Enteric Fever (Typhoid Fever)

Etiology and Microbiology

• Agent: S. Typhi (major cause); S. Paratyphi A, B, C (less frequent). Unlike non-typhoidal Salmonella, these serovars have no known animal reservoir - humans are the only host.
• S. Typhi possesses three key antigens: O (somatic), H (flagellar), and Vi (virulence/capsular polysaccharide). At least 80 phage types exist, useful for epidemiological tracing.
• Survives intracellularly in tissue macrophages; readily killed by drying, pasteurization, and common disinfectants.

Epidemiology

• Global burden: An estimated 9.2-21 million typhoid cases and 5 million paratyphoid cases occur annually, with 110,000-280,000 deaths per year.
• Endemic regions: Indian subcontinent (India, Pakistan, Bangladesh, Nepal), Eastern Mediterranean, and Africa bear the highest burden. Incidence can exceed 1,000 cases per 100,000 children in some urban areas of South Asia.
• In developed countries: Disease is rare; most cases (~78%) are travel-associated, predominantly from travelers to India, Pakistan, and Bangladesh. In the US, ~5,700 cases are estimated annually (far more than the ~350 reported).
• Highest incidence age group: 5-19 years. Males are more often affected; females have a higher chronic carrier rate.
• Transmission: Fecal-oral route via contaminated food or water. Risk factors include contaminated drinking water/ice, raw produce fertilized with sewage, street food, prior H. pylori infection (associated with reduced gastric acidity), and ill household contacts.

Pathogenesis

1. S. Typhi penetrates the small intestinal mucosa, particularly via M cells overlying Peyer's patches.
2. Organisms are phagocytosed by macrophages and transported to mesenteric lymph nodes.
3. A primary bacteremia follows, with seeding of the liver, spleen, gallbladder, bone marrow, and Peyer's patches.
4. Bacterial replication in macrophages and a secondary bacteremia produce the classic sustained fever.
5. The gallbladder is a key site of colonization - organisms re-enter the intestinal lumen in bile, causing characteristic hyperplasia, ulceration, and necrosis of Peyer's patches in the third/fourth week.

Clinical Course

• Headache: 80%
• Fever: >75%
• Chills: 35-45%
• Cough: 30%
• Anorexia: 55%
• Abdominal pain: 30-40%
• Nausea: 18-24%, vomiting: 18%
• Diarrhea: 22-28%; constipation: 13-16%

• Rose spots (~30%): Faint, salmon-colored, blanching maculopapular rash on the trunk/chest; 2-3 crops; lasts 2-5 days. S. Typhi can be cultured from biopsy of these lesions.
• Relative bradycardia (<50% at peak fever)
• Hepatosplenomegaly (3-6%)
• Coated tongue (51-56%)

Rose spots of enteric fever (S. Typhi / S. Paratyphi infection). Harrison's Principles of Internal Medicine 22e.

Complications (~27% of hospitalized patients)

• Intestinal hemorrhage (6%): From ulceration of Peyer's patches in the 3rd-4th week
• Intestinal perforation (1%): Life-threatening; requires immediate surgery + broad-spectrum antibiotics for polymicrobial peritonitis

• Meningitis, Guillain-Barré syndrome, neuritis
• "Muttering delirium" or "coma vigil" (picking at bedclothes - characteristic of typhoid encephalopathy)

Carriers

• Temporary (convalescent): Excrete bacilli for 6-8 weeks; 4% still positive at 3 months
• Chronic: Excrete for >1 year (sometimes decades); organisms persist in the gallbladder/biliary tract; faecal carriers more common than urinary carriers; Vi antibody present in ~80% of chronic carriers
• Famous historical example: "Typhoid Mary" - caused >1,300 cases over her lifetime

Diagnosis

• Blood culture: Positive in 40-80% during the first 2 weeks (sensitivity declines after week 2)
• Bone marrow culture: Most sensitive (85-95%), positive even after partial antibiotic treatment - preferred in antibiotic-pre-treated cases
• Stool culture: Positive in weeks 2-3; less sensitive early
• Rose spot biopsy: Can grow the organism

• Leukopenia/neutropenia (15-25%)
• Leukocytosis more common in children and in complications (perforation, secondary infection)
• Mildly elevated liver enzymes and muscle enzymes

• Widal test (anti-O and anti-H antibodies): Widely used but poor specificity and sensitivity; not reliable in endemic areas; cross-reactions common
• Typhidot: Detects IgM/IgG against a 50 kDa outer membrane protein - faster, more sensitive
• Vi antibody: Present in ~80% of chronic carriers - useful for carrier detection

Treatment

Antibiotic Therapy (based on susceptibility)

• XDR typhoid: Ongoing epidemic in Pakistan since 2016 (Sindh province); susceptible only to azithromycin and carbapenems. Multiple imported cases documented in the US and UK.
• In the US, >66% of S. Typhi isolates are DSC - empiric fluoroquinolones should NOT be used, especially in South Asia travelers.
• Relapse rates are lower with azithromycin than with fluoroquinolones or ceftriaxone.

• Corticosteroids (dexamethasone): For severe/complicated disease with delirium, coma, or shock - IV dexamethasone 3 mg/kg initial dose, then 1 mg/kg every 6 hours x 48 hours total

• 4 weeks of oral ciprofloxacin or norfloxacin (concentrated in bile)
• Cholecystectomy + antibiotics if medical therapy fails

Vaccination

• TCVs are recommended by WHO for routine immunization in endemic countries. A 2025 Cochrane review (PMID: 40326553) confirmed their superiority over earlier Vi polysaccharide vaccines in providing durable protection.
• Neither vaccine is 100% protective; food/water precautions remain essential.

Prevention and Control (Three Lines of Defence - Park's)

1. Control of reservoir: Early diagnosis + isolation; treatment of cases; identification and treatment of carriers (ampicillin/amoxicillin 4-6 g/day + probenecid x 6 weeks, or cholecystectomy); follow-up stool/urine cultures
2. Sanitation: Safe water supply, sewage treatment, food hygiene - the "weakest link in the chain"
3. Immunization: Especially for travelers to endemic areas and school-age children in endemic regions

Key Points to Remember

• Enteric fever is a misnomer - fever is present in >75% but abdominal pain in only 30-40%
• Rose spots are pathognomonic when present but seen in only ~30%
• Bone marrow culture is the gold standard diagnostic test
• XDR typhoid from Pakistan is a growing threat - only azithromycin and carbapenems work
• Chronic carriage (gallbladder) is a risk factor for gallbladder cancer
• Complications peak in the 3rd-4th week - intestinal perforation is the most feared surgical emergency

Hemorrhagic Stroke

Classification

Part 1: Intracerebral Hemorrhage (ICH)

Etiology and Causes

1. Hypertensive vasculopathy - most common; long-standing hypertension causes lipohyalinosis and degenerative changes in small penetrating arteries → rupture → deep/basal ganglia hemorrhage
2. Cerebral amyloid angiopathy (CAA) - amyloid deposition in cerebral vessel walls; typically in older adults; tends to cause lobar hemorrhages; increasingly important as hypertension control improves (now accounts for >50% of cases on some neurology services)

1. Primary (hypertensive) ICH
2. Ruptured saccular aneurysm
3. Ruptured arteriovenous malformation (AVM) / venous malformations
4. Cavernous angioma
5. Trauma (including posttraumatic delayed apoplexy)
6. Hemorrhagic disorders: leukemia, aplastic anemia, thrombocytopenia, liver disease, anticoagulant/thrombolytic therapy, hemophilia
7. Hemorrhage into brain tumors (primary or metastatic)
8. Septic embolism, mycotic aneurysm
9. Hemorrhagic transformation of ischemic stroke
10. Cerebral venous sinus thrombosis (CVST)
11. Sympathomimetic drugs (cocaine, amphetamines)
12. Moyamoya disease, PRES, RCVS

High-risk features suggesting secondary ICH: lobar location, intraventricular blood, and younger age.

Sites of Hemorrhage (and Clinical Features)

Pathophysiology

1. Mass effect from the hematoma
2. Activation of the coagulation cascade
3. Release of inflammatory cytokines
4. Blood-brain barrier (BBB) disruption
5. Perihematomal edema (develops over hours to days)
6. Raised intracranial pressure (ICP) → cerebral herniation

Hematoma Expansion

• Occurs in 20-40% of patients in the first few hours
• Contrast extravasation on CTA ("spot sign") predicts ongoing bleeding and hematoma expansion
• Expansion is a major determinant of poor outcome

Clinical Presentation

• Sudden onset focal neurologic deficits corresponding to hematoma location
• Headache (more common in ICH than ischemic stroke, but not universal)
• Nausea, vomiting
• Decreased level of consciousness (may progress rapidly to coma)
• Seizures (~10%)
• No single clinical feature reliably distinguishes ICH from ischemic stroke - neuroimaging is mandatory

Diagnosis

• Hyperdense (bright white) lesion = acute blood
• Highly sensitive for hemorrhages >1 cm
• Performed immediately; results guide all subsequent management

• Identifies underlying aneurysm, AVM, or fistula
• Detects "spot sign" (contrast extravasation = hematoma expansion risk)
• CT venography (CTV) to rule out CVST

• Better sensitivity for underlying lesions (tumors, cavernous malformations)
• Gradient echo (GRE) / susceptibility-weighted imaging (SWI) highly sensitive for microbleeds and subacute/chronic blood

ICH Score (Prognostic Scale)

Management of ICH

A. Airway/Breathing/Circulation

• Intubate for GCS ≤ 8 or deteriorating airway
• Maintain oxygen saturation >94%
• Avoid hypotension

B. Blood Pressure Control

• Target SBP <140 mmHg (AHA/ASA guidelines) for patients presenting with SBP 150-220 mmHg - safe and reduces hematoma expansion
• A 2025 meta-analysis (PMID: 40739079) confirms intensive BP lowering reduces hematoma expansion but does not clearly improve functional outcome - the evidence remains nuanced
• IV agents: labetalol, nicardipine, clevidipine
• Avoid excessive lowering (target MAP ≥ 70 mmHg to maintain cerebral perfusion)

C. Reversal of Anticoagulation

• Warfarin (INR elevated): Vitamin K (IV) + 4-factor prothrombin complex concentrate (4F-PCC) - preferred over FFP due to faster, more complete reversal
• Heparin: Protamine sulfate
• Direct oral anticoagulants (DOACs):
  • Dabigatran → Idarucizumab (specific reversal)
  • Factor Xa inhibitors (rivaroxaban, apixaban) → Andexanet alfa or 4F-PCC
• Antiplatelet agents: Platelet transfusion no longer routinely recommended (may worsen outcome)

D. ICP Management

• Head of bed at 30°
• Avoid hypotonic fluids
• Osmotic therapy: mannitol or hypertonic saline
• External ventricular drain (EVD) for hydrocephalus
• Avoid steroids (not beneficial in ICH, may worsen outcomes)

E. Glucose and Temperature Control

• Treat hyperthermia (>38°C) aggressively
• Treat hypo- and hyperglycemia
• Target normoglycemia

F. Seizure Management

• Clinical seizures: treat with levetiracetam or fosphenytoin
• Prophylactic antiepileptics not recommended routinely

G. Surgical Intervention

• Cerebellar hemorrhage >3 cm with neurological deterioration or brainstem compression → urgent surgical evacuation (suboccipital craniotomy)
• Supratentorial ICH: controversial - minimally invasive surgery (MIS) techniques (endoscopic evacuation, stereotactic aspiration) are gaining evidence
• A 2025 Cochrane review (PMID: 40673401) on surgery for supratentorial ICH found benefit for MIS approaches, though definitive evidence is still evolving
• Craniotomy for large superficial hemorrhages in deteriorating patients may be considered

Part 2: Subarachnoid Hemorrhage (SAH)

Etiology

• ~80%: Ruptured saccular (berry) aneurysms - small, thin-walled outpouchings at vessel bifurcations, particularly within the circle of Willis
• Remainder: AVMs, cavernous angiomas, mycotic aneurysms, CNS vasculitis, perimesencephalic hemorrhage (benign)
• ~25% of people with a berry aneurysm have multiple aneurysms

Clinical Presentation

• Onset may be associated with exertion, Valsalva, or sexual intercourse
• Headaches peaking >60 minutes after onset are unlikely to be SAH

• Syncope (often the initial manifestation)
• Nausea and vomiting
• Neck stiffness (meningismus)
• Photophobia
• Seizures

• Up to 20% have focal neurologic deficits
• Pupil dilation + third nerve palsy → posterior communicating artery aneurysm compressing CN III
• Altered or fluctuating consciousness (~50%)
• Subhyaloid (pre-retinal) hemorrhages on fundoscopy (Terson syndrome)

SAH Grading Scales

Diagnosis

1. Non-contrast CT head (first test): Highly sensitive for SAH in the first 6-12 hours (sensitivity ~98% within 6 h)
   • Hyperdense blood in the basal cisterns, Sylvian fissures, and sulci
2. Lumbar puncture (LP): If CT is negative but SAH is suspected (≥6 hours after headache onset)
   • Look for xanthochromia (yellow discoloration of CSF) - most specific finding
   • Elevated RBC count that does not decrease from tube 1 to tube 4
3. CT angiography (CTA): Non-invasive; good sensitivity (~95%) for aneurysms >3mm
4. Digital subtraction angiography (DSA): Gold standard for aneurysm identification and planning treatment; recommended in all cases of suspected aneurysmal SAH

Complications of SAH

• Occurs in ~30% of SAH patients
• Prevented and treated with nimodipine (oral calcium channel blocker) - the only drug proven to improve neurological outcome in SAH
• Maintained euvolemia (avoid dehydration)
• Induced hypertension if vasospasm is refractory ("triple H" therapy is now more refined - mainly hypertension + euvolemia)

Management of SAH

Immediate stabilization

• Airway, breathing, circulation
• Treat hypertension cautiously (do not drop BP precipitously before aneurysm is secured, as perfusion pressure may be needed)
• Analgesia and antiemetics
• Strict bed rest, quiet environment, avoid Valsalva

Securing the aneurysm (prevents rebleeding)

• Endovascular coiling: Preferred for most aneurysms; catheter-based; lower procedural morbidity
• Neurosurgical clipping: Open craniotomy; preferred for large/complex aneurysms or those with associated hematoma requiring surgical evacuation
• The choice between coiling and clipping depends on aneurysm morphology, location, patient age, and institutional expertise

Prevention of vasospasm/DCI

• Nimodipine 60 mg PO every 4 hours x 21 days (standard of care)
• Maintain euvolemia; avoid hypovolemia
• Serial transcranial Doppler (TCD) monitoring
• If vasospasm confirmed: induced hypertension, cerebral angioplasty ± intra-arterial vasodilators

ICP management

• EVD for hydrocephalus or ICP monitoring
• Head of bed at 30°

Key Distinguishing Features

Recent Evidence (2025)

• Blood pressure lowering in ICH (PMID: 40739079, 2025 meta-analysis): Intensive BP lowering (target SBP <140) reduces hematoma expansion, though functional outcome benefit remains uncertain at the population level.
• Surgery for supratentorial ICH (PMID: 40673401, Cochrane 2025): Evolving evidence supporting minimally invasive surgical evacuation over craniotomy.
• Cerebral amyloid angiopathy guidelines (PMID: 40721902, 2025): Updated international statement on CAA diagnosis and management, reflecting its growing role as a cause of lobar ICH.

Recent Neuroimaging Findings in Intracerebral Hemorrhage (ICH) - 2024-2026

1. Non-Contrast CT (NCCT): Hematoma Texture Signs for Predicting Expansion

• History of hypertension
• NCCT acquired within ≤3 hours of onset
• Combined heterogeneity (black hole + blend sign)
• Combined irregularity (satellite + island sign)

2. CT Angiography (CTA) and the Spot Sign - Critical Reappraisal

• Single-phase CTA spot sign features that improve predictive accuracy:
  • Number of spots (more = higher risk)
  • Volume of each spot
  • CT density of the spot
  • Co-localization with NCCT hypodensities (blend/black hole signs)
• Multiphase/dynamic CTA (newer approach) adds dynamic information:
  • Timing of contrast appearance
  • Volume increase over phases = active expansion
  • Volume decrease = tissue dispersion (different biology)
  • Density changes across phases

3. "CTA-for-All" in Acute ICH - Ending Diagnostic Nihilism

1. Etiological diagnosis: CTA identifies secondary causes (aneurysm, AVM, dural arteriovenous fistula, CVST, tumoral bleeding) in a clinically significant proportion - driving specific acute and secondary prevention decisions
2. Prognostication: CTA improves outcome prediction beyond NCCT alone
3. Treatment prediction: Spot sign and related features can predict HE expansion and select patients for targeted interventions
4. Safety: Minimal risk of contrast nephropathy; no meaningful procedural delay when integrated into standard stroke imaging protocol
5. Cost: A "CTA-for-all-ICH" approach is economically justified given diagnostic yield
6. Implementation: Simply continuing the same ischemic stroke imaging protocol through the hemorrhagic phase

4. Deep Learning and AI-Assisted Imaging in ICH

4a. DL for Hematoma Expansion Prediction from NCCT

• Best model: 2D-ResNet-101 achieved AUC = 0.777 on external validation
• Outperformed the BRAIN score and combined clinical-radiomics models (AUC improvement of 0.087-0.119)
• Gradient-weighted class activation mapping (Grad-CAM) revealed the model focused on hematoma margins and heterogeneous density regions - biologically plausible areas of active bleeding
• Key implication: NCCT-based DL can predict HE without requiring CTA, which is important in resource-limited settings

4b. AI-Driven Hematoma Segmentation and Surgical Planning

• nnU-Net-based automated hematoma and skull segmentation (Dice similarity coefficient 0.90 for hematoma, 0.99 for skull)
• CT reorientation using ocular landmarks
• Safety zone delineation with dual anatomical corridors
• Automated trajectory planning for minimally invasive surgery (MIS)

5. Perihematomal Edema (PHE) as an Imaging Biomarker

• PHE volume on CT/MRI predicts neurological deterioration independent of hematoma volume
• PHE growth in the acute stage (measured on serial CT) is now being modeled with prediction algorithms (Zhang et al., Clin Neurol Neurosurg, PMID: 39126898)
• A 2026 RCT post-hoc analysis (Polymeris et al., Neurocrit Care, PMID: 40399657) examined the relationship between hemoglobin levels and PHE after ICH, finding that lower hemoglobin correlates with greater PHE - suggesting anemia management as a potential imaging-linked therapeutic target
• APOE ε4 genotype influences PHE severity (Wang et al., 2025, PMID: 40764846): APOE ε4 carriers have significantly greater PHE, offering a radiogenomic link relevant to CAA patients
• A 2025 RCT (Chen et al., BMC Medicine, PMID: 41353144) used PHE on imaging as a primary outcome measure to assess normobaric hyperoxia as a neuroprotective intervention - PHE was meaningfully reduced in the treatment arm

6. Cerebral Amyloid Angiopathy (CAA) - Advanced MRI Biomarkers

• Lobar microbleeds on susceptibility-weighted imaging (SWI) / gradient echo (GRE)
• Cortical superficial siderosis (CSS) - linear hemosiderin deposits along cortical surface
• Centrum semiovale perivascular spaces (enlarged)
• White matter hyperintensities in CAA-specific patterns

• Amyloid PET (Pittsburgh Compound B, florbetapir): can detect vascular amyloid-β in vivo, potentially enabling pre-symptomatic CAA diagnosis
• The concept of "dynamic natural history" (periods of high CAA activity vs. remission) is now proposed to explain episodic imaging changes
• Iatrogenic CAA (from amyloid-β inoculation, e.g., via contaminated growth hormone) is a newly described entity with distinct neuroimaging characteristics - providing a unique "pure model" of CAA with known exposure time

7. Population-Based Neuroimaging Risk Assessment (2026 Perspective)

• Neuroimaging markers are now guiding both primary ICH prevention (e.g., white matter hyperintensity burden, microbleed counts guiding anticoagulation decisions) and secondary prevention (e.g., whether to restart anticoagulation after ICH)
• ICH survivors face competing risks: ICH recurrence vs. arterial ischemic events - neuroimaging phenotyping (lobar vs. deep ICH, microbleed distribution, CAA vs. hypertensive pattern) drives these individualized decisions
• Hematoma volume and perihematomal edema are becoming modifiable targets, not just prognostic markers
• Recovery after ICH is significantly slower than after ischemic stroke, with improvement documented through 1 year post-ictus - reinforcing the need for serial imaging follow-up

Summary Table: Recent Neuroimaging Advances in ICH