Reply to “Neurophysiological Testing to Diagnose Stiff‐Person Spectrum Disorder”

We thank the authors for their interest in our review on the neurophysiological features of stiff‐person spectrum disorders (SPSD) and their pathophysiological correlates. ¹ , ² We appreciate their emphasis on the diagnostic value of neurophysiological testing in this condition and agree that neurophysiology plays a significant role in the diagnostic process. In particular, we acknowledge their proposal that continuous motor unit activity (CMUA) and enhanced exteroceptive reflexes (ECR) could serve as “minimum neurophysiological criteria” to support a diagnosis of SPSD.

However, while CMUA and ECR testing could be readily adopted in clinical practice, their overall diagnostic contribution remains uncertain, particularly in less common SPSD subtypes such as stiff‐limb syndrome, progressive encephalomyelitis with rigidity and myoclonus, SPSD plus, and seronegative patients. SPSD encompasses a heterogeneous group of disorders with distinct immunophenotypes and variable presentation, which remain insufficiently investigated. The correlation between neurophysiological findings, clinical features and specific antibody profiles is currently poorly defined. ² This limits the ability to select appropriate tests for individual cases or to tailor the diagnostic approach based on symptom presentation or the antibody status.

A further challenge is the absence of standardized protocols for neurophysiological testing in SPSD. For instance, the recording is often limited to a small number of muscles (sometimes not those of clinical relevance), and significant variability exists in the recording settings. Even when considering surface EMG parameters, the evaluation of agonist/antagonist co‐contraction is not always consistently performed. ³

Moreover, while CMUA and ECR primarily assess dysfunction of inhibitory circuits at the spinal level, the presumed GABAergic dysfunction underlying SPSD likely extends throughout the central nervous system. This broader involvement can be explored using additional neurophysiological tools that target the brainstem (eg, brainstem reflexes) and the cortex (eg, transcranial magnetic stimulation, TMS). Nevertheless, the relationship between variables obtained by TMS or brainstem stimulation and CMUA/ECR has not been investigated, as data from these different techniques are usually not collected from the same patients within the same studies. ⁴ , ⁵ Thus, it remains unclear whether central dysfunction can be detected in the absence of the more typical EMG abnormalities. Including additional techniques could, however, strengthen diagnostic confidence. For example, in a study by Chia and coworkers, which proposed updated SPSD diagnostic criteria, the acoustic startle response was more frequently present in SPSD patients (58.0%) compared to CMUA in the paraspinal muscles (31.0%). ³ This suggests that incorporating a wider range of neurophysiological tests may improve detection rates.

As Lizzaraga and colleagues noted in their letter, the specificity of CMUA and enhanced ERC is difficult to quantify due to a lack of control subjects, a limitation that applies to the other neurophysiological parameters tested in SPSD. To determine the sensitivity and specificity of each test and to compare the diagnostic yield across different levels of the nervous system, a concerted effort is needed to perform comprehensive neurophysiological testing in large SPSD cohorts. Further studies using a standardized protocol could resolve methodological inconsistencies, define diagnostic criteria, and clarify the pathophysiology and antibody‐related mechanisms of SPSD, improving diagnostic accuracy and disease understanding.

Author Roles

(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique.

J.M.: 1A, 1B, 1C, 3A.

L.R.: 3B.

M.Z.: 3B.

B.B.: 3B.

K.P.B.: 3B.

A.L.: 1A, 1B, 1C, 3A, 3B.

Disclosure

Ethical Compliance Statement: The authors confirm that the approval of an institutional review board was not required for this work. Informed patient consent was not necessary for this work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Financial Disclosure/Conflict of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the previous 12 months: JM: Received a PhD research Scholarship from ICBAS/BIAL Foundation and support to attend scientific conferences/meetings from Orphalan, Sanofi, Novartis, UCB, Alnylam and Alexion. AL: is supported by EPSRC and MRC under the NEUROMOD+ Network (EP/W035057/1). She received honoraria from the Movement Disorder Society for educational activities.