Neuropathies

Question 1

Guillain-Barre Syndrome

Background and epidemiology

Answer 1

• Inflammatory, immune-mediated disease of PNS (peripheral nerves and nerve roots)
• Typical presentation:
  -Acute onset weakness & sensory symptoms in the lower limbs that ascend to involve the upper limbs and cranial nerves
• Most common cause of acute flaccid paralysis
• All age froups affected, incidence increases with increasing age
• Slightly > men
• Lifetime risk 1/1000
• **Subtypes (electrophysiology)
• **Acute inflammatory demyelinating polyradiculopathy (AIDP)
• Acute motor axonal neuropathy (AMAN)
• Acute motor sensory axonal neuropathy (AMSAN)
• **Clinical subtypes
• **See attached photo

Question 2

GBS

Clinical features

Answer 2

> 95% monophasic course
**2/3rds antecedant respiratory or diarrhoeal illness 4-6 weeks prior to neurological symptom onset
**Campylobacter most common, also CMV, EBV, myocoplasma, haemophilus, hepatitis E, ZIKA, COVID
Less common = non infectious triggers -> surgical, vaccination, immunosupression, pregnancy (risk of GBS higher with influenza than with influenza vaccines).
If GBS within 6-8 weeks of any vaccine -> recommend that the vaccine not be given again
Neurological nadir reached within 4 weeks (usually 2 weeks)
Recovery usually beings within 2-4 weeks of the nadir

Question 3

GBS

Pathology and pathogenesis

Answer 3

• **AIDP, AMAN and AMSAN - common pathological features
• **Complement activation
• Upregulation of Fc receptors for IgG
• Macrophage induced contact dependent injury. Schwann cell/myelin injury (AIDP), axon injury (AMAN/ASMAN)
• **acute autoimmune disorder triggered by environmental agents in genetically susceptible individuals
• Post-infectious molecular mimicry hypothesis
• **Antiganglioside antibodies considered pathogenetically relevant to AMAN& Miller Fisher syndrome
• Pathological relevance of antiglycan antibodes in AIDP is questionable

Question 4

Notes on AIDP

Answer 4

• Most common - up to 90%
• Initial symptoms - sensory or pain (radicular, back pain, paraesthesia) usually without sensory examination findings
• Predominantly motor polyradiculopathy with acute progressive symmetric weakness involving proximal and distal muscles - classic pattern ascending weakness but can start proximally and be confined to lower limbs
• **Reduced or absent DTRs
• 25-30% respiratory muscle weakness requiring ventilation
• **>50% cranial nerve involvement -> facial weakness, ophthalmoplegia, dysphagia, altered taste
• Dysautonomia in majority with variable severity -> sinus tachy, sinus arrhythmia, labile BP, orthostatic hypotension, abnormal sweating & pupil abnormalities
• Sphincter dysfunction can occur

Question 5

Notes on AMAN & AMSAN

Answer 5

**AMAN
**<10%, most common axonal form
Higher incidence Asia, Centra & South America
Motor weakness starting in lower limbs, can start in upper limbs or cranial nerves
Loss of reflexes corresponds to severity of weakness
- Sparing of muscle afferent fibres predominantly affected in AIDP
- Reflexes may be normal or increased
Minimal sensory impairment
Autonomic dysfunction less common than with AIDP

Question 6

Notes on Miller Fisher syndrome and Bickerstaf brainstem encephalitis

Answer 6

**Miller Fisher syndrome
**Triad of ophthalmoplegia, ataxia and areflexia
Often presents with diplopia
Sgnificant proportion do not have the classic triad or have additional features/overlap with classic GBS

**Bickerstaff brainstem encephalitis
**Ophthalmoplegia, ataxia, altered consciousness +/- hyperreflexia

Question 7

Differential diagnosis for GBS

Answer 7

**Infections affecting anterior horn cells
**West Nile virus, enteroviruses, rabies, polio
**NMJ disorders
**Myasthenic crisis, botulism
**Acute severe myopathies
**Immune-mediated necrotising myopathies, acute myositis, rhabdomyolysis
**Periodic paralysis
Acute/subacute neuropathies & polyradiculopathies
**Inflammatory.immune -> acute onset CIDP, vasculitic, neuropathy, sensory ganlionitis
Critical illness neuropathy
Metabolic -> DM, porphyra
Nutritional - thiamine deficiency
Infection - HIV, herpes viruses (CMV), lyme disease
Toxic - organophosphate, hexacarbons

Question 8

GBS

Diagnosis & Investigations

Answer 8

• Clinical features most important for diagnosis
• **Investigations
• **CSF - may not be positive in the first week.
• Normal cell counts, elevated protein, protein >80% after the first wek
• Nerve conduction studies and EMG -may not be diagnostic in the first week
• Imaging

Question 8

GBS

Diagnosis & Investigations

Answer 8

• Clinical features most important for diagnosis
• **Investigations
• CSF - may not be positive in the first week.
• **Normal cell counts, elevated protein, protein >80% after the first wek
• Mild increase in WCC in 10-15% (<50)
• IVIG can increase CSF WCC and protein if LP done after treatment commences
  **Nerve conduction studies and EMG -may not be diagnostic in the first week
• Imaging
• • Not routine, may be used to exclude differentials
• Gadolinium enhanced MRI -> nerve root enchancement - not specific but sensitive for GBS
• -Peripheral nerve ultrasound -> enlarged cervical nerve roots may be seen early in disease course

Question 8

Findings on NCS and EMG in GBS

Answer 8

**Early NCS findings
**Normal
Prolonged F waves (or absent responses) reflecting involvement of proximal nerve trunks/roots
AIDP: sural sparing pattern - preserved sural response, upper limb sensory responses absent or reduced amplitude
**Other NCS findings peak at 2 weeks post symptoms and depend on subtype
**AIDP: Prolonged distal motor latencies, reduced motor nerve conduction velocities, prolonged F wave latencies (or absent responses). Decreased compound muscle action potential amplitudes
ASMAN: Decrease compound muscle action potential amplitudes & decreased sensory nerve action potential amplitudes

Question 8

Antibody tests in GBS

Answer 8

**Miller Fisher
**GQ1b antibodies in 80%

Question 9

GBS

Management

Answer 9

**General principles slide attached
IVIG & PLEX
**Hasten recovery and equally efficacious
40-50% do not have a clinical respose
Combination treatment discouraged (not evidence for additional benefit)
2nd course of IVIG not beneficial in severe disease - A/W more adverse events including thromboembolic events
Early treatment preferable as may limit endoneurial inflammation & nerve injury
No clear guideline/recommendation of what to do with treatment failure

**IVIG
**Hastens recovery when given within 2 weeks of onset
Considered 1st line

**PLEX
**Evidence for hastening recovery when given up to 4 weeks after onset

Question 10

GBS

Treatment related fluctuations

Answer 10

**Definition
**Worsening of at least 1 point on the GBS disability scale after initial improvement or stabilisation within 8 weeks of disease onset
Occurs in up to 10% of patients treated with IVIG and PLEX
No evidence based treatment recommendation
General consensus is retreatment with the original treatment

Question 11

GBS

Outcomes and Prognosis

Answer 11

Monophasic >95%, recurs in <5%
Recovery usually within 2-4 weeks of nadir, can be delayed up to 6 months. Most completly recovery over 6-12 months
Residual deficits -> fatigue, pain, weakness, 20% unable to walk independently
Poor prognostic factors - age > 40 years, preceding diarrhoea, short interval from onset to nadir, mechanical ventilation, high grade neurological deficits on the GBS disability scale, persistently low CMAP amplitudes
Mortality rate 3-7%. Increased risk with advanced age, disease severity, mechanical ventilation, systemic infection , cardiopulmonary complications
Causes of death -> arrest from autonomic disturbance, respiratory failure, respiratory infection, pulmonary embolism

Question 12

Notes on newer developments in GBS

Answer 12

**Complement inhibitors
**Eculizumab (humanised Ab against C5)
**Neonatal Fc receptor inhibitors
Hypersialylated IVIG

Question 13

Notes on GBS associated with COVID infection and vaccination

Answer 13

**COVID infection related cases
**Common presentation sensorimotor demyelinating GBS with frequent facial palsy
Time between infection onset & neurological symptoms suggests a post-infectious mechanism

**COVID vaccination related cases
**GBS clinical variant noted to be prominent - bilateral facial weakness with paraesthesiasis
4 cases thought to be related to the AstraZeneca vaccine within 3 weeks

Question 14

Classification of peripheral nervous system

Answer 14

• Cranial nerves (except optic nerve which is an extension of the central nervous system)
• Spinal nerve roots
  ○ Dorsal root ganglia
• Peripheral nerve trunks, branches
• Autonomic nerves
• By convention, motor neurones (anterior horn cells) and their diseases are considered separately:
  ○ Neuronopathies vs neuropathies
  § Neuronopathies
  □ Anterior horn cell - motor neurone disease
  □ Dorsal root ganglia - sensory neuronopathy

Question 15

Classification of nerve fibres

Answer 15

**General rules
**Motor = large, myelinated
Sensory - touch, vibration, position -> large, myelinated fibres
Sensory - pain and temp - smaller, less myelinated/unmyelinated fibres
Autonomic - thin, unmyelinated

Question 16

Epidemiology of peripheral nerve disorders

Answer 16

• DM most common in developed countries

Question 17

Demyelinating vs axonal polyneuropathies

Answer 17

**Demyelinating
**E.g. GBS, CIDP, Paraprotieinaemia, hereditary motor sensory neuropathy , Refsum’s disease, HIV, amiodarone
- Usually acquired inflammatory conditions
- Often patchy, proximal
- Relatively rapid recovery - weeks to months
- Hereditary conditions of myelin usually diffuse and progressive

**Axonal
**E.g. alcohol, DM, Vasculitis, vitamin deficiencies
- Wallerian degeneration - axon and myelin sheath distal to injury degenerate
- Length dependent - most distal part of axon degenerates (most toxic and metabolic causes)(longest nerve fibres ares ones that reach feet -> first site of symptoms in a length dependent neuropathy)

Question 18

Clues in a systemic exam for peirpheral neuropathy

Answer 18

• Mees lines (transverse bands in nail beds)- Arsenic or thallium poisoning
  
  • Skin and mucous membranes for vasculitis rashes, livido reticularis
  • Alopecia - SLE, hypothyroidism, thallium poisoning, amyloidosis
  • Distal calf hair loss - distal symmetric axonal polyneuropathy
  • Nerve enlargement/thickened nerves: suggests demyelinating neuropathy, can also be seen in neoplasia, neurofibromatosis, leprosy
  • Optic atrophy - inherited neuropathies, vitamin B12 deficiency
  • General exam - orthostatic hypotension - autonomic involvement
  • Check vital capacity

Question 19

Clues in cranial nerve exam for peripheral neuropathy

Answer 19

○ Anosmia seen in B12 deficiency
○ Optic atrophy - leucodystrophies, B12 deficiencies
○ Abnormal pupils - impaired pupillary response to light - parasymathetic dysfunction in diabetes, GBS
○ Ophthalmoplegia - Miller fisher, botulism
○ Facial weakness - can be seen in GBS, sarcoidosis, Lyme disease
○ Facial numbness - Sjogren’s syndrome

Question 20

Clues on sensory examination for peripheral neuropathy

Answer 20

**Large fibre evaluation
**Vibration, proprioception, light touch, Romberg’s test

**Small fibre evaluation
**Pinprick, temperatire
Preserved reflexes

**Identify patterns
**Mononeuropathy
Distal symmetric polyneuropathy ?length dependent
Mononeuritis multiplex
Plexopathy
Radiculopathy
Genglionopathies - diseases affecting the dorsal root ganglion e.g. paraneoplastic( anti-Hu), Sjogren’s, HIV, heavy metals, cisplatin - non length dependent severe sensory loss including trunk and face, usually asymmetric

Question 21

Differentials for motor vs sensory neuropathy

Answer 21

**Motor
**GBS, CIDP, Multifocal motor neuropathy
Intoxication: lead, amiodarone, botulism
Porphyria, hereditary neuropathies

Motor less common than sensory, tend to affect proximal nerves first (exception if left which tends to affect common peroneal nerve and radial nerve distribution first)

**Sensory
**DM, B12 deficiency, uraemia, B6 intoxication
HIV, leprosy
Hereditary, amyloid
Sojogren’s sarcoid, paraneoplastic

Question 22

Differentials for autonomic vs somatic small fibre vs demyelinating polyneuropathies

Answer 22

**Autonomic **Autoimmune, GBS, botulism, porphyria, toxic, HSAN, DM, amyloid, paraneoplastic **Somatic small fibre **DM, IGT Alcohol Amyoid, HIV, Sjogren's, SLE, sarcoid HSAN Fabry **Demyelinating **CMT 1, HNPP GBS, CIDP Systemic illness (IBD, infection, CTD) MMM Paraproteinaemia

Question 22

Conditions A/W multiple entrapment neuropathies

Answer 22

1. HNPP 2. Amyloidosis 3. Myxoedema 4. DM 5. Acromegaly

Question 23

Notes on EMG/NCS in assessment of polyneuropathies

Answer 23

- Standard for evaluation fo large fibre neuropathy, normal in pure small fibre neuropathy - Help exclude muscle, radicular, motor neurone disesae - Differentiates axonal vs demyelinating - At least two limbs assessed SNAP = sensory nerve action potential CMAP = compound muscle action potential Axonal neuropathy = loss in amplitude of nerve action potentials, on needle EMG evidence of denervationof muscles Demyelinating = slowed conduction velocities, prolonged distal latencies, conduction block, temporal dispersion and prolonged minimym F wave latencies **Nerve conduction studies normal in small fibre neuropathy

Question 24

Utility of nerve biopsy in assessment of polyneuropathy

Answer 24

Best yield: acute/subacute, asymmetric, multifocal progerssive neuropathy 1. Mononeuritis multiplex, vasculitis, sarcoid 2. CIDP 3. Leprosy 4. Infiltrative disease (amyloid, neoplastic) 5. Diffuse progressive cryptogenic neuropathies Adverse effects: 1/3rd subjective and objective sensory findings - usually resolve over time e.g. pain

Question 25

Notes on diabetic neuropathy

Answer 25

- Axonal, length dependend - Pain common feature (including pre-diabetic) **Symmetric **Distal, symmetric axonal sensorimotor neuropathy - commonest Small fibre, painful neuropathy Autonomic neuropathy **Assymetric **Cranial neuropathy Multifocal or entrapment Radiculoplexus neuropathy - diabetic amyotrophy

Question 26

Notes on alcohol related neuropathy

Answer 26

- Length dependent sensory > motor, autonomic dysfunction - Often very painful - Treatment: cessation of alcohol, balanced diet, repletion of vitamins, neuropathic pain meds, opioids

Question 27

Notes on paraproteinaemia and neuropathy

Answer 27

- Monoclonal gammopathies more common in paitnets with neuropathy than general population - IgM more common - Anti-MAG antibody A/W DADS phenotype (Distal acquired demyelinating symmetric) - Anti-Gd1b antibody A/W sensory ataxic neuropathy and with cryoglobulinaemia - IgG paraprotein A/W myeloma, amyloidosis, POEMS syndrome (polyneuropathy, endocrinopathy, monoclonal protein and skin changes) Serum immunofixation electrophoresis more sensitive than serum protein electrophoresis

Question 28

Notes on Vitamin B12 deficiency

Answer 28

**Specific clinical features **Sudden onset Concomitant involvement of upper and lower limbs or onset in the upper limbs Painless sensory dominant symptoms Explained by concomitant myelopathy and neuropathy in B12 deficiency Recommend testing B12 and metabolites (MMA/Hcy) in patients with distal symmetric neuropathy - Serum B12 not sufficiency sensitive to diagnose deficiency - Metabolite testing reveals B12 deficiency in 5-10% of those with low normal B12 level (200-500) - Test B12 metabolites in neuropathy patients with a low normal B12 or a raised mean cell volume, and in all neuropathy patients with clinical features that specifically suggest B12 deficiency

Question 29

Notes on CIDP (Chronic inflammatory demyelinating polyradiculopathy)

Answer 29

- Acquired immune neuropathy, relapsing or progressive over > 8 weeks - Segmental inflammatory demyelinating and remyelination of peripheral nerves or nerve roots Classically: symmetric, motor predominant, proximal + distal, areflexic Variants: assymmetric/multifocal, sensory-dominant, DADs Diagnosis: EMG, CSF, MRI, nerve biopsy Treatment: steroids, IVIG, PLEX

Question 30

Hereditary motor and sensory neuropathy (Charcot-Marie-Tooth Disease) - features

Answer 30

1. Pes cavus 2. Distal muscle atrophy due to peripheral nerve degeneration; does not usually extend above th elbows or above the middle third of the thighs; peroneal muscle atrophy gives the legs the shape of an inverted champagne bottle 3. Absent reflexes 4. Slight or no sensory loss in the limbs 5. Thickened nerves 6. Optic atrophy, Argyll Robertson pupils (rare)