Overview
This lecture defines Encephalitis and places it within the wider category of “brain hurting” presentations, separating encephalopathy from acute brain inflammation and then separating Meningitis from encephalitis. It then covers the aetiology of primary (infectious) viral encephalitis in three virus groups, before focusing in depth on herpes simplex virus encephalitis: its epidemiology, its latency cycle, its route of transmission to the brain, its clinical and diagnostic features, and its treatment with acyclovir. A published case report closes the lecture by illustrating an unusual complication. The stated objectives were to define encephalitis, know the common causes, and be aware of HSV encephalitis diagnosis and treatment.
Encephalopathy versus acute brain inflammation
Two broad categories are contrasted using the same four features: fever, headache, focal neurological signs, and pleocytosis.
- Encephalopathy: fever, headache, focal neurological signs and pleocytosis are all uncommon. It is generally a chronic disease.
- Brain inflammation: the same four features are common. It branches into meningitis and encephalitis.
Chronic traumatic encephalopathy (CTE) is given as the worked example of an encephalopathy. CTE causes the protein tau to form around the brain’s blood vessels, interrupting normal functioning and eventually killing nerve cells. Four stages are shown as stained brain sections:
- Stage 1: no symptoms. Isolated spots of tau build up mostly around the frontal lobe, or the crown of the head.
- Stage 2: rage, impulsivity, depression. Symptoms begin to appear as defective tau protein affects more nerve cells in the brain’s frontal (top) lobes.
- Stage 3: confusion, memory loss. Tau deposits expand from the frontal (top) section to the temporal (side) section of the brain. The condition begins to affect the amygdala and the hippocampus, which impairs emotion and memory.
- Stage 4: advanced dementia. Tau deposits have overwhelmed the brain, killing many nerve cells and shrinking it by roughly half its size. The brain becomes deformed and brittle, and cognitive function is severely limited.
The CTE figure's caption text was small at render resolution; the stage wording above is transcribed as best legible.
Meningitis versus encephalitis
Acute brain inflammation divides by the tissue involved.
Meningitis is inflammation of the meninges (the coverings of the brain: dura mater, arachnoid mater, pia mater).
- Cerebral function is intact.
- Bacterial aetiology is usually more serious than viral.
Encephalitis is inflammation of the grey or white matter.
- Cerebral function is usually affected, giving:
- altered mental state
- motor or sensory deficits
- behaviour/personality changes
- speech/movement disorders
- Almost always serious, and a clinical emergency.
Encephalitis is almost always serious and is treated as a clinical emergency, whereas the distinguishing feature of meningitis is that cerebral function remains intact.
Aetiology of primary (infectious) viral encephalitis
The aetiology splits into three main categories of virus.
- Common viruses: including HSV (herpes simplex virus) and EBV (Epstein-Barr virus).
- Childhood viruses: including mumps and measles (both Paramyxoviridae, eSRNA-).
- Arboviruses (spread by mosquitoes, ticks and other insects): including Japanese, Kunjin, Murray Valley and West Nile encephalitis (Flaviviridae, eSRNA+), and tick-borne encephalitis.
HSV, measles and Japanese encephalitis are the three singled out as highlighted on the slide.
Global distribution of arboviral encephalitis
The world map legend covers: West Nile encephalitis; St Louis encephalitis; Japanese encephalitis; Murray Valley encephalitis; and areas with a combination of West Nile and St Louis encephalitis.
Arbovirus transmission cycles
JEV (Japanese encephalitis virus): a mosquito transmits the virus between amplification/reservoir hosts, which are pigs and wading birds/herons. Humans and horses are dead-end hosts.
WNV (West Nile virus): the enzootic vector (Culex spp.) transmits the virus among amplification/reservoir hosts, which are birds. Humans and horses are again dead-end hosts.
A vaccine carton labelled IXIARO is shown alongside these cycles; the remaining packaging text is too small to read.
Herpes simplex encephalitis: epidemiology
- More than 3.7 billion people under the age of 50 (more than 60%) are infected with the herpes simplex virus (WHO).
- HSV is the most common cause of encephalitis in New Zealand.
- The slide labels the virus “eDNAds”.
The images show progression from the peripheral lesion to the brain: the HSV virion capsid, a perioral herpes labialis (cold sore) lesion on the upper lip/nose, and an axial brain MRI with a bright (hyperintense) area in one temporal lobe.
"eDNAds" is written on the slide as-is with no expansion given. It appears to be shorthand for the virus's genome/structure classification, but the slide does not define it.
HSV latency cycle
The latency cycle, in the order shown:
- Productive infection occurs in epithelial cells, with virions replicating within the epithelial cell layer.
- A sensory neuron terminal lies among the epithelial cells; virus enters it.
- Infection by retrograde transport: the virus travels along the axon from the epithelium toward the sensory ganglion.
- In the sensory ganglion neuron cell body, the viral genome resides in the nucleus as the viral genome in latent state (episomal).
- Reactivation by anterograde transport: the virus travels back down the axon from the ganglion to the epithelial cells.
HSV transmission to the brain
Direct neuronal transmission of HSV from a peripheral site to the brain (usually the temporal lobe) occurs via the trigeminal or olfactory nerve.
The three phases shown:
- Primary infection: HSV infects the face, reaching facial sites served by the ophthalmic, maxillary and mandibular branches of CN V (the trigeminal nerve).
- Latent phase: these three branches converge on the trigeminal ganglion, where the virus resides. Meningeal branches also arise from the ganglion.
- Reactivation (lytic phase): the virus travels from the trigeminal ganglion to the brain, with the target labelled as the temporal lobe.
An inset anatomical drawing of the nasal/facial nerve supply is connected by a red arrow from the trigeminal ganglion, but its labels were illegible at render resolution.
HSV encephalitis: clinical manifestations and diagnosis
Clinical features with frequencies
- Alteration of consciousness: 97%
- Fever: 90%
- Headache: 81%
- Psychiatric symptoms: 71%
- Seizures: 67%
- Vomiting: 46%
- Hemiparesis: 38%
- Focal weakness: 33%
- Cranial nerve defects: 32%
- Memory loss: 24%
- Visual field loss: 14%
- Papilledema: 14%
Diagnosis
- MRI demonstrating temporal lobe involvement (a hyperintense area in one temporal lobe).
- CSF collection by lumbar puncture, with PCR amplification of virus DNA.
CSF findings:
| Parameter | Finding |
|---|---|
| WBC | Moderate |
| RBC | -/+ |
| Protein | Moderate |
| Glucose | Normal |
HSV encephalitis: treatment
- In untreated cases of herpes encephalitis, 50% to 75% of people die within 18 months.
- Treatment with acyclovir can increase survival up to 90%.
Acyclovir dosing regime (IV)
| Age group | Dose |
|---|---|
| Neonates and infants up to 3 months | 20 mg/kg/dose 8 hourly |
| Children 3 months to 12 years | 500 mg/m/dose 8 hourly |
| 12 years and over | 10 mg/kg/dose 8 hourly |
Mechanism of action
Acyclovir mimics the nucleoside guanosine. The two-panel mechanism:
In the cytoplasm (after the virion enters the cell and the viral genome enters the nucleus):
- Acyclovir is phosphorylated by herpes thymidine kinase to acyclovir monophosphate.
- Acyclovir monophosphate is phosphorylated to acyclovir diphosphate.
- Acyclovir diphosphate is phosphorylated to acyclovir triphosphate.
- Acyclovir triphosphate is directed into the nucleus.
In the nucleus:
- Acyclovir triphosphate is incorporated by herpes DNA polymerase into the growing DNA strand, base-paired with the template strand, acting as a guanosine mimic in the elongating chain.
Some structural labels within the mechanism figure were small; chemical detail beyond the labels named above was not resolvable.
Case report: an unusual course
Lal A, et al. BMJ Case Rep 2018 (doi:10.1136/bcr-2017-222499). “Herpes simplex virus (HSV) encephalitis in a young man: an unusual course.”
Learning points as given:
- Worsening of symptoms, after a good initial response, during treatment for HSV encephalitis is unusual.
- In the case of new neurological deficits while on appropriate treatment for HSV encephalitis, urgent neuroimaging should be pursued.
- Cerebral venous sinus thrombosis is a rare complication associated with HSV encephalitis and should be considered.
Imaging:
- (A) FLAIR MRI coronal view: hyperintensity in the left temporal lobe, consistent with HSV encephalitis.
- (B) T1-weighted axial view after contrast: filling defect, consistent with thrombus in the superior sagittal sinus.
- (C) Magnetic resonance venography (MRV): superior sagittal sinus thrombosis.
HSV can be a rare cause of cerebral venous sinus thrombosis (CVST). The patient was continued on acyclovir (antiviral, treatment for HSV encephalitis), started on intravenous heparin and bridged with warfarin (treatment of CVST), continued for 1 year.
Self-test
- Define encephalitis and state which brain tissue is involved.
- Distinguish encephalopathy from acute brain inflammation using the four features given in the lecture.
- List the four stages of chronic traumatic encephalopathy with the symptom description given for each.
- Explain how tau causes nerve cell death in CTE.
- Distinguish meningitis from encephalitis in terms of tissue involved, cerebral function, and clinical seriousness.
- List the four manifestations of affected cerebral function seen in encephalitis.
- Name the three meningeal layers identified in the lecture.
- List the three main viral categories causing primary (infectious) encephalitis, with an example virus from each.
- Which viral family and genome type are given for mumps and measles, and which for the Japanese, Kunjin, Murray Valley and West Nile encephalitis viruses?
- Describe the JEV transmission cycle, naming the vector, the amplification/reservoir hosts, and the dead-end hosts.
- Explain why humans and horses are described as dead-end hosts in the JEV and WNV cycles rather than reservoir hosts.
- State the global prevalence of HSV infection given by the WHO and the rank of HSV as a cause of encephalitis in New Zealand.
- Describe the five steps of the HSV latency cycle in order.
- Distinguish retrograde from anterograde transport in the HSV latency cycle by direction and by what each achieves.
- Describe the route by which HSV reaches the brain from a peripheral site, naming the nerves and the ganglion involved.
- Explain why HSV encephalitis characteristically involves the temporal lobe.
- List the three most frequent clinical features of HSV encephalitis with their percentages.
- State the two diagnostic investigations used for HSV encephalitis and what each demonstrates.
- List the four CSF parameters given and the expected finding for each in HSV encephalitis.
- State the mortality of untreated herpes encephalitis and the survival achievable with acyclovir.
- Give the IV acyclovir dose for each of the three age groups.
- Describe the steps by which acyclovir is activated and then acts, naming the two viral enzymes involved.
- Explain why acyclovir is selective for herpes-infected cells rather than uninfected host cells.
- A patient with confirmed HSV encephalitis responds well to acyclovir but then develops new neurological deficits while still on treatment. Predict what should be done next and name the rare complication that should be considered.
- Integrative: a returning traveller and a local patient both present with fever, headache and altered consciousness. Explain how the aetiological categories from this lecture, plus the imaging and CSF findings, would help you distinguish HSV encephalitis from an arboviral encephalitis.
Answers
Reveal answers
- Encephalitis is acute brain inflammation involving the grey or white matter. It is almost always serious and is a clinical emergency.
- In encephalopathy, fever, headache, focal neurological signs and pleocytosis are all uncommon, and it is generally a chronic disease. In brain inflammation, those same four features are common.
- Stage 1: no symptoms. Stage 2: rage, impulsivity, depression. Stage 3: confusion, memory loss. Stage 4: advanced dementia.
- Tau forms around the brain’s blood vessels, interrupting normal functioning and eventually killing nerve cells. By stage 4, tau deposits have overwhelmed the brain, killing many nerve cells and shrinking it by roughly half its size, leaving it deformed and brittle.
- Meningitis involves the meninges, cerebral function is intact, and bacterial aetiology is usually more serious than viral. Encephalitis involves grey or white matter, cerebral function is usually affected, and it is almost always serious and a clinical emergency.
- Altered mental state; motor or sensory deficits; behaviour/personality changes; speech/movement disorders.
- Dura mater, arachnoid mater, pia mater.
- Common viruses (HSV, EBV); childhood viruses (mumps, measles); arboviruses spread by mosquitoes, ticks and other insects (Japanese, Kunjin, Murray Valley, West Nile encephalitis, tick-borne encephalitis).
- Mumps and measles: Paramyxoviridae, eSRNA-. Japanese, Kunjin, Murray Valley and West Nile encephalitis: Flaviviridae, eSRNA+.
- A mosquito transmits the virus between amplification/reservoir hosts, which are pigs and wading birds/herons. Humans and horses are dead-end hosts.
- Because they are labelled dead-end hosts: the cycle runs between the vector and the amplification/reservoir hosts (pigs and wading birds for JEV, birds for WNV), and humans and horses do not feed the virus back into that cycle. [Slide labels them as dead-end hosts but does not elaborate further on the mechanism.]
- More than 3.7 billion people under the age of 50, over 60%, are infected with HSV (WHO). HSV is the most common cause of encephalitis in New Zealand.
- (i) Productive infection in epithelial cells. (ii) Virus enters a sensory neuron terminal lying among the epithelial cells. (iii) Infection by retrograde transport along the axon from epithelium toward the sensory ganglion. (iv) The viral genome resides in the sensory ganglion neuron nucleus in a latent, episomal state. (v) Reactivation by anterograde transport back down the axon to the epithelial cells.
- Retrograde transport carries the virus from the epithelium toward the sensory ganglion and establishes infection/latency. Anterograde transport carries the virus from the ganglion back down to the epithelial cells and constitutes reactivation.
- Direct neuronal transmission from a peripheral site to the brain, usually the temporal lobe, via the trigeminal or olfactory nerve. In primary infection HSV infects facial sites supplied by the ophthalmic, maxillary and mandibular branches of CN V; these converge on the trigeminal ganglion where the virus stays latent; on reactivation the virus travels from the trigeminal ganglion to the temporal lobe.
- Because transmission to the brain is direct and neuronal along the trigeminal or olfactory nerve, and the pathway from the trigeminal ganglion terminates at the temporal lobe, which is the labelled target on reactivation.
- Alteration of consciousness 97%, fever 90%, headache 81%.
- MRI, which demonstrates temporal lobe involvement (a hyperintense area in one temporal lobe); and CSF collection with PCR amplification of viral DNA.
- WBC moderate; RBC -/+; protein moderate; glucose normal.
- Untreated, 50% to 75% of people die within 18 months. Acyclovir can increase survival up to 90%.
- Neonates and infants up to 3 months: 20 mg/kg/dose 8 hourly. Children 3 months to 12 years: 500 mg/m/dose 8 hourly. 12 years and over: 10 mg/kg/dose 8 hourly.
- Acyclovir mimics the nucleoside guanosine. In the cytoplasm, herpes thymidine kinase phosphorylates acyclovir to the monophosphate, then to the diphosphate, then to the triphosphate. Acyclovir triphosphate enters the nucleus, where herpes DNA polymerase incorporates it into the growing DNA strand base-paired with the template.
- Both enzymes required are viral: herpes thymidine kinase performs the activating phosphorylation, and herpes DNA polymerase incorporates the activated drug. [Slide gives the two viral enzymes but does not elaborate further on selectivity.]
- Urgent neuroimaging should be pursued, because new neurological deficits while on appropriate treatment are unusual. The complication to consider is cerebral venous sinus thrombosis (superior sagittal sinus thrombosis in the case shown on FLAIR, contrast T1 and MRV). Management in the case report was to continue acyclovir, start intravenous heparin and bridge with warfarin, continued for 1 year.
- HSV falls in the common-virus category and is the most common cause of encephalitis in New Zealand, so a local patient with no travel fits it; arboviral encephalitis (Japanese, Kunjin, Murray Valley, West Nile, tick-borne) is acquired from mosquitoes, ticks and other insects in the geographic areas shown on the distribution map, so travel history matters. HSV is supported by MRI showing temporal lobe involvement and by CSF PCR amplification of viral DNA with moderate WBC, -/+ RBC, moderate protein and normal glucose. Confirming HSV also matters therapeutically, since acyclovir raises survival to up to 90% from an untreated mortality of 50% to 75% within 18 months.