Anti-MuSK myasthenia gravis (Anti-MuSK MG) is a chronic autoimmune disease caused by complement-independent dysfunction of the agrin-MuSK-Lrp4 com- plex, accompanied by the development of the pathological muscle fatigue and some- times muscle atrophy.
Anti-MuSK antibody myasthenia gravis (Anti-MuSK MG) is a chronic autoimmune disease caused by complement-independent dysfunction of the agrin-MuSK-Lrp4 complex, accompanied by the development of pathological muscle fatigue and sometimes muscle atrophy. Anti-MuSK MG is a subtype of seronegative acquired myasthenia gravis, occurring in 5-8% of all cases 1-3.
Four main clinical phenotypes of anti-MuSK MG were described: generalized form, oculobulbar form, lumbar-limb phenotype with involvement of the neck extensors and respiratory muscles, isolated ocular form 4-6.
One of the characteristic features of anti-MuSK MG is the presence of atrophy and fatty infiltration of the tongue, extraocular, mimic, masticatory and paravertebral muscles, detected by MRI and proton magnetic resonance spectroscopy (MRS) 5,7-11. This feature presents as a consequence of myopathic process in anti-MuSK antibody MG, which is confirmed by changes in the myopathic EMG pattern in 44-50% of cases. Those changes include a decrease in the MUAP durations, amplitudes and the presence of fibrillation potentials 3,7,12,13. Muscle atrophy is more common in patients with longer disease course 7,8. However, some cases of anti-MuSK MG were reported with a short course, characterized by the presence of neurogenic changes in the muscles 14-16. In the studies of experimental autoimmune MG in mice, a wide range of evidence was obtained in favor of denervation changes in muscles in anti-MuSK MG 17-19. At the same time, in humans, in most muscular morphological studies of the extremities, predominant myopathic 20-23 and rarer presynaptic neurogenic changes were observed 19. Thus, the exact nature of muscle damage in patients with anti-MuSK MG remains debated. The question is of importance since myogenic changes are less susceptible to respond to a therapeutic intervention.
In this article, we report reversible probably neurogenic changes, identified by nerve conduction studies (NCS), repetitive nerve stimulation (RNS), electromyography (EMG) and MRI, in paravertebral muscles in two patients with anti-MuSK antibody MG.
Subjects and methods
The examination and treatment of two patients: K. 51-year-old male and P. 44-year-old female with paraspinal-muscle weakness caused by anti-MuSK MG were carried out. The clinical, neurological examination and the quantitative myasthenia gravis score (QMGS) assessment were performed before and after the therapy.
All studies were conducted after the patients had signed the voluntary informed consent.
Laboratory methods included: general, biochemical blood analysis, determination of IgM, IgG and IgA levels (turbidimetric method, BTS-350, BioSystems, Spain), antibodies to antinuclear factor (ANF) by indirect immunofluorescence (iIF) test (Euroimmun, Germany), extractable nuclear antigen (ENA) by ELISA (Orgentec, Germany), anti-MuSK antibodies by ELISA (IBL, Germany), anti-AChR antibody test by ELISA (Medipan, Germany), anti-skeletal muscle antibodies (anti-SM) by iIF (Euroimmun, Germany), myositis-associated antibody test (MAA) (Mi2b, Ku, Pm-Scl100, PM-Scl75, Jo-1, SRP, PL-7, PL-12 EJ, OJ, Ro-52) (Euroimmun, Germany).
Instrumental methods consisted of: nerve conduction studies (NCS), repetitive nerve stimulation (RNS) (rhythmic stimulation 3 and 50 Hz), needle electromyography (EMG), whole-body MRI using T1-weighted, T2-weighted STIR-T2 weighted sequences in three orthogonal orientations (Philips Ingenia 1.5 Tl), chest CT (Aquilon 64, Toshiba).
Treatment of patient 2. (44 y.o.) included methylprednisolone tablets (0.8 mg/kg b.w.) by an alternating scheme and five cycles of medium-volume membrane plasma exchange using PCS-2 devices (Haemonetics, USA) according to the standard technique with an exfusion volume of 25-30% of the circulating plasma volume. The replacement of the exfused plasma was carried out with crystalloid solutions. Patient 1 (51 y.o.) received only methylprednisolone tablets (1.0 mg/kg b.w.) according to an alternating scheme. In both patients, when the methylprednisolone doses were decreased, azathioprine tablets (50 mg/day) were additionally prescribed.
Description of clinical cases
Patient 1 (male, 51 years old; 186 cm tall, weighting 79 kg; BMI - 22.8) presented with a 8-month disease duration. He complained of severe muscle weakness of the back and neck, with difficulties to maintain the head and posture, inability to extend the back from a forward bend. After 2 months, the patient noted the appearance of double vision. The severity of symptoms had no significant fluctuations during the day. The neurological examination before treatment revealed moderate weakness of the neck extensors (4 points) and severe weakness of the thoracic and lumbar paravertebral muscles (3 points). When the arms were extended forward, a compensatory deviation backward of the body by 10° was observed. Weakness in the facial and proximal muscles of the upper limbs was not observed (5 points). The QMGS score was 3/39 points. The patient was MGFA class 1. The neostigmine methyl sulfate test (0.05% 2 ml) was positive.
The level of anti-AChR antibodies were 0.24 nmol/L (norm of up to 0.45); anti-MuSK antibodies were more than 23.3 IU/ml (norm of up to 0.39 IU/ml); anti-SM antibodies - less than 1:20 (up to 1:20); ANF antibodies were 1: 640; anti-mitochondrial antibodies (PDC-AMA2; AMA) - 1:20 (less than 1:20); immunoblotting of antinuclear antibodies was normal. The IgM, IgG and IgA levels were normal.
On the whole-body MRI in m. multifidus at levels Th10 - L5 MR signal was heterogeneous, particularly on the left side due to areas of moderate hyperintensities on T2w images, with corresponding iso/hypointensities on T1w images. Those areas showed edematous changes. No signal anomaly was detected elsewhere, either in the paravertebral muscles or in the paravertebral soft tissues at other locations.
A L5-S1 disc protrusion was observed, up to 0.35 cm in size, without affection on the spinal roots. In the posterior group of thigh and leg muscles, mild fatty replacement was noted (Mercuri 1 grade 1 on a scale of 0 to 4).
Respiratory function indices were in the normal range.
On the repetitive nerve stimulation compound muscle action potentials (CMAP) decrement was revealed in the orbicularis oculi muscles (23%) and the proximal muscles of the upper extremities up to 65% (Tab. I). On the EMG in m. deltoideus, m. vastus lateralis, m. tibialis anterior, the MUAP amplitudes and durations were normal. In the proximal muscles increased polyphasia of MUAP was noted up to 26-33%. In m. erector spinae at the L1-L3 levels, neurogenic changes were revealed, represented by an increase in the MUAP amplitudes - 1814 μV (343-4172 μV), with a normal MUAP duration - 11.1 ms (8.43-16.4), an increase in polyphasic fibers up to 14%; the interference pattern corresponded to the neurogenic one. Spontaneous activity was represented by the multiple fibrillation potentials, positive sharp waves and single fasciculations.
After treatment, which included glucocorticosteroids (1.0 mg/kg b.w.in an alternate day scheme for 4 months, followed by a progressive decrease), patient 1 achieved complete clinical remission.
A control examination after 6 months of therapy showed a decrease in the anti-MuSK level to 8.13 IU/ml. At the MRI, the complete regression of edematous changes in the paravertebral muscles was observed (Fig. 1). On the RNS, the CMAP decrement in m. trapezius persisted. In m. erector spinae at the L1-L3 levels, less pronounced neurogenic changes were observed, indicated by lower MUAP amplitudes - 1610 μV (567-2942 μV), with a normal MUAP duration of 10.5 ms (9.07-14.6), an increase in polyphase fibers to 32%. The interference pattern corresponded to a neurogenic one. QMGS score - 0/39 points. The patient 1 was MGFA class 0 (Tab. I).
Patient 2 (female, 44 years old, height 166 cm; weight 68 kg; BMI - 24.7) with complaints of double vision, limitation of eye movements, the drooping eyelids and rapid fatigability of the neck extensors with the development of “dropped head” syndrome in the evening. The first episode of self-regressing isolated double vision, which lasted 2 weeks was observed 8 months ago. Ophthalmoparesis was observed within 4 months. On examination before the treatment, diplopia, ophthalmoparesis, convergent strabismus, hypomimia, weakness in the neck extensors were noted. She could not raise her head in a forward tilt position (2-3/5 points); she had weakness in the back extensors of the thoracic and lumbar regions (4 points). Muscle strength of the upper and lower extremities was normal (5 points). QMGS score - 17/39 points. The patient 2 was stage 2a according to MGFA. The neostigmine methyl sulfate test (0.05% 1.8 ml) was positive (Fig. 1).
The level of anti-AChR antibodies was 0.21 nmol/L (normal up to 0.45); antibodies to MuSK more than 25 IU/ml (norms up to 0.39 U/ml); anti-SM antibodies - less than 1:20 (the norm is up to 1:20). Blood cell count showed a relative lymphocytosis of up to 47.4% (norm 19.0-37.0%) with normal absolute lymphocyte number. On chest CT persistence of the thymus gland was revealed (7.6x11 mm, no clear contours).
At MRI, whole-body axial STIR and T2wi in the axial plane revealed the moderate edematous changes in m. multifidus at the Th12, L3-L5 levels, m. erector spinae at the L4, L5 levels on the left (Fig. 2A). On the T1w and T2w scans in sagittal, coronal and axial projections with fat suppression, the patient had protrusions of the L3-L5 intervertebral discs measuring 0.2-0.3 cm, without signs of nerve root compression. In the STIR and T2w images of extraocular muscles, moderate symmetric edematous changes in m. rectus lateralis and m. rectus inferior were observed in the absence of structural pathological changes on T1wi. The tongue did not reveal any pathological edematous change or pronounced fatty infiltration (Fig. 2I).
Respiratory function indices corresponded to the norm.
The RNS (rhythmic stimulation 3 Hz) revealed a M-response decrement in the mimic, pharyngeal and the proximal muscles of the upper extremities by 38% (Tab. I). The EMG in m. deltoideus, m. vastus lateralis, m. tibialis anterior showed normal values of the MUAP amplitudes and durations while the MUAP polyphasia in the proximal muscles was increased up to 23-40%. In the m. erector spinae at the L2-L4 levels, neurogenic changes were revealed, represented by the increased MUAP amplitudes - 1514 μV (292-3802 μV), with a normal MUAP duration - 11.9 ms (8.43-16.4), polyphase fibers - 9%; the interference patterns corresponded to the neurogenic one. Signs of spontaneous activities included multiple fibrillation potentials, single fasciculations, and positive sharp waves. The number of fasciculations prevailed on the left side where MRI identified more pronounced edematous changes.
After a 2-month treatment, which consisted of glucocorticosteroids (0.8 mg/kg b.w.) administered each other day and five medium-volume plasma exchanges, patient 1 reached a complete clinical remission. Methylprednisolone-dose was then gradually reduced and azathioprine (50 mg/day) was added.
A follow-up study 3 months after had been initiated showed the decreasing anti-MuSK antibodies to 7.26 IU/ml. A complete regression of the paravertebral muscles edematous changes was seen at the MRI, but a moderate edema still persisted in m. rectus inferior. On the RNS, the elevated CMAP decrement in m. orbicularis oculi persisted. The MUAP parameters of the paravertebral muscle were in the normal range. No spontaneous activity was detected, but the MUAP polyphasia remained up to 34%. QMGS score was 1/39 point (Fig. 1). The patient 2 was MGFA class 0.
The first clinical case was a rare example of anti-MuSK myasthenia gravis, manifested with an isolated lesion of the paravertebral muscles, predominantly of the lower thoracic and lumbosacral regions. That lesion included the pronounced difficulties in extending the trunk from bending forward and maintaining balance with arms extended forward. Previously, cases of primary involvement of the paravertebral muscles were described only in children (7 years). They were accompanied by the developing scoliosis and atrophy of these muscles at the cervical and thoracic levels 11,24. In both cases, the scoliotic deformity significantly decreased after treatment. The second case was characterized by a milder involvement of the axial muscles than in the first case. In particular, there was a moderate “dropped head” syndrome in the evening and mild involvement of the lower thoracic and lumbar paraspinal muscles, manifested by lumbar fatigue when standing. As it is known, the axial muscles are often involved at the cervical levels with the development of “dropped head” syndrome in patients with anti-MuSK MG 14,25-28, and even more often in patients over 60 years old with anti-AChR antibodies in 10% of cases 29,30, while in other anti-AChR patients, the lesion of the neck flexors prevails 31.
In both cases, primary involvement of the axial musculature prompted a whole-body MRI scan to rule out myopathies. Unexpected edematous asymmetric changes in the paravertebral muscles were revealed. These changes were more pronounced in the first patient (the MR signal hyperintensity on STIR, T2-WI, iso/hypointensity on T1-wi) in m. multifidus at the Th10-L5 levels and m. erector spine at the level of L5-S1 segments. Signal hyperintensity on STIR in combination with spontaneous activity on EMG characterizes muscle denervation in the acute (up to 1 month) and subacute phases (1-6 months) 32,33. Such changes are due to the expansion of the capillary bed and the increasing intercellular fluids 34, already developing 48 hours after denervation 35. Similar changes can be observed not only during denervation, but also during primary muscle inflammatory processes, including inflammatory myopathies 36. In both our cases, the presence of inflammatory myopathies was ruled out by normal level of CPK, AST, ALT, LDH, and myoglobin, as well as negative results of the myositis-associated and antimitochondrial antibodies. A STIR positivity at MRI has a sufficiently high relative sensitivity - 84% and specificity - 100% for detecting denervation (acute and subacute phases) when compared with EMG 37,38. In chronic phase (more than 6 months), an increase in muscle fat content and muscle atrophy are observed, which is accompanied by the development of the MR signal intensity on T1wi and a decrease in muscle mass. Similar changes are also observed in functional immobilization (for example, tendon rupture) and hereditary muscular dystrophies 32,33.
In most of the previously reported cases of anti-MuSK 24 and anti-AChR 39,40 MG, associated with the axial muscle damage (“dropped head” syndrome, camptocormia), the MR signs of fatty infiltration and paravertebral muscle atrophy were described even with or without the glucocorticosteroid therapy. In patients with anti-AChR MG, a summation of similar MR-changes, the “myopathic” EMG patterns in paraspinal muscles and resistant camptocormia has been stated by a number of authors as an independent rare comorbid condition – “paraspinal myopathy” 41,42. Similar cases of the anti-AChR MG and “paraspinal myopathy” were described in patients aged 70-85 years with a long course and poor control of MG symptoms. The presence of cases of reversible camptocormia, “dropped head” or “Leaning Tower of Pisa” syndrome during the treatment in patients with anti-AChR and anti-MuSK MG who have myopathic EMG signs with or without atrophy, but without fatty infiltration of the paravertebral muscles, probably indicates that the damage to this muscle group is one manifestation of myasthenia gravis 43-45. Thus, myasthenic weakness, leading to functional immobilization of the paravertebral muscles, probably determines the stage process of their affection. Initially, the development of early edematous changes is the same as for the acute and subacute phases of denervation, which corresponds to our cases. Subsequently, late changes, equivalent to chronic denervation, which corresponds to most of the previously described cases 41,42. This correlation indicates that the presence of the paravertebral-muscle lesion with anti-MuSK MG can lead to scoliotic deformity in childhood. At the same time in elderly patients with anti-MuSK, as well as anti-AChR MG, the paraspinal damages may cause camptocormia and “dropped head “syndrome.
The muscle MRI characteristics of the limbs in patients we described corresponded to the control muscles. The only exception was minimal signs of fatty infiltration in the lower extremities (grade 1 according to Mercuri), which was probably a consequence of a sedentary lifestyle 46.
Besides, in two patients, there were no edematous changes, fatty infiltration and atrophy of the tongue, mimic and masticatory muscles, probably due to short disease duration (4-6 months). These findings contradicted the typical signs of anti-MuSK MG, which were atrophy and fatty infiltration of m. orbicularis oculi, m. orbicularis oris, m. buccinators, tongue muscles 8, mm. pterygoidei, m. masseter and m. temporalis 9. In some cases, atrophy of the tongue muscles is reversible 24,47. The severity of atrophy and fatty infiltration depends on the duration of prednisolone therapy 8. However, in some cases, atrophies developed at an early stage even before the initiation of the treatment, which was most likely due to the independent role of anti-MuSK in this process 9,48. In particular, Punga, et al. (2011) showed that MuSK antibodies induced functional denervation, resulting in increased production of the skeletal-muscle-atrophy marker MuRF-1 (atrophy marker muscle-specific RING finger protein 1) 49 in a passively induced model of experimental autoimmune MG in mice 18,50. At the same time, a significantly greater increase in mRNA levels of MuRF-1 was observed in the masticatory muscles, while those levels decreased in the limb muscles (m. soleus). These findings explained the peculiarities of the atrophy distribution in anti-MuSK MG 18,50. The progression of atrophy under the anti-MuSK influence was also realized through overexpression of atrogin-1 and p21, which provoked a premature stop of the cell cycle and weakened the ability of satellite cells to replace lost muscle fibers 18,51,52.
Similar regularities were observed in the MR changes of the oculomotor muscles in anti-MuSK MG. Thus, in our second case, severe ophthalmoplegia lasting 4 months was characterized by moderate edematous changes (according to STIR) in m. rectus lateralis and m. rectus inferior, which corresponded to MR signs of early functional denervation. Whereas in cases of prolonged ophthalmoparesis (2-14 years) with anti-MuSK MG, the MR signs of pronounced atrophy in extraocular muscles were observed 5,6. In these cases, the least affected muscle was m. obliquus inferior.
Thus, muscular atrophy, especially of the mimic and bulbar muscles, has been a fairly common delayed consequence of anti-MuSK MG, reflecting the disease duration, the delayed initiation of therapy and/or the effect of prolonged exposure to high doses of glucocorticosteroids 53. The intricacy of mechanisms is supported by the variability of the prevalence of atrophy in anti-MuSK MG, from 5.7 54 to 23% 7. The assessment of muscle condition by MRI at the time of diagnosis is a important to estimate the possible functional recovery under therapy 6,9.
The CMAP decrement with RNS of 3 Hz was revealed in both clinical cases, while the decrement curve had a steadily progressive character, in contrast to the U-shaped form in anti-AChR MG 55. In both cases, there was no hypercholinergic reaction after the first supramaximal stimuli that performed with additional potentials after the M-response 56. This result may be due to the short duration of the disease and the low doses of acetylcholinesterase inhibitor (AChEI) used (up to 180 mg/day of pyridostigmine bromide). In the first case, the decrement distribution of the examined muscles mainly reflected the focal nature of the lesion with maximum values of the CMAP decrement up to 65% in m. trapezius. Whereas the second case was clinically similar to the generalized form of anti-AChR, characterized by a more diffuse distribution of the M-response decrement. The maximum values of the CMAP decrement corresponded to those values in the most affected muscle groups. The significant variability in the decrement distribution in anti-MuSK MG substantiated the rationality of more extended studies. At the same time, the diagnostic significance increased from 56.8 22 to 85% when the neuromuscular-conduction analysis included not only distal, but also proximal muscles of the extremities, as well as facial muscles 28,54,57.
Needle EMG was performed to determine the neurogenic nature of the hyperintense-signal areas (on STIR) of the paravertebral muscles. Paraspinal MUAPs had increased amplitudes and normal durations with a slightly increased polyphasia up to 14%. Whereas in the limb muscles without MR lesion signs, duration and amplitude MUAPs were normal, albeit with a significantly increased polyphasia up to 40%. Spontaneous activity was only detected in the STIR hyperintense areas in the paravertebral muscles and represented by a significant number of fibrillation potentials, positive sharp waves, and single fasciculation potentials. On turn-amplitude analysis, a neurogenic pattern of the interference curve was observed in the paravertebral muscles, characterized by a high amplitude with a reduced or normal frequency of turns. In both cases after the therapy, the MUAPs almost completely returned to normal. However, in most studies of anti-MuSK patients, the myopathic nature of EMG changes was reported: a decrease in the MUAP durations and amplitudes, the presence of fibrillation potentials 3,12,57. Myopathic MUAPs were observed in 62-80.6% of anti-MuSK patients in facial muscles 7,12, although in limb muscles, they were in 33-44% 7,13. It should be noted that the interpretation of MUAP changes in anti-MuSK and anti-AChR is questionable, when different stages of the denervation process are not taken into account. In particular Farrugia, et al. (2007) indicated that in 50% of anti-MuSK patients with MUAP myopathic patterns in turn-amplitude analysis, the interference curve was characterized by high amplitudes and low frequency of turns 12. This result was interpreted as an insufficient strength of studied-muscle contraction, and not a sign of early functional denervation 12.
In cases with predominant lesions of the paravertebral muscles, the myopathic nature of the MUAP changes was accompanied by muscle atrophy during a long disease course 11. At the same time, cases with a short duration of anti-MuSK MG and axial-muscle damages were described, characterized by reduced duration of MUAPs, increased polyphasia and pronounced spontaneous activity (fibrillation potentials, fasciculations, positive sharp waves), which was regarded as neurogenic changes and was a cause of amyotrophic lateral sclerosis (ALS) misdiagnosis 14-16,24. In some cases, EMG signs of fasciculations were accompanied by clinically evident fasciculations 16,58.
A similar nature of MUAP changes and the presence of spontaneous activity were described in studies of experimental autoimmune myasthenia gravis and in some clinical cases, in which denervation changes in the affected muscles were substantiated 18,19,21,59-65. The degree of nerve penetration in each muscle has been shown to correlate with their endogenous MuSK levels 18,66.
Summing up the available data, in anti-MuSK myasthenia gravis, most researchers have considered these muscle damages as myopathic process 1,3,7,12,22. Whereas our clinical examples have confirmed the presence of neurogenic changes at an early stage of anti-MuSK myasthenia gravis and indicated importance of immediate initiation of pathogenetic therapy to avoid the development of muscle atrophy and fatty infiltration.
Conflict of interest statement
The authors declare no conflict of interest.
The study was carried out with the financial support of the Ministry of Science and Higher Education of Russia, agreement No. 075-15-2021-1346.
The authors have contribuited equally to the work.
Figures and tables
|Muscles||Patient 1 (51 y.o.)||Patient 2 (44 y.o.)|
|А, mV||D, %||А, mV||D, %||А, mV||D, %||А, mV||D, %|
|M. orbicularis oculi||2.4||23||2.5||+ 0.2||0.45||38.4||0.99||34.2|
|M. digastricus vent. anterior||4.7||1.5||5.1||+ 0.8||3.61||18.6||6.78||+ 0.6|
|M. abductor digiti minimi||14.1||2.4||14.0||+ 0.4||9.4||2.4||10.3||+ 0.9|
|PAP (m. orbicularis oculi), %||112||108||127||123|
|Anti-MuSK antibodies, IU/ml||23.3||8.13||25.3||7.26|
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