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Takayasu Arteritis: Follow-up Investigations

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1. Clinical Assessment

• Blood pressure (both arms) — detect new asymmetry (>10 mmHg difference) suggesting progressive subclavian or aortic disease
• Peripheral pulse examination — loss or reduction of previously palpable pulses indicates disease progression
• Auscultation for bruits — over carotid, subclavian, renal, and aortic territories
• Symptoms review — claudication (upper > lower limb), carotidynia, headache, visual symptoms, renovascular hypertension, chest/abdominal pain

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2. Laboratory Investigations

Key point: ESR and CRP are unreliable markers of vascular disease activity. Normal inflammatory markers do not exclude active arteritis, and imaging remains essential for relapse detection. — Brenner and Rector's The Kidney; Current Surgical Therapy 14e

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3. Imaging Investigations

3a. MRI / MR Angiography (MRA) — Preferred modality for TA

• MRI is the preferred imaging modality per EULAR 2023 recommendations for TA
• Demonstrates wall oedema (active inflammation), wall thickening, gadolinium enhancement, and structural changes (stenosis/aneurysm)
• MRA provides luminography — identifies stenoses, occlusions, aneurysms, and collaterals
• No ionising radiation — preferred for serial follow-up studies (especially in young women)
• Limitation: Wall changes do not always correlate with disease activity; gadolinium avoidance needed in renal impairment

3b. CT Angiography (CTA)

• High-resolution assessment of vessel wall thickening, calcification, stenosis, aneurysms
• Preferred when MRI is contraindicated or unavailable
• Limitation: Radiation exposure — a concern given repeated imaging in young patients
• May demonstrate mural thickening with enhancement during active inflammation

3c. ¹⁸F-FDG PET/CT or PET/MRI

• Detects metabolically active vascular inflammation even before structural changes appear
• Particularly useful to differentiate active ("hot") from burned-out ("cold") disease
• Used for evaluating suspected relapse and assessing response to therapy
• Limitation: Not validated as a reliable measure of disease activity in follow-up; FDG uptake may reflect chronic remodelling; not widely available; radiation exposure

3d. Vascular Ultrasound (Duplex/Colour Doppler)

• Assesses carotid, subclavian, axillary, and renal arteries for wall thickening, flow velocity (stenosis), and intima-media thickness
• Useful at bedside and in serial monitoring — no radiation
• Detects the "macaroni sign" (circumferential wall thickening) in large vessels
• Limited to accessible vessels; operator-dependent; cannot image thoracic aorta directly

3e. Conventional (Catheter) Angiography

• Previously the gold standard; now largely replaced by CTA/MRA
• Provides luminography only — no vessel wall information
• Reserved for pre-intervention planning (angioplasty, stenting, bypass)
• Noninvasive imaging is preferred per ACR/VF 2021 and EULAR guidelines

Summary: Imaging Choice by Purpose

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4. Echocardiography

• Assess for aortic root dilation and aortic regurgitation (AR) — occurs in ~18% of TA patients due to ascending aortic inflammation
• AR requiring valve replacement affects approximately 15% of patients
• Also evaluates left ventricular function, coronary artery origins (coronary arteritis), pulmonary arterial pressure (pulmonary artery involvement in up to 50%)
• Annual or biennial echocardiography is recommended in patients with aortic involvement

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5. Blood Pressure Monitoring

• Serial bilateral arm BP measurement at every visit
• Ambulatory blood pressure monitoring (ABPM) for accurate assessment where subclavian/axillary disease affects peripheral readings
• Renal artery stenosis is a common cause of renovascular hypertension — renal duplex Doppler or CTA/MRA of renal arteries if BP is difficult to control

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6. Ophthalmologic Review

• Indicated in patients with carotid/vertebral involvement or symptoms
• Fundoscopy for hypertensive retinopathy, retinal vein/artery occlusion, optic atrophy
• Visual field assessment if visual symptoms occur

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7. ACR/VF 2021 Recommendations for Monitoring (TA in Remission)

• Strong recommendation: Long-term clinical monitoring over no monitoring in patients in apparent remission
• Inflammatory markers (ESR/CRP) to assist monitoring, acknowledging limitations
• Noninvasive imaging over catheter angiography
• In remission with asymptomatic elevation of inflammatory markers: increase monitoring frequency rather than automatically escalating immunosuppression
• In remission with new vascular inflammation on imaging (new stenosis or wall thickening): conditionally recommend treating with immunosuppression

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8. EULAR 2023 Imaging Recommendations (Relevant to TA Follow-up)

• MRI is the preferred imaging modality for TA (both diagnosis and follow-up)
• FDG-PET, CT, or ultrasound are acceptable alternatives
• Imaging not routinely recommended for follow-up — use when relapse is suspected or inflammatory markers are unreliable
• MR-angiography, CT-angiography, or ultrasound for long-term structural damage monitoring at sites of prior vascular inflammation

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Summary Table: Follow-up Investigations in TA

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Pelvic Inflammatory Disease (PID)

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Aetiology

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Risk Factors

• Age <25 years; sexually active
• Multiple or new sexual partners
• Previous PID or STI history
• Bacterial vaginosis
• Recent IUD insertion, D&C, TOP, hysterosalpingography
• Vaginal douching
• Menstruation (facilitates ascending infection)
• Protective: oral contraceptive pills, tubal sterilisation

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Clinical Spectrum

Endometritis (milder)

• Less severe tenderness; fewer constitutional symptoms
• Lower risk of subsequent tubal occlusion/infertility than salpingitis

Salpingitis (classic PID)

• Bilateral lower abdominal/pelvic pain — dull or aching, usually <3 weeks
• Abnormal vaginal discharge (mucopurulent cervicitis in majority)
• Abnormal uterine bleeding (~40%)
• Dysuria (~20%)
• Nausea, vomiting if peritonitis develops
• Examination: cervical motion tenderness (CMT), uterine tenderness, adnexal tenderness ± adnexal mass (in ~50%)
• Fever >38°C in only ~one-third

Perihepatitis (Fitz-Hugh–Curtis Syndrome)

• Right upper quadrant pleuritic pain ± tenderness in 3–10% of cases
• Can overshadow pelvic symptoms → mistaken for cholecystitis
• LFTs and RUQ ultrasound are nearly always normal
• Laparoscopy shows "violin-string" adhesions between liver capsule and peritoneum

Tubo-Ovarian Abscess (TOA)

• Severe illness, high fever, significant systemic toxicity
• Palpable adnexal mass
• Indication for hospitalisation and IV therapy

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Diagnosis

Minimum Diagnostic Criteria (CDC)

1. Cervical motion tenderness
2. Uterine tenderness
3. Adnexal tenderness

Additional Criteria (increase specificity)

• Temperature >38°C
• Mucopurulent cervical/vaginal discharge
• PMNs on wet prep of vaginal secretions (>30/HPF in cervical mucus)
• Elevated ESR (>15 mm/h — present in 75% with salpingitis) or elevated CRP
• WBC >10,000/µL (elevated in ~60%)
• Lab documentation of N. gonorrhoeae or C. trachomatis (endocervical or urine NAAT)

Laparoscopic confirmation

• Confirms salpingitis in ~60% of clinically suspected cases
• ~10–20% have endometritis alone; ~20–30% have an alternative diagnosis
• Required when diagnosis is uncertain, unilateral presentation, or failure to respond to therapy

Endometrial biopsy

• Histological endometritis (plasma cell infiltration) supports diagnosis
• Provides specimens for M. tuberculosis culture if suspected

Pregnancy test (β-hCG)

• Mandatory before diagnosing PID — exclude ectopic pregnancy

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Investigations

Microbiological

• High vaginal swab — microscopy (WBCs, clue cells, Gram stain)
• Endocervical NAAT — N. gonorrhoeae and C. trachomatis (recommended; negative result does NOT exclude PID)
• M. genitalium NAAT — increasingly recommended given its treatment implications (requires moxifloxacin if macrolide-resistant)
• Blood cultures if severe systemic illness or TOA suspected

Haematological/Biochemical

• FBC — leukocytosis
• ESR, CRP — elevated in majority; useful to monitor response
• β-hCG — mandatory to exclude ectopic pregnancy
• LFTs — near-normal in Fitz-Hugh-Curtis (helps distinguish from cholecystitis)
• HIV testing — HIV increases severity of salpingitis and risk of TOA

Imaging

• Normal in mild/early PID (does not exclude diagnosis)
• Thickened, fluid-filled fallopian tubes (club-shaped) = pyosalpinx
• Hydrosalpinx (chronic): tubular, folded, well-defined echogenic wall with short linear intraluminal echoes
• Enlarged, cystic ovaries = oophoritis
• Complex multilocular adnexal mass with debris = tubo-ovarian abscess
• Free pelvic fluid
• Colour Doppler distinguishes hydrosalpinx from pelvic varices

• Best for evaluating extent of disease and complications (especially pre-drainage planning)
• Findings: thickened uterosacral ligaments, haziness/stranding of pelvic fat, bulky uterus with abnormal endometrial enhancement, thickened fallopian tubes (pyosalpinx), complex pelvic abscess
• Gas in abscess cavity suggests gas-forming organisms or bowel fistula
• Free fluid adjacent to liver on CT → Fitz-Hugh-Curtis

• Highest soft-tissue resolution; best for complex or atypical cases
• Demonstrates: tubal wall thickening, intratubal fluid, increased tubal diameter (salpingitis); complex adnexal collections (TOA)
• Useful when ultrasound is inconclusive and patient is not pregnant
• Also identifies alternative pathology (endometriosis, ovarian torsion, etc.)

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Management

Indications for Hospitalisation and IV Therapy

1. Diagnosis uncertain; cannot exclude surgical emergency (appendicitis, ectopic)
2. Pregnancy
3. Pelvic/tubo-ovarian abscess suspected
4. Severe illness, vomiting precluding oral therapy
5. HIV infection
6. Failure of outpatient therapy (no improvement at 72-hour review)
7. Unable to follow or tolerate oral regimen
8. Some experts hospitalise all adolescents

Antibiotic Regimens (CDC 2021 / Harrison's 22e)

• Cefotetan 2 g IV q12h or Cefoxitin 2 g IV q6h
• + Doxycycline 100 mg IV/PO q12h
• Continue IV until 48h after clinical improvement → switch to oral doxycycline ± metronidazole to complete 14 days

• Clindamycin 900 mg IV q8h
• + Gentamicin loading dose 2 mg/kg IV, then 1.5 mg/kg q8h
• After improvement → clindamycin 450 mg PO QDS or doxycycline 100 mg PO BD to complete 14 days

M. genitalium

• If NAAT positive, add moxifloxacin 400 mg PO OD × 14 days (if macrolide-resistant or macrolide treatment fails)

IUD Management

• No routine removal required; retain unless no clinical improvement within 48–72 hours of antibiotics

Partner Notification and Treatment

• All sexual partners within the preceding 60 days must be traced and offered testing/treatment for N. gonorrhoeae and C. trachomatis

Follow-up

• 72-hour clinical review mandatory in all outpatients — assess response to treatment
• Persistent or worsening symptoms → hospitalise, reassess imaging (TVUS/CT), consider laparoscopy
• Test of cure for N. gonorrhoeae and C. trachomatis at 2 weeks
• Counsel on long-term sequelae (see below)

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Complications and Sequelae

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Differential Diagnosis

• Ectopic pregnancy (must exclude)
• Acute appendicitis
• Ovarian cyst complication (torsion, rupture)
• Endometriosis
• Urinary tract infection
• Irritable bowel syndrome / other GI disorders

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Bacterial Meningitis

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Epidemiology

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Aetiology by Age Group

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Pathophysiology

1. Nasopharyngeal colonisation → mucosal invasion → bacteraemia → seeding of the meninges
2. Bacterial cell-wall components (LPS, teichoic acid, peptidoglycan) stimulate microglia, astrocytes, and endothelial cells to release TNF-α, IL-1β, and other cytokines within 1–2 h of inoculation
3. Cytokines increase blood-brain barrier permeability → vasogenic oedema; leukocyte migration → cytotoxic oedema
4. Subarachnoid exudate obstructs CSF flow → communicating/obstructive hydrocephalus → interstitial oedema
5. Vasculitis of the large arteries at the base and cortical veins → ischemia, infarction, venous sinus thrombosis
6. Combined oedema types → raised ICP → herniation

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Clinical Presentation

Classic Triad (present in ~85% of adults)

1. Fever
2. Headache (severe, often described as "worst headache of life")
3. Neck stiffness (nuchal rigidity)

Additional Features

• Photophobia, phonophobia
• Nausea and vomiting (~35%)
• Kernig's sign — resistance to knee extension with hip flexed at 90°
• Brudzinski's sign — involuntary knee flexion on rapid neck flexion
• Seizures (~30%)
• Cranial nerve palsies, focal neurological signs (10–20%)
• Altered consciousness, confusion, stupor, coma
• Papilloedema (<1% early; if present early, suspect abscess/mass)

Meningococcal-Specific

• Non-blanching petechial/purpuric rash — pathognomonic clue; begins as maculopapular then becomes petechial → purpuric
• Check entire body including conjunctivae; may be difficult to see on darker skin
• Fulminant course (purpura fulminans, DIC) possible — death within hours

Age-Specific Variations

• Neonates: poor feeding, irritability, temperature instability, bulging fontanelle (late sign), apnoea, seizures in ~40%; nuchal rigidity unreliable <1 year
• Elderly: insidious onset, variable meningeal signs, lethargy, altered cognition, often no fever

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Predisposing Conditions

• Pneumococcal/sinusitis/otitis media (most common)
• Mastoiditis
• Basilar skull fracture with CSF rhinorrhea
• Alcoholism, diabetes, asplenia
• Hypogammaglobulinaemia, complement deficiency
• HIV/immunosuppression
• Recent neurosurgery, CSF shunt
• Perinatal exposure; non-immunised individuals

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Investigations

Immediate / Before LP

• β-hCG (if applicable), blood glucose (for CSF glucose ratio)
• Blood cultures ×2 — before antibiotics if possible but must NOT delay treatment
• FBC, U&E, LFTs, coagulation — screen for sepsis, DIC, organ dysfunction
• CRP, procalcitonin — elevated; support diagnosis
• Blood glucose — simultaneous with LP for CSF:serum ratio
• CT head — required before LP if ANY of the following:
  • Papilloedema
  • Focal neurological signs
  • Seizures
  • Altered consciousness / GCS <12
  • Immunocompromised
  • History of CNS disease (tumour, stroke, focal infection)

Do NOT delay antibiotics for CT or LP — treat first if any delay is anticipated.

Lumbar Puncture — CSF Analysis (Gold Standard)

Microbiology

• Gram stain — immediate; positive >60%
• Culture and sensitivity — gold standard; positive >80%; results guide targeted therapy
• CSF PCR panel (meningitis/encephalitis multiplex) — detects N. meningitidis, S. pneumoniae, L. monocytogenes, H. influenzae, viruses, fungi; rapid; useful if pre-treatment antibiotics reduce culture sensitivity
• Blood cultures — always; positive in ~50% of bacterial meningitis
• Throat swab / nasopharyngeal culture — for N. meningitidis in suspected meningococcal disease
• Skin lesion biopsy/Gram stain — if petechial/purpuric rash present; may reveal N. meningitidis

Neuroimaging

• CT head (pre-LP if indicated — see above): may show loss of sulci, cerebral oedema, hydrocephalus, empyema, abscess; meningeal enhancement is non-specific
• MRI brain with gadolinium: superior to CT; shows leptomeningeal enhancement (Fig. 143-2 in Harrison's); diffusion-weighted imaging identifies early ischaemia/infarction; NOT needed routinely but useful for complications
• Abnormalities on MRI (other than enhancement) suggest encephalitis or complications — not expected in uncomplicated meningitis

Other

• Urinary antigen (S. pneumoniae, H. influenzae type b) — can be positive even after antibiotics
• EEG — not routine; useful if seizures or to distinguish from HSV encephalitis (which causes periodic lateralising discharges)
• Echocardiogram — if infective endocarditis suspected as source

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Management

Emergency Priority: TIME TO ANTIBIOTIC = KEY DETERMINANT OF OUTCOME

Step 1: Empirical Antibiotics (immediate, do not delay)

Step 2: Dexamethasone (Adjunctive Therapy)

• Dexamethasone 0.15 mg/kg IV q6h × 4 days
• Give 10–20 min before or with the first dose of antibiotics
• Reduces meningeal inflammation, decreases risk of sensorineural hearing loss and neurological sequelae
• Most benefit for pneumococcal meningitis; recommended for all suspected community-acquired bacterial meningitis in adults pending culture results
• Discontinue if culture reveals an organism other than S. pneumoniae (debated for other organisms)

Step 3: Targeted (Pathogen-Directed) Therapy

Duration of Antibiotic Therapy

Step 4: Raised ICP Management

• Head elevation 30–45°
• Avoid hypotension and hypoxia
• Intubation and hyperventilation (PaCO₂ 25–30 mmHg) — for acute decompensation
• Mannitol 0.25–1 g/kg IV — osmotic agent for ICP reduction
• ICU monitoring; ICP monitoring device if severe

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Chemoprophylaxis for Close Contacts (Meningococcal Disease)

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Differential Diagnosis

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Complications

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Prognosis

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Asthma: Metered-Dose Inhaler (MDI)

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What is a pMDI?

• A pressurised canister containing the drug as a liquid suspension or solution in a hydrofluoroalkane (HFA) propellant (CFC-free since the early 2000s)
• A metering valve that releases a fixed dose on each actuation
• A plastic actuator (mouthpiece) through which the aerosol is inhaled

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Drugs Available as pMDI

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Pharmacology of Key pMDI Drugs

ICS (e.g., Budesonide, Beclomethasone)

• Reduce airway inflammation by suppressing eosinophils, macrophages, T-lymphocytes
• Reverse mucosal oedema, decrease capillary permeability, inhibit leukotriene release
• After months of regular use, reduce airway hyperresponsiveness to allergens, irritants, cold air, and exercise
• Only 10–20% of inhaled dose reaches the lungs; 80–90% deposits in the oropharynx/is swallowed
• Adverse effects (local): hoarseness, oropharyngeal candidiasis → prevent by rinsing mouth after use and using a spacer

SABAs (e.g., Salbutamol/Albuterol)

• Directly relax airway smooth muscle via β₂ receptor → ↑ cAMP → bronchodilation
• Onset: 5–15 min; duration: 3–6 hours
• No anti-inflammatory effect — must not be used as monotherapy in persistent asthma
• Adverse effects: tachycardia, tremor, hypokalaemia, hyperglycaemia (minimised with inhaled route vs systemic)
• Chronic overuse leads to β₂ receptor downregulation/desensitisation — sign of poorly controlled asthma

Formoterol (LABA — rapid-onset)

• Onset similar to salbutamol; duration ≥12 hours
• Because of rapid onset, ICS/formoterol combinations (e.g., budesonide/formoterol) can serve as both controller AND reliever — the basis of the GINA MART strategy (GINA 2025)

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pMDI Technique — Step-by-Step

Without Spacer (Open-Mouth or Closed-Mouth Technique)

1. Remove the cap and shake the inhaler well for 3–5 seconds (resuspends the drug)
2. Prime the inhaler if new or not used for >2 weeks (fire 2–4 test puffs into the air)
3. Stand or sit upright — allows optimal lung expansion
4. Exhale fully and gently away from the inhaler to empty the lungs
5. Place the mouthpiece between the lips (closed-mouth) — or hold 3–4 cm in front of the open mouth (open-mouth)
6. Begin inhaling slowly — then press the canister down in the first second of inhalation
7. Continue inhaling slowly, deeply, and fully over ~5 seconds ("slowly, gently, naturally, deeply, and comfortably")
8. Hold breath for 5–10 seconds (allows particles to settle in airways)
9. Breathe out slowly through the nose
10. Wait 30–60 seconds before the second puff (allows the valve to refill)
11. Replace the cap

Most common error: Inhaling too fast and/or failing to coordinate inhalation with actuation. Failure to inhale slowly and deeply is actually more common than pure hand-mouth coordination failure. — Fishman's Pulmonary Diseases and Disorders

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With Spacer (Valved Holding Chamber — Preferred)

1. Shake the inhaler and attach to the spacer
2. Prime the spacer first with 1 actuation (reduces electrostatic charge)
3. Exhale fully away from the spacer
4. Place the spacer mouthpiece in the mouth (lips sealed) — or apply face mask (for children/infants)
5. Fire ONE puff into the spacer — then inhale immediately
6. Inhale slowly and deeply over 3–5 seconds
7. Hold breath for 5–10 seconds
8. Breathe out slowly back through the spacer or through the nose
9. Wait 30–60 seconds, then repeat for the second puff
10. Never fire multiple puffs simultaneously into the spacer — each puff must be inhaled separately

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Advantages and Disadvantages of pMDI

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Spacer: Purpose and Benefits

1. Reduces oropharyngeal deposition — large, high-velocity particles impact the chamber walls rather than the pharynx
2. Eliminates coordination requirement — patient can inhale after actuating; critical for children, elderly, and patients with poor coordination
3. Reduces local ICS side effects — less drug deposited in the mouth/larynx → less hoarseness and oral candidiasis
4. Reduces systemic ICS absorption — less drug swallowed → less GI absorption → fewer systemic effects
5. Enriches lung-deposited aerosol with small particles — only fine particles (~1–5 µm) travel past the chamber and reach the lower airways

Spacers should be prescribed with the compatible pMDI only (different brands are not always interchangeable). — Fishman's Pulmonary Diseases

Spacer Maintenance

• Wash weekly with mild ionic detergent, air-dry (do not rub dry — creates electrostatic charge)
• Priming with 1 puff before use reduces electrostatic charge
• Replace every 6–12 months
• Rinse/wash spacer mouthpiece to prevent bacterial/fungal growth

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Types of MDI Devices

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GINA 2025 Treatment Steps: Inhaler Relevance

Key 2025 update: SABAs alone are no longer recommended as the sole reliever for adults and adolescents. All patients should be on ICS-containing therapy, with ICS-formoterol as the preferred reliever.

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Common MDI Technique Errors

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Monitoring pMDI Use

• Dose counter — modern pMDIs include dose counters; patients should not guess by shaking
• "Float test" — unreliable for determining remaining doses; not recommended
• Increasing frequency of SABA rescue use is a marker of worsening asthma control — not a goal in itself
• Electronic adherence monitors can be attached to pMDIs to track real-time use and improve adherence

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Tests for Filariasis

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Filarial Species: Diagnostic Overview

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1. Blood Examination for Microfilariae

Timing

Methods (in order of increasing sensitivity)

a) Wet Blood Film (direct)

• A drop of fresh anticoagulated blood on a slide with a coverslip
• Motile microfilariae can be identified under low-power microscopy
• Rapid but low sensitivity; useful for high microfilaraemia

b) Thick Blood Film (Giemsa-stained)

• 20–60 µL blood spread thick, lysed, fixed, and stained with Giemsa
• Allows species identification via morphological features
• Standard method; sensitivity depends on microfilaraemia level

c) Thin Blood Film

• 1–2 µL blood, stained with Giemsa/Field stain
• Allows detailed morphological study; less sensitive than thick film

d) Concentration Methods (increased sensitivity — preferred when microfilaraemia is low)

• 1–2 mL anticoagulated blood + 10 mL 2% formalin → centrifuge → examine sediment
• Fixes and concentrates microfilariae; allows detailed species identification
• Sensitivity superior to direct thick film

• Anticoagulated blood mixed with saline → passed through a 3–5 µm polycarbonate membrane filter
• Filter washed, dried, fixed, and stained — or examined directly for motile microfilariae
• Most sensitive parasitological technique for low-level microfilaraemia
• Can also be applied to hydrocele fluid and other body fluids

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2. Morphological Identification of Microfilariae

Key point: The B. malayi sheath staining bright pink is a rapid first step in distinguishing it from W. bancrofti and L. loa. — Medical Microbiology 9e

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3. Skin Snip (for O. volvulus and M. streptocerca)

• Method: A bloodless piece of superficial skin (1–3 mm) obtained using a corneal-scleral punch or lifting skin with a needle and cutting with a scalpel blade
• Multiple snips taken from iliac crest, scapular, and calf sites (bilateral)
• Placed in saline or tissue culture medium on a glass slide
• Incubated 2–4 hours (overnight in light infections) at room temperature
• Emergent microfilariae visualised under low-power microscopy
• Alternatively, the snip can be fixed and processed for PCR

Mazzotti Reaction (provocation test — historical)

• Oral DEC (50 mg single dose) provokes an intense dermal reaction (pruritus, rash) in O. volvulus infected patients within 1–3 hours due to dying microfilariae releasing antigens
• Useful when skin snips are negative but infection is suspected
• Risk of severe systemic reactions — now largely replaced by serological and PCR methods

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4. Circulating Filarial Antigen (CFA) Detection

For W. bancrofti (Bancroftian filariasis) — MOST IMPORTANT

• Detects soluble circulating antigens shed by adult female worms
• Key advantage: Can detect infection in amicrofilaraemic (cryptic) patients (those with adult worms but no detectable microfilaraemia in blood)
• Blood can be collected at any time of day or night — avoids the nocturnal timing constraint
• Two commercially available formats:
  • ELISA (lab-based; quantitative)
  • Immunochromatographic card test (ICT) / Filariasis Test Strip (FTS) — rapid point-of-care lateral flow format
• Sensitivity: 93–100%; Specificity: approaching 100% (rare false positives with Loa loa co-infection)
• Note: Approved for use in WHO lymphatic filariasis elimination programmes; not FDA-approved in the US

A newer ICT — the Alere Filariasis Test Strip (FTS) / STANDARD Q Filariasis Antigen Test — has shown improved sensitivity over older card tests in recent evaluation studies.

For B. malayi / B. timori

• No circulating antigen tests currently available
• Diagnosis relies on blood microfilariae examination + antibody tests

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5. Serology / Antibody Detection

• Detects anti-filarial antibodies (IgG, IgG4, IgE)
• Available through reference/specialist laboratories
• Useful in:
  • Travellers and expatriates (low microfilaraemia, pre-patent infections)
  • Early or cryptic infection
  • Tropical pulmonary eosinophilia (no detectable microfilaraemia)

Specific Tests

Caution: Seropositivity cannot be equated with active infection — residents of endemic areas can become sensitized without patent infection. Extensive cross-reactivity exists between filarial and other helminth antigens. — Harrison's 22e

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6. Polymerase Chain Reaction (PCR)

• Detects parasite DNA in blood, skin snips, or other fluids
• Available for W. bancrofti, B. malayi, and O. volvulus
• Most sensitive diagnostic technique — sensitivity equivalent to or greater than parasitological methods
• Particularly valuable when:
  • Microfilaraemia is very low (post-treatment monitoring)
  • Blood collected at wrong time of day
  • Blood drawn after partial treatment
• No commercially available platforms as of 2025; restricted to reference/research laboratories
• PCR on skin snips replacing incubation methods for O. volvulus in many settings

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7. Ultrasound (High-Frequency / Doppler)

• High-frequency ultrasound (7.5–15 MHz) of scrotal/inguinal lymphatics, breasts, lymph nodes
• Live adult worms show a characteristic continuous wriggling movement within dilated lymphatics — the "filarial dance sign"
• Worms visualised in lymphatics of the spermatic cord in up to 80% of men infected with W. bancrofti
• Doppler assessment demonstrates flow characteristics of dilated lymphatics
• Confirms active infection; helps guide response to treatment

Ultrasound is particularly useful in amicrofilaraemic patients where blood tests are negative but clinical signs suggest lymphatic infection. — Harrison's 22e

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8. Lymphoscintigraphy

• Radionuclide imaging of lymphatic drainage in the limbs
• Reliably demonstrates widespread lymphatic abnormalities in both subclinical microfilaraemic persons and those with clinical lymphatic pathology
• Delineates anatomical changes (lymphatic obstruction, abnormal drainage patterns)
• Principally a research tool and used for assessment of lymphoedema; not first-line for routine diagnosis

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9. Biopsy / Histopathology

• Excision of subcutaneous nodule (onchocercoma) for O. volvulus: demonstrates adult worm surrounded by fibrous tissue and inflammatory cells on H&E stain
• Lymph node / lymphatic vessel biopsy for lymphatic filariasis: adult worms in lymphatics with granulomatous reaction; not performed routinely
• Hydrocele fluid examination for microfilariae (useful in scrotal filariasis)
• Conjunctival examination in L. loa: adult worm may be visualised crossing the conjunctiva or subconjunctival space

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10. Supporting (Non-Specific) Tests

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Diagnostic Algorithm by Clinical Context

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Hemochromatosis

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Classification

1. Hereditary (Primary) Hemochromatosis

2. Secondary (Acquired) Hemochromatosis

• Chronic haemolytic anaemias with iron loading (β-thalassaemia, sideroblastic anaemia, myelodysplastic syndrome)
• Multiple blood transfusions
• Ineffective erythropoiesis → ↓ hepcidin via erythroferrone → ↑ iron absorption
• Chronic liver disease (alcoholic, viral hepatitis — exacerbate HFE iron loading)
• Dietary iron overload (African siderosis)

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Pathogenesis

• HFE, HJV (hemojuvelin), TFR2 act as hepatic iron sensors that together stimulate HAMP (hepcidin) expression when iron is sufficient
• Mutations in any of these genes → ↓ hepcidin → ↑ ferroportin expression on enterocytes → unregulated intestinal iron efflux → iron overload
• Iron accumulates at ~0.5–1 g/year; clinical disease develops when stores reach ~20 g (total body iron may exceed 50 g in severe cases — normal ~3–4 g)
• Iron toxicity: lipid peroxidation via free radical reactions, hepatic stellate cell activation → fibrosis, DNA damage → hepatocellular carcinoma risk

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Clinical Features

Presentation in Symptomatic Disease (typically 5th–6th decade in men, later in women)

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Diagnosis

Serum Iron Studies (First-Line Screening)

Diagnostic threshold: TSAT ≥45% (≥35% in premenopausal women) + elevated ferritin → proceed to HFE gene testing. A TSAT <45% with normal ferritin effectively excludes significant iron overload.

Note on ferritin: Ferritin >50,000 µg/L is usually NOT hemochromatosis — consider haemophagocytic lymphohistiocytosis or Still's disease. Hyperferritinemia with normal TSAT and cataracts in a young patient → hyperferritinaemia-cataract syndrome (FTL gene mutation).

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HFE Gene Testing (Genetic Diagnosis)

Genetic testing is not recommended in children (organ damage uncommon; risk of insurance discrimination/stigmatisation). Genetic testing has limited utility in non-Caucasian populations — HFE mutations rare in Asian/African populations; use clinical criteria + liver biopsy/MRI instead.

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Liver Biopsy (Selective Use)

• Ferritin >1000 µg/L
• Elevated LFTs / suspected cirrhosis
• Age >40 years (higher risk of fibrosis)
• When non-invasive tests are equivocal
• Non-HFE patients with iron overload of uncertain cause

• Prussian blue (Perls') stain — demonstrates hemosiderin as blue granules in hepatocytes
• Iron deposited initially in periportal hepatocytes (zone 1), spreading toward central vein with increasing load
• Hepatic iron index (HII) = µmol iron/g dry liver ÷ age — HII ≥1.9 supports HH (pre-genetic era marker; now less used)
• Fibrous septa, bridging fibrosis, micronodular cirrhosis in advanced disease

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MRI Liver (Non-invasive Iron Quantification)

• MRI T2 (R2) and T2 (R2) sequences** — detect and quantify hepatic iron concentration (HIC) non-invasively
• Can demonstrate moderate-to-severe iron overload; correlates with HIC
• Detects cirrhosis features (nodularity, ascites, splenomegaly), portal hypertension, and hepatocellular carcinoma
• Splenic iron on MRI — prominent in ferroportin disease (macrophage iron loading); absent or minimal in HFE-HH
• CT scan can also demonstrate iron overload (increased liver density), though MRI is more sensitive and quantitative

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Additional Investigations

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Diagnostic Algorithm

Elevated transferrin saturation (≥45%) and/or raised ferritin
            ↓
      HFE gene testing
            ↓
  C282Y homozygous ──────→ Iron studies confirm overload
                              Ferritin <1000 + normal LFTs + age <40
                              → No liver biopsy needed
                              Ferritin >1000 OR elevated LFTs OR age >40
                              → Liver biopsy (assess fibrosis/cirrhosis)
            ↓
  C282Y/H63D compound het → Monitor iron studies; biopsy if iron overload
            ↓
  No HFE mutations ────────→ MRI liver, exclude secondary causes
                              Consider TFR2, ferroportin, HJV gene testing
                              Liver biopsy for diagnosis/prognosis

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Family Screening

• First-degree relatives of a proband (C282Y homozygote) should be screened
• Siblings have a 25% risk of being homozygous (highest priority)
• Screen with: fasting TSAT + serum ferritin + HFE genotyping
• Relatives negative for HFE mutations require no further testing
• Relatives positive → monitor ferritin annually; commence phlebotomy when indicated

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Treatment

Phlebotomy (Venesection) — First-Line

• Induction phase: Remove 450–500 mL blood (=200–250 mg iron) weekly or twice weekly
• Target: Serum ferritin <50 µg/L (or 50–100 µg/L per AASLD) + TSAT <50%
• Monitor ferritin and haemoglobin before each session
• Induction phase typically takes 1–3 years depending on iron burden
• Maintenance phase: 3–4 venesections/year to maintain ferritin <50–100 µg/L
• With regular phlebotomy — life expectancy is normal if started before cirrhosis develops

Critical: Phlebotomy initiated before cirrhosis prevents progression to cirrhosis. Once cirrhosis is established, phlebotomy does not prevent hepatocellular carcinoma (which occurs in ~30% of cirrhotic hemochromatosis patients).

Iron Chelation — For Patients Who Cannot Tolerate Phlebotomy

• Deferoxamine (parenteral) — parenteral; used in secondary iron overload (thalassaemia, MDS)
• Deferasirox (oral) — used in transfusional iron overload
• Deferiprone (oral) — particularly effective for cardiac iron

Dietary/Lifestyle

• Avoid vitamin C supplements — ascorbic acid mobilises iron and may precipitate cardiac arrhythmias
• Avoid raw seafood (Vibrio vulnificus infection risk markedly increased in iron overload)
• Limit alcohol — exacerbates liver disease, worsens iron overload
• Moderate dietary iron — avoid supplemental iron; avoid excessive red meat; cooking in cast iron cookware discouraged

Liver Transplantation

• For end-stage cirrhosis from hemochromatosis
• Note: The transplanted liver has normal HFE genes → iron overload does not recur in the graft, but extrahepatic iron remains

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Prognosis

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IV Rate Control Agents for AF with Rapid Ventricular Response (RVR)

Before reaching for rate control agents: If the RVR is driven by a reversible trigger (sepsis, hypovolemia, PE, tamponade, thyrotoxicosis, decompensated HF), address the underlying cause first — rate control alone will be ineffective and potentially harmful.

Haemodynamic instability (severe hypotension, active ischaemia, decompensated HF) → urgent synchronised DC cardioversion, not pharmacological rate control.

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Absolute Contraindication Before Choosing Agent

• AV nodal blockers (beta-blockers, non-DHP CCBs, digoxin, adenosine) are contraindicated — blocking the AV node may accelerate conduction down the accessory pathway → ventricular fibrillation
• Treatment: Procainamide IV or electrical cardioversion

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IV Rate Control Drugs: Doses, Onset, and Key Points

1. Beta-Blockers — First-Line (haemodynamically stable, no decompensated HF)

Metoprolol Tartrate (IV)

Esmolol (IV) — Short-Acting, Titratable

Propranolol (IV)

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2. Non-Dihydropyridine Calcium Channel Blockers (Non-DHP CCBs) — First-Line (no HFrEF)

Diltiazem (IV) — Most Commonly Used IV CCB for AF

Verapamil (IV)

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3. Cardiac Glycoside

Digoxin (IV) — Second-Line / Adjunct

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4. Amiodarone (IV) — Reserve / Special Circumstances

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Drug Selection by Clinical Context

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Rate Control Targets (AHA/ACC)

• Strict: Resting HR ≤80 bpm (Class IIa — preferred if symptomatic or with HF)
• Lenient: Resting HR <110 bpm (Class IIb — acceptable if asymptomatic with preserved LV function)

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Quick Reference Summary Table

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Wernicke's Encephalopathy - Treatment

• Ophthalmoplegia (lateral rectus palsy, conjugate gaze palsy)
• Cerebellar ataxia
• Global confusion / altered mental status

The full triad is present in only 10–20% of cases — do not wait for all three features before treating. Any single feature in an at-risk patient is sufficient grounds for immediate treatment.

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Pathophysiology Relevant to Treatment

• Mammillary bodies
• Dorsomedial thalamic nuclei
• Periaqueductal grey matter
• Floor of the fourth ventricle
• Cerebellar vermis

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Causes (Treatment Must Address the Underlying Aetiology)

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Treatment Principle — Why Parenteral?

• Alcohol-related enteropathy and impaired active transport
• Vomiting
• Intestinal mucosal damage

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Thiamine Replacement Protocol

Acute/Established WE (Suspected or Confirmed)

Harrison's 22e: "Wernicke's disease is a medical emergency and requires immediate administration of high-dose thiamine, in a dose of 500 mg IV. The dose should be begun prior to treatment with IV glucose solutions and continued three times daily for 2–3 days."

Bradley and Daroff's Neurology: "A dose of 500 mg should be given IV in the acute stage, followed by 100 mg 3 times daily during the first week."

Adams and Victor's Principles of Neurology: Higher doses of 500 mg parenterally for several days are needed to replete vitamin stores in alcoholic patients — recommended in EFNS and Royal College of Physicians guidelines.

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Prophylaxis — At-Risk Patients Without WE

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Emergency Department / Pre-IV Glucose Rule

Give thiamine before any glucose-containing IV fluid in any malnourished, alcoholic, or nutritionally at-risk patient.

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Adjunct Treatments

1. Magnesium

• Mandatory co-treatment — magnesium is an essential cofactor for thiamine-dependent enzymes (transketolase requires Mg²+)
• Hypomagnesaemia is common in alcoholics and impairs thiamine utilisation
• Check serum magnesium; replace with IV magnesium sulphate (e.g., 2–4 g IV) if low, or give empirically
• Without magnesium repletion, thiamine therapy may be partially ineffective

2. Other B Vitamins

• Alcoholic and malnourished patients are typically deficient in multiple B vitamins (B2, B6, B12, folate, niacin)
• Administer a multivitamin B complex parenterally alongside thiamine
• Nicotinic acid deficiency can cause pellagra with concurrent neurological features
• Oral supplementation of all B vitamins should follow the parenteral course

3. Rehydration and Electrolyte Correction

• Correct hypokalaemia, hypophosphataemia (especially in refeeding states)
• IV crystalloids for dehydration
• Antiemetics (ondansetron, metoclopramide, prochlorperazine) for persistent vomiting — address the cause of poor intake

4. Nutritional Support

• Referral to dietitian once acute phase managed
• Balanced diet reinstated as soon as possible
• Oral thiamine 100 mg/day continued until full nutritional recovery

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Monitoring and Response to Treatment

Failure to respond to thiamine in 24–48 hours despite adequate IV dosing should prompt reconsideration of alternative diagnoses (hepatic encephalopathy, meningitis, subdural haematoma, septic encephalopathy) and review of magnesium replacement.

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MRI Findings (Diagnostic Support)

• Mammillary bodies (T1 post-contrast enhancement — highly specific)
• Dorsomedial thalami (bilaterally)
• Periaqueductal grey matter
• Tectum of midbrain
• Periventricular hypothalamus

Do not delay treatment to obtain imaging. MRI is supportive, not a prerequisite for starting thiamine.

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Progression to Korsakoff Syndrome — Prevention is the Goal

• Severe anterograde amnesia (inability to form new memories)
• Confabulation
• Relative preservation of immediate recall and long-term memory
• Personality change

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Treatment Summary at a Glance

SUSPECTED WE (any feature: confusion, ataxia, ophthalmoplegia, nystagmus, hypothermia, coma)
         ↓
GIVE THIAMINE FIRST — before any glucose
         ↓
500 mg IV TDS × 2–3 days
(dilute in 100 mL NS, infuse over 30 min)
         ↓
250 mg IV/IM OD × 5 days
         ↓
Oral thiamine 100 mg/day (maintenance)
         ↓
ALWAYS add: Mg²⁺ replacement + B-complex vitamins
+ Treat underlying cause
+ Nutritional support

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Subacute Combined Degeneration (SCD) of the Spinal Cord

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Aetiology and Causes of Cobalamin Deficiency

Important: Neurological features may be present with normal haematology — anaemia and macrocytosis are absent in up to 28% of cases with documented SCD. Never exclude B12 deficiency on the basis of a normal blood count.

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Pathogenesis

1. Methionine Synthase (methylcobalamin-dependent)

• Converts homocysteine → methionine (requires methylcobalamin as cofactor)
• Methionine is essential for S-adenosylmethionine (SAM) synthesis — the primary methyl donor for myelin synthesis, neurotransmitter metabolism, and DNA methylation
• Deficiency → ↑ homocysteine, ↓ SAM → impaired myelin maintenance

2. Methylmalonyl-CoA Mutase (adenosylcobalamin-dependent)

• Converts methylmalonyl-CoA → succinyl-CoA (enters Krebs cycle)
• Deficiency → accumulation of methylmalonyl-CoA and propionyl-CoA
• Propionyl-CoA displaces succinyl-CoA as a fatty acid synthesis primer → incorporation of odd-chain fatty acids into myelin lipids → structurally abnormal, unstable myelin

• Earliest and most prominent: posterior column demyelination (dorsal columns — proprioception, vibration)
• Subsequently: lateral column (corticospinal tract) involvement — upper motor neurone signs
• Peripheral nerve involvement: debated — most likely due to posterior root entry zone involvement rather than primary peripheral neuropathy in pure cobalamin deficiency

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Neuropathology

• Earliest change: Swelling of myelin sheaths with intramyelinic vacuole formation and separation of myelin lamellae
• Progressive change: Coalescence of small foci into larger vacuolated, sieve-like areas of tissue destruction
• Both myelin sheaths and axons are damaged; myelin involved earlier and more severely
• Begins in posterior columns of lower cervical/upper thoracic segments, spreads up and down the cord and anteriorly into lateral and anterior columns
• The lesion is a diffuse myelinopathy scattered irregularly through white matter — not confined to specific tract systems
• Brain white matter, optic nerves, and peripheral nerves can be affected in severe/advanced cases

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Clinical Features

Onset

• Insidious, progressive over weeks to months (subacute)
• Sensory symptoms almost always precede motor ones
• Both sides affected symmetrically — asymmetry or predominant motor onset from the start should suggest an alternative diagnosis

Sensory Symptoms (Posterior Column Involvement)

• Tingling, numbness, "pins and needles" in hands and feet — usually hands first, then feet
• Constant, progressive, distressing paresthesias
• Loss of vibration sense — most consistent sign; more prominent in feet/legs
• Loss of proprioception / joint position sense — in parallel
• Romberg sign positive — unsteady on standing with eyes closed
• Lhermitte sign may be present (electric shock sensation down the spine on neck flexion)

Motor Symptoms (Lateral Column Involvement)

• Leg stiffness, weakness (usually proximal lower limbs)
• Progressive spastic ataxic gait → eventually paraplegia if untreated
• Upper motor neurone signs: spasticity, clonus, extensor plantar responses (Babinski sign)
• Paradoxical finding: reflexes may be diminished or absent (due to peripheral neuropathy component) despite Babinski sign being present — this combination is a diagnostic clue

Cognitive / Neuropsychiatric

• Irritability, apathy, somnolence, suspiciousness, emotional instability
• Confusional states, psychosis, dementia — in advanced cases
• Neuropsychiatric symptoms (depression, cognitive impairment) can occasionally be the sole presenting feature

Visual

• Optic neuropathy — bilateral centrocaecal scotomata, visual impairment, optic atrophy — in severe/longstanding cases
• Visually evoked potentials may be abnormal subclinically

Bladder/Bowel

• Sphincteric disturbance in advanced cases (urinary urgency, retention, impotence)

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Investigations

1. Serum Vitamin B12 (Cobalamin)

Note: Serum B12 is not a reliable measure of tissue stores — levels can remain normal for months to years after absorption ceases.

2. Serum Methylmalonic Acid (MMA) — Most Sensitive/Specific Metabolic Test

• Normal: 73–271 nmol/L
• Elevated in cobalamin deficiency even when serum B12 is borderline-normal
• Reflects intracellular cobalamin availability directly
• Highly sensitive for true functional B12 deficiency

3. Serum Homocysteine

• Normal: 5.4–16.2 mmol/L
• Elevated in B12 deficiency (also elevated in folate deficiency — not specific to B12)
• Useful corroborating test

Best diagnostic combination: Low/low-normal serum B12 + elevated MMA + elevated homocysteine = high-confidence cobalamin deficiency. Elevated MMA with normal homocysteine = isolated B12 deficiency. Elevated homocysteine with normal MMA = folate deficiency.

4. Full Blood Count and Blood Film

• Macrocytic anaemia (MCV >100 fL) — classic but absent in up to 28% of neurological cases
• Hypersegmented neutrophils (>5 lobes in >5% of neutrophils, or any cell with ≥6 lobes)
• Megaloblastic changes in bone marrow smear
• Thrombocytopenia, leukopenia in severe cases

5. Investigations for Aetiology

6. MRI Spine (T2/FLAIR)

• Characteristic finding: Bilateral T2 hyperintensity in the posterior columns, appearing as a linear "inverted V" or "inverted U" signal on axial views
• Most commonly seen at C2–C5 levels
• May also involve the lateral columns in advanced disease
• Lesions may enhance with IV gadolinium in active disease
• MRI can be normal — especially early in the course; a normal MRI does not exclude SCD

7. Neurophysiology

• Somatosensory evoked potentials (SSEPs): Frequently abnormal — delayed central conduction — confirms posterior column involvement; useful when MRI is normal
• Nerve conduction studies: Variable — may show sensory axonal neuropathy or be normal; slowing of distal sensory conduction, reduced amplitude sensory potentials
• Motor evoked potentials: Affected in more advanced cases

8. CSF Analysis

• Usually normal
• Moderate protein elevation in some cases
• Used mainly to exclude MS, infection, or other myelopathies in the differential

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Differential Diagnosis

Critical clinical point: If both B12 and folate are deficient, always treat B12 first. Giving folate alone corrects the anaemia but may precipitate or worsen the neurological manifestations of SCD.

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Treatment

Vitamin B12 (Cyanocobalamin or Hydroxocobalamin) Replacement

Regimen for Established SCD (Neurological Disease)

Hydroxocobalamin vs. Cyanocobalamin

• Hydroxocobalamin (UK/Europe preferred) — longer duration of action (retained in tissues better); fewer injections needed long term; preferred in UK
• Cyanocobalamin (US) — effective but shorter tissue retention; requires more frequent dosing

Oral Maintenance (selected patients)

• High-dose oral cobalamin 500–2000 µg/day can be used for maintenance in patients with dietary deficiency (vegans) or food-cobalamin malabsorption (atrophic gastritis) where intrinsic factor mechanism is partially intact
• A small proportion (~1–2%) of dietary B12 is absorbed by passive diffusion even without intrinsic factor — this is exploited by high-dose oral therapy in pernicious anaemia
• Caveat: Oral treatment is not recommended as primary treatment for manifest SCD with neurological signs — parenteral therapy is safer and more reliable

Associated/Adjunct Management

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Response to Treatment and Prognosis

"The most important factor influencing response to treatment is the duration of symptoms... The greatest improvements occur in patients whose disturbance of gait has been present for less than 3 months." — Adams and Victor's Principles of Neurology 12e

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Nitrous Oxide (N₂O) - Special Note

• Elderly patients with unrecognised atrophic gastritis
• Vegans/vegetarians undergoing surgery
• Recreational N₂O abusers ("whippets")
• Operating room personnel with repeated low-level exposure

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Thyroid Storm (Thyrotoxic Crisis)

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Definition and Pathophysiology

• Adrenergic hyperactivity (increased catecholamine receptor sensitivity or upregulation)
• Relatively higher free thyroid hormone levels compared to uncomplicated thyrotoxicosis (increased T4 → T3 peripheral conversion, displacement of T4/T3 from binding proteins by precipitating stress)
• Multi-organ decompensation — the thyroid hormone load overwhelms the body's compensatory capacity

• T3 acts directly on nuclear thyroid hormone receptors → increases basal metabolic rate, thermogenesis, adrenergic receptor density, heart rate, and contractility
• Peripheral tissues outpace their metabolic capacity → heat production, high-output cardiac failure, hepatic dysfunction

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Precipitating Causes

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Clinical Features

Thermoregulatory

• High fever — often ≥40°C (104°F); fever out of proportion to apparent illness is a hallmark
• Diaphoresis, heat intolerance

Cardiovascular

• Marked tachycardia (often >140 bpm) — out of proportion to the degree of fever
• Atrial fibrillation — in 10–35% of cases; more common in elderly patients
• High-output cardiac failure: elevated systolic BP, widened pulse pressure
• Decompensated heart failure: pulmonary oedema, bibasal crepitations, pedal oedema
• Hypotension (from volume depletion or cardiac failure)

Central Nervous System

• Agitation, anxiety, restlessness (earliest CNS feature)
• Delirium, psychosis
• Extreme lethargy, confusion
• Seizures, coma (severe cases)

Gastrointestinal/Hepatic

• Nausea, vomiting, diarrhoea, abdominal pain
• Hepatic dysfunction: elevated liver enzymes, cholestatic jaundice (poor prognostic sign)

"Apathetic" Thyroid Storm (Elderly)

• Elderly patients may lack classic features — presenting instead with weakness, depression, and weight loss without obvious agitation; diagnosis easily missed

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Diagnostic Scoring: Burch-Wartofsky Point Scale (BWPS)

• ≥45: Highly suggestive of thyroid storm — begin immediate aggressive treatment
• 25–44: Impending thyroid storm — treat as storm
• <25: Unlikely thyroid storm

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Investigations

• Thyroid function: TSH (suppressed/undetectable <0.01 mU/L), free T4 (elevated), free T3 (elevated) — confirm thyrotoxicosis but do NOT delay treatment
• FBC: Leukocytosis (may reflect precipitating infection)
• BMP/electrolytes: Hyperglycaemia (catecholamine-mediated glycogenolysis, insulin inhibition); mild hypercalcaemia (bone resorption)
• LFTs: Elevated (hepatic involvement common; baseline needed — 30% of patients on PTU develop transient enzyme elevation)
• Serum cortisol: High (expected stress response); low cortisol → suspect adrenal insufficiency
• ECG: Sinus tachycardia most common; AF in 10–35%; PVCs, atrial flutter
• Chest X-ray: Exclude pneumonia (precipitant); assess for pulmonary oedema
• Blood/urine cultures: If infection suspected as precipitant
• Pregnancy test: Before starting treatment — affects antithyroid drug choice

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Treatment — Sequential and Simultaneous

Beta-blocker → Thionamide → Iodine (≥1 hour after thionamide) → Corticosteroid → Treat precipitant

Step 1 — Supportive Care (Immediate)

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Step 2 — Inhibit Peripheral Adrenergic Effects (Beta-Blockade)

Note: In high-output cardiac failure from thyroid storm, beta-blockers should be used cautiously with close monitoring — inotropic agents (digoxin if AF present) may be needed adjunctively.

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Step 3 — Inhibit New Thyroid Hormone Synthesis (Thionamides)

PTU black box warning (FDA 2010): Rare but severe hepatic failure — monitor LFTs; some authorities now prefer high-dose methimazole except in pregnancy or if T4→T3 conversion blocking is critical.

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Step 4 — Inhibit Thyroid Hormone Release (Iodine)

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Step 5 — Block T4 → T3 Peripheral Conversion (Corticosteroids)

Corticosteroids are essential for blocking peripheral conversion of T4 to T3. Their use is associated with improved survival. They also provide cover for potential concurrent adrenal insufficiency.

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Step 6 — Prevent Free Hormone Reabsorption (Enterohepatic Circulation Interruption)

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Step 7 — Identify and Treat the Precipitant

• Empirical broad-spectrum antibiotics if infection is suspected or cannot be excluded as a precipitant
• Treat underlying cause (e.g., DKA, MI, PE, surgical drainage of abscess)

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Step 8 — Definitive Therapy (After Stabilisation)

• Radioactive iodine (RAI) ablation — once patient is euthyroid and stable; most common definitive treatment for Graves' disease
• Thyroidectomy — for patients in whom RAI is contraindicated (e.g., pregnancy), for large goitres causing compression, or for rapid definitive treatment after medical stabilisation
• Patients must be rendered euthyroid before surgery to minimise perioperative risk

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Step 9 — Rescue Therapies (Refractory Cases)

• Therapeutic plasmapheresis / plasma exchange — removes circulating thyroid hormones rapidly
• Peritoneal dialysis / charcoal haemoperfusion — last resort

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Special Situations

Pregnancy

• First trimester: PTU is preferred (methimazole teratogenic — aplasia cutis, choanal atresia)
• Second/third trimester: Switch to methimazole (PTU has greater hepatotoxicity risk in pregnancy)
• Both PTU and methimazole cross the placenta and can cause foetal hypothyroidism — use lowest effective dose
• RAI is absolutely contraindicated in pregnancy

AF in Thyroid Storm

• Rate control with propranolol IV (preferred) or digoxin (if severe HF precludes beta-blockade)
• Most AF resolves once euthyroid state is restored
• Anticoagulation should be considered (high thromboembolic risk)

Beta-Blocker Contraindications

• Severe bronchospasm → use diltiazem for rate/adrenergic control
• Decompensated heart failure → use short-acting esmolol with careful titration; or reserpine/guanethidine as alternative

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Differential Diagnosis

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Prognosis and Monitoring

• Mortality with treatment: 10–30%
• Mortality without treatment: approaches 100%
• Death occurs from: high-output cardiac failure, arrhythmias, multi-organ failure, DIC, hypoxic brain injury, sepsis
• Hepatic failure with jaundice carries the worst prognosis
• Improvement in heart rate and temperature should be seen within 12–24 hours of appropriate therapy
• Thyroid hormone levels normalise over days to weeks (large thyroid hormone body stores)
• ICU admission mandatory for all cases

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Krait Bite (Bungarus species)

The Snake

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Venom Composition and Mechanism

Alpha-Bungarotoxins (postsynaptic neurotoxins)

• Competitive antagonists at the nicotinic acetylcholine receptor (nAChR) on the muscle end-plate
• Bind with very high affinity, blocking postsynaptic transmission
• In principle, antivenom can compete with these and reverse the blockade if given early

Beta-Bungarotoxins (presynaptic neurotoxins — more clinically important)

• Phospholipase A2 toxins that damage presynaptic nerve terminals
• Deplete acetylcholine vesicles and destroy the presynaptic membrane
• Once presynaptic damage occurs, the axon terminal must physically regrow — a process taking days to weeks
• Antivenom cannot reverse established presynaptic damage; it can only prevent progression if given before terminal destruction is complete

This explains why krait envenomation carries high mortality and why early antivenom is critical — delay is irreversible.

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Epidemiology

• India/Pakistan: 15,000–30,000 deaths/year from snakebite; B. caeruleus is one of the "Big Four" (alongside Russell's viper, saw-scaled viper, cobra)
• Sri Lanka: >60,000 bites and ~1,000 deaths/year; B. caeruleus is a major contributor
• Southeast Asia (Thailand): 88.6% of Bungarus bite patients develop neurotoxic signs within 8 hours; 76% require mechanical ventilation

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Clinical Features

The Bite Itself

• Often painless — the bite may not wake the sleeping victim
• Fang marks may be inconspicuous — small puncture wounds, often barely visible
• No significant local swelling, redness, or tissue destruction — this is a hallmark distinguishing krait from viper bites
• The victim may wake at night with symptoms but be uncertain they were bitten

Premonitory/Early Symptoms (Hours 1–4)

• Abdominal pain (colicky, crampy) — a distinctive feature of krait envenomation, thought to be autonomic in origin; present with or without paralysis
• Nausea, vomiting, diarrhoea
• Excessive salivation
• Profuse sweating
• Anxiety, restlessness

Neurotoxic Paralysis (Descending Flaccid Paralysis)

1. Ptosis — earliest and most reliable sign; "failure of lid retraction" when the patient looks upward; "hooding of the pupil"
2. External ophthalmoplegia — starting with loss of upward gaze, progressing to complete ophthalmoplegia
3. Facial and bulbar palsy — facial paralysis, inability to open mouth, dysarthria, dysphagia, pooling of secretions
4. Neck flexor weakness — patient cannot lift head off the pillow
5. Limb weakness — descending pattern, lower limbs usually last
6. Respiratory muscle paralysis — intercostal muscle failure, diaphragmatic involvement → respiratory failure and death

Respiratory arrest can occur within a few hours of severe envenomation, or may be delayed up to 10–24 hours. The speed of progression is unpredictable.

WHO Clinical Syndrome Classification for Krait (Syndrome 4A)

• Neurotoxic paralysis
• Minimal or no local effects at bite site
• Bitten while sleeping on the ground/floor
• With or without abdominal pain
• Likely snake: Krait

Other Features

• Autonomic effects: bradycardia, hypotension, hypersalivation, miosis or mydriasis
• Consciousness: usually preserved until respiratory failure supervenes — patients may be fully conscious while paralysed (this is extremely distressing)
• No haematotoxicity: no coagulopathy, no bleeding, WBCT normal

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Investigations

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Management

Pre-Hospital First Aid

1. Reassure the patient — calm handling reduces venom spread
2. Immobilise the bitten limb — splint + firm crepe bandage to reduce muscular movement (reduces lymphatic spread)
3. Pressure-immobilisation bandaging — for confirmed or strongly suspected elapid/krait bite: apply a firm crepe bandage along the entire limb from bite site upward; aim to delay venom absorption until the patient reaches a facility with intubation/ventilation capability

• Pressure: enough to occlude lymphatics but not arterial flow (~40–70 mmHg on limb)
• Keep patient as still as possible; do not walk

1. Transport immediately to a hospital with antivenom and ventilatory support — rapidly and passively
2. If neurological signs appear before reaching hospital and intubation is unavailable, apply a tight (arterial) tourniquet above the bite for no more than 2 hours (releasing for 1 min every 30 min) as a last resort to delay respiratory arrest

• Incisions, excisions, sucking, cauterisation
• Electric shock therapy
• Herbal/traditional remedies
• Ice packs
• Tourniquets unless neurotoxic elapid confirmed and facilities unavailable

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Hospital Management

Step 1 — Assessment and Monitoring

• All patients bitten by a krait (confirmed or suspected) require minimum 24 hours observation regardless of initial symptoms
• Attach pulse oximeter, set up IV access, continuous ECG monitoring
• Serial neurological examination: ptosis, upward gaze, swallowing, neck flexion strength, respiratory rate, peak expiratory flow / vital capacity
• Establish WBCT20 immediately to rule out viper coagulopathy

Step 2 — Secure the Airway Early

"Do not wait for respiratory arrest before intubating."

• Signs requiring urgent intubation:
• Ptosis with progressive ophthalmoplegia
• Inability to lift the head
• Dysphagia, pooling of secretions
• SpO₂ falling
• Vital capacity <15–20 mL/kg or PEF dropping rapidly
• Any bulbar palsy
• Early elective intubation and mechanical ventilation is lifesaving — respiratory failure can be sudden
• Patients may require days to weeks of ventilation for presynaptic neurotoxin damage to resolve

Step 3 — Antivenom (Definitive Treatment)

• Any neurotoxic sign (ptosis, ophthalmoplegia, facial palsy, dysphagia, limb weakness)
• Evidence of systemic envenomation
• Confirmed krait bite within 6 hours — some authorities recommend antivenom even before symptoms appear, given the near-universal development of neurotoxicity and high ventilation rate (76% in Thai series); retrospective data shows better outcomes with antivenom given within 4 hours of bite

• Polyvalent (polyspecific) antivenom covering Bungarus species — most commonly available in India, Sri Lanka, Southeast Asia
• In India: Central Research Institute (CRI) Kasauli or VINS/BHARAT polyvalent ASV — covers cobra, common krait, Russell's viper, saw-scaled viper (the "Big Four")
• In Thailand: Bungarus candidus monovalent antivenom (Thai Red Cross) — specific for Malayan krait
• Children require the same dose as adults (not weight-adjusted — the venom dose is the same regardless of body weight)

• Initial dose: typically 10 vials (10 mL each = 100 mL) of polyvalent ASV
• Dilute in 100–250 mL normal saline; infuse over 30–60 minutes IV
• Observe closely during infusion for anaphylaxis
• If signs persist or worsen, repeat dose within 1 hour
• Important: Antivenom cannot reverse established presynaptic terminal damage — it is most effective when given early, before full neurological paralysis develops

Pre-treatment with subcutaneous adrenaline, antihistamine, or hydrocortisone before antivenom infusion reduces early reactions (used routinely in some centres).

Step 4 — Anticholinesterase Therapy (Neostigmine Test)

1. Pre-medicate with atropine sulphate IV — adult: 0.6 mg; children: 50 µg/kg — to block muscarinic side effects
2. Give edrophonium (Tensilon) IV — adult: 10 mg; children: 0.25 mg/kg — slowly
3. Observe for improvement in ptosis, respiratory muscle strength, or swallowing within 5–10 minutes
4. If positive response → maintain on neostigmine 0.5–2.5 mg IM/SC every 30 min + atropine 0.6 mg

Step 5 — Supportive Care

Step 6 — Monitoring Recovery

• Neurological recovery follows reversal order — limb strength returns before bulbar function
• Ptosis is often last to resolve
• Pre-synaptic damage requires axonal regeneration — mechanical ventilation may be needed for 1–6 weeks in severe cases
• Serial peak flow / vital capacity guides extubation timing

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Prognosis

• Untreated respiratory paralysis → death
• With early antivenom + mechanical ventilation: mortality can be low, but neurological recovery is slow
• Full recovery is expected if the patient survives the respiratory phase
• In Taiwan: B. multicinctus bite carries 18% case mortality — one of the highest among krait species

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WHO Syndrome 4A Summary (Krait)

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Autoimmune Haemolytic Anaemia (AIHA) — Treatment

Classification — The Foundation of Treatment Decisions

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Diagnosis Checklist Before Treatment

• ↓ Hb, ↑ reticulocyte count, ↑ LDH, ↑ indirect bilirubin, ↓ haptoglobin, blood film: spherocytes (wAIHA), agglutination (CAD), fragmentation (mixed/PCH)

• Direct Antiglobulin Test (DAT / direct Coombs) — positive for IgG (warm), C3d (cold), or both
• Indirect Coombs — detects serum autoantibodies

• Lymphoproliferative: CLL, lymphomas
• Autoimmune: SLE, rheumatoid arthritis
• Infections: EBV, CMV, M. pneumoniae (cold AIHA), HIV, HCV
• Drugs: fludarabine, checkpoint inhibitors (anti-PD1, anti-CTLA4), alemtuzumab, methyldopa, penicillin
• Post-HSCT

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Supportive Care (All Types)

Folic Acid

• 5–10 mg/day orally in all patients with active AIHA
• Increased erythropoiesis depletes folate; deficiency mimics treatment failure

Blood Transfusion

• Indicated when: severe symptomatic anaemia (Hb <6–8 g/dL), haemodynamic compromise, significant cardiac comorbidity
• Do not withhold transfusion because of "incompatible crossmatch" — the DAT will always interfere with crossmatching in AIHA
• Blood bank must be notified; provide least-incompatible packed RBCs
• Transfuse slowly: ≤1 mL/kg/hour (transfused cells will also be destroyed)
• In CAD and PCH: use pre-warmed RBCs (warmed to 37°C through a blood warmer)
• Rate: no more than 1 unit at a time, with close observation

Plasma Exchange (Plasmapheresis)

• Temporary measure — removes circulating antibodies
• No robust evidence for efficacy; use for life-threatening haemolysis while waiting for definitive therapy to work, or pre-operatively in cardiac/cold-exposure surgery
• More rational in IgM-mediated disease (CAD) as IgM is largely intravascular

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WARM AIHA — Treatment Algorithm

First-Line: Corticosteroids

• 80–85% of patients show significant improvement within 2–3 weeks
• Complete remission (CR = Hb ≥12 g/dL, no haemolysis): only ~30%
• 50–60% become corticosteroid-dependent — requiring >10–15 mg/day to maintain remission
• Only ~1/3 achieve sustained off-treatment CR at 1 year

Second-Line: Rituximab (preferred before splenectomy)

Current consensus: Rituximab is the preferred second-line agent before splenectomy in adults, and increasingly used as first-line together with corticosteroids.

Third-Line: Splenectomy

Fourth-Line: Other Immunosuppressives / Cytotoxics

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COLD AGGLUTININ DISEASE (CAD) — Treatment

Key Differences from Warm AIHA

• Corticosteroids: generally NOT effective (IgM-mediated complement activation is not suppressed by steroids)
• Splenectomy: NOT effective (destruction occurs in liver, not spleen)
• Avoid cold exposure: essential and always first step

General Measures (All CAD Patients)

• Avoid cold — especially cold air, cold water, cold food/drink, cold IV fluids
• Prompt treatment of intercurrent infections (M. pneumoniae, EBV) — infections → ↑ C3/C4 → exacerbation of haemolysis
• Influenza and pneumococcal vaccination (infections precipitate crises)
• Use blood warmers for all IV fluids and transfusions

Acute/Transient CAD (Post-infection)

• Usually self-limiting over weeks to months as underlying infection resolves
• Prewarmed packed RBCs if transfusion required
• Antibiotics for underlying M. pneumoniae (azithromycin, doxycycline)
• Short course of corticosteroids occasionally considered for severe cases
• Monitor; most resolve without specific immunosuppressive therapy

Chronic CAD (Symptomatic, Transfusion-Dependent)

Sutimlimab provides rapid reduction of haemolysis but requires ongoing administration — it blocks complement but does not deplete the underlying autoantibody-producing B-cell clone. It is particularly useful while waiting for rituximab to take effect.

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MIXED AIHA

• Both IgG and IgM antibodies present
• Usually steroid-responsive (IgG component)
• Can be treated with corticosteroids and splenectomy
• Responds to immunosuppressive therapy

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DRUG-INDUCED AIHA

• Stop the offending drug — this is the primary treatment
• IgG drug-adsorption type (penicillin): haemolysis resolves once drug is stopped
• True autoantibody type (methyldopa, fludarabine, checkpoint inhibitors): may persist after drug withdrawal; treat as warm AIHA
• Checkpoint inhibitor-related AIHA: high-dose corticosteroids; consider rituximab; hold or permanently discontinue checkpoint inhibitor

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SECONDARY AIHA — Treat the Underlying Cause

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Response Definitions (Used for Treatment Decisions)

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Treatment Comparison Summary

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