Distinguishing features of lower motor neuron syndromes

By Alex Yartsev - 30/06/2015

The mysterious whole-body weakness is a favourite topic of the CICM examiners. In fact, for some reason the college perpetually want the candidates to compare various "weakening" disease states to Guillain-Barre Syndrome. This has now come up so many times that the number of SAQs now merits an unordered list:

Question 3 from the second paper of 2018: compare GBS with acute transverse myelitis
Question 20 from the first paper of 2016: compare GBS with myasthenia gravis.
Question 10 from the first paper of 2013: compare GBS with those of critical illness polyneuropathy.

Therefore, from a cynical exam-oriented standpoint, it would be worth knowing a lot about GBS because in such questions one stands a reasonable chance of scoring at least half the marks. The other condition does not matter quite so much; although having said this, transverse myelitis has appeared in Question 10 from the second paper of 2019 GBS itself is discussed in greater detail elsewhere. It also receives a thorough LITFL treatment. In this chapter, only comparisons of GBS with other conditions will be listed. For those wishing to have a more thorough and official resource, Garg et al (2017) offer an excellent description of the lower motor neuron syndromes.

Differential diagnosis of lower motor neuron syndromes

This list of plausible differentials was generated with the aid of this excellent article by Garg et al (2017). No effert was expended to make this list comprehensive or definitive.

Vascular causes
- spinal cord infarction
Infectious causes
- Polyomyelitis
- Epidural abscess
- Herpes zoster
Neoplastic causes
- Spinal canal tumour
Drug-related causes
- B12 deficiency
- Steroid-induced myopathy
Hereditary distal neuropathies
- Spinobulbar muscular atrophy (Kennedy's disease)
- genetically heterogeneous distal hereditary motor neuropathies
Autoimmune/ immune-mediated diseases
- Guillain-Barré syndrome
- multifocal motor neuropathy (MMN)
- Chronic inflammatory demyelinating polyneuropathy (CIDP)
- Multiple sclerosis
- Myasthenia gravis
- Eaton-Lambert syndrome
- Myositis and dermatomyositis
Iatrogenic causes
- Critical illness polyneuromyopathy

Guillain-Barre vs CIPN

In brief:

CIPN is associated with a severe illness, whereas GBS is associated with a mild one.
CIPN does not have autonomic dysfunction, whereas GBS does.
CIPN will not have any specific CSF findings, whereas GBS will have raised CSF protein and perhaps even a monocytosis
CIPN nerve conduction studies will not show any decrease in conduction velocity, whereas in GBS the cardinal feature is decreased conduction velocity.

The college answer is presented as a table.

A much better table is presented in the 2006 article by Upinder Dhand (Table 3, pp. 1034).

If one were to cut and paste this table into one's SAQ answer, the college examiners would have been very pleased. So impressive is it, that I have taken the liberty of reproducing it here with minimal modification, without any permission but with the best of intentions.

Differences between GBS and CIP

GBS CIP History and Examination

Recent GI or resp illness. Progressive bilateral symmetric paralysis. Subtypes can be more localized e.g. MF opthalmoplegia and ataxia. Sensory involvement is common. Areflexic. Autonomic involvement may be present

Always occurs in association with a critical illness in particular severe sepsis. May have an association encephalopathy in early stages. It is a symmetrical weakness. May have muscle tenderness, hyporeflexic, diminished distal sensation Not associated with autonomic involvement

Investigations

Albuminocytologic dissociation in CSF. Identification of infection with campylobacter, mycoplasma, EBV,Varicella, CMV. Elevated csf IGG levels and possible serum antiganglioside antibodies

Elevated CK which may be transient.

Nerve conduction studies and EMG

When the demyelinating form is present, you get a reduction in conduction velocity as well as reduction in CMAP. In axonal forms however it is only the distribution of the findings that helps determine the diagnosis.

Clinical Features and Laboratory Findings
Critical-Illness Polyneuropathy, Guillain-Barre´ Syndrome, and Critical Illness Myopathy
	Critical illness polyneuropathy	Guillain-Barre	Critical Illness Myopathy
Clinical setting	Sepsis Multiorgan failure Septic encephalopathy	Antecedent viral illness Surgery Campylobacter jejuni HIV	Neuromuscular blocking drugs Corticosteroids Asthma Organ transplant
Motor weakness	Generalised and distal	Generalised and ascending	Generalised and proximal
Reflexes	Diminished	Absent	Preserved but weak
Cranial nerve palsy	Rare	Common	Absent
Dysautonomia	Normal autonomic function	Frequent dysautonomia	Normal autonomic function
Sensory deficit	Distal	Normal sensation, or slightly altered	Normal sensation
CK level	Normal	Normal	Elevated
Nerve conduction	Reduced CMAP and SNAP amplitude (compound muscle action potentials and sensory nerve action potentials)	Marked slowing, conduction block	Reduced CMAP amplitude Normal SNAP amplitude
Needle EMG	Abnormal spontaneous activity Reduced recruitment Large polyphasic motor unit potentials (MUPs)	Abnormal spontaneous activity Reduced recruitment Normal MUPs (early in disease)	Minimal spontaneous activity Early recruitment Small polyphasic MUPs;
Direct muscle stimulation	Normal	Normal	Absent or reduced
Muscle biopsy	Neuropathic changes	Neuropathic changes	Myopathic changes Thick myosin filament loss Muscle fiber necrosis

Guillain-Barre vs. myasthenia gravis

It would be possible but pointless to replicate the table above with myasthenia gravis plugged into the CIPN slot. Instead, a more directed approach will be taken, where clinical features, investigations and treatment are discussed in a tabulated form, best suited to answer Question 20 from the first paper of 2016.

Thus:

Clinical Features of Guillain Barre Syndrome vs. Myasthenia Gravis
Features	Guillain-Barre	Myasthenia Gravis
Clinical setting	Antecedent viral illness; usually with diarrhoea Surgery Campylobacter jejuni HIV	Autoimmune diseases, eg. SLE Thyroid disease Pregnancy Thymoma
Motor weakness	Generalised and ascending Symmetrical Not fatiguable Weakness of the limbs is mainly distal Weakness is progressive	Eye muscles are the first to go Ptosis and diplopia are early features Fatiguability (weakness worse after sustained exercise) Neck extensor and flexor muscles Weakness of the limbs is mainly proximal Weakness fluctuates
Sensory loss	Mild or absent	No sensory loss
Reflexes	Absent	Reflexes are usually normal
Cranial nerve involvement	Common	Earliest manifestations are cranial nerve signs (ptosis and diplopia) Facial muscles become involved early; patients become expresisonless
Dysautonomia	Common	Uncommon

Investigations of Guillain Barre Syndrome vs. Myasthenia Gravis
Guillain Barre Syndrome	CSF protein is elevated GQ1b antibodies (Miller Fischer variant) Nerve conduction studies: Marked slowing, conduction block Electromyography: Abnormal spontaneous activity, reduced recruitment, normal MUPs (early in disease).
Myasthenia Gravis	Ice pack test: neuromuscular transmission should improve with cold; ptosis should be reversed when the eyelid is cooled with an icepack. Edrophonium challenge: 10mg of edrophonium is given to transiently antagonise acetylcholinesterase. The myasthenic patient should immediately regain their muscle strength. Acetylcholine receptor antibodies: (AChr-Ab) Muscle specific tyrosine kinase antibodies (MuSK-Ab) Repetitive nerve stimulation: the characteristic finding is a progressive decline in the CMAP amplitude. Electromyography: the characteristic finding is "abnormal jitter".

Management of Guillain Barre Syndrome vs. Myasthenia Gravis
Guillain Barre Syndrome	Intubation and ventilation Corticosteroids are counterproductive. Plasmapheresis works: 4 exchanges of 1-2 plasma volumes, over 1-2 weeks. Plasma exchange for Guillain-Barre syndrome aims to clear the aetiological autoantibody from the bloodstream. In essence, we say "we have no idea which antibody is causing the demyelination, so we will get rid of all of them". The evidence seems to support a 5-treatment regimen; it seems that six treatments are no better than four. Because there is no missing proteins to replace, the exchanged plasma can be FFP or albumin - it does not seem to matter to the resolution of disease. However, because FFP has a slightly higher risk of transfusion reactions, so in general albumin is the recommended replacement solution, unless there are specific reasons to replace blood proteins. IV immunoglobulin is at least as effective as plasmapheresis. Dose is 2g/kg, over 5 days. The college answer mentions a Cochrane review, probably referring to Hughes et al (2014) who demonstrated that in severe disease IVIG within the first 2 weeks "hastens recovery as much as plasma exchange".
Myasthenia Gravis	Thymectomy Clear-cut indication in thymoma In absence of thymoma, likelihood of remission is still twice as high if you get your thymus removed (Gronseth et al, 2000) The college answersuggests that thymectomy is "not recommended routinely for age>60", which probably refers to the recent British guidelines (Sussman et al, 2015). They recommend thymectomy for under-45s within 2 years of diagnosis. Maintenance therapy: Acetylcholinesterase inhibitors: pyridostigmine is the mainstay Immunosuppressants: Corticosteroids Azathioprine Mycophenolate Cyclosporine Crisis therapy: Intubation and ventilation Escalate steroids: eg. prednisolone 1mg/kg/d Acetylcholinesterase inhibitors: pyridostigmine as IV preparation Plasmapheresis Only useful as a short-term treatment Only applicable in myasthenic crisis Useful as a bridge to slower-acting immunosuppressants Useful preoperatively before thymectomy No real difference in outcomes when compared to IVIG (Gajdos et al, 2002) Intravenous immunoglobulin Like plasmapheresis, only useful as a short-term treatment and only applicable in myasthenic crisis Usually given as 2g/kg over 5 days (i.e. 0.4g/kg per day) A single dose of 1g/kg is probably equally effective (Gajdos, 2005)

GBS vs. acute transverse myelitis

This was the topic of Question 3 from the second paper of 2018. Judging by the pass rate of ~60%, many did not have much of an idea about the latter disease. In case future exam candidates wish to explore the topic further, they will find it well-reviewed in the paywalled UpToDate article by Krishnan et al (2016). Another inaccessible but excellent article is the 2004 paper by Harzheim et al, trapped in the dungeons of Elsevier. The freegan may avail oneself of the LITFL summary page and this excellent review paper by West (2013) which Chris Nickson links.

The college question wanted the two compared in terms of "relevant history, the clinical features, and the relevant investigation findings". The official college answer to this SAQ was actually quite extensive, and likely represents an earnest effort from the examiners. It would be difficult to improve on such an answer. One can merely rearrange the categories and add some irrelevant tidbits here and there. The product appears below.

Guillian-Barre versus Acute Transverse Myelitis
Guillian-Barré	Acute Transverse Myelitis
Pathophysiology
Acute inflammatory demyelinating peripheral neuropathy, associated with infection such as: Antecedent viral illness; usually with diarrhoea EBV HSV Campylobacter jejuni HIV	Autoimmune inflammation of the spinal cord; may be idiopathic or associated with other illnesses: Usually occurs as a postinfectious complication Can fall within the spectrum of coexisting MS Can coexist with acute disseminated encephalomyelitis Autoimmune diseases are associated (eg. SLE, scleroderma, etc)
Typical features of history
Sub-acute onset Ascending pattern of clinical signs	Often, very rapidly progressing Weakness nadir is achieved within 4 hours in some cases (though some take as long as 21 days)
Power
Bilaterally decreased Symmetrical Weakness ascends over time	Bilaterally decreased Symmetrical Weakness remains at and below the level of the lesion "Pyramidal" preference: flexors of the legs and the extensors of the arms
Tone
Flaccid Later, remains flaccid	Initially flaccid Later, hypertonic spasticity
Reflexes
Diminished or absent Later, remain diminished	Depressed initially Hyperreflexia subsequently
Cranial nerves
Usually, not involved Miller Fischer variant involves (usually, medullary) cranial nerves	Usually, not involved When it forms a part of the MS spectrum, there may be optic neuritis
Autonomic features
Usually present	Not usually involved, unless the level of the lesion is high High lesions may present with spinal shock
Sensory findings
Sensation usually preserved or oly mildly affected	Sensation is usually absent There is usually a distinct symmetrical sensory level
CSF features
Raised protein Usually no white cells Antibodies (Anti-GM1) or GQ1b antibodies in the Miller Fischer variant	Raised protein Lymphocytosis Specific immunology (NMO, ADEM)
Bloods
Nothing specific	Aquaporin-4 IgG antibodies
Nerve conduction studies
Marked slowing, conduction block	Reduced amplitude sensory nerve action potential (SNAP) Pathological F-wave responses Decreased conduction velocity of motor and sensory nerves.
Electromyography
Abnormal spontaneous activity, reduced recruitment, normal MUPs (early in disease). Later, reduced	Reduced amplitude of motor (MUP) action potentials
MRI
Noncontrast MRI is essentially normal Gadolinium reveals surface thickening and contrast enhancement on the conus medullaris and the nerve roots of the cauda equina	Noncontrast MRI reveals cord oedema at the level of the lesion (but in 40%, looks totally normal) Gadolinium-enhancing signal abnormality extending over one or more cord segments. Lesions ccupy most of the transverse diameter of the cord (2/3rds)
Management
Corticosteroids are counterproductive. Plasmapheresis works: 4 exchanges of 1-2 plasma volumes, over 1-2 weeks. IV immunoglobulin is at least as effective as plasmapheresis. Dose is 2g/kg.	High dose steroids arre first line (methylpred, 1g/day for 3-7 days) Plasmaphersesis is second-line a(5 exchanges over 10 days) Cyclophosphamide is occasionally recommended IV immunoglobulin is usually not recommended (anecdotal evidence only)

Electrophysiology findings in Guillain-Barre Syndrome

The nerve conduction findings of GBS have been asked about specifically in Question 2 from the first paper of 2019. The following were derived from a guideline by Asbury & Cornblath (1990):

Nerve conduction slowing in 80% of cases at some point during the illness (velocity is usually less than 60% of normal), which is consistent with demyelination
Specific characteristic findings:
- Partial conduction block
- Decreased M-responses
- Temporal dispersion
- Prolonged distal latencies
- Prolonged or absent F waves and H-reflexes
20% of cases have normal conduction studies
Sensory conduction studies are occasionally abnormal (reduction in evoked amplitude)
Axonal disease features absent or severely reduced compound muscle action potential amplitudes, with preserved conduction velocities

References

Oh's Intensive Care manual:

Chapter 57 (pp. 617) Neuromuscular diseases in intensive care by George Skowronski and Manoj K Saxena

van den Berg, Bianca, et al. "Guillain-Barre syndrome: pathogenesis, diagnosis, treatment and prognosis." Nature Reviews Neurology 10.8 (2014): 469-482.

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Harzheim, Michael, et al. "Discriminatory features of acute transverse myelitis: a retrospective analysis of 45 patients." Journal of the neurological sciences 217.2 (2004): 217-223.

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