Neurological Infections Flashcards
What are the 3 major concerns of neurological infections?
- the development of drug resistant infectious agents
- increasing number of immunocompromised human populations (people taking medications that are putting their immune systems at risk)
- the rising number of diseases previously considered rate (i.e. the ZIKA virus)
what four things are considered essential to prevent and treat resorting and emerging neurological infectious disease?
- education
- surveillance
- development of new drugs
- vaccines
What are 6 types of neurological infectious agents (with examples)?
- Bacterium (i.e. tuberculosis)
- Virus (i.e. HIV)
- Fungus (i.e. cryptococcus)
- Protozoa (i.e. malaria)
- Prion (i.e. BSE) –> from beef
- Helminth (i.e. cysticercosis)
What are the big 3 global neurological infectious agents?
- tuberculosis
- HIV/AIDS
- malaria
what are 2 unique aspects of CNS infections?
- localization of the infection dictates how it is clinically represented (i.e. if it presents in the CNS or PNS)
- Brain is an immune privileged organ (it has a lot of protection against foreign substances) things that help with this are blood-brain barrier protection and some innate (macrophases/neurophils) vs. adaptive (T cells/B-cells) immunity
there SHOULD be only innate immunity in the brain and no adaptive immunity however, if theres a severe infection the adaptive immune cells might come into the brain
What are 5 determinants of emerging infections?
- susceptible populations: poverty, war, famine, immunosuppression
- altered human and animal contact
- medical practices (more immunosuppressive medication)
- rapid and frequent global movement of animals and humans
- disrupted environments: climate change, and economic development
What is the summary of the evolution of West Nile virus?
mosquitos replicated in the water and infected birds, the birds then infected zoo animals and humans caught it from them and transformed the virus into a human version
this caused encephalitis (inflammation of the brain)
What has the highest annual global incidence of viral encephalitis?
japanese encephalitis
what are some of the symptoms of meningitis?
- headache/stiff neck/fever
- nuchal rigidity (inability to flex the neck forward due to rigidity of neck muscles)
- cranial neuropathies
what are two tests that can be done to test for meningitis signs?
- Kerning’s sign: neck pain associated with leg stretch
2. Brudzinski’s neck sign: stretch of the legs when neck is pulled upwards
what are some signs of encephalitis?
infection agents that affect the astrocytes in the brain
- headache
- fever
- confusion/altered behaviour (coma, seizure, focal signs)
What are some signs of myelitis?
- limb weakness
- back pain
- B & B dysfunction
- sensory loss (spinal cord infection)
What are signs of Absceess?
- focal signs
- fever
- seizure (focal infection in brain)
What is radiculopathy/neuropathy signs?
infection of the peripheral nerves (PNS)
- localized radicular pain
- fever
- weakness
How does the invasion of CNS via the meninges happen?
fibroblast and macrophages that infiltrate meninges and activate during infections
What is the neurological infection algorithm (how we come to a conclusion of prognosis)?
- presentation (syndrome/ acute vs. chronic)
- Infection risks (where it could’ve came from) including exposure, prophylaxis, season, co-morbities
- physical exam –> focal signs, extra ons features
- localization –> meninges, brain, spinal cord ?
- two things –> one is neuroimaging (CT and MRI) and other is blood test (CBC, electrolytes etc…)
- CSF tests (lumbar puncture)
- management (diagnosis of blood and neuroimaging leads to the possible treatment) –> is it supportive, is it specific?
- pronosticate –> morbidity and mortality
if at management stage you realize that its not the right diagnosis then you have to go back to a re-evaluation possibly at a brain imaging or blood test stage (usually takes multiple trials)
What are different types of CNS neural cells?
neurons, astrocytes, oligodendrocytes, endothelial cells and microglia/macrophages and BBB
what are different types of PNS cells?
neurons, schwann cells, macrophages protected by the BBB
how do the T and B cells (acquired immune cells) enter the BBB?
when theres an infection in the brain, it activates astrocytes and calls t and b cells and other non-CNS immune cells into the CNS.. this causes brain problems such as delirium and confusion etc…
t cells and neutrophils don’t reside in the BBB but can traffic in the nervous system and cause inflammation
What happens the microglia during infection and what do they do?
microglia is the brains phagocytes. Their bodies expand at time of activation
when the brain is in ‘normal’ state the microglia are immune ‘sensors’
but when the brain is under attack and micgrolia are activated they:
- phagocytosis
- chemotaxis
- antigen presentation
- cytotoxicity
- morphological changes
- proliferation
- respiratory burst
- they can release cytokines and clean up the environment and produce trophic growth factors to help myelin development
what is the role of astrocytes?
astrocytes are abundant and they produce trophic factors but they are susceptible to infections and they play a major role in the BBB
what makes up the BB?
endothelial cells in the BB are unique and energetically active (has a lot of mitochondria in CNS capillaries)
- they form tight junctions with one another and prevent cells and toxins from getting in
- astrocytes and microglia surround the BB for structural integrity
what are some viruses that the neurons are permissive to?
HSV, Rabies, west nile, nipah, equine encephalitis, mumps, measles
what are some viruses that the oligodendrocytes are permissive to?
JVC, CMV
what are some of the viruses that the microglia and perivascular macrophages are permissive to?
HIV and CMV
what are some of the viruses that target astrocytes?
equine encephalitis virus, HIV, JCV, CMV..etc..
What is a case of Mycobacterial neurological infections?
when different bacteria can manifest differently in the nervous system
- lepromatous leprosy
- thickened nerves in leproacy is related to tubercrulomas in the brain from tuberculosis
What are neurotropic retroviruses?
retroviruses are capable of infecting nervous system in both PNS and CNS and once you get it, its impossible to get rid of (i.e. HIV)
What are Human Endogenous Retroviruses (HERVs)
HERV’s constitute approx 8% of human genome
- HERVs are integrated into the human genome but are not replication competent (they aren’t replicated in the genome)
- however, HERV’s are implicated in the pathogenesis of cancer and autoimmune disease (they can produce proteins that can produce good or bad things)
What are some of HERV’s hosts and evolutional progression?
it has been in non human primates for a long time and several of them are important for placental formation
What is the HERV-W envelope glycoprotein (syncytin-1)?
syncitin-1 RNA and protein are increased in demyelinating lesions in multiple sclerosis and induce endoplasmic reticulum stress in glial cells
when expressed in mice, it causes MS-like symptoms
what is the global instances of HIV-1 Infection?
approx 35 Million people living with HIV
- 15 million receive antiretroviral therapy
- 71,000 canadians are HIV-infected
5,000 new infections in canada per year!!
HIV is lethal unless treated
- drugs are good but they have side effects
What are the sources of HIV-1 and HIV-2 ?
HIV has been in human population for approx 100 years
- it made its jump from non human primates to humans 100 years ago in central africa
- HIV-1 is in subsaharan africa and euripe and HIV 2 is mainly in non-human primates
Chimpanzees are presumed source of HIV-1 and humans got it from them
What is the disease course of HIV?
first is the primary infection (4-8weeks after contact with virus) and here the virus gets in the brain and rapidly divides
second is asymptomatic phase where the virus is dormant and replication of it declines (lasts for 10 years)
third is the AIDS phase, which lasts 1-4 years and can result in death… this is where the immune system is greatly damaged
fourth/last phase is the treatment phase… this phase could last more than 10 years depending on the progression and when the treatment was administered
what is a type of treatment giving to people with AIDS an when is it administered?
its called highly active antiretroviral therapy (HAART) and it is 3 different anti-retroviral drugs used to repair the immune system by shutting off replication of the virus
this is given some time during the AIDS phase
What is HAND?
HAND is HIV-associated neurological disorders
what percentage of the population with AIDS is affected with this and whats the prognosis?
affects 25% of people with HIV infection and after the development of AIDS and holds a poor survival prognosis
what are the features in HAND and the risk factors?
HAND is a spectrum disorder defined by asymptomatic neurocognitive impairment, minor cognitive-motor disorder and HIV associated Dementia
risk factors are high age, CCR5 delta32, APOE e4 (susceptible to alzhiemers), polymorphisms in promoters of TNF-alpha and MCP-1
what are HIV associated neurocognitive disorders?
- memory loss
- neuropsychiatric dysfunction (mania)
- immunodeficiency
- motor abnormalities
alzhiemers is a cortical syndrome
HAND is a SUBCORTICAL syndrome –> you get memory loss, mania, motor disabilities etc… in the cortex of immunodeficiency (similar to huntingtons)
What are some progression patterns of HAND?
some patients progress quickly into it and some take a slower amount of time
What is the quality of life among HIV+ patients with and without neurological disease (like HAND)
overall health score of patients with HAND vs. patients with other disorders and control shows that patients with HAND have the lowest health scores
What is the hallmark of HIV disease progression and HAND?
chronic immune activation … BIG LOSS OF NEURONS AND LOTS OF NEURONAL DAMAGE FROM ACTIVATION OF ACQUIRED IMMUNE CELLS
what two things contribute to neurodegeneration and eventual occurrence of HIV associated neurocognitive disorders (HAND)?
the host and viral factors both contribute. The immune system contributes to the damage done by inflammation driven by cytokines that activates astrocytes and the virus can directly damage neurons through apoptosis (programmed cell death)
What are some cures for HIV? how trust worthy are they?
success of BMT with virus resistant donor cells in the “berlin patient” –> supposed to be mutated normally .. bone marrow transplant caused him to have new blood and get ride of AIDS because his CCR5 in his new donor cell was mutated back to normal
current HAART regimens are sufficiently potent to consider elimination of HIV from all body reservoirs
What is Herpes Simplex Virus Encephalitis (HSE)?
- it effects 2-5 million annually
- immunocompromised patients are not at greater risk
- its associated with retinal necrosis (blindness)
- accurate detection for it is a PCR method with 94% specificity and 98% sensitivity (EEG is only good for seizure activity)
- morality is reduced 20% with use of acyclovir
- Glucocorticoids like steroids are beneficial
- likelihood of recurrence is low (less than 3% in a adults)
what is the source of HSE?
infection in the trigemnial ganglia via gingivitis, cold soar…etc…
it affects the trigemnial face nerves
the virus is most likely inhaled and hangs around in meninges via the trigemnial ganglia and can get activated via stress
its a rapidly activating virus which means that its symptoms are not slow to develop like HIV/AIDS
also associated with seizures
what are some new diagnostic techniques for neurological infections?
deep sequencing, metagenomics (next generation sequencing of taking brain tissue, sequencing it to get RNA and then identifying infectious gene for treatment), microarrays
what are new treatments for neurological infections?
micro RNA’s, antisense oligonucleotides, and repurposed drugs (for example, using drugs that are already out for treatment of neurological infections like intranasal insulin for HIV)
What is the human micro biome?
the human micrbiome is bacterial environments in different areas of our bodies for example our gut
its the types of bacteria that can live in different areas of our bodies (good or bad)
What is known about the brain-gut axis?
the brain was thought to be always sterile (free of bacteria) but there was a few cases where gut microbial translocation during HIV has been proposed as a cause of brain disease and both viruses and bacteria can be detected in the brain and CSF of patients without neurological diseases
theres robust action and interaction between gut and brain in mice/animal models
micro biomes in the gut can cross the blood brain barrier
this was first noticed by charles darwin
deep sequencing shows alpha-proteobacteria are predominate in the human brain
both conventional and deep sequencing show that alpha proteobacteria dominate the humana nd nonhuman primate brain and micro biome
