Acute meningoencephalitis differential
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"meningoencephalitis" AND "differential diagnosis"
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Acute Meningoencephalitis - Differential Diagnosis
Acute meningoencephalitis (fever + meningism + encephalopathy/altered consciousness) has a broad differential. The following framework organizes it by category, with clues and CSF patterns.
1. Viral (Most Common)
Herpesviruses
| Virus | Key Clues |
|---|---|
| HSV-1 | Most common sporadic fatal encephalitis; behavioural/personality change, temporal lobe seizures, olfactory hallucinations; MRI: medial temporal + insular FLAIR signal; EEG: periodic lateralized discharges |
| HSV-2 | More common in neonates and immunocompromised; also cauda equina neuritis + recurrent aseptic meningitis (Mollaret) |
| VZV | Vesicular rash (may be absent); reactivation in elderly/immunocompromised; can cause stroke via vasculitis |
| CMV | Almost exclusively immunocompromised (HIV, transplant); periventricular enhancement on MRI |
| EBV | Sore throat, lymphadenopathy, transient rash, mild icterus; atypical lymphocytosis |
| HHV-6 | Post-transplant; limbic encephalitis phenotype |
Enteroviruses (Coxsackie, Echovirus, Enterovirus 71)
- Peak: August-September
- Fecal-oral, family outbreaks, mostly children
- Herpangina (grayish vesicles), exanthem, pleurodynia, orchitis (group B Coxsackie)
- LMN weakness (echo, Coxsackie, EV-71)
Arboviruses (Arthropod-Borne)
| Virus | Geography/Season |
|---|---|
| West Nile | Americas; late summer; polio-like flaccid paralysis; elderly severely affected |
| Japanese B | East Asia |
| Eastern/Western Equine | Americas; high mortality (EEE) |
| La Crosse | US midwest; children |
| St. Louis | US; elderly |
| Tick-borne | Russia, E. Europe |
| Dengue | Tropics; back/muscle pain, retro-orbital headache |
CSF: initial PMN pleocytosis converting rapidly to lymphocytosis, normal glucose - Goldman-Cecil Medicine, p. 3229
Other Viruses
| Virus | Clue |
|---|---|
| Mumps | Late winter/spring; orchitis, parotitis; males 3x more |
| LCM (Lymphocytic choriomeningitis) | Rodent contact (mice, hamsters); autumn-winter; pulmonary infiltrates may precede |
| HIV (primary) | Seroconversion illness; rash, lymphadenopathy; high viral load |
| Rabies | Animal bite without prophylaxis; hydrophobia, aerophobia, ascending paralysis |
| Influenza | Parainfectious mechanism; rare direct invasion |
| Parvovirus B19 | Children (fifth disease); adults with altered immunity |
| Nipah/Hendra | South/Southeast Asia; bat exposure, agricultural contact |
2. Bacterial
Acute Pyogenic Meningitis (may have encephalopathy component)
- Neisseria meningitidis - young adults, clusters; purpuric rash (petechiae/palpable purpura); can cause Waterhouse-Friderichsen
- Streptococcus pneumoniae - all ages; often with pneumonia, sinusitis, mastoiditis, basilar skull fracture
- Listeria monocytogenes - neonates, elderly, immunocompromised, pregnant women; rhombencephalitis phenotype
- Group B Streptococcus - neonates
- E. coli K1 - neonates
- H. influenzae type b - unvaccinated children
- S. aureus / Gram-negatives - nosocomial, post-neurosurgery, post-trauma
Chronic/Subacute Bacterial Causes (may present acutely)
- Mycobacterium tuberculosis - subacute onset but may be acute; lymphocytes, very low glucose, very high protein; basal exudate; CN palsies; contact/travel history
- Treponema pallidum (neurosyphilis) - meningovascular form; syphilitic chancre history; positive serology
- Lyme disease (Borrelia burgdorferi) - tick exposure, erythema migrans; facial nerve palsy; radiculopathy
- Leptospirosis - water/animal exposure; jaundice, uveitis, renal failure (Weil disease)
- Rickettsia (RMSF, typhus) - rash (starts peripherally in RMSF, spreads centripetally); geographic/seasonal predilection; ~10% have CSF pleocytosis >100 cells
- Mycoplasma pneumoniae - atypical pneumonia; cold agglutinins
- Whipple disease - dementia, oculomasticatory myorhythmia, diarrhea, weight loss; PAS-positive organisms on biopsy
3. Fungal
| Organism | Setting |
|---|---|
| Cryptococcus neoformans | AIDS (CD4 <100), transplant; indolent-to-fulminant; India ink, CrAg; Virchow-Robin space expansion on MRI |
| Cryptococcus gattii | Immunocompetent; Pacific Northwest; cryptococcomas with mass effect |
| Candida | Nosocomial, NICU, immunocompromised; microabscesses |
| Aspergillus / Mucor | Neutropenic, diabetic ketoacidosis (Mucor); necrotizing vasculitis; hemorrhagic infarcts |
| Histoplasma, Coccidioides, Blastomyces | Endemic areas; primary pulmonary then CNS dissemination |
CSF: lymphocytic pleocytosis, low glucose, high protein; elevated opening pressure - Robbins, p. 4342-4354
4. Parasitic / Protozoal
| Organism | Key Features |
|---|---|
| Naegleria fowleri (Primary amebic meningoencephalitis) | Healthy young swimmers in warm freshwater; rapid fulminant course; amebae in CSF |
| Acanthamoeba / Balamuthia (Granulomatous amebic encephalitis) | Immunocompromised; subacute/chronic; skin lesions |
| Toxoplasma gondii | HIV (CD4 <100); multiple ring-enhancing lesions on MRI; may have focal signs |
| Plasmodium falciparum (Cerebral malaria) | Travel to endemic region; tropical fever pattern; RBCs in blood smear |
| Trypanosoma | Africa (T. brucei); sleeping sickness, hypersomnia; Winterbottom sign (posterior cervical LN) |
| Taenia solium (Neurocysticercosis) | Seizures; cystic lesions with scolex on MRI; endemic areas |
5. Non-Infectious Mimics - Critical "Must Not Miss"
Autoimmune / Paraneoplastic Encephalitis
- Anti-NMDA receptor encephalitis - young women, ovarian teratoma; psychiatric prodrome, memory loss, seizures, dyskinesias, autonomic instability; may follow HSV encephalitis
- Limbic encephalitis (LGI1, CASPR2, AMPAR, GABA-B antibodies) - temporal lobe signal on MRI, hyponatremia (LGI1 faciobrachial tonic seizures), associated malignancy
- Hashimoto encephalopathy - autoimmune thyroiditis; steroid-responsive; anti-TPO/anti-thyroglobulin antibodies
Source: Goldman-Cecil Medicine, p. 3232-3233
Parainfectious / Post-Infectious
- ADEM (Acute Disseminated Encephalomyelitis) - follows viral illness or vaccination by days-weeks; multifocal white matter lesions; children > adults
- PANDAS - post-streptococcal; pediatric neuropsychiatric symptoms
Structural / Vascular
- Brain abscess - focal signs precede/accompany; ring-enhancing lesion; lacks true nuchal rigidity
- Subdural empyema - focal signs disproportionate to fever; mass effect on CT/MRI
- Cerebral venous sinus thrombosis - prothrombotic states, OCP use, puerperium; headache, seizures, papilledema; no fever usually
- Superior sagittal sinus thrombosis - can mimic meningitis with fever + headache
- Subarachnoid hemorrhage - thunderclap headache; no prodromal fever; xanthochromia on CSF; blood on CT
Toxic / Metabolic
- Neuroleptic malignant syndrome - antipsychotic use; fever + rigidity + AMS + autonomic instability; markedly elevated CK
- Chemical meningitis - post-LP or spinal anesthesia; after metrizamide myelography; leakage from epidermoid/craniopharyngioma
Neoplastic
- Carcinomatous meningitis - known malignancy; can produce low glucose + PMN pleocytosis; CSF cytology positive
- Primary CNS lymphoma - especially EBV-related in HIV; may mimic encephalitis
CSF Profile - Quick Reference
| Condition | Cells | Glucose | Protein | Pressure |
|---|---|---|---|---|
| Bacterial (pyogenic) | 200-20,000 PMN | Very low (<45) | Very high (>50) | +++ |
| Viral / Aseptic | 100-1000 lymphocytes | Normal | Mod. elevated | Normal-+ |
| Fungal / TB | 100-1000 lymphocytes | Low | High | +++ |
| Spirochetal (syphilis, lepto) | 25-2000 lymphocytes | Normal or low | High | + |
| Subarachnoid hemorrhage | RBCs, xanthochromia | Normal | High | +++ |
| Paraneoplastic | Normal/mild lymphocytes | Normal | Mildly elevated | Variable |
Source: Jawetz, Melnick & Adelberg's Medical Microbiology 28e, Table 48-2
Approach to Narrowing the Differential
History clues:
- Season/geography (arboviruses, leptospirosis, endemic fungi)
- Animal/insect exposure (rabies, LCM, Lyme, tick-borne encephalitis, malaria)
- Immune status (fungal, CMV, Toxoplasma, Listeria, EBV-lymphoma)
- Age (neonates: GBS, E. coli, Listeria; young adults: N. meningitidis, enteroviruses, HSV; elderly: Listeria, pneumococcus)
- Rash character (meningococcal purpura vs. enteroviral maculopapular vs. RMSF peripheral petechiae)
- Preceding illness or vaccination (ADEM, parainfectious)
- Psychiatric prodrome in young woman (anti-NMDA receptor encephalitis)
Key investigations:
- Urgent CT before LP (if focal signs, papilledema, or immunocompromised)
- LP: opening pressure, cells + differential, glucose (with simultaneous blood glucose), protein, Gram stain + culture, PCR multiplex (HSV, EBV, CMV, enteroviruses, bacteria), CrAg, India ink, VDRL, AFB
- MRI brain with gadolinium: temporal lobes (HSV), periventricular (CMV), ring-enhancing (abscess, Toxo), multifocal white matter (ADEM, PML)
- Serology: arbovirus IgM/IgG, Lyme, Mycoplasma, Brucella
- Autoimmune panel: anti-NMDA-R, LGI1, CASPR2, AMPAR, GABA-B, VGKC
- Blood: malaria smear + PCR, blood cultures, procalcitonin, anti-TPO
Empirical treatment while awaiting results: acyclovir (10 mg/kg IV q8h) + empirical antibiotics (ceftriaxone + vancomycin ± ampicillin for Listeria) - do not delay for diagnosis - Tintinalli's Emergency Medicine, p. 1050-1052
Sources: Adams and Victor's Principles of Neurology 12th ed. | Goldman-Cecil Medicine | Harrison's Principles of Internal Medicine 22E | Robbins, Cotran & Kumar Pathologic Basis of Disease | Tintinalli's Emergency Medicine | Jawetz, Melnick & Adelberg's Medical Microbiology 28e | Symptom to Diagnosis 4th ed.
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Transfusion target
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"red blood cell transfusion" AND "restrictive" AND "threshold"
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PMID: 37824153
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Transfusion Targets (RBC)
Core Principle: Restrictive Strategy is the Default
Based on ~50 RCTs and the 2023 AABB International Guidelines (Carson et al., JAMA 2023, PMID 37824153), restrictive transfusion thresholds are non-inferior to liberal thresholds across virtually all adult patient populations. Transfusing at lower hemoglobin (Hb) levels results in equivalent rates of mortality, MI, stroke, pneumonia, thrombosis, and infection.
One unit of packed RBCs raises Hb by ~1 g/dL and Hct by ~3%.
Thresholds by Clinical Setting
| Clinical Context | Transfusion Threshold (Hb) | Target After Transfusion | Strength |
|---|---|---|---|
| General hospitalized adults (hemodynamically stable) | < 7 g/dL | 7-9 g/dL | Strong recommendation, moderate evidence |
| Critically ill adults (ICU) | < 7 g/dL | 7-9 g/dL | Strong; TRICC trial |
| Septic shock | < 7 g/dL | 7-9 g/dL | TRISS trial (no benefit from 9 g/dL target) |
| Cardiac surgery (peri-op) | ≤ 7.5 g/dL | 7.5-10 g/dL | SCA guidelines; TRACS trial |
| Orthopedic surgery | < 8 g/dL | - | FOCUS trial |
| Preexisting cardiovascular disease | < 8 g/dL | - | Moderate evidence |
| Acute coronary syndrome / acute MI | < 8 g/dL | - | Higher threshold appropriate |
| Upper GI hemorrhage | < 7 g/dL | - | Restrictive superior (Villanueva et al.); lower mortality and less rebleeding |
| Esophageal varices / portal hypertension | < 7 g/dL | 7-9 g/dL | Restrictive significantly reduces 6-week mortality |
| Hematologic/oncologic malignancies | < 7 g/dL | - | Conditional recommendation, low certainty (2024 Cochrane) |
| Pediatric ICU (stable, no hemoglobinopathy) | < 7 g/dL | - | Strong recommendation, moderate evidence |
| Pediatric congenital heart disease - biventricular repair | 7 g/dL | - | Conditional |
| Pediatric congenital heart disease - single-ventricle palliation | 9 g/dL | - | Conditional |
| Very preterm neonates | Separate ETTNO/TOP trial-based thresholds | - | 2024 guideline (PMID 38874929) |
Situations Warranting a Higher Threshold
From Goldman-Cecil Medicine:
- Symptomatic anemia (angina, dyspnea, orthostatic hypotension despite volume)
- Acute coronary syndrome / acute MI - Hb < 8 g/dL
- Severe thrombocytopenia (concurrent)
- Chronic transfusion-dependent patients
"Don't Transfuse By Number Alone" - Symptoms also Trigger
Clinical indications regardless of Hb level:
- Hemodynamic instability not responsive to fluids
- Symptomatic anemia (chest pain, signs of cardiac ischemia, tachycardia unresponsive to fluids)
- Active hemorrhage with estimated blood loss > circulating volume
Special Scenarios with Uncertainty
Acute neurologic injury (TBI, stroke, subarachnoid hemorrhage):
- Hb <9 g/dL and RBC transfusion are both independently predictive of poor outcome - this makes the decision difficult
- Evidence is insufficient to support a clear restrictive threshold in TBI; these patients are often excluded from major RCT
- Active trials are ongoing (2025 meta-analysis PMID 40518044 addresses this)
- Current practice: many centres use Hb 8-10 g/dL as a pragmatic target, individualized
Key Landmark Trials
| Trial | Population | Restrictive | Liberal | Result |
|---|---|---|---|---|
| TRICC (1999) | Critically ill ICU | Hb > 7 g/dL | Hb > 10 g/dL | No difference in mortality; less transfusion |
| TRACS (2010) | Post-cardiac surgery | Hct > 24% | Hct > 30% | No difference in 30-day mortality/morbidity |
| FOCUS (2011) | Hip fracture, CVD/DM > 50 yrs | Hb > 8 g/dL | Hb > 10 g/dL | No difference in walking test, mortality; 1/3 the transfusions |
| Villanueva (2013) | Upper GI hemorrhage | Hb < 7 g/dL | Hb < 9 g/dL | Restrictive: lower 6-week mortality, less rebleeding |
| TRISS (2014) | Septic shock | Hb < 7 g/dL | Hb < 9 g/dL | No benefit from higher target |
Other Blood Products - Triggers at a Glance
(Goldman-Cecil Medicine, Table 162-4)
| Component | Threshold |
|---|---|
| Platelets - prophylactic (hypoproliferative) | < 10,000/µL |
| Platelets - febrile, septic, minor procedure | < 20,000/µL |
| Platelets - surgery, LP, invasive procedure, active bleeding | < 50,000/µL |
| Platelets - neurosurgery / CNS bleeding | < 100,000/µL |
| FFP | Massive transfusion; PT/PTT > 1.5x normal with active bleeding |
| Cryoprecipitate | Fibrinogen < 100 mg/dL with active bleeding |
Sources: Goldman-Cecil Medicine | Barash Clinical Anesthesia 9e | Miller's Anesthesia 10e | Current Surgical Therapy 14e | 2023 AABB Guidelines, JAMA (PMID 37824153)
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