الفهرس 
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Abstract
Polyneuropathies (PNP) are among the most frequent neurological disorders and cause significant morbidity and use of resources. Assessment is based on clinical status and diagnostic tools. However, Finding the cause of neuropathic deficits remains a challenge in daily clinical routine. Although technical tools have improved and electrophysiological studies, skin and nerve biopsy, next generation sequencing, cerebrospinal fluid (CSF) analysis or antibody testing are established methods, the cause of PNP remains unclear in up to one third of patients. Imaging tools such as MRI of the roots and nerves could contribute to the diagnosis of immune mediated neuropathies, hereditary transthyretin (TTR) associated systemic amyloidosis and others in the recent past (Decard et al., 2018). However, their use is still limited to specialized centers. In contrast, ultrasound (US) is a widely distributed tool, which can visualize nerves and roots with high resolution and accuracy. A growing number of studies have been published in the last decade concerning ultrasound findings in polyneuropathies.
Neurofilament (NfL) is an intracellular glycoprotein and is a major structural component of neurons, which is mainly detected in larger neurons and their myelinated axons. It is formed of a triplet protein, of which the light subunit NfL is a vital part of the neurofilament core (Kuchel et al., 1997). It is principally important for maintaining the axonal caliber and thereby playing a crucial role in the structural and functional integrity of axons and their capacity to rapidly conduct nerve impulses (Jordanova et al., 2003).
This study aimed to identify the diagnostic role of neuromuscular ultrasound (NMUS) in detection of the characteristic sonographic findings among various neuropathies, then comparing the sonographic data with the electrophysiological findings, and finally correlating the clinical, electrophysiological, biomarker and sonographic data. This study employs a cross sectional design, including 58 patients (31 males, 27 females) with different causes of neuropathy, and 30 controls (15 males, 15 females) attending the Neurology, Internal Medicine and/or Rheumatology and Rehabilitation outpatient clinics at Minia University Hospital and and Specialized Leprosy hospital, during the period from September 2020 to February 2021.
Included cases of neuropathy were diagnosed by a combination of neuropathic symptoms and/or signs, plus abnormal laboratory findings & abnormal electrodiagnostic studies, according to the recommendations of the American Academy of Neurology, American Association of Electrodiagnostic Medicine (AAEM) and American Academy of Physical Medicine and Rehabilitation (England et al., 2005). In addition to symptoms and signs, we assessed neuropathy by functional assessment scores; Total neuropathy Score (TNS), Visual Analogue Scale (VAS), Leeds Assessment of Neuropathic Symptoms & Signs score (LANSS).
Patients included three main pathological groups: leprosy (20 patients), diabetes mellitus (20 patients) and other (18 total; 5 chronic Inflammatory Demyelinating Polyneuropathy (CIDP), 1 Acute axonal motor neuropathy (AMAN), 8 charcot Marie Tooth (CMT), and 4 vasculitis) along with a control group (30 participants). The patients were well matched to the controls, with no significant differences in age, sex distribution, anthropometric measures (weight, height, and body mass index) or other demographic data, apart from occupation. Differences in demographics between individual etiological groups and controls were also not statistically significant. Overall, 27 patients (45.6%) had demyelinating form of neuropathy, while 31 patients (53.4%) had axonal neuropathy. When those two groups were compared, the demyelinating group had significantly more males, and rural dwellers.
Clinically, patients with demyelinating neuropathies had significantly more trophic changes, while patients with axonal neuropathies had significantly more neuropathic pain. Also, axonal patients had significantly higher scores in the semi-objective Leeds Assessment of Neuropathic Symptoms & Signs scores (LANSS) scores than demyelinating patients. However, this difference was not significant in the subjective visual analogue scale (VAS), or in the overall severity of neuropathy assessed by total neuropathy score (TNS).
Comparing the different laboratory measures, patients had significantly higher ESR, random blood sugar (RBS) and serum neurofilament light chain (NfL) levels than controls. The differences in ESR and NfL from controls were evident in both demyelinating and axonal groups, while the difference in RBS was significantly higher in the axonal group. When NfL was compared across etiological categories, it was found to be highest in CMT I, and lowest in AMAN, though the difference between etiological groups was not significant.
As for ultrasound findings, the CSA of all studied nerves (median, ulnar, tibial, fibular, sural, C5, C6, and vagus) was significantly increased in patients than controls, which was most significant in upper and lower limb nerves and least significant in the cervical roots and vagus nerves. This difference in CSA was more apparent in demyelinating patients, while the difference in CSA was not significant between axonal patients and controls in c5, c6, vagus nerve and most sites examined in limb nerves (apart from some common entrapment sites). Further analysis showed that CSA was significantly increased in demyelinating than axonal neuropathy group at all measured sites.
Correlation of CSA of examined nerves and neuropathy measures (TNS, VAS) showed a statistically significant positive correlation at different sites. LANSS score showed a positive correlation with CSA of median nerve at wrist, and negative correlation with CSA of fibular nerve at fibular head, CSA of vagus nerve at common carotid bifurcation and at thyroid gland levels.
Another ultrasonographic finding, echogenicity, was also significantly abnormal in neuropathy patients versus controls. Echogenicity changes in the form of decreased echogenicity with or without loss of fascicular pattern, increased echogenicity, or mixture between both in the fascicles of a single nerve at a certain site, were detected significantly more frequently than controls in most examined sites of peripheral nerves and the vagus nerve, but not in the cervical roots. These changes in echogenicity however did not significantly differ between demyelinating and axonal patients.
Of interest, was the presence of positive doppler signals in all measured nerves of both upper and lower limbs in assessed cases, significantly more than controls. This difference in doppler signals was more apparent in demyelinating patients than in axonal cases.
Comparing different electrophysiological parameters between axonal and demyelinating groups showed statistically significant difference in distal motor latencies of ulnar, fibular nerves, sensory peak latencies of ulnar and sural nerves as well as in conduction velocities of ulnar, sural, tibial, and fibular nerves. There was a significant difference in amplitudes of median, ulnar, and sural nerves. Overall, the conduction velocities were significantly less, and distal latencies were significantly delayed in demyelinating versus axonal neuropathies.
As for the correlation of electrophysiological parameters and NMUS, there was a significant correlation between motor distal latencies and CSA of corresponding upper and lower limb nerves, but the correlation of sensory distal latencies with CSA was not significant. On the other hand, the amplitude of both motor and sensory evoked responses was negatively correlated significantly with CSA of corresponding upper limb nerves, but not with lower limb nerves. Conduction velocity however showed a peculiar pattern, with motor conduction velocities of the median nerve negatively correlated significantly with CSA at the forearm and arm, while sensory conduction velocities of the ulnar nerve were negatively correlated significantly with CSA of the ulnar nerve at all examined sites. In the lower limbs, CSA of examined nerves showed significant negative correlations with motor conduction velocity of the tibial and fibular nerves and sensory conduction velocity of the sural nerve. Overall, there were positive correlation between sonographic CSA of studied nerves with distal latencies and negative correlation with conduction velocity and amplitude evoked responses detected by NCS, though this correlation was not uniformly significant, varying according to different aetiologies. Generally, most correlations between NMUS and NCS parameters were weak (r<0.45) even for the significant correlations.
Overall, however, there was poor agreement between NMUS data and electrodiagnostic tests in classifying patients as axonal versus demyelinating (Cohen’s k= 0.12). Sonographic measures such as changes in CSA, echogenicity and doppler signals can be present at different nerves and sites in both demyelinating and axonal neuropathies, complementing electrophysiological data to diagnose a specific disease.
Ultrasound in Leprotic Neuropathies:
Our study showed a statistically significant differences in CSA of almost all of measurement sites of the different nerves compared to control groups. Differences in CSA were noticed more in a focal pattern along the course of different nerves at entrapment and non-entrapment sites. It is worthwhile to mention that the focal enlargement pattern observed in ulnar nerve CSA showed the greatest CSA few mm above elbow. Moreover, distinct significant changes were observed in sonographic echogenicity in leprotic cases in many of measured sites in both upper and lower limbs, in the form of decreased echogenicity with or without loss of fascicular pattern, reflecting underlying ongoing pathology. Additionally, leprotic cases had significantly higher positive doppler signals compared to controls in many of measurement sites of the different nerves, reflecting an ongoing inflammatory process.
Regarding Ultrasound in Hereditary Neuropathies:
Our study revealed that almost no significant difference was found in the examined nerves of axonal CMT group compared to controls in the upper limbs, lower limbs and in the nerves of the neck region. Some cases showed darker (more hypoechoic) fascicles; however, the echogenicity changes were not statistically significant compared with controls at all measured sites. Same was for the presence of doppler signals, which were not found to be positive in axonal CMT cases. On the other hand, patients with demyelinating CMT (CMT 1) forms showed a significant increase in CSA in almost all of measurement sites of the different nerves. However, in the neck region, no significant difference was found between CMT 1 group and controls. Furthermore, diffuse enlargement was noticed throughout the course of median and ulnar nerves. Similar changes were detected in lower limb nerves as well. In the neck region there was no significant enlargement of cervical roots as well as vagus nerve at different measurement sites. No significant differences were noticed in echogenicity and doppler signals between patients with demyelinating CMT form and controls as well like in the axonal CMT form.
Ultrasound in Immune-Mediated Neuropathies:
Our study revealed a significant difference in CSA in almost all of the measurement sites of the different nerves. Maximal enlargement sites were the more proximal ones along the course of different nerves. In the neck region there was significant enlargement of cervical roots as well as vagus nerve at different measurement sites. Further assessment revealed noticeable changes in sonographic echogenicity in many measurement sites of different nerves, of specific significance was the more proximal sites in nerves of both upper and lower limbs, in addition to the echogenicity of cervical root C6, and the echogenicity of vagus nerve at common carotid bifurcation. Echogenicity changes took the form of decreased echogenicity, increased echogenicity, or mixture between both, with or without altered fascicular pattern in the fascicles of a single nerve at a certain site. Additionally, as opposed to hereditary neuropathies, CIDP patients showed more significantly positive doppler signals in many of measurement sites of the different nerves. All of these findings may be attributed to the ongoing inflammatory process.