Electrodiagnostic criteria for Guillain–Barrè syndrome: A critical revision and the need for an update
Highlights
► In addition to axonal degeneration, the pathophysiology of acute motor axonal neuropathy (AMAN) is characterised by reversible conduction failure (RCF) which can be recognised only by serial recordings. ► The current electrodiagnostic criteria for Guillain–Barré syndrome (GBS) do not consider RCF, and may erroneously classify patients with AMAN with RCF as acute inflammatory demyelinating polyradiculoneuropathy or AMAN with axonal degeneration. ► More reliable electrodiagnostic criteria should be devised, taking RCF into account, focussing on temporal dispersion and including the requirement of serial recordings, for both diagnosis and prognosis.
Introduction
Guillain–Barré syndrome (GBS) is an acute, immune-mediated disorder of the peripheral nervous system and the most frequent cause of post-infectious neuromuscular paralysis worldwide with an incidence between 0.6 and 4 cases per 100,000 (Hughes and Rees, 1997). Although acute ascending paralytic illness has been recognised for centuries, only in 1916 Guillain, Barré and Strohl captured the critical features of the disease (Guillain et al., 1916). In the following decades, in spite of the precise original description, the range of disorders encompassed under the heading of GBS expanded and the eponym was used to indicate any type of acute polyneuritis. The term GBS was at risk of becoming meaningless and the need for exact diagnostic criteria was emphasised (Osler and Sidell, 1960). The occasion came with the mass swine flu vaccination of 1976 in the United States and the occurrence of more than one thousand cases of GBS, over 4000 legal actions filed against the federal government and more than three billions of dollars requested in damages (Asbury and Cornblath, 1990). The National Institute of Neurological and Communicative Disorders and Stroke was urged to promulgate diagnostic guidelines for GBS for field studies and as an instrument of tort law (Asbury et al., 1978). It should be underlined that in those years GBS was considered an inflammatory demyelinating polyneuritis due to a cell-mediated immune response towards a myelin protein antigen, in close analogy with experimental allergic neuritis, and was synonymous of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) (Asbury et al., 1969, Arnason and Soliven, 1993). In the 90s, GBS was recognised to include also two primary axonal subtypes: acute motor axonal neuropathy (AMAN) and acute motor and sensory axonal neuropathy (AMSAN) associated with antecedent Campylobacter jejuni infection and autoantibodies to gangliosides (Feasby et al., 1986, Yuki et al., 1990, Yuki et al., 1999, McKhann et al., 1993, Rees et al., 1995, Ho et al., 1995).
AIDP, AMAN and AMSAN are difficult to distinguish on clinical grounds alone and electrophysiology plays a determinant role in GBS diagnosis, classification of the subtypes and in establishing the prognosis. In the last three decades, different electrodiagnostic criteria sets have been proposed to diagnose AIDP and to differentiate primary demyelinating from primary axonal subtypes. This article focusses on the currently employed electrophysiologic criteria for the diagnosis of GBS subtypes, highlights the electrophysiologic and immunopathologic correlates of the axonal subtypes, shows the possible pitfalls in electrodiagnosis to finally conclude that more reliable electrodiagnostic criteria should be devised.
Section snippets
The electrodiagnostic criteria for AIDP
Historically, Lambert and Mulder in 1963 reported, in 49 GBS patients, that during the first 3 weeks of illness 14% had no abnormality of conduction, 61% had conduction velocity (CV) less than 70% of the normal mean and 25% had only prolonged distal motor latencies (DMLs). Asbury et al. (1978) summarised the electrophysiological features and highlighted the parameters useful for GBS diagnosis: (1) approximately 80% of patients have evidence of nerve conduction slowing or block at some point
The electrodiagnostic criteria for AMAN
Ho’s and Hadden’s criteria sets were based on the initial assumption that AMAN was characterised pathophysiologically by simple axonal degeneration (Table 1). The AMAN electrodiagnosis was based on no evidence of demyelination and reduced CMAP amplitude (<80% of the lower limit of normal) in two or more nerves (Fig. 1A). As it is known from observations in amyotrophic lateral sclerosis and axonal GBS that motor nerves with very low CMAP amplitudes due to axonal degeneration may show prolonged
Reversible conduction failure in AMAN
AMAN patients with antibody to gangliosides may show in some nerves rapidly reversible CB/slowing, which was named reversible conduction failure (RCF) (Kuwabara et al., 1998) (Fig. 1, Fig. 2). In these patients, CB in intermediate nerve segments promptly resolves, distal CMAP amplitudes rapidly increase and DMLs, when prolonged, return to normal values without the development of excessive TD and polyphasia of CMAPs. These features are clearly different from what is usually found in AIDP
The case of acute motor CB neuropathy
In 2003, Capasso et al. reported two patients who acutely developed symmetric weakness without sensory symptoms. Both patients had antecedent diarrhoea (C. jejuni was isolated from one) and high titres of IgG antibodies to GM1, GD1a and GD1b. Electrophysiological studies showed reduction of distal CMAP amplitudes and early partial motor CB in intermediate nerve segments with normal sensory conductions even at the sites of motor CB. Distal CMAP amplitudes normalised and CB resolved in 2–5 weeks,
Length-dependent conduction failure
In AMAN an abnormal amplitude reduction of proximal CMAP, which at serial recordings disappears because distal CMAP amplitude decreases and equalises proximal CMAP without development of excessive TD or other features of demyelination, may be observed (Fig. 4). This pattern was named length-dependent CMAP amplitude reduction and initially thought to be due to demyelinating lesions scattered along the nerve followed by axonal degeneration (van der Meché et al., 1988). However, this pattern may
Immunopathologic, electrophysiologic and clinical correlates in AMAN and AMCBN
A better understanding of the immunopathologic correlates of AMAN with axonal degeneration, AMAN with RCF and AMCBN comes from experimental models. Rabbits sensitised with GM1 or C. jejuni lipo-oligosaccharide develop anti-GM1 IgG antibodies and flaccid paralysis (Yuki et al., 2001, Yuki et al., 2004, Caporale et al., 2006). Immunohistochemistry showed sequential pathologic changes starting with IgG deposit at the nodes of Ranvier, complement activation with the formation of the membrane attack
The electrodiagnostic criteria of AMSAN
Feasby et al. described a total of eight patients with an acute motor and sensory neuropathy who met the clinical criteria for GBS, but in whom almost all motor and sensory nerves became unexcitable within 10 days after onset with the development of extensive denervation at EMG (Feasby et al., 1986, Feasby et al., 1993). Most of the patients required mechanical ventilation and the outcome was poor. Autopsies and nerve biopsies showed axonal degeneration without demyelination or inflammation.
Sensory conductions in AIDP, AMAN and AMSAN
Sensory conduction studies are not included in the electrodiagnostic criteria sets of AIDP or AMAN. However, abnormal sensory conductions were found in 85% of AIDP patients in the median and ulnar nerves and in 38% in the sural nerves, confirming that sensory nerve conduction, especially in the distal nerve segments, is impaired in almost all AIDP patients and that a normal or relatively spared sural response, in association with the appropriate clinical syndrome, is characteristic of AIDP (
Frequency of GBS subtypes and pitfalls in electrodiagnosis
The reported relative frequency of GBS subtypes varies around the world. In Europe and North America, AIDP is the most frequent totalling up to 90% of GBS (Hadden et al., 1998). The AIDP frequency decreases to 63% in Israel (Kushnir et al., 2008), to 46% in Pakistan (Shafquat et al., 2006), to 36% in Japan (Ogawara et al., 2000), to 24% in China (Ho et al., 1995) and to 22% in Bangladesh (Islam et al., 2010). The frequency of AMAN is 4% in Europe and North America (Hadden et al., 1998), 7% in
The need for a terminological consensus
Rapid resolution of CB and conduction slowing without development of excessive TD has been named RCF to distinguish it from classical demyelinating CB (Kuwabara et al., 1998). Other terms have been used to identify this phenomenon: functional CB, physiologic CB, CB in axonal neuropathy and axonal CB (Griffin et al., 1995, Kokubun et al., 2010, Hong et al., 2011). The CMAP amplitude reduction along the nerve length which disappears at follow-up because of reduction of distal CMAP amplitude has
The need for an update of electrophysiologic criteria
It is evident that there is the necessity to develop more reliable electrodiagnostic criteria to recognise AIDP and axonal GBS subtypes and to investigate their real frequency in different countries. As axonal GBS subtypes are more frequently associated with antibodies to gangliosides (Ho et al., 1999, Ogawara et al., 2000, Sekiguchi et al., 2012), one strategy could be to review serial electrophysiological studies from GBS patients who had preceding diarrhoea and antibodies against GM1, GM1b,
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