Sialidosis is considered to be a disease with primary involvement of the CNS, and the involvement of PNS was rare reported. Our study revealed two intriguing findings: (1) the peculiar phenomenon in the late response study and (2) the painful paresthesia at the early stage of disease.

An intriguing finding in our study is the abnormalities in late response study, including the changes in the persistence and latency of F-wave, the presence of a repeater F-wave, and a “very late response” with high amplitude. The change in F-wave latency with normal motor conduction velocity is considered to correspond to a lesion in the proximal peripheral nerve or spinal cord. The repeater F-waves have been proposed to be related to lower motor neuron dysfunction or disinhibition due to upper motor neuron dysfunction [9,10,11]. The involvement of upper and lower motor neurons in previous autopsy studies supported that the change in F-waves was related to sialidosis [11, 12].

The presence of very late responses and giant waves has not been reported in previous studies. The difference in the shape and amplitude with normal F-waves, in addition to having a significantly prolonged latency, indicated that its pathology may be differ from traditional changes in F-waves [13, 14]. The proximal conduction time of the F wave could be calculated as 0.5*(F-M-1), with F being the latency of the F-wave, M being the distal latency, and the central conduction time estimated to be 1 millisecond. A very prolonged F-wave could be observed in Charcot-Marie-Tooth disease type 1, because the motor nerve conduction velocity is very slow. In the very late response observed in our patients, the latency was significantly prolonged compared with the estimated F-wave latency, which was calculated from the distal latency (M), motor nerve conduction velocity (MCV), and estimated distance between the stimulation and cord (D): \(Estimated F \left(ms\right) =M+\frac+1.\) Since the nerve conduction velocity and distal latency remained largely within normal limits, a prolonged central conduction time (much longer than 1 ms) is likely to be the cause of the changes. On the other hand, the origin of enlarged F-wave amplitude, previous studies had reported a possible relationship with lower motor dysfunction [15] although the involvement of the upper neurons could not be ruled out definitely [16]. Study on the myoclonus generator of sialidosis also revealed evidence indicating involvement of subcortical circuits, which result in motor hyperexcitability [17]. Considering that interneuron and upper motor neuron modify the excitability of lower motor neurons, we assume that the prolonged latency may result from aberrant interneuron cycles within the spinal cord, while the increased amplitude may be caused by disinhibition from the cortical-subcortical pathways, as had been reported by previous studies of sialidosis.

Our study revealed that patients may present with intermittent painful paresthesia as an initial symptom of sialidosis, which has rarely been described in previous studies. A case series documented that one of the 5 patients reported having painful neuropathy [18], while sensory deficits were found among 8 of 17 patients in another study [19]. In our study, all patients reporting these symptoms did not have continuous numbness or other negative symptoms. In the evaluation, all patients reported normal results on clinical sensory examination and quantitative sensory testing. As a result, this symptom should belong to positive symptoms, which may be related to ectopic activities or central disinhibition. In a previous pathological study, storage materials were noted in the Schwann cells of sural nerves [8]. Sialic acid accumulations had also been reported to be present in the dorsal root ganglion [12]. Combining the electrophysiological study of the peripheral nerve system that we provided, the origin of painful paresthesia may be the peripheral nerve. However, the hyperexcitability described above may also contribute to patients’ presence of painful paresthesia, for which the development of hyperalgesia and allodynia may be due to excessive responses and inadequate suppressive mechanisms to aberrant ectopic activities or benign sensory stimulations experienced by the patient [17].

Our study has several limitations. First, despite active recruitment of study subjects, we could only enroll 6 cases in our study. This is largely due to the rare nature of sialidosis, and study of a larger cohort with longer follow-up may reveal more abnormalities in the PNS for this disease. Second, many other techniques had been developed to further evaluate the pathophysiology of peripheral nerve disorders, such as nerve/skin biopsy, peripheral nerve imaging, and nerve excitability study. Incorporation of these techniques in future studies may lead to better understanding of the pathophysiology of this unique phenomenon in sialidosis.