Antibody-associated CNS-diseases

Question 1

Antigen?

Answer 1

An antigen isany substance that causes your immune system to produce antibodies against it. This means your immune system does not recognize the substance, and is trying to fight it off. An antigen may be a substance from the environment, such as chemicals, bacteria, viruses, or pollen

Question 2

Pathophysiology

Answer 2

The disordered physiological processes associated with disease or injury

Question 3

Corticosteroids

Answer 3

Areman-made drugs that closely resemble cortisol, a hormone that your adrenal glands produce naturally. Also an ineffective immunotherapy towards Nuclear and cytoplasmatic neuronal antigens

Question 4

Plasmapheresis

Answer 4

Plasmapheresis is a term used to refer toa broad range of procedures in which extracorporeal separation of blood components results in a filtered plasma product.. Also an ineffective immunotherapy towards Nuclear and cytoplasmatic neuronal antigens

Question 5

Intravenous immune globulin (IVIG)

Answer 5

Intravenous immune globulin(“IVIG”) is a product made up of antibodies that can be given intravenously (through a vein). Antibodies are proteins that your body makes to help you fight infections. Also an ineffective immunotherapy towards Nuclear and cytoplasmatic neuronal antigens

Question 6

Anti-Hu Encephalitis

Answer 6

Nuclear and cytoplasmatic neuronal antigens disorder. Causes sensory neuronopathy, limbic encephalopathy, cerebellar degeneration. In case descriptions loss of hearing and severe ataxia was seen

Question 7

Catatonic stupor

Answer 7

a state of significantly decreased reactivity to environmental stimuli and events and reduced spontaneous movement. A case-based symptom of NMDA-R Ab-encephalitis

Question 8

Pneumonia

Answer 8

an infection of one or both of the lungs caused by bacteria, viruses, or fungi. It is a serious infection in which the air sacs fill with pus and other liquid. A case-based symptom of NMDA-R Ab-encephalitis

Question 9

Plasmapheresis

Answer 9

a method of removing blood plasma from the body by withdrawing blood, separating it into plasma and cells, and transfusing the cells back into the bloodstream. It is performed especially to remove antibodies in treating autoimmune conditions.

Question 10

Pareses

Answer 10

a condition of muscular weakness caused by nerve damage or disease; partial paralysis. NOT as symptom of Stiff person syndrome.

Question 11

Paraneoplastic syndromes

Answer 11

a group of rare disorders that are triggered by an abnormal immune system response to a cancerous tumor known as a “neoplasm.” Amphiphysin belongs to this group.

Question 12

Presynaptic inhibition

Answer 12

the suppression of neurotransmitter release from a neuron by inhibitory input onto its presynaptic terminal

Question 13

Immunoglobulin G (IgG)

Answer 13

a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. The type of antibodies relevant for Amphiphysin

Question 14

Intrathecal

Answer 14

the fluid-filled space between the thin layers of tissue that cover the brain and spinal cord.

Question 15

phenotype

Answer 15

refers tothe observable physical properties of an organism. A phenotype of Stiff person syndrome has been discovered.

Question 16

3 main types of Antibody associated diseases

Answer 16

1. Nuclear and cytoplasmatic neuronal antigens
2. Membrane bound synaptic antigens
3. Intracellular synaptic antigens

Question 17

Most common tumor type for Nuclear and cytoplasmatic neuronal antigens

Answer 17

SCLS (Small Cell Lung carcinoma)

Question 18

Things Nuclear and cytoplasmatic neuronal antigens have in common

Answer 18

• Related to malignant tumor
• Pathophysiological role unclear
• „Markers“ of disease
• May be the consequence of a cytotoxic T cell reaction to - the tumor or to neurons
• No transfer to animal model using

Question 19

How do we treat disorders that develops from Nuclear and cytoplasmatic neuronal antigens?

Answer 19

Immunotherapies are often ineffective, but tumors needs to be treated

Question 20

What does the Membrane bound synaptic antigens disorders have in common?

Answer 20

• Often no tumor (but watch out in NMDA-R abs)
• Pathophysiological role clearly defined
• Animal models available
• Symptoms can be imitated by antagonists

Question 21

Common NMDA-R Ab-encephalitis things

Answer 21

Mostly young women (80%), rarely men and children
Women in 60% have an ovarian teratoma
Prodromi: headache, nausea, fever, diarrhea
2-10 days later illusions, paranoia
Loss of language function, mutism
Seizures, loss of autonomic regulation

In 75% recovery
Treatments: Corticosteroids, IVIG, PE, tumor surgery
Death in 4-5%

Question 22

Pathophysiology of NMDA-R AK-Encephalitis

Answer 22

Abs block the NMDA-R on GABAergic neurons of the thalamus and of the frontal cortex –> leads to disinhibition of postsynaptic glutamatergic neurons and thus to glutamatergic and dopaminergic dysregulation in the frontal cortex

Question 23

What kind of antigen is related to stiff person syndrome?

Answer 23

Intracellular synaptic antigens

Question 24

Characteristics of stiff person syndrome

Answer 24

Prevalence about 1:1 million
double as common in females as in males
Starts in middle age

Prodomi with stiffness and pain
Progress to proximal stiffness (of the trunk)
Painful spasms can be triggered by surprise
Increased lumbar lordosis (inward curve of the lumbar spine)
Normal sensory function, no pareses, normal cognitive functions
Patients often has agoraphobia and anxiety
Symptoms can be triggered my emotional stress

Question 25

Stiff person syndrome often occurs when we have antibodies towards?

Answer 25

• Glutamate-decarboxylase (GAD-65)
• GABA-A-receptor-associated protein (GABARAP)
• Glycine receptors
• Amphiphysin (synaptic protein): often paraneoplastic
• Gephyrine (anchor protein for GABA- and glycine receptors in the membrane)

All of these impair the inhibitory system

Question 26

What does Glutamate-decarboxylase (GlyR) antibodies do?

Answer 26

Block GABA synthesis and the transport of GABA into the synaptic vesicles

Question 27

What does Glycine receptors (GAD-65) antibodies do?

Answer 27

Disturb function of the glycine receptors

Question 28

What does Amphiphysin receptors antibodies do?

Answer 28

Blocks the ability of vesicles to detach from the membrane

Question 29

Symptom treatments of Stiff person syndrome

Answer 29

Symptoms treatment

• Benzodiazepines – GABA-A agonist
• Baclofen – GABA-B agonist

Question 30

Causal treatment of Stiff person syndrome

Answer 30

Causal treatment

• Corticosteroids
• IVIG
• Plasmapheresis

Question 31

Can patient’s IgG be transferred to a rodent model of Stiff person disorder?

Answer 31

Yes

Question 32

What proves that it’s the antibodies to Amphiphysin that causes the symptoms seen in SPS and not something else in the IgG?

Answer 32

Geis et al. 2012 showed in mouse models that only IgG including the Anti-Amphiphysin antibodies cause the symptoms that was observed (and not just the IgG that had been stripped of these antibodies)

Question 33

What domain of Amphiphysin binds to Dynamin to help the vesicle detach?

Answer 33

SH3

Question 34

Geis et al. 2010 uses double stains of VGAT and Anti-amphiphysin antibodies to prove what?

Answer 34

That Anti-amphiphysin antibodies binds directly on the VGAT

Question 35

Geis et al. 2010 uses double stains of Bassonn and Anti-amphiphysin antibodies to prove what?

Answer 35

That Anti-amphiphysin antibodies and Bassonn are localized close to each other, but they don’t overlap

Question 36

Which neurotransmitters are affected by anti-amphiphysin antibodies?

Answer 36

We see substantial decrease in GABA release and a slight decrease in release of glutamate

Question 37

What characterizes Frequency-dependent Inhibition?

Answer 37

The higher the frequency of the electrical stimulation, the quicker will the depression of the signal be

Question 38

How is Frequency-dependent Inhibition changed in muscles affected by anti-amphiphysin IgG?

Answer 38

We don’t see a depression to the same extent that we usually would if we increase the frequency