Dear Editor,
We thank Finsterer et al. for their interest in our recently published article, “Jitter
and muscle fiber conduction velocity in long COVID fatigue” Kouyoumdjian JA, Yamamoto LAR, Graca CR. Arq Neuropsiquiatr. 2025 Jan;83(1):1–8. doi:
10.1055/s-0045-1802961.” We appreciate their thoughtful comments and the opportunity to clarify further
and discuss some of the points raised.
Our initial impression is that the authors of the letter[1] focused mainly on issues not directly related to our research project, which led
to two foundational publications: one presenting reference values for jitter parameters
in the tibialis anterior muscle using a concentric needle (CN) and intramuscular micro-axonal
electrical activation;[2] and another establishing reference values for muscle fiber conduction velocity (MFCV)
in situ,[3] a technique described initially in Erik Stålberg's 1966 Ph.D. thesis[4] and recently revitalized by our team using the single-fiber electromyography (SFEMG)
software.
This project ultimately culminated in the current article and a secondary, recently
published study,[5] totaling four interdependent publications analyzing jitter and MFCV. We have developed
substantial expertise in these methods, as evidenced by key contributions including
the multicenter study on CN jitter parameters,[6] the SFEMG guidelines published by the International Federation of Clinical Neurophysiology,[7] and the monograph on jitter using CN electrodes published by the American Association
of Neuromuscular and Electrodiagnostic Medicine.[8] More recently, we launched the Atlas of Concentric Needle Jitter,[9] a free online resource with approximately 400 recordingsperformed entirely by Kouyoumdjian
and reviewed by Stålberg and Sanders, which also addresses one of the commenters'
concerns.
FIRST ISSUE
None of the cases studied showed signs of inflammatory myopathy or rhabdomyolysis
during acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
As previously noted, no patient required hospitalization, aside from brief diagnostic
visits. Immune-mediated necrotizing myopathy is rare and typically presents with limb
weakness, requiring inpatient care. Mild CK elevations (up to 4-fold) were common,
but rhabdomyolysis involves much higher CK levels, dark urine, and renal failure,
all of which were absent in our cohort. Thus, there is no evidence of muscle involvement
during the acute phase.
SECOND ISSUE
Myositis-associated antibodies were not assessed, as investigating inflammatory myopathies
or their presence during acute infection was beyond the study's scope. In Brazil,
such testing was not routinely available during the pandemic. Our focus was on long
COVID (LC), which affects an estimated 4 million Brazilians and shares clinical features
with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and postviral fatigue
syndrome (PVFS). These conditions lack defined etiopathogenic mechanisms but present
overlapping symptoms, including fatigue, sleep disturbances, and brain fog. Diagnosis
relies on clinical criteria, including those defined by Fukuda et al.[10] and Carruthers et al.,[11] as there are no specific biomarkers.
While jitter studies exist for ME/CFS, no systematic evaluations have been done for
LC, nor has MFCV been described in this context. Our study aimed to examine these
two peripheral motor parameters—jitter and MFCV—in LC cases, focusing not on rare
nosological entities, but on the frequent “muscle-like” symptoms shared across these
still poorly defined syndromes: tiredness (relieved by rest), fatigue (not relieved),
and postexertional malaise.
THIRD AND FOURTH ISSUES
The interview and neurophysiological examination were conducted on the same day, with
testing following immediately after the interview. In all cases, the interval between
acute SARS-CoV-2 infection and the onset of LC symptoms—mostly persistent from the
acute phase—exceeded 6 months.
The commenters suggest that other conditions may have developed in the interim to
explain possible abnormalities in SFEMG. However, this test evaluates neuromuscular
transmission, and disorders in this system are rare, especially given the large number
of individuals reporting fatigue. In patients with confirmed SARS-CoV-2 infection
and no alternative diagnosis, LC remains a valid clinical entity. Furthermore, we
found no statistically significant abnormalities in any group. All results were within
normal limits. Slightly increased jitter was observed in one control, one LC-no, and
two LC-yes participants, all of whom were negative for anti-acetylcholine (anti-AChR)
antibodies and did not exhibit clinical weakness.
FIFTH ISSUE
During the pandemic, clusters of SARS-CoV-2 infection frequently occurred within families.
In a few early cases (12.5%), diagnosis was based on positive antibodies, accepted
due to the simultaneous occurrence of illness in multiple relatives. In the majority
(87.5%), infection was confirmed by polymerase chain reaction (PCR).
SIXTH ISSUE
The sixth point suggests we overlooked immunological complications beyond myopathy
or neuromuscular transmission disorders in LC. However, our study specifically aimed
to assess neuromuscular transmission via SFEMG and MFCV. As noted, LC shares features
with ME/CFS and PVFS, conditions with unclear pathophysiology.
Our findings do not support a role for neuromuscular transmission dysfunction or myopathy
in the symptoms of LC. While other mechanisms may contribute, exploring them was outside
the scope of our study. Notably, the commenters' title “Long COVID may not be explained
by skeletal muscle involvement, but rather by other, more compelling pathophysiological
concepts” aligns with our own conclusion: “The electrophysiological findings did not
indicate that muscle fiber or NMJ dysfunction was a relevant factor in this condition.”
In conclusion, the commenters that the study has limitations affecting its results
and interpretation. However, these limitations—primarily the small sample size due
to the complexity of the tests—are already acknowledged in our Discussion. In fact,
their conclusion aligns with ours: that skeletal muscle involvement alone does not
explain LC symptoms, and other pathophysiological mechanisms are likely involved.
Bibliographical Record
João Aris Kouyoumdjian, Leticia Akemi Rama Yamamoto, Carla Renata Graca. Reply to
the letter “Long-COVID may not be explained by skeletal muscle involvement, but rather
by other, more compelling pathophysiological concepts”. Arq Neuropsiquiatr 2025; 83:
s00451812889.
DOI: 10.1055/s-0045-1812889
