A patient presenting with fever + confusion is a neurological emergency. The core question is: Is there a CNS infection? If yes, what kind — and how do we treat it before irreversible damage occurs? This lecture teaches you a systematic clinical approach to differentiate CNS infections (meningitis, encephalitis, brain abscess) from non-CNS causes of fever with altered mental state, and covers the aetiologies, investigations (especially CSF interpretation), and management of each entity.

1) Clinical approach in patients presenting with fever and confusion 2) Common differential diagnoses in patients presenting with fever and confusion 3) Common aetiologies, clinical presentation, investigations, and management of patients with meningitis, encephalitis and brain abscess

Do not image everyone before LP. Routine pre-LP cranial imaging delays diagnosis and treatment. WHO 2025 recommends imaging first when there is a meaningful risk of a space-occupying lesion with shift: GCS < 10, focal neurological signs, cranial-nerve deficits, papilloedema, new-onset seizure in an adult, or severe immunocompromise. If imaging is unavailable, defer LP while these features persist. Stabilisation and antimicrobials must not wait.

The relevant danger is not “raised ICP” in the abstract—opening pressure may be raised in uncomplicated meningitis—but a pressure gradient from severe oedema or a space-occupying lesion with mass effect/midline shift. A normal CT does not by itself prove that LP is safe; interpret the scan with the examination and clinical trajectory.

• Non-contrast CT is rapid for mass effect, haemorrhage and hydrocephalus.
• Contrast CT or, preferably, contrast MRI better demonstrates abscess, leptomeningeal enhancement and tuberculoma.
• MRI with diffusion-weighted imaging is more sensitive for encephalitis and helps distinguish a pyogenic abscess from other ring-enhancing lesions.

• ~500 mL/day produced (by choroid plexus)
• Absorbed across the arachnoid villi by a valve-like mechanism
• Functions: mechanical support, regulating ionic composition, removal of metabolites
• Total volume in adults: ~150 mL; turnover ~3–4 times per day

Reading the circulation diagram: choroid plexus produces CSF in the ventricles → lateral ventricles → foramina of Monro → third ventricle → cerebral aqueduct → fourth ventricle → foramina of Magendie/Luschka → subarachnoid space around brain and cord → arachnoid granulations → dural venous sinuses. This anatomy links disease to complications: basal inflammatory exudate can obstruct circulation/reabsorption and cause hydrocephalus; arachnoid-granulation dysfunction more often produces a communicating pattern.

Diagnostic:

• CNS infections
• SAH where CT non-contrast is non-revealing (xanthochromia)
• Inflammatory conditions of the CNS (e.g. CNS vasculitis)
• Demyelinating disorders (e.g. multiple sclerosis — oligoclonal bands)
• Malignant disorders of the CNS (cytology)

Therapeutic:

• Therapeutic drainage of raised CSF pressure, especially repeated LP in cryptococcal meningitis when safe
• Intrathecal drug delivery uses lumbar access, but epidural anaesthesia is performed in the epidural space and is not an LP
• A large-volume tap may be used diagnostically/prognostically in suspected normal-pressure hydrocephalus; established hydrocephalus usually needs cause-specific or neurosurgical treatment

Also stabilise before LP if the airway is unprotected, there is respiratory compromise, shock, uncontrolled seizure or an uncorrected bleeding risk. Extensive/rapidly spreading purpura is another reason to defer. Numerical platelet and INR cut-offs vary across guidelines and institutions; the lecture's platelet < 50 × 10⁹/L and INR > 1.4 are common conservative thresholds, not universal biological boundaries. [12,13]

Headache, radicular symptoms and low back pain, bleeding, infection, cerebral herniation

The lecture recommends collecting at least 5 mL; collect adequate volume and allocate tubes according to local laboratory protocol

• Opening pressure measured in the relaxed lateral decubitus position before substantial CSF removal; the lecture gives 6–20 cm H₂O, while many adult references use an approximate upper reference around 20–25 cm H₂O depending on technique and patient factors
• Colour (normal: colourless; turbid/pus/xanthochromia/blood-stained)
• Total cell count + differential (normal adult CSF: < 5 nucleated cells/µL, not per mL)
• Glucose (+ paired serum glucose) ← this is mandatory; CSF glucose must always be interpreted as a ratio
• Protein (normal: 0.15–0.45 g/L)

The slide photographs contrast clear, colourless normal CSF with yellow xanthochromic CSF. Xanthochromia means coloured supernatant, most importantly bilirubin formed after in-vivo haemoglobin breakdown in subarachnoid haemorrhage; it is not synonymous with “red cells present.” High CSF protein and marked hyperbilirubinaemia can also colour CSF. A traumatic tap can add red cells without true bilirubin xanthochromia.

The photographic sequence shows the practical logic: lateral decubitus positioning permits an interpretable opening pressure; maximal lumbar flexion widens the interspinous spaces; the skin is prepared and draped using aseptic technique; local anaesthetic is infiltrated; the spinal needle is connected to a manometer before fluid is drained; CSF is then distributed into sterile labelled containers. Do not aspirate CSF forcefully. Recheck the patient neurologically and provide post-procedure safety-netting for post-dural-puncture headache, radicular pain, infection and bleeding.

Multiplex panels are adjuncts, not rule-out tests. They cover a limited pathogen list, may yield false positives, and do not replace Gram stain, bacterial culture and susceptibility testing. ^[12]

Non-microbiological tests:

• Oligoclonal bands — demyelinating disorders
• Cytology — CNS malignancy
• Autoimmune markers — autoimmune encephalitis (e.g. anti-NMDA receptor antibodies)

1. Calculate the glucose ratio (CSF glucose ÷ paired serum glucose):

   • Preserved ratio supports viral disease but is not definitive
   • Ratio ≤0.4 strongly raises bacterial, TB, fungal or malignant meningitis; the lecture's < 0.5 rule is a deliberately sensitive exam shortcut

2. Look at the predominant cell type:

   • PMN predominant + low glucose → bacterial meningitis
   • Lymphocyte predominant + low glucose → TB, fungal, partially-treated bacterial, malignant
   • Lymphocyte predominant + normal glucose → viral

3. Use protein and cell-count magnitude as context, not vetoes:

   • Very high neutrophils support pyogenic bacterial meningitis
   • Moderate lymphocytic/mixed pleocytosis with very high protein and low glucose supports TB/fungal disease, but overlap is substantial

2021 MCQ Q52 ^[4]: CSF: 80 cells/µL, 75% lymphocytes, protein 1.0 g/L, glucose 3.6 mmol/L, serum glucose 6 mmol/L.

• Glucose ratio = 3.6/6 = 60% (normal!)
• Lymphocytic predominance
• Protein raised
• Among the supplied choices, the preserved glucose ratio and lymphocyte predominance make viral meningitis (D) the best fit despite the higher-than-classic protein. “Best fit” is different from biological certainty.

2022 MCQ Q55 ^[5]: CSF: 180 cells/µL, 70% neutrophils/25% lymphocytes, protein 2.5 g/L, glucose 5.2 mmol/L, serum glucose 14 mmol/L.

• Glucose ratio = 5.2/14 = 37% ( < 50% → low!)
• The mixed/neutrophil-predominant pleocytosis could occur in pyogenic or early TB meningitis, while the modest cell count plus very high protein and low ratio favours TB among the supplied options.
• The keyed answer later in this note is C — tuberculous meningitis. The previous paragraph calling the same data “classic bacterial meningitis” was internally inconsistent and over-relied on neutrophil predominance.

Inflammation of the leptomeninges: caused by infection (bacterial, viral, fungal), neoplastic infiltration, or drug-induced aseptic meningitis

Routes of infection:

1. Direct spread from nearby structures — respiratory tract, ear (otitis media), sinus (sinusitis), dental infections, skull fractures
2. Haematogenous spread from a distant septic focus — e.g. pneumonia, infective endocarditis

The lecture labels TB meningitis a “very common” local cause. Treat this as an in-house emphasis to maintain a low diagnostic threshold in Hong Kong, not as a timeless incidence estimate.

Pathophysiology:

Rupture of a superficial infective granuloma on the pia mater into the subarachnoid space. May have concomitant pulmonary/systemic disease.

Clinical presentation:

Onset slower than bacterial meningitis. Fever and headache for several days to weeks.

From senior notes ^[7]: TB meningitis classically presents in three phases:

1. Prodromal phase (1–3 weeks): malaise, headache, low-grade fever, personality changes
2. Meningitic phase: meningism, protracted headache, vomiting, lethargy, confusion, cranial nerve/long tract signs
3. Paralytic phase: stupor, seizure, hemiparesis, death if untreated

Investigations [1,15]:

• Send adequate CSF for mycobacterial culture and a WHO-recommended molecular NAAT such as Xpert MTB/RIF or Ultra according to local availability. Smear is insensitive, culture is slow and no single negative test excludes TB meningitis.
• Neuroimaging (CT/MRI): hydrocephalus, meningeal enhancement, intracranial tuberculomas, cerebral infarct
• CXR, sputum AFB smear and culture

The slide montage reads left-to-right as acid-fast bacilli on microscopy, a chest radiograph without an obvious dramatic pulmonary focus, and contrast CT showing dense basal cisternal enhancement with small ring-enhancing tuberculomas. The key lesson is that pulmonary imaging can be unrevealing while CNS imaging shows the classic basal exudative pattern.

Management ^[1]:

• High mortality and morbidity amongst survivors
• Anti-TB treatment should be started if suspicious of TB meningitis (even if smear and PCR negative as limited sensitivity)
• Isoniazid, rifampicin, pyrazinamide, ethambutol
• Current standard adult framing: usually 2 months HRZE followed by 10 months HR (12 months total), adjusted for susceptibility, toxicity and specialist advice; HIV alone is not a routine indication for 18 months ^[15]
• Concomitant use of dexamethasone (tapering dose, given parenterally initially) — reduces risk of death and disability

Presentation:

• Subacute onset of headache and cognitive impairment
• 50% have underlying immunodeficiency (HIV, immunosuppressants, transplant recipients)

Investigations:

• Measure opening pressure and send CSF cryptococcal antigen (CrAg) plus fungal culture. CSF may show lymphocytes, raised protein and low glucose, but advanced HIV can produce little or no pleocytosis.
• The slide's Indian-ink image shows budding yeasts surrounded by clear halos where the polysaccharide capsule excludes the dark background. This is visually classic but less sensitive than CrAg and should not be the primary rule-out test.
• Serum CrAg supports disseminated infection/screening, but suspected meningitis still requires CSF assessment when safe.

Management ^[14]:

• Regimens depend on HIV status, resources and local infectious-disease policy. WHO's preferred HIV-associated regimen is single high-dose liposomal amphotericin B plus 14 days of flucytosine and fluconazole, followed by fluconazole consolidation and maintenance. Other settings may use daily liposomal amphotericin B plus flucytosine for the induction phase.
• Measure pressure at the diagnostic LP and use therapeutic repeat LPs for symptomatic raised ICP; this is a major survival intervention omitted from the slide. Mannitol, acetazolamide and routine corticosteroids do not substitute for CSF drainage.
• Monitor amphotericin-related renal/electrolyte toxicity and flucytosine-related cytopenias. In HIV, ART timing requires specialist coordination because starting too early increases cryptococcal IRIS risk.

Most immunocompetent adults with enteroviral meningitis recover with supportive care, but “benign and self-limiting” is not universal. HSV-2 and VZV can cause recurrent or complicated meningitis; neonates, older adults and immunocompromised patients need broader assessment, and encephalitis or myelitis changes urgency and treatment.

Common viruses:

Enteroviruses (echo, Coxsackie, polioviruses), HSV types 1 and 2, VZV, CMV, EBV, HIV

Management:

• Supportive care is appropriate for uncomplicated enteroviral meningitis after bacterial meningitis has been excluded.
• Treat HSV/VZV when clinically indicated and involve specialists for immunocompromised hosts; do not assume every lymphocytic CSF pattern is harmless.

• Meningeal adhesions → raised ICP, obstructive hydrocephalus, cranial nerve palsies
• Arteritis / thrombophlebitis → cerebral infarction
• Seizures and epilepsy
• Local spread of infection (cerebritis, cerebral abscess, subdural effusion/empyema)
• Intellectual impairment, cerebral palsy
• SIADH
• DIC
• Septic shock

Encephalitis is brain inflammation with cerebral dysfunction, caused by infection, autoimmunity or post-infectious inflammation. Altered mental status is central; fever, new seizures, focal deficits, CSF pleocytosis, compatible MRI or EEG abnormalities add support. Meningitis and encephalitis overlap as meningoencephalitis, and severe meningitis itself may impair consciousness—so “preserved cerebral function” is an oversimplification. [17,18]

Herpes viruses (HSV, VZV) — HSV-1 most common cause Enteroviruses, Influenza virus, Adenovirus, CMV, EBV, HIV Flaviviruses (e.g. Japanese encephalitis virus) Rabies virus

Inflammatory response involving the cortex, white matter, basal ganglia and brainstem Distribution of lesions varies with virus type:

Inclusion bodies may be present in neurons and glial cells. The lecture says polymorphonuclear perivascular infiltration, but typical viral encephalitis more often shows lymphocytic/mononuclear perivascular cuffing with microglial activation; neutrophils can occur early or with selected viruses. Neuronal degeneration and diffuse glial proliferation, often with cerebral oedema

• Fever
• Headache
• Focal neurological signs — dysphasia, hemiplegia, visual field defects
• Seizures
• Confusion
• Altered level of consciousness — mild lethargy to deep coma

From the Neurology Introduction lecture ^[9]: the triad of viral encephalitis is fever, confusion and convulsion.

Neuroimaging:

• CT: hypodensity in frontotemporal lobes (HSV)
• MRI: hyperintensity (T2/FLAIR) in frontotemporal lobes (HSV); bilateral thalamic hyperintensity (Japanese encephalitis)

The image pair makes the anatomic pattern concrete: HSV-1 shows asymmetric left medial temporal/insular T2 hyperintensity, whereas Japanese encephalitis shows bilateral thalamic hyperintensity. These are high-yield distributions, not perfectly specific signatures. MRI is more sensitive than CT and diffusion/haemorrhagic sequences can reveal early HSV disease. ^[17]

CSF:

• Lymphocytic predominant pleocytosis (neutrophils may predominate in early stages)
• Normal glucose, mild elevation in protein
• Positive pathogen-specific CSF PCR or intrathecal antibody test, depending on the virus; a negative result may need timing-aware repetition

Send HSV PCR on all suspected encephalitis CSF. A negative result very early in illness does not exclude HSV; if the syndrome or temporal MRI remains compatible, continue aciclovir and repeat CSF PCR after 3–7 days. Routine viral culture is not recommended. ^[17]

EEG:

Temporal lateralised periodic discharges (LPDs, formerly PLEDs) can support HSV encephalitis but are not pathogen-specific. EEG's most urgent role is detecting nonconvulsive seizures/status in a confused or comatose patient. ^[17]

Aciclovir 10 mg/kg IV every 8 hours for 14–21 days is a common adult HSV regimen; adjust for renal function and body-weight convention, ensure hydration and monitor creatinine Should be started in ALL patients with suspected viral encephalitis Significantly reduced mortality of HSV encephalitis Antiseizure medications may be needed

Bacteria may enter the brain substance by:

• Penetrating trauma
• Direct spread from paranasal sinuses or the middle ear
• Haematogenous spread — may lead to multiple abscesses
• Untreated congenital heart disease is a risk factor (right-to-left shunting can result in bacteria directly affecting the brain; increased risk of developing infective endocarditis; immunocompromised state)

Why right-to-left shunts? Normally, blood passes through the lungs where the pulmonary capillary bed filters out bacteria. With an R→L shunt (e.g. Fallot's tetralogy), bacteria bypass the lung filter and seed the brain directly.

Initial cerebritis evolves into central pus, a vascular granulation-tissue/collagen capsule and surrounding reactive gliosis with vasogenic oedema.

This explains ring enhancement: the vascularised capsule enhances while the necrotic/purulent core does not. On MRI, pus characteristically restricts diffusion, helping distinguish a pyogenic abscess from many necrotic tumours.

Can present over days to weeks

• Headache
• Changes in mental status
• Focal neurological deficits
• Seizures
• Raised intracranial pressure

Note: fever may be absent or low-grade in brain abscess — unlike meningitis where fever is typically high.

• CT brain: single or multiple hypodense lesions, ring enhancement with contrast, surrounding cerebral oedema
• Lumbar puncture potentially hazardous (mass effect → herniation risk)
• Stereotactic CT-guided aspiration or incision and drainage are important to aid microbiological diagnosis

The paired CT images show the same left temporal lesion before and after contrast: on the non-contrast scan it is a rounded hypodense intra-axial lesion with extensive surrounding vasogenic oedema and sulcal effacement; after contrast it develops a smooth ring-enhancing capsule around a non-enhancing core. Ring enhancement is not specific—necrotic tumour, metastasis, tuberculoma and toxoplasmosis remain alternatives. MRI with diffusion-weighted imaging is the preferred diagnostic study when available. ^[16]

• Community-acquired, immunocompetent: a third-generation cephalosporin plus metronidazole is the ESCMID-recommended empirical regimen, then narrow to aspiration/culture results.
• Post-neurosurgical: a carbapenem plus vancomycin or linezolid is recommended rather than merely “consider vancomycin.” Severe immunocompromise needs additional pathogen-directed coverage with specialist input.
• Source control: aspiration or excision is recommended whenever feasible (toxoplasmosis is an important exception). In a stable patient, antibiotics may briefly await aspiration only if neurosurgery can occur promptly, preferably within 24 hours; never withhold in severe disease.
• Duration: commonly 6–8 weeks, individualised to drainage, organism, imaging response and host factors.
• Treat clinical seizures, but routine primary antiseizure prophylaxis is not recommended. Reserve glucocorticoids for severe symptoms from perifocal oedema or impending herniation because they may reduce capsule enhancement and antimicrobial penetration. Hyperosmolar therapy is a temporary rescue for impending herniation, not routine abscess treatment.

The coronal meningeal diagram localises these entities: dura lines the skull, arachnoid bridges the sulci, and pia closely follows the cortical surface. CSF and major vessels occupy the subarachnoid space; meningitis primarily inflames pia-arachnoid (leptomeninges). Pus between skull and dura is epidural; pus between dura and arachnoid is subdural; pus within cortex/white matter is a brain abscess. Subdural empyema can spread widely because the subdural compartment is a potential space.

Bacteria, viruses, fungi, protozoa (rare)

Acute (hours–days), subacute (days–weeks), chronic (symptoms > 4 weeks)

1. Common condition with high mortality and morbidity if treatment delayed
2. Quick septic workup including blood cultures before antibiotics only when this causes no treatment delay
3. Early lumbar puncture if no contraindications
4. Initial high-dose broad-spectrum parenteral antibiotics that penetrate the blood-brain barrier, subsequent streamlining with availability of microbiological results
5. Regular monitoring of neurological status and vital signs
6. Look for the primary infective focus AND complications
7. Close liaison with microbiologist, neurologist and neurosurgeon

SAQ (see 2019 Q10 ^[3]):

• "A 35-year-old man with fever and confusion for 2 days, develops generalised tonic-clonic convulsion. No focal neurological deficit."
  • Most likely clinical diagnosis? → Viral encephalitis / meningoencephalitis
  • Three investigations? → MRI brain (CT if MRI unavailable or urgent pre-LP imaging is indicated), LP with CSF analysis/PCR when safe, and EEG; also obtain blood cultures and metabolic/sepsis tests
  • Three infective causes? → HSV, enterovirus, Japanese encephalitis
  • Empirical antimicrobial therapy? → IV aciclovir + IV ceftriaxone (cover both viral and bacterial until differentiated)

MCQ — CSF interpretation (appears almost every year):

• Given CSF values + serum glucose → calculate ratio → identify the best-fitting pattern
• A preserved ratio with lymphocytes supports viral disease; a low ratio with neutrophils supports pyogenic bacterial disease; a low ratio with lymphocytic/mixed cells and very high protein supports TB/fungal/partially-treated bacterial disease. Expect overlap.

MCQ — LP contraindications:

• For the lecture's exam stems, remember platelets < 50 × 10⁹/L and INR > 1.4; clinically, follow local procedure policy.
• Papilloedema, GCS < 10, focal/CN signs, new adult seizure or severe immunocompromise → image before LP/defer LP, without delaying treatment. ^[12]

MCQ — Organism associations:

• S. suis + pigs
• Cryptococcus + immunosuppression
• HSV encephalitis + temporal lobe involvement
• Japanese encephalitis + thalamus
• Young woman + psychiatric symptoms + dyskinesia = anti-NMDA receptor encephalitis