To explore suggestive evidence of focal proximal demyelination in multifocal motor neuropathy (MMN) without overt evidence of conduction block, we conducted sonographical assessment of cervical nerve roots in 9 MMN patients, 22 ALS patients, and 17 control subjects. The mean diameters of the C5 and C6 roots in MMN patients were significantly larger than those in ALS and controls, especially on the clinically dominant side. Although non-specific, sonography can be a potentially useful diagnostic procedure to support the diagnosis of MMN, even when overt conduction block is lacking

Izumi, Yuishin

Kaji, Ryuji

Nodera, Hiroyuki

Takamatsu, Naoko

Tokushima University Institutional Repository

INTRODUCTIONMultifocal motor neuropathy (MMN) is a demyelinating neu-ropathy characterized by predominant involvement of motor nerves.MMN can mimic ALS and other lower motor neuron diseases, but,as MMN is treatable by intravenous immune globulin (IVIg) andother immunomodulating therapies (1), its differential diagnosisis important. The diagnosis of MMN is particularly difficult when itsdiagnostic hallmarks, conduction block (CB) and anti -gangliosideantibody are not demonstrable. In a recent study, CB was identifiedin only 60% of MMN patients (2). Sonography of the peripheralnerves was recently reported to detect signs of widespread de-myelination including in proximal nerve segments of MMN pa-tients with CB (3). Thus, the aim of the present study was to assesswhether sonography of the nerve roots can identify nerve hypertro-phy as a suggestive evidence of demyelination in MMN patientswithout CB and further, to help differentiate MMN from ALS. ALSwas chosen for comparison because MMN is still one of the mostcommon masqueraders of ALS when upper motor neuron sign isnot obvious.SUBJECTS AND METHODSSubjectsRecordings were made from nine patients with MMN (all men),22 with ALS (15 men), and from 17 normal controls (11 men) inTokushima University Hospital, Japan. All the patients with MMNand ALS were ambulatory. The inclusion criteria for the patientswith MMN were the following : (A) progressive muscle atrophyand weakness involving only a few peripheral nerves or roots, with-out sensory involvement, (B) lack of upper motor neuron signs,pathological reflexes, or bulbar symptoms/signs, (C) the lack ofradiological abnormality of the cervical spine in an MRI scan, (D)lack of CB according to published electrodiagnostic criteria (4),and (E) most importantly, the presence of clinical improvement ofthe affected limb with IVIg therapy (2 g/kg given over 5 consecutivedays), defined as the improvement of the pre- versus post- thera-peutic modified MRC score (1-5 scale including 4- and 4+ grades)equal to or greater than 2 in at least two of the affected muscles(5, 6). The mean duration of our clinical follow up of the MMN pa-tients was 42.3 months (range : 18-107 months) and all the patientsremained ambulatory. The mean number of patients undergoingIVIg treatment was 9.9 (range : 4-17) with reproducible post- thera-peutic improvement.Inclusion criterion for the ALS group was to meet either theclinically definite, or clinically probable (with or without laboratorysupport) revised El Escorial ALS criteria. Of note, our ALS patientshad predominantly lower motor involvement at the time of thesonographic assessment, thus its clinical distinction from MMNwas not straightforward. The control group was made up of indi-viduals with no neurological symptoms or signs. Either MRI orplain four-angle x-ray of the cervical spine was performed in thecontrol subjects to confirm the lack of significant degenerativespine disease. All the patients and control subjects gave informedconsent to participate in the study. This study was performed inaccordance with the principles embodied in the Declaration ofHelsinki and was approved by the Institutional Review Board atTokushima University.Nerve conduction studyNerve conduction studies were performed with percutaneousstimulating and recording electrodes (Viking IV, Nicolet, Madison,USA). Compound muscle action potentials (CMAP) were elicitedwith distal and proximal stimulation of the median nerve (at thewrist with 7 cm stimulating-recording distance and at the elbow)and of the ulnar nerve (at the wrist with 7 cm stimulating-recordingdistance and on the forearm below the elbow). Distal motor laten-cies (DL) and motor nerve conduction velocities (CV) were thencomputed. Sixteen to 32 stimulations at 1 Hz were given to elicitat least 10 F-waves and their minimum latency was recorded. Ad-ditional sites of stimulation (axilla and Erb’s point for the mediannerve and above the elbow ; axilla and Erb’s point for the ulnarnerve) demonstrated neither CB nor temporal dispersion in anyof the subjects. Tibial and peroneal nerves were also stimulatedaccording to standard techniques, and DLs and CVs were withinnormal limits in all subjects.ORIGINALCervical root sonography to differentiate multifocal motorneuropathy from ALSHiroyuki Nodera, Yuishin Izumi, Naoko Takamatsu, and Ryuji KajiDepartment of Neurology, Tokushima University, Tokushima, JapanAbstract : To explore suggestive evidence of focal proximal demyelination in multifocal motor neuropathy (MMN)without overt evidence of conduction block, we conducted sonographical assessment of cervical nerve roots in9 MMN patients, 22 ALS patients, and 17 control subjects. The mean diameters of the C5 and C6 roots in MMNpatients were significantly larger than those in ALS and controls, especially on the clinically dominant side.Although non-specific, sonography can be a potentially useful diagnostic procedure to support the diagnosis ofMMN, even when overt conduction block is lacking. J. Med. Invest. 63 : 104-107, February, 2016Keywords : multifocal motor neuropathy, ALS, Nerve root sonographyReceived for publication November 19, 2015 ; accepted December 28,2015.Address correspondence and reprint requests to Hiroyuki Nodera, MD,Department of Neurology, Tokushima University, 3 -18 -15 Kuramotocho,Tokushima-City 770-8503 Japan and Fax : +81-88 -633-7208.The Journal of Medical Investigation Vol. 63 2016104SonographyThe cervical roots were visualized by high-resolution echosono-graphy (Nemio, Toshiba, Japan) using an 11-MHz linear probe.The subjects were examined in the supine position with the headturned upward. By placing the probe on the lateral aspect of theneck, a coronal oblique plane enabled a longitudinal view of thecervical roots, which were seen as hypoechoic structures, and easymeasuring of their diameters at a point 2 cm distal to the transverseprocess. The C6 nerve root was easily identified, as the neighbor-ing C6 vertebra is characterized by a vertebral artery passingthrough its transverse foramina and by its prominent anterior tu-bercle compared with that of the C7 vertebra. The C5 and C6 nerveroots were identified and their diameters measured. As the C7 andC8 roots may not be visualized in some patients, especially in obeseindividuals, we analyzed only C5 and C6 roots. The nerve rootsappeared to be round, thus the measurements were not influencedby flattening. As the lower cervical roots were deep and their meas-urements possibly inaccurate, they were excluded from the pre-sent study. The sonography technician was blind to the clinicaldiagnoses.Statistical analysisANOVA withBonferroni post hoc analysis (for comparison amongMMN, ALS, and control groups) was used for data analysis (SPSS20.0, Chicago, U.S.A.). P -values less than 0.05 were consideredto be significant.RESULTSThe clinical and electrodiagnostic data are summarized in Table 1.The average age of the MMN patients was slightly less than that ofthe other two groups due to one young patient. Other than the maledominancy in MMN, the clinical features were similar among thegroups. In MMN, two patients had shoulder involvement, five hadpredominantly forearm and finger involvement, and one had diffusearm weakness. There were no significant electrodiagnostic differ-ences between the MMN and ALS patients. Among the control sub-jects, eight had cervical MRI and nine had plain cervical x-ray, noneof whom showed evidence of significant degenerative spine disease.Figure 1A shows the sonographic finding of an MMN patient witha thick C6 nerve root suggestive of demyelination. In Figure 1B,Table 1. Summary of patient characteristics and electrodiagnostic features of the CMAP.Characteristic/Feature Nerve MMN ALS ControlAge (range) 49.1(16 -61) 60.3(47 -77) 62.0 (23 -79)N (male/female) 9(9/0)* 22(15/7) 17 (11/6)Distal latency of CMAP (ms)median 4.00.5 4.20.6ulnar 3.20.5 3.60.7Amplitude of CMAP (mV)median 4.22.2 2.41.6ulnar 5.62.3 4.23.3Conduction velocity (m/s)median 57.03.9 55.14.7ulnar 58.44.4 58.07.3Minimum F-latency (ms)median 28.03.0 29.15.3ulnar 27.81.8 28.73.2*P0.05 male/female compared with controls. Electrodiagnostic study was performed on the clini-cally dominant side.Figure 1. Cervical root swelling in an MMN patient. (A) Sonographic image of the left C6 nerve root of a patient with multifocal motor neuropathy(MMN). The root diameter, just distal to the dorsal root ganglia, was thicker (4.9 mm) than the normal upper limit (4 mm) consistent with demye-lination. (B) The T2-weighted MRI image of the same MMN patient demonstrated a thick left C6 nerve root (arrow) with a diameter of 4.7 mm,comparable with that obtained by ultrasound. Note the thicker nerve roots on the symptomatic left side compared with those on the right.The Journal of Medical Investigation Vol. 63 February 2016 105the MRI imaging corroborated the sonographic finding. As a group,the patients with MMN had larger nerve root diameters than thosewith ALS or the control groups, with the normal upper limit of boththe C5 and C6 diameters being 4.0 mm (Figures 2 and 3). Of note,the root diameters in MMN were asymmetric, with the clinicallyaffected roots tending to show increased diameters. In MNN pa-tients, the percentage of thick C6 nerve roots was higher than thatof C5 roots (77% vs. 55%, respectively) on the clinically dominantside, likely reflecting the clinical involvement in our MMN patients.By contrast, the root diameters of some ALS patients were thinnerthan those of controls, suggesting axonal degeneration.DISCUSSIONIn the present study, we have shown that sonography can detectfocal thickness of a cervical nerve root in MMN to suggest demye-lination that can differentiate MMN from ALS, which has beendemonstrated to have pathologically thinner nerve roots due toatrophy (7), and from normal controls.The role of peripheral nerve sonography to detect nerve enlarge-ment and changes in echogenicity have been previously described.Demyelinating neuropathies such as chronic inflammatory demye-linating polyneuropathy (CIDP) and Charcot-Marie-Tooth diseaseshow diffusely thickened peripheral nerves and nerve roots (8, 9).MRI and sonography are also able to detect focal enlargement ofnerves, plexuses and nerve roots due to infection, inflammation,infiltration and neoplasm (10). Recent comparison between MRIand sonography in CIDP showed that the two techniques are rele-vant in detecting microstructure such as nerve fascicles, such thatsonography could replace MRI in daily practice due to its afford-ability (11).In MMN, peripheral nerves at the sites of CB and at electrodi-agnostically normal sites were reported to be demyelinated (12, 13)and demonstrated increased diameters by MRI (14). This findingwas confirmed by a recent report employing high resolution sonogra-phy in MMN patients (3, 15, 16), but its utility for differential diag-nosis, especially in MMN patients without solid diagnostic evidence(e.g., CB and/or anti -ganglioside antibodies), had been little ex-plored. We have thus demonstrated that, in patients with otherwisetypical MMN but no overt CB, sonography can provide evidenceof demyelination. Sonography would be particularly useful in diag-nosing a patient with predominantly lower motor neuron involve-ment and in predicting the therapeutic efficacy of intravenousimmunoglobuiln in MMN (17).That said, some of the MMN patients in the present study hadnormal root diameters and several explanations are possible : (A)the demyelination was focal and the examined C5 or C6 nerve rootswere not significantly affected, (B) the roots were initially thick-ened, but later became thinner due to secondary axonal degenera-tion, (C) the focal demyelination existed somewhere other than atthe root level, and (D) the presence of chronic motor axonal neu-ropathy, which shows no clear evidence of demyelination, but hasonly axonal degeneration (i.e., thinning of the peripheral nerve)(18).Because sonographicdetectionofnerve thicknesshasalso beenreported in other demyelinating neuropathies, the finding shouldFigure 2. The diameters of the C5 nerve roots in MMN, ALS and controlgroups. The 95-percentile value in the control group, taken as the normalupper limit, was 4 mm (dotted lines). In MMN, the mean diameters werelarger than in both the control and ALS groups. The increased thicknesswas more significant on the clinically weaker side (open circles).Figure 3. The diameters of the C5 nerve roots in MMN, ALS and controlgroups. Similar to the C5 root (Figure 2), the mean diameters were largerin MMN than in both the control and ALS groups. The root diameters ofsome of the ALS patients were thinner than the controls, suggestive ofaxonal degeneration.106 H. Nodera, et al. Nerve root sonographybe interpreted according to the clinical information. A noviceechosonographer may not be able to obtain the appropriate cross-sectional and longitudinal images, leading to either over- or under-diagnosis of nerve swelling and atrophy. However, under an expe-rienced hand, measurements of a nerve size have been reportedto have high intra- and inter -observer reliability. By using similarrecording methods, Sugimoto, et al. reported coefficients of vari-ation in normal individuals. Their intra- and inter -observer coeffi-cients of variation of the C5-C7 nerve roots ranged from 5.5 to 14.3%(19). Another limitation is that we did not compare the sizes of thenerve roots by sonography and MRI in all the subjects. AlthoughMRI might have lower operator-dependency than sonography,MRI might not depict nerve roots with the largest cross-sectionalplane, thus accurate comparison might not be possible.Despite this limitation and its non-specificity, sonographic de-tection of nerve thickness may suggest focal demyelination andthus may support the diagnosis of MMN, especially in those caseswithout overt CB.(2) Further study is needed to elucidate the lo-cations of the “electrically silent” nerve swelling and thus suggesta diagnostic protocol to detect such likely demyelinating lesions.ACKNOWLEDGEMENTSWe thank Drs. Masafumi Harada and Motohiro Hirasawa for ob-taining and interpreting the MRI scan of the cervical nerveroots.REFERENCES1. Kaji R, Shibasaki H, Kimura J : Multifocal demyelinating mo-tor neuropathy : cranial nerve involvement and immunoglobu-lin therapy. Neurology 42 : 506-9, 19922. Delmont E, Azulay JP, Giorgi R, Attarian S, Verschueren A,Uzenot D, Pouget J : Multifocal motor neuropathy with andwithout conduction block : a single entity? Neurology 67 : 592-6, 20063. Beekman R, van den Berg LH, Franssen H, Visser LH, vanAsseldonk JT, Wokke JH : Ultrasonography shows extensivenerve enlargements in multifocal motor neuropathy. Neurol-ogy 65 : 305-7, 20054. AAEM : Consensus criteria for the diagnosis of partial con-duction block. Muscle Nerve 22 : S225-S9, 19995. Miyashiro A, Matsui N, Shimatani Y, Nodera H, Izumi Y,Kuwabara S, Imai T, Baba M, Komori T, Sonoo M, Mezaki T,Kawamata J, Hitomi T, Kawamata J, Hitomi T, Kohara N,Arimura K, Hashimoto S, Arisawa K, Kusunoki S, Kaji R, Japa-nese Multifocal Motor Neuropathy Study G : Are multifocalmotor neuropathy patients underdiagnosed? An epidemiologi-cal survey in Japan. Muscle Nerve 49 : 357-61, 20146. Busby M, Donaghy M : Chronic dysimmune neuropathy. Asubclassification based upon the clinical features of 102 pa-tients. J Neurol 250 : 714-24, 20037. Sobue G, Matsuoka Y, Mukai E, Takayanagi T, Sobue I : Pa-thology of myelinated fibers in cervical and lumbar ventralspinal roots in amyotrophic lateral sclerosis. J Neurol Sci 50 :413-21, 19818. Di Pasquale A, Morino S, Loreti S, Bucci E, Vanacore N,Antonini G : Peripheral nerve ultrasound changes in CIDPand correlations with nerve conduction velocity. Neurology84 : 803-9, 20159. Noto YI, Shiga K, Tsuji Y, Mizuta I, Higuchi Y, Hashiguchi A,Takashima H, Nakagawa M, Mizuno T : Nerve ultrasounddepicts peripheral nerve enlargement in patients with geneti-cally distinct Charcot-Marie-Tooth disease. J Neurol Neuro-surg Psychiatry, 201410. Khadilkar SV, Yadav RS, Soni G : A practical approach to en-largement of nerves, plexuses and roots. Pract Neurol 15 : 105-15, 201511. Pitarokoili K, Schlamann M, Kerasnoudis A, Gold R, Yoon MS :Comparison of clinical, electrophysiological, sonographic andMRI features in CIDP. J Neurol Sci 357 : 198-203, 201512. Kaji R, Oka N, Tsuji T, Mezaki T, Nishio T, Akiguchi I, KimuraJ : Pathological findings at the site of conduction block in mul-tifocal motor neuropathy. Ann Neurol 33 : 152-8, 199313. Taylor BV, Dyck PJ, Engelstad J, Gruener G, Grant I : Multi-focal motor neuropathy : pathologic alterations at the site ofconduction block. J Neuropathol Exp Neurol 63 : 129-37, 200414. Van Es HW, Van den Berg LH, Franssen H, Witkamp TD,Ramos LM, Notermans NC, Feldberg MA, Wokke JH : Mag-netic resonance imaging of the brachial plexus in patients withmultifocal motor neuropathy. Neurology 48 : 1218-24, 199715. Grimm A, Decard BF, Athanasopoulou I, Schweikert K,Sinnreich M, Axer H : Nerve ultrasound for differentiation be-tween amyotrophic lateral sclerosis and multifocal motor neu-ropathy. J Neurol 262 : 870-80, 201516. Loewenbruck KF, Liesenberg J, Dittrich M, Schafer J, PatznerB, Trausch B, Machetanz J, Hermann A, Storch A : Nerve ul-trasound in the differentiation of multifocal motor neuropathy(MMN) and amyotrophic lateral sclerosis with predominantlower motor neuron disease (ALS/LMND). J Neurol, 201517. Nobile -Orazio E, Cappellari A, Meucci N, Carpo M, TerenghiF, Bersano A, Priori A, Barbieri S, Scarlato G : Multifocalmotor neuropathy : clinical and immunological features andresponse to IVIg in relation to the presence and degree ofmotor conduction block. J Neurol Neurosurg Psychiatry 72 :761-6, 200218. Kaji R, Kusunoki S, Mizutani K, Oka N, Kojima Y, Kohara N,Kimura J : Chronic motor axonal neuropathy associated withantibodies monospecific for N-acetylgalactosaminyl GD1a.Muscle Nerve 23 : 702-6, 200019. Sugimoto T, Ochi K, Hosomi N, Mukai T, Ueno H, TakahashiT, Ohtsuki T, Kohriyama T, Matsumoto M : Ultrasonographicreference sizes of the median and ulnar nerves and the cer-vical nerve roots in healthy Japanese adults. Ultrasound inmedicine & biology 39 : 1560-70, 2013The Journal of Medical Investigation Vol. 63 February 2016 107

Cervical root sonography to differentiate multifocal motor neuropathy from ALS

http://repo.lib.tokushima-u.ac.jp/files/public/11/111162/2018030613581022339/jmi_63_1-2_104.pdf

Cervical root sonography to differentiate multifocal motor neuropathy from ALS

Abstract

Similar works

Full text

Available Versions

Tokushima University Institutional Repository