Department of Neurology, Inha University Hospital, Inha University College of Medicine, Incheon, Korea
Correspondence to Soonwook Kwon Department of Neurology, Inha University Hospital, Inha University College of Medicine, 27 Inhang-ro, Jung-gu, Incheon 22332, Korea Tel: +82-32-890-3708 Fax: +82-504-036-1753 E-mail: sw1214kwon@inha.ac.kr
• Received: July 8, 2025 • Revised: September 5, 2025 • Accepted: October 27, 2025
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Since 2020, updates in the diagnostic criteria for various neuromuscular diseases have emerged by advancements in electrophysiological studies, biomarker research, and imaging modalities. These developments reflect an effort to improve diagnostic accuracy and allow for earlier intervention. This review summarizes the most recent revisions in the diagnostic criteria for amyotrophic lateral sclerosis, primary lateral sclerosis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, and myasthenia gravis.
Neuromuscular diseases (NMDs) are a broadly defined group of disorders that all involve injury or dysfunction of peripheral nerves, neuromuscular junction, or muscle.1 NMDs arise from pathological processes targeting specific anatomical sites, including the motor or sensory neuron cell bodies (e.g., amyotrophic lateral sclerosis [ALS], sensory ganglionopathies), axons (e.g., axonal peripheral neuropathies, brachial plexopathies), Schwann cells (e.g., chronic inflammatory demyelinating polyradiculoneuropathy [CIDP]), the neuromuscular junction (e.g., myasthenia gravis [MG], Lambert-Eaton myasthenic syndrome), or the muscle itself (e.g., inflammatory myopathies, muscular dystrophies). In some conditions, such as motor neuron diseases, there is concomitant involvement of the central nervous system, although the majority of neuromuscular diseases are confined to the peripheral nervous system.
Timely and precise diagnosis plays a critical role in facilitating the early initiation of appropriate therapeutic interventions, while concurrently minimizing the utilization of unnecessary diagnostic procedures.2,3 In recent years, advancements in electrodiagnostic studies, biomarker research, and neuroimaging have been achieved to improve the early and accurate diagnosis of NMDs.
This review aims to compare recent updates to the diagnostic criteria of five major neuromuscular disorders (ALS, primary lateral sclerosis [PLS], Guillain-Barré syndrome [GBS], CIDP, and MG) with their previous frameworks. In addition, this review provides an overview of recent advances in electrophysiological studies that support the diagnostic workup of these conditions.
AMYOTROPHIC LATERAL SCLEROSIS
ALS is a progressive neurodegenerative disorder that affects both upper (UMN) and lower motor neurons (LMN).4 It is characterized by a clinical course that typically begins in a focal region and gradually spreads, accompanied by muscle atrophy, fasciculations, and bulbar symptoms such as dysarthria and dysphagia. Progressive respiratory decline is common in ALS and a leading cause of morbidity and mortality, with forced vital capacity decreasing most rapidly by approximately 2-3% per month after reaching an inflection point at around 63% predicted.5 Respiratory complications, particularly respiratory failure and pulmonary infections, account for the majority of deaths, and the median survival is approximately 2-5 years from symptom onset, although it may be as short as 1.4 years in respiratory-onset ALS.6
The diagnostic criteria for ALS have undergone several revisions over the past decades to improve diagnostic sensitivity and reduce delays. The El Escorial criteria (EEC), established in 1994 by the World Federation of Neurology, were based on the identification of UMN and LMN signs across defined anatomical regions, and classified patients into four categories: suspected, possible, probable, and definite ALS (Table 1).7 Although these criteria offered high specificity, their complexity and limited sensitivity, particularly in early-stage or bulbar-onset, often led to diagnostic delays and confusion among both clinicians and patients.8 To assess the limitations, the revised EEC were introduced in 2000, incorporating electromyography (EMG) findings through the addition of the “laboratory-supported probable ALS” category (Table 1).9 Although the revised EEC (rEEC) achieved high specificity, their limited sensitivity in early-stage ALS, partly due to the strict requirement for active denervation findings (fibrillation potentials and positive sharp waves) for LMN signs, led to diagnostic delays and hindered patient enrollment in clinical trials, particularly in bulbar-onset cases.10,11 In 2008, the Awaji criteria were proposed to further enhance diagnostic yield by integrating EMG features as equivalent to clinical signs of lower motor neuron dysfunction (Table 1).12 Notably, fasciculation potentials were recognized as valid markers of active denervation. The Awaji criteria eliminated the laboratory-supported probable category but retained the possible, probable, and definite classifications. Compared to the rEEC, the Awaji criteria demonstrated improved diagnostic sensitivity, particularly in patients with bulbar-onset ALS.13
Limitations of the rEEC and Awaji criteria are their complexity with multiple diagnostic categories, which contributes to diagnostic errors and low interrater reliability, limiting their applicability in multicenter trials.13 In addition, up to 22% of patients classified as "possible ALS" may die without ever meeting criteria for "probable" or "definite" ALS, excluding them from clinical trials.14 Furthermore, patients with UMN signs in two regions but no LMN involvement may be misclassified as possible ALS, though they may ultimately have PLS, affecting diagnostic accuracy and research outcomes.
The Gold Coast criteria were developed to address the complexity and limitations of prior ALS diagnostic criteria including the rEEC and Awaji criteria.15 These new criteria define ALS based on three core components (Table 1): 1) progressive motor impairment following previously normal function, 2) evidence of UMN and LMN dysfunction in at least one region (or LMN signs in two regions), and 3) exclusion of mimicking conditions. LMN involvement can be demonstrated clinically or through EMG findings (e.g., fibrillation, fasciculation, or chronic neurogenic changes).
Compared to previous diagnostic criteria, the Gold Coast criteria demonstrated consistently higher sensitivity across ALS subtypes, including bulbar- and lower limb-onset disease. 11 This represents a significant improvement over the rEEC and Awaji criteria, particularly when considering only the “definite” or “probable” diagnostic categories. Despite the increase in sensitivity, the Gold Coast criteria maintain a level of specificity comparable to earlier standards in certain cohorts, although a tendency toward lower specificity has been observed. Reported sensitivities for the Gold Coast criteria range from 88.2% to 96.6%, exceeding those of the revised El Escorial (62.2-85.1%) and Awaji (81.1-85.3%) criteria, whereas specificities, although comparable in some studies (88.5% vs. 95.5-96.2%), have been markedly lower in others (17.4%), potentially yielding an unacceptable rate of false positive ALS diagnoses for a disease of this severity.16-19 This balance between sensitivity and specificity is of particular importance in clinical practice, where early recognition of ALS can lead to more timely interventions, improved multidisciplinary care, and enhanced patient planning.
Furthermore, the improved sensitivity observed in early-stage disease and in patients with shorter symptom duration may facilitate earlier diagnosis and timely intervention.11 In addition, the simplified, single-tiered structure of the Gold Coast criteria improves clarity for both clinicians and researchers. This streamlined approach reduces diagnostic ambiguity, enhances interrater reliability, and facilitates standardized enrollment in clinical research, ultimately supporting broader applicability in both real-world clinical settings and controlled trial environments.
Despite these advantages, the Gold Coast criteria has still several limitations. First, similar to previous diagnostic criteria, the confirmation of UMN signs in the Gold Coast criteria depends on clinical evidence; increased deep tendon reflex, presence of pathological reflexes, spasticity, and slowed poorly coordinated voluntary movement. However, increased deep tendon reflex and presence of pathological reflexes may be obscured due to muscle wasting, weakness, or degeneration of descending excitatory motor pathways from propriospinal projections.20,21 Accordingly, the objective biomarkers or neurophysiological techniques to support the detection of UMN dysfunction remains an important area for further refinement of diagnostic criteria. Second, differentiating ALS from its clinical variants presents an ongoing diagnostic challenge. Although it remains unclear whether progressive muscular atrophy (PMA) represents a distinct entity from ALS, corticospinal tract degeneration is absent in approximately 50% of PMA at autopsy, and the frequency of ALS-related genetic mutations often differs from that observed in ALS.22 In addition, although the Gold Coast criteria improve the exclusion of PLS, they may inadvertently delay the diagnosis of ALS in patients who initially present with a UMN-dominant phenotype.
PRIMARY LATERAL SCLEROSIS
PLS is a rare upper motor neuron disorder characterized by slowly progressive spasticity and weakness, typically beginning in the lower limbs and presenting around the age of 50, with a male predominance.23 Compared to ALS, PLS has a more indolent course and is less frequently associated with the need for gastrostomy or non-invasive ventilation. Additional clinical features may include bladder instability, extrapyramidal symptoms, and frontotemporal dysfunction, though the latter is less common than in ALS. Pathologically, PLS shows minimal TDP-43 involvement, distinguishing it from ALS and supporting its classification as a distinct clinical entity.24
The diagnostic criteria for PLS have evolved significantly over time. In 1945, Stark and Moersch first described PLS as a progressive UMN syndrome without sensory or LMN involvement, based purely on clinical observation.25 In 1992, Pringle et al.26 proposed more structured criteria, requiring at least 3 years of isolated UMN symptoms and allowing only minor, non-progressive EMG abnormalities. Additionally, several ancillary findings have been proposed to support the presence of UMN dysfunction, including abnormalities in motor evoked potentials, focal atrophy of the precentral gyrus on magnetic resonance imaging (MRI), and decreased glucose metabolism in the pericentral region as demonstrated by positron emission tomography (PET) scan. In 2006, Gordon et al.27 recommended a longitudinal approach, suggesting that a definitive diagnosis of PLS should only be made after 4 years of persistent UMN signs without LMN involvement. This strategy aimed to improve the accuracy of distinguishing PLS from early-stage UMN-predominant ALS.27
The 2020 international consensus diagnostic criteria for PLS represent a significant refinement over earlier standards. Gordon criteria required a prolonged symptom duration, at least 3 years of isolated UMN signs, before a definitive diagnosis could be made, leading to substantial diagnostic delays and limiting patients’ access to clinical trials (Table 2).28 In addition, the criteria also focus on the classic symmetric, lower-limb onset form and overlook atypical variants, apply a binary classification without intermediate stages, and rely solely on clinical follow-up without integrating biomarkers such as MRI, diffusion tensor imaging, or transcranial magnetic stimulation. In contrast, the 2020 criteria introduced a tiered classification system, including the categories of “probable PLS” for patients with 2 years to 4 years of progressive UMN dysfunction and “definite PLS” for those with ≥4 years of symptoms. This change facilitates earlier diagnosis and allows for closer monitoring and inclusion in research at earlier stages of disease.
EMG abnormalities can complicate the distinction between PLS and UMN-predominant ALS, as some patients with PLS may exhibit minor, non-progressive denervation signs. Pringle et al.26 allowed limited fibrillations or increased insertional activity in a few muscles, while Gordon et al.27 reported that some patients with mild EMG abnormalities progressed to ALS within 3-4 years. However, subsequent studies have not consistently confirmed such a transition, and most minimal EMG findings have remained clinically stable. Several large cohort studies found no significant clinical differences between patients with normal and mildly abnormal EMG results. Reflecting these observations, minimal EMG abnormalities confined to a few muscles are now generally considered acceptable. This perspective supports the inclusion of a “probable PLS” category for patients with progressive UMN signs of 2 years to 4 years duration, allowing for earlier diagnosis and eligibility for clinical trials.
Emerging neurophysiological and neuroimaging modalities provide supportive evidence for PLS and may assist in differentiating it from UMN-predominant ALS. Techniques such as transcranial magnetic stimulation, beta-band intermuscular coherence, and magnetoencephalography offer quantitative assessments of UMN dysfunction, while lower neurofilament levels and distinct cerebrospinal fluid (CSF) chitinase profiles reflect the slower progression characteristic of PLS.29,30 Compared with UMN-predominant ALS, PLS more frequently exhibits marked “knife-edge” atrophy of the precentral gyrus, and iron-sensitive T2*-weighted MRI demonstrates motor cortex hypointensity in nearly all PLS patients versus approximately three-quarters of those with UMN-predominant ALS.31 T2-weighted hyperintensity of the corticospinal tracts can be observed in both conditions; however, its early appearance (within roughly 9-10 months of symptom onset) is more often reported in UMN-predominant ALS and is associated with a threefold faster disease progression.32 Diffusion tensor imaging shows that, compared with ALS, PLS has greater involvement of the rostral corticospinal tracts and motor callosal fibers, particularly those linking the primary motor cortex and supplementary motor area, suggesting early cortical degeneration and interhemispheric spread.33 In PET imaging, focal hypometabolism of the precentral gyrus “stripe sign” has been described in PLS, although its prevalence has not been systematically quantified.34 Despite their promise, these tools require further prospective validation before they can be incorporated into standard diagnostic algorithms.
Hereditary spastic paraplegia (HSP) is another upper motor neuron disease that requires differential diagnosis from PLS.23 Compared with HSP, PLS more often presents in the fifth to sixth decade of life, is predominantly sporadic, more frequently involves bulbar musculature, and may exhibit subtle cognitive or extrapyramidal manifestations, whereas HSP is more commonly associated with family history, onset in the second to third decade of life, dorsal column sensory involvement, and a more indolent course. Nevertheless, clinical differentiation can be challenging, particularly in adult-onset, symmetric lower-limb presentations. Complicated forms of HSP may also manifest diverse additional neurological features that may overlap with the PLS. Although pyramidal pathway abnormalities on brain MRI, such as focal atrophy of the precentral gyrus and corticospinal tract hyperintensities, are more common in PLS, they have also been reported in HSP.35 Transcranial magnetic stimulation can serve as a useful adjunctive tool by demonstrating cortical inexcitability, a neurophysiological signature more characteristic of PLS.36 In parallel, genetic studies for HSP-, combined with longitudinal follow-up, is crucial to distinguish the two diseases.23
GBS
GBS is an acute-onset, immune-mediated polyradiculoneuropathy characterized by rapidly progressive, symmetrical limb weakness and generalized areflexia.37 Cranial nerve involvement, particularly bilateral facial palsy, is common, and patients may also present with sensory disturbances, autonomic dysfunction, and in severe cases, respiratory insufficiency requiring mechanical ventilation. Most cases are preceded by infection, such as Campylobacter jejuni or cytomegalovirus, and the annual incidence is approximately 1 to 2 per 100,000 individuals, with higher rates observed in older adults and a male predominance.
Over the past three decades, diagnostic criteria for GBS have evolved significantly. The clinical criteria proposed by Asbury and Cornblath38 in 1990, but lacked sensitivity in atypical cases. In 2011, the Brighton criteria introduced a tiered system of diagnostic certainty by incorporating cerebrospinal fluid analysis and electrodiagnostic findings.39 Leonhard et al.40 proposed a more pragmatic and clinically applicable approach to GBS diagnosis and management through a ten-step method. Most recently, the 2023 European Academy of Neurology and Peripheral Nerve Society (EAN/PNS) guideline expanded diagnostic strategies by integrating updated clinical definitions, electrophysiologic subtyping, serologic testing, and advanced neuroimaging.41
The 2023 EAN/PNS revised diagnostic guideline was developed to provide an evidence-based, internationally applicable framework aimed at optimizing diagnostic accuracy, enabling earlier recognition, and guiding appropriate treatment across the entire clinical spectrum of GBS.41 Major changes from earlier include the explicit addition of acute-onset chronic inflammatory demyelinating polyradiculoneuropathy (A-CIDP) to the differential diagnosis recognizing that approximately 5% of patients initially diagnosed with GBS will have continued progression beyond 8 weeks or ≥3 treatment-related fluctuations, and the identification of autoimmune nodopathy, associated with antibodies to nodal-paranodal proteins such as contactin-1 (CNTN1), neurofascin-155 (NF155), and Caspr1 as a distinct mimic to be considered in atypical or treatment-refractory cases. The guideline also advises against routine anti- ganglioside antibody testing in typical motor sensory GBS, while recommending anti-GQ1b testing for suspected Miller Fisher syndrome, and reserves MRI or nerve ultrasound for atypical presentations or when A-CIDP is suspected.
The role of electrodiagnostic testing is still important to confirm the diagnosis of GBS and to exclude possible mimics such as A-CIDP, vasculitic neuropathy, and motor neuron disease (Table 3). Nerve conduction studies and EMG should ideally be performed within the first week of symptom onset, although abnormalities may be subtle or absent early in the course, necessitating repeat studies. Electrophysiologic evidence of demyelination, such as prolonged distal motor latencies, slowed conduction velocities, temporal dispersion, and partial conduction block, provides strong diagnostic support. The absence or prolongation of F-waves and H-reflexes, particularly in the tibial nerve, are also sensitive early indicators of proximal conduction failure. A characteristic and highly specific finding for demyelinating forms such as acute demyelinating inflammatory polyneuropathy (AIDP) is the sural sparing pattern, in which sensory nerve action potentials in the sural nerve remain preserved despite abnormalities in upper limb sensory responses.
Additional valuable findings include A-waves, which are late motor responses occurring after the compound muscle action potential (CMAP) and before the F-wave. These waves are often seen in demyelinating neuropathies and reflect re-excitation of motor neurons due to collateral branching or ephaptic transmission. The presence of multiple or prolonged A-waves, particularly in the early phase, may precede other abnormalities and serve as an early marker of proximal involvement. Facial nerve conduction studies are also important in patients with cranial nerve involvement. These can reveal prolonged distal latency or reduced amplitude, consistent with demyelinating neuropathy of the facial nerve. Blink reflex studies, which assess both the trigeminal afferent and facial efferent pathways, are especially useful in patients with facial weakness. Abnormalities such as delayed or absent R1 and R2 responses provide additional supportive evidence of brainstem or proximal nerve root involvement, even in cases where limb nerve conduction studies are inconclusive.
Despite these diagnostic advances, several challenges persist in electrodiagnosis. In the early stages, findings may be minimal, leading to false-negative interpretations. Furthermore, classification into demyelinating or axonal subtypes can be misleading. For example, nodo-paranodopathies may exhibit reversible conduction failure without true axonal degeneration, mimicking axonal forms such as acute motor axonal neuropathy (AMAN). Conventional criteria such as those by Ho or Rajabally utilize differing thresholds and definitions, which contributes to variability in subtype classification between centers. Additionally, low CMAP amplitudes may reflect either conduction block or axonal loss, which has prognostic implications that remain difficult to resolve without serial testing. For this reason, the EAN/PNS guideline recommends caution in assigning subtypes based on a single early study and advocates for repeated evaluations. In addition to serial testing, careful assessment for the development of temporal dispersion can aid in differentiating AIDP from AMAN, as demyelinating conduction block in AIDP often evolves into increased CMAP duration, whereas AMAN typically occurs without temporal dispersion.42 This may represent pseudo-conduction block from length-dependent CMAP reduction due to progressive distal axonal inexcitability, with distal CMAPs initially preserved for days before inexcitability advances with time and nerve length.
Complementing electrodiagnosis, advanced imaging modalities such as high-resolution nerve ultrasound and magnetic resonance neurography (MRN) provide further diagnostic value. Ultrasound can detect nerve root or plexus thickening, increased cross-sectional area, and fascicular enlargement, particularly in AIDP. MRN may reveal gadolinium enhancement or swelling of the cauda equina or cranial nerves, such as the facial or oculomotor nerves, reinforcing the diagnosis in patients with atypical or inconclusive electrophysiologic findings. These imaging tools are especially beneficial in pediatric patients or when electrodiagnostic studies are technically limited or poorly tolerated.
CIDP
CIDP is an acquired immune-mediated neuropathy characterized by progressive or relapsing motor and sensory dysfunction. The disease course typically spans at least 8 weeks, distinguishing it from AIDP. Clinically, patients exhibit symmetrical proximal and distal weakness, sensory loss, and areflexia. CIDP occurs across all age groups but is most common in middle-aged adults, with a male predominance. The pathophysiology involves segmental demyelination and inflammatory infiltrates in peripheral nerves, though no specific biomarker has yet been identified.
The earliest structured criteria, proposed in the 1980s by Dyck et al,43 required 6 months of progression and relied on evidence from nerve conduction study, CSF study, and nerve biopsy. These evolved into the American Academy of Neurology 1991 research criteria, which introduced a tiered system (definite, probable, possible CIDP) incorporating clinical, physiological, pathological, and CSF parameters.44 However, the strict requirements limited their clinical sensitivity, as a definite diagnosis required pathological confirmation and even a possible diagnosis demanded abnormalities in three out of four detailed nerve conduction parameters, which often excluded patients with incomplete electrodiagnostic findings. The European Federation of Neurological Societies and Peripheral Nerve Society (EFNS/PNS) released consensus guidelines in 2005, revised in 2010.45,46 These guidelines integrated a broader range of clinical and electrodiagnostic features while offering flexibility through "supportive" criteria such as elevated CSF protein, nerve imaging, biopsy findings, and treatment response. The EFNS/PNS criteria offered three levels of diagnostic certainty and became the most widely adopted due to their practical balance between sensitivity and specificity.
The 2021 revision of the EFNS/PNS criteria, jointly endorsed by the EAN and PNS, introduced substantial changes to address limitations of the 2010 version. While the 2010 EFNS/PNS criteria significantly improved diagnostic accuracy compared to earlier criteria, they were associated with reduced specificity and frequent misdiagnosis, especially in patients with atypical CIDP presentations. One major change in 2021 EAN/PNS was that the number of diagnostic levels was reduced from three to two: “CIDP” and “possible CIDP”. This simplification was based on evidence showing minimal difference in diagnostic accuracy between the prior “definite” and “probable” categories, and aimed to streamline clinical decision-making without compromising diagnostic validity. Another change was the replacement of the term “atypical CIDP” with “CIDP variants”, reflecting a more precise classification of distinct clinical and electrophysiological phenotypes. These include distal CIDP (also known as distal acquired demyelinating symmetric neuropathy), multifocal CIDP (e.g., Lewis-Sumner syndrome), focal CIDP, motor CIDP, and sensory CIDP. Each subtype now has defined electrodiagnostic criteria. For example, “motor-predominant CIDP” and “sensory-predominant CIDP” refer to cases where mild abnormalities in the opposite modality do not exclude diagnosis, whereas “motor CIDP” and “sensory CIDP” require the absence of such findings. Notably, approximately 70% of patients initially presenting with sensory CIDP progress to overt motor involvement, suggesting a transient phase rather than a distinct disease entity. While the 2010 EFNS/ PNS criteria primarily relied on abnormalities in motor nerve conduction studies, the updated criteria now require abnormalities in both motor and sensory nerve conduction for a diagnosis of typical CIDP (Table 4). At least two motor nerves must meet defined demyelination thresholds, and at least two sensory nerves must demonstrate abnormal findings.
The updated criteria also recognized A-CIDP, a form that mimics GBS at onset and comprises approximately 13% of CIDP cases, with 5% of GBS cases later reclassified as A-CIDP. Unlike GBS, these patients deteriorate beyond 8 weeks or experience repeated relapses.
Several conditions previously grouped with CIDP are excluded. Chronic immune sensory polyradiculopathy, which clinically resembles sensory CIDP but shows normal motor and sensory nerve conduction studies with abnormal somatosensory evoked potentials, is no longer considered a CIDP variant. Similarly, autoimmune nodopathies, characterized by antibodies against paranodal proteins such as CNTN1, NF155, Caspr1, and neurofascin-140/186 (NF140/186), have been excluded. These conditions often present with acute or subacute onset, ataxia, cranial nerve involvement, and poor response to intravenous immunoglobulin (IVIg). For instance, anti-CNTN1 antibodies are associated with acute motor or ataxic features and resistance to IVIg; anti-NF155 with early-onset distal weakness, tremor, and ataxia; and anti-Caspr1 with neuropathic pain and cranial nerve involvement. Pathologically, these nodopathies lack macrophage-mediated demyelination and inflammation, further distinguishing them from CIDP. Rituximab may be effective in some cases, underscoring their distinct immunopathological profiles.
Supportive criteria in the 2021 EAN/PNS guidelines play an important role when patients do not meet electrophysiological criteria. These include: 1) objective treatment response (quantified by scales such as inflammatory neuropathy cause and treatment, medical research council sum score, or grip strength); 2) CSF protein elevation; 3) imaging evidence of root/plexus hypertrophy on MRI or ultrasound; and 4) characteristic nerve biopsy findings. Imaging and CSF studies add further value in selected cases, particularly when distinguishing CIDP from mimics such as POEMS syndrome, hereditary neuropathies, or diabetic polyradiculopathy.
Recently, a large multicenter study compared the diagnostic performance of the 2021 EAN/PNS and 2010 EFNS/PNS criteria in 330 CIDP patients and 166 controls. The 2021 EAN/PNS criteria demonstrated higher specificity (98% vs. 84% for definite/probable CIDP) but lower sensitivity (74% vs. 85%) compared to the 2010 criteria. Even when supportive criteria were included, EAN/PNS sensitivity rose modestly to 77%, still lower than EFNS/PNS.47 Notably, EAN/PNS criteria were particularly more specific in diagnosing sensory and distal variants of CIDP, while EFNS/PNS criteria maintained superior sensitivity in typical CIDP. More extensive nerve conduction studies (at least four motor and four sensory nerves) improved sensitivity slightly in both systems but at a small cost to specificity.
MYASTHENIA GRAVIS
Myasthenia gravis is a chronic autoimmune disorder of the neuromuscular junction (NMJ) characterized by fluctuating weakness of voluntary muscles, typically worsening with exertion and improving with rest.48 It often begins with ocular symptoms such as ptosis and diplopia, but may generalize to involve bulbar, limb, or respiratory muscles. Approximately 80-85% of generalized cases are associated with autoantibodies against the acetylcholine receptor (AChR), while 5-8% have antibodies against muscle-specific tyrosine kinase (MuSK), and a smaller proportion possess antibodies to low-density lipoprotein receptor-related protein 4.
The diagnosis of MG relies on a combination of clinical assessment, serological testing, and electrophysiological studies targeting the NMJ. Repetitive nerve stimulation (RNS) and single-fiber EMG (SFEMG) are pivotal in detecting impaired neuromuscular transmission. Low-frequency RNS (2-5 Hz) evaluates postsynaptic dysfunction and is particularly useful for generalized MG (gMG). A decrement greater than 10% in compound muscle action potential amplitude, typically observed between the first and fourth or fifth responses, is considered abnormal. This pattern is often U-shaped, reflecting partial recovery via secondary vesicle mobilization. The diagnostic sensitivity of RNS is approximately 85.9% in gMG, but markedly lower in ocular MG (oMG), reaching only 25%. Sensitivity improves when weak or clinically involved muscles are tested, especially after a brief period of maximal voluntary isometric effort, which can transiently restore transmission efficacy.
SFEMG measures neuromuscular jitter and is the most sensitive test for MG, with abnormal findings in up to 99% of gMG and 100% of oMG cases. It detects subtle transmission failure even in asymptomatic muscles. Facial muscles, such as the orbicularis oculi and frontalis, are particularly informative in oMG or MuSK-antibody-positive MG. Jitter analysis may be performed via voluntary activation or electrical stimulation, with the latter offering utility in non-cooperative patients or children.
Recently, the revised Japanese clinical guidelines for MG were published in 2022 (Table 5).49 As in the 2014 guidelines, 50 the revised criteria include clinical symptoms and confirmatory tests such as antibody assays for AChR and MuSK, along with bedside evaluations including the eyelid fatigability test and the ice pack test. However, it was recognized that a substantial number of patients, particularly those negative for both antibodies, remained undiagnosed or misclassified. To overcome this limitation, the 2022 guidelines newly incorporate the therapeutic response to plasmapheresis as supportive diagnostic evidence. When MG is strongly suspected based on clinical features and other diseases have been ruled out, a clear clinical improvement following plasmapheresis may now aid in establishing a diagnosis.
Another major advancement in the 2022 guidelines is the introduction of a new clinical classification system for MG, derived from registry-based cluster analysis of treatment responses and disease characteristics.51 This system, referred to as the O/g-ELTMuN classification, delineates six distinct clinical subtypes (Table 6).
Other recent studies have proved to suggest promising supportive tools for improving the diagnosis of MG, particularly in patients with ocular symptoms. Valko et al.52 conducted a prospective, blinded diagnostic study to assess the utility of repetitive ocular vestibular-evoked myogenic potentials (roVEMP) in diagnosing oMG among patients presenting with ptosis or diplopia. The test involved delivering 30 Hz bone-conducted vibration to the forehead while recording responses from the inferior orbital muscles, and the diagnostic parameter was the percentage decrement in response amplitude (the mean amplitude of the sixth to ninth responses compared to the first two). A unilateral decrement greater than 9% was considered positive. Among 89 patients, roVEMP showed high sensitivity (88.2%) but low specificity (30.2%), indicating that while it is not suitable as a standalone test, it may serve as a useful adjunct to rule out MG, particularly in seronegative or ambiguous cases. In addition, video-oculography (VOG) has also been shown to aid in the diagnosis of MG by quantitatively assessing oculomotor fatigability. In a prospective case-control study, 75 cycles of horizontal and vertical saccades and smooth pursuits were recorded using a three-dimensional VOG system, and the decrement in oculomotor range was calculated by comparing the second movement to the average of the last five.53 Among 46 MG patients and 24 healthy controls, a vertical saccadic range decrement of ≥6.4% provided the best diagnostic performance, with a sensitivity of 78.3% and specificity of 95.8%. This study demonstrated that VOG-based measurement of saccadic and pursuit fatigability is a non-invasive, objective, and reliable method that may be particularly useful in diagnosing ocular or seronegative MG when conventional tests yield inconclusive results.
CONCLUSION
Recent updates to the diagnostic criteria for neuromuscular diseases exhibit several common trends aimed at improving clinical applicability and diagnostic accuracy. First, complex and multi-tiered classification systems have been simplified to enhance sensitivity and facilitate earlier diagnosis. These streamlined frameworks are increasingly supported by adjunctive modalities such as neurophysiologic testing, imaging, and treatment responsiveness that help differentiate neuromuscular diseases from their mimics in routine practice. Second, the identification of novel serologic biomarkers has enabled delineation of disease subtypes, particularly in conditions like CIDP, where autoimmune nodopathies with specific antibody profiles are now recognized as distinct from conventional CIDP. This reflects a growing role for immunological tools in refining both diagnosis and treatment strategies. Third, diagnostic criteria are evolving to incorporate real-world clinical insights. For instance, in MG, the inclusion of therapeutic response as a supportive diagnostic element acknowledges the practical realities of diagnosis in seronegative or ambiguous cases.
Despite these advances, further refinement is needed. Ongoing research into electrophysiologic, serologic, and imaging biomarkers offers the potential to further enhance diagnostic accuracy. Incorporating these emerging tools into future diagnostic frameworks guided by robust prospective validation will be essential for achieving earlier, more precise, and individualized diagnosis across the spectrum of neuromuscular disorders.
Notes
Conflicts of Interest
The author has declared no conflicts of interest.
Table 1.
Comparison of El Escorial, revised El Escorial, Awaji, and Gold Coast criteria for amyotrophic lateral sclerosis
El Escorial (1994)
Revised El Escorial (2000)
Awaji (2008)
Gold Coast (2020)
Clinically definite
Clinically, 1) UMN plus LMN signs in the bulbar and two spinal regions or 2) UMN plus LMN signs in three spinal regions
- Same as previous criteria
- Same as previous criteria
- Single diagnostic category
- LMN dysfunction is defined by clinical, electrophysiological, or neuropathological examination
- UMN and LMN dysfunction in at least one body region or
- LMN dysfunction in at least two body regions
- LMN dysfunction was defined clinically or by electrophysiological assessment
Clinically probable
Clinically, UMN plus LMN signs in at least two regions with UMN signs rostral to LMN signs
- Same as previous criteria
- Same as previous criteria
- LMN dysfunction is defined by clinical, electrophysiological, or neuropathological examination
Clinically probable-laboratory supported
None
Clinically, 1) UMN plus LMN signs in 1 region or UMN signs alone in 1 region and 2) LMN by EMG criteria in at least 2 regions
Deleted
Clinically possible
Clinically, 1) UMN plus LMN signs in one region or 2) UMN signs in two or more regions or 3) LMN signs are rostral to UMN signs
- Same as previous criteria
- Same as previous criteria
- LMN dysfunction is defined by clinical, electrophysiological, or neuropathological examination
Clinically suspected
Clinically, LMN signs in two or more regions
Deleted
UMN, upper motor neuron; LMN, lower motor neuron; EMG, electromyography.
Table 2.
2020 International Consensus Criteria of primary lateral sclerosis (PLS)
Core principles
The diagnosis of PLS requires
1) The presence of
- Age ≥25 years
- Symptoms of progressive UMN dysfunction for at least 2 years
- Signs of UMN dysfunctiona in at least two of three regions: lower extremity, upper extremity, bulbar
2) The absence of
- Sensory symptoms (unexplained by comorbid condition)
- Alternative diagnosis: UMN pathology demonstrated on neuroimaging, or identified through biofluid testing that provides a plausible alternative explanation for the clinical syndrome
Diagnostic certainty
Duration of the absence of significant active LMN degeneration from symptom onset
- Probable PLS: 2-4 years
- Definite PLS: 4 or more years
UMN, upper motor neuron; LMN, lower motor neuron.
aClinical signs, including spasticity and associated weakness, pathological hyperreflexia (including Hoffman’s sign and bilateral extensor toe responses), pseudobulbar affect.
bMinimally increased insertional activity and positive sharp waves or fibrillation potentials in extremity muscles are permitted.
Table 3.
2023 EAN/PNS Summary: Clinical, Laboratory, and Electrophysiologic Features of Guillain-Barré Syndrome (GBS)
Clinical features for sensory-motor or motor GBS
Electrophysiologic features
Required features
Potential electrodiagnostic features within the first week
- Progressive weakness of arms and legs
- Sensory and/or motor conduction abnormalities (suggestive of polyneuropathy)
- Tendon reflexes absent or decreased in affected limbs
- Absent H-reflexes
- Progressive worsening for no more than 4 weeks
- Prolonged or absent F-waves
Supportive features
- Prolonged distal motor latencies
- Relative symmetry
- Facial nerve: increased distal latency or reduced CMAP amplitude
- Relatively mild/absent sensory symptoms and signs
- Blink reflex: absent or prolonged R1 and R2 responses
Electrophysiologic diagnostic criteria of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)
2010 EFNS/PNS criteria
2021 EAN/PNS crteria
Motor nerve conduction criteria
1) Definite at least one of the following
1) Definite at least one of the following
Prolonged distal motor latency
≥50% above ULN in 2 nerves (excluding CTS)
Reduced motor conduction velocity
≥30% below LLN in 2 nerves
Prolonged F-wave latency
≥30% above ULN in 2 nerves
≥20% above ULN in 2 nerves
Absent F-wave
In ≥2 nerves if CMAP ≥20% LLN and ≥1 other demyelinating parameter in ≥1 other nerve
Conduction block
- ≥50% proximal-to-distal CMAP amplitude reduction in ≥2 nerves
- ≥30% proximal-to-distal CMAP amplitude reduction in ≥2 nerves
- In ≥1 nerve + ≥1 other demyelinating parameter in another in ≥1 other nerve
- In 1 nerve + ≥1 other demyelinating parameter in ≥1 other nerve (except absence of F-waves)
Abnormal temporal dispersion
>30% duration increase between the proximal and distal negative peak CMAP in ≥2 nerves
>30% duration increase between the proximal and distal negative peak CMAP in ≥2 nerves (at least 100% in the tibial nerve)
Prolonged CMAP duration
- In ≥1 nerve
- In ≥1 nerve
• Median ≥6.6 ms
• (LFF 2 Hz) median >8.4 ms, ulnar >9.6 ms, peroneal >8.8 ms, tibial >9.2 ms
• Ulnar ≥6.7 ms
• (LFF 5 Hz) median >8.0 ms, ulnar >8.6 ms, peroneal >8.5 ms, tibial >8.3 ms
• Peroneal ≥7.6 ms
• (LFF 10 Hz) median >7.8 ms, ulnar >8.5 ms, peroneal >8.3 ms, tibial >8.2 ms
• Tibial ≥8.8 ms
• (LFF 20 Hz) median >7.4 ms, ulnar >7.8 ms, peroneal >8.1 ms, tibial >8.0 ms
- ≥1 other demyelinating parameter in ≥1 other nerve
- ≥1 other demyelinating parameter in ≥1 other nerve
2) Probable
- ≥30% proximal-to-distal CMAP amplitude reduction in ≥2 nerves
- In 1 nerve + ≥1 other demyelinating parameter in ≥1 other nerve
3) Possible as in 1) but in only one nerve
2) Weakly supportive of demyelination: as in 1) but in only one nerve
Sensory nerve conduction criteria
Not included
1) CIDP
• Sensory conduction abnormalities (prolonged distal latency, or reduced SNAP amplitude, or slowed conduction velocity outside of normal limits) in two nerves
2) Possible CIDP
• As in (1)
• Sensory CIDP with normal motor NCS needs to fulfil A or B
A) Sensory nerve conduction velocity <80% of LLN (for SNAP amplitude >80% of LLN) or <70% of LLN (for SNAP amplitude <80% of LLN) in at least two nerves
B) Sural sparing pattern
Requirement for diagnosis
≥1-2 demyelinating features in ≥2 motor nerves (depending on level)
≥2 demyelinating features in ≥2 motor nerves + ≥2 sensory nerves with abnormal conduction (for typical CIDP)
EFNS/PNS, European Federation of Neurological Societies/Peripheral Nerve Society; EAN, European Academy of Neurology; ULN, upper limit of normal; CTS, carpal tunnel syndrome; LLN, lower limit of normal; CMAP, compound muscle action potential; LFF, low-frequency filter; SNAP, sensory nerve action potential; NCS, nerve conduction study.
Table 5.
Japanese clinical guideline for myasthenia gravis (MG)
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Advancements in diagnostic criteria for neuromuscular diseases
Advancements in diagnostic criteria for neuromuscular diseases
El Escorial (1994)
Revised El Escorial (2000)
Awaji (2008)
Gold Coast (2020)
Clinically definite
Clinically, 1) UMN plus LMN signs in the bulbar and two spinal regions or 2) UMN plus LMN signs in three spinal regions
- Same as previous criteria
- Same as previous criteria
- Single diagnostic category
- LMN dysfunction is defined by clinical, electrophysiological, or neuropathological examination
- UMN and LMN dysfunction in at least one body region or
- LMN dysfunction in at least two body regions
- LMN dysfunction was defined clinically or by electrophysiological assessment
Clinically probable
Clinically, UMN plus LMN signs in at least two regions with UMN signs rostral to LMN signs
- Same as previous criteria
- Same as previous criteria
- LMN dysfunction is defined by clinical, electrophysiological, or neuropathological examination
Clinically probable-laboratory supported
None
Clinically, 1) UMN plus LMN signs in 1 region or UMN signs alone in 1 region and 2) LMN by EMG criteria in at least 2 regions
Deleted
Clinically possible
Clinically, 1) UMN plus LMN signs in one region or 2) UMN signs in two or more regions or 3) LMN signs are rostral to UMN signs
- Same as previous criteria
- Same as previous criteria
- LMN dysfunction is defined by clinical, electrophysiological, or neuropathological examination
Clinically suspected
Clinically, LMN signs in two or more regions
Deleted
Core principles
The diagnosis of PLS requires
1) The presence of
- Age ≥25 years
- Symptoms of progressive UMN dysfunction for at least 2 years
- Signs of UMN dysfunctiona in at least two of three regions: lower extremity, upper extremity, bulbar
2) The absence of
- Sensory symptoms (unexplained by comorbid condition)
- Active LMN degenerationb
- Alternative diagnosis: UMN pathology demonstrated on neuroimaging, or identified through biofluid testing that provides a plausible alternative explanation for the clinical syndrome
Diagnostic certainty
Duration of the absence of significant active LMN degeneration from symptom onset
- Probable PLS: 2-4 years
- Definite PLS: 4 or more years
Clinical features for sensory-motor or motor GBS
Electrophysiologic features
Required features
Potential electrodiagnostic features within the first week
- Progressive weakness of arms and legs
- Sensory and/or motor conduction abnormalities (suggestive of polyneuropathy)
- Tendon reflexes absent or decreased in affected limbs
- Absent H-reflexes
- Progressive worsening for no more than 4 weeks
- Prolonged or absent F-waves
Supportive features
- Prolonged distal motor latencies
- Relative symmetry
- Facial nerve: increased distal latency or reduced CMAP amplitude
- Relatively mild/absent sensory symptoms and signs
- Blink reflex: absent or prolonged R1 and R2 responses
- Indirect discharges resembling A-waves (distinct from F-waves)
- Recent history of infection (<6 weeks), (possibly also surgery)
- Distal CMAP duration >8.5 ms (using 2-10 kHz bandpass)
Findings which make GBS less likely
Supportive findings in suspected Miller Fisher syndrome
- Asymmetric weakness (marked and persistent)
- Sural sparing pattern
- Severe respiratory dysfunction at onset with mild limb weakness
- Sensory and/or motor conduction abnormalities consistent with polyneuropathy
- Predominant sensory signs at onset (paresthesia often occur) with mild weakness
Supportive laboratory features
- Fever at onset
CSF
- Sensory level, or extensor plantar responses
- Increased protein; normal protein does not rule out diagnosis
- Hyperreflexia (initial hyper-reflexia does not exclude GBS)
- White cells usually <5 × 106/L
- Bladder/bowel dysfunction (does not exclude GBS)
Ganglioside antibodies
- Abdominal pain or vomiting
- Anti-GQ1b antibodies usually present in Miller Fisher syndrome
- Nystagmus
- Alteration of consciousness (except in BBE)
- No further worsening after 24 hours
- Relatively slow worsening (2-4 weeks) with mild weakness
- Continued worsening >4 weeks or ≥3 TRFs (consider A-CIDP)
2010 EFNS/PNS criteria
2021 EAN/PNS crteria
Motor nerve conduction criteria
1) Definite at least one of the following
1) Definite at least one of the following
Prolonged distal motor latency
≥50% above ULN in 2 nerves (excluding CTS)
Reduced motor conduction velocity
≥30% below LLN in 2 nerves
Prolonged F-wave latency
≥30% above ULN in 2 nerves
≥20% above ULN in 2 nerves
Absent F-wave
In ≥2 nerves if CMAP ≥20% LLN and ≥1 other demyelinating parameter in ≥1 other nerve
Conduction block
- ≥50% proximal-to-distal CMAP amplitude reduction in ≥2 nerves
- ≥30% proximal-to-distal CMAP amplitude reduction in ≥2 nerves
- In ≥1 nerve + ≥1 other demyelinating parameter in another in ≥1 other nerve
- In 1 nerve + ≥1 other demyelinating parameter in ≥1 other nerve (except absence of F-waves)
Abnormal temporal dispersion
>30% duration increase between the proximal and distal negative peak CMAP in ≥2 nerves
>30% duration increase between the proximal and distal negative peak CMAP in ≥2 nerves (at least 100% in the tibial nerve)
Prolonged CMAP duration
- In ≥1 nerve
- In ≥1 nerve
• Median ≥6.6 ms
• (LFF 2 Hz) median >8.4 ms, ulnar >9.6 ms, peroneal >8.8 ms, tibial >9.2 ms
• Ulnar ≥6.7 ms
• (LFF 5 Hz) median >8.0 ms, ulnar >8.6 ms, peroneal >8.5 ms, tibial >8.3 ms
• Peroneal ≥7.6 ms
• (LFF 10 Hz) median >7.8 ms, ulnar >8.5 ms, peroneal >8.3 ms, tibial >8.2 ms
• Tibial ≥8.8 ms
• (LFF 20 Hz) median >7.4 ms, ulnar >7.8 ms, peroneal >8.1 ms, tibial >8.0 ms
- ≥1 other demyelinating parameter in ≥1 other nerve
- ≥1 other demyelinating parameter in ≥1 other nerve
2) Probable
- ≥30% proximal-to-distal CMAP amplitude reduction in ≥2 nerves
- In 1 nerve + ≥1 other demyelinating parameter in ≥1 other nerve
3) Possible as in 1) but in only one nerve
2) Weakly supportive of demyelination: as in 1) but in only one nerve
Sensory nerve conduction criteria
Not included
1) CIDP
• Sensory conduction abnormalities (prolonged distal latency, or reduced SNAP amplitude, or slowed conduction velocity outside of normal limits) in two nerves
2) Possible CIDP
• As in (1)
• Sensory CIDP with normal motor NCS needs to fulfil A or B
A) Sensory nerve conduction velocity <80% of LLN (for SNAP amplitude >80% of LLN) or <70% of LLN (for SNAP amplitude <80% of LLN) in at least two nerves
B) Sural sparing pattern
Requirement for diagnosis
≥1-2 demyelinating features in ≥2 motor nerves (depending on level)
≥2 demyelinating features in ≥2 motor nerves + ≥2 sensory nerves with abnormal conduction (for typical CIDP)
- Positive on edrophonium chloride (Tensilon) test
- Positive on repetitive stimulation test
- Jitter increase on single fiber electromyography test
D. Suppotive diagnostic finding
History of improvement by plasmapheresis
Determination
Diagnosis of myasthenia gravis is made if either of the below is true
Definite: diagnosis of MG made if either of the below is true
- One or more items from A is true and any item of B is true
- One or more items from A is true and any item of B is true
- One or more items from A is true, and any item of C is true and other diseases can be ruled out
- One or more items from A is true and any item of C is true and other diseases can be ruled out
Probable: one or more items from A is true and D is true and other diseases can be ruled out
Type of MG
Description
Ocular MG (oMG)
All forms of ocular MG regardless of auto-antibody status or thymus histology
Generalized early-onset MG (g-EOMG)
AChR-positive generalized MG without thymoma, onset age <50 years
Generalized late-onset MG (g-LOMG)
AChR-positive generalized MG without thymoma, onset age ≥50 years
Generalized thymoma-associated MG (g-TAMG)
Thymoma-associated MG that includes all ages
Generalized MuSK antibody-positive MG (g-MuSKMG)
Generalized MG with positive MuSK antibodies
Generalized seronegative MG (g-SNMG)
Generalized MG without AChR or MuSK antibodies such as LRP4-positive generalized MG
Table 1. Comparison of El Escorial, revised El Escorial, Awaji, and Gold Coast criteria for amyotrophic lateral sclerosis
UMN, upper motor neuron; LMN, lower motor neuron; EMG, electromyography.
Table 2. 2020 International Consensus Criteria of primary lateral sclerosis (PLS)
UMN, upper motor neuron; LMN, lower motor neuron.
Clinical signs, including spasticity and associated weakness, pathological hyperreflexia (including Hoffman’s sign and bilateral extensor toe responses), pseudobulbar affect.
Minimally increased insertional activity and positive sharp waves or fibrillation potentials in extremity muscles are permitted.
Table 3. 2023 EAN/PNS Summary: Clinical, Laboratory, and Electrophysiologic Features of Guillain-Barré Syndrome (GBS)
