Low-Intensive Electropulse Therapy for Correction of Clinical
and Functional Manifestations of Neuropathy in Multiple Myeloma
Victor A. Drobyshev1, Oleg I. Zakhariya2,
Stanislav G. Abramovich3*, Marsel A. Kadyrov4, Alexander A. Markov5
1Department of Hospital Medicine and Medical Rehabilitation,
Novosibirsk State Medical University, 630091, Krasny Ave., 52. Novosibirsk, Russian
Federation
2Department of Therapy, Hematology and Transfusiology, Novosibirsk
State Medical University, 630091, Krasny Ave., 52. Novosibirsk, Russian Federation
3Department of Physiotherapy and Balneology, Irkutsk State
Medical Academy of Postgraduate Education Branch of the Russian Medical Academy
of Continuing Professional Education 664049,
100 Yubileyniy Microdistrict, Irkutsk, Russian Federation
4Department of Geology of Oil and Gas Fields, Tyumen Industrial
University 625000, 56 Volodarsky Str., Tyumen, Russian Federation
5Department of Traumatology and Orthopedics with the course of children's traumatology INPR,
Tyumen State Medical University, 625023, 54 Odesskaya Str., Tyumen, Russian Federation
*Corresponding Author E-mail:
prof.Abramovich@yandex.ru
ABSTRACT:
Polychemotherapeutic drugs can affect neuros system in
patients with myeloma, which can worsen their quality of life and promote disease
progression. The authors studied the dynamics of pain syndrome, microcirculation
status and parameters of quality of life in patients with multiple myeloma complicated
by peripheral polyneuropathy under polychemotherapy. In the course of the present
study 106 patients were examined and divided into the three groups: in group I the
patients were indicated standard polychemotherapy supplemented with the course of
dynamic electroneurostimulation, in group II the patients were treated with placebo
procedures along with the basic treatment, and in group III the patients received
standard treatment. It was established that by the end of the therapy pain syndrome
intensity decreased in patients from group I by 1.8 times, initially elevated pain
threshold decreased by 24.4% and basal microcirculatory parameters improved by 1.4
times, whereas in the comparison groups significant changes were not observed. The
treatment influenced on the quality of life: in group I the score of physical functioning
(SF-36 questionnaire) increased by 1.5 times in comparison with the baseline, the
score of general health perception and vitality increased by 1.7 and 1.5 times,
respectively, which significantly differed from analogue parameters score in the
comparison groups. It was established that introduction of dynamic electroneurostimulation
into the treatment plan of patients with multiple myeloma reduced pains intensity,
decreased pain threshold, stimulated microhemocirculation and contributed to improvement
of quality of life that allowed the patients to continue their specific polychemotherapy.
KEYWORDS: Dynamic electroneurostimulation, peripheral
polyneuropathy, pain syndrome, impulse amplitude, basal microcirculation.
INTRODUCTION:
It is known that patients with multiple myeloma are prone
to neurotoxic effect of the majority of polychemoterapeutic drugs that provoke neurologic
symptoms manifestation associated with the influence of the therapy on neurovascular
structures1. This worsens patients quality of life and often interferes
with the course of polychemotherapy, which promotes the disease progression2.
Local or regional hemocirculation impairment is a significant
factor in the development and progression of peripheral polyneuropathy3,
wherein venous drainage impairment is one of the factors that compresses neurovascular
bundle and perivascular nerve plexuses, which often leads to the development of
neurodystrophy4. In particular, indication to patients with multiple
myeloma Bortezomib like drugs, that exert neurotoxic effect, significantly increased
the rate of peripheral polyneuropathy incidence even at the early stage of the disease1.
Clinical picture of multiple myeloma, associated with osteodestructive
process, is characterized by reflectory and compression syndrome that determines
the irritation of nerve guides and leads to the development of chronic pain symptom
complex, as well as angiospastic and myotonic syndromes5,6. These nervous
system impairments, known as paraproteinemic neuropathy, are associated with the
presence of pathologic immunoglobulins in blood that act as antibodies and damage
axons, myelin sheath, surrounding connective tissue and endoneural capillaries7.
All the above mentioned facts justify the development and
implementation of new low cost technologies for pain syndrome relief in patients
with multiple myeloma, which is especially relevant due to the Decree of the Ministry
of Healthcare of the Russian Federation №1343n dated 12.21.2012 “Guidelines
on palliative care to adult population”. Published research data shows that low
intensity electroimpulses reduce receptors activation and optimize microcirculatory
processes, which promotes pain relieving and spasmolytic effects 8. Dynamic
electroneurostimulation (DENS) is a modern method of electrical impulse therapy
that is based on microcurrents with constantly changing amplitude and duration of
impulse, wherein its pain relieving effect is exerted by multilevel reflectory and
neurochemical reactions that activate body regulatory9. The rationale
for the present study is explained by lack of research data in the available scientific
literature on the influence of dynamic electroneurostimulation on the intensity
of pain, microcirculation and quality of life in patients with multiple myeloma.
MATERIAL AND METHODS:
The research was held at the municipal hematologic center
of the “State Clinical Hospital №2” in Novosibirk. During the study 106 patients
with verified diagnosis of multiple myeloma (ICD-10 code C90.0) complicated with
peripheral polyneuropathy (ICD-10 code G63.1*) were examined. Duration of the disease
varied from 5 months to 1.5 years. There were 37.0% (40 people) of male and 63.0%
(68 people) of female patients aged from 47 to 69 (average patient age 58.1 ±4.8
years old).
Pain syndrome in lumbar spine was registered in all the
patients, in thoracic spine and upper limbs–in 50% (54 patients) and in lower
limbs–in 20.4% (22 patients). Peripheral sensor polyneuropathy, manifested as “tingling”,
“numbness” and “creeps”, was registered in 100% of patients.
The study exclusion criteria were the following: patient
immobility; somatic diseases at the stage of decompensation (myocardial infarction,
heart rhythm disturbance like persistent form of atrial aflutter or fibrillation,
heart failure FC 2B-3, chronic kidney disease of stage III and higher by М.А.
Ratner classification, respiratory failure stage 2-3); general contraindications
to physiotherapy (fever, acute inflammation processes, cachexia, acute infectious
diseases, active tuberculosis, diagnosed or suspected malignant neoplasms, bleeding
and angiostaxis, cardiovascular diseases with congestive heart failure, aortic and
major vessels aneurism, central nervous system disease with fast excitement onset,
individual physical factor idiosyncrasy); recent pathological fractures of tubular
bones in medical history).
The patients were distributed into groups by the code of
dynamic electroneurostimulation course that were blindly chosen by the patients.
According to the study design, the patients were distributed into the three groups:
patients from group I (main), that included 42 patients, received the basic treatments
and additionally a course of dynamic electroneurostimulation by the apparatus “DiaDENS-PKM”;
patients from group II (comparison group I), that included 34 patients, received
basic treatment and additionally an imitation of dynamic electroneurostimulation
(placebo) course by the apparatus “DiaDENS-PKM”; patients from group III (comparison
group II), that included 30 patients, received only basic treatment. The control
group included 30 healthy men and women aged from 25 to 55.
Basic treatment complex included Bortezomib (reversible
inhibitor of chymotripsin like activity in the 26S proteasome in mammals) polychemotherapy
according to the recommended protocols. Besides, treatment plans with melphalan
and prednisolone were used.
All the patients gave written informed consent for the
study participation. The form of voluntary informed consent was inspected and approved
by the local ethical committee.
General examination included neurologist and hematologist
examinations, general blood test, common urine test, biochemical blood assay, cranial,
pelvic and spinal bones X-ray imaging, bone marrow examination (aspiration biopsy
and trepanobiopsy), immunoelectrophoresis of blood and urine proteins, ECG.
Neurological examination was performed in a standard manner
by conventional methods of evaluation of afferent and efferent cranial nerves functioning.
Verification of peripheral polyneuropathy was performed based on patients complaints,
medical history and neurological examination.
For evaluation of pain syndrome intensity the authors used
verbal rating scale (VRS, 1986) and visual analogue scale (VAS, 1986); quantitative
parameters of pain sensitivity were estimated with algometer (normal value for healthy
people is 0.5 mm).
Microcirculation status was evaluated by laser Doppler
flowmetry (LDF) with laser analyzer of superficial capillary blood flow rate (LАКК-01)
in the projection of maximal painfulness. Apart from microcirculation parameters,
the authors assessed slow vasomotor fluctuations (LF) associated with rhythmic activity
of microcirculatory components and pulse fluctuations (CF) that reflect pulse wave
conduction to microcirculatory bloodstream (CF). Functional test was performed under
breathholding for evaluation of bloodstream reduction response to activation of
sympathetic nervous system10.
Quality of life was assessed by SF-36 questionnaire.
DENS therapy was performed throughout all the hospitalization
period (15 days) according to the guidelines provided by the apparatus inventors.
Portable applicator was placed on the neck and collar area (inions, projection of
C2 vertebra). The applied current frequency was 70-10 Hz, output power was 5 units
and duration time was 15 minutes. Besides, an applicator was placed on liver area
with frequency 60 Hz, output power was 5 units and duration time was 10
minutes.
Statistical analysis of the obtained data was performed
by the software package Statistics 17.0. Normality of features distribution was
checked by Kholmogorov-Smirnova criterion. For evaluation of statistical significance
of differences (before and after the treatment) under normal distribution, the authors
used Student’s t-test for analogue pairs. When distribution was abnormal, Wilcoxon’s
t-test was used. Analysis of qualitative parameters was performed by Fisher’s t-test.
If the studied sampling distribution was abnormal, non-parametric Kruskal-Wallis
test was performed. The data was expressed as «mean±error of the mean» (М±m).
Critical level of significance during statistical analysis was set as 0.05.
RESULTS AND DISCUSSION:
Initially, all the patients complained on moderate rheumatic
and dull pain in different areas of spine and limbs. Dynamic observation, performed
during the treatment, revealed the following data: moderate pain intensity remained
in 19.0% of patients from group I on the 5th day of treatment with DENS
and mild pain intensity–in 81.0%, whereas in group II mild and moderate pain intensity
was observed equally in 50% of patients, and in group III 30% of patients had moderate
pain intensity and 70% of patients had mild pain intensity. By the 9th
day of treatment mild pain remained in 85.0% of patients and moderate pain-only
in 15.0%. By this time, 60% of patients had mild pain intensity and 40% of patients
had moderate pains. In group III, 30% of patients had moderate pains and 70% of
patients had mild pains. By the 15th day of treatment, mild pains remained
in 40.5% of patients in group I, the rest patients had pain syndrome relieved. In
group II mild pain remained in 2/3 (58.8%) of patients, and in group III pains remained
in 50% of the patients.
Fig. 1: Dynamics of pain syndrome intensity by
VAS in the treatment groups (in score points)
Note: *–significance of differences in comparison with baseline
data (р<0.05).
The dynamics of pain syndrome evaluation by visual analogue
scoring VAS showed that if initial intensity of pain syndrome was moderate or severe,
by the end of the treatment course patients from group I had pain syndrome intensity
reduced by 1.8 times (p=0.018), which corresponded with mild pain intensity (Figure
1), whereas in group II the pain intensity reduced by 1.3 times (p=0.029), and in
group III–by 1.2 times (p=0.035), which remained to correspond with moderate pain
intensity.
Pain threshold parameters values, assessed by algometer,
showed that initial pain threshold was elevated by 2.0 times as compared to normal
values, which indicated on hypesthesia. By the end of the treatment, in the group,
where patients received the treatment along with dynamic electroneurostimulation,
pain threshold decreased by 24.4%, whereas in the groups of placebo and basic treatment
the pain threshold decreased only by 8.3% and 8.1%, respectively (Figure 2).
Initially, all the patients had spastic type changes in
microcirculation which was characterized by the reduction of microcirculation by
1.4 times as compared to the control values (р=0.028) and indicated on hemoperfusion
difficulties in the studied area due to feeding vessels spasm. After the period
of observation, patients from group I had basal microcirculatory parameter value
increased by 1.4 times (p=0.026), whereas in other comparison groups the parameters
did not change significantly (Table 1).
Fig. 2: Pain threshold change dynamics in
the treatment groups
Note: *–significance of differences in comparison with
baseline data (р<0.05).
Antitonic influence of dynamic electroneurostimulation
was confirmed by vasomotor fluctuations change (LG) that decreased by 1.2 times
in group I as compared to baseline (p=0.017), whereas parameters of pulse fluctuations
amplitude (CF) increased by 1.2 times (р=0.042), which was confirmed by hemoperfusion
improvement in the damaged area. In the comparison groups LF and CF parameters did
not differ significantly by the end of the treatment.
To evaluate the quality of life of patients, the authors
used SF-36 questionnaire before the treatment and 6 months after the treatment (Table
2). Significant improvement of quality of life nearly by all the scoring parameters,
that characterized physical and psychological state, was observed in patients from
group I. Statistically significant improvement was observed in physical functioning
(PF) that reflected the physical state under physical exercises (self-care, walking,
stair climbing, loads carrying, etc). Thus, in group I initial average PF score
of 28.6±3.1 increased by 1.5 times and was equal to 42.1±3.3 (p=0.004). In the control
groups maximal PF value was equal to 35.0±2.7, which did not exceed 1.2 times. Significant
changes were also observed in parameters of general health status and vitality (GH,
VT), that reflected patients evaluation of their current health status and treatment
prognosis. In group I, VT parameter scoring, that was initially equal to 26.4±2.7,
increased to 46.9±3.0, i.e. by 1.7 times (p=0.008), whereas in the control groups
this parameter score increased only by 1.3 times. In group I, GH parameter scoring
increased by 1.53 times, which was equal to 44.3±2.5, as compared to initial score
28.9±2.9 (p=0.007). In the control groups, GH parameter scoring increased by 1.3
times.
CONCLUSION:
Introduction of dynamic electroneurostimulation into the
basic treatment plan of patients with multiple myeloma contributes to the correction
of peripheral polyneuropathy associated with Bortezomib therapy that exerts neurotoxic
effect. After the course of optimized DENS therapy, qualitative and quantitative
parameters of pain intensity significantly decreased, pain sensitivity threshold
lowered and microcirculatory processes improved in comparison with the analogue
parameters in comparison groups. The obtained results indicate on pain relieving
and microcirculation stimulating effect of DENS therapy in patients with multiple
myeloma, which makes it possible to continue the required specific chemotherapy.
ACKNOWLEDGEMENT:
Not applicable.
CONFLICT OF INTEREST:
The authors declare
no conflict of interest.
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