Neuro-microcirculatory interrelationships in patients with kyphoscoliosis associated with neurological deficits

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BACKGROUND

Spinal deformities, such as kyphosis and scoliosis, may lead to spinal canal stenosis and subsequently to compression of the vascular-nerve structures, including the spinal cord. Imaging modalities for radiological–clinical and anatomical diagnostics [1] do not show the quantitative characteristics of the degree of damage and restoration of spinal cord function and the dynamics of the neurological status. Moreover, stenosis can cause changes in neurologic function parameters, such as the myelinated type A fibers and thin unmyelinated C-fibers. Myelinated structures contribute to specific functions within the body such as movements and deep sensitivity. Conversely, unmyelinated sympathetic and thin sensory fibers are involved in adaptation processes, tropism, patho- and sanogenesis, and pain systems. Sympathetic activity is associated with dystrophy, and sensory peptidergic nerve fibers play a crucial role in restorative processes, sanogenesis, and recovery [2]. In evaluating myelinated structures, including in spinal stenosis, electroneuromyography (ENMG) methods are used to determine the diagnostically significant indicators, namely, the amplitude of action potentials, motor and sensory response parameters, impulse conduction velocity and F-wave [3], and evoked potentials (somatosensory, cognitive, etc.) [4]. However, the state of thin unmyelinated and poorly myelinated fibers in spinal stenosis has not been studied; this may be due to the fact that these fibers have low conduction velocity and thus cannot be assessed using traditional ENMG. Thin fibers in the limbs are represented by sympathetic vegetative postganglionic C-fibers (vasomotor, to a lesser extent sweat-secreting, etc.) and sensory A-delta and C-fibers for pain and temperature sensitivity (sensory function, as well as trophic function, associated with neuropeptide secretion). Parasympathetic innervation is absent in the tissues of the limbs. In the field of vertebrology, some studies have investigated the function of thin nerve fibers. For example, using the thermography method, the role of the somatosympathetic reflex in the diagnosis of discopathy of the lumbar spine was determined [5].

Laser Doppler flowmetry (LDF) with spectral wavelet analysis of blood flow oscillations is a commonly used noninvasive method for assessing microcirculation [2, 6–9]. In the amplitude–frequency wavelet spectrum of the LDF records of microhemocirculatory signals, several characteristic frequency intervals ranging from 0.005 to 2 Hz were identified, each of which was associated with a specific physiological effect in skin microcirculation. This facilitates noninvasive assessment of the regulation of microcirculatory tissue systems. These include active tone-forming effects (endothelial, neurogenic, and myogenic) and passive effects caused by changes in pressure in microvessels (cardiac and respiratory) [2, 10]. Because the tone-forming ranges of 0.02–0.046 Hz and 0.047–0.069 Hz are associated, respectively, with sympathetic vasomotor adrenergic and sensory peptidergic influences on microvessels, respectively, the functional state of vasomotor sympathetic and sensory peptidergic innervation can be diagnosed noninvasively [2, 10]. This technique was first proposed in 2004 [10]. Regarding the range of microvessel perfusion oscillations, sympathetic adrenergic influences and accompanying angiospastic manifestations are considered ergotropic and sensory peptidergic, myogenic, and endothelial influences are trophotropic. The predominance of ergotropic factors is associated with degenerative–dystrophic processes, and the prevalence of trophotropic components of the regulation of microcirculatory tissue systems is linked to regeneration and restorative processes [2].

Notably, microcirculatory tissue systems are among the first to respond in the development of sanogenesis; therefore, the use of LDF indicators with wavelet analysis of blood flow oscillations before and after spinal surgeries is promising for the detection of the vector of functional dynamics [2, 9].

MATERIALS AND METHODS

Study design

A monocentric cohort retrospective comparative study was performed.

Eligibility criteria

At the N.N. Priorov National Medical Research Center of Traumatology and Orthopedics, 20 patients with spinal deformities associated with neurological deficits of varying severity were examined using the LDF method and operated on: 17 patients were below 18 years old (13.9±2.6 years) and three were adults. In the pediatric group, 10 cases of grade IV idiopathic kyphoscoliosis with Frankel neurological status C (seven patients) and D (three patients) and seven cases of thoracolumbar kyphosis that developed against hypoplasia of the Th12-L1 vertebral bodies were noted. This group of patients had spinal canal stenosis of 54.1±19.1%, assessed according to computed tomography (CT) myelography of the deformity apex in the sagittal plane. In adult patients, kyphotic deformity of the thoracic and thoracolumbar spine was registered. Examination showed a spinal canal stenosis of 53.3±16.4%. Frankel neurological status C (two patients) and D (one patient) were noted.

Study conditions

The patients were examined before the surgery, 1–2 weeks after surgery following regression of acute postoperative pain syndrome, and 3–6 months, 6–12 months, and more than a year after the surgery.

Method of medical intervention

Instrumental correction and fixation of the deformity without direct decompression of the spinal canal were performed in seven patients and two-stage surgical treatment involving dorsal stabilization of the spinal deformity and anterior decompression of the spinal canal in ten patients. Posterolateral decompression of the spinal canal was conducted in three patients.

Methods of recording outcomes

General examination including assessment of the neurological status and radiation diagnostics (i.e., postural radiographs of the spine and CT and magnetic resonance imaging of the spine with assessment of spinal stenosis) were carried out. Patients with severe kyphoscoliosis underwent CT myelography with subsequent design of individual full-size 3D models of the spine and myeloradicular structures made of plastic.

 

Fig. 1. An example of recording the wavelet spectrum of blood flow fluctuations according to laser Doppler flowmetry data before surgery.

Note. Horizontally — frequency ranges in Hz: e (endothelial), n (neurogenic), m (myogenic), rv (respiratory venular), c (cardiac). Vertically — the amplitude of fluctuations in blood flow in perfusion units. The red arrow is the activation of oscillations in the range of sympathetic adrenergic regulation of microvessels in the infrared channel. Sensory peptidergic activity has not been recorded.

 

Fig. 2. An example of recording the wavelet spectrum of blood flow fluctuations according to laser Doppler flowmetry 8 months after surgery.

Note. Horizontally — frequency ranges in Hz: e (endothelial), n (neurogenic), m (myogenic), rv (respiratory venular), c (cardiac). Vertically — the amplitude of fluctuations in blood flow in perfusion units. The red arrow indicates the absence of sympathetic adrenergic activity in the infrared channel and its marked decrease in the red recording channel. The blue arrow indicates the pronounced activity of sensory peptidergic regulation in the infrared recording channel.

 

Fig. 3. An example of recording the wavelet spectrum of blood flow fluctuations according to laser Doppler flowmetry 1.5 years after surgery.

Note. Horizontally: frequency ranges in Hz — e (endothelial), n (neurogenic), m (myogenic), rv (respiratory venular), c (cardiac). Vertically — the amplitude of fluctuations in blood flow in perfusion units. The red arrow indicates the absence of sympathetic adrenergic activity in the red and infrared recording channels. The blue arrow is the activation of sensory peptidergic regulation in the infrared recording channel. The double blue arrow is the synchronization of the frequency of myogenic activity in the red and infrared channels.

 

LDF with wavelet analysis was performed in all stages of the examination (Figs. 1–3). A perfusion study, with determination of the average microcirculation index (M, in perfusion units (p.u.)), was performed at the level of the pad of the distal phalanx of the big toe using a two-channel LAKK-02 device with a semiconductor laser (probing in the red and infrared channels) [2, 9]. The LDF results were processed using spectral amplitude–frequency wavelet analysis to characterize the factors of microcirculation regulation in the ranges of sympathetic adrenergic regulation (0.02–0.046 Hz), sensory peptidergic influences (0.047–0.069 Hz), and myogenic oscillations (0.07–0.145 Hz). The maximum average amplitude of oscillations in each range, normalized by the root-mean-square deviation (σ), was determined by the equation A/σ, where A is the amplitude value in p.u. according to the previously described technique [2, 9] (Figs. 1–3).

Statistical analysis

Statistical processing was performed using the Biostat 4.03 program. The Mann–Whitney test was used to compare two samples. Quantitative data were presented as mean ± standard deviation.

Ethical considerations

The study was conducted according to the standards of the local ethics committee (meeting no. 7, dated August 5, 2021) and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. All patients (or their representatives) signed an informed consent to participate in the study.

RESULTS

After surgical treatment, the relative magnitude of spinal canal stenosis in patients in the postoperative period was 27.5±14.7% (before surgery: 54.1±19.1%). Eight patients with the Frankel C neurological status (in the form of lower mixed deep paraparesis) showed positive dynamics up to Frankel D. Seven of 12 patients with preoperative neurological status Frankel D did not show changes in neurological deficit, whereas five patients showed regression of neurological disorders up to Frankel E. The outcomes of surgical treatment of patients were assessed as good. In 13 patients (65%), regression of neurological deficit was detected during the follow-up period of 3–6 months after surgery. The delta of deformity correction in this group of patients was 29.3±12.1%.

 

Fig. 4. Frequency of activity of sympathetic adrenergic and sensory peptidergic regulation of microvessels in the wavelet spectrum of blood flow fluctuations, %.

Note. H — sympathetic adrenergic regulation of microvessels, SP — sensory peptidergic regulation of microvessels, IRed — infrared.

 

Figure 4 and Table 1 present the results of the study using the LDF method.

Examples of recording the wavelet spectrum of blood flow oscillations are shown in Figures 1–3.

Based on the data presented, during the postoperative recovery, clear dynamics of the functional state of thin nerve fibers were noted (Fig. 4). Under physiological rest conditions in healthy individuals (control group), the sympathetic adrenergic regulation was predominant, whereas trophotropic sensory peptidergic activity was detected in the wavelet spectrum in no more than 30% of cases. In patients in the preoperative period, this distribution was preserved; however, in precapillary microvessels (red channel recordings), sensory peptidergic regulation was not detected in the wavelet spectrum. After the surgery, a progressive change in the vector of nervous control of microcirculatory tissue systems was noted, namely, a distinct increase in the contribution of trophotropic sensory peptidergic innervation against a decrease in the representation of the ergotropic sympathetic adrenergic channel of regulation. The highest trophotropic contribution was observed in the time interval of 6–12 months after the surgery, regarding it as the most active recovery period.

 

Table 1. Indicators of laser Doppler flowmetry before and after surgical treatment

Examination interval	An./σ R	An./σ IR	Asp./σ R	Asp./σ IR	Am./σ R	Am./σ IR	M, p.u. R	M, p.u. IR
Before surgery	0.45±0.12	0.53±0.11	–	0.38±0.08	0.38±0.04	0.24±0.03	1.1±0.07	11.7±1.1
1–2 weeks after surgery	0.4±0.2	0.64±0.04*	0.57±0.12*	0.53±0.05*	0.41±0.09	0.3±0.08	2.3±0.05*	10±1.5
3–6 months after surgery	0.6±0.1	0.65±0.06*	0.41±0.08*	0.54±0.04*	0.39±0.07	0.19±0.1	2.34±0.04*	13±1.4
6–12 months after surgery	0.37±0.07*	0.44±0.06*	0.47±0.11*	0.43±0.04*	0.43±0.03*	0.28±0.05	5.4±0.09*	13±2.3
More than 1 year after surgery	0.45±0.15	0.5±0.12	0.32±0.07*	0.54±0.12*	0.35±0.1	0.34±0.04*	7.2±1.1*	18.7±1.5*
Control (n=20)	0.4±0.09	0.48±0.1	0.27±0.1	0.29±0.1	0.45±0.07	0.4±0.03	5.1±0.09	11.8±1.3

Note. *, p <0.05 for data in dynamics after surgery compared with preoperative results; R, red channel; IR, infrared channel.

 

The quantitative indices of the state of microcirculation and its regulation are of interest (Table 1). The preoperative period was characterized by low values of perfusion (M, p.u.) of the microvascular bed in the red recording channel, reflecting predominantly nutritive blood flow, absence of trophotropic sensory peptidergic oscillations in the same recording channel, and relatively low values of the amplitudes of myogenic blood flow oscillations associated with capillary perfusion. Positive changes of microvascular indices were determined after the surgery. The M value significantly increased, especially in the red recording channel. Moreover, the activity of sensory peptidergic nerve fibers increased and was maintained starting from the early postoperative period. Sympathetic adrenergic activity significantly decreased 6–12 months after the surgery.

DISCUSSION

In the present study, the laser Doppler flowmetry method was used to evaluate thin unmyelinated nerve fibers. LDF is widely used in modern fundamental and clinical medicine to evaluate microcirculatory tissue systems. In PubMed alone, approximately 12,000 publications on this topic in various fields of medicine were found. The advantages of the method are noninvasiveness, harmlessness of research, and the possibility of unlimited control over time, and for Russian devices of the LAKK series, it is also a computer quantitative analysis of records using spectral wavelet analysis of blood flow oscillations. This quantitative approach enables evaluation of the factors regulating microcirculation, including the functional state of thin unmyelinated nerve fibers involved in the innervation of microvessels (vasomotor sympathetic and sensory peptidergic). This is especially valuable for traumatology and orthopedics, as the results of LDF characterize not only the purely vascular component of tissue tropism implemented at the level of microcirculation but also the condition of the nervous component of tropism implemented through thin nerve fibers [2, 9]. Currently, this opportunity has become even more crucial owing to the fact that neurophysiological diagnostics in traumatology and orthopedics, including vertebrology, is based on an electrophysiological approach with an assessment of conductivity along myelinated nerve fibers. However, this approach is ineffective for diagnosing unmyelinated innervation.

The choice of the skin of the plantar surface of the big toe as the LDF registration zone was due to the high density of unmyelinated fibers, including perivascular, in the skin of the plantar and palmar surfaces in humans [9].

Results indicate that the contribution of trophotropic sensory peptidergic regulation begins to increase 3–6 months after surgery, reaches a maximum in 6–12 months, and decreases slightly, but remains a year or more after surgery. In this context, the participation of the ergotropic channel of regulation associated with sympathetic fibers is maintained at all stages; however, their contribution to the control of microcirculatory tissue systems decreased starting from month six after surgery, reaching a minimum in 6–12 months.

Among the quantitative parameters of microcirculation, the average perfusion value M demonstrated a clear progression in dynamics after the surgery. In quantitative terms, for cases of representation in the wavelet spectrum, the activity of the trophotropic sensory peptidergic channel of regulation (the values of the normalized amplitudes of blood flow oscillations of the corresponding genesis) increased significantly after surgery, and the activity of the ergotropic sympathetic channel (the values of the amplitudes of oscillations of the sympathetic adrenergic genesis) significantly decreased 6–12 months after surgery.

The obtained data indicate the significant participation of thin nerve fibers in the recovery processes after decompression surgeries in the spinal canal zone and in creating anatomical conditions for neurophysiological reparation in the spinal cord.

CONCLUSION

Using the LDF with spectral wavelet analysis of blood flow oscillations enables evaluation of the dynamics of the state of thin unmyelinated nerve fibers and recovery processes in patients with kyphoscoliotic spinal deformities associated with spinal cord compression. After surgery, the activity of trophotropic sensory peptidergic nerve fibers and microcirculatory bed perfusion increased and were maintained since the early postoperative period. Ergotropic sympathetic adrenergic activity significantly decreased 6–12 months after surgery. Maximum mobilization of trophotropic neurogenic mechanisms of sanogenesis was noted 6–12 months after the intervention.

ADDITIONAL INFO

Autor contribution. All authors confirm that their authorship meets the international ICMJE criteria (all authors have made a significant contribution to the development of the concept, research and preparation of the article, read and approved the final version before publication). The greatest contribution is distributed as follows: A.I. Krupatkin and I.M. Militsa — data collection and analysis, writing the text of the article, analysis of literary sources; A.G. Nazarenko and A.A. Kuleshov — writing and editing the text of the article; M.S. Vetrile, I.N. Lisyansky, S.N. Makarov — editing the text of the article.

Funding source. The authors state that there is no external funding when conducting the research and preparing the publication.

Competing interests. The authors declare that they have no competing interests.

Consent for publication. The patient gave his written consent for publication of his medical data.

ДОПОЛНИТЕЛЬНО

Вклад авторов. Все авторы подтверждают соответствие своего авторства международным критериям ICMJE (все авторы внесли существенный вклад в разработку концепции, проведение исследования и подготовку статьи, прочли и одобрили финальную версию перед публикацией). Наибольший вклад распределён следующим образом: А.И. Крупаткин и И.М. Милица — сбор и анализ данных, написание текста статьи, анализ литературных источников; А.Г. Назаренко и А.А. Кулешов — написание и редактирование текста статьи; М.С. Ветрилэ, И.Н. Лисянский, С.Н. Макаров — редактирование текста статьи.

Источник финансирования. Авторы заявляют об отсутствии внешнего финансирования при проведении исследования и подготовке публикации.

Конфликт интересов. Авторы декларируют отсутствие явных и потенциальных конфликтов интересов, связанных с проведённым исследованием и публикацией настоящей статьи.

Информированное согласие. Авторы получили письменное согласие пациента на публикацию его медицинских данных.

About the authors

Anton G. Nazarenko

N.N. Priorov National Medical Research Center of Traumatology and Orthopedics

Email: nazarenkoag@cito-priorov.ru
ORCID iD: 0000-0003-1314-2887
SPIN-code: 1402-5186

MD, Dr. Sci. (Medicine), professor of RAS

Russian Federation, 10 Priorova str., 127299 Moscow

Alexander I. Krupatkin

N.N. Priorov National Medical Research Center of Traumatology and Orthopedics

Email: krup.61@mail.ru
ORCID iD: 0000-0001-5582-5200
SPIN-code: 3671-5540

MD, Dr. Sci. (Medicine), professor

Russian Federation, 10 Priorova str., 127299 Moscow

Alexander A. Kuleshov

N.N. Priorov National Medical Research Center of Traumatology and Orthopedics

Email: cito-spine@mail.ru
ORCID iD: 0000-0002-9526-8274
SPIN-code: 7052-0220

MD, Dr. Sci. (Medicine)

Russian Federation, 10 Priorova str., 127299 Moscow

Igor M. Militsa

N.N. Priorov National Medical Research Center of Traumatology and Orthopedics

Author for correspondence.
Email: igor.milica@mail.ru
ORCID iD: 0009-0005-9832-316X
SPIN-code: 4015-8113
Russian Federation, 10 Priorova str., 127299 Moscow

Marchel S. Vetrile

N.N. Priorov National Medical Research Center of Traumatology and Orthopedics

Email: vetrilams@cito-priorov.ru
ORCID iD: 0000-0001-6689-5220
SPIN-code: 9690-5117

MD, Cand. Sci. (Medicine)

Russian Federation, 10 Priorova str., 127299 Moscow

Igor N. Lisyansky

N.N. Priorov National Medical Research Center of Traumatology and Orthopedics

Email: lisigornik@list.ru
ORCID iD: 0000-0002-2479-4381
SPIN-code: 9845-1251

MD, Cand. Sci. (Medicine)

Russian Federation, 10 Priorova str., 127299 Moscow

Sergey N. Makarov

N.N. Priorov National Medical Research Center of Traumatology and Orthopedics

Email: moscow.makarov@gmail.com
ORCID iD: 0000-0003-0406-1997
SPIN-code: 2767-2429

MD, Cand. Sci. (Medicine)

Russian Federation, 10 Priorova str., 127299 Moscow

References

Supplementary files