Meningitis is an inflammation of the meninges surrounding the brain and spinal cord, most commonly caused by infectious agents such as bacteria, viruses, or fungi, presenting with headache, neck stiffness, and fever.

Meningitis

2. Epidemiology

Age Group	Most Common Bacterial Pathogens
Neonates (< 1 month)	Group B Streptococcus (S. agalactiae), E. coli, Listeria monocytogenes ^[2]^[3]^[5]
Infants (1–3 months)	GBS, E. coli, Listeria, also early S. pneumoniae, N. meningitidis
Children (3 months – 5 years)	N. meningitidis, S. pneumoniae, H. influenzae type b ^[5]
Children/Young Adults	N. meningitidis, S. pneumoniae ^[2]
Adults	S. pneumoniae (most common), N. meningitidis ^[2]^[3]
Elderly (> 60 years)	S. pneumoniae, N. meningitidis, Gram-negative bacilli, Listeria monocytogenes ^[2]

High Yield – Age-Related Aetiology

The bimodal Listeria risk (neonates and elderly/immunocompromised) is a classic exam question. Think of Listeria whenever you see extremes of age or immunocompromised states. ^[2]^[3]

3. Risk Factors

Understanding risk factors helps you predict the likely organism and guides empirical therapy.

Risk Factor	Mechanism / Why It Matters
Extremes of age (neonates, elderly)	Immature/declining immune function; neonates lack mature complement, opsonisation, IgG; elderly have immunosenescence
Immunocompromised states (HIV, post-transplant, chemotherapy, chronic steroid use)	Impaired cell-mediated immunity → susceptibility to Listeria, Cryptococcus, TB, Toxoplasma
Asplenia / hyposplenia (splenectomy, sickle cell disease)	Spleen is critical for clearing encapsulated bacteria; loss → overwhelming infection with S. pneumoniae, N. meningitidis, H. influenzae (the classic encapsulated trio) ^[6]^[7]
Diabetes mellitus	Impaired neutrophil function, ↑ susceptibility to S. pneumoniae, Klebsiella (liver abscess → endogenous endophthalmitis and meningitis)
Alcoholism / chronic liver disease	Impaired complement, opsonisation, neutrophil function → ↑ risk S. pneumoniae ^[2]
Chronic kidney disease	Uraemic immune dysfunction
Complement deficiency (especially terminal complement C5–C9)	Cannot form the membrane attack complex → ↑↑ susceptibility to Neisseria species specifically

Risk Factor	Mechanism
CSF leak (e.g., base of skull fracture, post-neurosurgery)	Direct communication between subarachnoid space and non-sterile environments (nasopharynx, paranasal sinuses) → recurrent S. pneumoniae meningitis ^[2]
Cochlear implants	Foreign body + surgical tract → ↑ risk of S. pneumoniae meningitis
Indwelling CSF devices (VP shunt, EVD)	Biofilm formation → S. epidermidis, S. aureus, Gram-negative bacilli ^[2]
Contiguous infection (otitis media, sinusitis, mastoiditis, dental abscess)	Direct spread from nearby structures ^[1] — organisms extend through bone or dural defects into meninges
Skull fracture	Dural tear → direct inoculation

Risk Factor	Relevant Organism
Close contact / crowding (dormitories, military barracks)	N. meningitidis ^[3]
Exposure to raw pork / pigs	Streptococcus suis ^[2]^[3]
Unpasteurised milk/soft cheese	Listeria monocytogenes ^[2]
Travel to meningitis belt	N. meningitidis serogroup A
TB contact / endemic area	Mycobacterium tuberculosis ^[1]^[4]
HIV	Cryptococcus neoformans, TB, Toxoplasma
Neurosurgery	S. aureus, S. epidermidis, Gram-negative bacilli
IV drug use	S. aureus, Gram-negative bacilli

4. Anatomy and Function of the Meninges

Understanding the anatomy is essential to grasp why meningitis presents the way it does and where the infection actually sits.

5. Aetiology (with Pathophysiology)

Category	Timeline	Typical Causes
Acute meningitis	Hours to days	Bacteria or viruses ^[1]
Subacute / chronic meningitis	Days to weeks to months	Mycobacteria, fungi, or atypical bacteria ^[1]

5.2 Acute Bacterial Meningitis (Pyogenic)

5.2.2 Specific Bacterial Pathogens

5.3 Viral (Aseptic) Meningitis

"Aseptic" meningitis historically means meningitis with negative routine bacterial cultures — it includes viral causes (most common), but also partially-treated bacterial meningitis, TB, fungal, drug-induced, and autoimmune causes.

5.4 Subacute / Chronic Meningitis

5.4.1 Tuberculous Meningitis (TBM)

Very common cause of meningitis in Hong Kong ^[1] — this cannot be overstated for local practice.

Stage	Description
I	Fully conscious, no focal neurological deficits
II	Confusion/lethargy OR focal neurological deficit (e.g., CN palsy, hemiparesis)
III	Stupor/coma ± dense neurological deficit

Higher stage = worse prognosis.

Category	Examples
Infective	TB, Cryptococcus, Brucella, Actinomyces, Listeria, cysticercosis, amoeba
Non-infective: malignant	Leptomeningeal carcinomatosis (CA breast, CA lung, leukaemia, lymphoma)
Non-infective: inflammatory	Sarcoidosis, SLE, Behçet's disease
Drug-induced aseptic meningitis	NSAIDs, IVIG, TMP-SMX, intrathecal agents

6. Classification

Type	Timeline	Key Causes
Acute	< 1 week	Bacterial (pyogenic), viral
Subacute	1–4 weeks	TB, partially-treated bacterial, fungal
Chronic	> 4 weeks	TB, Cryptococcus, syphilis, malignancy, sarcoidosis

Category	Examples
Bacterial (pyogenic)	S. pneumoniae, N. meningitidis, H. influenzae, GBS, E. coli, Listeria, S. suis, S. aureus
Viral (aseptic)	Enterovirus, HSV-2, mumps, HIV, VZV, EBV, arboviruses
Mycobacterial	M. tuberculosis
Fungal	Cryptococcus neoformans, Coccidioides, Histoplasma
Parasitic	Angiostrongylus cantonensis (eosinophilic meningitis), cysticercosis, amoeba
Non-infectious	Malignancy, sarcoidosis, SLE, Behçet's, drug-induced

Parameter	Normal	Bacterial	Viral	TB	Fungal (Crypto)
Appearance	Clear, colourless	Turbid/purulent	Clear	Clear/slightly turbid, fibrin web	Clear
Opening pressure	6–20 cmH₂O	↑↑↑	Normal/mildly ↑	↑↑	↑↑↑
WBC	< 5/μL	↑↑↑ (100–10,000+)	↑ (10–500)	↑↑ (50–500)	↑ (20–500)
Predominant cell	—	Neutrophils	Lymphocytes	Lymphocytes	Lymphocytes
Protein	0.15–0.45 g/L	↑↑	Normal/mildly ↑	↑↑↑ (can be very high, up to 2–6 g/dL) ^[2]	↑↑
Glucose (CSF:serum ratio)	> 0.6	↓↓ (< 0.4)	Normal	↓↓ (very low)	↓↓
Special tests	—	Gram stain, culture, PCR	Viral PCR	AFB smear/culture, PCR, ADA	India ink, CrAg

CSF Interpretation – High Yield Learning Point

"Bacterial meningitis shows neutrophilic pleocytosis with low glucose and high protein. Viral meningitis demonstrates lymphocytic predominance with normal glucose. TB meningitis presents with lymphocytes, very low glucose, and markedly elevated protein." ^[10]

Remember: glucose is low in bacterial and TB because bacteria/mycobacteria consume glucose and the inflamed meninges have impaired glucose transport across the BBB. Glucose is normal in viral meningitis because viruses don't consume glucose the same way.

7. Clinical Features

7.1 Symptoms

Pathogen	Distinctive Symptoms	Pathophysiological Basis
N. meningitidis	Petechial/purpuric rash, arthralgia	Meningococcal endotoxin → DIC → consumption of platelets + clotting factors → petechiae/purpura; septic emboli
S. suis	Hearing loss	Organising exudate damages CN VIII/cochlea
S. pneumoniae	History of preceding URTI/otitis media/sinusitis/pneumonia	Direct spread from contiguous infection
Listeria	Prodrome of fever + GI symptoms; brainstem symptoms (diplopia, dysphagia, dysarthria)	Tropism for brainstem (rhombencephalitis)
TBM	Insidious onset over days to weeks; weight loss, night sweats	Granulomatous inflammation is inherently slower than pyogenic
Enterovirus	Rash, conjunctivitis, diarrhoea, pharyngitis, hand-foot-mouth	Enteroviruses infect gut epithelium → viraemia → CNS; also cause mucocutaneous manifestations

7.2 Signs

Sign	Complication	Mechanism
Purpura fulminans	DIC (meningococcal)	Endotoxin-mediated coagulation cascade activation
Hypotension, shock	Septic shock / Waterhouse-Friderichsen	Vasodilation (sepsis) + adrenal haemorrhage
Focal neurological deficit	Cerebral infarction	Obliterative endarteritis of leptomeningeal arteries
Hearing loss (Weber/Rinne testing)	CN VIII damage	Exudate damaging cochlear nerve; labyrinthitis
↑ Head circumference (infants)	Hydrocephalus	CSF obstruction by adhesions
Opisthotonus	Severe meningeal irritation / raised ICP	Extreme hyperextension of spine due to intense reflex spasm

Pathophysiological Process	Clinical Manifestation
Meningeal inflammation → nociceptor stimulation	Headache, neck stiffness, photophobia
Raised ICP (vasogenic + cytotoxic + interstitial oedema)	Headache, vomiting, ↓ consciousness, papilloedema, Cushing's triad
Cranial nerve entrapment in basal exudate	CN palsies (III, IV, VI, VII, VIII), hearing loss
Obliterative endarteritis of leptomeningeal arteries	Cerebral infarction → focal neurological deficits, hemiparesis, aphasia
DIC (especially meningococcal)	Petechiae, purpura, Waterhouse-Friderichsen syndrome
CSF flow obstruction by adhesions	Hydrocephalus → worsening ↑ ICP
SIADH (CNS disease)	Hyponatraemia → seizures, ↓ consciousness
Direct brain parenchymal damage (meningoencephalitis)	Altered mental status, seizures, focal deficits
Cytotoxic factors from bacteria + neutrophils	Cytotoxic cerebral oedema → ↑ ICP

High Yield Summary

Definition: Meningitis = inflammation of the leptomeninges, defined by ↑ WBC in CSF. Distinguish from meningism (signs without CSF inflammation).
Epidemiology: In HK, TBM is a very common cause. S. pneumoniae is the commonest bacterial cause in adults. S. suis is a unique local pathogen (pork exposure → SNHL).
Risk factors: Extremes of age, immunocompromised, asplenia (encapsulated organisms), CSF leak, neurosurgery, complement deficiency (Neisseria), contiguous infections (sinusitis, otitis).
Source of infection: Direct spread from nearby structures (ear, sinus, dental) or haematogenous spread from distant septic foci.
Pathophysiology: Bacteria cross BBB → multiply in immunologically privileged CSF → bacterial components trigger cytokine storm → BBB disruption → vasogenic/cytotoxic/interstitial oedema → ↑ ICP → ↓ cerebral perfusion. Pus can organise into adhesions → hydrocephalus. Endarteritis obliterans → cerebral infarction. CN damage at base of brain → hearing loss.
Classical triad: Fever + headache + neck stiffness — but complete triad present in only ~44%.
Meningeal signs: Kernig's (hamstring spasm on knee extension), Brudzinski's (hip flexion on neck flexion) — specific but insensitive. Bulging fontanelle in infants.
Red flags requiring immediate LP/treatment: Petechial rash with fever, altered consciousness, focal neurological deficits, seizures.
CSF patterns: Bacterial (↑ neutrophils, ↓ glucose, ↑ protein), viral (↑ lymphocytes, normal glucose), TB (↑↑↑ lymphocytes, ↓↓ glucose, ↑↑↑ protein).
TBM: Insidious onset, triphasic illness, basal meningeal adhesions → CN palsies + hydrocephalus, endarteritis obliterans → infarction.
Listeria: Extremes of age + immunocompromised; resistant to cephalosporins → must add ampicillin.
Chemoprophylaxis: Meningococcal contacts → ciprofloxacin or IM ceftriaxone; H. influenzae contacts → rifampicin.

Active Recall - Meningitis (Definition, Epidemiology, Risk Factors, Aetiology, Pathophysiology, Clinical Features)

Differential Diagnosis of Meningitis

The clinical presentation of meningitis — fever, headache, neck stiffness, altered mental status, seizures — is not unique to meningeal infection. Many conditions can mimic it, and conversely, several different aetiologies can cause true meningitis. The differential diagnosis therefore operates on two levels:

What else could present like meningitis? (i.e., DDx of the syndrome of fever + headache + neck stiffness ± altered consciousness)
Given that the patient has true meningitis (confirmed CSF pleocytosis), what is the aetiology? (i.e., DDx within meningitis itself)

Both levels are clinically critical — you must simultaneously consider alternative diagnoses and narrow the aetiological cause of true meningitis.

GC Lecture Slide – Learning Outcomes

"Common differential diagnosis in patients presenting with fever and confusion" is explicitly listed as a learning outcome of the GC 051 lecture ^[1]. The emphasis is on the clinical approach to a patient with fever + neurological symptoms — not just meningitis, but its close mimics.

9.2 Level 1: Conditions That Mimic Meningitis (DDx of the Syndrome)

These are conditions that present with some combination of fever, headache, neck stiffness, or altered consciousness but are not meningitis.

Condition	Key Differentiating Features	Why It Mimics Meningitis
Encephalitis	Altered mental status, personality/behavioural change, seizures, focal deficits are prominent; meningeal signs may be absent or mild	Brain parenchymal inflammation causes cerebral dysfunction; often co-exists with meningitis (meningoencephalitis). "Presence or absence of normal brain function is the important distinguishing feature between meningitis and encephalitis" ^[14]^[15] — patients with pure meningitis retain normal cerebral function; those with encephalitis have altered mental status, personality and behavioural change, sensory or motor deficits, speech and movement disorders ^[14]^[15]
Subarachnoid haemorrhage	Thunderclap headache (sudden onset, maximal at onset), ± ↓ consciousness; blood in subarachnoid space irritates meninges → true meningism, but LP shows xanthochromia and RBCs, not WBCs	Blood in the subarachnoid space chemically irritates meninges → neck stiffness, photophobia. Low-grade fever can occur reactively. The key is the sudden onset (seconds, not hours/days) and CT showing subarachnoid blood ^[16]
Brain abscess	Fever, seizures, focal neurological deficits (FND) ^[3]; headache progressive over days to weeks; often preceded by sinusitis/otitis/dental infection or haematogenous source (IE, lung abscess). Meningeal signs less prominent unless abscess ruptures into subarachnoid space/ventricles	Expanding intracranial mass causes ↑ ICP → headache and confusion. Fever from the infective focus. LP is contraindicated if mass effect present (risk of herniation). Cross-sectional imaging to exclude intracranial mass before LP ^[17]
Subdural empyema	Collection of pus between dura and arachnoid ^[3]; often spreads from sinusitis, AOM, mastoiditis, or trauma/operative wounds ^[3]. Rapidly progressive with fever, headache, focal deficits, seizures, ↓ consciousness	Meningeal irritation from adjacent pus; raised ICP from mass effect. CT/MRI shows crescentic extra-axial collection
Cerebral venous sinus thrombosis (CVST)	Headache (may be thunderclap or progressive), seizures, focal deficits; risk factors include OCP, pregnancy, thrombophilia, dehydration	Headache and ↑ ICP mimic meningitis; fever may be present if septic thrombosis (e.g., from sinusitis/otitis). Diagnosed by CT/MR venography
Raised ICP from any cause (tumour, hydrocephalus)	Progressive headache worse with Valsalva/lying down, papilloedema, ↓ consciousness, CN VI palsy (false localising)	↑ ICP causes headache, vomiting, and altered consciousness — the same triad as meningitis minus the fever. However, if a tumour becomes necrotic or causes chemical meningitis, fever may develop
Ventriculitis	Complication of severe meningitis or rupture of brain abscess, high mortality ^[3]; ↓ consciousness, fever, high CSF WCC	Usually not a primary DDx but a complication that makes meningitis worse

Meningitis vs. Encephalitis — The Core Distinction

"Patients with meningitis may have altered mental status and appear lethargic but their cerebral function remains normal. Seizures and post-ictal states can be seen with meningitis alone and should not be construed as definitive evidence of encephalitis." ^[14]^[15]

In practice, the distinction is often blurred because meningoencephalitis is common (infection of both meninges and brain). However, abnormal cerebral function (personality change, aphasia, hemiparesis, movement disorders beyond what would be explained by post-ictal state or ↑ ICP) points toward encephalitis.

Condition	Key Differentiating Features	Why It Mimics Meningitis
Systemic sepsis with delirium	Source of infection identifiable (pneumonia, UTI, intra-abdominal); confusion is part of sepsis-associated delirium; neck stiffness absent or mild. Meningitis, encephalitis, and brain abscess are listed as precipitating factors for delirium ^[18]	Sepsis → systemic inflammatory response → cerebral dysfunction (septic encephalopathy) → confusion + fever. No true meningeal inflammation. LP is normal
Sinusitis / mastoiditis / otitis media	Localised facial/ear pain, purulent discharge, preceding URTI; headache is frontal or periorbital, not generalised; no true meningism	Contiguous spread can cause meningitis (so these are both DDx and RF for meningitis). As standalone conditions they cause headache + fever but without meningeal signs. Complications of sinusitis include meningitis and intracranial abscess ^[16]
Severe systemic viral infection (e.g., influenza)	Myalgia, respiratory symptoms, self-limiting; may have headache and "neck ache" from myalgia but no true nuchal rigidity	High fever + generalised body aches (including neck muscles) + headache + malaise can resemble meningitis clinically. LP is normal
Drug-induced meningism	Temporal relationship with drug administration (NSAIDs, IVIG, TMP-SMX, intrathecal agents); resolves when drug stopped	Drug components can irritate meninges → "aseptic meningitis" with actual CSF pleocytosis but sterile cultures. This is technically drug-induced meningitis, not just meningism
Heat stroke	Hyperthermia ( > 40°C), altered consciousness, history of heat exposure; may have meningism	Extreme hyperthermia → cerebral dysfunction + meningeal irritation. LP is normal unless concurrent CNS pathology

This is a common clinical trap — not all neck stiffness is meningeal.

Condition	How to Distinguish
Cervical spondylosis	Usually causes generalised stiffness (not just flexion-extension) ^[2] — restriction in all planes of movement, worse with rotation/lateral flexion; no fever; chronic history
Cervical muscle spasm / torticollis	Unilateral, often positional; no fever or systemic upset
Cervical lymphadenitis / retropharyngeal abscess	Tender lymph nodes; sore throat; odynophagia; limited neck extension; fever present but from local infection
Subarachnoid haemorrhage	True meningism (blood irritating meninges) but LP shows xanthochromia/blood, not infection
Tonsillar / peritonsillar abscess	Odynophagia, trismus, "hot potato" voice; neck movement restricted due to pain, not true meningism
Vertebral osteomyelitis / epidural abscess	Back pain, point tenderness over spine, fever; neurological deficits from cord compression (not meningeal irritation)

9.3 Level 2: Aetiological Differential Diagnosis Within Confirmed Meningitis

Once LP confirms CSF pleocytosis, the next step is determining the cause. The tempo of illness and CSF profile are the two most powerful tools.

Tempo	Causes	Key Clinical Clues
Hyperacute (hours)	N. meningitidis (often preceded by URTI, purpuric rash, DIC), S. pneumoniae (explosive onset, rapid progression to death in hours) ^[2]	Rapidly deteriorating patient with sepsis features
Acute (1–5 days)	Bacterial (pyogenic), viral	Acute febrile illness with meningeal signs
Subacute (days to weeks)	TB (most common locally) ^[2], partially-treated bacterial, fungal, Listeria (can be subacute), neurosyphilis	Insidious onset of malaise, headache, low-grade fever for days to weeks ^[1]^[2]; CN palsies; contact/risk factors
Chronic ( > 4 weeks)	TB, Cryptococcus, sarcoidosis, malignancy, SLE, Behçet's, syphilis	Progressive neurological deficit over weeks to months; investigations for underlying cause essential

The CSF examination is the single most important investigation. The pattern of pleocytosis, glucose, and protein narrows the differential dramatically.

CSF Pattern	Predominant Cell	Glucose	Protein	Most Likely Aetiology
Neutrophilic pleocytosis, ↓↓ glucose, ↑↑ protein	Neutrophils	Low ( < 0.4 CSF:serum ratio)	High	Bacterial (pyogenic) meningitis ^[10]
Lymphocytic pleocytosis, normal glucose, normal/↑ protein	Lymphocytes	Normal	Normal or mildly ↑	Viral meningitis ^[10]
Lymphocytic pleocytosis, ↓↓ glucose, ↑↑↑ protein	Lymphocytes	Very low	Very high (up to 2–6 g/dL) ^[2]	TB meningitis ^[10]
Lymphocytic pleocytosis, ↓ glucose, ↑↑ protein, +ve CrAg	Lymphocytes (± monocytes)	Low	High	Cryptococcal meningitis (DDx of TBM ^[2])
Lymphocytic pleocytosis, normal glucose, ↑ protein, malignant cells on cytology	Lymphocytes ± malignant cells	Normal or low	High	Leptomeningeal carcinomatosis
Mixed/lymphocytic pleocytosis, low glucose, ↑ protein, +ve VDRL	Lymphocytes	Low	High	Neurosyphilis ^[19]
Eosinophilic pleocytosis	Eosinophils	Normal or low	↑	Parasitic (Angiostrongylus cantonensis, cysticercosis), drug-induced, fungal (Coccidioides)
Elevated protein, normal WCC (albuminocytological dissociation)	Few cells	Normal	High	Guillain-Barré syndrome ^[10] — this is not meningitis but can cause neck stiffness and back pain

The TB vs. Cryptococcus Dilemma in Hong Kong

TBM and cryptococcal meningitis have very similar CSF profiles (lymphocytic, low glucose, high protein) and are both common in Hong Kong, especially in HIV patients. Key differentiators:

CrAg (cryptococcal antigen in CSF and serum) — highly sensitive and specific for cryptococcal meningitis
CSF ADA (adenosine deaminase) — raised in TBM
CSF AFB smear/culture/PCR — definitive for TBM but low sensitivity for smear (~10–20%)
India ink — low sensitivity (~50%) for Cryptococcus; CrAg is far superior
"D/dx: cryptococcal meningitis" is explicitly noted as the main DDx of TBM ^[2]

Pitfall	Explanation
Early viral meningitis may show neutrophils	In the first 24–48 hours, viral meningitis can have a neutrophilic predominance that later shifts to lymphocytes. If unsure, repeat LP at 12–24 hours
Partially-treated bacterial meningitis	Prior antibiotic administration can partially sterilise cultures and shift the CSF profile toward a "lymphocytic, low glucose" pattern mimicking TBM. Always ask about prior antibiotics
Listeria meningitis may show mixed cells	Listeria can cause a polymorphonuclear or mixed cellular response, unlike most other causes of lymphocytic meningitis
TB meningitis early on may show neutrophils	The earliest stages of TBM can have a neutrophilic predominance before the classic lymphocytic pattern emerges
Normal CSF does NOT exclude early meningitis	LP performed very early (within hours of symptom onset) may show a normal CSF. If clinical suspicion is high, empirical treatment should be started and LP repeated

Clue	Favoured Diagnosis	Why
Non-blanching purpuric rash ^[5]	N. meningitidis	DIC → dermal microthrombi → petechiae/purpura
Preceding otitis media / sinusitis / pneumonia	S. pneumoniae	Direct contiguous spread or bacteraemia from respiratory source ^[2]^[3]
Exposure to raw pork / pigs	S. suis	Enters through skin wounds → haematogenous → CNS ^[2]^[3]
Unpasteurised milk / soft cheese	Listeria	Foodborne → bacteraemia → crosses BBB ^[2]^[3]
Insidious onset, weight loss, night sweats, TB contact	TBM	Granulomatous inflammation is inherently slow ^[1]^[2]
HIV / severe immunosuppression	Cryptococcus, TB, Listeria, CMV	Impaired cell-mediated immunity ^[2]
Complement deficiency (C5–C9)	Neisseria meningitidis	Cannot form membrane attack complex → recurrent Neisseria infections ^[20]
Asplenia	S. pneumoniae, N. meningitidis, H. influenzae	Spleen clears encapsulated bacteria; loss → overwhelming infection ^[6]^[7]
CSF leak / skull fracture	S. pneumoniae (recurrent)	Direct communication between nasopharynx and subarachnoid space ^[2]^[3]
Post-neurosurgery / VP shunt / EVD	S. aureus, S. epidermidis, Gram-negative bacilli	Nosocomial inoculation, biofilm formation on foreign material ^[2]
SNHL developing during meningitis	S. suis, TBM	Exudate damage to CN VIII / cochlea ^[2]
Rhombencephalitis (brainstem signs)	Listeria	Tropism for brainstem → cranial nerve palsies, ataxia ^[2]
Genital ulcers / sexual history / pupillary abnormalities	Neurosyphilis	Syphilitic meningitis → meningovascular disease → general paresis ^[19]
Summer, young child, hand-foot-mouth disease	Enterovirus	Faeco-oral spread, seasonal, benign course ^[2]
Dormitory / military barracks	N. meningitidis	Droplet transmission in crowded settings ^[2]^[3]
Recent travel to meningitis belt (sub-Saharan Africa)	N. meningitidis serogroup A	Epidemic meningococcal disease

These conditions cause true CSF pleocytosis and meningeal irritation but are not caused by infection.

Category	Examples	Key Features
Malignant meningitis (leptomeningeal carcinomatosis)	CA breast, CA lung, leukaemia, lymphoma ^[2]	Chronic progressive headache, CN palsies, radiculopathy; CSF shows malignant cells on cytology; glucose may be low
Inflammatory / autoimmune	Sarcoidosis, SLE, Behçet's disease ^[2]	Multisystem disease features; CSF lymphocytic; may respond to immunosuppression
Chemical meningitis	Post-neurosurgery (blood or foreign material in CSF), ruptured dermoid/epidermoid cyst, intrathecal drugs	Temporal relationship with procedure; sterile cultures
Drug-induced aseptic meningitis	NSAIDs, IVIG, TMP-SMX, intrathecal methotrexate	Temporal relationship with drug; resolves on withdrawal; recurs on re-challenge
Parameningeal infections	Epidural abscess, subdural empyema ^[3]	Reactive CSF inflammation without direct meningeal infection; source must be found on imaging

Chronic meningitis (> 4 weeks) has five categories: meningeal infections, parameningeal infections, chemical meningitis, malignancy, and autoimmune inflammatory disorders ^[14]^[15]

9.5 Special DDx Considerations by Clinical Scenario

From the headache approach ^[16]^[23]:

Red Flag	Points Toward Meningitis (Over Primary Headache)
Systemic upset (constitutional symptoms, fever)	CNS infections, neoplastic, vasculitis ^[16]^[23]
Neurological symptoms (confusion, focal symptoms, LOC, seizures, meningism)	Intracranial pathologies (vascular, neoplastic, infection) ^[16]^[23]
Meningococcaemic rash	DIC due to systemic N. meningitidis infection ^[16]^[23]
New and sudden onset	SAH, CVST, pituitary apoplexy, infections ^[16]^[23]
Worse when supine, with exertion/cough	Raised ICP (could be from hydrocephalus secondary to meningitis)

The following structured approach integrates the differential diagnosis:

High Yield Summary — Differential Diagnosis of Meningitis

Key DDx of the meningitis syndrome (fever + headache + neck stiffness + altered consciousness):

Intracranial infections: encephalitis, brain abscess, subdural empyema, ventriculitis
Vascular: SAH (blood irritates meninges → meningism), CVST
Systemic sepsis with septic encephalopathy (delirium mimicking meningitis)
Non-meningeal causes of neck stiffness: cervical spondylosis, retropharyngeal abscess, cervical lymphadenitis

Key DDx within confirmed meningitis (CSF pleocytosis):

Bacterial: S. pneumoniae (MC adult, explosive), N. meningitidis (purpuric rash, DIC), H. influenzae (children), Listeria (extremes of age, I/C), S. suis (raw pork, SNHL), GBS (neonates), Gram-negatives (neonates, elderly, post-surgical)
Viral: Enterovirus (MC, benign), HSV-2 (recurrent), mumps, HIV
TB: most common cause of meningitis locally — subacute, triphasic, basal meningitis, CN palsies
Fungal: Cryptococcus — HIV/immunosuppressed, ↑↑↑ ICP
Non-infective: leptomeningeal carcinomatosis, sarcoidosis, SLE, Behçet's, drug-induced

Critical clinical clues:

Purpuric rash → meningococcal
Pork exposure → S. suis
Immunocompromised → Cryptococcus, Listeria, TB
CSF leak → recurrent pneumococcal
Insidious onset weeks → TBM
CN palsy "combinations that don't make sense" → TBM

Active Recall - Differential Diagnosis of Meningitis

References

^[1] Lecture slides: GC 051. Fever and confusion_meningitis and encephalitis; suppurative brain infection.pdf (slides on differential diagnosis, TBM, learning outcomes) ^[2] Senior notes: Ryan Ho Neurology.pdf (Section 7.1 Meningitis, pp. 142–145) ^[3] Senior notes: Maksim Medicine Notes.pdf (Section 9.6 CNS infections, p. 196) ^[5] Senior notes: Adrian Lui Pediatrics Notes.pdf (Section 14.2.2 Meningococcal infection, p. 474) ^[6] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf (OPSI and vaccination, p. 20) ^[7] Senior notes: Gen Clerk Anaes + Microbiology Summary.pdf (Listeria coverage and prophylaxis, pp. 14, 27) ^[10] Senior notes: Learning_Points_All_Lectures.txt (Neurology learning point 1 – CSF analysis patterns) ^[14] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Meningitis overview and classification, p. 1179) ^[15] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (Meningitis overview and classification, p. 500) ^[16] Senior notes: Ryan Ho Fundamentals.pdf (Headache red flags, p. 313) ^[17] Lecture slides: GC 013. Emergency radiology.pdf (Cross-sectional imaging before LP, p. 18) ^[18] Senior notes: Ryan Ho Psychiatry.pdf (Delirium precipitants and DDx, p. 75) ^[19] Senior notes: Ryan Ho Urogenital.pdf (Neurosyphilis, p. 246) ^[20] Senior notes: Jerry's immunodeficiencies.pdf (Complement deficiency and encapsulated bacteria, p. 4) ^[21] Paediatrics: Febrile seizures_ Clinical features and evaluation - UpToDate.pdf (DDx of febrile seizures, pp. 13, 19) ^[22] Senior notes: Block A - Rheumatology Interactive Tutorial.pdf (Headache DDx including meningitis, p. 1) ^[23] Senior notes: Adrian Lui Pediatrics Notes.pdf (Headache red flags, p. 109)

Diagnostic Criteria, Diagnostic Algorithm, and Investigation Modalities

10.2 Diagnostic Algorithm — The Time-Critical Sequence

The sequence of investigations in suspected meningitis is not "investigate first, treat later." It is a carefully choreographed sequence designed to obtain the best diagnostic specimens while never delaying life-saving empirical therapy.

The Golden Sequence – High Yield

Blood culture → Dexamethasone → Empirical Antibiotics → CT scan (if indicated) → LP ^[3]

This sequence is from the Maksim Medicine Notes and is the standard approach taught at HKU. The key principle: empirical antibiotics should not be delayed for CT or LP. If there is any delay in obtaining LP (e.g., waiting for CT), give antibiotics first.

10.3 Investigation Modalities — Detailed Breakdown

Investigation	Key Findings and Interpretation	Why It Matters
CBC + differential count ^[1]	↑ WBC with left shift (neutrophilia) in bacterial meningitis; lymphocytosis in viral; may be normal or low in overwhelming sepsis (bad sign — exhausted marrow)	Gives a quick systemic picture; leukopenia in bacterial meningitis is a poor prognostic sign
LFT, RFT ^[1]	Assess organ function; ↓ Na⁺ suggests SIADH (a known complication — meningitis is a CNS cause of SIADH ^[11])	Hyponatraemia → seizures, ↓ consciousness; guide fluid management
Inflammatory markers (ESR, CRP) ^[1]	↑ in bacterial and TB; may be normal in viral	PCT > 0.5 ng/mL has high specificity for invasive bacterial illness (bacteraemia or meningitis) — sensitivity 82%, specificity 86% in young children ^[24]. CRP > 20 mg/L has sensitivity 87% for serious bacterial illness ^[24]
Blood culture ^[1]^[2]	80% positive in H. influenzae, < 50% in pneumococcus/meningococcus ^[2]. Identifies the organism + sensitivity profile even if CSF culture is negative	Must obtain ≥ 2 sets before starting antibiotics ^[2]. Positive blood culture may be the only microbiological confirmation if LP is delayed or CSF culture sterilised by prior antibiotics
Clotting profile ^[1]	Assess for DIC (especially meningococcal sepsis — ↑ PT/APTT, ↓ fibrinogen, ↑ D-dimer, ↓ platelets) and prepare for LP (to check it is safe to insert a needle into the subarachnoid space)	LP is contraindicated if severe coagulopathy (risk of epidural/spinal haematoma)
Blood gas ^[1]	Metabolic acidosis in septic shock (lactic acidosis); respiratory alkalosis from hyperventilation due to pain/fever	Guides resuscitation; severe metabolic acidosis in meningococcal sepsis = poor prognosis
Paired serum glucose	Must be taken simultaneously with CSF glucose to calculate the CSF:serum glucose ratio. Normal ratio > 0.6	Without the paired serum glucose, the CSF glucose value is uninterpretable. A CSF glucose of 3.0 mmol/L is "normal" if serum glucose is 5.0 (ratio 0.6) but "very low" if serum glucose is 10.0 (ratio 0.3)
HIV test	Check in all patients with meningitis where aetiology is unclear, especially if TB or Cryptococcus suspected	Alters the differential, treatment duration, and prophylaxis strategy

10.3.2 Lumbar Puncture (LP) and CSF Analysis

LP is the single most important investigation in meningitis. It provides the diagnosis.

Parameter	Normal	Bacterial	Viral	TB	Cryptococcal	Autoimmune
Appearance	Clear	Cloudy / turbid	Clear	Opalescent (± fibrin web/clot)	Clear / slightly turbid	Clear
Opening pressure	6–20 cmH₂O	> 20	10–20	> 20	>> 20 (often very high)	Normal
WBC (cells/μL)	< 5	↑↑↑ (hundreds to thousands)	10–100	100–300	Variable (can be modest)	Normal or mildly ↑
Predominant cell	—	Polymorphs (neutrophils) ^[10]	Lymphocytes ^[10]	Lymphocytes ^[10]	Lymphocytes	Lymphocytes
Protein (g/L)	0.15–0.45	0.5–2.0	0.4–0.8	0.5–3.0 (can be very high, up to 2–6 g/dL) ^[2]	↑↑	> 0.5
Glucose (mmol/L)	> 50% of blood glucose	< 50% of BG ^[3]^[10]	> 50% of BG ^[3]^[10]	< 50% of BG ^[3]^[10]	< 50% of BG	Normal

Adapted from ^[3]^[10].

Why Is CSF Glucose Low in Bacterial and TB Meningitis But Normal in Viral?

Two mechanisms reduce CSF glucose in bacterial and TB meningitis:

Bacterial/mycobacterial metabolism: organisms directly consume glucose as a carbon source
Impaired glucose transport: inflammation of the choroid plexus and meninges disrupts the facilitated transport of glucose from blood to CSF (via GLUT1 transporters)

Viruses do not consume glucose in the same way (they hijack host cell machinery but don't metabolise glucose independently). Additionally, viral meningitis causes less intense inflammation of the choroid plexus, so glucose transport remains relatively intact.

Test	What It Detects	Key Points
Gram stain	Bacterial morphology	"The Gram stain is the most important" ^[25]. Quick (~15 min), guides initial antibiotic choice. Sensitivity ~60–90% in untreated bacterial meningitis, drops dramatically after antibiotic exposure
CSF culture + sensitivity	Definitive organism identification + antibiotic susceptibility	Gold standard for bacterial identification. Takes 24–72h for pyogenic bacteria. Sensitivity drops with prior antibiotics
PCR (nucleic acid amplification)	Pathogen DNA/RNA	"Request for rapid test by nucleic acid amplification or antigen detection assay especially if patients already on antibiotics or difficult-to-grow microbe is suspected" ^[25]. Highly sensitive and specific; not affected by prior antibiotics
AFB smear	Acid-fast bacilli (mycobacteria)	Very low sensitivity (~10–20%) for TBM; positive result is diagnostic but negative does NOT exclude TB
AFB culture	M. tuberculosis	Takes 2–8 weeks on liquid media (MGIT). Most sensitive culture method but slow. Send ≥ 5 mL ^[2]^[25]
TB PCR (e.g., GeneXpert MTB/RIF)	M. tuberculosis DNA + rifampicin resistance	Sensitivity 82%, specificity 99% ^[2]. Much faster than culture (results in hours). Detects rifampicin resistance simultaneously
ADA (adenosine deaminase)	Marker of T-cell activation	Elevated in TBM. Useful adjunctive test. Not perfectly specific (also elevated in lymphoma, partially-treated bacterial meningitis)
India ink	Cryptococcus capsule	Low sensitivity (~50%). Visualises the polysaccharide capsule as a clear halo around yeast cells. Being replaced by CrAg
Cryptococcal antigen (CrAg)	Cryptococcus neoformans capsular polysaccharide antigen	Highly sensitive and specific. Can also be detected in serum. Better than India ink. Lateral flow assay gives result in minutes ^[2]^[3]
CSF VDRL	Neurosyphilis	Highly specific but low sensitivity (~30–70%) for neurosyphilis. A positive CSF VDRL is diagnostic ^[19]
Viral PCR panel	HSV-1, HSV-2, VZV, CMV, EBV, enterovirus	PCR is the standard for viral CNS infections. HSV PCR has sensitivity ~96%, specificity ~99%
Cytology	Malignant cells	For suspected leptomeningeal carcinomatosis. Sensitivity improves with repeated large-volume LP
Latex agglutination / bacterial antigen detection	Bacterial capsular antigens	Detects S. pneumoniae, N. meningitidis, H. influenzae, GBS antigens. Useful when Gram stain is negative or patient pre-treated with antibiotics ^[3]

CSF Gram stain findings ^[2]^[3]:

Organism	Gram Stain Appearance
S. pneumoniae	Gram-positive diplococci
N. meningitidis	Gram-negative diplococci
H. influenzae	Pleomorphic Gram-negative coccobacilli
L. monocytogenes	Gram-positive rods (coccobacilli)

High Yield – Gram Stain Morphology

Being able to match the Gram stain to the organism is a classic exam question:

GP diplococci in pairs → think Pneumococcus
GN diplococci (coffee-bean shaped, intracellular) → think Meningococcus
GN pleomorphic coccobacilli → think H. influenzae
GP rods → think Listeria

Pitfall	Explanation
Traumatic tap	Blood introduced by the needle itself → RBCs in CSF. To distinguish from true SAH: (1) RBC count decreases from bottle 1 to bottle 3 in traumatic tap, (2) no xanthochromia in traumatic tap, (3) supernatant is clear in traumatic tap vs. yellow (xanthochromic) in SAH
Early viral meningitis → neutrophils	In the first 24–48h of viral meningitis, neutrophils may predominate. Repeat LP at 12–24h shows shift to lymphocytes
Partially-treated bacterial meningitis	Prior antibiotics can: (a) sterilise cultures, (b) shift WCC from neutrophils → lymphocytes, (c) partially normalise glucose. CSF may then mimic TB or viral. Always ask about prior antibiotic use
Early TB meningitis → neutrophils	Initial stages of TBM can show neutrophilic predominance before the classic lymphocytic pattern develops
Normal CSF early	LP performed very early (within hours of onset) may show normal CSF. If clinical suspicion is high, treat empirically and repeat LP
"A finding of pleocytosis in the CSF in a patient with a febrile seizure should be considered a sign of bacterial meningitis until proven otherwise" ^[21]	Do not dismiss CSF pleocytosis as "reactive" to seizure in a febrile child — this is meningitis until proven otherwise

10.3.3 Neuroimaging

MRI is superior to CT for evaluating complications of meningitis and for certain aetiologies:

Sequence	Findings	Clinical Significance
T2/FLAIR	Hyperintensity in affected areas	HSV encephalitis: mesial temporal lobe and inferior frontal lobe hyperintensity ^[3]. TB: tuberculoma, basal meningeal inflammation
DWI	Restricted diffusion in areas of infarction	Detects ischaemic stroke complicating meningitis (from endarteritis obliterans)
Post-gadolinium T1	Meningeal enhancement (especially basal in TBM) ^[2]	Confirms meningeal inflammation; basal predominance strongly suggests TBM
T1 post-contrast	Tuberculoma with rim enhancement ^[2]	Parenchymal granuloma; differential includes brain abscess, metastasis
MRV	Cerebral venous thrombosis	Complication of meningitis or differential diagnosis
Hydrocephalus	Dilated ventricles	More suggestive of non-viral aetiology (especially TBM, cryptococcal) ^[2]

Imaging findings in TBM: meningeal enhancement (especially basal), hydrocephalus, tuberculoma with rim enhancement ± cerebral infarction ^[2]

Modality	Indication
CXR	Look for concurrent pulmonary TB (abnormal in ~50% of TBM) ^[2], pneumonia (source of pneumococcal meningitis)
XR skull / sinus / mastoid	Identify contiguous source (sinusitis, mastoiditis, skull fracture) ^[3]
CT/MRI sinus	If sinusitis-related meningitis suspected (especially intracranial complication)

Investigation	Indication	Interpretation
EEG	Suspected encephalitis; non-convulsive status epilepticus	Diffuse slowing in encephalitis; periodic lateralising epileptiform discharges (PLEDs) in temporal lobe = classic for HSV encephalitis ^[2]
TST (Mantoux) / IGRA	Suspected TBM	Positive only means positive T-cell response — does not indicate protective immunity ^[4]. Cannot distinguish latent TB from active disease ^[4]. False negatives in immunocompromised and overwhelming active TB infection ^[4]. Adjunctive test — cannot confirm or exclude TBM alone
Throat swab / NPA	Viral meningitis (enterovirus, respiratory viruses)	May isolate the virus from a non-CNS site, supporting the diagnosis
Stool culture / PCR	Enteroviral meningitis	Enteroviruses shed in stool — recovery of enterovirus from stool + compatible CSF supports the diagnosis
Complement levels (CH50, AH50)	Recurrent meningococcal meningitis	C5–C9 deficiency: low CH50, low AH50 ^[20]. C3 deficiency: low CH50, low AH50, low C3. Suspect complement deficiency in anyone with recurrent Neisseria infections
Serum procalcitonin (PCT)	Differentiating bacterial from viral meningitis	PCT > 0.5 ng/mL has sensitivity 82%, specificity 86% for invasive bacterial illness ^[24]. Very useful when CSF is equivocal

Suspected Aetiology	Key Investigations	Definitive Test
Bacterial (pyogenic)	Blood culture, CSF Gram stain + C/ST, bacterial antigen detection	CSF culture + sensitivity
Viral	CSF viral PCR panel (HSV, VZV, CMV, EBV, enterovirus)	CSF PCR
TB	CSF AFB smear/culture, TB PCR (GeneXpert), ADA; CXR, TST/IGRA	CSF AFB culture (gold standard but slow); PCR (fast, sensitive 82%, specific 99%) ^[2]
Cryptococcal	CSF CrAg (lateral flow assay), India ink, CSF/blood culture	CSF CrAg (most sensitive rapid test)
Neurosyphilis	CSF VDRL, CSF FTA-ABS; serum treponemal (TPPA/FTA-ABS) and non-treponemal (VDRL/RPR) serology	CSF VDRL positive = diagnostic ^[19]
Autoimmune	CSF cytology, flow cytometry; serum ANA, anti-dsDNA, ACE level	Depends on specific condition (e.g., biopsy for sarcoidosis)
Malignant (leptomeningeal)	CSF cytology (repeated large-volume LP to increase sensitivity), flow cytometry, MRI with gadolinium (meningeal enhancement)	CSF cytology showing malignant cells

10.4 Diagnosis of TBM — A Special Focus

TBM deserves separate attention because it is the most common cause of meningitis in Hong Kong ^[1], yet it is diagnostically challenging.

Step	Action	Expected Finding
LP	Send ≥ 5 mL CSF	↓ Glucose, ↑↑↑ protein (up to 2–6 g/dL), ↑ WBC (lymphocyte predominant) ^[2]
CSF microbiology	AFB smear, AFB culture, TB PCR (GeneXpert), ADA	PCR fastest and most useful; culture definitive but slow
CXR	Look for pulmonary TB	Abnormal in ~50% ^[2]
TST / IGRA	Check for TB immune response	Positive in many, but can be false-negative in active TB, immunocompromised ^[4]. Does not distinguish latent from active ^[4]
Neuroimaging (MRI preferred)	Look for basal meningeal enhancement, hydrocephalus, tuberculoma, infarction	Meningeal enhancement especially basal, hydrocephalus, tuberculoma with rim enhancement ± cerebral infarction ^[2]
Fundoscopy	Look for choroidal tubercles	Pathognomonic if present (especially in miliary TB in children)

Stage	Description	Significance
I	Fully conscious, no focal neurological deficits	Best prognosis
II	Confusion/lethargy OR focal neurological deficit (e.g., CN palsy, hemiparesis)	Intermediate prognosis
III	Stupor/coma ± dense neurological deficit	Worst prognosis

Contraindication	Reason	Action
Signs of raised ICP with mass effect (focal signs, papilloedema, ↓ GCS, posterior fossa signs)	Risk of tonsillar/uncal herniation (coning) — removal of CSF from below reduces pressure below the tentorium → brain herniates downward through the foramen magnum	Do CT first; if mass lesion → do NOT LP; treat empirically
Severe coagulopathy or thrombocytopenia (INR > 1.5, platelets < 50 × 10⁹/L)	Risk of epidural/spinal haematoma compressing the spinal cord or cauda equina	Correct coagulopathy first if possible; or treat empirically
Skin infection over LP site	Risk of introducing skin organisms into subarachnoid space	Choose alternative site or defer
Cardiorespiratory compromise	Patient too unstable for positioning	Stabilise first; treat empirically

In ALL cases where LP is delayed or contraindicated, empirical antibiotics (± dexamethasone) must be given immediately.

Repeat LP to assess response when poor clinical response or persistent fever > 8 days ^[2]:

Expected findings of improving meningitis: ↑ protein (may lag behind), lymphocytosis (shift from neutrophils), normalising glucose
Reasons for poor response ^[2]:
- Persistence of primary cause (e.g., ongoing pneumonia, SBE, mastoiditis, otitis)
- Cerebritis or small early cerebral abscess → bacteria partially resistant
- Inadequate immunity → prolonged antibiotics required for immunocompromised patients

High Yield Summary — Diagnosis of Meningitis

Gold standard: LP with CSF analysis — appearance, opening pressure, cell count + differential, protein, glucose (with paired serum glucose), Gram stain, culture, PCR.
Time-critical sequence: Blood culture → Dexamethasone → Empirical Abx → CT (if indicated) → LP. Never delay antibiotics for imaging.
CT before LP indications: altered consciousness, focal signs, papilloedema, seizure, immunocompromised.
CSF patterns:
- Bacterial: neutrophilic, ↓ glucose ( < 50% BG), ↑ protein, cloudy
- Viral: lymphocytic, normal glucose, clear
- TB: lymphocytic, ↓↓ glucose, ↑↑↑ protein (up to 2–6 g/dL), opalescent
- Cryptococcal: lymphocytic, ↓ glucose, ↑↑ protein, very high opening pressure, +ve CrAg
Gram stain morphology: GP diplococci = Pneumococcus; GN diplococci = Meningococcus; GN coccobacilli = H. influenzae; GP rods = Listeria.
TBM diagnosis: CSF AFB smear (low sensitivity), culture (slow), PCR/GeneXpert (sensitivity 82%, specificity 99%), ADA; CXR; MRI (basal enhancement, hydrocephalus, tuberculoma).
Repeat LP if no improvement after 8 days — look for persistent source, abscess, or resistance.

Active Recall - Diagnosis of Meningitis

References

^[1] Lecture slides: GC 051. Fever and confusion_meningitis and encephalitis; suppurative brain infection.pdf (Investigations slide, CT before LP, learning outcomes) ^[2] Senior notes: Ryan Ho Neurology.pdf (Section 7.1 Meningitis — Investigations and approach, pp. 145–146) ^[3] Senior notes: Maksim Medicine Notes.pdf (Section 9.6 CNS infections — Investigations and CSF table, p. 197) ^[4] Senior notes: Gen Clerk Anaes + Microbiology Summary.pdf (CNS TB, MRC staging, TST/IGRA, pp. 30, 34) ^[7] Senior notes: Gen Clerk Anaes + Microbiology Summary.pdf (Listeria coverage in meningitis, p. 27) ^[10] Senior notes: Learning_Points_All_Lectures.txt (Neurology learning point 1 — CSF analysis patterns) ^[11] Senior notes: Block A - Electrolyte and Acid-Base Disorders.pdf (SIADH — CNS causes, p. 21) ^[17] Lecture slides: GC 013. Emergency radiology.pdf (LP gold standard for meningitis, cross-sectional imaging before LP, p. 18) ^[19] Senior notes: Ryan Ho Urogenital.pdf (Neurosyphilis diagnosis, CSF VDRL, p. 246) ^[20] Senior notes: Jerry's immunodeficiencies.pdf (Complement deficiency — C5–C9, CH50, AH50, p. 4) ^[21] Paediatrics: Febrile seizures: Clinical features and evaluation - UpToDate.pdf (CSF pleocytosis in febrile seizure = meningitis until proven otherwise, p. 14) ^[24] Paediatrics: Fever without a source in children 3 to 36 months of age: Evaluation and management - UpToDate.pdf (PCT and CRP diagnostic accuracy for IBI/meningitis, pp. 6, 10) ^[25] Lecture slides: GC 101. Diagnosis of infections [Handouts].pdf (CSF collection: volumes, glass bottles, Gram stain importance, special requests, p. 3)

Management of Meningitis

Before diving into specific regimens, understand the overarching principles — they explain why every step of the management algorithm is the way it is.

GC Lecture Slide – General Points on CNS Infections

The GC 051 lecture outlines the management framework ^[1]:

"Common. High mortality and morbidity if treatment delayed"
"Quick septic workup including blood culture before start of antibiotics"
"Early lumbar puncture if no contraindications"
"Initial high-dose broad spectrum parenteral antibiotics that penetrate the blood-brain barrier, subsequent streamlining of antibiotics with availability of microbiological results"
"Regular monitoring of neurological status and vital signs"
"Look for the primary infective focus and also complications"
"Close liaison with microbiologist, neurologist and neurosurgeon"

Let's dissect why each of these principles exists:

Principle	Rationale (First Principles)
High-dose antibiotics	The BBB restricts antibiotic penetration into the CSF. Even when inflamed, penetration is incomplete. Higher systemic doses → higher CSF concentrations → more effective bactericidal activity. This is why we use "meningitic doses" (e.g., ceftriaxone 2 g Q12h rather than the usual 1–2 g Q24h for other infections)
IV only — do NOT change to PO antibiotics ^[2]^[3]	Oral antibiotics achieve unpredictable and generally insufficient CSF levels. CNS infections require guaranteed, high, and sustained antibiotic concentrations in the CSF
Broad-spectrum initially → streamline later	You don't know the organism yet. The empirical regimen must cover the most likely and most dangerous pathogens. Once culture and sensitivity results are available (24–72h), narrow the spectrum to reduce resistance and side effects
BBB penetration	Not all antibiotics cross the BBB well. Cephalosporins (especially 3rd generation), penicillins (at high doses), metronidazole, chloramphenicol, and carbapenems have good CSF penetration. Aminoglycosides and 1st-generation cephalosporins do NOT penetrate well
Dexamethasone BEFORE or WITH first antibiotic dose	When antibiotics lyse bacteria, cell wall components (LPS, teichoic acid) are released → massive cytokine storm → worsening cerebral oedema and inflammation → more damage. Dexamethasone given before or simultaneously with the first antibiotic dose dampens this inflammatory surge. Given after antibiotics have already triggered the storm, it is less effective

11.3 Empirical Antibiotic Therapy

Empirical therapy is what you give before you know the organism. The choice depends on the patient's age, immune status, and risk factors — because these predict the most likely pathogen.

Clinical Scenario	Additional Agent	Why
Likely pneumococcal or TB	+ IV dexamethasone 0.15 mg/kg Q6h ^[3]	Anti-inflammatory: reduces hearing loss, neurological complications, and mortality in pneumococcal meningitis; reduces long-term sequelae in TBM
Advanced age ( ≥ 50), pregnancy, or immunocompromised	+ IV ampicillin 2 g Q4h ^[3]^[7]	Covers Listeria monocytogenes — intrinsically resistant to cephalosporins. These groups are at highest risk for Listeria. "Consider adding ampicillin for Listeria coverage on top of ceftriaxone if you encounter high-risk patients with meningitis" ^[7]
Risk of Pseudomonas (e.g., post-neurosurgery, nosocomial, neutropenic)	+ IV meropenem (CNS dosage) ^[3]	Meropenem has excellent CSF penetration + anti-Pseudomonal activity. Ceftriaxone does NOT cover Pseudomonas
Risk of drug-resistant S. pneumoniae	± IV vancomycin 500 mg Q12h ^[3]	Covers penicillin-resistant pneumococcus. "Not common in HK" ^[3] but recommended under IMPACT 2014 guidelines ^[2]. "Vancomycin as first line is controversial. However, it is currently recommended under IMPACT2014 guidelines to cover S. pneumoniae" ^[2]
Post-neurosurgical / VP shunt / EVD	IV vancomycin + IV meropenem (or ceftazidime)	Covers S. aureus, S. epidermidis (vancomycin) and Gram-negative bacilli including Pseudomonas (meropenem/ceftazidime)

The Big Four of Empirical Meningitis Therapy

For a typical adult with suspected bacterial meningitis, the empirical regimen is:

IV Dexamethasone 0.15 mg/kg Q6h — give FIRST (before or with antibiotics)
IV Ceftriaxone 2 g Q12h — backbone agent
± IV Vancomycin — if penicillin-resistant pneumococcus suspected
± IV Ampicillin 2 g Q4h — if Listeria risk (elderly, immunocompromised, pregnant)

Plus IV Acyclovir 10 mg/kg Q8h if encephalitis is on the differential.

Age Group	Empirical Regimen	Rationale
Neonates ( < 1 month)	IV ampicillin + IV gentamicin (or IV cefotaxime)	Covers GBS, E. coli, Listeria. Ceftriaxone is avoided in neonates (displaces bilirubin from albumin → risk of kernicterus)
Infants (1–3 months)	IV ampicillin + IV cefotaxime (or ceftriaxone)	Transition period — still need Listeria coverage (ampicillin) + cover for H. influenzae, S. pneumoniae, N. meningitidis (cephalosporin)
Children ( > 3 months)	IV ceftriaxone 50 mg/kg Q12h ± dexamethasone	Same principles as adults; ceftriaxone covers the main paediatric pathogens

Why NOT Ceftriaxone in Neonates?

Ceftriaxone is highly protein-bound and competes with bilirubin for albumin binding sites. In neonates with physiological jaundice, displacing bilirubin increases the free (unconjugated) bilirubin level → crosses BBB → kernicterus (bilirubin encephalopathy). Use cefotaxime instead — same spectrum but does not displace bilirubin.

11.4 Adjunctive Dexamethasone — The Rationale in Detail

Dexamethasone is one of the most important and most frequently examined aspects of meningitis management.

Anti-inflammatory actions: reduce rate of hearing loss, other neurological complications and mortality ^[3]:

Condition	Dexamethasone Regimen	Evidence
Pneumococcal meningitis	0.15 mg/kg IV Q6h for 4 days ^[2]^[3]	De Gans trial (NEJM 2002): ↓ mortality from 15% to 7%, ↓ unfavourable outcomes, ↓ hearing loss. Strongest evidence
S. suis meningitis	Same regimen	IV dexamethasone × 2–4 days for S. pneumoniae, S. suis only (no effect in others) ^[2]. ↓ hearing loss in S. suis
TB meningitis	IV dexamethasone for 6–8 weeks ^[3]^[4] — usually a tapering course: 0.4 mg/kg/day for week 1, then gradually tapered	Thwaites trial (NEJM 2004): ↓ mortality in TBM. "Due to severity, apart from the anti-TB therapy, remember the use of adjunct steroid to reduce inflammation" ^[4]
Brain abscess with significant cerebral oedema	Dexamethasone if with significant cerebral oedema ^[3]	Reduces mass effect; however, steroids impair WBC function and may ↓ antibiotic penetration, so used only when oedema is causing herniation risk
Cryptococcal meningitis	NOT indicated ^[3]	No benefit shown; may worsen outcomes (impairs cell-mediated immunity needed to control Cryptococcus). Raised ICP in cryptococcal meningitis is managed by serial therapeutic LPs or VP shunt, not steroids

11.5 Definitive (Pathogen-Directed) Treatment

Once culture and sensitivity results are available (usually 24–72h), empirical therapy is streamlined to the most appropriate narrow-spectrum agent.

Duration of treatment depends on pathogen (do NOT change to PO antibiotics) ^[3]:

Pathogen	Recommended Antibiotic	Duration	Notes
N. meningitidis	IV ceftriaxone (or IV benzylpenicillin if sensitive)	≥ 7 days ^[3] (some sources say 5–7 days)	Relatively benign prognosis compared to pneumococcal
H. influenzae	IV ceftriaxone	≥ 7 days ^[2]^[3]
S. pneumoniae	IV ceftriaxone ± vancomycin (stop vancomycin if penicillin-sensitive on C/ST)	10–14 days ^[2]^[3]	Most aggressive pyogenic cause; longer treatment reflects higher complication rate
L. monocytogenes	IV ampicillin (± IV gentamicin for synergy in first 7 days)	14–21 days ^[2]^[3]	Cephalosporins do NOT cover Listeria — must use ampicillin. Gentamicin provides synergistic bactericidal activity
S. agalactiae (GBS)	IV ampicillin or IV benzylpenicillin	14–21 days ^[2]^[3]
Gram-negative bacilli (E. coli etc.)	IV ceftriaxone or IV meropenem (if ESBL)	≥ 21 days ^[2]^[3]	Longer duration because Gram-negative meningitis has higher relapse rate
S. suis	IV benzylpenicillin	10–14 days
S. aureus (MSSA)	IV flucloxacillin (or IV nafcillin)	4–6 weeks	Post-neurosurgical; long treatment due to biofilm and deep-seated infection
S. aureus (MRSA)	IV vancomycin ± rifampicin	4–6 weeks
S. epidermidis (shunt infection)	IV vancomycin + shunt removal	Until shunt removed + CSF sterile for 10 days	Foreign body must be removed for cure

Key Principle: Do NOT Switch to Oral Antibiotics

Modify treatment after known culture and sensitivity, but DO NOT change to PO therapy ^[2]. This is because oral antibiotics do not achieve reliable, bactericidal CSF concentrations for CNS infections. The entire course must be IV.

HRZE × 2 months + HR × 10 months (total 12 months) ^[3]

Component	Drug	Mechanism	Key Side Effects
H	Isoniazid	Inhibits mycolic acid synthesis (cell wall)	Hepatotoxicity, peripheral neuropathy (→ give pyridoxine/B6 to prevent)
R	Rifampicin	Inhibits DNA-dependent RNA polymerase	Hepatotoxicity, orange discolouration of body fluids, potent CYP450 inducer (many drug interactions)
Z	Pyrazinamide	Disrupts membrane transport (exact mechanism debated)	Hepatotoxicity, hyperuricaemia
E	Ethambutol	Inhibits arabinosyltransferase (cell wall)	Optic neuritis (↓ visual acuity, ↓ colour vision — must monitor!)

Key points for TBM management:

Longer duration than pulmonary TB (12 months vs. 6 months for pulmonary) — because CNS is a sanctuary site with poor drug penetration and high morbidity if relapse occurs
IV dexamethasone for 6–8 weeks ^[3]^[4] — tapering course; shown to ↓ mortality
HIV testing ^[3] — TB and HIV are closely linked; co-infection alters management (timing of ART, immune reconstitution inflammatory syndrome risk)
Repeat LP to monitor CSF changes ^[3] — assess treatment response
VP shunt if hydrocephalus develops ^[4] — "V/P shunt if necessary" ^[4]
Pyridoxine (vitamin B6): give alongside isoniazid to prevent peripheral neuropathy (isoniazid depletes pyridoxine → impaired nerve function)

IV Amphotericin B 1 mg/kg over 4–6h + PO 5-flucytosine for ≥ 2 weeks, then PO fluconazole 400 mg daily for ≥ 8 weeks ^[2]^[3]

Phase	Regimen	Duration	Notes
Induction	IV amphotericin B 0.7–1 mg/kg daily + PO/IV 5-flucytosine 25 mg/kg Q6h ^[2]	≥ 2 weeks	Amphotericin B ("ampho-terrible") — nephrotoxic, hypokalaemia, infusion reactions. Pre-hydrate with NS and supplement K⁺. Flucytosine provides synergistic fungicidal activity
Consolidation	PO fluconazole ≥ 400 mg/day ^[2]	≥ 8 weeks until CSF normal
Maintenance (secondary prophylaxis)	PO fluconazole 200 mg/day	Until immune reconstitution (CD4 > 200 for ≥ 6 months on ART in HIV patients)	Prevents relapse in immunocompromised

Critical management points:

Dexamethasone is NOT indicated for cryptococcal meningitis ^[3] — steroids impair the very cell-mediated immunity needed to control the fungus
Raised ICP is the major cause of morbidity/mortality — managed by serial therapeutic LPs (remove 20–30 mL CSF per session until opening pressure < 20 cmH₂O) or VP shunt if refractory
If in an HIV patient, do NOT start ART immediately — wait ≥ 4–5 weeks after antifungal induction. Starting ART too early causes immune reconstitution inflammatory syndrome (IRIS) → paradoxical worsening

No specific treatment for viral meningitis → usually benign and self-limiting (within days) ^[2]

Agent	When to Use	Regimen
Supportive care	All viral meningitis	Analgesia (paracetamol, NSAIDs), antiemetics, IV fluids, rest
IV Acyclovir	HSV encephalitis (or meningoencephalitis)	10 mg/kg Q8h IV for 14 days ^[3] (2 weeks, not 10–14 days for confirmed HSV). 70% mortality if untreated ^[2] — always start empirically if encephalitis is on the differential and stop only if HSV PCR is negative

Why does acyclovir work against HSV but not other viruses?

Acyclovir = acyclic guanosine analogue. It is preferentially phosphorylated by viral thymidine kinase (TK) — an enzyme that HSV and VZV have but most other viruses lack. Once phosphorylated, acyclovir triphosphate is incorporated into viral DNA by viral DNA polymerase → chain termination → halts viral replication. Human cells have much lower affinity for acyclovir → selective toxicity.

IV ceftriaxone 2 g Q12h + IV metronidazole 500 mg Q8h ^[3]

Component	Covers	Why
Ceftriaxone	Streptococci, Gram-negatives	Good CSF/abscess penetration
Metronidazole	Anaerobes (Bacteroides, Fusobacterium, Peptostreptococcus)	Brain abscesses from dental/sinus/otic sources often have anaerobic flora. Metronidazole has excellent CNS penetration
Dexamethasone	If with significant cerebral oedema ^[3]	Reduces mass effect, but use judiciously (impairs WBC function)

Consult neurosurgery for drainage ^[3] — antibiotics alone are insufficient for large abscesses ( > 2.5 cm). Surgical options: stereotactic aspiration (preferred) or craniotomy with excision
Duration: 6–8 weeks ^[3]
Consider prophylactic anticonvulsant for brain abscess / subdural empyema ^[3] — seizure risk is high due to cortical irritation

Problem	Management	Rationale
Raised ICP	Consult neurosurgery for ICP control (e.g., EVD, mannitol) ^[2]; head elevation 30°; avoid hypotonic fluids; hyperventilation (short-term)	Cerebral oedema and hydrocephalus are the main drivers of raised ICP in meningitis
Seizures	IV lorazepam (acute), then phenytoin or levetiracetam for ongoing control	Seizures increase ICP and cerebral metabolic demand → worsen brain injury
Hydrocephalus	VP shunt or EVD (temporary)	CSF flow obstruction by meningeal adhesions → communicating hydrocephalus (especially in TBM)
Hyponatraemia (SIADH)	Fluid restriction (if mild); hypertonic saline (if severe/symptomatic)	Meningitis is a CNS cause of SIADH ^[11] → dilutional hyponatraemia → cerebral oedema → seizures
DIC (meningococcal)	Platelet transfusion, FFP, cryoprecipitate as needed; treat underlying infection	Endotoxin-mediated activation of coagulation cascade → consumption of clotting factors and platelets
Septic shock	IV fluids, vasopressors (noradrenaline), ICU admission	Meningococcal sepsis can cause refractory shock (Waterhouse-Friderichsen syndrome with adrenal haemorrhage → give IV hydrocortisone)
Cerebral infarction	Supportive; may need rehabilitation	Endarteritis obliterans → infarction; no role for thrombolysis in septic infarcts

11.8 Chemoprophylaxis for Contacts

Post-exposure prophylaxis for contacts — because N. meningitidis spreads by droplet transmission, close contacts have a 500–800× higher risk.

Prophylaxis for contacts of meningococcal meningitis (direct contact of < 3 ft for ≥ 8 h) ^[3]:

Regimen	Dose	Notes
PO rifampicin	600 mg Q12h × 2 days (adults); 10 mg/kg BD × 4 days (children) ^[2]^[3]	First choice in most guidelines. Rifampicin turns body fluids orange (warn patients; affects contact lenses)
PO ciprofloxacin	500 mg × 1 dose ^[3] (or 250 mg)	"Single dose oral ciprofloxacin" ^[7] — convenient single-dose option
IM ceftriaxone	250 mg × 1 dose ^[3]	"If contraindications for ciprofloxacin (young children, pregnant women)" ^[7] — safe in pregnancy and paediatrics

Who qualifies as a contact?

Household members
Intimate contacts (kissing)
Healthcare workers who performed mouth-to-mouth resuscitation, intubation, or suctioning without PPE
Close contacts in institutional settings (dormitories, military) — direct contact < 3 ft for ≥ 8 hours ^[3]

Vaccine	Target	Schedule (HK context)
PCV13/PCV15/PCV20 (pneumococcal conjugate)	S. pneumoniae	Part of HK childhood immunisation programme (PCV13 at 2, 4, 12 months). PPSV23 for high-risk adults
Hib vaccine	H. influenzae type b	Available in private sector in HK ^[5]. Dramatically reduced Hib meningitis incidence worldwide
Meningococcal vaccine (MenACWY conjugate, MenB recombinant)	N. meningitidis serogroups A, C, W-135, Y, B	Meningococcal B vaccine only available in private in HK ^[5]. Recommended for travellers to endemic areas, asplenic patients, complement-deficient patients
BCG	M. tuberculosis	Given at birth in HK. Provides some protection against severe forms of childhood TB including TBM, but protection is imperfect

Pre-splenectomy vaccination (or post-splenectomy within 2 weeks if emergency) ^[6]:

Pneumococcus, H. influenzae type b, Meningococcus, Influenza ^[6]
Asplenic patients are at lifelong risk of overwhelming post-splenectomy infection (OPSI) from encapsulated organisms

Condition	Antimicrobial	Steroid	Duration	Special Points
Bacterial (empirical)	IV ceftriaxone 2 g Q12h ± vancomycin ± ampicillin	IV dexa 0.15 mg/kg Q6h × 4 days	By pathogen (see 11.5.1)	Do NOT switch to PO. Add ampicillin if Listeria risk
TBM	HRZE × 2m + HR × 10m (total 12m)	IV dexa × 6–8 weeks (tapering)	12 months	VP shunt if hydrocephalus; pyridoxine with INH
Cryptococcal	Amphotericin B + flucytosine → fluconazole	NOT indicated	Induction ≥ 2w, consolidation ≥ 8w, then maintenance	Serial therapeutic LP for raised ICP; delay ART if HIV
HSV encephalitis	IV acyclovir 10 mg/kg Q8h	Dexa if ↑ ICP	14 days (minimum)	70% mortality if untreated; start empirically
Brain abscess	IV ceftriaxone + IV metronidazole	If significant oedema	6–8 weeks	Neurosurgical drainage if > 2.5 cm; prophylactic anticonvulsant
Viral meningitis	Supportive only (unless HSV)	Not indicated	Self-limiting (days)	Reassurance; symptomatic relief
Neurosyphilis	IM procaine penicillin + probenecid (or IV benzylpenicillin)	Not routinely	17 days (IM) or 10–14 days (IV)	Stops but does not reverse disease

High Yield Summary — Management of Meningitis

Golden sequence: Blood culture → Dexamethasone → Empirical Abx → CT (if indicated) → LP. Never delay antibiotics for CT or LP.
Empirical regimen: IV ceftriaxone 2 g Q12h + IV acyclovir 10 mg/kg Q8h. Add ampicillin if Listeria risk (elderly, immunocompromised, pregnant). Add vancomycin if resistant pneumococcus suspected.
Dexamethasone: 0.15 mg/kg IV Q6h, first dose BEFORE or WITH first antibiotic dose. Indicated for pneumococcal (4 days), S. suis (4 days), and TBM (6–8 weeks). NOT for cryptococcal meningitis.
Duration: H. influenzae ≥ 7d; S. pneumoniae 10–14d; Listeria/GBS 14–21d; Gram-negatives ≥ 21d. All IV — no PO switch.
TBM: HRZE 2 months + HR 10 months (total 12 months) + dexamethasone 6–8 weeks + pyridoxine + VP shunt if hydrocephalus.
Cryptococcal: Amphotericin B + flucytosine ≥ 2 weeks → fluconazole ≥ 8 weeks. NO steroids. Serial LP for raised ICP.
Chemoprophylaxis: Meningococcal contacts — rifampicin or ciprofloxacin or IM ceftriaxone. H. influenzae contacts — rifampicin.
Monitor: Neuro obs Q1–2h. Repeat LP if no improvement at 48–72h. Look for complications (hydrocephalus, infarction, SIADH, abscess).

Active Recall - Management of Meningitis

References

^[1] Lecture slides: GC 051. Fever and confusion_meningitis and encephalitis; suppurative brain infection.pdf (General points on CNS infections, investigations) ^[2] Senior notes: Ryan Ho Neurology.pdf (Section 7.1 Meningitis — Management, pp. 145–146) ^[3] Senior notes: Maksim Medicine Notes.pdf (Section 9.6 CNS infections — Management, p. 198) ^[4] Senior notes: Gen Clerk Anaes + Microbiology Summary.pdf (CNS TB — adjunct steroid, VP shunt, p. 34) ^[5] Senior notes: Adrian Lui Pediatrics Notes.pdf (Section 14.2.2 — vaccines for meningococcus, pneumococcus, Hib, p. 474) ^[6] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf (Pre-splenectomy vaccination, p. 20) ^[7] Senior notes: Gen Clerk Anaes + Microbiology Summary.pdf (Listeria ampicillin coverage, meningococcal prophylaxis, pp. 14, 27) ^[11] Senior notes: Block A - Electrolyte and Acid-Base Disorders.pdf (SIADH — CNS causes including meningitis, p. 21)

Complications of Meningitis

Complications are what make meningitis a feared diagnosis. Understanding them requires tracing each back to the underlying pathophysiology described in earlier sections. The complications can be broadly categorised into intracranial, systemic, long-term sequelae, and pathogen-specific complications.

Complications mainly occur in pyogenic and chronic meningitis ^[2].

GC Lecture Slide – Complications of Meningitis (High Yield)

The GC 051 slide lists the following complications directly ^[1]:

Meningeal adhesions → raised intracranial pressure, 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
Syndrome of inappropriate secretion of anti-diuretic hormone (SIADH)
Disseminated intravascular coagulation
Septic shock

12.1 Intracranial Complications

CN palsies: III, IV, VI are the commonest; VIII involvement tends to persist ^[2].

Mechanism: two routes of CN damage —
1. Compression due to brain swelling — raised ICP pushes brain tissue against bony structures, compressing adjacent nerves ^[8]^[9]
2. Perineuritis due to adjacent meningeal inflammatory reaction — the nerve passes through inflamed, purulent meninges → inflammatory infiltrate directly damages the nerve ^[8]^[9]

CN VI (abducens nerve) is the most commonly affected nerve ^[8]^[9]. Why?

CN VI has the longest intracranial segment adjacent to the brainstem ^[8]^[9] — it runs along the ventral surface of the pons, through Dorello's canal under the petroclinoid ligament, then traverses the cavernous sinus. Its long, exposed course makes it vulnerable to both:
- Raised ICP — as ICP rises, the brainstem is pushed downward, stretching CN VI where it is tethered at its exit point → unilateral or bilateral lateral rectus palsy → "cannot look out" → convergent squint
- Basal meningeal inflammation — CN VI passes through the basal cisterns where exudate is thickest (especially in TBM)

Other CNs affected:

CN III, IV — also traverse the basal cisterns; commonly involved in TBM ^[2]
CN VII — may be affected in basal meningitis, causing facial weakness
CN VIII — sensorineural hearing loss (see below); VIII involvement tends to persist ^[2], meaning it often does not recover even after successful treatment
CN II — optic neuritis or optochiasmic arachnoiditis (especially in TBM — encasement of optic nerve and chiasma by thick TB exudates) ^[26]; also CN II compression by dilated 3rd ventricle pushing on the optic chiasm in hydrocephalus

TBM and Cranial Nerves

"Think TBM in CN palsy combinations that don't make sense" ^[2] — if a patient has, say, CN III + CN VI + CN VIII palsies, this does not fit any single anatomical lesion. It fits basal meningitis — where multiple CNs traversing the base of the brain are damaged by exudate at different points. TBM is the classic cause of this pattern in Hong Kong.

Local spread of infection: cerebritis, cerebral abscess, subdural effusion / empyema ^[1]^[2].

Complication	Pathophysiology	Clinical Features	Management
Cerebritis	Direct extension of infection from meninges into superficial brain parenchyma → ill-defined area of inflammation and necrosis	Progressive focal deficits, ↑ fever, ↓ GCS	Prolonged IV antibiotics; if progresses to abscess → drainage
Cerebral abscess	Cerebritis matures: liquefactive necrosis → cavity filled with pus, surrounded by fibrotic capsule	Headache, focal deficits, seizures, ↑ ICP. CT/MRI: ring-enhancing lesion	IV ceftriaxone + metronidazole × 6–8 weeks; neurosurgical aspiration/drainage if > 2.5 cm
Subdural effusion	Sterile or infected fluid collects between dura and arachnoid — common in infants with H. influenzae or pneumococcal meningitis	↑ head circumference (infants), persistent fever, bulging fontanelle, seizures. CT shows subdural collection	Observation if small/sterile; surgical drainage if symptomatic or infected (→ subdural empyema)
Subdural empyema	Collection of pus between dura and arachnoid ^[3] → rapidly expanding intracranial infection with mass effect	High fever, rapid deterioration, focal deficits, seizures, ↓ GCS. CT/MRI: crescentic extra-axial collection	Neurosurgical emergency: craniotomy for drainage + prolonged IV antibiotics
Ventriculitis	Complication of severe meningitis or rupture of brain abscess; high mortality ^[3]	Persistent fever, ↓ GCS despite treatment; CT may show enhancing ventricular walls, debris/fluid levels in ventricles	IV + intrathecal/intraventricular antibiotics (via EVD); very poor prognosis

12.2 Systemic Complications

12.3 Long-Term Sequelae

TBM deserves a separate mention because its complication profile is particularly severe and distinctive:

Complication	Incidence in TBM	Mechanism	Clinical Consequence
Hydrocephalus	Up to 80% ^[26]	Basal exudate → adhesions → CSF obstruction	↑ ICP, ↓ GCS, deteriorating vision. Requires VP shunt
Stroke / Cerebral infarction	26% ^[26]	Endarteritis obliterans, especially perforator arteries (basal ganglia, internal capsule)	Hemiparesis, aphasia, cognitive decline
CN palsies	Common	Basal meningeal scarring — especially CN II, VI, VII, VIII ^[26]	Diplopia, facial weakness, hearing loss, visual loss
Visual loss	~25% ^[26]	Optochiasmatic arachnoiditis (encasement of optic nerve and chiasma by TB exudates), dilated 3rd ventricle compressing optic chiasma, ↑ ICP, endarteritis of optic nerve and chiasmal vessels ^[26]	Bilateral visual loss, bitemporal hemianopia
Hyponatraemia	Common	SIADH or CSWS ^[26]	Seizures, worsening cerebral oedema
Seizures	Common	Focal cortical ischaemia, hyponatraemia	Focal or generalised; can be status epilepticus
Spinal involvement	Variable	Myelitis, arachnoiditis (spinal cord compression by thickened meninges → paraparesis) ^[2]	Paraplegia, bladder dysfunction
Tuberculoma	Variable	Parenchymal granuloma; may paradoxically enlarge during treatment (immune reconstitution)	Mass effect, seizures, focal deficits

Prognosis: 21% mortality, 66% mild or no disability → warn patient/family of ~1/3 chance of poor outcome ^[2]

Parameter	Bacterial Meningitis	TBM	Viral Meningitis
Mortality	15–25% overall (higher for pneumococcal ~20%, lower for meningococcal ~10%)	20–50% (higher at MRC Stage III)	< 1% (unless HSV encephalitis: 70% untreated)
Neurological sequelae	~30% of survivors	Very high (especially if MRC Stage II–III)	Rare
SNHL	10–30% (depends on pathogen)	Common, often bilateral	Very rare
Epilepsy	~5%	Higher (cortical infarction common)	Very rare

Category	Complications
Raised ICP / Mass effect	Cerebral oedema (vasogenic, cytotoxic, interstitial); hydrocephalus (communicating > obstructive); cerebellar herniation
Cranial nerves	CN III, IV, VI palsies (most common); CN VIII → SNHL (most persistent); CN II → visual loss; CN VII → facial weakness
Cerebrovascular	Endarteritis obliterans → ischaemic infarction; cortical venous thrombosis → haemorrhagic infarction; mycotic aneurysm → SAH
Seizures	Acute seizures (~10%); chronic epilepsy (~5%)
Local spread	Cerebritis → brain abscess; subdural effusion/empyema; ventriculitis
Systemic	SIADH → hyponatraemia; DIC (especially meningococcal); septic shock; Waterhouse-Friderichsen syndrome; renal failure; peripheral gangrene
Long-term	SNHL; intellectual impairment; cerebral palsy; behavioural/cognitive deficits; epilepsy

High Yield Summary – Complications of Meningitis

From the GC 051 lecture slide ^[1]:

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

Key pathogen-specific associations:

Meningococcal → DIC, purpura, Waterhouse-Friderichsen, septic shock, peripheral gangrene, renal failure
Pneumococcal → highest mortality (~20%), infarction, SNHL
S. suis → SNHL (especially common and persistent)
TBM → hydrocephalus (80%), CN palsies (basal), infarction (26%), visual loss (25%), spinal involvement

CN VI is the most commonly affected nerve (longest intracranial course). CN VIII damage tends to persist (hearing loss often permanent).

SIADH → check Na⁺ frequently; hyponatraemia worsens cerebral oedema and seizure risk.

Prognosis: ~21% mortality; ~1/3 chance of significant disability.

Active Recall – Complications of Meningitis

References

^[1] Lecture slides: GC 051. Fever and confusion_meningitis and encephalitis; suppurative brain infection.pdf (Complications of Meningitis slide, p. 34; Bacterial Meningitis III — meningococcal complications, p. 27) ^[2] Senior notes: Ryan Ho Neurology.pdf (Section 7.1.4 Complications, p. 145; clinical features of complications, pp. 142–144) ^[3] Senior notes: Maksim Medicine Notes.pdf (Complications of CNS infection, p. 198; disease entities, p. 196) ^[8] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Complications of meningitis, p. 1191) ^[9] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (Complications of meningitis, p. 512) ^[11] Senior notes: Block A - Electrolyte and Acid-Base Disorders.pdf (Causes of SIADH — CNS causes including meningitis, p. 21) ^[26] Senior notes: Ryan Ho Respiratory.pdf (TBM complications — stroke, hydrocephalus, CN palsies, visual loss, hyponatraemia, transverse myelitis, p. 79) ^[27] Lecture slides: GC 051. Fever and confusion_meningitis and encephalitis; suppurative brain infection.pdf (Bacterial Meningitis III — meningococcal sepsis complications, p. 27)

High Yield Summary

Definition: Meningitis = inflammation of the leptomeninges, defined by ↑ WBC in CSF. Distinguish from meningism (signs without CSF inflammation).
Epidemiology: In HK, TBM is a very common cause. S. pneumoniae is the commonest bacterial cause in adults. S. suis is a unique local pathogen (pork exposure → SNHL).
Risk factors: Extremes of age, immunocompromised, asplenia (encapsulated organisms), CSF leak, neurosurgery, complement deficiency (Neisseria), contiguous infections (sinusitis, otitis).
Source of infection: Direct spread from nearby structures (ear, sinus, dental) or haematogenous spread from distant septic foci.
Pathophysiology: Bacteria cross BBB → multiply in immunologically privileged CSF → bacterial components trigger cytokine storm → BBB disruption → vasogenic/cytotoxic/interstitial oedema → ↑ ICP → ↓ cerebral perfusion. Pus can organise into adhesions → hydrocephalus. Endarteritis obliterans → cerebral infarction. CN damage at base of brain → hearing loss.
Classical triad: Fever + headache + neck stiffness — but complete triad present in only ~44%.
Meningeal signs: Kernig's (hamstring spasm on knee extension), Brudzinski's (hip flexion on neck flexion) — specific but insensitive. Bulging fontanelle in infants.
Red flags requiring immediate LP/treatment: Petechial rash with fever, altered consciousness, focal neurological deficits, seizures.
CSF patterns: Bacterial (↑ neutrophils, ↓ glucose, ↑ protein), viral (↑ lymphocytes, normal glucose), TB (↑↑↑ lymphocytes, ↓↓ glucose, ↑↑↑ protein).
TBM: Insidious onset, triphasic illness, basal meningeal adhesions → CN palsies + hydrocephalus, endarteritis obliterans → infarction.
Listeria: Extremes of age + immunocompromised; resistant to cephalosporins → must add ampicillin.
Chemoprophylaxis: Meningococcal contacts → ciprofloxacin or IM ceftriaxone; H. influenzae contacts → rifampicin.

High Yield Summary — Differential Diagnosis of Meningitis

Key DDx of the meningitis syndrome (fever + headache + neck stiffness + altered consciousness):

Intracranial infections: encephalitis, brain abscess, subdural empyema, ventriculitis
Vascular: SAH (blood irritates meninges → meningism), CVST
Systemic sepsis with septic encephalopathy (delirium mimicking meningitis)
Non-meningeal causes of neck stiffness: cervical spondylosis, retropharyngeal abscess, cervical lymphadenitis

Key DDx within confirmed meningitis (CSF pleocytosis):

Bacterial: S. pneumoniae (MC adult, explosive), N. meningitidis (purpuric rash, DIC), H. influenzae (children), Listeria (extremes of age, I/C), S. suis (raw pork, SNHL), GBS (neonates), Gram-negatives (neonates, elderly, post-surgical)
Viral: Enterovirus (MC, benign), HSV-2 (recurrent), mumps, HIV
TB: most common cause of meningitis locally — subacute, triphasic, basal meningitis, CN palsies
Fungal: Cryptococcus — HIV/immunosuppressed, ↑↑↑ ICP
Non-infective: leptomeningeal carcinomatosis, sarcoidosis, SLE, Behçet's, drug-induced

Critical clinical clues:

Purpuric rash → meningococcal
Pork exposure → S. suis
Immunocompromised → Cryptococcus, Listeria, TB
CSF leak → recurrent pneumococcal
Insidious onset weeks → TBM
CN palsy "combinations that don't make sense" → TBM

High Yield Summary — Diagnosis of Meningitis

Gold standard: LP with CSF analysis — appearance, opening pressure, cell count + differential, protein, glucose (with paired serum glucose), Gram stain, culture, PCR.
Time-critical sequence: Blood culture → Dexamethasone → Empirical Abx → CT (if indicated) → LP. Never delay antibiotics for imaging.
CT before LP indications: altered consciousness, focal signs, papilloedema, seizure, immunocompromised.
CSF patterns:
- Bacterial: neutrophilic, ↓ glucose ( < 50% BG), ↑ protein, cloudy
- Viral: lymphocytic, normal glucose, clear
- TB: lymphocytic, ↓↓ glucose, ↑↑↑ protein (up to 2–6 g/dL), opalescent
- Cryptococcal: lymphocytic, ↓ glucose, ↑↑ protein, very high opening pressure, +ve CrAg
Gram stain morphology: GP diplococci = Pneumococcus; GN diplococci = Meningococcus; GN coccobacilli = H. influenzae; GP rods = Listeria.
TBM diagnosis: CSF AFB smear (low sensitivity), culture (slow), PCR/GeneXpert (sensitivity 82%, specificity 99%), ADA; CXR; MRI (basal enhancement, hydrocephalus, tuberculoma).
Repeat LP if no improvement after 8 days — look for persistent source, abscess, or resistance.

High Yield Summary — Management of Meningitis

Golden sequence: Blood culture → Dexamethasone → Empirical Abx → CT (if indicated) → LP. Never delay antibiotics for CT or LP.
Empirical regimen: IV ceftriaxone 2 g Q12h + IV acyclovir 10 mg/kg Q8h. Add ampicillin if Listeria risk (elderly, immunocompromised, pregnant). Add vancomycin if resistant pneumococcus suspected.
Dexamethasone: 0.15 mg/kg IV Q6h, first dose BEFORE or WITH first antibiotic dose. Indicated for pneumococcal (4 days), S. suis (4 days), and TBM (6–8 weeks). NOT for cryptococcal meningitis.
Duration: H. influenzae ≥ 7d; S. pneumoniae 10–14d; Listeria/GBS 14–21d; Gram-negatives ≥ 21d. All IV — no PO switch.
TBM: HRZE 2 months + HR 10 months (total 12 months) + dexamethasone 6–8 weeks + pyridoxine + VP shunt if hydrocephalus.
Cryptococcal: Amphotericin B + flucytosine ≥ 2 weeks → fluconazole ≥ 8 weeks. NO steroids. Serial LP for raised ICP.
Chemoprophylaxis: Meningococcal contacts — rifampicin or ciprofloxacin or IM ceftriaxone. H. influenzae contacts — rifampicin.
Monitor: Neuro obs Q1–2h. Repeat LP if no improvement at 48–72h. Look for complications (hydrocephalus, infarction, SIADH, abscess).

High Yield Summary – Complications of Meningitis

From the GC 051 lecture slide ^[1]:

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

Key pathogen-specific associations:

Meningococcal → DIC, purpura, Waterhouse-Friderichsen, septic shock, peripheral gangrene, renal failure
Pneumococcal → highest mortality (~20%), infarction, SNHL
S. suis → SNHL (especially common and persistent)
TBM → hydrocephalus (80%), CN palsies (basal), infarction (26%), visual loss (25%), spinal involvement

CN VI is the most commonly affected nerve (longest intracranial course). CN VIII damage tends to persist (hearing loss often permanent).

SIADH → check Na⁺ frequently; hyponatraemia worsens cerebral oedema and seizure risk.

Prognosis: ~21% mortality; ~1/3 chance of significant disability.

Meningitis

1. Definition

2. Epidemiology

2.1 Global Perspective

2.2 Hong Kong Context

2.3 Age-Specific Epidemiology

3. Risk Factors

3.1 Host Factors

3.2 Anatomical / Structural Factors

3.3 Epidemiological / Exposure Factors

4. Anatomy and Function of the Meninges

4.1 The Three Meningeal Layers (Superficial → Deep)

4.2 The Leptomeninges and Subarachnoid Space

4.3 The Blood-Brain Barrier (BBB)

4.4 CSF Circulation (Relevant to Complications)

5. Aetiology (with Pathophysiology)

5.1 Classification by Temporal Course

5.2 Acute Bacterial Meningitis (Pyogenic)

5.2.1 Pathophysiology of Bacterial Meningitis

5.2.2 Specific Bacterial Pathogens

(a) Streptococcus pneumoniae (Pneumococcus)

(b) Neisseria meningitidis (Meningococcus)

(c) Haemophilus influenzae type b (Hib)

(d) Listeria monocytogenes

(e) Streptococcus suis

(f) Group B Streptococcus (GBS, S. agalactiae)

(g) Gram-Negative Bacilli (E. coli, Klebsiella, etc.)

(h) Staphylococcus aureus and S. epidermidis

5.3 Viral (Aseptic) Meningitis

5.3.1 Aetiology

5.3.2 Clinical Features

5.4 Subacute / Chronic Meningitis

5.4.1 Tuberculous Meningitis (TBM)

Pathophysiology

Clinical Presentation — Classically a triphasic illness [2][4]:

Source

Complications

Staging (MRC Staging, Lancet 1948) [4]

Treatment Overview (briefly — detailed management later)

5.4.2 Cryptococcal Meningitis

5.4.3 Other Chronic / Atypical Causes [2]

5.5 Source of Infection — Summary

6. Classification

6.1 By Temporal Course

6.2 By Aetiology

6.3 By CSF Profile (Critical for Diagnosis — Preview)

7. Clinical Features

7.1 Symptoms

7.1.1 The Classical Triad: Fever + Headache + Neck Stiffness [1][3][8]

7.1.2 Other Meningeal Irritation Symptoms

7.1.3 Signs of Brain Parenchymal Involvement (Meningoencephalitis)

7.1.4 Non-Specific Systemic Symptoms

7.1.5 Pathogen-Specific Symptoms

7.1.6 Symptoms in Special Populations

7.2 Signs

7.2.1 Signs of Meningeal Irritation

7.2.2 Signs Related to Specific Pathogens

7.2.3 Focal Neurological Signs

7.2.4 Signs of Raised ICP

7.2.5 Signs of Complications

7.2.6 Signs in TBM Specifically

8. Summary of Pathophysiology → Clinical Features Linkage

Active Recall - Meningitis (Definition, Epidemiology, Risk Factors, Aetiology, Pathophysiology, Clinical Features)

References

9.1 Approach to the Differential: Fever + Confusion / Headache + Neck Stiffness

9.2 Level 1: Conditions That Mimic Meningitis (DDx of the Syndrome)

9.2.1 Intracranial Pathologies

9.2.2 Systemic / Non-CNS Conditions

9.2.3 Conditions Causing "Neck Stiffness" Without Meningitis

9.3 Level 2: Aetiological Differential Diagnosis Within Confirmed Meningitis

9.3.1 By Tempo of Illness

9.3.2 By CSF Profile — The Definitive Differentiator

9.3.3 Pitfalls in CSF Interpretation

9.3.4 Clinical Clues to Narrow the Aetiological Differential

9.4 Non-Infective Causes of Meningitis (Important but Often Forgotten)

9.5 Special DDx Considerations by Clinical Scenario

9.5.1 Fever + Seizure in a Child

9.5.2 New-Onset Headache in the Elderly

9.5.3 Headache Red Flags That Suggest Meningitis Over Primary Headache

9.6 Summary Decision Framework