Central nervous system Flashcards
1
Q
Which cells are the primary cells forming the blood-brain barrier?
A
Astrocytes
2
Q
In which space is CSF located?
A
Subarachnoidal space
3
Q
Which type of lymphocyte can be found in the brain? Where are they found?
A
T-cells, located in the perivascular space
4
Q
How do T-cells migrate migrate out of the CSF? (2)
A
- Via lymphatic vessels in the meningeal spaces
- Via blood vessels to the deep cervical nodes
5
Q
Which bacterial CNS infections are commonly found in neonates? (4)
A
- E. coli
- L. monocytogenesis
- Staphylococci & enterococci -> in vulnerable children
- Pneumococci
6
Q
Where do E. coli that cause CNS infections in neonates often come from?
A
Maternal faecal flora
7
Q
Which bacterial CNS infections are commonly found in adults? (4)
A
- Pneumococci
- Meningococci
- Staphylococcus
- H. influenzae
8
Q
What are the mechanisms by which meningitis causes brain damage? (2)
A
- Inflammatory damage to the brain tissue
- Endothelium & astrocytes start to leak, causing oedema & brain compression
9
Q
Via which spaces do inflammatory cells enter the subarachnoidal space?
A
Virchow-Robin spaces (perivascular space)
10
Q
What is a severe systemic complication of N. meningitidis meningitis?
A
Waterhouse-Friedrichsen syndrome
11
Q
What is Waterhouse-Friedrichsen syndrome? (3)
A
- Diffuse intravascular coagulation
- Bilateral haemorrhage of the adrenal glands
- Sepsis
12
Q
What is cerebritis?
A
Encephalitis -> inflammation of brain tissue
13
Q
What is the most common result of bacterial encephalitis?
A
Abcess formation
14
Q
What are common sources of bacteria causing brain abscesses? (3)
A
- Endocarditis
- Pneumonia/pulmonary infections
- Abdominal infections (peritonitis)
15
Q
What happens in case of m. tuberculosis infection of the brain?
A
Granulomatous infection with obstruction of blood vessels, leading to blockage of CSF ducts (increased intracranial pressure) and infarctions
16
Q
Which bacterium causes syphilis?
A
Treponema pallidum
17
Q
What kind of CNS infection does syphilis cause?
A
Meningo-vascular inflammation
18
Q
How can neurosyphilis be prevented?
A
Antibiotics
19
Q
Which part of the CNS is typically affected by syphilis? What is the effect of this?
A
Dorsal roots of the spinal chord -> disruption of sensory neurons
20
Q
Which bacterium causes Lyme disease?
A
Borrelia burgdorferi
21
Q
How is Lyme’s diseasae transmitted?
A
Ixodes ticks
22
Q
What are acute symptoms of Lyme’s disease? (4)
A
- Fever
- Migratory bull’s-eye rash
- Muscular/joint pain
- Meningeal irritation, causing headaches
23
Q
How does HSV1 enter the body?
A
Through mucous membranes
24
Q
What is the genetic makeup of HSV1?
A
DNA virus
25
Where does HSV1 establish infection?
Dorsal ganglia
26
Where does HSV1 typically cause encephalitis, if it infects the brain?
Basal side
27
What is the genetic makeup of rabies virus?
RNA virus
27
True or false: rabies virus only infects humans
False; rabies virus can affect all mammals
28
How is rabies virus transmitted?
Infected secretions (saliva)
29
How does rabies virus travel to the brain?
Retrograde axonal transport
30
To which viral family does poliomyelitis belong?
Enterovirus
31
Risk of paralysis due to polio [decreases/increases] with age
Increases
32
How many % of polio-infected individuals are symptomatic?
5-8%
33
What are known neurological complications of COVID-19? (4)
1. Cerebral haemorrhage
2. Encephalitis
3. Ischemic stroke due to increased coagulation
4. Hypoxia & systemic inflammation
34
In which patient group do parasitic infections of the CNS most often occur?
Immunocompromised individuals
35
What are parasites that commonly cause infection of the CNS? (3)
1. Cryptococcus
2. Amoeba
3. Toxoplasma
36
What kind of disease does cryptococcal infection of the brain cause?
Chronic meningitis
37
What is a group of auto-immune diseases that commonly affects the brain?
Vasculitis
38
Into which two groups can vasculitids that infect the brain be grouped?
1. Systemic vasculitis
2. Primary granulomatous vasculitis
39
What is ADEM? What triggers it?
Acute demyelinating encephalomyelitis -> caused by virus
40
What is immune privilege (definition)?
Permissiveness/proneness of tissue/anatomical site develop and sustain immune activity
41
By which features can malignancies avoid the immune system? (3) Why is this relevant for understanding CNS immunity?
1. Modulation of cytokine environment
2. Not displaying proteins/potential antigens on MHCII
3. Seclusion in seperate compartments through a physical barrier
These mechanisms can also be found in CNS immunity
42
What are the unique features of the blood-brain barrier? (4)
1. Overlapping tight junctions between endothelial cells
2. Active pumps that remove molecules from the CNS
3. High amount of pericytes
4. Presence of a perivascular space
43
How do overlapping tight junctions between endothelial cells contribute to the blood-brain barrier?
Prevent spontaneous passing of cells and molecules
44
How does the ratio of endothelial cells:pericytes in the CNS differ from the rest of the body?
Higher amounts of pericytes per endothelial cell in the CNS than in the rest of the body
45
What is the function of pericytes in the blood-brain barrier?
Contribute to a controlled immune environment by producing pro- and anti-inflammatory cytokines
46
By which 2 basal membranes is the perivascular space coverd?
1. Basement membrane of the endothelium
2. Glia limitans
47
What is the glia limitans?
Clutched together end feet of astrocytes
48
What is the function of the glia limitans?
Tight border that controls entry of cells & molecules into the CNS
49
The perivascular space is very [sterile/immunogenic]
Immunogenic -> contains a lot of immune cells
50
Why is the perivascular space an opportune site for immune surveillance of the brain?
Contains a continuous flow of interstitial fluid towards the veins, to remove waste -> waste products = potential antigens
51
How are waste products transported out of the perivascular space?
Interstitial fluid with waste products flows along the postcapillary venules, towards the veins and is drained from the CNS
52
What is the structural makeup of the perivascular space. What is the function of this makeup?
Contains interstitial matrix & mesenchymal structures, allowing for the maintainance of resident and surveilling lymphocyte populations
53
What is a characteristic of T-cells in the perivascular space?
Express inhibitory markers
54
True or false: the perivascular space does not contain APCs under physiological substances
False
55
Which APC population can mainly be found in the perivascular space?
Perivascular macrophages
56
What is the difference between perivascular macrophages & microglia when it comes to:
1. Phagocytosis
2. Activation threshold
3. Antigen-presentation
4. Expression of costimulation
1. Both perivascular macrophages & microglia have phagocytic activity
2. Perivascular macrophages are easily activated by IFN-γ, whereas microglia require multiple cytokines to be activated
3. Perivascular macrophages are strong antigen-presenters, microglia are moderate antigen-presentors
4. Perivascular macrophages express many costimulatory molecules, while microglia have few costimulatory molecules
57
What is the most important mechanism controlling the influx of inflammatory cells into the brain parenchyma?
Interaction between APCs and T-cells in the perivascular space
58
What is required for a T-cell to be able to enter the brain parenchyma?
Reactivation in the perivascular space
59
True or false: inflammatory mediators are only present in the PVS (and not in the parenchyma) under physiological circumstances
True
60
Apart from restricting entry into the brain, which mechanism also prevents inflammation inside the brain parenchyma?
High expression of anti-inflammatory cytokines (TGF-β) & anti-inflammatory markers (CD200)
61
What is an important anti-inflammatory cytokine of the brain parenchyma?
TGF-β
62
What is an important anti-inflammatory surface marker of the brain parenchyma?
CD200
63
Which two routes can cells take to enter the perivascular space?
1. Meningeal vasculature
2. Choroid plexus -> cells end up in the subarachnoid space, and eventually in the perivascular space
64
Why is knowledge on how (T-)cells enter the brain useful in diseases? (2)
1. Can be used for prevention of cell entry in case of neuroinflammatory diseases
2. Can be used to promote cell entry in case of infections
65
How do inflammatory cells recognize they are in the brain?
Brain endothelium contains a unique set of integrins
66
Why is knowledge on the integrins expressed by endothelium in the brain useful?
Can be used to block integrin interaction -> prevents extravasation of inflammatory cells specifically in the brain
67
Via which two routes do inflammatory cells leave the brain? (2)
1. Sinuses
2. Lymphatic vessels in the meninges
68
Where do lymphatic vessels in the meninges drain to?
Deep cervical lymph nodes
69
What is the most common cause of encephalitis?
Viral infection
70
What is the incidence of viral encephalitis?
5-10/100.000 persons/year
71
How many different viruses have been implicated in viral encephalitis?
~100
72
What is the difficulty in diagnosing viral encephalitis?
(Initial) symptoms are very aspecific
73
What are symptoms of viral encephalitis? (6)
1. Fever
2. Headache
3. Behavioural changes
4. Altered level of consciousness
5. Focal neurological deficits
6. Seizures
74
Which groups of viruses are known to cause viral encephalitis? (5)
1. Herpesviruses
2. Enteroviruses
3. Paramyxoviruses (rare)
4. Zoonotic causes
5. Rest group
75
Which herpesviruses can cause viral encephalitis? (5)
1. HSV1
2. HSV2
3. CMV
4. EBV
5. HHV6
76
Which enteroviruses can cause viral encephalitis? (3)
1. Poliovirus
2. Coxsackievirus
3. EV71
77
Which paramyxoviruses can cause viral encephalitis? (3)
1. Measles
2. Mumps
3. Rubella
(note: this is rare!)
78
Which zoonotic viruses can cause viral encephalitis? (3)
1. Arboviruses: WNV/JEV
2. Rabies virus
3. Nipah virus
79
What is an important characteristic of zoonotic viruses that can cause viral encephalitis?
They are geographically restricted
80
What are the main routes of viral entry into the CNS? (2)
1. Hematogenous
2. Migration via peripheral nerves
81
Which viral families reach the brain by hematogenous dissemination? (2)
1. Enteroviruses
2. Arboviruses
82
Which viral families reach the brain by migration via peripheral nerves? (2)
1. Rabies virus
2. Herpesviruses
83
What are the mechanisms of damage in viral encephalitis? (2)
1. Direct cytopathic effect
2. Immune responses
84
Which two mechanisms contribute to immune-mediated damage to the brain parenchyma in viral encephalitis?
1. Antiviral immune response kills infected cells
2. Viral infection of microglia can exacerbate immune response
85
Which viruses cause relatively mild encephalitis? (3)
1. Enterovirus
2. Mumps
3. LCM
86
Which viruses cause mild-fatal encephalitis?
Arboviruses
87
Which kinds of viral encephalitis are always fatal? (2)
1. Rabiesvirus
2. Herpesviruses
88
Which three major groups of arboboviruses can cause viral encephalitis?
1. Flaviviridae
2. Togaviridae
3. Buyaviridae
89
Which viruses that can cause viral encephalitis belong to the flaviviridae? (3)
1. Japanese encephalitis
2. Tick-borne encephalitis
3. West Nile Virus
90
Which viruses that can cause viral encephalitis belong to the togaviridae? (2)
1. Eastern equine encephalitis
2. Western equine encephalitis
91
Which virus that can cause viral encephalitis belongs to the buyaviridae?
La Crosse encephalitis
92
How many % of WNV infections experiences symptoms? What are the main symptoms?
20%, mainly experiencing flu-like symptoms
93
What is the mortality of symptomatic WNV infections in the general population, and in the elderly?
General population: 10%
Elderly: up to 35%
94
True or false: the majority of symptomatic WNV cases will experience rest symptoms
False; most cases will have complete recovery
95
What are rest symptoms of WNV infection? (4)
1. Fatigue
2. Myalgia
3. Residual tremor
4. Parkinsonism
96
Which group of the herpesviruses is neurotropic?
Alphaherpesviridae
97
Where do (most) herpesviruses establish latency?
Trigeminal ganglion
98
To which three regions can HSV disseminate from the trigeminal ganglion? What are the effects of this?
1. Mouth -> cold sores
2. Eyes -> herpes keratitis
3. Brain -> encephalitis
99
What is a unique property of neurons in the trigeminal ganglion that allows herpesviruses of the brain?
They are pseudobipolar -> allow for axonal transport in both directions
100
Which virus most commonly causes herpes encephalitis?
HSV1
101
How many % of all viral encephalitis is caused by HSV1?
11-22%
102
What is the incidence of herpes encephalitis?
4/1.000.000/year
103
What is the mortality of herpes encephalitis if untreated/treated?
Untreated: 70%
Treated: 30%
104
What is the treatment of herpes encephalitis?
(Early) acyclovir
105
How many % of cases of HSV encephalitis retain morbidity?
>70%
106
What are the main rest symptoms of herpes encephalitis? (2)
1. Neurological deficits
2. HSV retinitis
107
Which age groups are most at risk of herpes encephalitis?
Individuals at extremes of age
108
Which brain lobes are mainly affected by herpes encephalitis?
Inferior frontal and anterior temporal lobes
109
Which diagnostics should be used in case of suspected viral encephalitis? (3)
1. Symptomatology
2. PCR on CSF
3. Local antibody production tests
110
What should be the immediate treatment of suspected viral encephalitis?
Immediately start acyclovir in case it is HSE -> most common cause of encephalitis
111
How many % of meningitis cases are caused by:
1. N. meningitidis
2. S. pneumoniae
3. H. influenzae
N. meningitidis = 20%
S. pneumoniae = 50%
H. influenzae = 5%
112
Why is S. pneumoniae the bacterium causing most CNS infections, even if it preferentially infects the lungs?
Streptococcus infections are far more common than meningococcus infections
113
Which local infections can S. pneumoniae cause? (3)
1. Sinusitis
2. Otitis media
3. Other paranasopharyngeal infections
114
How many % of people is asymptomatic carrier of n. meningitidis?
5-15%
115
What are diseases that can be caused by n. meningitidis? (5)
1. Petechiae
2. Pneumonia
3. Meningitis
4. Sepsis
5. Shock
116
How many global cases of meningococcal meningitis are there every year?
500.000
117
How many global cases of mortality due to meningococcal meningitis are there every year?
50.000
118
What are risk factors for S. pneumoniae meningitis? (3)
1. Immunocompromised
2. Splenectomy
3. Genetic polymorphisms
119
What are risk factors for meningococcal carriage? (2)
1. Smoking
2. Living in an infected household
120
What are clinical features of bacterial meningitis? (10)
1. Headache
2. Nausea/vomiting
3. Photophobia
4. Fever
5. Neck stiffness
6. Altered mental status
7. Rash/petechia
8. Signs of local infection
9. Neurological deficits
10. Epileptic seizures
121
What causes neck stiffness in bacterial meningitis?
Increased pressure on the meninges
122
Which feature is characteristic for meningococcal meningitis?
Petechia
123
Which diagnostics are used to diagnose bacterial meningitis? (3) On which material?
Lumbar punction, determining:
1. Purulence
2. Leucocytes
3. Low glucose
124
What are systemic complications of bacterial meningitis? (3) In how many % of cases do they occur?
1. Cardiorespiratory failure: 30%
2. Hyponatremia: 25%
3. Disseminated intravascular coagulation: 8%
125
What are neurological complications of bacterial meningitis? (7) In how many % of cases do they occur?
1. Cerebrovascular complications = 25-30%
2. Meningo-encephalitis = 15-20%
3. Seizures = 15-25%
4. Hearing loss = 15-20%
5. Brain oedema = 5-10%
6. Hydrocephalus = 3-8%
7. Transtentorial herniation
126
What causes cerebrovascular complications in bacterial meningitis? (2)
1. Arteriitis
2. Decreased cerebral perfusion
127
What causes hydrocephalus in bacterial meningitis? (2)
1. Purulent CSF
2. Vein thrombosis
128
What is the standard initial treatment for bacterial meningitis?
Ceftriaxone + amoxicillin & dexamethasone
129
How many % of bacterial meninigitis result in:
1. Mortality
2. Moderate disability
3. No disability
1. Mortality = 21%
2. Moderate disability = 10%
3. No disability = 66%
130
Which kinds of disability can remain after bacterial meningitis? (5)
1. Hearing loss
2. Cognitive impairment
3. Aphasia
4. Hemiparesis
5. Quadriparesis
131
Which two strategies do bacteria employ to survive in the bloodstream and cause meningitis?
1. Bacterial capsule protects them against complement-mediated bacteriolysis & phagocytosis
2. Acquisition of iron from transferrin
132
What is the most effective way of preventing bacterial meningitis?
Vaccines
133
Which vaccines protect against bacterial meningitis? (3)
1. HiB
2. N. meningitidis A, C, W, Y
3. S. pneumoniae
134
What is the age of symptom onset of MS?
20-50 years
135
What is the female:male ratio of MS patients?
3:1
136
What is the prevalence of MS in Northern Europe?
1,5-2/1000
137
What are known risk factors for MS? (4)
1. EBV
2. Smoking
3. Low vitamin D
4. Genetic makeup
138
Which risk factor is always implicated in MS?
EBV
139
Which three different disease patterns can be identified in MS?
1. Relapsing-remitting MS (RRMS)
2. Secondary progressive MS (SPMS)
3. Primary progressive MS (PPMS)
140
How many % of MS patients start with RRMS
85%
141
Which pathological processes are involved in MS? (3)
1. CNS inflammation
2. Demyelination
3. Neurodegeneration
142
True or false: demyelination in MS is irreversible
False; demyelination is reversible (this is also the cause of relapsing-remitting MS)
143
Which processes constitute neurodegeneration in MS? (3)
1. Loss of synapses
2. Loss of axons
3. Loss of neurons
144
What is the hallmark of RRMS?
White matter flares
145
What happens to microglia in white matter lesions in MS?
They are activated by T-cells and attain a macrophage phenotype
146
Which cells are primarily responsible for direct damage to oligodendrocytes & neurons in RRMS?
Activated microglia
147
Which model is used for the study of inflammatory white matter lesions in MS? What kind of response is present here?
Auto-immune encephalitis -> induced auto-immune response to myelin
148
What is focal axonal degeneration?
Degeneration of axons due to macrophage attack
149
What are the stages in focal axonal degeneration? (3)
1. Normal axon
2. Swelling & thinning
3. Breakage
150
True or false: focal axonal degeneration is reversible
True; focal axonal degeneration is PARTIALLY reversible
151
What is the hypothesized role for Ca2+ in focal axonal degeneration?
Intra-axonal [Ca2+] drives focal axonal degeneration
152
The further axons get damaged in focal axonal degeneration, the [lower/higher] the amount of Ca2+ in axons
The more axons get damaged, the higher [Ca2+] -> amount of Ca2+ predicts axonal fate
153
What happens when extracellular Ca2+ is removed from axons undergoing focal axonal degeneration? What does this signify?
Axon is rescued -> calcium causing focal axonal degeneration is most likely from the extracellular space and not from the axolemma
154
How does extracellular calcium enter axons during focal axonal degeneration?
Leaky membrane due to physical damage
155
What is the main cause of progressive MS? Which three processes are involved?
Loss of brain tissue
1. Demyelination
2. Loss of synapses
3. Loss of neurons
156
What is the primary part of the brain in which neurons are lost in progressive MS?
Cerebral cortex
157
True or false: in progressive MS, brain damage occurs due to presence of a high amount of inflammatory cells in the cortex
False; during PMS, inflamamtory cells are mostly absent form the cortex
158
Where are inflammatory cells located in progressive MS? How do they hypothetically cause damage to brain tissue?
Meninges; they are involved in cortical pathology by secreting inflammatory factors that activate microglia
159
What are the main pathogenic cells in progressive MS, responsible for damage to neurons?
Microglia
160
Which three types of microglia can be identified in (post mortem) brain tissue of MS patients?
1. MS0
2. MS1
3. MS2
161
What are MS0 microglia?
Microglia similar to healthy controls
162
What are MS1 microglia?
Microglia with a classical microglial activation profile, expressing CD68 + MHCII, with low expression levels of homeostatic markers
163
What are MS2 microglia?
MS-specific phenotype, with high branching & low expression of homeostatic & activation markers
164
Where can MS1 and MS2 microglia be found in MS patients?
Adjacent to meningeal inflammation in PMS
165
What is the animal model for progressive MS?
Chronic meningeal inflammation (CMI)
166
True or false: MS1 stage of microglia precedes MS2 stage
True
167
What is the current hypothesis on the pathology of PMS? (3)
1. Meningeal (B-)cells secrete inflammatory factors
2. Loss of microglia-mediated neuroprotection
3. Impaired neuronal mitochondrial transport, leading to necroptosis
168
How many % of MS can be genetically explained?
19%
169
What are the most important genes implicated in MS?
MHCII
170
How is MS diagnosed?
1. Clinical picture
2. Supportive evidence: MRI, CSF
3. No better explanation
171
Which tests can be performed on CSF to diagnose MS? (2)
1. Oligoclonal bands
2. Increased IgG index
172
Which adaptive immune cells are physiologically present in the brain, and which aren't?
T-cells are present, B-cells are absent
173
The CSF contains [less/more] lymphocytes than blood
Less
174
How does the profile of lymphocytes in CSF differ from blood? (3)
1. Blood contains naive cells, CSF does not
2. Blood contains both T- and B-cells, CSF only T-cells
3. Blood contains both CD4+ and CD8+ T-cells (CD4+>CD8+), CSF nearly exclusively CD4
175
What is the predominant T-cell type found within the brain? Where are they found? Which characteristic markers do they express?
CD4+ tissue-resident memory T-cells, found in the perivascular unit and expressing CD68 & CD103
176
Which three possibilities for the initiation of detrimental immune responses have been hypothesized?
1. Cells get primed & activated by antigens in the periphery, then cross react to the CNS and cause focal inflamation
2. Regulary T-cells patrolling the CNS get activated by local cues/mediators
3. Disease starts within the brain parenchyma by presentation of antigens by microglia
177
Tregs function [poorly/normally/strongly] in MS
Poor Treg function
178
Which processes are targeted by current MS therapies? (5)
1. APC-T-cell interaction
2. Clonal expansion of T-cells
3. Migration of T-cells
4. Trafficking into the CNS of T-cells
5. Inflammatory cell depletion
179
Which therapeutic strategy is most potent in MS?
Inflammatory cell depletion
180
What is the downside of current MS therapies, aimed at preventing T-cell activation/entry into the CNS?
Therapies are poor at stopping flares after they have aready began
181
What is remarkable about circulating CD4+ T-cells in RRMS?
Increased amount of CD4+ T-cells with cytotoxic phenotype
182
What is remarkable about B-cells in RRMS? What characterizes them?
B-cells with a phenotype prone to CSF-infiltration, express CXCR3
183
How many % of patients with RRMS have grey matter lesions?
38%
184
Cells extravasate and enter the PVS. What needs to happen before they can enter into the CNS?
Activation in the PVS
185
What are, very globally, the four pathogenic steps of RRMS?
1. Cells activated in lymph nodes and enter the bloodstream
2. Cells cross blood-brain barrier and enter the PVS
3. Cells are activated in the PVS and enter the parenchyma
4. Cells contribute to inflammation, loss of myelin & loss of axons
186
True of false: during progressive MS, attacks are completely absent
False; although they are rare, they still can occur during progressive MS
187
True or false: we currently have therapies that curb progressive MS
False; current therapeutics are only effective in RRMS
188
Which cell types can be found in white matter lesions of people with progressive MS? (3)
1. Myeloid cells
2. T-cells
3. B-cells
189
Where do myeloid cells found in white matter lesions of patients with progressive MS come from?
They are the result of local expansion of macrophage-like cells
190
What is thought to fuel progressive MS pathology?
Excretion of inflammatory mediators by (mainly) T-cells
191
B-cells are present in [lower/higher] numbers than T-cells in progressive MS white matter lesions
Lower
192
Presence of B-cells in white matter lesions in progressive MS is prognostically [favourable/unfavourable]
Presence of B-cells = unfavourable
193
What is the presence of B-cells in white matter lesions in progressive MS correlated with? (4)
1. Early mortality
2. Higher amount of inflammatory lesions
3. High number of T-cells in inflammatory lesions
4. More intrathecal IgG production
194
Why can presence of IgG/oligoclonal bands be used as a progression marker for progressive MS?
They point to the presence of B-cells, which are prognostically unfavourable
195
How is presence of IgG against myelin in progressive MS important from a pathological point of view?
Can fuel breakdown of tolerance of microglia to myelin and activate demyelination
196
In progressive MS, follice-like structures can form in the meninges. What is their presence associated with? (3)
1. Earlier onset of disease
2. Faster accumulation of disability
3. Earlier death
