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Pure motor mononeuropathy with distal conduction block: an unusual presentation of multifocal motor neuropathy with conduction blocks
Clinical Neurophysiology 115 (2004) 2323–2328 www.elsevier.com/locate/clinph
Pure motor mononeuropathy with distal conduction block: an unusual presentation of multifocal motor neuropathy with conduction blocks S. Vucic, K. Dawson, D. Sun, D. Cros* Department of Neurology, Bigelow 1256, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114, USA Accepted 4 May 2004
Abstract Objective: To report an hitherto undescribed presentation of Motor Neuropathy with Multifocal Conduction Block (MMNCB). Methods: Description of two patients presenting with complete paralysis of the 3 heads of the trapezius muscle (case one) and progressive weakness of finger extension (case 2). Results: Nerve conduction studies (NCS) established that the corresponding nerves were distally inexcitable. In the affected muscles, no voluntary activity was elicited in both patients with spontaneous activity noted in patient 2. Systematic NCSs documented an asymptomatic, partial conduction block (CB) in a median nerve forearm segment in both patients. Neurophysiological follow-up after a dramatic response to intravenous immunoglobulins demonstrated recovery of the initially unobtainable motor responses. Conclusions: This indicates that a complete, distal CB of the motor fibers destined to the trapezius muscle in patient 1, and to the extensor indicis proprius in patient 2, had caused the heralding deficits. Significance: These findings underscore the possibility of distal CB in this disorder and the need for extensive NCSs, including asymptomatic nerves, for an accurate diagnosis. q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Multifocal motor neuropathy with conduction block; Spinal accessory nerve; Intravenous immunoglobulin; Distal conduction block
1. Introduction Multifocal motor neuropathy with conduction blocks (MMNCB) is an immune-mediated motor neuropathy. The clinical features include progressive, asymmetric weakness and atrophy of the extremities more often affecting the arms (Parry and Clarke, 1988; Pestronk et al., 1988). Sensory symptoms, if present, are mild and sensory deficits are never present. High titers of antibodies against the GM1ganglioside are found only in a subset of patients (22 – 85% of patients) (Nobile-Orazio, 2001) and response to immunomodulating therapy, such as intravenous immunoglobulin (IVIg), noted in 79% (Nobile-Orazio, 2001), may assist in the diagnosis. Neurophysiologic studies are essential in the diagnosis of MMNCB, revealing conduction block (CB) in two or more motor nerve segments with preserved sensory nerve conduction studies (NCS), based on a recent consensus * Corresponding author. Tel.: þ 1-617-726-3642; fax: þ1-617-726-2019. E-mail address: [email protected] (D. Cros).
statement (Olney et al., 2003). Recently, these criteria were deemed too restrictive, based on a series of patients with monofocal motor neuropathy and CB who responded to IVIg (Felice and Goldstein, 2000; Jafari et al., 2000; Van den Berg-Vos et al., 2000). However, before a diagnosis of MMNCB is ruled out, extensive motor NCS including asymptomatic nerves is in our opinion indispensable. In support of this, we report two patients presenting with a mononeuropathy affecting pure motor nerves that were distally inexcitable on presentation. Systematic NCSs demonstrated the presence of an additional, asymptomatic CB in each patient. Neurophysiologic reevaluation after response to IVIg established the diagnosis of distal CB that caused the presenting deficit, a finding hitherto undescribed in this disorder.
2. Case reports Case 1. A 42-year-old man presented with a 6-month history of right shoulder pain, weakness and atrophy of
1388-2457/$30.00 q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2004.05.003
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Fig. 1. (A) Anterior view of the shoulder girdle demonstrating atrophy and weakness of the right trapezius muscle, one week before IVIg treatment. (B). Anterior view of the shoulder girdle showing improvement in right trapezius muscle atrophy, 5 weeks after the first course of IVIg. (C) Posterior view of the shoulder girdle demonstrating atrophy of the right trapezius muscle, one week before IVIg therapy. (D) Posterior view of the shoulder girdle demonstrating improvement in right trapezius muscle atrophy, 5 weeks after the first course of IVIg.
the right trapezius muscle (Fig. 1A –C). A diagnosis of brachial neuritis was made at another institution, despite atypical features such as persistence of pain for months after onset. No sensory symptoms or weakness in other extremities were noted. Past medical history and family history were unremarkable. Examination revealed apparent atrophy of the right upper trapezius muscle, weakness of right shoulder elevation (Medical Research Council [MRC] score 3), and scapular winging increasing with shoulder abduction. The right sternocleidomastoid muscle strength was normal. Muscle bulk, strength, tendon reflexes were otherwise normal. No fasciculations, tremors, or long-tract signs were noted. Sensory examination was normal. The other cranial nerves were normal. The following investigations were unremarkable: GM1 antibody titers, full blood count, electrolytes, urea, creatinine, liver function tests, serum creatine kinase, immunoglobulin studies, serum immunofixation, antinuclear antibodies, antineutrophil cytoplasmic antibodies, rheumatoid factor, complement levels, anti-Ro, and anti-La antibodies, and cerebrospinal fluid profile. Following a 5-day course of IVIg (2 g/kg), dramatic resolution in the right trapezius muscle weakness (MRC score 5) and apparent atrophy occurred (Fig. 1B –D). The shoulder discomfort subsided, as it was probably secondary to strain on soft tissues because of functional failure of the trapezius muscle. An attempt to taper the IVIg dose over the ensuing 4 months caused a recurrence of weakness and pain. This again responded promptly to a 5-day course of IVIg at the initial dose. The patient has been followed clinically for 5 years without recurrence of weakness on monthly IVIg therapy (35 g/month).
Case 2. A 53-year-old woman developed painless, progressive weakness of finger extension over a 2-year period. This began with digit III extension weakness and gradually spread to affect digits II and then digit IV. She was initially diagnosed with right posterior interosseous nerve (PIN) syndrome and underwent surgical exploration and neurolysis of the PIN without benefit. No sensory loss or weakness in the other extremities was noted. Past medical and family history was unremarkable. Clinical examination revealed severe weakness of right finger extension (MRC 2 – 3) with mild atrophy of the forearm extensor muscles. Muscle bulk, strength, and tendon reflexes were otherwise normal. No fasciculations, tremor, or long-tract signs were present. Sensory examination was normal. Cranial nerve examination was normal. Laboratory testing, as in case 1, was unremarkable. The cerebrospinal fluid was unremarkable. Following a 4-month course of treatment with IVIg (2 g/kg for 4 consecutive months) marked improvement in right finger extension (MRC grade 4) developed. The improvement in muscle strength was maintained for 3 years, during a gradual taper of the monthly dose until a dose of 25 g/month was reached. At this point, the PIN weakness recurred and subsequently improved with the doubling of the IVIg dose (50 g/month). Since then the patient has been successfully maintained on that dose for the last 2 years.
3. Methods NCS were performed on either the Oxford-Teca Synergy or Medelec-Teca Sapphire Premier electromyography machines (Oxford Instruments, Manor Way, Old Woking, Surrey, England). Skin temperature was maintained at 32 8C in the upper extremities and 30 8C in the lower extremities. Motor nerves were evaluated to the cervical nerve roots in the upper limbs and popliteal fossa in the lower limbs. The following nerves and nerve segments were studied; median nerve to the abductor pollicis brevis (APB) muscle (stimulation at the wrist, antecubital fossa, axilla, cervical root); ulnar nerve to the abductor digiti minimi muscle (stimulation at the wrist below and above the elbow, axilla and cervical root); radial nerve to the extensor indicis proprius (EIP) and triceps muscles (stimulation at the forearm, above the elbow, in the axilla and at the cervical root); musculocutaneous nerve to the biceps brachii muscle (stimulation from the cervical root); spinal accessory nerve to the 3 heads of the trapezius muscle (stimulation in the posterior triangle at the posterior border of the mid-portion of the sternocleidomastoid muscle) (case 1); tibial nerve to the flexor hallucis brevis muscle (stimulation at the ankle and popliteal fossa); common peroneal nerve to the extensor digitorum brevis muscle (stimulation at the ankle, below the fibular head and at the popliteal fossa). Near-nerve electrical cervical nerve root stimulation (CNRS) was performed
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according to methods previously reported (Berger et al., 1987). Collision studies were used for determining the compound motor action potentials (CMAP) amplitudes from the APB muscles on stimulation of the cervical roots. Surface Ag/AgCl disk electrodes were used for stimulation and recording the CMAP. Median, ulnar, radial, and sural sensory nerve action potentials were recorded orthodromically. All nerves and nerve segments were studied bilaterally. For each CMAP, amplitude and area of the negative peak were determined. The degree of CMAP amplitude and area reduction for consecutive stimulation sites were calculated and expressed as a percentage. For the median, ulnar, and radial nerves, definite partial CB was defined as greater than 50% reduction in amplitude and 40% reduction in area between proximal and distal stimulation sites. For the tibial and common peroneal nerves, definite partial CB was defined as greater than 60% reduction in amplitude and 50% reduction in area between the proximal and distal stimulation sites. A diagnosis of CB required a distal CMAP amplitude of greater than 1 mV. Needle electromyography (EMG) was performed using a disposable, 20-gauge concentric needle electrode (Oxford Instruments, Manor Way, Old Woking, Surrey, England).
4. Results Case 1. The right spinal accessory NCS revealed an absent CMAP response from the upper, middle, and lower heads of the trapezius muscle. A partial CB (71%) was noted in the right median nerve forearm segment, with prolonged F-wave latency and normal median nerve distal CMAP amplitude (Table 1). Other motor and sensory NCSs were normal. EMG revealed absence of voluntary activity in all 3 heads of the trapezius muscle without spontaneous activity (SA) (fibrillations and/or positive sharp waves). In the right APB muscle, no SA was seen and fast-firing motor unit action potentials (MUAPs) of normal amplitude
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and configuration were noted on voluntary contraction. Reduced recruitment pattern was noted in the right APB muscle. Needle examination was otherwise normal. Followup NCSs after IVIg therapy, revealed resolution of CB in the right median nerve forearm segment and normalization of the CMAP amplitude in the 3 heads of the right trapezius muscle (Table 1; Fig. 2A). The other motor and sensory NCSs remained normal. Needle EMG of the 3 heads of the trapezius and APB muscles was normal. Subsequent NCS, 2-years post-symptom onset, while on IVIg treatment showed no new CBs. Case 2. The right radial motor NCS revealed an absent CMAP response when recording from the EIP muscle. Partial CB (57%) was noted in the right median nerve forearm segment with prolonged F-response latency (Fig. 2B). The other NCSs were normal. Needle EMG demonstrated abundant SA in the EIP and extensor digitorum communis (EDC) muscles, with no voluntary activity in EIP and single unit recruitment in EDC. The MUAP was of prolonged duration and increased amplitude. In addition, fast-firing MUAPs, of normal amplitude and configuration, were noted in the right APB muscle. Reduced recruitment pattern was noted in the right APB muscle. EMG was otherwise normal. Follow-up NCSs, 3 months after the first course of IVIg, revealed normalization of the right EIP CMAP amplitude and resolution of the right median nerve CB (Table 1; Fig. 2C and D). Needle examination of the EIP muscle showed no SA with persistence of large amplitude, long duration MUAPs with low mixed recruitment. Three subsequent NCSs over the following 3 years, while on IVIg treatment, revealed no new CBs.
5. Discussion These cases exemplify diagnostic challenges in MMNCB that have not been so far reported in the literature: on the one hand presentation with involvement of a single motor nerve, which obscures the dissociation of motor from sensory
Table 1 Pre and post-treatment conduction studies of abnormal nerves Patient
Nerve
Muscle
Stimulation site
CMAP amp. (mV) at baseline
CMAP amp. (mV) after IVIg therapy
Case 1
R XIth Cranial nerve R Median
UT MT LT APB
R Radial
EIP
R Median
APB
PT PT PT Wrist Elbow Forearm Elbow Wrist Elbow
0 0 0 12.3 3.5 (72)* 0 0 8.3 3.6 (57)*
3.6 3.2 3.5 13.6 11.5 (15)* 5.3 3.2 7.6 6.3 (17)*
Case 2
RXI, right spinal accessory nerve; UT, upper trapezius; MT, middle trapezius; LT, lower trapezius; PT, posterior triangle; APB, abductor pollicis brevis; EIP, extensor indicis; CMAP, compound muscle action potential; CB, conduction block; *( ) CMAP amplitude percentage decrement from wrist to antecubital fossa stimulation.
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Fig. 2. (A) Case 1: Recording from the trapezius muscle stimulating the spinal accessory nerve in posterior triangle after IVIg therapy (calibration 2 mV, 5 ms): upper, middle and lower refer to the corresponding heads of the muscle. (B and C) Case 2: Partial motor conduction block in the forearm segment of the right median nerve before IVIg treatment [B] (calibration 10 mV, 5 ms). (C) Resolution of median nerve conduction block after IVIg treatment (calibration 5 mV/5 ms): wrist and forearm refer to stimulation sites. (D) Case 2: Recording over the extensor indicis proprius muscle after IVIg treatment (calibration: 5 mV, 5 ms): forearm and elbow refer to stimulation sites.
deficits, and on the other hand the occurrence of a distal CB in the affected nerves, such that established diagnostic criteria, relying on comparison of CMAPs obtained on distal and proximal stimulation relative to the site of pathology, are inapplicable (Olney et al., 2003). The diagnosis of MMNCB was first suspected by the finding of asymptomatic CB in the median nerve forearm segments of both patients. Further suspicion arose following the rapid response to treatment with IVIg. This response enabled a retrospective diagnosis of distal CB in clinically symptomatic nerves, demonstrating a multifocal pattern characteristic of MMNCB. The absence of the CMAP in the symptomatic muscles (trapezius in case 1 and EIP in case 2) resulted from complete distal CB. In patient 1, this was confirmed by absence of voluntary activity on EMG testing, and rapid normalization of neurophysiologic findings with IVIg treatment. In patient 2, although neurophysiologic evidence of axonal loss and motor unit remodeling was present, the rapid normalization of the CMAP amplitude and MUAP recruitment pattern, with IVIg therapy, was in keeping with resolution of a distal CB (Cros and Triggs, 1994).
The apparent atrophy of the right trapezius muscle in case 1 was probably related to muscle hypotonia. Muscle spindles are thought to be essential to normal muscle tone (McComas, 1996). Ongoing stretch of the muscle spindles, particularly frequent in muscles tonically fighting the action of gravity such as the upper trapezius, generates motor activity that may be the clinical substrate of muscle tone. Interestingly, there are very few clinical studies of muscle tone and hypotonia (Thomas and Ajuriaguerra, 1949). Normal tone includes the expected passive resistance to stretch, pressure, and deformability of muscle. Hypotonia develops in a muscle immediately after division of its motor nerve and is characterized by flaccidity, decreased firmness to palpation, and increased extensibility, presumably because the afferent and efferent arcs of the tonic myotatic reflex are interrupted. This is seen in pathologic states with widespread dorsal root pathology, such as the historical cases of tabes dorsalis in which hypotonia of the trunk erector and hip extensor muscles may result in flexion of the trunk (Thomas and Ajuriaguerra, 1949). Complete CB replicates this pathophysiology through interruption of the efferent limb of the reflex arc. Hence, the scapular winging
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and the shoulder droop shown in Fig. 1, resulting from hyperextensibility of paralyzed muscles, may mimic the clinical features of atrophy in the upper trapezius muscle. The rapid restoration of trapezius muscle bulk and tone following IVIg treatment supports this interpretation (Fig. 1). A lack of correlation between partial motor CB and muscle weakness has been previously reported in demyelinating polyneuropathies (Oh et al., 1992; Van Asseldonk et al., 2003). Specifically, Van Asseldonk et al. (2003) noted CB in 35% of nerves innervating muscles with normal strength, as measured by the MRC scale, in patients with MMNCB. Moreover, Oh et al. (1992) noted motor CBs in patients with clinically pure sensory CIDP. The pathophysiologic mechanisms underlying this phenomenon are unclear. We hypothesize that, based on the partial involvement of motor fascicles suggested by the biopsy studies of Kaji et al. (1993), some motor axons connected to fasttwitch motor units characterized by a high twitch force remain functional. The corresponding motor units are recruited at a high firing rate in the brisk, strong contraction required to generate maximum force in manual muscle testing (Desmedt and Godaux, 1977; Tanji and Kato, 1973). It seems possible that in some cases of partial CB, enough of these axons remain functional to generate a brief, ballistic contraction deemed normal by experienced clinicians, as in the reports mentioned above and our cases. It is possible that clinical muscle weakness would have ensued after a sustained contraction from the patient, as the fast-twitch motor units are fatigable. Alternatively, the degree of CB may have been overestimated through the process of interphase cancellation (Kimura, 1993; Lange et al., 1992). Given the limitations of conventional NCSs in detecting CB in the proximal and distal nerve segments, the neurophysiologic assessment should be as extensive as possible, including CNRS, prior to concluding that CB is not present (Menkes et al., 1998; Van Asseldonk et al., 2003). CNRS relies on the principle of a current stimulating the proximal portion of the motor axons at or close to their emergence from the spinal cord (Berger et al., 1987; Cros et al., 1990; Mills et al., 1987). This current may be induced by either a rapidly varying magnetic field, produced by a magnetic coil placed over the lower neck area (Cros et al., 1990), an electric field produced by needle electrode (cathode) inserted at the C7 vertebral body (Berger et al., 1987), or a high-voltage percutaneous stimulation delivered over the back of the neck (Mills et al., 1987). A reduction in the CMAP area and amplitude of more than 50% is considered diagnostic of proximal CB (Lange et al., 1992; Raynor et al., 1998). Although, magnetic CNRS is painless, it is best used to rule out CB, as supramaximal stimulation cannot be achieved in a third of subjects (Cros et al., 1990). Our patients underwent transcutaneous electrical CRNS to avoid this potential pitfall. In addition, repeat NCSs after response to treatment may prove to be the only means in
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diagnosing distal CB, as previously reported (Triggs et al., 1992). Long-term follow-up studies of IVIg treatment in MMNCB have reported clinical improvement (Azulay et al., 1997; Bouche et al., 1995; Van den Berg-Vos et al., 2002), although new sites of CB and ongoing axonal degeneration developed despite maintenance IVIg therapy (Van den Berg-Vos et al., 2002). In our report, the resolution of CBs persisted with ongoing IVIg treatment after several years of follow-up. Furthermore, there was resolution of ongoing axonal loss and evidence of reinnervation in patient 2. This suggests that, in these patients, the therapeutic regimen induced and maintained a full remission, although both patients have remained IVIg-dependent.
References Azulay JP, Rihet P, Pouget J, Cador F, Blin O, Boucraut J, Serratrice G. Long term follow up of multifocal motor neuropathy with conduction block under treatment. J Neurol Neurosurg Psychiatry 1997;62: 391– 4. Berger AR, Busis NA, Logigian EL, Wierzbicka M, Shahani BT. Cervical root stimulation in the diagnosis of radiculopathy. Neurology 1987;37: 329– 32. Bouche P, Moulonguet A, Younes-Chennoufi AB, Adams D, Baumann N, Meininger V, Leger JM, Said G. Multifocal motor neuropathy with conduction block: a study of 24 patients. J Neurol Neurosurg Psychiatry 1995;59:38–44. Cros D, Triggs WJ. There are no neurophysiologic features characteristic of ‘axonal’ Guillain-Barre syndrome. Muscle Nerve 1994;17:675–7. Cros D, Chiappa KH, Gominak S, Fang J, Santamaria J, King PJ, Shahani BT. Cervical magnetic stimulation. Neurology 1990;40:1751 –6. Desmedt JE, Godaux E. Ballistic contractions in man: characteristic recruitment pattern of single motor units in man. J Physiol (Lond) 1977; 264:673–93. Felice KJ, Goldstein JM. Monofocal motor neuropathy: improvement with intravenous immunoglobulin. Muscle Nerve 2000;25:674–8. Jafari H, Carlander B, Camu W. Monofocal motor neuropathy responsive to intravenous immunoglobulins. Muscle Nerve 2000;23:1610–1. Kaji R, Oka N, Tsuji T, Mezaki T, Nishio T, Akiguchi I, Kimura J. Pathological findings at the site of conduction block in multifocal motor neuropathy. Ann Neurol 1993;33:152 –8. Kimura J. Consequences of peripheral nerve demyelination: basic and clinical aspects. Can J Neurol Sci 1993;20(4):263– 70. Lange DJ, Trojaborg W, Latov N, Hays AP, Younger DS, Uncini A, Blake DM, Hirano M, Burns SM, Lovelace RE, Rowland LP. Multifocal motor neuropathy with conduction block: is it a distinct clinical entity? Neurology 1992;42:497–505. McComas AJ. Skeletal muscle form and function, 1st ed. Champaign, IL: Human Kinetics; 1996. Menkes DL, Hood DC, Ballesteros RA, Williams DA. Root stimulation improves the detection of acquired demyelinating polyneuropathies. Muscle Nerve 1998;21:298 –308. Mills KR, Murray NM, Hess CW. Magnetic and electrical transcranial brain stimulation: physiological mechanisms and clinical applications. Neurosurgery 1987;164– 8. Nobile-Orazio E. Multifocal motor neuropathy. J Neuroimmunol 2001;115: 4–18. Oh SJ, Joy JL, Kuruoglu R. Chronic sensory demyelinating neuropathy: chronic inflammatory demyelinating polyneuropathy presenting as a pure sensory neuropathy. J Neurol Neurosurg Psychiatry 1992;55: 677– 80.
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Olney RK, Lewis RA, Putnam TD, Campellone Jr JV, American Association of Electrodiagnostic Medicine. Consensus criteria for the diagnosis of multifocal motor neuropathy. Muscle Nerve 2003;27:117–21. Parry GJ, Clarke S. Multifocal acquired demyelinating neuropathy masquerading as motor neuron disease. Muscle Nerve 1988;11:103– 7. Pestronk A, Cornblath DR, Ilyas AA, Baba H, Quarles RH, Griffin JW, Alderson K, Adams RN. A treatable multifocal motor neuropathy with antibodies to GM1 ganglioside. Ann Neurol 1988;24:73–8. Raynor EM, Shefner JM, Ross MH, Logigian EL, Hinchey JA. Root stimulation studies in the evaluation of patients with motor neuron disease. Neurology 1998;50:1907– 9. Tanji J, Kato M. Firing rate of individual motor units involuntary contractions of abductor digiti minimi muscle in man. Exp Neurol 1973;40:771–83. Thomas A, De Ajuriaguerra J. Etude semeiologique du tonus musculaire. Paris: Flammarion; 1949. 483 pp.
Triggs WJ, Cros D, Gominak SC, Zuniga G, Beric A, Shahani BT, Ropper AH, Roongta SM. Motor nerve inexcitability in Guillain-Barre syndrome. The spectrum of distal conduction block and axonal degeneration. Brain 1992;115:1291–302. Van Asseldonk JT, Van den Berg LH, Van den Berg-Vos RM, Wieneke GH, Wokke JH, Franssen H. Demyelination and axonal loss in multifocal motor neuropathy: distribution and relation to weakness. Brain 2003;126:186 –98. Van den Berg-Vos RM, Franssen H, Wokke JH, Van Es HW, Van den Berg LH. Multifocal motor neuropathy: diagnostic criteria that predict the response to immunoglobulin treatment. Ann Neurol 2000; 48:919–26. Van den Berg-Vos RM, Franssen H, Wokke JH, Van den Berg LH. Multifocal motor neuropathy: long-term clinical and electrophysiological assessment of intravenous immunoglobulin maintenance treatment. Brain 2002;125:1875–86.
Pure motor mononeuropathy with distal conduction block: an unusual presentation of multifocal motor neuropathy with conduction blocks S. Vucic, K. Dawson, D. Sun, D. Cros* Department of Neurology, Bigelow 1256, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114, USA Accepted 4 May 2004
Abstract Objective: To report an hitherto undescribed presentation of Motor Neuropathy with Multifocal Conduction Block (MMNCB). Methods: Description of two patients presenting with complete paralysis of the 3 heads of the trapezius muscle (case one) and progressive weakness of finger extension (case 2). Results: Nerve conduction studies (NCS) established that the corresponding nerves were distally inexcitable. In the affected muscles, no voluntary activity was elicited in both patients with spontaneous activity noted in patient 2. Systematic NCSs documented an asymptomatic, partial conduction block (CB) in a median nerve forearm segment in both patients. Neurophysiological follow-up after a dramatic response to intravenous immunoglobulins demonstrated recovery of the initially unobtainable motor responses. Conclusions: This indicates that a complete, distal CB of the motor fibers destined to the trapezius muscle in patient 1, and to the extensor indicis proprius in patient 2, had caused the heralding deficits. Significance: These findings underscore the possibility of distal CB in this disorder and the need for extensive NCSs, including asymptomatic nerves, for an accurate diagnosis. q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Multifocal motor neuropathy with conduction block; Spinal accessory nerve; Intravenous immunoglobulin; Distal conduction block
1. Introduction Multifocal motor neuropathy with conduction blocks (MMNCB) is an immune-mediated motor neuropathy. The clinical features include progressive, asymmetric weakness and atrophy of the extremities more often affecting the arms (Parry and Clarke, 1988; Pestronk et al., 1988). Sensory symptoms, if present, are mild and sensory deficits are never present. High titers of antibodies against the GM1ganglioside are found only in a subset of patients (22 – 85% of patients) (Nobile-Orazio, 2001) and response to immunomodulating therapy, such as intravenous immunoglobulin (IVIg), noted in 79% (Nobile-Orazio, 2001), may assist in the diagnosis. Neurophysiologic studies are essential in the diagnosis of MMNCB, revealing conduction block (CB) in two or more motor nerve segments with preserved sensory nerve conduction studies (NCS), based on a recent consensus * Corresponding author. Tel.: þ 1-617-726-3642; fax: þ1-617-726-2019. E-mail address: [email protected] (D. Cros).
statement (Olney et al., 2003). Recently, these criteria were deemed too restrictive, based on a series of patients with monofocal motor neuropathy and CB who responded to IVIg (Felice and Goldstein, 2000; Jafari et al., 2000; Van den Berg-Vos et al., 2000). However, before a diagnosis of MMNCB is ruled out, extensive motor NCS including asymptomatic nerves is in our opinion indispensable. In support of this, we report two patients presenting with a mononeuropathy affecting pure motor nerves that were distally inexcitable on presentation. Systematic NCSs demonstrated the presence of an additional, asymptomatic CB in each patient. Neurophysiologic reevaluation after response to IVIg established the diagnosis of distal CB that caused the presenting deficit, a finding hitherto undescribed in this disorder.
2. Case reports Case 1. A 42-year-old man presented with a 6-month history of right shoulder pain, weakness and atrophy of
1388-2457/$30.00 q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2004.05.003
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Fig. 1. (A) Anterior view of the shoulder girdle demonstrating atrophy and weakness of the right trapezius muscle, one week before IVIg treatment. (B). Anterior view of the shoulder girdle showing improvement in right trapezius muscle atrophy, 5 weeks after the first course of IVIg. (C) Posterior view of the shoulder girdle demonstrating atrophy of the right trapezius muscle, one week before IVIg therapy. (D) Posterior view of the shoulder girdle demonstrating improvement in right trapezius muscle atrophy, 5 weeks after the first course of IVIg.
the right trapezius muscle (Fig. 1A –C). A diagnosis of brachial neuritis was made at another institution, despite atypical features such as persistence of pain for months after onset. No sensory symptoms or weakness in other extremities were noted. Past medical history and family history were unremarkable. Examination revealed apparent atrophy of the right upper trapezius muscle, weakness of right shoulder elevation (Medical Research Council [MRC] score 3), and scapular winging increasing with shoulder abduction. The right sternocleidomastoid muscle strength was normal. Muscle bulk, strength, tendon reflexes were otherwise normal. No fasciculations, tremors, or long-tract signs were noted. Sensory examination was normal. The other cranial nerves were normal. The following investigations were unremarkable: GM1 antibody titers, full blood count, electrolytes, urea, creatinine, liver function tests, serum creatine kinase, immunoglobulin studies, serum immunofixation, antinuclear antibodies, antineutrophil cytoplasmic antibodies, rheumatoid factor, complement levels, anti-Ro, and anti-La antibodies, and cerebrospinal fluid profile. Following a 5-day course of IVIg (2 g/kg), dramatic resolution in the right trapezius muscle weakness (MRC score 5) and apparent atrophy occurred (Fig. 1B –D). The shoulder discomfort subsided, as it was probably secondary to strain on soft tissues because of functional failure of the trapezius muscle. An attempt to taper the IVIg dose over the ensuing 4 months caused a recurrence of weakness and pain. This again responded promptly to a 5-day course of IVIg at the initial dose. The patient has been followed clinically for 5 years without recurrence of weakness on monthly IVIg therapy (35 g/month).
Case 2. A 53-year-old woman developed painless, progressive weakness of finger extension over a 2-year period. This began with digit III extension weakness and gradually spread to affect digits II and then digit IV. She was initially diagnosed with right posterior interosseous nerve (PIN) syndrome and underwent surgical exploration and neurolysis of the PIN without benefit. No sensory loss or weakness in the other extremities was noted. Past medical and family history was unremarkable. Clinical examination revealed severe weakness of right finger extension (MRC 2 – 3) with mild atrophy of the forearm extensor muscles. Muscle bulk, strength, and tendon reflexes were otherwise normal. No fasciculations, tremor, or long-tract signs were present. Sensory examination was normal. Cranial nerve examination was normal. Laboratory testing, as in case 1, was unremarkable. The cerebrospinal fluid was unremarkable. Following a 4-month course of treatment with IVIg (2 g/kg for 4 consecutive months) marked improvement in right finger extension (MRC grade 4) developed. The improvement in muscle strength was maintained for 3 years, during a gradual taper of the monthly dose until a dose of 25 g/month was reached. At this point, the PIN weakness recurred and subsequently improved with the doubling of the IVIg dose (50 g/month). Since then the patient has been successfully maintained on that dose for the last 2 years.
3. Methods NCS were performed on either the Oxford-Teca Synergy or Medelec-Teca Sapphire Premier electromyography machines (Oxford Instruments, Manor Way, Old Woking, Surrey, England). Skin temperature was maintained at 32 8C in the upper extremities and 30 8C in the lower extremities. Motor nerves were evaluated to the cervical nerve roots in the upper limbs and popliteal fossa in the lower limbs. The following nerves and nerve segments were studied; median nerve to the abductor pollicis brevis (APB) muscle (stimulation at the wrist, antecubital fossa, axilla, cervical root); ulnar nerve to the abductor digiti minimi muscle (stimulation at the wrist below and above the elbow, axilla and cervical root); radial nerve to the extensor indicis proprius (EIP) and triceps muscles (stimulation at the forearm, above the elbow, in the axilla and at the cervical root); musculocutaneous nerve to the biceps brachii muscle (stimulation from the cervical root); spinal accessory nerve to the 3 heads of the trapezius muscle (stimulation in the posterior triangle at the posterior border of the mid-portion of the sternocleidomastoid muscle) (case 1); tibial nerve to the flexor hallucis brevis muscle (stimulation at the ankle and popliteal fossa); common peroneal nerve to the extensor digitorum brevis muscle (stimulation at the ankle, below the fibular head and at the popliteal fossa). Near-nerve electrical cervical nerve root stimulation (CNRS) was performed
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according to methods previously reported (Berger et al., 1987). Collision studies were used for determining the compound motor action potentials (CMAP) amplitudes from the APB muscles on stimulation of the cervical roots. Surface Ag/AgCl disk electrodes were used for stimulation and recording the CMAP. Median, ulnar, radial, and sural sensory nerve action potentials were recorded orthodromically. All nerves and nerve segments were studied bilaterally. For each CMAP, amplitude and area of the negative peak were determined. The degree of CMAP amplitude and area reduction for consecutive stimulation sites were calculated and expressed as a percentage. For the median, ulnar, and radial nerves, definite partial CB was defined as greater than 50% reduction in amplitude and 40% reduction in area between proximal and distal stimulation sites. For the tibial and common peroneal nerves, definite partial CB was defined as greater than 60% reduction in amplitude and 50% reduction in area between the proximal and distal stimulation sites. A diagnosis of CB required a distal CMAP amplitude of greater than 1 mV. Needle electromyography (EMG) was performed using a disposable, 20-gauge concentric needle electrode (Oxford Instruments, Manor Way, Old Woking, Surrey, England).
4. Results Case 1. The right spinal accessory NCS revealed an absent CMAP response from the upper, middle, and lower heads of the trapezius muscle. A partial CB (71%) was noted in the right median nerve forearm segment, with prolonged F-wave latency and normal median nerve distal CMAP amplitude (Table 1). Other motor and sensory NCSs were normal. EMG revealed absence of voluntary activity in all 3 heads of the trapezius muscle without spontaneous activity (SA) (fibrillations and/or positive sharp waves). In the right APB muscle, no SA was seen and fast-firing motor unit action potentials (MUAPs) of normal amplitude
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and configuration were noted on voluntary contraction. Reduced recruitment pattern was noted in the right APB muscle. Needle examination was otherwise normal. Followup NCSs after IVIg therapy, revealed resolution of CB in the right median nerve forearm segment and normalization of the CMAP amplitude in the 3 heads of the right trapezius muscle (Table 1; Fig. 2A). The other motor and sensory NCSs remained normal. Needle EMG of the 3 heads of the trapezius and APB muscles was normal. Subsequent NCS, 2-years post-symptom onset, while on IVIg treatment showed no new CBs. Case 2. The right radial motor NCS revealed an absent CMAP response when recording from the EIP muscle. Partial CB (57%) was noted in the right median nerve forearm segment with prolonged F-response latency (Fig. 2B). The other NCSs were normal. Needle EMG demonstrated abundant SA in the EIP and extensor digitorum communis (EDC) muscles, with no voluntary activity in EIP and single unit recruitment in EDC. The MUAP was of prolonged duration and increased amplitude. In addition, fast-firing MUAPs, of normal amplitude and configuration, were noted in the right APB muscle. Reduced recruitment pattern was noted in the right APB muscle. EMG was otherwise normal. Follow-up NCSs, 3 months after the first course of IVIg, revealed normalization of the right EIP CMAP amplitude and resolution of the right median nerve CB (Table 1; Fig. 2C and D). Needle examination of the EIP muscle showed no SA with persistence of large amplitude, long duration MUAPs with low mixed recruitment. Three subsequent NCSs over the following 3 years, while on IVIg treatment, revealed no new CBs.
5. Discussion These cases exemplify diagnostic challenges in MMNCB that have not been so far reported in the literature: on the one hand presentation with involvement of a single motor nerve, which obscures the dissociation of motor from sensory
Table 1 Pre and post-treatment conduction studies of abnormal nerves Patient
Nerve
Muscle
Stimulation site
CMAP amp. (mV) at baseline
CMAP amp. (mV) after IVIg therapy
Case 1
R XIth Cranial nerve R Median
UT MT LT APB
R Radial
EIP
R Median
APB
PT PT PT Wrist Elbow Forearm Elbow Wrist Elbow
0 0 0 12.3 3.5 (72)* 0 0 8.3 3.6 (57)*
3.6 3.2 3.5 13.6 11.5 (15)* 5.3 3.2 7.6 6.3 (17)*
Case 2
RXI, right spinal accessory nerve; UT, upper trapezius; MT, middle trapezius; LT, lower trapezius; PT, posterior triangle; APB, abductor pollicis brevis; EIP, extensor indicis; CMAP, compound muscle action potential; CB, conduction block; *( ) CMAP amplitude percentage decrement from wrist to antecubital fossa stimulation.
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Fig. 2. (A) Case 1: Recording from the trapezius muscle stimulating the spinal accessory nerve in posterior triangle after IVIg therapy (calibration 2 mV, 5 ms): upper, middle and lower refer to the corresponding heads of the muscle. (B and C) Case 2: Partial motor conduction block in the forearm segment of the right median nerve before IVIg treatment [B] (calibration 10 mV, 5 ms). (C) Resolution of median nerve conduction block after IVIg treatment (calibration 5 mV/5 ms): wrist and forearm refer to stimulation sites. (D) Case 2: Recording over the extensor indicis proprius muscle after IVIg treatment (calibration: 5 mV, 5 ms): forearm and elbow refer to stimulation sites.
deficits, and on the other hand the occurrence of a distal CB in the affected nerves, such that established diagnostic criteria, relying on comparison of CMAPs obtained on distal and proximal stimulation relative to the site of pathology, are inapplicable (Olney et al., 2003). The diagnosis of MMNCB was first suspected by the finding of asymptomatic CB in the median nerve forearm segments of both patients. Further suspicion arose following the rapid response to treatment with IVIg. This response enabled a retrospective diagnosis of distal CB in clinically symptomatic nerves, demonstrating a multifocal pattern characteristic of MMNCB. The absence of the CMAP in the symptomatic muscles (trapezius in case 1 and EIP in case 2) resulted from complete distal CB. In patient 1, this was confirmed by absence of voluntary activity on EMG testing, and rapid normalization of neurophysiologic findings with IVIg treatment. In patient 2, although neurophysiologic evidence of axonal loss and motor unit remodeling was present, the rapid normalization of the CMAP amplitude and MUAP recruitment pattern, with IVIg therapy, was in keeping with resolution of a distal CB (Cros and Triggs, 1994).
The apparent atrophy of the right trapezius muscle in case 1 was probably related to muscle hypotonia. Muscle spindles are thought to be essential to normal muscle tone (McComas, 1996). Ongoing stretch of the muscle spindles, particularly frequent in muscles tonically fighting the action of gravity such as the upper trapezius, generates motor activity that may be the clinical substrate of muscle tone. Interestingly, there are very few clinical studies of muscle tone and hypotonia (Thomas and Ajuriaguerra, 1949). Normal tone includes the expected passive resistance to stretch, pressure, and deformability of muscle. Hypotonia develops in a muscle immediately after division of its motor nerve and is characterized by flaccidity, decreased firmness to palpation, and increased extensibility, presumably because the afferent and efferent arcs of the tonic myotatic reflex are interrupted. This is seen in pathologic states with widespread dorsal root pathology, such as the historical cases of tabes dorsalis in which hypotonia of the trunk erector and hip extensor muscles may result in flexion of the trunk (Thomas and Ajuriaguerra, 1949). Complete CB replicates this pathophysiology through interruption of the efferent limb of the reflex arc. Hence, the scapular winging
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and the shoulder droop shown in Fig. 1, resulting from hyperextensibility of paralyzed muscles, may mimic the clinical features of atrophy in the upper trapezius muscle. The rapid restoration of trapezius muscle bulk and tone following IVIg treatment supports this interpretation (Fig. 1). A lack of correlation between partial motor CB and muscle weakness has been previously reported in demyelinating polyneuropathies (Oh et al., 1992; Van Asseldonk et al., 2003). Specifically, Van Asseldonk et al. (2003) noted CB in 35% of nerves innervating muscles with normal strength, as measured by the MRC scale, in patients with MMNCB. Moreover, Oh et al. (1992) noted motor CBs in patients with clinically pure sensory CIDP. The pathophysiologic mechanisms underlying this phenomenon are unclear. We hypothesize that, based on the partial involvement of motor fascicles suggested by the biopsy studies of Kaji et al. (1993), some motor axons connected to fasttwitch motor units characterized by a high twitch force remain functional. The corresponding motor units are recruited at a high firing rate in the brisk, strong contraction required to generate maximum force in manual muscle testing (Desmedt and Godaux, 1977; Tanji and Kato, 1973). It seems possible that in some cases of partial CB, enough of these axons remain functional to generate a brief, ballistic contraction deemed normal by experienced clinicians, as in the reports mentioned above and our cases. It is possible that clinical muscle weakness would have ensued after a sustained contraction from the patient, as the fast-twitch motor units are fatigable. Alternatively, the degree of CB may have been overestimated through the process of interphase cancellation (Kimura, 1993; Lange et al., 1992). Given the limitations of conventional NCSs in detecting CB in the proximal and distal nerve segments, the neurophysiologic assessment should be as extensive as possible, including CNRS, prior to concluding that CB is not present (Menkes et al., 1998; Van Asseldonk et al., 2003). CNRS relies on the principle of a current stimulating the proximal portion of the motor axons at or close to their emergence from the spinal cord (Berger et al., 1987; Cros et al., 1990; Mills et al., 1987). This current may be induced by either a rapidly varying magnetic field, produced by a magnetic coil placed over the lower neck area (Cros et al., 1990), an electric field produced by needle electrode (cathode) inserted at the C7 vertebral body (Berger et al., 1987), or a high-voltage percutaneous stimulation delivered over the back of the neck (Mills et al., 1987). A reduction in the CMAP area and amplitude of more than 50% is considered diagnostic of proximal CB (Lange et al., 1992; Raynor et al., 1998). Although, magnetic CNRS is painless, it is best used to rule out CB, as supramaximal stimulation cannot be achieved in a third of subjects (Cros et al., 1990). Our patients underwent transcutaneous electrical CRNS to avoid this potential pitfall. In addition, repeat NCSs after response to treatment may prove to be the only means in
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diagnosing distal CB, as previously reported (Triggs et al., 1992). Long-term follow-up studies of IVIg treatment in MMNCB have reported clinical improvement (Azulay et al., 1997; Bouche et al., 1995; Van den Berg-Vos et al., 2002), although new sites of CB and ongoing axonal degeneration developed despite maintenance IVIg therapy (Van den Berg-Vos et al., 2002). In our report, the resolution of CBs persisted with ongoing IVIg treatment after several years of follow-up. Furthermore, there was resolution of ongoing axonal loss and evidence of reinnervation in patient 2. This suggests that, in these patients, the therapeutic regimen induced and maintained a full remission, although both patients have remained IVIg-dependent.
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