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NEUROLOGY > PNS, NMJ, myopathy dz > Flashcards

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

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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
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3
Q

Lesions of diabetic neuropathy and expected electrodiagnostic changes

A

Demyelination predominates

MNC studies find reduced conduction velocity

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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

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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

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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)

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7
Q

Causes of polyneuropathy in insulinoma

A

Autoimmune - molecular mimicry suspected

Also hypoglycemia

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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

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9
Q

Toxins that can cause polyneuropathy

A

Heavy metal

Vincristine and Cisplatin through microtubule damage

Organophosphates

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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

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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

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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

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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

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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

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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

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16
Q

Pre-synaptic causes of NMJ dysfunction

A

ick

Snake

Botulism

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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

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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)

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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
Q

Comparative incidence of thymic mass in MG dogs vs caats

A

3% vs 52% in cats

26
Q

Pharmacological testing for Myaesthenia gravis

A

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
Q

Adverse effects of ACh esterase inhibitors

A

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
Q

Electrodiagnostic findings in acquired MG

A

Normal EMG and evoked CMAP

But decremental decrease in CMAP with repetitive nerve stimulation

29
Q

Evidence for use of immunosuppression in acquired MG

A

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
Q

Mainstay of acquired MG treatment and differences in JVIM 2022 Tx recommendations in cats vs dogs

A

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
Q

Prognosis in thymoma associated MG

A

Thymectomy required to achieve complete remission

–> NB anaesthesia carries high risk in MG patients and can see clinically relevant post-op exacerbation

32
Q

Outcome in dogs vs cats

A

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
Q

Definition of disease remission in acquired MG

A

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
Q

Types of congenital myaesthenic syndromes and their pathogenesis /findings

A

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
Q

Diagnosis of Congenital Myasthenic syndrome

A

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
Q

Treatment in congenital myasthenic syndromes

A

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
Q

Effect of Organophosphate toxicity

A

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
Q

Cause and symptoms of Labrador retriever episodic collapse

A

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
Q

Typical findings of myopathy

A

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
Q

Diagnostic evaluation for suspected myopathy

A

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
Q

Inflammatory causes of myopathy

A

Immune mediated polymyositis
(Boxers, Vizsla, Newfoundland, GSD)
–> look for SLE

MMM

Extraocular myositis

Dermatomyositis

Infectious - Toxo, Neo, Lepto, Clostridial, FIV
(Hepatozoonosis, Leishmaniasis, Borrelia)

42
Q

Types of Muscular Dystrophy in dogs/cats, inheritance pattern if known

A

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
Q

Muscle fibre types

A

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
Q

Endocrine causes of myopathy and pathoegenesis

A

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
Q

Pathogenesis of hypoK myopathy in Burmese and other cats

A

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
Q

Metabolic causes of myopathy

A

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

NEUROLOGY (9 decks)

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