MRI Signs of Meningitis

1. Direct Signs

Leptomeningeal Enhancement (post-contrast T1 / CE-FLAIR)

• Pyogenic/viral meningitis: thin, smooth, diffuse enhancement
• TB/fungal/carcinomatous meningitis: thick, nodular, predominantly basal enhancement
• Best detected on post-contrast FLAIR rather than standard post-contrast T1, because CE-FLAIR suppresses normal vascular enhancement and makes pathological leptomeningeal enhancement more conspicuous.

FLAIR Sulcal Hyperintensity (pre-contrast)

DWI Subarachnoid High Signal

2. MRI Sequences Summary

3. Complications - MRI Signs

4. Etiology-Specific Patterns

Bacterial (Pyogenic)

• Usually normal in uncomplicated cases
• When abnormal: thin smooth leptomeningeal enhancement, sulcal FLAIR signal
• Complications (empyema, abscess, ventriculitis) show restricted diffusion on DWI
• Infarcts in 30% of neonates - Grainger & Allison's Diagnostic Radiology

Tuberculous Meningitis

• Basal meningeal enhancement (interpeduncular cistern, middle cerebral artery cisterns) - hallmark
• Communicating hydrocephalus in 50% of adults, 85% of children
• Perforator territory infarcts (basal ganglia, internal capsule, brainstem)
• Tuberculomas: T1 low, T2 low (caseated) with rim or target-sign enhancement
• MRI superior to CT for basal enhancement, hydrocephalus, and infarcts

Fungal (Cryptococcus)

• Often unremarkable on MRI
• Gelatinous pseudocysts along Virchow-Robin spaces (basal ganglia, midbrain) - isointense to CSF, bilateral, symmetric
• Basal leptomeningeal enhancement when present
• Cryptococcomas = granulomas in basal ganglia, similar to tuberculomas

Carcinomatous / Chronic Meningitis

• Thick nodular leptomeningeal enhancement, often in basal cisterns
• More irregular vs. the thin smooth enhancement of acute infection
• Cranial nerve enhancement (follow nerves for thickening/signal)

Key Practical Points

1. CE-FLAIR > CE-T1 for detecting leptomeningeal enhancement (suppresses background vascular signal)
2. Normal MRI does not exclude meningitis - LP is required
3. MRI before LP is indicated when: focal neurological signs, papilloedema, GCS <12, uncontrolled seizures
4. DWI restriction in subarachnoid spaces = poor prognosis marker
5. Basal enhancement + hydrocephalus + perforator infarcts = TB until proven otherwise

Cerebellar Signs in Tonsillar Ectopia (Chiari I Malformation)

Overview

1. Compression of the cerebellar tonsils, caudal brainstem, and upper cervical cord at the foramen magnum
2. Disruption of CSF flow dynamics at the craniocervical junction
3. Syringomyelia from pressure-wave transmission into the central canal of the cord (in ~50-70% of symptomatic cases)

Age-Adjusted Normal Limits for Tonsillar Position

Cerebellar and Posterior Fossa Signs

1. Headache - "Chiari Headache"

• Suboccipital, pressing, continuous (waxing and waning, not episodic)
• May radiate behind the eyes or to the vertex
• Almost never hemicranial
• Triggered or worsened by Valsalva maneuvers - coughing, sneezing, laughing, straining, bearing down
• Exacerbations can be explosive rather than throbbing

2. Cerebellar Ataxia

• Gait ataxia with difficulty in tandem standing and walking
• Most typical finding on neurological exam: a vestibular-generated dysequilibrium
• Limb ataxia may be present but is less prominent than gait ataxia
• Favored by Chiari over syrinx as the cause: when ataxia is present alongside nystagmus - Adams & Victor's Principles of Neurology, 12th Ed.

3. Nystagmus - The Most Specific Ocular Sign

Key caveat: Despite DBN being the "classic" finding, it is rarely seen even with tonsillar herniation as striking as 20 mm. Nystagmus is difficult to appreciate even with Fresnel lens examination - Bradley & Daroff's Neurology, 12th Ed.

4. Other Ocular Motor Abnormalities

• Impaired smooth pursuit (especially downward gaze)
• Impaired VOR cancellation
• Saccadic dysmetria (hypermetric or hypometric saccades)
• Skew deviation - accentuated or alternating on lateral gaze
• Internuclear ophthalmoplegia (INO)
• Square-wave jerks

5. Oscillopsia and Vestibular Symptoms

• Oscillopsia brought on or accentuated by head movements
• Dizziness and vertigo (75.8% prevalence in symptomatic CM-I vs 17-18% in tonsillar ectopia without CM-I criteria)
• Cervical pain with head movement

Long Tract and Brainstem Signs (When Medulla Descends)

Syringomyelia Overlay (CM-I Associated)

• Cape-like dissociated sensory loss (pain and temperature lost, light touch preserved) over shoulders and arms
• Wasting and weakness of the hands/upper limbs
• Painless burns or injuries to the hands (classic presentation)
• Segmental areflexia in upper limbs with hyperreflexia below

Special Points

• Children <3 years: vomiting and gastric reflux may be the sole manifestations
• Pediatric presentation: oropharyngeal dysfunction, scoliosis, failure to thrive
• Neurological exam is often completely normal - even with significant herniation
• Symptoms are typically exacerbated by any action that increases intrathoracic or intraabdominal pressure (Valsalva)
• At least a quarter of symptomatic patients first develop symptoms following minor head or neck injury

MRI Evaluation

• Best sequence: T2-weighted sagittal MRI of brain + cervical spine
• Assesses: tonsil position, posterior fossa volume, syrinx, brainstem compression
• Phase-contrast (cine) MRI: evaluates CSF flow at foramen magnum - pulsatile systolic tonsillar descent and obstruction of CSF flow are positive findings predictive of surgical response
• Dynamic MRI useful when clinical presentation is equivocal

Clinical Tests for Cerebellar Signs

Mnemonic: DANISH

Domain 1: Gait and Stance

Normal Gait Observation

• Variable stride length
• Veering to one side (toward the side of the lesion in unilateral disease)
• Wide-based gait - compensatory in moderate-severe ataxia
• Staggering, inability to maintain a straight line

Tandem (Heel-to-Toe) Walking

Single-leg Stance / Hopping

Detecting subtle difficulty: observe patients running or walking up/down stairs - these stress the system more than level walking - Bradley & Daroff's Neurology in Clinical Practice

Domain 2: Stance and Truncal Stability

Romberg's Test

• Stand with feet together, arms by sides
• First with eyes open, then eyes closed
• Positive Romberg = patient falls when eyes are closed but not open → implies proprioceptive or vestibular deficit (not pure cerebellum)
• Cerebellar lesion: patient is unsteady with both eyes open and closed (the cerebellum cannot integrate the remaining senses - it is a processing, not sensing, problem)

Balance requires input from proprioception, vestibular system, and vision. At least 2 are needed. Romberg removes vision. If the patient falls only with eyes closed, the cerebellar integration is intact but one of the other two systems is deficient - Shambaugh Surgery of the Ear

Sharpened (Tandem) Romberg

Sitting Without Back Support

Domain 3: Upper Limb (Hand) Tests

1. Finger-Nose-Finger Test (FNF)

• Their own nose
• The examiner's outstretched index finger

• Intention tremor - oscillation that increases as the target is approached (pathognomonic of cerebellar disease)
• Past-pointing (dysmetria) - over- or undershooting the target
• Decomposition of movement - jerky, broken up action
• Perform with eyes open and then eyes closed (closed removes visual correction and exaggerates cerebellar dysmetria; worsening = cerebellar; remaining the same = proprioceptive problem)

2. Finger Chase Test

3. Dysdiadochokinesia Test (Rapid Alternating Movements)

• Rate - normal is rapid and regular
• Rhythm - should be uniform
• Amplitude - should be consistent

4. Rebound Test (Stewart-Holmes Sign)

5. Hyperdysmetria / Overshoot on Resistance

Domain 4: Lower Limb Tests

Heel-Shin Test

• Patient lies supine
• Lifts one leg, places the heel on the opposite knee, then slides it down the shin to the ankle
• Repeat several times, then with the other leg

Domain 5: Speech

Scanning/Staccato Speech

• Slow with irregular force and rhythm
• Unnecessary hesitations between words
• Words broken into separate syllables (scanning or syllabic speech)
• May sound explosive or slurred
• Distinct from dysarthria of upper/lower motor neuron origin

Domain 6: Eye Movement Examination

SARA Scale (Formal Clinical Rating)

Summary: Localizing Value

A key principle: cerebellar signs are ipsilateral to the lesion (unlike upper motor neuron signs which cross). The patient veers toward the side of the lesion. - Bradley & Daroff's Neurology in Clinical Practice

Chiari Malformation

Historical Background

Classification

Chiari I Malformation - Deep Dive

Epidemiology

• Prevalence ~0.1-1% of the general population (Goldman-Cecil: ~1% on cranial MRI)
• Women affected 3x more often than men
• Hereditary tendency - transmissibility rate approaching 12%
• Majority of patients are asymptomatic; symptoms usually emerge in adolescence or early adulthood

Pathophysiology - Five Mechanisms of Tonsillar Herniation

MRI Findings

Chiari I - T2 sagittal MRI showing low-lying tonsils (8 mm below foramen magnum) and syringomyelia

Key MRI Features

• Best sequence: T2-weighted sagittal brain + cervical spine
• Tonsil descent measured from McRae line (basion to opisthion)
• Tonsils appear peg-shaped (pointed, not rounded) in CM-I
• Crowded foramen magnum; obliteration of cisterna magna
• Cervical syrinx (central T2-bright cavity in cord)
• Phase-contrast (cine) MRI: obstruction of CSF flow at foramen magnum is a positive finding predicting surgical response

Age-Adjusted Normal Limits

Clinical Features (CM-I)

Symptom Frequency (n=364 patients, Milhorat et al. 1999)

The "Chiari Headache"

• Suboccipital, pressing, continuous (not episodic, not hemicranial)
• Radiates behind eyes or to vertex
• Exacerbated by Valsalva: coughing, sneezing, laughing, straining, bearing down
• Exacerbations can be explosive - not throbbing
• May respond to carbonic anhydrase inhibitors (topiramate, acetazolamide)
• Does NOT respond to triptans or beta-blockers

Neurological Syndromes in CM-I (Adams & Victor)

1. Raised ICP - headache
2. Progressive cerebellar ataxia
3. Progressive spastic quadriparesis (long tract compression)
4. Downbeating nystagmus
5. Cervical syringomyelia syndrome - segmental amyotrophy + dissociated sensory loss (pain/temperature lost, light touch preserved) in hands/arms

Important mimics: multiple sclerosis, foramen magnum tumor. Onset may be acute after neck hyperextension (dental work, hairdressing, chiropractic manipulation).

Children

• <3 years: vomiting and gastric reflux may be the sole symptoms
• Older children: oropharyngeal dysfunction, scoliosis, failure to thrive

Chiari II Malformation

• Nearly always associated with myelomeningocele (lumbosacral)
• Involves herniation of vermis, tonsils, fourth ventricle, and medulla (brainstem descent)
• Midbrain "beaking" on sagittal MRI (posterior midbrain elongation)
• Foramen magnum is enlarged (unlike CM-I where it is constricted)
• Hydrocephalus is invariably associated

CM-II Clinical Features

• Lower cranial nerve abnormalities: laryngeal stridor, tongue fasciculations, sternomastoid paralysis (head lag on pull-to-sit), facial weakness, deafness, bilateral abducens palsies
• Progressive hydrocephalus
• Cerebellar signs emerge later in childhood/adolescence
• Seizures, cognitive delay, paraplegia, sphincter dysfunction (from associated myelomeningocele)

Posterior Cranial Fossa Morphology Comparison

Management

CM-I

• Headache and neck pain respond best to surgery
• Ataxia and nystagmus tend to persist after decompression
• Syrinx usually resolves or stabilizes after PFD

CM-II

• Surgical repair of myelomeningocele
• VP or ventriculoperitoneal shunting for hydrocephalus
• Bladder management (intermittent catheterization)
• Prognosis depends on severity of brain abnormalities

Meningitis vs Encephalitis: Clinical Signs and Symptoms

Conceptual Distinction

"Encephalitis is inflammation of the brain parenchyma, characterized by neurologic dysfunction early in the course of illness." - Frameworks for Internal Medicine

Meningitis - Clinical Features

Core Triad (present together in only ~44% of adults)

1. Fever
2. Headache - severe, generalized (87% of bacterial cases)
3. Neck stiffness (nuchal rigidity) (83% of bacterial cases)

Symptoms (Bacterial Meningitis - 696 cases, van de Beek et al.)

Classic Meningeal Signs (Signs of Meningeal Irritation)

1. Nuchal Rigidity

• Resistance to passive neck flexion (forward bending)
• Specific to meningitis - resistance is predominantly on forward flexion only
• Rotation from side to side is preserved (helps distinguish from cervical spondylosis, which resists movement in all directions)
• Disappears in deep coma
• Stiffness in the first few degrees of flexion is more specific; stiffness in the latter part is more sensitive but less specific - Adams & Victor

2. Kernig's Sign

• Hip flexed to 90°, then attempt to extend the knee
• Positive: inability/pain on extending the leg (hamstring spasm due to nerve root irritation)
• Sensitivity: ~30% for bacterial meningitis

3. Brudzinski's Sign

• Passive forward flexion of the neck causes involuntary flexion of the hips and knees
• Part of a "flexor protective reflex"
• Sensitivity: ~30% for bacterial meningitis

Both Kernig and Brudzinski signs have low sensitivity (~30%) individually but high specificity. Their absence does not exclude meningitis - Goldman-Cecil Medicine

4. Jolt Accentuation

• Horizontal rotation of the head at 2-3 Hz worsens the headache
• Sensitivity ~97%, specificity lower - useful screening sign

Other Signs by Etiology

Complications Producing Additional Signs

• Cranial nerve palsies (III, IV, VI, VII) - 5-10% of adults
• Seizures (focal or generalized) - 20-30%
• Papilledema - raised ICP
• Sensorineural deafness (CN VIII, cochlear spread)
• Altered mental status progressing to stupor and coma as disease advances

Encephalitis - Clinical Features

Diagnostic Criteria (IDSA/International Encephalitis Consortium)

• Fever (>38°C) within 72 hours
• New-onset seizures
• New focal neurological findings
• CSF pleocytosis (>5 WBC/µL)
• Abnormal neuroimaging (new parenchymal changes)
• Abnormal EEG consistent with encephalitis

Core Clinical Features

Side-by-Side Comparison

CSF Comparison

Key Distinguishing Principle

Thyroid Eye Signs (Thyroid Eye Disease / Graves' Ophthalmopathy)

Background

Pathophysiology in Brief

The Complete List of Named (Eponymous) Signs

Eyelid Signs (Upper Lid)

Eyelid Signs (Lower Lid)

Conjunctival Signs

Extraocular Muscle Signs

Pupillary Signs

Generalized / Other Signs

The Four Clinical Domains (Critical Sequelae)

1. Eyelid Disorders

• Lid retraction (Dalrymple - #1 most common sign)
• Lid lag (Von Graefe)
• Lagophthalmos - inability to fully close the eyes (exposure risk)
• Staring / wide-eyed appearance
• Reduced blink rate (Stellwag)
• Periorbital edema

2. Ocular Surface Disorders (Active Phase)

• Conjunctival injection (Goldzeiher)
• Chemosis (conjunctival edema)
• Exposure keratopathy - from lagophthalmos and incomplete blinking
• Gritty sensation, photophobia, tearing, dry eye
• Corneal ulceration (sight-threatening)

3. Motility Disorders / Extraocular Muscle Disease

• Restrictive myopathy - "tight" not "weak" muscle (fibrosis)
• Muscle involvement order - mnemonic: "I'M SO" (in decreasing frequency):
  • I - Inferior rectus (most common → hypotropia, elevation deficit)
  • M - Medial rectus (→ esotropia, abduction deficit)
  • S - Superior rectus
  • O - Obliques (least common)
  • Lateral rectus is rarely affected; XT in TED should raise suspicion for co-existing myasthenia gravis
• Vertical diplopia (asymmetric IR involvement) is the most common presentation
• Diplopia often worse in the morning and improves through the day - Localization in Clinical Neurology

4. Optic Neuropathy (Sight-Threatening)

• Caused by compression of optic nerve at orbital apex by enlarged extraocular muscles
• Signs: ↓ visual acuity, ↓ colour vision, RAPD (relative afferent pupillary defect), visual field defect
• Proptosis alone can stretch the optic nerve
• Rare but serious - present in 3-5% of TED cases

Proptosis (Exophthalmos)

• Present in up to one-third of thyroid patients
• Purely axial (straight forward) - distinguishes from other orbital masses
• Measured with Hertel exophthalmometer (normal <21 mm; asymmetry >2 mm significant)
• Increased resistance to retropulsion on pressing the globe back
• Most common cause of bilateral proptosis in adults

Disease Phases (Rundle Curve)

Clinical Activity Score (CAS) - 7-Point Scale

1. Spontaneous orbital pain
2. Gaze-evoked orbital pain
3. Eyelid swelling (due to active TED)
4. Eyelid erythema
5. Conjunctival redness
6. Chemosis
7. Inflammation of caruncle or plica

NOSPECS Classification

Urgent Referral Criteria

• Rapid deterioration in visual acuity
• Visual acuity <6/18
• Decreased colour vision
• RAPD
• Corneal ulceration
• Ocular nerve palsies
• Unacceptable cosmetic progression

Thalassemia

Overview

1. Decreased red cell production (ineffective erythropoiesis)
2. Decreased red cell lifespan (hemolysis from unpaired globin chain precipitation)

Genetics and Molecular Basis

β-Thalassemia Mutations (3 classes)

1. Splicing mutations - most common cause of β⁺; create ectopic splice sites in introns
2. Promoter region mutations - reduce transcription 75-80%; cause β⁺
3. Chain terminator mutations (nonsense / frameshift) - most common cause of β⁰; no functional β-globin produced - Robbins & Cotran Pathologic Basis of Disease

Pathogenesis of β-Thalassemia

• Reduced β-globin → relative excess of α-globin
• Unpaired α-chains are insoluble - precipitate within erythroblasts
• → Ineffective erythropoiesis (most erythroblasts die in marrow)
• → Extravascular hemolysis (aggregate-containing cells destroyed in spleen)
• → Severe anemia → tissue hypoxia → EPO ↑ → marrow expansion → skeletal deformities
• Erythroferrone (from expanding erythroid mass) suppresses hepcidin → ↑ gut iron absorption → iron overload
• Plus transfusions add further iron → secondary hemochromatosis

β-Thalassemia - Clinical Syndromes

β-Thalassemia Minor (Trait)

• Genotype: β⁺/β or β⁰/β (heterozygous)
• Mild microcytic, hypochromic anemia - usually asymptomatic
• Splenomegaly may be present
• Blood smear: microcytosis, hypochromia, basophilic stippling
• Elevated HbA₂ (4-6%) - diagnostic hallmark
• Often detected incidentally on CBC evaluation

β-Thalassemia Intermedia

• Genotype: β⁺/β⁺, β⁺/β⁰, or unusual heterozygous forms
• Moderate anemia (Hb usually >7 g/dL), does not always require regular transfusions
• Splenomegaly, bone marrow hyperplasia, elevated HbF
• Iron overload develops but is less extreme than major
• Variable transfusion requirements

β-Thalassemia Major (Cooley's Anemia)

• Genotype: β⁰/β⁰, β⁺/β⁰, or β⁺/β⁺ (homozygous/compound heterozygous)
• Presents at 6-9 months of age when HbF → HbA switch occurs
• Hb 3-6 g/dL if untransfused

Clinical Features

α-Thalassemia - Clinical Syndromes

Key Note on Genotypes

• Southeast Asian carriers often have both deletions in cis (--/αα) → offspring can inherit --/-- → Hb Bart's is possible
• Other populations: deletions in trans (α-/α-) → --/-- is not possible in offspring

HbH Disease

• β₄ (HbH) tetramers are unstable → Heinz bodies → splenic removal
• Chronic hypochromic microcytic anemia with hemolytic crises on oxidant stress
• Avoid oxidant drugs (primaquine, sulfonamides, nitrofurantoin, dapsone, naphthalene)
• Unlike β-thalassemia: hemolysis > ineffective erythropoiesis, but bone marrow expansion can still cause deformities

Blood Film Findings

Diagnosis

Key distinction: Iron deficiency anemia vs β-thalassemia trait - both cause microcytic hypochromic anemia. Iron deficiency: ↓ ferritin, ↑ TIBC, normal HbA₂. β-thalassemia trait: normal iron stores, elevated HbA₂.

Management

β-Thalassemia Major

β-Thalassemia Minor

• No treatment needed
• Genetic counseling for at-risk couples
• Avoid unnecessary iron supplementation

α-Thalassemia (HbH disease)

• Supportive - avoid oxidant drugs and infections
• Folic acid supplementation
• Transfusions during hemolytic crises

Complications of Iron Overload (Secondary Hemochromatosis)

• Heart → dilated cardiomyopathy, arrhythmias (leading cause of death)
• Liver → cirrhosis, hepatocellular carcinoma
• Pancreas → diabetes mellitus ("bronze diabetes")
• Pituitary/gonads → growth retardation, delayed puberty, infertility
• Thyroid/parathyroid → hypothyroidism, hypoparathyroidism
• Skin → bronze discoloration

Prognosis

• Untransfused β-thalassemia major: death in early childhood
• With transfusion + chelation: survival into 3rd decade common; overall outlook remains guarded
• With HSCT or gene therapy: potentially curative
• β-thalassemia minor: normal life expectancy; no treatment needed

Sick Sinus Syndrome (Sinus Node Dysfunction)

Definition

Arrhythmias Encompassed by SSS

ECG Images

SA Exit Block - Types

Epidemiology

• Predominately affects the elderly (1 in 600 cardiac patients >65 years)
• Incidence increases with age; median age ~68 years at diagnosis
• No significant sex predilection
• Familial forms exist (autosomal dominant with variable penetrance, or recessive)

Causes

Intrinsic Causes (Direct SA Node Disease)

Extrinsic Causes (Reversible - Must Exclude First)

Genetic Basis (Familial SSS)

Pathology

• Fibrosis and fatty infiltration of the SA node
• Nodal-atrial discontinuity
• Inflammatory/degenerative changes in peri-nodal nerves and ganglia
• Occlusion of the SA nodal artery
• Process often extends to the AV node and His-Purkinje system (hence associated AV block)

Clinical Features

Symptoms (from end-organ hypoperfusion)

Important: Symptoms must correlate with ECG findings. ECG abnormalities without symptoms are not sufficient for SSS diagnosis. Bradycardia during sleep or in athletes may be physiologic.

Physical Examination

• Bradycardia (may be irregular if with AF)
• Irregular pulse during tachy-brady episodes
• Signs of heart failure if severe
• Often normal between episodes

Diagnosis

Management

1. Treat Reversible Causes First

• Withdraw offending drugs (beta-blockers, CCBs, digoxin, antiarrhythmics)
• Correct electrolyte abnormalities, hypothyroidism
• Treat sleep apnea

2. Permanent Pacemaker - Definitive Treatment

• Symptomatic sinus bradycardia
• Symptomatic sinus pauses
• Symptomatic chronotropic incompetence
• Tachy-brady syndrome (pacemaker allows safe use of rate-controlling drugs for tachyarrhythmia)

Key principle: Atrial pacing is preferred over ventricular pacing in SSS - reduces AF risk and preserves AV synchrony. Dual-chamber pacing is recommended because of the ~15-20% rate of associated AV block in SND - Braunwald's Heart Disease

3. Anticoagulation

• Patients with AF component are at increased stroke risk → anticoagulate per CHA₂DS₂-VASc score

4. Rate Control in Tachy-Brady

• Pacemaker must be implanted before starting rate-control drugs (beta-blockers, CCBs) to prevent dangerous pauses

Prognosis

• SSS is slowly progressive over time
• Underlying cardiac disease, not SSS itself, drives mortality
• Risk of sudden cardiac death is low with appropriate pacing
• AF develops in up to 50% over time - significant stroke risk
• Pacemaker implantation controls symptoms but does not alter the natural history of the underlying disease