Length Dependent or Independent Sensory Loss? The Answer May Be 0.33

A commonly encountered question in the electrodiagnostic (EDX) laboratory is whether sensory loss on EDX testing is length-dependent or independent. In other words, is the EDX pattern of sensory nerve injury more indicative of non-length-dependent neuropathy (NLDN) or of a (more typical) length-dependent neuropathy (LDN)? When sensory nerve action potentials (SNAPs) are globally absent or near absent in the upper and lower limbs, the EDX interpretation is rather straightforward. However, things get challenging when lower and/or upper limb sensory nerve amplitudes are only mildly or moderately reduced. Herein comes the value of the article in this issue of Muscle & Nerve, titled “Sural/radial amplitude ratio: a useful tool to diagnose non-length-dependent neuropathy,” authored by Pegat et al. [1] Worthy of mention is that members of this study group developed the “Camdessanche criteria” for sensory neuronopathy (SNN), which represent the clinical diagnostic gold standard for NLDN [2]. In the present study, investigators evaluated the discriminative value of the sural to radial amplitude ratio (SRAR) in separating NLDN from LDN. Salient among NLDN are SNN and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), which were both evaluated in the present study. SNN, also termed “sensory ganglionopathy,” is a unique manifestation of polyneuropathy distinct in its clinical and EDX presentations from distal symmetric sensory polyneuropathy [2]. Not infrequently encountered in the EDX laboratory, SNN is caused by disproportionate damage to the dorsal root ganglion due to a host of potential etiologies. Such etiologies include Sjogren's syndrome, paraneoplastic neuropathy, FGFR3 associated neuropathy, certain forms of chemotherapy induced polyneuropathy (especially cisplatinum), and cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS syndrome), as well as RFC1 repeat expansion disorders, among others [3]. A large percentage of cases remain idiopathic despite extensive evaluation and even nerve biopsy. Clinically, patients report gait unsteadiness, hand clumsiness, dense acral numbness, and sometimes facial numbness, although symptoms may be more subtle or even indiscernible in some patients. On neurologic examination, SNN often manifests with length independent sensory loss (i.e., upper limb greater than or equal to lower limb vibratory, position, and/or pinprick loss), disproportionate proprioceptive sensory loss relative to vibratory sensory loss, sensory asymmetry between limbs, gait ataxia, appendicular ataxia (sometimes with pseudo-athetosis), and diffuse areflexia to hyporeflexia, although, again, examination findings may be minimal and purportedly “length dependent” at times [2]. Timely and accurate identification of SNN on EDX testing is critical because it helps narrow the differential diagnosis and alerts the evaluating provider to the potential for immunotherapeutic intervention and genetic testing. Despite the critical role played by the 2009 Camdessanche criteria in standardizing our clinical assessment of SNN, no standardized EDX cut offs exist for upper and lower limb SNAPs in ascertaining SNN. Thus, it is often left to the discretion of each individual EDX medicine specialist to decide. While the 2009 Camdessanche criteria employed a 30% cutoff for upper limb median, ulnar, and radial SNAPs as the lower limits of normal, the authors at the time did not provide a justification for this value, and it is also not universally applied across testing centers. Hence, there is inconsistency between EDX medicine specialists in how sensory nerve conduction abnormalities are interpreted, and thus, as to whether a diagnosis of SNN is or is not made. While some EDX medicine specialists employ the generic term “sensory polyneuropathy” in their reports without commenting on length-dependence or independence, this practice risks missing those SNN cases where additional work-up is warranted and where immunotherapeutic intervention may potentially help reverse disease. In contradistinction to SNN, CIDP is a well-recognized chronic progressive and relatively symmetric acquired immune neuropathy with well-characterized and validated clinical and EDX parameters [4]. Despite the robustness of the EDX criteria for CIDP, as codified in the 2021 EAN/PNS guideline statement [4], standardized cutoffs or quantitative approaches to sensory abnormalities remain lacking. This is despite the 2021 EAN/PNS guidelines requiring that sensory nerve conduction abnormalities be present in at least two nerves to establish the diagnosis and highlighting the value of the “sural sparing” pattern, in which the sural nerve remains relatively unaffected, while the median or radial SNAPs are disproportionately affected. A 2007 study found the combined presence of abnormal radial + normal sural sensory responses to be quite sensitive and specific in predicting CIDP (as opposed to LDN) [5], yet this practice is not as widely adopted in the assessment of CIDP as it perhaps should be. Part of that problem is that quantitative cutoffs in assessing this “sural sparing” pattern are lacking. In the present paper, Pegat et al. recruited 30 patients fulfilling possible or probable Camdessanche clinical criteria for SNN, 30 patients fulfilling EAN/PNS 2021 criteria for CIDP (typical or variant), and 30 patients with LDN, defined as clinical sensory or sensory-motor neuropathy with length-dependent distribution and not fulfilling the Camdessanche clinical criteria. For inclusion in any of the three arms, patients were required to have recordable SNAP values from both the radial and sural sensory nerves and that there be at least one abnormal SNAP for the radial and/or sural sensory nerves. Investigators then assessed the discriminative performance of the SRAR in separating NDLN (which included both SNN and CIDP patients) from LDN, accounting for such factors as the pre-test probability of NLDN as well as the likelihood of performing additional laboratory testing. For each subject, sural and radial sensory nerves did not have to be on the same side and, if bilateral values were available for the radial and/or sural nerves, the lower of the two values was used to calculate the ratio. Furthermore, SNN patients were grouped by etiology, be it immune-mediated, inherited, or other. The investigators found a SRAR cutoff of 0.33 to be the optimal threshold in discriminating NLDN from LDN, to be equally valid across all three etiologic groups of SNN, and to be equally valuable for both SNN and CIDP. Worth mentioning is that 20/30 CIDP and 18/30 SNN patients had what appeared to be length-dependent sensory EDX loss (sural sensory amplitude < radial sensory amplitude), yet the SRAR cutoff was > 0.33 in 15/20 CIDP patients and 15/18 SNN patients, further substantiating the utility of the SRAR cutoff value in identifying NLDN. In addition, among the 6 CANVAS patients who had SRAR calculated, all had a putative length-dependent EDX pattern, yet all 6 had a SRAR > 0.33. The authors are not the first to explore SRAR as a diagnostic measure in polyneuropathy. Its use goes back to the 1990s as a tool to discern polyneuropathy (SRAR 0.29) from healthy controls (SRAR 0.70), with cutoffs of 0.34–0.40 at the time deemed sensitive, specific, and age-independent in identifying polyneuropathy [6-8]. Nevertheless, debate exists as to whether age or sex impacts SRAR (the present study found neither factor impactful). Also, some advocate bilateral averaging of SRAR rather than using unilateral values, given the frequent lack of symmetric involvement. In addition, previous investigators have demonstrated the utility of a 0.30 SRAR cutoff in diagnosing SNN in spinocerebellar ataxia (SCA), a hereditary disorder not unlike CANVAS in its combined cerebellar and peripheral nerve involvement [9-11]. One must apply the 0.33 cutoff to NLDN with care. Both SNN and CIDP, but especially SNN, are diagnoses guided by the clinical context and pre-test probability. As the authors point out, healthy subjects can have SRAR values that exceed 0.33. Furthermore, the 0.33 cutoff value is greatly limited by the fact that both sural and radial sensory responses must be present. In practice, the absence of one or both in the setting of suspected SNN, and even CIDP, is as likely, if not more likely, to occur. Finally, normative radial and sural sensory amplitude values vary between laboratories (especially for the radial nerve), and so the presence of “normal” sensory amplitude responses should not negate clinical suspicion if one strongly suspects SNN. The value of the present study is its simplicity, practicality, and ability to fill a major unmet need in the EDX evaluation of NLDN. It is worth noting that in SNN, up to 32% of patients initially present with a distal symmetric polyneuropathy clinical phenotype, with only a quarter having ataxia at the time [12]. This is particularly true of CANVAS, which is gaining increased recognition as an underdiagnosed cause of SNN [13]. In such instances, it is only the EDX testing that can uncover the length-independent nature of the disorder. Furthermore, even among clinically diagnosed SNN or EDX-proven CIDP patients, as shown in the present study, up to two-thirds have what appears to be length-dependent SNAP findings. With that said, SRAR cannot be calculated in a sizeable number of patients with SNN, CIDP, or LDN due to absent radial sensory or sural responses (up to 40%–45% of patients in the present study), further underscoring the centrality of a thorough clinical assessment and diagnostic workup with ancillary testing if needed. For suspected SNN, application of the clinical Camdessanche criteria becomes paramount in such clinical contexts. In closing, it is through the judicious application of the 0.33 SRAR cutoff that we may be well on our way to a more cogent, standardized, and quantitative EDX path to diagnosing non-length-dependent sensory loss. It is fair to say what the 2009 Camdessanche criteria did to our clinical assessment of length-independent sensory loss, the present paper does to its EDX assessment. A. M. Stino: writing – original draft, writing – review and editing. A.M.S. has served as a paid consultant for Argenx, CSL Behring, Takeda, Sanofi, Immunovant, Annexon, and has received support from Bristol Myers Squibb and the GBS-CIDP Foundation. The author confirms that he has read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. The author declares no conflicts of interest. The author has nothing to report.