Encephalitis

• Incidence: approximately 5–8 per 100,000 population per year for all-cause encephalitis; infectious encephalitis accounts for ~50%, with the remainder being autoimmune or unknown
• Despite extensive investigation, no cause is identified in 30–60% of cases (the so-called "encephalitis of unknown aetiology")
• Herpes simplex encephalitis (HSE) is the most common cause of sporadic fatal encephalitis worldwide — incidence ~1 per 250,000–500,000 per year
• Epidemic causes include Japanese B encephalitis, dengue fever, influenza, West Nile virus, Nipah virus ^[1]

• Japanese encephalitis (JE): historically endemic in southern China/Southeast Asia; rare in urban HK due to vaccination and mosquito control, but remains important in differential for travellers and residents near rural areas with pig farming (pigs = amplifying host)
• Enterovirus encephalitis: enterovirus 71 (EV-A71) outbreaks periodically occur in the Asia-Pacific region, including HK, particularly affecting young children
• Enteroviruses (MC viral cause of meningitis/encephalitis) ^[2] — worth noting that while enteroviruses are the most common cause of viral meningitis, HSV-1 remains the most important cause of sporadic encephalitis due to its severity
• Herpes simplex virus type 1 remains the most common identifiable sporadic cause, same as worldwide
• Autoimmune encephalitis (particularly anti-NMDA receptor encephalitis) has been increasingly recognised, especially in young women with ovarian teratoma
• Autoimmune encephalitis is a key DDx ^[2]

• Neonates: HSV-2 (acquired perinatally), enterovirus
• Children: enterovirus, HSV-1, ADEM (post-infectious), mumps (pre-vaccination era), measles
• Adults: HSV-1, VZV, enterovirus, autoimmune encephalitis
• Elderly/immunocompromised: CMV, VZV, Listeria, toxoplasmosis, PML (JC virus), HIV encephalopathy

• The brain parenchyma consists of neurons, glial cells (astrocytes, oligodendrocytes, microglia), and their supporting vasculature
• Unlike the meninges (which are primarily connective tissue barriers + CSF-containing spaces), the parenchyma is the computational tissue — damage here produces neurological deficits, not just irritation signs

• Formed by tight junctions between endothelial cells of cerebral capillaries, reinforced by astrocyte foot processes and pericytes
• Normally excludes most pathogens and immune cells from the CNS
• In encephalitis: pathogens breach the BBB via:
  • Haematogenous spread (viraemia → crossing BBB): most viruses
  • Retrograde axonal transport along peripheral nerves: HSV-1 (via olfactory/trigeminal nerve), rabies (via peripheral motor nerves)
  • Direct extension from adjacent infected structures (e.g., sinusitis, otitis media → rare in viral encephalitis, more relevant for brain abscess)
• BBB breakdown → vasogenic cerebral oedema → raised ICP

• HSV-1 encephalitis characteristically involves the temporal lobes (inferomedial temporal cortex, insular cortex, orbitofrontal cortex)
• Why temporal lobes? HSV-1 establishes latency in the trigeminal ganglion → reactivation spreads retrogradely along the trigeminal nerve (meningeal branches) to the temporal lobe and frontal lobe base, which are supplied by these branches. Alternatively, via olfactory mucosa → olfactory tract → orbitofrontal/medial temporal cortex
• This explains the classic HSE features: temporal lobe seizures, aphasia (dominant hemisphere), personality/behavioural change, olfactory hallucinations, memory impairment (hippocampus is in the medial temporal lobe)

• Structures: hippocampus, amygdala, cingulate gyrus, hypothalamus, mammillary bodies
• Function: memory formation, emotion, autonomic regulation
• Limbic encephalitis (whether infectious [HSV] or autoimmune [anti-NMDA-R, anti-LGI1]) preferentially involves these structures → psychiatric symptoms (personality change, agitation, psychosis), memory impairment, seizures, autonomic instability

• Contains cranial nerve nuclei, reticular activating system (RAS), respiratory/cardiovascular centres
• Brainstem encephalitis (rhombencephalitis): Listeria monocytogenes classically; also enterovirus 71
• Produces: cranial nerve palsies, ataxia, reduced consciousness (RAS involvement), respiratory failure

• Cerebellitis/cerebellar encephalitis: VZV is a classic cause of post-infectious cerebellar ataxia in children
• Cerebellar ataxia (esp in VZV) ^[1]

• Three layers: dura mater, arachnoid mater, pia mater
• Subarachnoid space contains CSF — this is the space sampled by lumbar puncture
• Meningeal inflammation → headache, neck stiffness, photophobia (these are the "meningitic" symptoms that overlay encephalitic features)

^[1][2]

These are chronic/subacute infections with very different clinical courses:

^[1]

• Virus enters the CNS via:
  • Haematogenous spread: viraemia → crossing the BBB (most arboviruses, enteroviruses)
  • Neuronal retrograde transport: virus travels along axons from peripheral nerve to CNS (HSV-1 via trigeminal/olfactory nerve; rabies via motor nerves from bite site)
  • Olfactory route: directly from nasal mucosa → olfactory bulb → frontal/temporal lobes
• Once in the CNS, the virus:
  • Replicates within neurons and glial cells → direct cytopathic effect → neuronal death
  • Triggers innate immune response: microglial activation, astrocyte reactivity, complement activation
  • Triggers adaptive immune response: T-cell infiltration (predominantly CD8+ cytotoxic T cells), antibody production
  • The immune response itself causes significant collateral damage — this is a double-edged sword

• Post-infectious/parainfectious: ADEM

  • Molecular mimicry: viral antigens share epitopes with myelin components (e.g., myelin basic protein, myelin oligodendrocyte glycoprotein)
  • Cross-reactive T cells and antibodies attack CNS myelin → perivenular demyelination
  • This explains why ADEM occurs days to weeks AFTER the infection (time needed for adaptive immune response to develop)

• Autoimmune encephalitis (e.g., anti-NMDA-R):

  • Antibodies target surface/synaptic proteins on neurons
  • Anti-NMDA-R antibodies cause internalization of NMDA receptors → reduced glutamatergic transmission → the clinical syndrome (psychiatric features, seizures, movement disorders, autonomic instability)

• BBB breakdown → vasogenic oedema
• Neuronal injury → cytotoxic oedema
• Both contribute to raised intracranial pressure → headache, vomiting, papilloedema, reduced consciousness, risk of herniation
• Raised ICP in encephalitis/meningitis: vasogenic cerebral oedema (increased BBB permeability) + cytotoxic cerebral oedema (cytotoxic factors from pathogen and neutrophils) ^[3][4]

• Inflamed, oedematous cortex → disruption of normal inhibitory-excitatory balance
• Causes of seizure: acute symptomatic seizure may be caused by virtually any acute brain insult, e.g., encephalitis ^[5]
• CNS infections (classically encephalitis) are a classic cause of status epilepticus ^[5]
• Temporal lobe involvement (HSV) → focal seizures with secondary generalisation
• Metabolic derangements secondary to encephalitis (hyponatraemia from SIADH, hypoglycaemia) → further lower seizure threshold

• Brain inflammation → hypothalamic/posterior pituitary dysfunction → inappropriate ADH secretion → dilutional hyponatraemia
• CNS causes of SIADH: meningitis, encephalitis, brain abscess, head trauma, SAH, CVA, raised ICP ^[6]
• This creates a vicious cycle: hyponatraemia → cerebral oedema → seizures → worsening neurological status

These are conditions where the brain/meninges are directly infected, but the pathology is different from viral encephalitis.

This is the most common mimic in clinical practice. A patient with pneumonia, UTI, or any systemic infection can develop confusion from the systemic inflammatory response — this is septic encephalopathy, NOT encephalitis.

• Why it mimics: Fever ✓, altered mental status ✓, sometimes seizures ✓
• Why it's NOT encephalitis: The brain parenchyma is not inflamed; the confusion is from systemic cytokine effects, metabolic derangements (uraemia, electrolyte disturbances, hypoxia, hypoglycaemia), or organ failure
• How to differentiate:
  • CSF is normal (no pleocytosis, normal glucose/protein) — this is the key distinguishing investigation
  • MRI brain is normal (no parenchymal signal changes)
  • Source of infection is identifiable elsewhere (CXR for pneumonia, MSU for UTI, blood cultures)
  • Clinical picture improves with treatment of the underlying infection

These are non-infectious causes of altered mental status that can co-exist with fever (e.g., from a concurrent infection) and thus mimic encephalitis.

Autoimmune encephalitis is a differential diagnosis of patients presenting with fever and confusion ^[8] Rare ^[8] May be associated with underlying malignancies and infections that have triggered an immune response against the brain parenchyma ^[8]

This is important because it is treatable but often missed if not considered.

Increasing number of antibodies being recognised — most common being anti-NMDA (N-methyl-D-aspartate) receptor encephalitis ^[8] Most commonly affects young women and children ^[8] Associated with ovarian teratomas ^[8] Clinical presentation: ^[8]

• Viral-like prodrome
• Neuropsychiatric symptoms (altered cognition, behavioural changes – psychosis, aggression, catatonia...)
• Abnormal movements (orofacial, limb or trunk dyskinesias)
• Seizures
• Altered consciousness
• Autonomic dysfunction

Why it mimics viral encephalitis: The presentation can be near-identical — subacute onset of confusion, seizures, psychiatric symptoms, fever (low-grade). CSF may show lymphocytic pleocytosis. MRI may show signal changes.

How to differentiate:

• Clinical trajectory: autoimmune encephalitis tends to have a more subacute progression (days to weeks) compared to acute viral encephalitis (hours to days for HSV)
• Psychiatric features prominent early: in anti-NMDA-R encephalitis, psychiatric symptoms (psychosis, catatonia, agitation) are often the presenting features — many patients are initially admitted to psychiatry before the diagnosis is made
• Movement disorders: orofacial dyskinesias are characteristic of anti-NMDA-R encephalitis and unusual in viral encephalitis
• CSF: may show lymphocytic pleocytosis (like viral), but HSV PCR is negative; specific antibody testing (anti-NMDA-R Ab in CSF and serum) is diagnostic
• MRI: may be normal or show non-specific changes (unlike HSV which has characteristic temporal lobe changes)
• Look for teratoma: pelvic ultrasound / CT / MRI in young women

From the senior notes, the differential diagnosis of encephalitis includes ^{[3][4][9][10]}:

• Brain tumours (primary/metastatic) — can present with confusion, seizures, focal deficits; fever may co-exist from concurrent infection or tumour fever
• Subdural haematoma — especially in elderly/alcoholics; fluctuating consciousness; CT: crescent-shaped collection
• Cerebral venous sinus thrombosis — headache, seizures, focal deficits, altered consciousness; risk factors: OCP, pregnancy, prothrombotic states; MRI/MRV diagnostic

• Nonconvulsive status epilepticus (NCSE): Sepsis with nonconvulsive status epilepticus ^[8] — a patient with systemic infection may have NCSE causing prolonged altered consciousness without obvious convulsions. EEG is required for diagnosis
• Post-ictal state (Todd's paralysis): After a seizure, the patient may be confused with focal neurological deficits. This resolves within hours. Important to distinguish from evolving encephalitis

• Toxic encephalopathy ^{[3][4][9][10]}
• Drug toxicity (e.g., lithium, phenytoin, carbamazepine overdose), illicit drugs (methamphetamine, MDMA), alcohol intoxication/withdrawal
• Neuroleptic malignant syndrome (NMS): fever + rigidity + altered consciousness + autonomic instability; caused by dopamine antagonists (antipsychotics); elevated CK
• Serotonin syndrome: fever + clonus + agitation + altered consciousness; caused by serotonergic drugs; onset within hours of drug change
• History and urine toxicology screen are key

Syphilis ^{[3][4][9][10]} — neurosyphilis can present as meningoencephalitis (acute or chronic). Important to check RPR/VDRL and FTA-ABS, especially with risk factors (MSM, HIV co-infection). Increasingly relevant in HK where syphilis incidence has been rising.

The differential of febrile seizure includes ^[14]:

CNS infection, encephalopathy, genetic epilepsy, and nonepileptic events (e.g., shaking chills). Meningitis and encephalitis are the main concerns in a child presenting with fever and seizures ^[14]

A thorough history and examination will usually detect signs of meningitis such as altered consciousness, bulging fontanelle (infants), petechial rash, and/or meningeal signs ^[14].

The DDx of acute hemiplegia ^[15][16] includes:

• Stroke (ischaemic or haemorrhagic) — most common cause overall
• Encephalitis (viral, hypertensive, Wernicke) ^[15][16]
• Brain abscess ^[15][16]
• Brain tumour ^[15][16]
• Todd's paralysis (postictal) ^[15][16]
• Hemiplegic migraine ^[15][16]

If there is fever, encephalitis and brain abscess rise to the top of the differential.

Must consider opportunistic CNS infections:

• Toxoplasmosis: ring-enhancing lesions, basal ganglia predilection; anti-toxoplasma IgG usually positive
• Cryptococcal meningoencephalitis: elevated opening pressure, India ink, CrAg
• CMV ventriculoencephalitis: periventricular enhancement
• PML: multifocal non-enhancing white matter lesions (JC virus)
• Primary CNS lymphoma: solitary or few ring-enhancing lesions (cf toxoplasma which tends to be multiple)
• TB meningoencephalitis: basal meningeal enhancement, hydrocephalus

EEG: often abnormal in acute encephalitis. Diffuse slow waves and spike activities. Focality in temporal lobe is strongly suggestive of HSV encephalitis ^[3][4]

EEG – periodic slow-wave activity / lateralisation epileptiform discharges involving the frontotemporal lobes in HSV encephalitis ^[8]

EEG: generalised slow waves (encephalopathic changes), periodic lateralising epileptiform discharges (e.g. in HSV encephalitis), other epileptiform activities ^[8]

Why is EEG useful?

1. Supports diagnosis when CSF/MRI are equivocal
2. Detects subclinical seizures / NCSE — a patient who remains unconscious despite treatment may be in non-convulsive status epilepticus
3. Localises the abnormality (temporal lobe → HSV)
4. Monitors response to treatment

EEG: Evaluation in encephalitis, sporadic CJD ^[18]

These serve to (a) identify systemic clues, (b) exclude metabolic mimics, and (c) look for specific aetiologies.

Bloods: CBC d/c, LRFT (for SIADH), clotting profile, glucose, blood C/ST ^[2]

Urine/Stool/Throat swab: for viral culture ^[3][4]

Brain biopsy: as last resort → seldom necessary ^[1]

• Brain biopsy is the gold standard ^[17] for HSV encephalitis — but in practice, almost never needed due to the excellent sensitivity of CSF HSV PCR
• Reserved for cases where:
  • The patient is deteriorating despite empirical treatment
  • All other investigations are non-diagnostic
  • A treatable cause (e.g., lymphoma, unusual infection) is suspected
• Tissue sent for: histopathology, viral culture, PCR, electron microscopy, immunohistochemistry

This is the single most important treatment decision in suspected encephalitis.

Aciclovir 10 mg/kg IV three times per day for 2–3 weeks for HSV encephalitis ^[8] Should be started in all patients with suspected viral encephalitis ^[8] Significantly reduced mortality of HSV encephalitis ^[8]

Empirical treatment: IV acyclovir 10 mg/kg Q8H for 10–14 days ^[3][4] (Note: current guidelines favour 14–21 days for confirmed HSV; GC lecture says 2–3 weeks ^[8])

How aciclovir works — from first principles:

Aciclovir = "acyclo-" (without a complete cycle) + "vir" (virus). It is a guanosine analogue that lacks a 3'-hydroxyl group on its sugar ring.

1. Selective activation: Aciclovir is a prodrug that requires phosphorylation to become active. The first phosphorylation step is performed by viral thymidine kinase (TK) — an enzyme only present in cells infected by herpes viruses (HSV, VZV). This is why aciclovir is selectively toxic to infected cells and has minimal toxicity to uninfected cells.
2. Mechanism of action: Aciclovir triphosphate (the active form) competes with deoxyguanosine triphosphate (dGTP) for incorporation into viral DNA by viral DNA polymerase → once incorporated, the missing 3'-OH group means no further nucleotides can be added → chain termination → viral DNA replication stops.
3. Selectivity: Viral DNA polymerase has a much higher affinity for aciclovir triphosphate than human DNA polymerase → selective antiviral effect with minimal host toxicity.

Contraindications and cautions:

Because bacterial meningitis cannot always be excluded at presentation (especially early when CSF may show neutrophilic predominance), empirical antibiotics should be given alongside aciclovir if there is any possibility of bacterial infection.

Empirical treatment: IV ceftriaxone 2g Q12h + aciclovir 10mg/kg Q8h ^[2]

Why ceftriaxone specifically?

• Third-generation cephalosporin → broad gram-negative and gram-positive coverage
• Excellent CSF penetration (especially in inflamed meninges where BBB permeability is increased)
• Long half-life → Q12H dosing
• Note: meningitic dosing (2g Q12H) is higher than standard dosing (1-2g Q24H) because you need to achieve adequate CSF concentrations above MIC

IV dexamethasone 0.15 mg/kg Q6H for 4 days (1st dose before or together with antibiotics) ^[2]

Why dexamethasone? The inflammatory response to bacterial meningitis (neutrophil infiltration, cytokine release, BBB breakdown) causes significant collateral damage — cerebral oedema, raised ICP, vasculitis, ischaemia. Dexamethasone dampens this inflammatory cascade.

When to use dexamethasone in encephalitis:

IV aciclovir 10 mg/kg Q8H for 2–3 weeks ^[8]

Foscarnet: treatment of choice if aciclovir resistance (occasionally in immunocompromised hosts) ^[20]

Foscarnet ("phosphono-formic acid") directly inhibits viral DNA polymerase without requiring activation by viral TK → effective against TK-deficient aciclovir-resistant strains. Main toxicity: nephrotoxicity, electrolyte disturbances (hypocalcaemia, hypomagnesaemia).

No specific treatment ^[2] Serology × 2 (14 days apart) ^[2]

• No specific antiviral therapy for most of these
• Management is supportive: seizure control, ICP management, fluid/electrolyte management, ICU support
• Influenza encephalopathy: oseltamivir may be given but evidence of CNS benefit is limited

HRZE × 2 months + HR × 10 months (total 12 months) ^[2] IV dexamethasone for 6–8 weeks ^[2] HIV testing ± repeat LP to monitor CSF changes ^[2]

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]

• Serial therapeutic LPs may be needed to manage raised ICP (opening pressure in crypto can be extremely high → therapeutic drainage to reduce pressure)
• Monitor for amphotericin B toxicity: nephrotoxicity, hypokalaemia, hypomagnesaemia, anaemia

This is the management section that follows directly from the GC lecture:

Initial investigation and management approach similar to that of CNS infections ^[8] Infective aetiologies must be excluded ^[8] Blood and CSF for autoimmune antibodies (e.g. anti-NMDA receptor antibodies) if clinical suspicion ^[8]

Management ^[8]:

• Close monitoring as patients may develop refractory seizures, autonomic instability
• Immunotherapy
  • Acute stage – high dose intravenous prednisolone, intravenous immunoglobulin, plasmapheresis
  • Subsequent treatment with oral corticosteroids / steroid sparing agents
• Anti-seizure medications if seizures
• Supportive care

From the Handbook of Internal Medicine ^[21]:

Treatment of autoimmune encephalitis: 1. Immunotherapy — early immunotherapy can improve outcome

• First line immunotherapy:
  • High dose corticosteroids (IV methylprednisolone 1g/day for 3–7 days, followed by oral prednisolone with slow taper)
  • Intravenous immunoglobulin (IVIg) 0.4 g/kg/day for 5 days
  • Plasma exchange
• Second line immunotherapy: Can be considered if there is no meaningful clinical or radiological response to optimised first-line immunotherapy after 2–4 weeks; includes IV rituximab / cyclophosphamide 2. Symptomatic treatment — apart from immunotherapy, it is important to treat the co-existing seizures, movement disorders, sleep and autonomic dysfunction 3. ICU admission may be considered in patients with status epilepticus, especially when they are intubated 4. In NMDA encephalitis patients with ovarian teratoma, tumour resection is associated with faster rate of recovery and reduced relapse rate

Treatment summary for autoimmune encephalitis:

IV ceftriaxone 2g Q12H + IV metronidazole 500 mg Q8H ^[2] Consult NS for drainage ^[2] Duration of treatment: 6–8 weeks ^[2]

Antiseizure medications may be needed ^[8]

SIADH caused by CNS infections (meningitis, encephalitis, brain abscess) ^[6][22]

Comes quick, correct quick; comes slow, correct slow ^[22] — acute symptomatic hyponatraemia (seizures, coma) warrants rapid partial correction. Chronic hyponatraemia must be corrected slowly to avoid central pontine myelinolysis (CPM) — also called osmotic demyelination syndrome.

• NG tube feeding if patient unable to swallow safely (reduced consciousness, dysphagia)
• DVT prophylaxis: LMWH (enoxaparin) + compression stockings (immobilised patients at high risk of DVT/PE)
• Pressure sore prevention: regular turning
• Physiotherapy/occupational therapy: begin early to optimise functional recovery

This is one of the most feared acute complications and a hallmark of encephalitis.

CNS infections (classically encephalitis) are a classic cause of status epilepticus ^[5][19]

Why does encephalitis cause seizures?

• Inflamed, oedematous cortex → disruption of the normal balance between excitatory (glutamatergic) and inhibitory (GABAergic) neurotransmission → synchronous neuronal discharges → seizures
• Temporal lobe involvement (HSV-1) → particularly epileptogenic because the hippocampus and mesial temporal structures have the lowest seizure threshold in the brain
• Metabolic derangements secondary to encephalitis (hyponatraemia from SIADH, hypoglycaemia) further lower the seizure threshold
• Focal seizures are due to focal arterial ischaemia or infarction, cortical venous thrombosis with haemorrhage, or focal cerebral oedema ^[3][4]
• Generalised seizures are due to cerebral anoxia or hyponatraemia ^[3][4]

Status epilepticus in encephalitis:

• Status epilepticus: MEDICAL EMERGENCY! → the later a seizure is stopped, the more difficult it is to be stopped ^[5][19]
• Mortality: 3–20% (↑ if prolonged seizure or identified acute brain insult) ^[5][19]
• Both convulsive and non-convulsive SE can occur — the latter is particularly dangerous because it may go unrecognised (patient appears unconscious but without obvious convulsions → diagnosed only by EEG)

Workup and treat possible underlying cause: Tumour, Infection, CNS infection, Autoimmune encephalitis, Metabolic causes. Prevent complications ^[23]

Management:

• Acute: IV lorazepam → IV phenytoin/levetiracetam → ICU with continuous EEG if refractory
• Antiseizure medications may be needed ^[8]
• Consider ICU admission, continuous EEG monitoring ^[23]

Why does encephalitis cause raised ICP?

• Vasogenic oedema: BBB breakdown → plasma proteins and fluid leak into brain interstitium
• Cytotoxic oedema: direct neuronal injury → cellular swelling
• Both → ↑brain volume within the fixed cranial vault → ↑ICP

Clinical features of raised ICP:

• Progressive headache (worse lying down, coughing, straining)
• Vomiting (often projectile)
• Altered mental status, papilloedema ^[3][4]
• Cranial nerve palsy — CN VI (abducens nerve) is the most commonly affected nerve due to its long intracranial segment adjacent to the brainstem ^[3][4] — this is a false localising sign (it doesn't tell you where the lesion is; it just tells you the ICP is high)
• Cerebellar herniation ^[3][4] — the most catastrophic outcome; uncal or tonsillar herniation → brainstem compression → death

Management: Elevate head of bed 30°; osmotic therapy (mannitol, hypertonic saline); dexamethasone (in bacterial/TB, controversial in viral); hyperventilation (temporary bridge); neurosurgical decompression if refractory.

Arteritis / thrombophlebitis → cerebral infarction ^[8]

Why does encephalitis cause stroke?

• Brain parenchymal inflammation spreads to involve cerebral blood vessels → infectious vasculitis → vessel wall damage, thrombus formation → cerebral infarction
• Cortical venous thrombosis: inflammation of cortical veins → venous thrombosis → venous infarction with haemorrhagic transformation
• Particularly prominent in:
  • TB meningoencephalitis: stroke — infarcts observed in 26% of TBM ^[24] — due to basal meningeal inflammation affecting the Circle of Willis and its branches
  • VZV encephalitis: VZV can directly infect cerebral artery walls → VZV vasculopathy → large or small vessel ischaemic stroke (can occur weeks to months after VZV infection/reactivation)
  • Bacterial meningitis: cerebral infarction, haemorrhage, vasculitis and mycotic aneurysm ^[3][4]

Syndrome of inappropriate secretion of anti-diuretic hormone (SIADH) ^[8] CNS causes of SIADH: meningitis, encephalitis, brain abscess, head trauma, SAH, CVA, raised ICP ^[6]

Why does encephalitis cause SIADH?

• Hypothalamic and posterior pituitary inflammation/dysfunction → inappropriate (non-osmotically stimulated) release of ADH → excessive water reabsorption in collecting ducts → dilutional hyponatraemia
• Also contributes: raised ICP itself can trigger ADH release

Clinical consequences:

• Hyponatraemia symptoms: malaise, lethargy, headache → confusion, convulsion, coma ^[6]
• Creates a vicious cycle: hyponatraemia → worsens cerebral oedema → further lowers seizure threshold → more seizures → more brain damage

Must also consider cerebral salt wasting syndrome (CSWS) as an alternative cause of hyponatraemia in CNS disease — involves inappropriate natriuresis leading to volume depletion (cf SIADH which is euvolaemic). Management differs: CSWS requires volume replacement + sodium, while SIADH requires fluid restriction.

Meningeal adhesions → raised intracranial pressure, obstructive hydrocephalus ^[8] Communicating hydrocephalus is more common when inflammation produced by the infection impedes normal absorption of CSF from subarachnoid space via arachnoid villi → formation of arachnoid granulation adhesions ^[3][4]

Why does encephalitis (and meningoencephalitis) cause hydrocephalus?

• Communicating hydrocephalus (most common): inflammatory exudates and adhesions in the subarachnoid space → block CSF reabsorption at the arachnoid granulations → CSF accumulates → ventricular dilatation
• Obstructive hydrocephalus: in severe cases, inflammatory exudates or oedema can obstruct CSF flow pathways (e.g., cerebral aqueduct, 4th ventricle outlets)
• Particularly prominent in TB meningoencephalitis — hydrocephalus (80%) ^[24] — due to thick basal exudates blocking CSF flow

Management: VP shunt or external ventricular drain (EVD); treat underlying infection.

Cranial nerve palsies ^[8] — result from:

• Direct inflammatory involvement of CN nuclei in the brainstem (brainstem encephalitis / rhombencephalitis)
• Compression due to brain swelling or perineuritis due to adjacent meningeal inflammatory reaction ^[3][4]
• Raised ICP → CN VI palsy (false localising sign — the long intracranial course makes it susceptible to stretch)
• Basal meningeal scarring, especially CN II, VI, VII, VIII ^[24] — particularly in TB

• CN II: optic neuritis or papilloedema → visual loss
• CN VI: diplopia (lateral rectus palsy → inability to abduct the eye → esotropia)
• CN VII: facial palsy (LMN pattern if brainstem involved)
• CN VIII: sensorineural hearing loss (SNHL) — especially Strep suis ^[2] but also seen in other bacterial meningoencephalitis and viral causes

Local spread of infection (cerebritis, cerebral abscess, subdural effusion / empyema) ^[8]

• Cerebritis → brain abscess: poorly treated or fulminant encephalitis can lead to focal collections of pus. This is more common with bacterial aetiologies than viral, but can occur in any CNS infection.
• Subdural empyema: pus collection between dura and arachnoid — a neurosurgical emergency
• Ventriculitis: complication of severe meningitis / rupture of brain abscess, high mortality ^[2]

Disseminated intravascular coagulation ^[8]

• Severe systemic infection/sepsis → widespread activation of coagulation cascade → consumption of clotting factors and platelets → paradoxical bleeding tendency
• Particularly associated with meningococcal meningoencephalitis → Waterhouse-Friderichsen syndrome (bilateral adrenal haemorrhage from DIC)

• Most prominent in anti-NMDA receptor encephalitis and rabies encephalitis
• Manifestations: labile BP, tachycardia/bradycardia, central hyperthermia, cardiac arrhythmias, central hypoventilation
• Can be life-threatening → ICU monitoring required
• Close monitoring as patients may develop refractory seizures, autonomic instability ^[8]

These are common in any patient with prolonged reduced consciousness:

• Memory deficits (anterograde amnesia): the most common and most debilitating sequela of HSV encephalitis
  • Why? Bilateral hippocampal damage (hippocampus is in the medial temporal lobe — directly in the "line of fire" for HSV-1)
  • Can be devastating: patients may lose the ability to form new memories entirely (severe anterograde amnesia, similar to Korsakoff syndrome)
• Executive dysfunction: difficulty with planning, problem-solving, multitasking — due to frontal lobe damage (HSV involves orbitofrontal cortex)
• Attention/concentration deficits: diffuse cortical damage
• Intellectual impairment ^[3][4][8]

• Disinhibition, emotional lability, aggression, apathy, social withdrawal
• Why? Limbic system (amygdala) and orbitofrontal cortex damage → disruption of emotional regulation and social cognition
• Can be profoundly disabling for patients and families
• Particularly common after HSV encephalitis (temporal-frontal predilection)

• Aphasia: expressive (Broca's) or receptive (Wernicke's) — if dominant hemisphere temporal/frontal lobe damaged
• Dysarthria: if brainstem/cerebellar involvement
• Difficulties in speech disorder ^[1]

• Post-encephalitic epilepsy: a significant proportion of encephalitis survivors develop chronic epilepsy
• Risk is highest with HSV encephalitis (temporal lobe involvement → temporal lobe epilepsy, the most common cause of pharmacoresistant epilepsy ^[5][19])
• Typically presents as focal seizures (temporal lobe origin) with or without secondary generalisation
• Seizures and epilepsy listed as a complication of meningitis/meningoencephalitis ^[8]
• Management: long-term anti-seizure medications; refractory cases may require surgical evaluation (anterior temporal lobectomy or amygdalohippocampectomy)

• Hemiparesis/hemiplegia: from cortical or subcortical damage, ischaemic infarction (vasculitis-related)
• Acute flaccid paralysis: characteristic of enterovirus 71 and Japanese encephalitis (anterior horn cell tropism, polio-like syndrome)
• Movement disorders: parkinsonism, dystonia, choreoathetosis — particularly after JE (basal ganglia/thalamic damage) or post-encephalitic parkinsonism (historically described after encephalitis lethargica)
• Cerebral palsy ^[8] — in neonatal/infantile encephalitis, brain damage during the critical developmental period can result in cerebral palsy

• SNHL (especially Strep suis) ^[2]
• Also occurs with other bacterial meningoencephalitis (S. pneumoniae, N. meningitidis) — due to cochlear nerve (CN VIII) damage from inflammation
• Hearing assessment should be performed in all survivors of bacterial meningoencephalitis

• Optic neuritis, optic atrophy, cortical visual impairment
• Visual loss (~1/4 in TBM): due to optochiasmic arachnoiditis, raised ICP, endarteritis ^[24]
• Retinitis in CMV encephalitis (immunocompromised)

• Depression, anxiety, PTSD, psychosis
• Anti-NMDA-R encephalitis survivors may have prolonged psychiatric symptoms (months to years)
• HSV encephalitis survivors may develop Klüver-Bucy syndrome (bilateral temporal lobe damage → hyperorality, hypersexuality, visual agnosia, placidity, hypermetamorphosis) — rare but classic