PNS, NMJ, myopathy dz Flashcards

1
Q

Systemic causes of polyneuropathy

A

Major ones are DM and hypoTH

Less severe:
Anaemia, reduced perfusion, hypoxaemia, hypokalaemia, hypoglycemia

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Pathogenesis of DM neuropathy

A

4 main theories
- Sorbitol and fructose accumulation due to metabolic disturbances and initiation of Polyol pathway –> depletion of myoinositol which is needed for normal membrane function

  • reduced Na/K ATPase function due to energy deficit
  • Reduced IGF1 without insulin, this is involved in nerve regeneration
  • Vascular alterations: hyperglycemia induced increase in vasoconstrictor tone and reduced NO production
    Also hyperviscosity of blood
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Lesions of diabetic neuropathy and expected electrodiagnostic changes

A

Demyelination predominates

MNC studies find reduced conduction velocity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Pathogenesis of hypoTH neuropathy

A

Thought to be contributed to by:

  • glycosaminoglycan and glycogen accumulation within schwann cells
  • Altered Na/K ATPase activity/expression
  • Compression neuropathies due to build up of myxoedema

Ischaemia from vascular changes due to atherosclerosis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Disorders with assoc to hypoTH, Electrodiagnostic findings

A

HypoTH has been associated with CN neuropathies including: facial nerve paralysis, trigeminal neuropathy, megaoesophagus, laryngeal paralysis, vestibular symptoms

May also have occasional generalised ascending LMN paresis has been reported and was responsive to thyroxine supplementation

EMG - denervation changes (increased insertional activity, fibrillations, sharp waves)

NCS - reduced CMAP and reduced conduction velocities

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Inherited polyneuropathies

A

Motor neuropathy - defects of ventral horn with weakness but preserved reflexes. progressive disease in Britt Spaniels and Main Coon

Peripheral myelinopathy
Results in varied conduction speed and can regenerate (leading to conduction block)

Distal sensorimotor polyneuropathy (Alaskan Malamute and Doberman)
–> affects all neuron types and results in reduced tone and reflexes. Starts distally affecting long neurons first

Sensory neuropathy - affects dorsal horn neurons more.
(JRT, Dachshund)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Causes of polyneuropathy in insulinoma

A

Autoimmune - molecular mimicry suspected

Also hypoglycemia

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Different inflammatory neuropathies in dogs and their electrodiagnostic findings

A

Acute polyradiculoneuritis - immune mediated (CM and humoral) demyelination and neuron damage (especially ventral root affected)
–> EMG denervation changes (increased insertional activity and denervation potentials); with reduced NCV and reduced compound muscle AP generation.

Chronic demyelinating polyneuropathy
Immune mediated damage to myelin
EMG may show denervation changes, but see conduction block on NCS and reduced compound muscle action potential

Sensory polyganglioradiculoneuritis
–> affects dorsal root ganglia and sensory nerves. Unknown aetiology
–> normal EMG and motor nerve studies
Sensory nerve studies are abnormal
–> ataxia (proprioceptive); hypalgesia; dysphagia an self mutilation

Brachial plexus neuritis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Toxins that can cause polyneuropathy

A

Heavy metal

Vincristine and Cisplatin through microtubule damage

Organophosphates

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Diagnosis of autonomic polyneuropathy (Dysautonomia)

A

Schirmer tear test - reduced production due to loss of PSNS

Dilute pilocarpine - cholinergic agonist. Dilute formula will cause rapid ciliary constriction of pupil if denervated hypersensitivity

Atropine response test - bradycardia does not improve as the HR reduction is due to loss of sympathetic tone

Orthostatic hypotension test - without autonomic function BP will drop when limbs are elevated

Bethanecol test - will enable emptying of bladder

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Causes of polyneuropathy in cats

A

D - Main coon motor polyneuropathy, Siberain cat recurrent motor neuropathy reported JVIM 2020

A - distal axonopathy of Birmans, hyperchylomicronemia

M - Diabetic neuropathy
Hyperthyroid

N - paraneoplastic
Tyrosine/phenylalanine deficiency

I - immune mediated polyneuropathy (JVIM 2022), Toxo, FeLV and FIV

T - organophosphates, vincristine, pyrethrins

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

JVIM 2022 Feline immune mediated polyneuropathy findings
And electro diagnostic results

A

55cats - mostly young, often had recurrent episodes, normal sensation

All had pelvic limb weakness and 67% FL weakness,
75% reduced reflexes

ElectroDx - abnormal motor nerve conduction and denervation changes on EMG

31 nerve biopsies - inflammatory infiltrates directed at nerve fibres, nodes of Ranvier and Schwann cells - suggestive of IM process

Recovery in 91% of cats on no treatment, 90% that got steroids and 90% that got L-carnitine
. All in similar period of time 3-4 weeks

3 cats only recovered after immunosuppression - so may be some form of immune mediated component

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Pathogenesis of Ixodes Tick paralysis and clinical signs

A

Neurotoxin produced that enters circulation and interferes with release of Ach into synapse of NMJ by blocking Ca influx

–> acute rapidly progressive flaccid paralysis
(Ixodes more potent thatn Dermatocenter tick in US)

Normal EMG with reduced CMAP when peripheral motor nerves stimulated

Ixodes toxin also causes autonomic signs of urinary dysfunction, cardiac dysfunction, pupillary dilation, megaoesophagus, pulmonary oedema, dysphonia

Tx - hyperimmune serum, phenoxybenzamine and ACP, may need ventilation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Potential presentations of NMJ disorder

A

Flaccid paralysis

Episodic weakness, exacerbated by exercise

Short choppy gait - especially if ACH esterase interference causing overstimulation of muscle fibres

Paraparesis or tetraparesis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Diagnostic tests in NMJ disease

A

Evaluate for cardiac disease, metabolic disturbance and phaeochromocytoma

CBC, Biochem, ACTHST, TT4/TSH, urine NMN, CK, blood gas pre and post exercise (including lactate)

Anti-AChR Ab titres

Serum cholinesterase activity - identifies organophsphate toxicity
Tick Search

Electrodiagnostic

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Pre-synaptic causes of NMJ dysfunction

A

ick

Snake

Botulism

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

How does snake neurotoxin cause paralyssi

A

Binds to ACh R irreversibly preventing conduction of nerve signal to muscles

May also inhibit ACh release

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

How does botulinum toxin interfere with neuromuscular conduction and clinical signs

A

Absorbed from GIT after toxin activated by low pH (type C toxin in dogs/cats)

–> in blood able to bind nerve terminals of cholinergic neurons and is internalised

–> within nerve terminal interferes with SNARE proteins that cause NT vesicle exocytosis

–> no NT release (ACh) when nerve potential arrives.

–> flaccid LMN paralysis and autonomic dysfunction (altered HR, mydriasis, urinary rertension; dry eye; megaoesophagus)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Pathogenesis of acquired MG

A

Ab against alpha1 subunit of nicotinic ACh R on muscle fibres. Thought to be molecular mimicry cause

AutoAb binds –> complement mediated destruction of ACh R, and Ab cross-linking causes receptor internalisation
Also directly inhibits binding of R by presence of Ab.

–> reduced receptor number means muscle fibre has diminished ability to respond to neuron signal –> repeated firing exhausts the remaining ACHR (which are internalised after binding ACh) –> desensitisation to further signalling and fatigue.

20
Q

Diseases assoc with acquired MG

A

Hypothyroidism

Thymoma

MMM and polymyositis
Hypoadrenocorticism

Thioureylene medications in cats - reversible loss of self tolerance

21
Q

Signalment of acquired MG in dogs

A

Bimodal age distribution: <4 > 9y

Breeds: GSD, Golden Ret, Labrador,

Females

22
Q

Presentation for different forms of acquired MG

A

Focal = weakness in 1 or more skeletal muscle group: facial, oesophageal, pharyngeal, laryngeal

Acute fulminant = rapidly progressive, very severe weakness that is generalised in most cases
–> respiratory failure and death in many cases
Lack of improvement at rest

Generalised = appendicular skeletal weakness +/- facial, oesophageal. pharyngeal or laryngeal weakness.
–> generally worsens with activity, starting with HLs then progressive weakness

23
Q

What causes seronegative MG

A

Negative or low level early in disease process, so repeat in 1-2 months

Majority of Ab already bound to Sk muscle receptor

congenital disease - no autoAb present

prior immunosuppressive Tx

Autoantibodies directed at a different binding site on receptor –> MUSK site reported in dogs

24
Q

Proposed groups of acquired MG in dogs/cats in JVIM 2022 review and the subgroups with prognostic significance

A

Acute Fulminant with or without thymoma

Generalised with or without thymoma
+/- thiourylene medications
+/- Seronegative

Focal with or without thymoma

Subgroups: thymic mass, cats on thiourylene medications

Other subgroups
Seronegative

25
Comparative incidence of thymic mass in MG dogs vs caats
3% vs 52% in cats
26
Pharmacological testing for Myaesthenia gravis
ACh esterase inhibitors - narrow therapeutic index Neostigmine - given IV and rapid onset of action , almost 100% excreted by 24h Edrophonium - given parenterally and has onset of effects within 10 minutes Pyridostigmine - slower onset of action and can be given orally. Metabolised in liver
27
Adverse effects of ACh esterase inhibitors
Cholinergic symptoms: Bradycardia --> sinus arrest SLUD Vomiting Paradoxical exacerbation of muscle weakness and fatiguability. Cholinergic crisis: GI upset, respiratory distress (from increased secretions and bronchospasm); miosis, altered HR, cardiospasm, sweating, cramps. Generally seen with overdose Can reverse with atropine or glycopyrrolate Cats reported to have increased susceptibility to side effects
28
Electrodiagnostic findings in acquired MG
Normal EMG and evoked CMAP But decremental decrease in CMAP with repetitive nerve stimulation
29
Evidence for use of immunosuppression in acquired MG
Trials with MM, cyclosporine, azathioprine have not reported success Use of corticosteroids considered risky due to their exacerbation of muscular weakness and potentially to increase risk of adverse effects should aspiration occur secondary to megaO. --> recommended to start at anti-inflammatory dose and titrate up. Cats may be more tolerant of adverse effects than dogs. Also reported to have more of a response compared to dogs. TPE reported in one dog in addition to corticosteroids and had clinical remission and is used in humans with all acquired MG forms.
30
Mainstay of acquired MG treatment and differences in JVIM 2022 Tx recommendations in cats vs dogs
Supportive care - avoid GA as this can worsen symptoms dramatically Prevention of aspiration and management if it occurs - ABx, O2, coupage, Start pyridostigmine then add corticosteroids at anti-inflammatory doses in dogs. Cats - start with steroids s more tolerant to AEs and more likely to have benefit. More prone to pyridostigmine AEs so need to titrate carefully.
31
Prognosis in thymoma associated MG
Thymectomy required to achieve complete remission --> NB anaesthesia carries high risk in MG patients and can see clinically relevant post-op exacerbation
32
Outcome in dogs vs cats
Spontaneous remission reported in cats without any interventions, though some require ongoing Tx 1y mortality in dogs is 40-60% regardless of type vs 15% in cats Recent JVIM study reported death in 35% of dogs. And that remission less likely in older dogs and those presenting with regurgitation or high ACh R Ab titres JVIM 2020 long term outcome in cats reported excellent outcome in all even 4 that did not receive any treatment --> in dogs that go into remission (and dont have thymoma) then prognosis is excellent long term.
33
Definition of disease remission in acquired MG
Normalisation of AChR antibody titres, correlates well with clinical resolution of symptoms. More likely to occur in dogs with focal or generalised forms not associated with thymoma
34
Types of congenital myaesthenic syndromes and their pathogenesis /findings
Presynaptic = ACh synthesis defect (CHAT protein); Normal AChR. Reported in Old Danish Pointing Dogs Onset is 12 - 16 weeks of age, and a period of exercise is required before observation of skeletal muscle weakness and fatigability Decremental response on repetitive nerve stimulation No response to AChEi. Guanidine can result in electrophysiological improvement Response to albuterol (BAdr thought to stabilise the NMJ) Synaptic = defect in AChE (COLQ gene) Onset is 2-8 (up to 23 in cats) weeks of age. Known breed mutations in Labrador, Golden Retriever, Sphynx and Devon Rex cats. Genetic testing available Normal EMG (decremental response on RNS) , biopsy, negative Ab, Pyridostigmine makes fatagaility and muscle weakness worse. Post-synaptic = deficiency of postsynaptic nic AChR (CHRNE mutation) Reported in JRT and Heideterrier breeds, genetic testing available Normal EMG, decremental RNS, Administration of AChE-inhibitor results in electrophysiologic as well as temporary clinical improvement.
35
Diagnosis of Congenital Myasthenic syndrome
Genetic tests: Labrador and Gold Ret and cats with COLQ gene mutation JRT with CHRNE mutation Ultrastructural identification of ACh R deficiency Consistent clinical signs and development at young age Negative AChR-Ab testing Decremental response to RNS on electrodiagnostics with function otherwise normal on MNC and EMG. Edrophonium challenge test - improvement in post-synaptic disease, but can worsen synaptic disease or cause cholinergic crisis
36
Treatment in congenital myasthenic syndromes
Synaptic - worsen with AChEi but can improve with B2 adrenergic agonists --> thought to stabilise NMJ membrane and decrease dispersion of ACh R Post-synaptic - responde to pyridostigmine but generally transient benefit as drug resistance develops Most reported CMSs in dogs and cats have an unfavourable out-come and are fatal. However certain Jack Russell terriers and DevonRexes respectively affected by CHRNE- and COLQ-associated CMS cansurvive for years,
37
Effect of Organophosphate toxicity
Inhibitors of ACh Esterase --> accumulation of ACh in synaptic cleft (organophosphates are irreversible inhibitors, carbamates are reversible) --> ongoing muscle stimulation and cholinergic effects --> tremors, weakness, CNS dysfunction, SLUD Can use atropine to antagonise ACh effects
38
Cause and symptoms of Labrador retriever episodic collapse
Strenuous exercise or increased temperature --> hyperventilation, collapse with paretic and ataxic pelvic limbs and reduced pelvic reflexes Recover within 10-30mins but severe episodes can result in death Thought to be caused by defect in NT recycling (endocytosis process) Genetic test available Presentation at 2-24 months Reduce frequency of events with diazepam and phenobarbitone EMG, muscle bx and pyruvate levels are normal.
39
Typical findings of myopathy
weakness, exercise intolerance, stiff stilted gait. Myotactic reflexes usually will stay intact but patellar reflexes can be lost in select myopathies Atrophy, focal or generalised is a frequent finding as well as myalgia. Voice change, dyspnoea, dysphagia, megaoesophagus may develop with muscles of the tongue, larynx, pharynx, or oesophagus.
40
Diagnostic evaluation for suspected myopathy
CK Persistent elevation of four to five times normal values indicating ongoing muscle damage. ALT and AST may also be elevated. Lactate, pyruvate and carnitine levels may be abnormal at rest or after exercise. This may be more useful in mitochondrial and lipid storage myopathies. Infectious agents, 2M antibodies, genetic testing Electromyography might be able to confirm muscle or nerve disease. Muscle biopsy indicated in most cases
41
Inflammatory causes of myopathy
Immune mediated polymyositis (Boxers, Vizsla, Newfoundland, GSD) --> look for SLE MMM Extraocular myositis Dermatomyositis Infectious - Toxo, Neo, Lepto, Clostridial, FIV (Hepatozoonosis, Leishmaniasis, Borrelia)
42
Types of Muscular Dystrophy in dogs/cats, inheritance pattern if known
result in progressive muscle degeneration, repeated cycles of regeneration and progressive weakness Dystrophin mutations most common --> cytoskeletal protein that deficiency of causes altered membrane permeability --> cycles of degeneration and regeneration X-linked inheritance, variable pentrace. Golden Rets, Tibetan Spaniel, Rotti, GSP, Cocker Spaniel. Also reported in cats May affect cardiac muscle as well Progression of signs is variable, can be severe and fatal in young pups to later onset especially in cats. May cause megaoesophagus. Sarcoglycan deficiency - autosomal disease in Devon Rex and Boston Terrier --> does not cause CK elevation --> membrane instability leads to cellular apoptosis Laminin alpha 2 deficiency
43
Muscle fibre types
1 - slow twitch, long aerobic activities have more mitochondria, more Mgb for O2 storage. More prominent in anti-gravity muscles 2 - fast twitch: short fast bursts of activity Higher glycogen content,
44
Endocrine causes of myopathy and pathoegenesis
HAC - alters muscle metabolism reducing protein synthesis and increasing catabolism, predominantly affecting type 2 myofibres --> weakness and pseudomyotonia with chronicity HypoTH --> type 2 myofibre atrophy with chronicity that is responsive to Tx
45
Pathogenesis of hypoK myopathy in Burmese and other cats
The result of a mutation in NaCl transporter in DCT --> K+ wasting through alterations in electrolyte exchange Persistent hypokalemia --> hyperpolarisation of muscle cells and elevation in CK/AST --> generalised weakness manifesting as ventroflexion, head bob Genetic test available and can supplement to Tx affected individuals Consider looking for aldosterone excess in older animals
46
Metabolic causes of myopathy
Glycogen storage disease --> hypoglycaemia and glycogen accumulation in myofibres Lipid STORAGE dISEASE - LIPID DROPLETS IN MYOFIBRES Mitochondrial disorders - have concurrent neurological signs in many and elevated lactate PFK defect in English Springer spaniel results in haemolytic anaemia as well Congenital Myotonia of Min Schnauzers due to K channel defet Periodic paralysis due to hypokalaemia in cats