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Encephalitis Flashcards

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1
Q

What is encephalitis?

A

Inflammation of the brain

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2
Q

What are the main pathological signs of encephalitis?

A

▪️Oedema
▪️Destruction of tissue when infection persists
▪️Parenchymal haemorrhages and intravascular thrombosis

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3
Q

What is the main diagnostic criteria for encephalitis?

A

▪️Altered mental state
▪️Lasting 24 hours or longer
▪️No alternative identified cause

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4
Q

What is considered in the minor diagnostic criteria for encephalitis?

A

▪️Fever
▪️Generalised or partial seizures
▪️New onset focal neurological findings
▪️Increased CSF WBC count
▪️Abnormality of brain parenchyma on neuroimaging
▪️Abnormality on EEG

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5
Q

What are the three main types of encephalitis?

A

▪️Infectious (42%)
▪️Immune-mediated (21% although increasing)
▪️Unknown (37%)

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6
Q

What is the most common category of infectious encephalitis?

A

Viral encephalitis

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7
Q

What is the most common cause of infectious encephalitis in the west?

A

Herpes simplex virus

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8
Q

Non-viral causes of infectious encephalitis are much more _____________

A

Region specific

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9
Q

How does viral encephalitis differ from viral meningitis?

A

▪️Life-threatening (not benign)
▪️Not self-limiting so needs intervention
▪️Frequently causes neurological damage
▪️Host inflammatory response is significant and can cause damage on its own

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10
Q

What are ubiquitous pathogens?

A

Microorganisms found almost everywhere

(E.g. Herpes simplex virus type 1, VZV, HIV, enteroviruses)

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11
Q

What is the most common cause of infectious encephalitis in the world?

A

Japanese encephalitis virus

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12
Q

What is a zoonotic virus?

A

A virus transmitted from animals to humans, e.g. through ticks

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13
Q

What is the most common region specific pathogen in Europe?

A

Tick-borne encephalitis virus

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14
Q

Where is West Nile virus typically localised to?

A

▪️North Africa
▪️America

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15
Q

Where are chikungunya and zika virus typically localised to?

A

▪️Sub-Saharan Africa
▪️South America

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16
Q

What are the main factors to consider when diagnosing infectious encephalitis?

A

▪️Travelling history
▪️History of bites
▪️Exposure to disease animals and humans
▪️Age
▪️Health status (vaccinations, immune status)
▪️Occupation

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17
Q

Who is most at risk from less common pathogens?

A

▪️Younger people
▪️Older adults
▪️Immunocompromised patients

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18
Q

What symptoms are common across infectious encephalitis types?

A

▪️Fever
▪️Altered consciousness
▪️Headache

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19
Q

What symptoms are specific to rhabdoviruses (rabies)?

A

▪️Hypersalivation and dysphagia
▪️Hydrophobia
▪️Aerophobia
▪️Multiple organ failure (almost always fatal)

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20
Q

What symptoms are more specific to retroviruses (e.g. HIV)?

A

▪️Mental concentragion and severe cognitive change
▪️Personality change
▪️Apathy
▪️Social withdrawal

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21
Q

What symptoms are typically seen with herpesviruses?

A

▪️Seizure
▪️Focal neurological deficits
▪️General encephalopathy

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22
Q

What more specific symptoms might be seen with arboviruses?

A

▪️Muscle aches
▪️Lack of muscle coordination
▪️Disorientation
▪️Convulsions
▪️Coma

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23
Q

What are the most common types of arbovirus?

A

▪️West Nile virus
▪️Japanese encephalitis virus
▪️Zika virus
▪️Tick-borne encephalitis virus

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24
Q

What specific symptoms might be seen with influenza virus?

A

▪️Febrile seizures
▪️Convulsions
▪️Ataxia
▪️Status epilepticus

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25
What symptoms have been seen with coronavirus 2 (covid) encpehalitis?
▪️Delirium/altered mental status ▪️Aphasia ▪️Dysarthria ▪️Seizures
26
How does covid related encephalitis show on MRI?
▪️Florid manifestations (severe) ▪️ADEM-like = demyelination often post infection
27
What is the germ theory of disease?
Microorganism/pathogens cause disease when they invade the body (as oppose to "bad air" in the miasma theory)
28
What is the hallmark of Immune-mediated disease?
Expression of autoantibodies
29
What are the two types of autoantibodies that might be seen with immune-mediated encephalitis?
▪️Directly pathogenic autoantibodies ▪️Non-pathogenic autoantibodies as part of an immune inflammatory process
30
What are examples of immune-mediated encephalitis where the autoantibodies are NOT pathogenic?
▪️Connective tissue diseases and vasculitis (e.g. Lupus) ▪️Hashimoto encephalitis ▪️Basal ganglia encephalitis (encephalitis lethargica) ▪️ADEM (acute disseminated encephalomyelitis)
31
What are the two major types of antigen associated with antibody-associated encephalitis?
▪️Intracellular antigens ▪️Neuronal surface antigens
32
What are immunoglobulins (Ig) ?
Antibodies
33
What is the main class of immunoglobulin that causes anti-body associated encephalitis?
IgG Y-shaped with binding arms (bind to antigen) and body
34
What is an epitope?
The part of the antigen that the immune system recognises, illiciting an immune response to the pathogen
35
What is a paratope?
The antigen-binding site on the antibody
36
What is limbic encephalitis?
An inflammatory disease of the hippocampus, amygdala, insula, and frontobasal regions which presents as a distinct clinical syndrome
37
What are the main clinical manifestations of limbic encephalitis?
▪️Cognitive change (anterograde memory or confusion) ▪️Seizures (temporal lobe or generalised) ▪️Psychiatric manifestations (mood change, psychosis, hallucinations, delusions) ▪️"Extra-limbic" symptoms (language, movement disorder)
38
When does limbic encephalitis usually present?
▪️ Predominantly elderly ▪️ In less than 3 months ▪️ Often paraneoplastic - driven by tumour elsewhere
39
What might you see with investigations of limbic encephalitis?
▪️ T2 FLAIR areas of hyperintensity in one or both medial temporal lobes (bright, inflammation) ▪️ Focal slowing in temporal lobes on EEG ▪️ Epileptic discharges in 45% ▪️ Lymphocytic pleocytosis and OCBs in CSF
40
What is classic paraneoplastic encephalitis?
▪️ Target is intracellular (e.g., Hu, Ma, GAD) - not exposed to circulating antibody ▪️ Other factor disrupts the membrane ▪️ Antibody is secondary to another cause of disease (e.g., tumour)
41
What is novel antibody-mediated encephalitis?
▪️ Target is extracellular (e.g., NMDAR, CASPR2, LGI1) - easily accessible to circulating antibody ▪️ Usually non-paraneoplastic ▪️ Antibody is primary cause for the disease
42
Why is it important to distinguish between paraneoplastic (intracellular) and non-paraneoplastic (extracellular) causes of encephalitis?
Intracellular targets usually do not respond so well to immunotherapy and steroids - need to treat the primary cause (e.g., remove tumour)
43
What determine whether an antibody is pathogenic?
▪️ Present during clinical manifestations (detectable in blood or tissue) ▪️ Interacts with protein expressed on cell membrane ▪️ Transfer replicates disease in an animal model ▪️ Active immunisation produces model of disease ▪️ Improvement occurs with immunosuppression
44
What are the main pathogenic mechanisms of autoantibodies?
▪️ Direct disruption of the epitope (e.g., agonist or antagonist on receptor) ▪️ Internalisation - receptor enters cell and gets broken down ▪️ Complement activation
45
How can we detect pathogenic antibodies if we know the target?
Cell-based assay ▪️grow (incubate) receptors ▪️add patients CSF/blood ▪️look for binding to receptor with fluorescence, indicating antibody is present
46
How can we detect pathogenic antibodies if we don't know the target?
▪️ Live rodent primary neuronal cultures ▪️ Look for patterns of staining on rodent tissue sections
47
What are the main triggers of autoimmune encephalitis?
▪️ Tumours (5-60%) ▪️ Previous infection (e.g., HSV and NMDAR encephalitis) ▪️ Drugs (isolated cases) ▪️ Majority unknown
48
What is the most common form of autoimmune encephalitis and what antibodies is it associated with?
▪️ NMDAR encephalitis ▪️ NMDAR antibodies
49
What antibodies are associated with limbic encephalitis?
▪️ LGI1 antibodies (also faciobrachial dystonic seizures) ▪️ Paraneoplastic antibodies
50
What antibodies are associated with Morvan's syndrome?
CASPR2 antibodies
51
What antibodies are associated with progressive encephalomyelitis with rigidity and myoclonus (PERM)?
Glycine receptor antibodies (also stiff-person syndrome, cerebella ataxia)
52
What is the most common antigen target in limbic encephalitis?
Leucine-rich glioma inactivated protein 1 (LGI1) ▪️ Highly expressed in hippocampus ▪️ Secreted protein that targets voltage-gated potassium channels to stabilise them
53
What are the main components of the VGKC-complex?
▪️ Voltage-gated potassium channel (VGKC) ▪️ LGI1 ▪️ CASPR2 ▪️ Contactin2
54
What are the main signs of limbic encephalitis associated with LGI1 antibodies?
▪️ Subacute onset of memory loss, seizures, and personality change ▪️FBDS ▪️ Predominantly men in their 50s-60s ▪️ Tumours in less than 10% ▪️ Low plasma sodium
55
What is the prognosis of LGI1 limbic encephalitis?
▪️ Most respond well to immunotherapies and return to work ▪️ Can be long-term cognitive deficits
56
What is typically seen on MRI scans of individuals following LGI1 limbic encephalitis?
▪️ Marked hippocampal atrophy explaining anterograde and retrograde episodic defects ▪️ Particularly hippocampus CA3 volume - predicts episodic defects? ▪️Increased medial temporal lobe signal (bright)
57
What antibody is associated with faciobrachial dystonic seizures?
LGI1 antibodies
58
How do you treat faciobrachial dystonic seizures?
▪️ Poor response to AEDs ▪️ Very good response to immunosuppressive treatment ▪️ Timely treatment can prevent cognitive impairment
59
Where is CASPR2 protein expressed?
▪️ Park of the VGKC-complex in CNS at the synapses ▪️ At juxtaparanodes of Ranvier in PNS
60
What neurological condition may be caused by CNS CASPR2 antibodies and where would the antibodies be detectable?
Limbic encephalitis Detectable in serum and CSF
61
What neurological syndrome may be caused by both CNS and PNS CASPR2 antibodies and where would these antibodies be detectable?
Morvan syndrome Detectable in serum only
62
What neurological condition may be caused by peripheral CASPR2 antibodies and where would these be detectable?
Neuromyotonia (myasthenia) Detectable in serum only
63
What type of tumour is most associated with Morvan syndrome and neuromyotonia?
Thymoma
64
What are the main symptoms of neuromyotonia?
▪️ Spontaneous muscular activity of peripheral nerve origin ▪️ Muscle cramps ▪️ Stiffness ▪️ Myokymia (eyelid twitch) ▪️ Sweating ▪️ Pain
65
How do you treat acquired neuromyotonia and Morvan's syndrome?
Plasma exchange (circulate blood to remove antibodies) and immunosuppression
66
What are the main symptoms of Morvan's syndrome?
▪️ Neuromyotonia ▪️ Insomnia ▪️ Confusion ▪️ Hallucinations Also memory loss, excessive REM, excessive salivation, cardiac arrhythmia, constipation?
67
What are the core signs of CASPR2 antibody-mediated encephalitis?
▪️ Cerebral symptoms (cognition, epilepsy) ▪️ Cerebellar symptoms ▪️ Peripheral nerve hyperexcitability ▪️ Autonomic dysfunction ▪️ Insomnia ▪️ Neuropathic pain ▪️ Weight loss
68
What conditions are previously seen in up to 30% of patients with CASPR2-associated encephalitis?
Thymoma and myasthenia gravis
69
What rarer targets may be considered in limbic encephalitis?
▪️ AMPA receptor (rare) ▪️ GABA a & b receptors (more common) ▪️ DPPX (potassium channel associated protein) (rare)
70
What symptoms and signs might be seen with LE associated with AMPAR antibodies?
▪️ Amnesia ▪️ Sometimes psychosis ▪️ Seizures ▪️ Refractory status epilepticus ▪️ Often paraneoplastic (e.g., thymoma, lung, breast)
71
What symptoms and signs might be seen with LE associated with GABA a and b receptor antibodies
▪️ Predominantly seizures ▪️ Cerebellar ataxia ▪️ B has strong association with small cell lung cancer (SCLC)
72
What symptoms and signs might be seen with LE associated with DPPX antibodies?
▪️ Diarrhoea ▪️ Weight loess ▪️ Myoclonus ▪️ Tremors ▪️ Excessive startle (hyperplexia)
73
Who is most commonly affected by NMDAR encephalitis?
▪️ Young people ▪️ Females ▪️ People with ovarian teratomas ▪️ Can affect children
74
What is the most common presentation of NMDAR encephalitis?
Psychiatric
75
What are the main symptoms of NMDAR encephalitis?
▪️ Florid psychotic features ▪️ Seizures ▪️ Amnesia ▪️ Facial grimacing and chewing ▪️ Mutism ▪️ Choreoathetoid limb movements/catatonia ▪️ Autonomic failure (often end up in ITU) ▪️ Reduced level of consciousness
76
How should you treat someone who presents with autoimmune encephalitis/relapsed response following previous infection?
With immunosuppressants NOT more anti-virals
77
What are the main conditions on the spectrum of NMDAR antibody diseases that may be seen in adults and children?
▪️ Classic NMDAR-Ab encephalitis ▪️ Partial phenotypes with predominant psychosis, seizures, or cognitive impairment ▪️ Relapse following HSV encephalitis
78
What are the main challenges associated with antibody-mediated diseases?
▪️ Diagnosis cannot rely on antibody testing results - sometimes need to start treatment before results ▪️ Other diagnostic tests can appear normal, particularly when testing serum ▪️ Response to treatment can be partial and take many months ▪️ Early immunotherapy is key ▪️ MRI doesn't always show anything ▪️ Healthy individuals may test positive
79
What are the three diagnostic criteria for possible autoimmune encephalitis?
1. Subacute onset of WM deficits, altered mental status, or psychiatric symptoms 2. At least one of: focal CNS findings, seizure, CSF pleocytosis, MRI features 3. Reasonable exclusion of other causes
80
What is the first line treatment for autoimmune encephalitis?
Immunotherapy: ▪️ Steroids with plasma exchange ▪️ Immunoglobulins (e.g. rituximab) ▪️ Stronger immunosuppressants if not responding
81
What treatment is needed for someone with infectious encephalitis?
Anti-virals DO NOT USE IMMUNOSUPPRESSION

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