (pain from non-painful stimuli), hyperpathia, shooting/lancinating pains
• Negative symptoms: numbness, loss of sensation
• Distribution is stocking-and-glove - starts at the toes/soles, ascends symmetrically; fingertips become involved when sensory loss reaches the knee
• Small fiber loss: pain + temperature loss with preserved vibration/proprioception
• Large fiber loss: loss of vibration + proprioception with preserved pain/temperature

Motor Symptoms and Signs

• Distal weakness appearing after sensory symptoms (later)
• Foot drop (weakness of toe and foot dorsiflexion - first motor sign)
• Wasting of intrinsic foot muscles and anterior compartment of lower leg
• "Inverted champagne bottle" leg appearance (CMT)
• High-stepping gait (foot drop)
• Areflexia / hyporeflexia - deep tendon reflexes lost distally, then progressively proximally

Autonomic Features (when small fibers and autonomic nerves involved)

• Postural hypotension (orthostatic fall in BP without compensatory heart rate rise)
• Heat intolerance, anhidrosis
• Bowel dysfunction (constipation or diarrhoea)
• Bladder dysfunction (neurogenic bladder)
• Erectile dysfunction
• Abnormal skin changes (atrophy, hair loss)

Pattern of Distribution

• Harrison's 22E, p. 3638-3640; Rosen's Emergency Medicine, p. 1519-1520

6. Diagnosis and Investigations

Clinical Approach (7 Key Questions - Harrison's)

1. What systems are involved? (sensory, motor, autonomic)
2. What is the distribution of weakness? (proximal + distal vs distal only; focal vs symmetric)
3. What is the nature of sensory involvement? (large vs small fiber)
4. Is there upper motor neuron involvement?
5. What is the temporal evolution? (acute, subacute, chronic)
6. Is there a hereditary basis?
7. Are there predisposing conditions, drugs, or toxins?

Electrodiagnostic Studies (EDx) - Most Important

• Nerve conduction studies (NCS):
  • Axonal: reduced amplitude of sensory nerve action potentials (SNAPs) and compound muscle action potentials (CMAPs); mild NCV slowing
  • Demyelinating: markedly slowed NCV (< 38 m/s in motor nerves for acquired), conduction block, prolonged distal latencies
• Needle electromyography (EMG): shows denervation changes (fibrillations, positive sharp waves) in axonal disease; reduced recruitment

Blood Tests (Screening)

• High-yield initial panel (Rosen's): fasting blood glucose, serum B12, serum protein immunofixation electrophoresis
• Full workup: CBC, comprehensive metabolic panel, HbA1c or OGTT, TSH, LFTs, renal function
• Inflammatory markers: ANA, ANCA, anti-Ro/La (Sjögren's), complement levels
• Paraneoplastic antibodies (anti-Hu, anti-Yo) if malignancy suspected
• HIV serology, hepatitis B and C serology
• Lyme serology, if endemic area
• Serum protein electrophoresis + immunofixation (MGUS/myeloma)
• Porphyrins (urine) if porphyria suspected
• Heavy metal screen (urine arsenic, lead)

Nerve Biopsy

• Sural nerve biopsy - used when diagnosis unclear
• Findings: axonal loss, demyelination, inflammation, vasculitis, amyloid deposits (Congo red staining), onion bulbs (CMT1)

Skin Punch Biopsy

• Intraepidermal nerve fiber density (IENFD) - gold standard for small fiber neuropathy diagnosis
• Reduced fiber density confirms small fiber neuropathy

CSF (Lumbar Puncture)

• GBS/CIDP: albuminocytological dissociation - elevated CSF protein with normal cell count

Genetic Testing

• CMT and hereditary neuropathies - PMP22 duplication (CMT1A), MPZ mutations (CMT1B)

Nerve Imaging

• MRI of nerve roots/plexus - for plexopathy, nerve tumors, radiculopathy
• Ultrasound of peripheral nerves - enlargement in CIDP, hereditary neuropathies
• Rosen's Emergency Medicine, p. 1520; Harrison's 22E, p. 3638-3641

7. Complications

• Harrison's 22E, p. 3638; Rosen's Emergency Medicine, p. 1520

Summary mnemonic for causes - "DANG THERAPIST": Diabetes, Alcohol, Nutritional, Guillain-Barré, Thyroid, Hereditary, Endocrine/Entrapment, Renal (uremia), Amyloid/Autoimmune, Paraneoplastic, Infectious, Systemic (vasculitis), Toxins/drugs.

Duchenne Muscular Dystrophy (DMD)

1. Definition

• Tietz Textbook of Laboratory Medicine 7th Edition, p. 2732

2. Aetiology

Genetic Basis

• DMD is caused by mutations in the DMD gene located at chromosome Xp21.2
• The DMD gene is one of the largest genes in the human genome - spanning 2.4 million base pairs (2.4 Mb) with 79 exons
• The gene encodes the protein dystrophin (3,685 amino acids; molecular weight 427 kDa)

Types of Mutations

• Most deletions cause frameshift mutations - the translational reading frame is disrupted, producing a truncated, nonfunctional dystrophin protein (contrast with Becker MD where the reading frame is preserved, producing a partially functional, shorter protein)
• Approximately 30% of cases arise from new (de novo) mutations (no family history)
• Family history is present in ~70% of patients

Inheritance Pattern

• X-linked recessive - almost exclusively affects males
• Carrier females are usually asymptomatic (protected by the normal X chromosome)
• Up to 20% of female carriers can show mild symptoms (manifesting carriers) - muscle weakness, elevated CK, or dilated cardiomyopathy - depending on degree of X-inactivation (lyonization)
• Can also occur in females with Turner syndrome (45, X0) or X-autosome translocations
• Henry's Clinical Diagnosis and Management, p. 1655; Tietz 7E, p. 2732; Campbell's Operative Orthopaedics 15E

3. Predisposing Factors

4. Pathogenesis

Role of Dystrophin

1. Actin-binding domain (N-terminal)
2. Central rod domain (spectrin-like repeats)
3. Cysteine-rich domain
4. C-terminal domain

Normal Function of DAPC

• Connects the actin cytoskeleton to the extracellular matrix (ECM)
• Stabilizes the sarcolemma (muscle cell membrane) during repeated contraction-relaxation cycles
• Transmits contractile force from muscle sarcomeres to the ECM
• Maintains calcium (Ca2+) homeostasis in the muscle cell

What Happens in DMD (Absence of Dystrophin)

1. Sarcolemmal instability: Without dystrophin, the sarcolemma becomes fragile and tears during contraction
2. Calcium influx: Membrane microbreaks allow uncontrolled entry of extracellular Ca2+ into the muscle fiber
3. Protease activation: Elevated intracellular Ca2+ activates calcium-dependent proteases (calpains), leading to protein degradation
4. Immune infiltration: Immune cells (neutrophils, macrophages, T-cells) and cytokines flood the damaged muscle
5. NF-κB dysregulation: Abnormal signaling via NF-κB, MAPK, and PI3K/AKT pathways amplifies inflammation
6. ECM breakdown: Dysregulation of matrix metalloproteinases impairs normal muscle repair
7. Failed regeneration: Repeated cycles of degeneration and regeneration eventually exhaust satellite (stem) cells
8. Fibrofatty replacement: Muscle tissue is ultimately replaced by adipose and connective (fibrotic) tissue - leading to irreversible loss of function

Cardiac Pathogenesis

• Dystrophin is also expressed in cardiac muscle
• Loss leads to cardiac fibrosis → dilated cardiomyopathy (DCM) with left ventricular dilation and congestive heart failure

Cognitive Involvement

• Dystrophin has shorter isoforms (Dp140, Dp71) expressed in the brain
• Loss of these isoforms explains the non-progressive cognitive impairment seen in ~30% of DMD patients
• Tietz 7E, p. 2732

5. Clinical Features and Signs

Neonatal / Early Infancy

• Usually normal at birth
• Early motor milestones may be reached on time, but with subtle delay
• Toe walking is often the first sign noticed by parents

Early Childhood (Age 2-5 years)

• Mean age of diagnosis: 41 months
• Delayed walking or waddling (Trendelenburg) gait
• Frequent falls
• Difficulty running, climbing stairs, or rising from the floor
• Gowers' sign - characteristic sign where the child "walks up" his own legs using his hands when rising from the floor (compensates for weak proximal leg muscles)
• Pseudohypertrophy of calves - calves appear large and firm due to replacement of muscle by fat and connective tissue (not true muscle hypertrophy)

Established Disease (Age 5-10 years)

• Progressive proximal muscle weakness - predominantly affecting the pelvic girdle and shoulder girdle initially
• Lordotic posture - exaggerated lumbar lordosis to maintain balance
• Waddling gait
• Contractures develop at hips, knees, and ankles (equinus deformity)
• Weakness of shoulder girdle muscles (deltoid, trapezius)
• Scoliosis develops as spinal muscles weaken - further compromises respiratory function

Wheelchair-Bound Stage (Age 10-15 years)

• Most DMD patients require wheelchairs between 10 and 15 years of age
• Upper limb weakness progresses
• Scoliosis worsens

Cardiac Features

• Dilated cardiomyopathy (DCM) - most common cardiac manifestation
• Cardiac involvement detectable by echo by age 10; symptomatic by teens/early adulthood
• Tachycardia, dyspnoea, orthopnoea
• Rhythm and conduction abnormalities

Respiratory Features

• Chronic respiratory insufficiency develops in all patients as respiratory muscles (diaphragm, intercostals) weaken
• Initially nocturnal hypoventilation; later daytime respiratory failure
• Recurrent chest infections

Cognitive / Behavioural Features

• Non-progressive mild cognitive impairment (average IQ ~20 points below normal)
• Higher rates of attention-deficit hyperactivity disorder (ADHD), autism spectrum features, learning difficulties
• Not progressive - does not worsen with disease stage

Gastrointestinal

• Smooth muscle involvement: gastroparesis, constipation, pseudo-obstruction
• Dysphagia in advanced disease

6. Diagnosis and Investigations

Step 1: Clinical Suspicion

• Boy with delayed walking, Gowers' sign, pseudohypertrophy of calves, family history

Step 2: Serum Creatine Kinase (CK)

• Massively elevated CK - typically >10 times the upper limit of normal (often 20-100x)
• CK is highest in early life (even in neonates) and decreases as muscle mass is lost over time
• This is the most important initial screening test
• CK can also be elevated in carrier females

Step 3: Genetic (DNA) Testing - Confirmatory in ~95%

• Multiplex Ligation-Dependent Probe Amplification (MLPA) - most widely used; tests all 79 exons for deletions and duplications
• Multiplex PCR - detects deletions in key exons rapidly; identifies ~98% of deletions
• Next-Generation Sequencing (NGS) - used when MLPA is negative; detects point mutations and small insertions/deletions
• Microarray comparative genomic hybridisation (CGH) - alternative for deletion/duplication screening

Step 4: Muscle Biopsy (used in ~5% where DNA testing is inconclusive)

• Histology: Variation in fiber size, necrosis, inflammation (inflammatory infiltrate), fibrosis, and fiber regeneration (basophilic regenerating fibers)
• Immunohistochemistry (IHC): Complete or near-complete absence of dystrophin staining at the sarcolemma (using antibodies against N-terminal, rod, and C-terminal domains)
• Western blot: Absent or severely reduced dystrophin band
• "Onion bulb" formations are NOT present (those are seen in hereditary demyelinating neuropathies)

Additional Investigations

• Tietz 7E, p. 2732-2733; Henry's, p. 1655-1656

7. Complications

Prognosis

• Without glucocorticoid treatment: wheelchair-bound by age 10-12; death from cardiorespiratory failure typically in late teens to early 20s
• With glucocorticoids (prednisolone/deflazacort): extends ambulation by 2-5 years; significantly delays respiratory and cardiac decline
• With modern multidisciplinary care + non-invasive ventilation + cardiac medications: median survival now into the 30s
• Novel gene-based therapies (exon skipping - e.g., eteplirsen for exon 51 skip; ataluren for nonsense mutations) are extending outcomes further

DMD vs Becker MD - Key Distinction

• Tietz 7E, p. 2733; Campbell's Operative Orthopaedics 15E

Guillain-Barré Syndrome (GBS)

1. Definition

• Motor weakness + areflexia + paresthesias + albuminocytological dissociation in CSF (elevated protein with normal cell count)
• Adams and Victor's Principles of Neurology 12E, p. 1299; Bradley and Daroff's Neurology, p. 2663

2. Aetiology

Infectious Triggers (Most Common)

Non-Infectious Triggers

• Vaccinations: Swine flu vaccine (1976) - notable association; adenoviral COVID-19 vaccines (marginal increase); influenza vaccines (~2 cases per million doses); generally idiosyncratic
• Surgical operations or trauma (causal relationship uncertain)
• Lymphoma (especially Hodgkin disease)
• Systemic autoimmune diseases
• Immune checkpoint inhibitors (cancer immunotherapy)
• Pregnancy (postpartum period)

Idiopathic

• Adams and Victor's 12E, p. 1299-1300; Miller's Anesthesia 10E, p. 12034

3. Predisposing Factors

4. Pathogenesis

Core Mechanism: Molecular Mimicry + Autoimmunity

1. Preceding infection exposes the immune system to microbial antigens (e.g., C. jejuni lipopolysaccharide - LPS)
2. These antigens structurally resemble gangliosides on peripheral nerve myelin or axolemma (molecular mimicry)
3. The immune system generates cross-reactive antibodies and T cells against nerve antigens
4. Autoreactive T cells and antibodies attack peripheral nerves and nerve roots

AIDP (Demyelinating) Pathogenesis - Most Common in West

• Complement deposition on the outer surface of myelin (Schwann cell) is the earliest immunologic event
• Complement activation → membrane attack complex (MAC) formation → myelin vesiculation and destruction
• Macrophage infiltration: Macrophages (the dominant cell in lesions) invade the myelin sheath and strip it from the axon (macrophage-mediated demyelination)
• Perivascular mononuclear inflammatory infiltrates in nerve roots and peripheral nerves
• Injury most severe at nerve roots and proximal nerve segments
• Demyelination causes conduction block → weakness; slowed NCV on nerve conduction studies
• Axons are relatively spared early → potential for complete recovery (remyelination)

AMAN (Axonal) Pathogenesis - Common in China/Asia

• Anti-GM1 and anti-GD1a ganglioside antibodies (often associated with C. jejuni infection)
• Antibodies target gangliosides on the axolemma (node of Ranvier)
• Complement and macrophages invade the periaxonal space, damaging the axon directly
• Axonal degeneration with minimal inflammation/demyelination
• Recovery is prolonged and often incomplete due to axonal loss

Miller-Fisher Syndrome (MFS) Pathogenesis

• Anti-GQ1b antibodies (GQ1b ganglioside is concentrated in cranial nerve myelin, especially III, IV, VI, and cerebellar afferents)
• Causes the classic triad: ophthalmoplegia + ataxia + areflexia

Net Effect

• Loss of myelin → conduction failure → ascending flaccid paralysis
• Autonomic fibers also involved → autonomic instability
• Nerve roots (cauda equina) often earliest and most severely affected
• Robbins & Kumar Basic Pathology, p. 808; Adams and Victor's 12E, p. 1300-1303; Bradley & Daroff's Neurology

5. Clinical Features and Signs

Prodrome

• 1-3 weeks before neurological symptoms: upper respiratory tract infection (most common) OR gastroenteritis (C. jejuni)

Onset

• Paraesthesias (tingling, burning, numbness) in fingers and toes - usually the first neurological symptom
• Pain and aching in muscles of hips, thighs, and back (can mimic lumbar disc disease - important diagnostic trap)

Cardinal Features

Motor Involvement (by stage)

• Early: Lower limb weakness, difficulty walking
• Intermediate: Upper limb weakness, truncal weakness
• Severe: Respiratory muscle paralysis (diaphragm + intercostals)
• Respiratory failure: Develops in 20-30% of cases - most important life-threatening complication

Cranial Nerve Involvement (in ~50%)

• Facial diplegia (bilateral facial palsy) - most common cranial nerve sign (>50% of patients)
• Dysphagia, dysarthria (bulbar palsy)
• Ophthalmoplegia (in Fisher variant or severe GBS)

Autonomic Dysfunction (common in severe GBS)

• Sinus tachycardia (most common)
• Bradycardia
• Fluctuating hypertension and hypotension (dangerous - can cause cardiovascular collapse)
• Facial flushing, anhidrosis or episodic diaphoresis
• Urinary retention (in ~15% of patients early in disease)
• Ileus / constipation

Key Signs on Examination

• Flaccid paralysis (hypotonia)
• Absent deep tendon reflexes (areflexia)
• Preserved consciousness (GBS does not affect the brain)
• No fever at onset (fever suggests alternative diagnosis)
• Sensory loss variable - proprioception and vibration affected more

GBS Subtypes Summary

• Adams and Victor's 12E, p. 1299-1303; Miller's Anesthesia 10E, p. 12034

6. Diagnosis and Investigations

Diagnostic Criteria (Brighton Collaboration / Asbury & Cornblath)

1. Progressive weakness of both legs and arms
2. Areflexia or hyporeflexia

• Progression over days to 4 weeks
• Relative symmetry
• Mild sensory symptoms
• Bifacial palsy
• Autonomic dysfunction
• Absence of fever at onset
• Recovery beginning 2-4 weeks after progression stops

Investigations

1. Cerebrospinal Fluid (CSF) - Lumbar Puncture

• Albuminocytological dissociation - the classic finding:
  • Elevated CSF protein (>0.45 g/L, often 1-10 g/L)
  • Normal or near-normal cell count (<10 cells/μL)
• CSF may be normal in first week (protein rises over 1-2 weeks)
• Elevated white cells (>50) should prompt consideration of alternative diagnoses (e.g., viral meningitis, Lyme)

2. Nerve Conduction Studies (NCS) / EMG - Most Informative

3. Antibody Testing

• Anti-GQ1b antibodies - positive in >85% of Miller-Fisher Syndrome cases
• Anti-GM1 antibodies - positive in AMAN; associated with worse recovery
• Anti-GD1a antibodies - AMAN/AMSAN (C. jejuni-associated)

4. Blood Tests

• Full blood count, metabolic panel, LFTs, renal function
• Search for causative pathogen: Campylobacter stool culture/serology, CMV, EBV, HIV, hepatitis serology, Lyme titres
• Electrolytes (hyponatraemia from SIADH can occur)

5. Pulmonary Function Tests (Bedside)

• Forced Vital Capacity (FVC): key monitoring tool
  • FVC <20 mL/kg - requires close observation/ICU admission
  • FVC <15 mL/kg - probable need for intubation
• Maximal Inspiratory Pressure (MIP) < -30 cm H2O - indicates impending respiratory failure
• Erasmus GBS Respiratory Insufficiency Score (EGRIS) - validated tool for ICU admission decisions
• Note: Hypercarbia is a late sign - do not wait for it

6. ECG

• Cardiac arrhythmias (tachycardia, bradycardia), conduction blocks from autonomic involvement

7. MRI Spine / Brain

• May show enhancement of spinal nerve roots (particularly cauda equina) on gadolinium MRI
• Used to exclude other diagnoses (transverse myelitis, cord compression)
• Bradley & Daroff's Neurology, p. 2663; Miller's Anesthesia 10E, p. 12034-12035

7. Complications

Prognosis

• Monophasic illness: progression → plateau → recovery
• Most patients begin improving 2-4 weeks after peak
• ~85% regain independent walking by 6 months
• Recovery can be protracted over months to years in axonal subtypes
• Poor prognostic indicators: axonal subtype, older age, rapid progression to nadir, positive anti-GM1 antibodies, need for ventilation, no recovery at 3 weeks

Treatment Summary (for context)

• IVIg (2g/kg over 5 days) - first-line; equivalent to plasma exchange
• Plasmapheresis (plasma exchange) - removes offending antibodies; first-line
• Corticosteroids - NOT effective and NOT recommended in GBS
• Respiratory support - early intubation based on FVC/MIP thresholds
• Cardiac monitoring - continuous ECG in ICU
• DVT prophylaxis, physiotherapy, nutritional support
• Robbins & Kumar Basic Pathology, p. 808; Miller's Anesthesia 10E, p. 12035; Bradley & Daroff's Neurology

Cluster Headache

1. Definition

• Harrison's Principles 22E; Bradley & Daroff's Neurology; Adams and Victor's Neurology 12E

2. Aetiology

Central Mechanisms

• Hypothalamic dysfunction - the core central driver; the hypothalamus (particularly the posterior/ventral hypothalamic region) acts as a biological clock generating the striking circadian and circannual periodicity
• PET imaging studies show activation of the ipsilateral ventral diencephalon (posterior hypothalamic grey matter) during cluster attacks induced by nitroglycerin - not seen in other headaches
• Volumetric MRI studies show increased grey matter volume in the diencephalon in cluster headache patients
• Likely involves a defect in CNS biological clock (suprachiasmatic nucleus) - explaining why attacks are time-locked

Trigeminovascular Activation

• The trigeminal nerve (V1 - ophthalmic division) mediates pain signals from the orbit and periorbital region
• Trigeminovascular activation releases CGRP (calcitonin gene-related peptide) - elevated in external jugular venous blood during attacks
• CGRP causes vasodilation and neurogenic inflammation around cranial blood vessels

Parasympathetic Activation

• Hypothalamic output activates the cranial parasympathetic system via the sphenopalatine (pterygopalatine) ganglion and facial nerve (VII)
• This produces: lacrimation, conjunctival injection, nasal congestion, rhinorrhea, eyelid edema
• Vasoactive intestinal polypeptide (VIP) levels are elevated in cranial venous blood during attacks - evidence of cranial parasympathetic activation

Sympathetic Deficiency (Horner's Syndrome)

• Parasympathetic-driven vasodilation → perineural edema around the internal carotid artery in the carotid canal → neurapraxic injury to ascending postganglionic sympathetic fibres → ptosis + miosis (partial Horner syndrome)

Secondary / Symptomatic Causes (Important to Exclude)

• Cluster headache-like pain can be caused by:
  • Intracranial aneurysms
  • Parasellar or peritentorial meningiomas
  • Pituitary adenoma
  • Nasopharyngeal cancer surrounding the carotid artery
  • Wegener's granulomatosis of the soft palate
• These are sometimes called symptomatic TACs and must be excluded especially in atypical cases
• Bradley & Daroff's Neurology, p. 2490; Harrison's 22E, p. 869

3. Predisposing Factors

4. Pathogenesis

Step-by-Step Mechanism

1. Circadian/Circannual Trigger: A dysfunction in the posterior hypothalamic pacemaker (likely involving the suprachiasmatic nucleus) generates periodic, time-locked signals that initiate cluster periods. This explains why attacks occur at the same clock hour each day ("alarm clock headache").
2. Hypothalamic Activation: The posterior hypothalamic region becomes activated, sending signals downstream to the trigeminal nucleus caudalis and cranial autonomic pathways.
3. Trigeminovascular Activation: Activation of the ophthalmic (V1) division of the trigeminal nerve initiates pain. CGRP and substance P are released from trigeminal nerve terminals, causing vasodilation and neurogenic inflammation in meningeal/orbital vessels.
4. Cranial Parasympathetic Activation: Hypothalamic output drives the superior salivatory nucleus → greater petrosal nerve → sphenopalatine (pterygopalatine) ganglion, releasing VIP and acetylcholine → vasodilation, lacrimation, nasal congestion, rhinorrhea.
5. Carotid Artery Dilation + Sympathetic Injury: Parasympathetic-driven dilation of the internal carotid artery and perivascular edema compress the postganglionic sympathetic plexus on the carotid wall → partial Horner syndrome (ptosis + miosis).
6. Trigemino-Parasympathetic Reflex: A positive feedback loop - trigeminal pain signals re-activate the parasympathetic outflow, amplifying autonomic symptoms.
7. Attack Termination: Mechanism unclear; may involve central inhibitory mechanisms and/or exhaustion of the trigeminovascular system.

Carotid Artery Dilation

• Ipsilateral carotid dilation occurs during attacks but is not specific to cluster headache - seen with other ophthalmic division pain; considered an epiphenomenon rather than the primary driver.
• Bradley & Daroff's Neurology, p. 2490

5. Clinical Features and Signs

Epidemiology

• Prevalence: ~1 in 500 (0.1-0.2%)
• Episodic form: 90% of patients - cluster periods 7 days to 1 year, separated by remissions ≥3 months
• Chronic form: 10% - attacks >1 year without remission OR remissions <3 months
• Male:female ratio ~3-5:1 (but clinically identical in both sexes)

Pain Characteristics - CLASSIC

Ipsilateral Autonomic Features (at least ONE required for diagnosis)

• Conjunctival injection (red eye)
• Lacrimation (tearing)
• Nasal congestion (blocked nostril during attack)
• Rhinorrhoea (nasal drainage signals end of attack)
• Ptosis (drooping eyelid) - may become permanent with repeated attacks
• Miosis (small pupil)
• Forehead and facial sweating / flushing
• Eyelid oedema
• Aural fullness
• Together, ptosis + miosis = partial Horner syndrome (ipsilateral to pain)

Behavioural Features (Distinctive - Differentiates from Migraine)

• Patients are agitated, restless, pacing, rocking
• May press on the eye or bang their head on walls
• Cannot lie still (CONTRAST with migraine patients who prefer lying still in a dark quiet room)
• Some patients go outdoors even in cold weather
• Some consider or attempt suicide during severe attacks

Associated Features

• Nausea, unilateral photophobia and phonophobia (unlike bilateral in migraine)
• Temporal artery prominence and tenderness during attacks
• Increased intraocular pressure during attacks (CONTRAST with migraine: normal pressure)
• Skin hyperalgesia over scalp and face

Physical Appearance

• Patients often have coarse facial skin, deep nasolabial folds
• Higher incidence of hazel eye colour
• Heavy smokers

Triggers During Active Cluster Period (Not During Remission)

• Alcohol (most reliable trigger)
• Nitroglycerin
• Histamine
• Volatile substances

6. Diagnosis and Investigations

Diagnosis is Primarily Clinical (ICHD-3 Criteria)

• Severe unilateral orbital/supraorbital/temporal pain lasting 15-180 minutes
• At least ONE ipsilateral cranial autonomic feature OR sense of agitation/restlessness
• Attacks occur in cluster periods

Investigations - To Confirm Diagnosis and Exclude Secondary Causes

1. MRI Brain with Gadolinium (MANDATORY for new-onset cluster headache)

• Exclude pituitary adenoma, aneurysm, cavernous sinus lesion, parasellar tumour, posterior fossa lesion
• MRI of pituitary specifically recommended - pituitary adenomas can mimic cluster headache exactly
• Consider MRI angiography (MRA) if aneurysm suspected

2. MRI/CT Head

• Usually normal in primary cluster headache
• Structural lesions cause "symptomatic TACs" and must be excluded

3. Blood Tests

• Routine: FBC, ESR, CRP (to exclude temporal arteritis / inflammatory cause in older patients)
• No specific blood test confirms cluster headache

4. Intraocular Pressure Measurement

• Increased during attacks (distinguishes from migraine where it is normal)

5. Headache Diary

• Confirms cluster periodicity, circadian pattern, attack duration, frequency

6. Diagnostic Response Trial

• Response to 100% oxygen (10-12 L/min for 15-20 min) or subcutaneous sumatriptan supports the diagnosis

7. Polysomnography (if sleep apnoea suspected)

• Sleep apnoea co-exists with nocturnal cluster headache in some patients

Differential Diagnosis (Critical)

• Bradley & Daroff's Neurology, p. 2490-2492; Harrison's 22E, p. 879; Adams and Victor's 12E

7. Complications

Cluster Headache vs Migraine - Key Differences

• Adams and Victor's 12E, p. 201

Tension-Type Headache (TTH)

1. Definition

• Adams and Victor's Neurology 12E, p. 201; Kaplan & Sadock's, p. 1980

2. Aetiology

Psychological and Emotional Causes (Most Important)

• Stress - the most commonly identified trigger; physical and emotional stress
• Anxiety - chronic anxiety is present in the majority of patients with protracted TTH
• Depression - approximately one-third of patients with persistent TTH have recognisable depression (Lance & Curran); TTH and depression have a bidirectional relationship
• Fatigue and sleep disturbance
• Mental exertion and poor concentration

Musculoskeletal / Peripheral Causes

• Pericranial muscle tenderness - sustained contraction or tenderness of scalp, neck, and shoulder muscles (trapezius, splenius capitis, temporalis, sternocleidomastoid)
• Cervical musculoskeletal dysfunction and trigger points
• Poor posture (particularly prolonged desk/computer work)
• Temporomandibular joint (TMJ) dysfunction
• Cervical spondylosis

Central Sensitization (in Chronic TTH)

• Sensitization of central nociceptive pathways in the trigeminal nucleus and supraspinal structures
• Inadequate endogenous anti-nociceptive (pain inhibitory) circuitry
• Nitric oxide (NO) - implicated as a key mediator that creates central sensitization to sensory stimulation from cranial structures; inhibitors of nitric oxide synthase reduce muscle hardness and pain in chronic TTH

Noradrenergic System

• A 2026 systematic review (PMID: 41559550) identifies noradrenergic system dysfunction as a major driver of TTH pathophysiology, with dysregulation of descending noradrenergic pain modulation

Other Contributing Factors

• Medication overuse (leading to chronic daily headache)
• Hormonal fluctuations (though less prominent than migraine)
• Irregular eating, dehydration, bright light, noise

3. Predisposing Factors

4. Pathogenesis

Episodic TTH - Peripheral (Myofascial) Mechanism

1. Psychological stress, poor posture, or fatigue triggers sustained or increased activity in pericranial and cervical muscles (temporalis, frontalis, sternocleidomastoid, trapezius)
2. Pericranial myofascial tenderness develops - activation of peripheral nociceptors (A-delta and C-fibres) in muscles and tendinous insertions
3. Nociceptive input is transmitted via the trigeminal nerve and upper cervical spinal nerve roots to the trigeminal nucleus caudalis
4. This results in referred pain perceived across the frontal, temporal, and occipital regions - the "band-like" or "vice-like" pressure sensation
5. Note: Despite the historical name "tension headache," most patients with TTH do NOT show elevated EMG activity in pericranial muscles at rest, and muscle contraction alone does not fully explain the syndrome

Chronic TTH - Central Sensitization Mechanism

1. Repeated peripheral nociceptive input from pericranial muscles over time leads to central sensitization of second-order trigeminal neurons in the brainstem
2. The threshold for pain transmission is lowered - even normal sensory input triggers pain
3. Inadequate descending pain inhibition (from the periaqueductal grey, rostral ventromedial medulla, and noradrenergic pathways) fails to suppress incoming nociceptive signals
4. Nitric oxide (NO) produced by neurons and glial cells contributes to central sensitization by increasing neuronal excitability, widening receptive fields, and sensitizing nociceptors
5. Serotonergic and noradrenergic dysregulation - reduced serotonin and noradrenaline in CSF of chronic TTH patients impairs descending inhibitory control
6. This explains why chronic TTH is often continuous, resistant to simple analgesics, and responds better to tricyclic antidepressants (which enhance noradrenergic and serotonergic tone)

Summary of Two-Tier Model

• Adams and Victor's 12E, p. 203; Scott-Brown's Otorhinolaryngology Vol 1, p. 1304

5. Clinical Features and Signs

General Characteristics

• Most common headache disorder - affects approximately 30-78% of the general population at some point in their lives
• More common in women; more likely to arise in middle age compared to migraine

ICHD-3 Classification

Pain Characteristics

Associated Features (What is Present)

• Fullness, tightness, or pressure sensation ("head in a vice," "head may burst")
• Tenderness and tightness of neck and shoulder muscles (trapezius)
• Skin hyperaesthesia over the scalp (patients may feel they have sinusitis)
• Tender trigger points in the neck and shoulder areas
• Occipitonuchal tightness
• Mild sensitivity to light or sound (but NOT both simultaneously; if both present, migraine is more likely)

What is ABSENT (Important for Diagnosis)

• No nausea or vomiting (anorexia may occur)
• No persistent throbbing quality
• Not both photophobia AND phonophobia (at most one)
• No aura
• No clear unilateral lateralization
• Activity does not worsen pain
• No autonomic features (no lacrimation, rhinorrhoea, ptosis)
• Headache does NOT seriously interfere with daily activities (contrast with migraine)

Behavioural Features

• Patients are generally able to continue functioning (unlike cluster or migraine)
• Sleep is usually undisturbed (though headache returns soon after waking)
• Common analgesics have limited effect in moderate-severe TTH

Psychiatric Co-morbidity

• Anxiety - chronic anxiety present in majority of patients with protracted TTH
• Depression - ~1/3 of persistent TTH patients have clinical depression
• Headache may arouse fears of brain tumour (though risk is <1 in 1,000)

6. Diagnosis and Investigations

Diagnosis is Clinical - Based on ICHD-3 Criteria

• A. ≥10 episodes, 1-14 days/month for ≥3 months
• B. Headache lasts 30 minutes to 7 days
• C. At least 2 of the following pain features:
  1. Bilateral location
  2. Pressing/tightening quality (non-pulsating)
  3. Mild or moderate intensity
  4. Not aggravated by routine physical activity
• D. Both of:
  1. No nausea or vomiting (anorexia may occur)
  2. No more than one of photophobia or phonophobia
• E. Not attributed to another disorder

Investigations (To Exclude Secondary Causes)

Red Flags Requiring Investigation ("SNOOPCC")

• Systemic symptoms (fever, weight loss, rash)
• Neurological symptoms or signs (weakness, diplopia, ataxia)
• Onset sudden (thunderclap - worst headache of life)
• Older age (>50 years, new headache)
• Progressive headache worsening over weeks
• Positional change affecting headache
• Change in headache pattern
• Cough/exertion/Valsalva-triggered headache

Investigations When Red Flags Present

In Pure, Typical TTH

• No investigations required if headache pattern is typical and no red flags are present
• Diagnosis made clinically

7. Complications

TTH vs Migraine vs Cluster Headache - Quick Comparison

• Kaplan & Sadock's, p. 1980; Adams and Victor's 12E, p. 201-203; Harrison's 22E

Amyotrophic Lateral Sclerosis (ALS)

1. Definition

• Amyotrophic = muscle wasting (no muscle nutrition - from denervation)
• Lateral = the lateral columns of the spinal cord (corticospinal tracts)
• Sclerosis = gliotic hardening of the lateral corticospinal tracts

• Incidence: ~2 per 100,000 per year
• Prevalence: 5-8 per 100,000
• Mean age of onset: 55-60 years
• Male:female ratio ~1.2-1.6:1 (male predominance; female predominance in bulbar-onset form)
• Mean survival from symptom onset to death: ~3 years; ~20% survive to 5 years; ~10% to 10 years
• Goldman-Cecil Medicine, p. 4069; Bradley & Daroff's Neurology; Robbins & Kumar Basic Pathology

2. Aetiology

A. Sporadic ALS (SALS) - 90% of cases

• No identifiable genetic cause in most cases
• Aetiology remains unknown; likely multifactorial
• Various environmental, occupational, and lifestyle factors investigated but none proven conclusively

B. Familial ALS (FALS) - 5-10% of cases

• >40 ALS susceptibility genes identified to date

Environmental / Putative Risk Factors (Not Proven)

• Strenuous physical exercise (elite athletes, military veterans)
• Head trauma
• Smoking - independent risk factor for sporadic ALS (dose-dependent)
• Lead and heavy metal exposure
• High dietary glutamate intake
• Military service (Persian Gulf War veterans - ~2x risk)
• Electromagnetic field exposure (investigated but unproven)
• Goldman-Cecil Medicine, p. 4069; Bradley & Daroff's Neurology, p. 2156

3. Predisposing Factors

4. Pathogenesis

A. Genetic / Molecular Mechanisms

1. SOD1 Mutations (20% FALS)

• Mutations in the superoxide dismutase 1 gene generate misfolded, aggregated SOD1 protein
• Misfolded SOD1 spreads in a prion-like, templated propagation pattern
• Triggers: oxidative stress, unfolded protein response, mitochondrial dysfunction, excitotoxicity, and impaired axonal transport
• Non-cell-autonomous toxicity: mutant SOD1-expressing astrocytes and microglia actively damage neighboring motor neurons via undefined mechanisms
• Normal astrocytes are protective; this suggests glial cells play a key role

2. C9orf72 Hexanucleotide Repeat Expansion

• GGGGCC repeat expansion in C9orf72 → RNA foci that sequester RNA-binding proteins
• Altered nucleocytoplasmic transport
• Aberrant translation of the expanded RNA into toxic dipeptide repeat proteins (DPRs) in the cytoplasm
• Leads to RNA processing defects

3. TDP-43 and FUS Pathology (Common to Most ALS)

• TDP-43 (TAR DNA-binding protein 43) and FUS are RNA-binding proteins normally in the nucleus
• In ALS: TDP-43 mislocalises to the cytoplasm, forming ubiquitinated, phosphorylated inclusions
• Loss of nuclear TDP-43 function + toxic cytoplasmic aggregates → disrupted RNA processing and splicing
• TDP-43 inclusions are the cardinal pathological hallmark in >95% of ALS cases (all except SOD1-ALS)
• This convergence of C9orf72, TDP-43, and FUS on RNA processing suggests RNA dysregulation is a core pathogenic mechanism

B. Cellular Mechanisms

C. Pathological Features (Morphology)

• Atrophy of the precentral gyrus (motor cortex)
• Pallor and sclerosis of the lateral corticospinal tracts in the spinal cord
• Thinning of ventral spinal roots and hypoglossal nerves
• Obvious skeletal muscle atrophy

• Loss of ≥50% of anterior horn cells in spinal cord
• Diffuse astrocytic gliosis in spinal grey matter
• Loss of myelinated fibres in anterior roots
• Ubiquitinated TDP-43 cytoplasmic inclusions in residual motor neurons (compact or skein-like) - cardinal feature
• Neurogenic muscle atrophy: clusters of angular atrophic fibres, fibre-type grouping
• Relative preservation of: Onuf's nucleus (pelvic floor), cranial nerve nuclei III, IV, VI (extraocular muscles) - explains intact bladder/bowel and eye movements until very late
• Goldman-Cecil Medicine, p. 4069; Robbins & Kumar Basic Pathology, p. 856

5. Clinical Features and Signs

Onset Pattern

• ~75% of patients: Spinal onset - focal, asymmetric, distal extremity weakness
• ~25% of patients: Bulbar onset - slurred speech and/or dysphagia (more common in elderly women)
• Rare: Respiratory onset - dyspnoea at presentation

The Cardinal Feature: Coexisting UMN + LMN Signs in the SAME region

Lower Motor Neuron (LMN) Signs

• Weakness and muscle wasting (atrophy)
• Fasciculations (spontaneous firing of motor units - most visible in large proximal muscles)
• Hyporeflexia or absent deep tendon reflexes (in severely wasted muscles)
• Muscle cramps (may be the earliest symptom)
• Flaccidity / hypotonia

Upper Motor Neuron (UMN) Signs

• Spasticity and increased tone
• Hyperreflexia (brisk reflexes incongruously present in wasted, weak limbs - a hallmark clue)
• Babinski sign (extensor plantar response)
• Slow, effortful, strained speech (spastic dysarthria)
• Pseudobulbar affect (inappropriate laughing or crying)

Limb Onset Presentation

• Upper limbs: Thenar eminence and intrinsic hand muscle wasting; clumsiness; inability to button clothes or write; triceps and finger flexors relatively spared until late
• Lower limbs: Foot drop (ankle dorsiflexion weakness); hip flexion weakness; pyramidal pattern (flexors weaker than extensors)
• Muscle cramps often precede weakness

Bulbar Involvement (25% at onset; eventually most patients)

• Dysarthria - initially slurred speech when fatigued; evolves to:
  • Spastic component: tight, strangled, strained voice quality (UMN)
  • Flaccid component: nasal speech, hypophonia (LMN - palatal weakness)
• Dysphagia - difficulty swallowing liquids first (nasal regurgitation), then solids
• Sialorrhoea (pooling of saliva - cannot swallow it efficiently)
• Pseudobulbar affect - emotional lability, uncontrolled laughing/crying (UMN)
• Tongue wasting and fasciculations (LMN)
• Jaw jerk brisk (UMN)
• Facial muscle weakness

Respiratory Involvement

• Diaphragm and intercostal muscle weakness
• Orthopnoea (worse lying flat - diaphragm weakness)
• Dyspnoea on exertion → at rest
• Nocturnal hypoventilation (often the first respiratory sign - disturbed sleep, morning headaches)
• Recurrent chest infections

Cognitive and Behavioural Features

• ~50% of ALS patients have some degree of cognitive impairment
• ~5-15% develop frontotemporal dementia (FTD) - especially C9orf72 mutation carriers
• Executive dysfunction, behavioural changes (disinhibition, apathy)
• Language and memory usually preserved until late

What is PRESERVED in ALS (Important)

• Extraocular movements (oculomotor nuclei spared)
• Bladder and bowel control (Onuf's nucleus in sacral cord preserved)
• Sensation - purely sensory symptoms are absent (sensory nerves unaffected)
• Intellectual function - usually preserved (though cognitive overlap with FTD exists)
• Consciousness

End-Stage Disease

• All four limbs affected; tetraplegia
• Unable to swallow (PEG tube required)
• Unable to communicate verbally
• Respiratory failure requiring ventilator support

6. Diagnosis and Investigations

Diagnosis is Clinical - Based on El Escorial / Awaji Criteria

• Evidence of LMN degeneration (clinical, electrophysiological, or neuropathological)
• Evidence of UMN degeneration (clinical examination)
• Progressive spread within a region or to other regions
• Absence of an alternative diagnosis explaining the findings

Electrophysiology - Most Important Investigation

1. Nerve Conduction Studies (NCS)

• Usually normal (pure motor disease; sensory nerves unaffected)
• Motor amplitudes may be reduced with severe atrophy
• Normal or near-normal conduction velocities (no primary demyelination)
• Normal sensory nerve action potentials (SNAPs) - key distinguishing feature from polyneuropathy

2. Needle EMG - Confirmatory

• Fibrillations (spontaneous denervation potentials)
• Positive sharp waves
• Fasciculation potentials - characteristic
• Large, long-duration, polyphasic motor unit action potentials (chronic reinnervation)
• Reduced interference pattern on maximal effort
• Awaji criteria: fasciculations alone (without fibrillations) can fulfill LMN criterion

Neuroimaging

• MRI brain and spine - to exclude structural causes mimicking ALS (cervical spondylotic myelopathy, foramen magnum lesion, motor cortex tumour)
• MRI brain in ALS: may show T2/FLAIR signal change along corticospinal tracts and cortical atrophy of precentral gyrus (UMN degeneration) - not diagnostic but supportive

Blood Tests

• FBC, ESR, CRP, glucose, TFTs, B12, electrolytes (to exclude metabolic causes)
• Serum creatine kinase (CK) - mildly to moderately elevated (muscle denervation)
• Anti-GM1 ganglioside antibodies - elevated in multifocal motor neuropathy (an important ALS mimic - treatable!)
• Paraneoplastic antibody screen
• Heavy metal screen (lead, mercury) - if toxic neuropathy suspected

Genetic Testing

• C9orf72 repeat expansion - strongly recommended in all ALS patients (especially with family history or FTD features)
• SOD1 mutation testing (informs eligibility for tofersen - a targeted therapy)
• Full ALS gene panel - in familial cases

CSF Analysis

• Usually normal in ALS
• Mild elevation of CSF protein possible
• Used to exclude mimics (inflammatory conditions)

Pulmonary Function Tests

• Forced Vital Capacity (FVC) - key monitoring parameter; FVC <50% predicted indicates need for NIV
• Sniff Nasal Inspiratory Pressure (SNIP) - useful when mask leak makes spirometry unreliable
• Polysomnography if nocturnal hypoventilation suspected

Muscle Biopsy (rarely needed)

• Neurogenic atrophy: angular atrophic fibres, fibre-type grouping
• Used if diagnosis is unclear

Key ALS Mimics to Exclude

7. Complications

Prognosis

• Median survival: 2-3 years from symptom onset (not diagnosis)
• ~20% alive at 5 years; ~10% alive at 10 years
• Poorer prognosis: bulbar onset, older age, rapid progression, FVC already low at diagnosis, C9orf72 mutation
• Better prognosis: young onset, limb onset, slow progression, female sex, respiratory-sparing phenotype
• ALS with PLS variant: much slower progression (>10 years)
• Stephen Hawking (diagnosed age 21) survived >50 years - exceptional outlier

Disease-Modifying Treatment (Brief Reference)

• Riluzole (anti-glutamate agent) - only conventional DMARD; extends survival by ~2-3 months
• Edaravone (free radical scavenger) - FDA approved; modest benefit in select patients
• Tofersen (antisense oligonucleotide targeting SOD1 mRNA) - FDA approved 2023 for SOD1-ALS; a recent 2025 meta-analysis (PMID: 39820998) confirms it reduces neurofilament light chain (a biomarker of neurodegeneration) and slows progression
• NIV (non-invasive ventilation) - improves quality of life and extends survival by ~7 months
• PEG tube - maintains nutrition when dysphagia is severe
• Multidisciplinary team care is essential

Key clinical pearl: The simultaneous presence of UMN signs (spasticity, hyperreflexia, Babinski sign) AND LMN signs (wasting, fasciculations, weakness) in the same body region, with preserved sensation and normal cognition, is the defining clinical hallmark of ALS.

• Goldman-Cecil Medicine, p. 4069-4070; Bradley & Daroff's Neurology; Robbins & Kumar Basic Pathology, p. 855-856

Multiple Sclerosis (MS)

1. Definition

• It is the most common demyelinating disorder and the leading cause of non-traumatic neurological disability in young adults
• Prevalence: ~1 per 1,000 individuals in the USA and Europe
• Age of onset: typically 20-40 years; rare before puberty or after 50 years
• Women affected twice as often as men (F:M = 2:1)
• Robbins & Kumar Basic Pathology, p. 852; Adams and Victor's Neurology 12E, p. 920

2. Aetiology

A. Genetic Factors

• HLA-DRB1*1501 allele - strongest genetic risk factor; each copy confers ~3-fold increased risk
• 15-fold higher risk if a first-degree relative has MS
• ~150-fold higher risk in monozygotic twins (but concordance is only ~30% - confirming that genes alone are insufficient)
• Additional susceptibility loci: IL-2 receptor (CD25) and IL-7 receptor genes - both involved in T cell regulation and tolerance
• Genome-wide association studies have identified >200 susceptibility loci

B. Environmental Triggers

C. Autoimmune Mechanism

• Robbins & Kumar Basic Pathology, p. 852; Adams and Victor's 12E, p. 920

3. Predisposing Factors

4. Pathogenesis

Step-by-Step Immune Mechanism

1. Peripheral sensitization: In a genetically susceptible individual (HLA-DRB1*1501), T cells reactive to myelin antigens escape thymic deletion (failure of central tolerance). Environmental triggers (likely EBV via molecular mimicry) activate these autoreactive T cells in the periphery.
2. BBB breakdown and CNS entry: Activated CD4+ Th1 and Th17 cells cross the blood-brain barrier (BBB) via upregulation of adhesion molecules (VLA-4/α4β1 integrin on T cells binds VCAM-1 on endothelium). This is the mechanism of action of natalizumab (anti-VLA-4).
3. Inflammatory cascade within CNS:
   • Th1 cells secrete IFN-γ → activate microglia and macrophages → myelin stripping
   • Th17 cells secrete IL-17 → recruit neutrophils and further leukocytes → amplify inflammation
   • CD8+ T cells directly kill oligodendrocytes (via MHC class I)
   • B cells and antibodies - play important roles; anti-myelin antibodies with complement activation (success of anti-CD20 therapy confirms B cell importance)
   • Activated macrophages and microglia engulf and destroy the myelin sheath
4. Demyelination: Myelin sheath is destroyed while axons are relatively spared initially. Demyelinated axons conduct impulses slowly or not at all → clinical deficits (relapse).
5. Oligodendrocyte response: Surviving oligodendrocyte precursors migrate into the plaque and attempt remyelination → incomplete recovery of function (remission). Shadow plaques represent partially remyelinated areas.
6. Axonal injury and neurodegeneration (progressive phase): With repeated attacks, axons themselves are damaged - swollen axons, axonal transection at plaque edges. Neurofilament light chain (NfL) released into CSF/blood is a biomarker of axonal injury. Progressive axonal loss drives irreversible disability independent of relapse activity (PIRA - Progression Independent of Relapse Activity).
7. Chronic inactive plaque: End-stage lesion - gliosis (astrocytic scar), minimal myelin, axonal loss, no inflammation.

Morphology of MS Plaques

• Discrete, slightly depressed, glassy, grey-tan lesions (plaques)
• Predilection sites: periventricular white matter (periventricular lesions - most characteristic), optic nerves/chiasm, brainstem, cerebellum, corpus callosum, cervical spinal cord
• Sharply defined borders ("punched-out" appearance)

• Abundant macrophages stuffed with myelin debris (ongoing demyelination)
• Perivascular lymphocytic cuffing (T cells, B cells)
• Lesions often centred on small veins (perivenular location)
• Axons relatively preserved but may be reduced

• Inflammation resolves
• Hypocellular - gliosis, astrocyte proliferation
• Little to no myelin; axonal loss
• Robbins & Kumar Basic Pathology, p. 852-854; Adams and Victor's 12E

5. Clinical Features and Signs

Clinical Types (Course)

Cardinal Clinical Features by Location

1. Optic Neuritis (25% as first manifestation)

• Subacute loss of vision in one eye over days
• Retrobulbar (orbital) pain on eye movement (characteristic)
• Central scotoma (cecocentral scotoma involving macula + blind spot)
• Afferent pupillary defect (Marcus Gunn pupil) - pupil dilates when light swings from the unaffected to the affected eye
• Dyschromatopsia (impaired colour vision, especially red-green)
• Uhthoff's phenomenon - temporary worsening of vision with heat/exercise (due to increased temperature impairing demyelinated axon conduction)
• Recovery: 87% recover to 20/25 visual acuity by 5 years

2. Spinal Cord (Most Common Site)

• Weakness (paraparesis or quadriparesis) - UMN pattern (spastic)
• Sensory disturbances - numbness, tingling, vibration loss, loss of proprioception
• Lhermitte's sign - brief electric shock-like sensation radiating down the spine and limbs on neck flexion (stretching the demyelinated cervical cord)
• Bladder dysfunction - urgency, frequency, hesitancy, incontinence; neurogenic bladder
• Bowel dysfunction - constipation; incontinence in advanced disease
• Sexual dysfunction - erectile dysfunction; loss of libido

3. Brainstem / Cerebellum

• Internuclear ophthalmoplegia (INO) - bilateral INO in a young adult is virtually pathognomonic of MS; caused by lesion in the medial longitudinal fasciculus (MLF); impaired adduction of one eye + nystagmus in the abducting eye
• Diplopia - VI nerve palsy, INO
• Nystagmus (horizontal, vertical, or pendular)
• Ataxia - cerebellar: gait ataxia, limb ataxia, intention tremor
• Dysarthria - scanning or explosive speech
• Vertigo and dysphagia (brainstem lesions)
• Facial numbness or weakness (trigeminal or facial nerve involvement)

4. Cerebral Hemispheres

• Cognitive impairment - ~40% of MS patients; executive dysfunction, memory impairment, attention, processing speed
• Fatigue - the most common symptom overall; out of proportion to disability; often debilitating
• Depression - lifetime prevalence ~50%; suicide rate 2-7x the general population
• Pseudobulbar affect (~10%)
• Headaches (more prevalent than general population)
• Rarely: seizures (~5%)

Key Symptoms Summary (MNEMONIC: "WOBUD" + Lhermitte + Uhthoff)

• Weakness (spastic paraparesis)
• Optic neuritis (visual loss + orbital pain)
• Bladder/bowel dysfunction
• Uhthoff's and Lhermitte's sign
• Double vision (INO, diplopia) + Dizziness (cerebellar)

Characteristic Signs on Examination

6. Diagnosis and Investigations

McDonald Criteria (2017) - Core Diagnostic Framework

• DIS: Lesions in ≥2 of 5 characteristic CNS regions (periventricular, cortical/juxtacortical, infratentorial, spinal cord, optic nerve)
• DIT: ≥2 attacks at different times, OR simultaneous presence of gadolinium-enhancing and non-enhancing T2 lesions on single MRI, OR appearance of new T2 or gadolinium-enhancing lesion on follow-up MRI, OR positive CSF (OCBs)

1. MRI Brain and Spine - Most Important Investigation

• T2/FLAIR sequences: Hyperintense (white) plaques
  • Periventricular lesions - "Dawson's fingers" - ovoid lesions perpendicular to ventricles along medullary veins (periventricular)
  • Cortical/juxtacortical, infratentorial (brainstem, cerebellum), spinal cord lesions
• T1 sequences with gadolinium: Enhancing lesions = active/acute plaques (BBB breakdown)
• T1 "black holes": Chronic axonal loss
• Spinal cord MRI: Cervical cord lesions (short segment, <2 vertebral levels in MS - distinguishes from NMO)

2. CSF Analysis (Lumbar Puncture)

• Oligoclonal bands (OCBs) - IgG bands present in CSF but NOT serum; positive in >85-90% of MS patients; highly supportive of diagnosis
• Elevated IgG index (>0.7)
• Elevated myelin basic protein (MBP) during acute attacks
• Cell count: mild lymphocytosis (5-50 cells/μL) during relapses; normal between attacks
• Normal or mildly elevated protein
• No albuminocytological dissociation (contrast with GBS)

3. Evoked Potentials

• Visual Evoked Potentials (VEPs): Prolonged P100 latency (>110 ms) - evidence of optic nerve demyelination; useful even if no visual symptoms (subclinical demyelination)
• Somatosensory Evoked Potentials (SSEPs): Detect subclinical spinal cord or cerebral lesions
• Brainstem Auditory Evoked Potentials (BAEPs): Detect brainstem plaques

4. Optical Coherence Tomography (OCT)

• Measures retinal nerve fibre layer (RNFL) thickness - atrophy indicates prior optic neuritis
• Increasingly used as a biomarker of neurodegeneration in MS

5. Blood Tests (To Exclude Mimics)

• Anti-AQP4 antibodies (anti-aquaporin-4 / NMO-IgG) - if neuromyelitis optica (NMO/NMOSD) is suspected (bilateral optic neuritis, long spinal cord lesions)
• Anti-MOG antibodies (myelin oligodendrocyte glycoprotein) - MOG antibody disease (another MS mimic)
• ANA, anti-dsDNA, ANCA (exclude SLE, vasculitis)
• Syphilis serology (VDRL/TPHA)
• B12, folate (subacute combined degeneration of cord)
• HIV, Lyme serology
• Chest X-ray / ACE level (sarcoidosis)

6. Disability Assessment

• Expanded Disability Status Scale (EDSS): Standard disability scale 0-10; EDSS 6.0 = requires walking aid; EDSS 8.0 = restricted to wheelchair; EDSS 10 = death due to MS

7. Complications

Prognosis

• Highly variable; MRI lesion load, early disability, and age of onset predict prognosis
• In the pre-treatment era, ~50% needed a walking aid within 15 years
• With modern highly effective disease-modifying therapies (DMTs): evolution to SPMS now <1%/year (vs 3%/year historically)
• Normal or near-normal lifespan with modern management (reduced by ~6-10 years in severe cases)

Key DMT Classes (Brief Reference)

• Interferons (IFN-β1a, IFN-β1b) and glatiramer acetate - first-line immunomodulators
• Natalizumab (anti-VLA-4) - blocks T cell CNS entry
• Ocrelizumab (anti-CD20) - depletes B cells; approved for both RRMS and PPMS
• Cladribine, alemtuzumab, HSCT - high-efficacy lymphocyte-depleting therapies
• Relapses treated with IV methylprednisolone (shortens duration but does not change final recovery)

Diagnostic pearl: In a young woman presenting with optic neuritis, bilateral INO, Lhermitte's sign, or a combination of sensory + visual + bladder symptoms separated in time and anatomical location - MS must be the primary diagnosis until proven otherwise.

• Robbins & Kumar Basic Pathology, p. 852-854; Adams and Victor's Principles of Neurology 12E, p. 920-930; Bradley & Daroff's Neurology; Harrison's 22E