Case `1 - PNS syndromes Flashcards
1
Q
LEMS - symptoms + prognosis
A
- muscle weakness (proximal and symmetrical)
- post-activation facilitation
- ocularbulbar weakness
- autonoic dysfunction (dry mouth, constipation, speech)
- respiratory failure
- LEMS typically responds positively to symptomatic and immunosuppressive therapies
o Upon diagnosis, approximately 60% of patients maintain their independence in daily activities, and this proportion increases to 85% within a year of treatment. - The life expectancy of LEMS patients depends on whether it is paraneoplastic or non-paraneoplastic (NT-LEMS).
2
Q
LEMS - definition
A
- Neuromuscular junction disorder affecting communication between nerves and muscles by targeting VGCCs - can manifest due to a paraneoplastic syndrome or a primary autoimmune disorder.
o The majority of cases are associated with small-cell lung cancer (SCLC) - Can be categorized into either paraneoplastic (tumor associated) or non-paraneoplastic (no tumor).
o Approx. 60% of LEMS patients have an underlying tumor, predominantly small cell lung cancer among others (LEMS can predict the diagnosis of SCLC by 5 to 6 years). - Approx. 60-75% of patients are male, the onset age peaks at 35, with a larger peak at 60
3
Q
LEMS - diagnosis
A
- clinical assessment
- serology (find VGCC Abs =90% of patients)
- electrodiagnostic testing (NCS is normal but motor unit have lower conduction, EMG lower activity, RNS decremental 3Hz - incremental 10Hz)
4
Q
LEMS - pathophysiology
A
85 – 95% of the patients have Autoantibodies against the P/Q-type VGCC, which is a specific subtype of VGCC enriched at the nerve endings of motor neurons controlling muscle contraction
- Binding by the antibodies leads to a functional loss of VGCC due to blockage, crosslinking-induced internalization, and destruction of the receptor.
- This results in reduced calcium entry and therefore insufficient neurotransmitter release, being the cause of muscle weakness.
- In addition to impacting muscle function, the autonomic nervous system is also attacked by autoantibodies targeting N-type VGCCs.
- Can be paraneoplastic (SCLC) or have genetic (HLA) origins
5
Q
LEMS - treatment
A
- symptomatic: ACh based therapies
o 3,4-DAP: medication blocks presynaptic potassium channels, prolonging the action potential duration and depolarization, increasing presynaptic calcium influx through VGCCs and subsequent ACh release.
o Guanidine: enhances ACh release following a nerve action potential.
o Acetylcholinesterase inhibitors: pyridostigmine - Immunomodulating or immunosuppressive therapies:
o Intravenous immune globulin (IVIG): increase Ab turnover rate
o Steroids and other immunosuppressive agents: azathioprine, cyclosporine, corticosteroids
o Rituximab: monoclonal antibody targets CD20 receptors found on B lymphocytes
6
Q
neuromyotonia - definition
A
- Neuromyotonia (NMT) is a disorder of generalized peripheral nerve hyperexcitability (PNH), manifesting as spontaneous, continuous muscle activity of peripheral nerve origin.
- It is characterized clinically by muscle twitching at rest (visible myokymia), cramps, which can be triggered by voluntary or induced muscle contraction, and impaired muscle relaxation, or pseudomyotonia (delay in relaxation after reflex contraction).
- There are hereditary and acquired forms of the disorder. The acquired form occasionally develops in association with peripheral neuropathies or after radiation treatment, but more often is caused by an autoimmune condition
7
Q
neuromyotonia - symptoms + prognosis
A
- Muscle Stiffness and Fasciculations: Progressive muscle stiffness accompanied by widespread fasciculations (involuntary muscle twitches or small, spontaneous contractions of muscle fibers) leading to weakness.
- Continuous Muscle Activity: Characterized by continuous muscle activity detected on electromyography (EMG), occurring even at rest and unaffected by local nerve blockade.
- Autonomic and Central Nervous System Involvement: Patients may experience sensory symptoms (paraesthesia, pain), autonomic disturbances (excessive sweating, tachycardia, diarrhoea), and central nervous system symptoms (insomnia, mood changes, anxiety, depression).
– Long-term prognosis is uncertain, and has mostly to do with the underlying cause; i.e. autoimmune, paraneoplastic, infection, toxicity etc.
- Most examples of NMT are autoimmune and not associated with cancer. NMT is linked mostly to lung and thymus cancer. In these cases, the underlying cancer will determine prognosis.
- NMT disorders are now amenable to treatment and their prognoses are good. Many patients respond well to treatment, which usually provides significant relief of symptoms. Some cases of spontaneous remission have been noted.
8
Q
neuromyotonia - pathophysiology
A
- Forty percent of patients with Neuromyotonia have antibodies against voltage-gated potassium channels (VGKC), more precisely against the contactin-associated protein-2 (CASPR2), being part of the VGKC-complex.
- The interaction of CASPR2 with the cell-surface protein TAG-1 is necessary for the recruitment if VGKC subunits and IgG4 anti-CASPR2 antibodies were shown to result in a decrease of VGKC due to blocking of the antigen.
- Some patients also have autoantibodies against the leucine-rich, glioma inactivated 1 protein (LGI1), being part of the VGKC-complex as well.
o However, commonly LGI1 is found in VGKC-mediated diseases affecting the central nervous system, such as the Morvan syndrome, rather than in peripheral neurological syndromes - The decrease as well as blocking of the potassium channels on the motor nerve results in hyperexcitability as potassium ions are hindered from moving out of the neuron to restore the resting membrane potential
9
Q
neuromyotonia - treatment
A
- Anticonvulsants: such as phenytoin, carbamazepine, sodium valproate, lamotrigine and acetazolamide, which primarily reduce neuronal repetitive firing through interaction with voltage-gated sodium channels. → These channels are responsible for initiating and propagating action potentials (nerve impulses).
o By blocking sodium channels, anticonvulsants decrease the excitability of neurons and reduce the likelihood of abnormal electrical activity that leads to seizures.
o Anticonvulsants can also work by increased GABAergic transmission, decreased glutamate, blockage of calcium channels, etc. - Immunosuppression: prednisolone (corticosteroids), methotrexate and azathioprine, although not all will respond fully.
- Plasma exchange: Severe symptoms may be ameliorated for up to 4 weeks (filter toxins and unhealthy antibodies out of the blood).
- IVIg
10
Q
MuSK/LRP4 - symptoms + prognosis
A
- In general myasthenia gravis is a severe but treatable condition.
- However, the exact prognosis depends on several factors, e.g. the subtype, symptom severity and treatment response.
- MuSK-associated myasthenia gravis patients do often have more severe symptoms, a rapid progression to generalized muscle weakness within 2-3 weeks, and an increased risk of respiratory crisis.
Furthermore, this subtype responds less well to acetylcholinesterase inhibitors as a treatment, which further complicates the matter. - LRP4-seropositive patients are mostly characterized by a relatively mild symptom severity and a lower risk of respiratory crisis.
Therefore, comparing both the MuSK and LRP4 subtype, the former is associated with a worse prognosis
11
Q
Musk- pathophysiology
A
- Monovalent MuSK-IgG4 autoantibodies block MuSK-LRP4 interaction preventing MuSK activation and leading to the dispersal of AChR clusters.
- Lower levels of divalent MuSK IgG1, 2, and 3 antibody subclasses are also present but their contribution to the pathogenesis of the disease remains controversial.
AChR-MG: IgG1 and IgG3 - Monovalent IgG4 (due to hinge alterations leading to Fab arm exchange) does not allow for divalent-dependent internalization of the antigen (no antigen-crosslinking), a mechanism widely recognized in antibody-mediated diseases.
- Additional single amino acid differences in the CH2 domain of IgG4 render it unable to bind to C1q to activate the complement cascade or FcγR to activate immune cells.
- Instead, IgG4 antibodies can only block the function of a protein or inhibit its interaction with other proteins The inhibition of MuSK phosphorylation was shown to be dependent on IgG4 antibodies, which prevented the binding of LRP4 to MuSK MuSK is therefore not able to respond to agrin stimulation and, consequently, the entire AChR clustering cascade is inhibited.
12
Q
LRP4 - pathophysiology
A
- Lrp4 is the postsynaptic receptor of nerve-derived agrin.
- The binding of agrin to Lrp4 activates MuSK and initiates a cascade of events leading to the aggregation of AChRs in the neuromuscular junction and to retrograde signalling.
- Lrp4 antibodies are present in 2–50% of double seronegative MG cases
- Many Lrp4-MG patients also have antibodies against agrin.
- Lrp4 antibodies are mostly of the IgG1/IgG2 subclass and are believed to be directly pathogenic by disrupting the activation of MuSK with potentially more patho mechanisms
- The antibodies exerted their action through the disruption of the interaction between LRP4 and agrin, leading to inhibition of AChR-mediated neuromuscular transmission in this model system through inhibited agrin-induced MuSK activation and AChR clustering
- In addition, complement deposits at the neuromuscular junction might contribute to pathogenicity
- They may (unsure if clustered densely enough for this) decrease cell surface LRP4 of muscle cells via crosslinking-induced internalization and ADCC
13
Q
Musk/LRP4 - diagnosis
A
- Clinical examination:
* symptomatology - Serological testing
* quantification of serum auto-antibodies against MuSK, LRP4, AChR
* seropositive, if serum levels are above 0.5 nmol/L
* methods: radioimmunoassay, ELISA or cell based assay → radioimmunoassay as most sensitive method - Electrophysiological testing
* repeated nerve stimulation:
* motor neuron is repeatedly stimulated and subsequent muscle responses are recorded
* healthy people: muscle action potential amplitudes remain stable
* MG patients: muscle action potential amplitudes decrease with each successive stimulus → 10% decrement between the first and fourth stimulus is suggestive of an impaired neuromuscular transmission
* single-fiber electromyography
* assessment of variability in time it takes for an action potential to travel between neighboring muscle fibers of one motor unit (=jitter)
* MG patients: increased jitter
4) Tensilon test
* intravenous administration of short-acting acetylcholinesterase inhibitor and muscle strength is compared before and after administration
* MG patients: temporal increase of acetylcholine levels improve symptoms for a short period of time.
* In the MuSK associated MG subpopulation, Tensilon test results are mostly negative since they are less responsive to acetylcholinesterase inhibitor treatment.
14
Q
Musk/LRP4 - treatment
A
- Conventional immunosuppression
- Corticosteroids are used as immunosuppressive medications to target the underlying autoimmune response and reduce the production of autoantibodies that contribute to the disease process. For example: oral prednisone and prednisolone, glucocorticoids.
- Non-steroidal immunosuppressants have a delayed response, which is longer for azathioprine (several months) and shorter for cyclosporine (1–2 months – vry nasty stuff).
- Rituximab
- Rituximab is a monoclonal antibody medication used to treat various autoimmune disorders. It works by targeting and depleting B cells, which are involved in the immune response and play a role in the development of autoimmune diseases.
- Short term treatment
- Human immunoglobulin exchange (IVIg) and plasma exchange (PLEX) are fast-acting treatments and are typically used in patients with acute severe MG when a rapid response is crucial for example to treat myasthenic crisis (respiratory insufficiency). As their effect is short-lived (4–12 weeks), additional immunotherapy is usually needed.
15
Q
GBS - definition
A
- Guillain-Barré syndrome (GBS) is an autoimmune disorder of the peripheral nervous system
- An uncommon condition, Guillain-Barré Syndrome only affects one or two people per 100,000.
- Often preceded by an infection C. jejuni (food poisoning), Mycoplasma pneumoniae (upper respiratory tract infection), Haemophilus influenzae (ear infection, bronchitis and other infections), cytomegalovirus and Epstein-Barr virus
- Subtypes of GBS include:
- Acute Inflammatory Demyelinating Polyneuropathy (AIDP)
- Acute motor and sensory axonal neuropathy (AMSAN)
- Acute motor axonal neuropathy (AMAN)
- Miller-Fisher variant
- Acute panautonomic neuropathy
