Przegląd Lekarski 2017 / 74 / 12 643

Marta BANACH1

Maria RAKOWICZ1

Rafał ROLA2

Jakub ANTCZAK1

Judyta JURANEK3,4

Wioletta KRYSA5

Anna SULEK5

1Department of Clinical Neurophysiology, Institute of Psychiatry and Neurology, Head:Dr n.med. Wojciech Jernajczyk Present address: Department of Neurology, Collegium Medicum, Jagiellonian UniversityHead:Prof. Agnieszka Słowik

2Department of Neurology, Institute of Psychiatry and NeurologyHead:Prof. Halina Sienkiewicz-Jarosz

3New York University Langone Medical CenterHead:Prof. Ann Marie Schmidt

4Department of Pathology, Faculty of Medical Sciences, University of Warmia and Mazury Head:Prof. Joanna Wojtkiewicz

5Department of Genetics, Institute of Psychiatry and NeurologyHead:Prof. Małgorzata Bednarska-Makaruk

Additional key words:myotonic dystrophy 1 and 2polyneuropathynerve conduction studyperipheral nervous system

Dodatkowe słowa kluczowe: dystrofia miotoniczna typu 1 i 2 polineuropatiabadanie neurograficzneobwodowy układ nerwowy

Address for correspondence:Dr Marta Banach, Department of Neurology Collegium Medicum, Jagiellonian University ul. Botaniczna 3, 31-503 Krakow, Poland phone: +48 12 424 86 00, fax: +48 12 424 86 26 e-mail: martabanach@yahoo.com

The Authors have no conflict of interest to report

Received: 22.01.2017Accepted: 13.11.2017

ORIGINAL PAPERS

Peripheral nerve lesions in patients with myotonic dystrophy types 1 and 2

Uszkodzenia nerwów obwodowych u pacjentów z dystrofią miotoniczną typu 1 i 2

Introduction: PN is well docu-mented in 20-30% patients with DM1 by electrophysiological and patholog-ical findings. The underlying causes of these lesions remain unclear. The controversy centres around the fact whether peripheral neuropathy (PN) in DM is primary or secondary to oth-er causes such as diabetes, thyroid abnormalities or drugs taken.

Objectives: We aimed to establish the prevalence and electrophysiologi-cal characteristics of peripheral nerve lesion in both types of DM in patients molecularly confirmed, without any known co-morbidities affecting pe-ripheral nerve function.

Material and Methods: Forty pa-tients (20 DM1 and 20 DM2) under-went the electroneurography (ENG) of sensory fibers of the median and ulnar, (orthodromically), sural and su-perficial peroneal nerves (antydromi-cally). The motor nerve conduction velocity of the axillar, ulnar, median, tibial, peroneal and femoral nerves was determined. The F wave and H reflex were performed. All patients took a semi-structured questionnaire interview and neurological examina-tion.

Results: Among patients with ob-served peripheral nerve lesions, 30% DM1 and 25% DM2 patients had poly-neuropathy of predominantly axo-nal origin. Motor lesions were more prevalent than sensory ones, with the peroneal nerve being the most commonly affected in both types of DM. Similarly to DM1, none of DM2 patients complained of any sensory symptoms of neuropathy, however 65% of them complained of muscu-loskeletal pain. Excessive, trouble-some sweating of hands and trunk was present in 45% of all patients. Upper limb tremor was noted in 38% patients.

Conclusions: The prevalence and electrophysiological characteristics of peripheral nerve lesions were simi-lar in both types of DM, except for the autonomic impairment and muscu-loskeletal pain, which seems to be more prevalent in DM2 patients. We

Wstęp: Udokumentowano obec-ność neuropatii u około 20-30% chorych z DM1 zarówno z użyciem technik neurofizjologicznych jak i neuropatologicznych. Dotychczas jednak przyczyny obserwowanych uszkodzeń u tych chorych pozostają niejasne. Pozostaje kwestią dysku-syjną czy neuropatia obwodowa u pa-cjentów z DM ma charakter pierwotny, czy jest wtórna do toksycznego wpły-wu stosowanych leków, zaburzeń czynności tarczycy lub współistnieją-cej cukrzycy.

Cel: Celem badania była ocena częstości występowania oraz charak-teru zmian w obwodowym układzie nerwowym u pacjentów z potwierdzo-nymi molekularnie z dystrofią mio-toniczną typu 1 (DM1) i typu 2 (DM2), bez żadnych znanych współistnieją-cych schorzeń powodujących zmiany w obwodowym układzie nerwowym. Materiał i Metodyka: W badaniach wzięło udział 40 pacjentów (20 DM 1 i 20 DM 2). Wykonano badanie neuro-graficzne (ENG) włókien czuciowych nerwów: pośrodkowego i łokciowe-go (ortodromowo) oraz strzałkowego powierzchownego i łydkowego (an-tydromowo) oraz włókien ruchowych nerwu pachowego, pośrodkowego, łokciowego, udowego, strzałkowego i piszczelowego. Oceniano również odpowiedzi późne: falę F i odruch H. Przeprowadzono ukierunkowany wywiad oraz badanie neurologiczne. Wyniki: Częstość występowania oraz elektrofizjologiczna charakterystyka uszkodzeń nerwów obwodowych była podobna w obu typach DM. U 30% pa-cjentów z DM1 i u 25% z DM2 wykaza-no elektrofizjologiczne zmiany wska-zujące na polineuropatię Dominowało uszkodzenie nerwów o charakterze aksonalnym z przewagą uszkodzenia włókien ruchowych i najczęstszym uszkodzeniem nerwów strzałowych. U 65% pacjentów z DM2 występował ból mięśniowo-szkieletowy a u 45% pacjentów nadmierna potliwość.

Wnioski: Opierając się na wyni-kach naszych badań, wnioskujemy iż uszkodzenie obwodowego ukła-du nerwowego jest częste i stanowi

644

IntroductionMyotonic dystrophy type 1 (DM1) and

2 (DM2) are autosomal dominant inherited neuromuscular disorders, clinically charac-terized by myotonia, muscle dysfunction, and multisystemic complications [1]. Both disorders, although caused by unrelated genes, share the same RNA-mediated pa-thomechanism [2,3]. DM1 is caused by an expanded unstable CTG trinucleotide repe-at in the 3’UTR of the dystrophia myotoni-ca-protein kinase (DMPK) gene located on chromosome 19, while DM2 is caused by a CCTG tetranucleotide repeat expansion of the nucleic acid-binding protein (CNBP, formerly zinc finger protein 9, ZNF9) loca-ted on chromosome 2 [4,5]. Recent studies have shown that expanded CUG or CCUG repeats lead to toxic RNA accumulation wi-thin the nucleus and this pathological pro-cess, known as the RNA gain-of-function, contributes to multisystemic pathophysiolo-gy of DM1 and DM2 [2,6,7].

Both diseases have common clini-cal characteristics, with DM1 being more symptomatic than DM2 [5,8]. Myotonia and slow-progressing muscle weakness are the first and the most predominant clinical ma-nifestations of DM, often accompanied by cognitive impairment, hyperglycemia, car-diac conduction abnormality, sleep-related breathing disorders, posterior capsular ca-taracts and endocrine changes [9-11]. The most distinctive feature differentiating DM1 from DM2 is the initial location of clinical-ly detectable muscle weakness. In DM1, it occurs distally and primarily affects the finger flexors and tibialis anterior muscle, while in DM2, it is first detectable in the pro-ximal musculature of the lower extremity, hence its former name “proximal myotonic myopathy” (PROMM) [12,13]. Both dise-ases can be further differentiated by the severity of central nervous system (CNS) impairment. Depression, mental retarda-tion, memory loss and white matter atrophy are pronounced and common in DM1, whi-le only a small percentage of DM2 patients present these symptoms and usually in a milder form [11,12].

While CNS impairment is well eviden-ced as part of DM clinical manifestation [14-16], the involvement of the peripheral nervous system (PNS) has been less stu-died. A few available studies reported that abnormalities in nerve conduction studies in patients with DM resulted from myogenic changes or incidental concomitant radicu-lopathy rather than from peripheral poly-neuropathy [17]. However, in recent years, a growing number of research with more extensive electrophysiological testing sug-gested a major role of PNS impairment in the pathogenesis of DM1 [18-20].

While electrophysiological studies of peripheral nerves have been extensively conducted in DM1 patients, there is limi-

ted data on peripheral nerve dysfunction and impaired conduction velocity in DM2 patients. Here, in this study, we aimed to investigate PNS pathology in DM patients and to provide comparative characteristics of peripheral neuropathy in DM1 and DM2 patients.

Materials and MethodsSubjectsThe study included 40 patients with

DM1 and DM2 (age range, 20-58 years and 18-60 years, respectively, which is the normal age range for the onset of the disease [8]). All patients provided written informed consent to participate in the stu-dy. The study protocol performed in accor-dance with the ethical standards laid down in the Declaration of Helsinki and its later amendments and was approved by the ethics committee of the Institute of Psy-chiatry and Neurology, Warsaw, Poland. None of the patients were diagnosed with uremia, hepatopathia, alcoholism, toxic exposure, diabetes mellitus, or any other conditions causing damage to the PNS. Patients with a prior diagnosis of radicu-lopathy or common entrapment neuropa-thies were excluded from the study. In all patients, the diagnoses of DM1 and DM2 were genetically confirmed and routine laboratory examinations including creati-nine phosphokinase, oral glucose toleran-ce, thyroid function and hepatic tests were performed. Patients underwent a semi--structured questionnaire interview, stan-dard neurological examination (performed according to a standardized protocol by the same neurologist), and an extensive electrophysiological examination of peri-pheral nerve functions. None of the enrol-led patients complained of symptoms sug-gesting neuropathy such as dysesthesia, numbness or sensory loss in feet and/or hands.

Electrophysiological examinationThe electrophysiological examination

was conducted using a Viking IV electro-myograph (Nicolet Biomedical Incorpora-ted, Madison, USA) according to standard protocols [21]. In all patients, the electro-physiological examination of motor and sensory fibers of the median, ulnar, axil-lary, peroneal, sural, and tibial nerves was performed [30]. Surface silver electrodes or ring finger electrodes were used to stimu-late the nerve. The duration of stimuli was 0.2 ms at all sites. Sensory nerve action potentials (SNAP) and compound motor action potentials (CMAP) were recorded with two surface cup electrodes (8 mm in diameter) 3 cm apart.

The results of the examinations were compared with our own reference stan-dards and with those adopted from the li-terature [21].

Sensory nerve conduction studies: Sensory fibers were stimulated repetiti-vely, with supramaximal power at a rate of 2 Hz. The signal obtained from 20 sti-muli was averaged. An orthodromic con-figuration was used to test the nerves of the upper extremities and an antidromic one-to test the nerves of the lower extre-mities.

Motor nerve conduction studies: Single supramaximal stimuli were used to excite the peripheral nerve portions and the repeti-tive stimuli of the same intensity, at a rate of 1 Hz, were used to obtain the F wave.

In the upper limbs, stimulations were carried out over the left ulnar and right me-dian nerves at the following sites: 1) ulnar nerve: at the wrist, below and above the elbow, at the axilla, and at the supraclavi-cular fossa (the CMAP was recorded from the abductor digiti minimi); 2) median ne-rve: at the wrist, elbow, axilla, and suprac-lavicular fossa (The CMAP was recorded from the abductor pollicis brevis); and 3) left axillary nerve: at the supraclavicular fossa (the CMAP was recorded from the deltoid).

In the lower limbs, stimulations were carried out over the right peroneal and left tibial nerves at the following sites: 1) pero-neal nerve: at the ankle, under the fibular head, and at the lateral half of the popliteal fossa (the CMAP was recorded from the extensor digitorum brevis); 2) tibial nerve: at the ankle and in the middle of the popli-teal fossa (the CMAP was recorded from the abductor halluces); and 3) right femoral nerve: at the inguinal fossa (the CMAP was recorded from the rectus femoris). Accor-ding to the criteria of Hermans et al. [22], adapted from Oh et al. [23], the diagnosis of peripheral neuropathy was established when a patient had one absent F or H re-sponse at CMAP equal to or larger than 2 mV, along with prolonged distal motor latency and/or reduced nerve conduction velocity (NCV) in at least two nerves or re-duced NCV or absent response in at least one sensory nerve.

Statistical analysisThe distribution of continuous varia-

bles for normality was tested with One--Sample Kolmogorov-Smirnov test and data are presented as mean±SD or me-dian (range). Categorical variables are reported as frequency counts and per-centages. Differences in variables be-tween subgroups were evaluated by the unpaired t-test or Mann-Whitney U-test. Categorical variables were analyzed by the Pearson chi-square test. All analy-ses were performed using SPSS softwa-re version 15.0 (SPSS Inc., Chicago, IL, USA). A value of p <0.05 at a two-sided level was considered statistically signifi-cant.

conclude that peripheral nerve lesions are common and constitute an integral part of DM manifestation.

integralną część objawów DM. Częstość występowania i charakter zmian w badaniu neurofizjologicznym zarów-no w DM1 jak i w DM2 jest podobna. U pacjentów z DM2 znacznie częściej występuje zajęcie układu autonomicz-nego oraz bólu mięśniowo-szkieletowego.

M. Banach et al.

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ResultsClinical examination Muscle weakness was found in all pa-

tients with DM1 and occurred more often in distal than in proximal muscles; deep reflexes were depressed or absent in 53% of the patients. None of the patients com-plained of any sensory symptoms indica-tive of the presence of sensory neuropa-thy such as dysesthesia, numbness, or sensory loss in the feet or hands or both. A detailed neurological examination of the sensory nervous system remained within normal range.

All patients with DM2 showed muscle weakness or muscular atrophy, limited or predominant to the proximal upper and/or lower limb; excessive, troublesome sweat-ing of hands and trunk was present in 45% of all patients; 60% of all patients had calf muscle hypertrophy. Tendon reflexes were present in all DM2 patients however in 65%

of them the reflexes were increased. In 55 % of all patients, myotonic symptoms were mild, causing no functional problems. Simi-larly to DM1, none of DM2 patients com-plained of any sensory symptoms of neu-ropathy, however 65% of them complained of musculoskeletal pain. Upper limb tremor was noted in 38% patients.

Electrophysiological examination In DM1 30% of the patients showed

general preclinical (i.e., visible only in neu-rophysiological testing) changes correspon-ding to neuropathy, 25% showed unequal distribution of the changes corresponding to multiple mononeuropathy or only in a single nerve (Tab. I). The changes observed were predominantly axonal except several en-trapment neuropathies causing focal demy-elination. In 47% of the patients, the H-reflex was absent despite normal conduction velo-city of tibial and sural nerves.

In DM2 25% of the patients showed ge-neral preclinical changes corresponding to neuropathy and 15% showed variation in the distribution of changes corresponding to mononeuropathy (Tab. II).

All neuropathic patients showed clear sings of axonal neuropathy. In 19% of the patients, the H-reflex was absent despite normal conduction velocity of tibial nerves. None of the patients with DM2 showed electrophysiological features of segmental or generalized demyelination.

No statistically significant differences were seen between the peripheral neuro-pathy as defined by Oh in DM1 (30%) ver-sus DM2 (25%) patients.

Comparative analysis revealed a trend towards higher incidence of H-reflex ab-sence in DM1 (47%) versus DM2 (19%) patients, however it did not reach statistical significance.

Table I Detailed characteristics of electrophysiological changes observed in DM1 patients.Elektrofizjologiczna charakterystyka pacjentów z DM 1.

Patient No./sex/age Affected nervesTypes of abnormalities

DiagnosisSNCS MNCS

2/M/28; 4/F/27

none normal normal6/M/20; 7/F/37

13/M/46; 18/F/42

20/M/40; 14/M/25none normal unobtainable H reflex ambilateralis

11/M/20

3/F/58 R, L median ↓CNAP, ↓NCV not available bilateral median neuropathy; unobtainable H reflex ambilateralis

8/M/57 L median, R median ↓CNAP normal bilateral median neuropathy

9/M/29 R, L ulnar; R, L median ↓CNAP amplitude ↓CMAP, ↑DML, ↓NCV sensorimotor axonal neuropathy

10/F/41 L median, R peroneal normal ↓CMAP median and peroneal neuropathy

12/F/44 L axillary normal ↓CMAP, ↑DML axillary neuropathy; unobtainable H reflex L

15/F/56 L tibial, L median ↓NCV, F wave ↓CMAP tibial and median neuropathy

16/M/27 R peroneal normal ↓CMAP peroneal neuropathy

17/F/43 R median, R ulnar, L tibial ↓CNAP ↓CMAP, ↑DML, ↓NCV sensorimotor axonal neuropathyunobtainable H reflex ambilateralis

9/M/21

R ulnar, R peroneal, L sural

L axillary, L tibial, L median

↓SNAP, ↓NCV ↑DML, ↓CMAP, ↓NCV sensorimotor axonal neuropathy

5/F/51R ulnar; R, L sural, L tibialR peroneal superficialis,

R peroneal↓CNAP

↑DML, unobtainable F wave↓CMAP

sensorimotor, axonal neuropathy

1/F/48

L axillary, L median, R femoral

R ulnar, R peroneal, L sural

R peroneal superficialis

↓CNAP, ↓NCV ↑DML, ↓CMAP, ↓NCV sensorimotor axonal neuropathy

unobtainable H reflex ambilateralis

About one third patients did not show any signs of electrophysiological abnormalities, one fourth of all patients had absent H-reflex, and the remaining patients showed a different degree of electrophysiological abnormalities localized mostly in long nerves or both short and distal nerves; in one case, changes were limited to short nerves only. Abbreviations: CMAP-compound muscle action potential; CNAP-compound nerve action potential; DML-distal motor latency; F-female; M-male; NCV-nerve conduction velocity; MNCS -motor nerve conduction study; SNCS-sensory nerve conduction study; L -left; R-right; ↓-decrease, ↑-prolongationBadanie elektrofizjologiczne nie wykazało żadnych nieprawidłowości u jednej trzeciej wszystkich pacjentów, u jednej czwartej pacjentów wykazano brak odruchu H, pozostali pacjenci wykazali różnego stopnia zaburzenia elektrofizjologiczne, głównie w obrębie długich i/lub krótkich nerwów; w jednym przypadku zmiany ograniczone były tylko do nerwu krótkiego.

646

Discussion Here, in this paper we demonstrated

that the peripheral nervous system dys-functions are quite common among DM patients, irrespective of DM type. After exc-luding all secondary factors, we found that 55% of all DM1 and 40% of all DM2 pa-tients showed a range of neuropathic ab-normalities in electrophysiological studies, suggesting a possible link between the dysfunction of the PNS and pathogenesis of DM regardless of genotype differences. Additionally, we found that almost half of all DM1 (47%) patients and one-fourth of all DM2 (19%) patients and had absent H-re-flex despite normal nerve conduction study results, likely due to the selective muscle fiber atrophy or mild axonal degeneration or both [24-26].

Lower limb mononeuropathies or mul-tiple mononeuropathies were observed in 25% of all DM1 and 15% of all DM2 pa-tients, often resulting from compression or entrapment and are frequently diagnosed in patients with prior muscle weakness and impaired motor mobility who are usually more susceptible to fractures than the ge-neral population [27].

Furthermore, we observed that there was a difference in symptomatic manifesta-tion of PNS dysfunctions between DM1 and DM2. Compared with DM1 patients those with DM2 were three-fold more susceptible to autonomic abnormalities manifested as excessive sweating of the hands, trunk, and lower extremities, suggesting that in the pathogenesis of DM2, the autonomic nervous system likely plays a significant role, while in DM1, its involvement is less apparent, at least at the clinical level [5].

Our study showed that the observed neuropathy is essentially axonal in nature and likely results from a rapid loss of fibers rather than demyelination, in accordance to

earlier reports showing predominantly axo-nal degeneration and less prominent de--remyelination in the sural nerve of patients with DM [18,28,29]. Similarly, morphome-tric studies in DMSXL transgenic mice--a classical laboratory model for myotonic dystrophy, demonstrated a selective loss of motor axons (axonopathy and neuronopa-thy) neurons [30]. Decreased axonal exci-tability reflecting a Na+ channel dysfunc-tion in DM patients may be an explanation for neuromuscular complaints like muscle pain [31]. Another possible explanation for the pain noted in some DM patients might be due to the damage of small fibers often observed in peripheral neuropathy [32-34].

The majority of neuropathic changes were recorded in lower limb motor nerves. Motor abnormalities were more frequent than sensory ones, with the peroneal ne-rve being the most commonly affected in both types of DM. This finding is consistent with earlier electrophysiological and clinical studies where the number of motor units was significantly reduced in DM patients as assessed by the motor unit number es-timation technique [35-37] and with clinical and electrophysiological assessments re-vealing that motor dysfunction was more prevalent than sensory abnormalities [19,20]. The possible explanation of this phenomenon was muscle atrophy evoked by the prolonged duration of the disease or concomitant polyradiculopathy [26], howe-ver this mechanism cannot possibly play a significant role in patients with DM2, who-se disabilities and atrophy were not severe and were limited to the proximal muscles of the lower limbs.

Pathogenesis of neuropathy in myoto-nic dystrophy remains unclear, however studies show that there is a positive cor-relation between the presence of neuro-pathy and age, gender and the duration of

the disease. It has been shown that older male DM patients with longer duration of the disease are at higher risk of developing neuropathy compared to the control group [20, 38]. Furthermore, it has been also ob-served that DM1 patients who suffer from sleep apnea are more susceptible to deve-loping peripheral nerve changes compared to DM patients without this condition [39]. This observation is consistent with results of clinical studies on chronic pulmonary di-sorder patients who manifested higher inci-dence of peripheral neuropathy correlated with pulmonary function deficiencies and sleep apnea [40-42].

Finally, a number of studies also de-monstrated that there was a co-incidence of DM with hereditary motor and sensory neuropathies (HMSN) magnifying the need for early neurological screening and elec-trophysiological evaluations [43-46].

Molecular mechanisms underlying the observed changes in the peripheral ne-rve and corresponding clinical symptoms remain unclear, however recent studies conducted in DMSXL mice showed that the incidence of peripheral neuropathy might be linked to the highly increased number of unstable CTG repeats (<1300) and severi-ty of the disease [19].

It might be also speculated that DNA repair defects or the transcription chan-ges in DM1 or DM2 related genetic loci and subsequent accumulation of mRNA with expanded nucleotide repeats deregu-lates the function of muscleblind and the RNA binding family of proteins, leading to inappropriate pre-mRNA splicing and, in the long term, resulting in peripheral nerve dysfunction observed in patients with DM [19,47,48].

The results of our study indicate that peripheral neuropathy is a relatively com-mon feature of DM pathophysiology. The

Tabela IIDetailed characteristics of electrophysiological changes observed in DM2 patients.Elektrofizjologiczna charakterystyka pacjentów z DM 2.

Patient No./sex/age Affected nervesType of abnormalities

DiagnosisSNCS MNCS

1/M/19; 2/F/38; 3/F/47

none normal normal4/F/65; 6/F/33; 7/M/28

12/M/31; 13/F/46; 15/F/2616/F/55; 19/M/21;20/M/18

14/F/42 R tibial; ↓Amp. tibial neuropathy unobtainable H reflex R

8/M/35 R ulnar ↓Amp. ↓NCV ulnar neuropathy

9/F/60 L median ↓Amp., ↓NCV normal median neuropathy

5/F/34 R, L peroneal superficialis; R ulnar; L sural; L, R peroneal; R, L tibial ↓Amp. ↑DML, ↓NCV

unobtainablesensorimotor neuropathy

unobtainable H reflex bilaterally

10/M/49 R ulnar, L median, L sural ↓Amp., ↓NCV ↓NCV↑DML, ↓NCV

sensorimotor neuropathyunobtainable H reflex L

11/F/60 R, L peroneal superficialis; R, L peroneal; R, L tibial ↓Amp. ↓F wave CV (L)

↓NCV sensorimotor neuropathy

17/M/46 R, L ulnar, L median, R peroneal ↓Amp., ↓NCV ↑DML sensorimotor neuropathy

18/M/46 R ulnar, L median, R peroneal ↓Amp. normal sensorimotor neuropathyunobtainable H reflex bilaterally

M. Banach et al.

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frequency and characteristics of peripheral involvement is similar in DM2 and DM1, except for the autonomic impairment, which seems to be more frequent in DM2 patients. We conclude that PNS abnorma-lities are a common factor accompanying DM and constitute an integral part of DM manifestation.

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