Journal of the Neurological Sciences, 1978, 38 : 129-144
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© Elsevier/North-Holland Biomedical Press
M Y A S T H E N I A IN PATIENTS W I T H D E R M A T O M Y O S I T I S Clinical, Electrophysiological and Ultrastructural Studies
C. VASILESCU, G. BUCUR, A. PETROVICI and A. FLORESCU Institute of Neurology and Psychiatry, Bucharest 75622 (Romania)
(Received 22 August, 1977) (Accepted 30 March, 1978)
SUMMARY In 4 patients with clinical signs of dermatomyositis, confirmed by electromyography and muscle biopsy, a form of muscle fatigue was detected which was expressed clinically by predominantly proximal motor deficit, with phonation and deglutition disturbances, slightly influenced by prostigmine. In all patients, stimulation of the ulnar nerve at 3-10 Hz induced a decrement of muscle-evoked potentials in abductor digiti minimi and at 15-50 Hz an increment at the end of the trains (1.2 sec in duration) of repetitive stimulation (preceded in two cases by a decrement in the response to the fifth stimulus in the train). Stimulation at 30 Hz for 10 sec resulted in a transient facilitation, followed (at 3 Hz stimulation) by postactivation exhaustion which disappeared after 5-15 min. The post-tetanic facilitation, the incremental response and the myasthenic symptoms reverted to normal under treatment with corticosteroids, an immunosuppressor agent and guanidine hydrochloride. A mixed, pre- and postsynaptic mechanism is presumed to underlie the muscle fatigue in our patients. Electron microscopy of muscle biopsies disclosed zones of necrosis and, in incipient stages, large agglomerations of glycogen that had disorganized the structure of myofibrils. The end-plates in the biopsies were larger than normal and the cholinesterase reaction was hyperactive. Serum immunoelectrophoretic and electrophoretic d a t a - - increase of IgG and IgM, decrease of IgA and hypergammaglobulinaemia - - point to a possible autoimmune mechanism of the neuromuscular disorders in our patients.
Requests for reprints to: Dr. Constantin Vasilescu, Institute of Neurology and Psychiatry, C.P. 5880, Sos. Berceni 10-12, Bucharest 75622, Romania.
130 INTRODUCTION Cases of myasthenia gravis associated with polymyositis and cases of polymyositis displaying certain symptoms of the myasthenic type have been described, but muscle fatiguability characteristic of myasthenia gravis is not a usual feature of dermatomyositis. In 4 cases in which dermatomyositis was associated with clinical signs of myasthenic type, we performed a detailed clinical, electrophysiological and ultrastructural study in an attempt to obtain a correct interpretation of the symptoms and to determine effective therapy both of the primary disease and of the myasthenic symptoms. Estimation of the severity of the dermatomyositis was according to the classification proposed by Walton and Adams (1958) and by Barwick and Walton (1963) for polymyositis. METHODS
Electrophysiological techniques All the electrophysiological recordings were obtained with a type 14A21 twochannel DISA electromyograph. Stimulation was through surface electrodes, type 13K62, using a square wave of 0.1 msec duration of supramaximal intensity (150~ greater than the intensity inducing maximal electrical response in the muscles investigated) and 1-100 Hz frequency. Successive stimulus trains 1.2 sec in duration were applied at 3 min stimulus-free intervals. Muscle-evoked potentials (MEPs) in the abductor digiti minimi on stimulation of the ulnar nerve at the wrist were recorded from type 13K60 surface electrodes. The surface recordings were made with bellytendon leads under isometric conditions. A ground electrode was placed between the stimulating and recording electrodes. The skin under all electrodes was cleansed with alcohol, and the skin impedance was reduced with electrode paste. As errors may occur in the recording of MEPs if the distance between the surface electrode and the muscle varies during contraction, we fixed the small, thin (6 x 12 x 1.5 ram) plates of the electrode, 15 mm far from each other, on a rigid plastic plate. This was then fastened to the skin on the hypothenar eminence, with an elastic band, in a belly-tendon arrangement. With a view to minimizing hand and finger movements we fixed the forearm, hand and fingers on a stand with a heavy base (similar to that used by Slomid, Rosenfalck and Buchthal 1968). The intramuscular temperature in the abductor digiti minimi and near the stimulating cathode at the ulnar nerve at the wrist was 34.5-35 °C in all muscles investigated. For temperature measurements we used a DISA 14G05 Biological Temperature Unit with 13L10 Concentric Needle Electrode with Temperature Sensor. The MEP recordings were taken (i) under basic conditions, (ii) after a 10-min ischaemia (at 130 mm Hg pressure) of the respective limb, (iii) 30--40 min after i.m. injection of prostigmine and (iv) after treatment with prednisone or an immunosuppressor agent and guanidine hydrochloride. On the 5th stimulation in the trains 1,2
131 sec in duration, a decrement may appear. The degree of neuromuscular (NM) block was indicated by the formula D5 = 1 - - ~ , in which V is the voltage of the MEPs, while the accompanying figure is the ordinal number of the respective potential in the train (1.2 sec in duration) of stimuli at frequencies from 3 to 100 Hz. Hence, V1 is the voltage of the first potential in such a train. The letter D indicates the decrement, D5 being the decrement of the fifth response in the train. When an increment occurs, it is denoted as I. This was considered by Desmedt (1973a) to be a sensitive method of detecting N M block. In the present paper, the values of the peak-to-peak amplitude are given, as a rule, for the first, fifth and last potentials of the train.
Histological techniques For light-microscopic examinations, biopsies were taken from the muscle studied. The tissue was fixed in 10 ~ formalin solution. Longitudinal and transverse sections 5 # m thick, were cut and stained with haematoxylin-eosin (HE). In Case 1, the tissue was also prepared for histochemistry at the time of biopsy. The sections were stained with HE, succinic dehydrogenase (SDH), lactic dehydrogenase (LDH) and nicotinamide adenine dinucleotide dehydrogenase (NADH). Serial frozen sections of the muscles in Case 1 were stained with the method of Koelle and Friedenwald (1949) for determination of cholinesterase activity. Electron microscopy The biopsy fragments for electron microscopy were cut immediately after sampling, into 1-mm a blocks. These were fixed in 2 . 5 ~ buffered glutaraldehyde, postfixed in osmium tetroxide, embedded in Vestopal and cut in very thin sections that were stained with uranyl acetate and lead citrate and examined on a HU-11 H I T A C H I electron microscope. Treatment Treatment of dermatomyositis with prednisone given in the doses suggested by Walton 0971) and by De Vere and Bradley (1975), wasd beneficial. In Case I where prednisone was ineffective, a cytostatic substance (Chlorambucil) was successfully administered. Symptomatic therapy of the muscle fatigue, consisting of a combination of prostigmine and guanidine hydrochloride, was applied. REPORT OF CASES AND RESULTS OF INVESTIGATIONS
Case 1 M. F., a female aged 24 with dermatomyositis and myasthenic symptoms. The disease began 6 months before admission to hospital and worsened progressively.The most significantsigns were marked weakness on walking and in other voluntary movements, increasing in the course of the day and on exertion; induration of limb muscles; phonation and deglutition disturbances (dysphagia with reflux of fluids through the nose). On admission (10.1.1975)the patient exhibited oedematous violaceousplaques localizedperiorbitally and on the external aspect of the hands and forearms. There was marked loss of weight and greatly diminished muscle power, the patient being unable to stand or walk. Dysphonia and dysphagia persisted. Sedimentation rate: 51/h; 89/2h.
132
Serum electrophoresis. Albumin 33~o; globulins ...... 6 7 ~ : (tl ~: 2%, ¢~2 : 1 6 ~ , /~ 19%, 30 ~ (hypoalbuminaemia and hypergammaglobulinaemia). Serumimmunoelectrophoresis. lgG : 2 1 5 1 U ( N ~:- 1 0 0 ± 5 0 1 U ) , I g A 401U(N 100~ 50 IU), IgM -- 228 IU (N 100 ± 50 1U). Electromyogram. In the biceps brachii, gastrocnemius and 1st dorsal interosseous no resting potentials were recorded. On maximal contraction there was a low-voltage interference tracing (600 I~V amplitude) with a 7-msec mean duration of motor unit potentials (MUPs) and increased percentage of polyphasic M UPs. Muscle biopsy was taken from the gastrocnemius. Light microscopy showed multiple perivascular lympho-histiocytic infiltrates, intense proliferation of subsarcolemmal nuclei and, in some of the muscle fibres, central nuclei. Treatment. Administration of prostigmine was followed after 30 min by a slight improvement in muscle power and in swallowing and phonation. Prednisone failed to influence the clinical picture and was withdrawn. Treatment was continued with chlorambucil (0.2 mg/kg b.w.), while for the muscle fatigue we gave guanidine hydrochloride in doses that were gradually increased to 50 mg/kg b.w., and prostigmine. After 3 weeks of such therapy there was progressive improvement leading to recovery of the muscular and cutaneous symptoms. There was gradual disappearance of fatiguability and ofdeglutition and phonation disturbances, complete resolution of skin flush and oedema and the sedimentation rate and electromyogram (EMG) became normal. Further course of disease. In October 1976, i.e. 17 months after discharge from hospital, the patient again developed the symptoms of the disease. As she was unresponsive to corticotherapy, she was again treated with chlorambucil and guanidine hydrochloride. The clinical symptomatology characteristic of dermatomyositis, the muscle fatigue and the biochemical alterations remitted within two weeks of initiation of therapy. The cause of dermatomyositis remained obscure, no malignant tumour being detected. ~:-
7
Case 2 D.G., a 46-year-old male with dermatomyositis and muscle fatigue. The disease had begun 16 months before hospitalization, with cutaneous palmar lesions of the dermatomyositis type, followed in a few weeks by muscle weakness and diffuse muscular pain. After tonsillectomy, proximal weakness of the upper and lower limbs developed and increased with fatigue. Muscle pain was exacerbated by mild trauma. Dysphagia for fluids and solids, dyspnea and dysphonia (hoarse voice, interrupted speech implying great effort) also occurred following tonsillectomy. Oedema was present in the lower limbs and cheeks. Sedimentation rate: 40/h, 70/2h. Serum electrophoresis. Albumin ~ 48 %. Globulins : 52 %: al -- 5 %, as - 13 %, [J = 15 ~ , -
19700.
Electromyogram. In the tibialis anterior, biceps brachii, gastrocnemius and extensor digitorum communis no resting potentials were recorded. On maximal contraction there was a low-voltage interference tracing ('450/tV, mean amplitude) with a 5 msec mean duration of MUPs, and increased percentage of polyphasic MUPs. Muscle biopsy. The biopsy taken from the deltoid muscle showed intense proliferation of su~sarcolemmal nuclei. Some of the fibres contained central nuclei. Course of disease. Under treatment with prednisone and prostigmine there was definite improvement of the clinical, biochemical and electromyographic abnormalities. Case 3 C,N., a female aged 18 with dermatomyositis and muscle fatigue. Onset of disease with muscle weakness occurred 5 months before admission to hospital and was soon followed by diffuse muscle pain, both spontaneous and on palpation. After admission, gait impairment was noted. At the end of the day walking was no longer possible without support. Muscle weakness was most marked in the muscles of the pelvic girdle, but weakness was also present in the shoulder girdle. Swallowing of solids was impaired. Sedimentation rate: 48/h, 80/2h. Serum electrophoresis. Albumin -- 42 %. Globulins : 58 %: al - 7 %, as - 11%, fl - 11%, :, = 2 9 % .
Muscle biopsy taken from the biceps brachii disclosed a diffuse, moderate lymphocytic infiltration (nodulous in certain zones), perivascular infiltrates and degeneration of muscle fibres. Electromyogram. In the tibialis anterior, biceps brachii and deltoid no resting potentials were
133 recorded. On maximal contraction there was an interference tracing of low (500 #V) mean amplitude with 3.5 msec mean duration of MUPs and increased percentage of polyphasic MUPs. Treatment and course of disease. Following administration of prednisone, guanidine hydrochloride and prostigmine, definite improvement of the clinical, biochemical and EMG features occurred. Case 4
V.A., a female aged 42 with dermatomyositis and muscle fatigue. The onset of the disease was with muscle pain and tenderness and transient arthritis in the wrist and finger joints. Predominantly proximal weakness in the upper and lower limbs was enhanced on exertion and fatigue. The gait was impaired. She had dysphagia, especially for solids, and a nasal voice. These symptoms did not remit following anticholinesterase medication. The skin of the forearm and calves showed changes typical of dermatomyositis. Reynaud's phenomenon was present. Sedimentation rate was 13/h and 30/2h. Serum electrophoresis. Albumin : 46 %. Globulins : 54 ~ : cq - 8 %, a2 : 11%, fl = 15 %, ? -- 20%. Serum immunoelectrophoresis. IgG : 200 IU, IgA : 40 IU, IgM - 250 IU. Electromyogram. In tibialis anterior, biceps brachii and deltoid muscles no resting potentials were recorded. On maximal contraction there was an interference pattern of low (800 #V) mean amplitude with a 4 msec duration of MUPs and increased percentage of polyphasic MUPs. Muscle biopsy taken from the biceps brachii showed atrophy of muscle fibres and perivascular histiocytic infiltrates with proliferation of subsarcolemmal nuclei. Treatment and course of disease. Under treatment with large doses (60 mg/day) of prednisone given for a month, continued with maintenance doses (20 mg/day) and guanidine hydrochloride for a further two months, the cutaneous, muscular and biochemical alterations remitted. Glycosuria found after the first month of treatment with prednisone, necessitated reduction of the dose. There was definite improvement of the motor deficit and of the disturbances of phonation and deglutition. RESULTS Electrophysiology
In all 4 cases, tests for d i s o r d e r s o f n e u r o m u s c u l a r t r a n s m i s s i o n showed a d e c r e m e n t o f response to s t i m u l a t i o n at low frequencies (1-10 Hz) a n d an i n c r e m e n t at h i g h e r frequencies (15-50 Hz). In Case 1 t h e change in r e a c t i v i t y o c c u r r e d at 15 H z when the i n c r e m e n t a p p e a r e d . A t 30 H z s t i m u l a t i o n for 10 sec a t r a n s i e n t facilitation (increase by + 4 5 % in M E P voltage as c o m p a r e d to the value before s t i m u l a t i o n ) occurred at the end o f s t i m u l a t i o n , which was followed (at 3 Hz) by a p o s t a c t i v a t i o n e x h a u s t i o n (decrease b y - - 5 0 % in the M E P a m p l i t u d e ) t h a t d i s a p p e a r e d after 5-15 min (Fig. 1). T h e d e c r e m e n t (Ds) increased with increasing s t i m u l a t i o n frequency (Fig. 1). A t 15-50 H z there was a m a r k e d d e c r e m e n t (Ds) with, at the end o f the train, a m i n o r i n c r e m e n t o f p e a k - t o - p e a k voltage o f p o t e n t i a l s (Fig. 2A). U n d e r the influence o f ischaemia there was a fall in the M E P a m p l i t u d e (Fig. 2B). T h r e e weeks after daily a d m i n i s t r a t i o n o f i m m u n o s u p p r e s s o r agent a n d guanidine h y d r o c h l o r i d e the i n c r e m e n t a n d the p o s t - t e t a n i c facilitation were no longer f o u n d at a n y s t i m u l a t i o n frequency, b u t the d e c r e m e n t persisted (Fig. 3). I n Case 2 p r o s t i g m i n e i n d u c e d a decrease in the d u r a t i o n ( f r o m 12 to 8 msec) o f M E P s which b e c a m e synchronized, a n d d i s a p p e a r a n c e o f their p o l y p h a s i c aspect (Fig. 4, F2: transverse ' s p e c i a l ' r e c o r d i n g ) p r e s e n t before injection (Fig. 4, F I : transverse ' s p e c i a l ' recording).
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Fig. 1. Patient M.F. T h e M E P s in the a b d u c t o r digiti m i n i m i o n s t i m u l a t i o n o f the ulnar nerve at wrist, at various stimulation frequencies, u n d e r basic conditions, a before tetanization (at 3 Hz); b ~ at the e n d o f a tetanization at 30 Hz, 10 sec in duration ; c-1 at various time intervals (10 sec-20 rain) after tetanization.
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Fig. 4. Patient D.G. MEPs in the abductor digiti minimi on stimulation of the ulnar nerve at wrist. A1-F1 ~ under basic conditions. Az-F2 ~ 40 rain after administration of 3 mg prostigmine. CI-Fa = transverse ("special") recording. Calibration: 10 msec/2 mV/Division. C2-F2 = transverse ("special") recording. Calibration : 10 msec/5 mV/Division.
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Fig. 5. Patient C.N. MEPs in abductor digiti minimi on stimulation of the ulnar nerve at wrist. A1-E1 = under basic conditions. A2-E~= 40 min afteri.m, injection of 3 mg prostigmine. I: MEPs on application of the first train of repetitive stimulation (25 Hz). II: MEPs on application of the 15thconsecutive train of stimuli at the same frequency. In Case 3, at frequencies above 10 Hz, there was an increment in the fifth potential (15) which persisted up to the end of the trains and increased gradually with increasing stimulation frequency. The voltage of the first potential (V1) was equal to that of the potentials at the end of the last train in a continuous series of 15 trains (25 Hz), each 1.2 sec in duration (Fig. 5, I-II). On using an increased number of successive trains of repetitive stimulation at 25 Hz, the defect of N M transmission disappeared on application of the 15th train. As compared to the initial 1.85 mV (V1) voltage, there was a +31 ~ increment of the 5th response (V5 = 2.42 mV) and a q- 19 ~ increment at the end (V2s ---- 2.2 mV) of the first train of repetitive stimulation. On application of the 15th successive train, V1 exhibited the same values as V5 (2.42 mV), while V2s decreased to 2.2 mV. In Case 4 the decrement increased with increasing stimulation frequency: D5 was - - 1 0 ~ at 3 Hz, --29 ~ at 6 Hz and reached ---44 ~ at 25 Hz, but at this frequency the amplitude of V2s attained the value of the first response (V1). On higher-frequency stimulation (15-50 Hz) a minor increment (not exceeding + 13 ~ ) was noted. At 30 Hz for 10 sec, a transient facilitation occurred. This was followed by a postactivation exhaustion (--40 ~o) which disappeared after 5-15 minutes. In all 4 cases prostigmine injection was followed by an increment in the amplitude of potentials, which varied from one case to another. Thus, for example, the MEP voltage increased by + 185 ~ (from 0.7 to 2 mV) in Case 3 and by +229 ~ (from 1.7 to 5.6 mV) in Case 2. The MEP decrement (Cases 1 and 4) was unaffected by prostigmine. EMG alterations In all 4 cases the E M G alterations were of the myopathic type, and no spontaneous activity was present.
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Fig. 6. Patient D.G. Biopsy from the deltoid muscle. Muscle fibres sectioned longitudinally. Intense proliferation of subsarcolemmal nuclei, Some of the fibres show central nuclei. HE, : 360.
Histological findings Muscle b i o p s y in all 4 cases showed perivascular a n d interstitial i n f l a m m a t o r y cells with d e s t r u c t i o n o f muscle fibres in Cases 1 a n d 3. In Case 2 there was an intense p r o l i f e r a t i o n o f s u b s a r c o l e m m a l nuclei and, in some muscle fibres, central nuclei (Fig. 6). H i s t o c h e m i c a l e x a m i n a t i o n in Case 1 showed a m o r e intense e n z y m a t i c activity at the p e r i p h e r y o f t y p e I fibre. L D H activity was m o r e m a r k e d in the cells r o u n d the muscle fibres. The e n d - p l a t e s were larger t h a n n o r m a l , displaying a very intense cholinesterase activity (Fig. 7).
Fig. 7. Patient M.F. The end-plates are large with intense cholinesterase activity and a rich network of neurofibrils. Biopsy from the gastrocnemius muscle stained by the method of Koelte and Friedenwald for cholinesterase activity, x 700.
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Fig. 8. Patient M.F. Focal deposits of glycogen. Some of the deposits are in the vicinity of damaged myofibrils. Widening of the tubules of sarcoplasmic reticutum, x 20,000.
Fig. 9. Patient M.F. Two zones of necrosis surrounded by deposits of glycogen (subsarcolemmic). Diffuse and focal deposits of glycogen, x 20,000.
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Electron microscopy Examination performed in Case 1 disclosed zones of necrosis surrounded by glycogen deposits while in the earlier stages of disease large agglomerations of glycogen (focal and diffuse) had disorganized the structure of myofibrils (Figs. 8 and 9). DISCUSSION In our patients with dermatomyositis, correlation of clinical symptoms of myasthenia with the EMG, biopsy and MEP data suggests that the underlying mechanism of the myasthenic symptoms has both a pre- and a postsynaptic component. The presence of a decrement above 10 ~ in all the 4 cases at lower-frequency (3-10 Hz) stimulation and the occurrence in Cases 1 and 4 of a 'dip' between the initial decrement and the secondary increment at higher-frequency (15-50 Hz) stimulation and of post-tetanic facilitation followed by a postactivation exhaustion clearly show that muscle weakness, dysphonia and dysphagia constitute a syndrome of myasthenia developing concomitantly with or later in the course of dermatomyositis (within several months). This assumption is in agreement with the data reported by Johns, Crowley, Miller and Campa (1971) who described the syndrome of myasthenia in patients with polymyositis, included by these authors in the group D ('polymyositis with late myasthenia'). The diagnosis of dermatomyositis with concomitant, and particularly with late myasthenic symptoms, was made in our cases on the basis of several elements such as cutaneous alterations characteristic of dermatomyositis with predominantly proximal muscle weakness and deglutition and phonation disturbances, which were slightly responsive to prostigmine. Also contributing to the diagnosis were the myopathic type EMG changes and the MEP alterations (above 10 ~ decrement, post-tetanic facilitation followed by postactivation exhaustion) that have been described by Desmedt (1957, 1973a) as characteristic of myasthenia gravis. We found in our Cases 1 and 4, at the end of the train of higher-frequency (15-50 Hz) stimulation, a minor increment which was preceded at the fifth potential (Ds) by a characteristic 'dip' that increased with the increasing stimulation frequency and became enhanced following application of a number of successive trains. These data are in agreement with those of Struppler (1955), Lambert, Rooke, Eaton and Hodgson (1961), Slomi6 et al. (1968) and Desmedt (1973a) who showed that the 'dip' increased with the rate of stimulation and with the severity of involvement. The characteristic (above 40 ~) increment found in our Cases 2 and 3 at higher-frequency stimulation does not argue against the interpretation that the myasthenic symptoms are here the expression of a syndrome of myasthenia occurring in the course of dermatomyositis, for it is known that in slight involvement (as in our Cases 2 and 3), the decrement is less important and can be swamped by the increment (Desmedt 1973a). One might, therefore, conclude that the different reactivity in our 4 cases was due to the different degrees of involvement - - severe in Case 1, moderate in Case 4 and slight in Cases 2 and 3 - - as revealed by our MEP data. The diagnosis of dermatomyositis in these 4 cases, made on the basis of clinical
141 and MEP data, was confirmed by the presence of biochemical alterations such as the elevated sedimentation rate, serum hypergammaglobulinaemia, increase of IgG and IgM and decrease of IgA. In addition, serum electrophoretic and immunoelectrophoretic data point to a possible autoimmune mechanism of the NM transmission disorders in these patients. In this connection, it should be mentioned that, in experimental studies, Toyka, Drachman, Griffin, Kao and Winkelstein (1977) have shown that 'highly purified' IgG determines a 'myasthenogene' activity. Since myasthenia gravis is regarded as an autoimmune disease, it is of interest that this condition may be associated with concomitant or late polymyositis (K~Srner and Regli 1965; Klein and Lennartz 1966; Namba, Brunner and Grob 1973; Reznik 1974; Hopf and Thorwirth 1977; Huffmann and Leven 1977). Johns et al. (1971) found this association in 15 ~o of their cases, distributed in two groups-- 'myasthenia with late polymyositis' and 'concomitant myasthenia and polymyositis'. Cases of polymyositis displaying in their course a syndrome of myasthenia have also been described (Benedek 1944; Christensen and Levison 1950; Reese and Harman 1954; Bonduelle, Bouygues and Coulon 1955; Garcin, Lapresle, Gruner and Scherrer 1955; Pearson 1964; Barraquer-Bordas, Peres-Serra and Salisachs-Rowe 1965; Jesel, Stoebner, Zenglein and Isch 1969; Walton 1971 ; Namba et al. 1973; Cacquet, Festal, Deslign~res, Pierres, Lapresle and Laroche 1974; De Vere and Bradley 1975; Reuck, Thiery, De Coster and Van der Eecken 1976; Hopf and Thorwirth 1977; Huffmann and Leven 1977). Matthews and Burne (1953) described two cases of chronic polymyositis in which the only signs at the onset and for several months, were abnormal muscle fatigue and bilateral palpebral ptosis. Garcin et al. (1955) held the view that the clinical symptomatology in polymyositis is that of atypical myasthenia manifested by motor deficit involving the proximal segments of the limbs and the pharyngeal and ocular muscles. In our cases with dermatomyositis, prostigmine had a slight effect upon the myasthenic symptoms, varying from one patient to another, and unlike myasthenia gravis, it did not reverse the defect of NM transmission disclosed by the MEP study. The reported effect of prostigmine on the myasthenic symptoms in dermato- or polymyositis are contradictory. While a number of authors reported a good effect (Christensen and Levison 1950; Briickel, Pfeiffer and Krficke 1951; Reese and Harman 1954; Bonduelle et al. 1955; Garcin et al. 1955; Johns et al. 1971), others have shown that the results were doubtful or even absent (Matthews and Burne 1953; Cacquet et al. 1974; Hopf and Thorwirth 1977; Huffmann and Leven 1977). The histological and ultrastructural alterations in our patients suggest an affection of end-plates. Such an affection has been incriminated in myasthenia gravis by CoErs and Desmedt (1959) who found dysplastic elongated end-plates on light microscopy. It seems that the transient disappearance of the polyphasic feature of MUPs and their synchronization, noted in our Case 2 following administration of prostigmine, resulted in a transient restoration of the geometry of synaptic cleft and folds which had been noted by Engel and Santa (1973) in myasthenia gravis. On the other hand, it appears that in our Case 1, the decrement which persisted after 3 weeks of treatment with immunosuppressor agent and guanidine hydrochloride, might be
142 determined by the myositic lesions and by the change in the size (enlargement) and reactivity of end-plates. Failure of prostigmine to influence the decrement might be related to the presence of larger-than-normal end-plates in the biopsy and to the muscle fibre lesions evidenced by our EMG, histological and ultrastructural examinations. This assumption is supported by some data in myasthenia gravis: Engel and Santa (1973) found a change in the geometry of synaptic cleft and folds; Simpson (1969, 1971) showed that acetylcholine (ACh) quanta would produce a smaller postsynaptic depolarization even if both quantum size and end-plate reactivity to ACh were normal; Elmqvist (1973) found that the fall in the amplitude of the compound muscle action potentials is due to reduction in the number of muscle fibres in which action potentials are elicited. In our opinion, the 'dip' occurring in the fifth response to higher-frequency (15-50 Hz) stimulation appears to indicate the severity of the myasthenic defect which persisted after immunosuppressor or prednisone therapy and was uninfluenced by prostigmine. In contrast, the increment which, in our Cases 2 and 3 with less severe dermatomyositis and myasthenic symptoms, was suppressed by treatment with prednisone and guanidine hydrochloride or (in Case 3) by repetitive higher-frequency stimulation, appears to be characteristic of less severe myasthenic symptoms. The increment and post-tetanic facilitation which disappeared after the treatment, would be the effect of a presynaptic mechanism. An increment above 40 ~o has been described not only in myasthenia gravis (0zdemir and Young 1971 ; Desmedt 1973a), but also in the Lambert-Eaton syndrome, experimental magnesium ion poisoning, low calcium ion concentration, neomycin or botulinum toxin (Etmqvist and Lambert 1968; Elmqvist 1973). A reduction in the amount of ACh per vesicle (quantum size) may be incriminated in our Cases 2 and 3. Such a reduction was reported by Elmqvist (1973) and Elmqvist and Lambert (1968) in myasthenia gravis where it produced a proportional reduction of end-plate potential amplitude without change in the decremental pattern. The fact that on application of the last (15th) train (at 25 Hz) we found in Case 3 a rise in the amplitude of V1, might be explicable, as Desmedt (1973b) presumes in myasthenia gravis, by the changes in the number of quanta released per volley, which depend on the availability of readily releasable quanta and on potency of the electro-secretory process in the pre-synaptic membrane. ACKNOWLEDGEMENTS The authors wish to thank Dr. Graziella Marcovici, Dr. Marilena Alexianu and Dr. N. Anghelescu for helpful discussion on the interpretation of the histological data.
REFERENCES Barraquer-Bordas, L., J. Peres-Serraand P. Salisachs-Rowe(1965) Polymyositechroniquenodulaire focaleavec syndromemyasth6nique,Rev. neuroL, 113: 69-73. Barwick, D. D. and J. N. Walton(1963) Polymyositis,Amer. J. Med., 35: 646-659.
143 Benedek, L. (1944) Pseudomyasthenisches Syndrom bei Polymyositis interstitialis chronica fibrosa, Mschr. Psychiat. Neurol., 109: 93-99. Bonduelle, M., P. Bouygues and J. Coulon (1955) Le syndrome myasth6nique des polymyosites, Rev. neuroL, 92: 546-551. Br~ckel, K. W., E. F. Pfeiffer and W. Kriicke (1951) Das dermatomyositische Syndrom, Hautarzt, 2: 148-156. Cacquet, R., G. Festal, S. Deslign6res, M. Pierres, J. Lapresle and C. Laroche (1974) Polymyosite ~t forme myasth6nique, thymome, d6g6n6rescence musculaire lisse, Nouv. Presse mdd., 3 : 743-746. Christensen, E. and H. Levison (1950) Chronic polymyositis, Acta psychiat. (Kbh.), 25:137-152. CoErs, C. and J. E. Desmedt (1959) Mise en 6vidence d'une malformation caract6ristique de la jonction neuromusculaire dans la myasth6nie - - Correlation histo- et physiopathologique, Acta neurol. belg., 59: 539-561. Desmedt, J. E. (1957) Nature of the defect of neuromuscular transmission in myasthenic patients - "Post-tetanic exhaustion", Nature (Lond.), 179: 156-157. Desmedt, J. E. (1973a) The neuromuscular disorder in myasthenia gravis, Part 1 (Electrical and mechanical response to nerve stimulation in hand muscles). In: J. E. Desmedt (Ed.), New Developments in Electromyography and Clinical Neurophysiology, Vol. 1, Karger, Basel, pp. 241-304. Desmedt, J. E. (1973b) The neuromuscular disorder in myasthenia gravis, Part 2 (Presynaptic cholinergic metabolism, myasthenic-like syndromes and a hypothesis). In: J, E. Desmedt (Ed.), New Developments in Electromyography and Clinical Neurophysiology, 1Iol. 1, Karger, Basel, pp. 305342. DeVere, R. and W. G. Bradley (1975) Polymyositis - - Its presentation, morbidity and mortality, Brain, 98 : 637-666. Elmqvist, D. (1973) Neuromuscular transmission defects. In" J. E. Desmedt (Ed.), New Developments in Electromyography and Clinical Neurophysiology, 1Iol. 1, Karger, Basel, pp. 229-240. Elmqvist, D. and E. H. Lambert (1968) Detailed analysis of neuromuscular transmission in a patient with the myasthenic syndrome sometimes associated with bronchogenic carcinoma, Proc. Mayo Clin., 43 : 689-713. Engel, A. G. and T. Santa (1973) Motor endplate fine structure - - Quantitative analysis in disorders of neuromuscular transmission and prostigmine-induced alterations. In: J. E. Desmedt (Ed.), New Developments in Electromyography and Clinical Neurophysiology, Vol. 1, Karger, Basel, pp. 196228. Garcin, R., J. Lapresle, J. Gruner and J. Scherrer (1955) Les polymyosites, Rev. neurol., 92:465-510. Hopf, H. C. and V. Thorwirth (1977) Myasthenie-Myositis-Myopathie. In: G. Hertel, H. G. Mertens, K. Ricker and K. Schimrigk (Eds.), Myasthenia gravis und andere Sti~rungen der neuromuskuliiren Synapse, Thieme, Stuttgart, pp. 142-147. Huffmann, G. and B. Leven (1977) Myasthenie und Polymyositis. In: G. Hertel, H. G. Mertens, K. Ricker and K. Schimrigk (Eds.), Myasthenia gravis und andere St6rungen der neuromuskuliiren Synapse, Thieme, Stuttgart, pp. 147-150. Jesel, M., P. Stoebner, J. P. Zenglein and F. Isch (1969) Syndrome myasth6niforme et polymyosite - Correlations cliniques, 61ectromyographiques et ultrastructurales dans deux cas, Rev. Oto-neuroophtal., 41 : 173-183. Johns, T. R., W. J. Crowley, J. A. Miller and J. F. Campa (1971) The syndrome of myasthenia and polymyositis with comments on therapy, Ann. N. Y. Acad. Sci., 183: 64-71. Klein, H. O. and K. J. Lennartz (1966) Zur Syntropie von Myasthenia gravis, Polymyositis, Myokarditis und Thymom - - Zugleich ein Beitrag zur Pathogenese, Dtsch. med. Wschr., 91 : 1727-1730. Koelle, G. B. and J. S. Friedenwald (1949) A histochemical method for localizing cholinesterase activity, Proc. Soc. exp. Biol. (N.Y.), 70: 617-622. K/)rner, F. and F. Regli (1965) Zur Syntropie von Myasthenie und Myositis, Dtsch. reed. Wschr., 90: 1950-1954. Lambert, E. H. and D. Elmqvist (1971) Quantal components of end-plate potentials in the myasthenic syndrome, Ann. N. Y. Acad. Sci., 183 : 183-199. Lambert, E. H., E. D. Rooke, L. M. Eaton and C. H. Hodgson (1961) Myasthenic syndrome occasionally associated with bronchial neoplasm - - Neurophysiologic studies. In: H. R. Viers (Ed.), Myasthenia Gravis, Thomas, Springfield, I11., pp. 362-410. Matthews, W. B. and J. C. Burne (1953) The neurological aspect of dermatomyositis, J. Neurol. Neurosurg. Psychiat., 16: 49-55. Namba, T., N. G. Brunner and D. Grob (1973) Association of myasthenia gravis with pemphigus vulgaris, candida albicans infection, polymyositis and myocarditis, J. neurol. Sci., 20: 231-242.
144 Ozdemir, C. and R. R. Young ( 1971 ) Electrical testing in myasthenia gravis, Ann. N. Y. Acad. Sci., I ~3 : 286-302. Pearson, C. M. (1964) Polymyositis and related disorders, ln: J. N. Walton (Ed.), Disorders oJ Voluntary Muscle, Churchill, London, pp. 305-335. Reese, H. and J. W. Harman (1954) A hitherto unclassified muscular disorder, Trans. Amer. neural. Ass., 79 : 82-87. Reuck, J. De, E. Thiery, W. DeCoster and H. Van der Eecken (1976) Myasthenic syndrome in polymyositis, Europ. Neurol., 14:275-284. Reznik, M. (1974) Deux cas de syndrome myasth6nique avec thymome, polymyosite, myocardite et thyroidite, J. neurol. Sci., 22: 341-351. Simpson, J. A. (1969) The defect in myasthenia gravis. In: E. E. Bittar and N. Bittar (Eds.), Biological Basis o f Medicine, Academic Press, London, pp. 345-348. Simpson, J. A. (1971) A morphological explanation of the transmission defect in myasthenia gravis, Ann. N.Y. Acad. Sci., 183: 241-247. Slomi6, A., A. Rosenfalck and F. Buchthal (1968) Electrical and mechanical responses of normal and myasthenic muscle, Brain Res., 10: 1-78. Struppler, A. (1955) Experimentelle Untersuchungen zur Pathogenese der Myasthenie, Z. ges. exp. Med., 125 : 244-273. Toyka, K. V., D. B. Drachman, A. Pestronk, D. E. Griffin, 1. Kao and J. A. Winkelstein (1977) Die pathogenetische Bedeutung yon "myasthenogenen" Immunoglobulinen. In: G. Hertel, H. G. Mertens, K. Ricker and K. Schimrigk (Eds.), Myasthenia gravis und andere St6rungen der neuromuskuliiren Synapse, Thieme, Stuttgart, pp. 19-22. Walton, J. N. (1971) Polymyositis and related disorders, Presse mdd., 79: 435-438. Walton, J. N. and R. D. Adams (1958)Polymyositis, Livingstone, Edinburgh.
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© Elsevier/North-Holland Biomedical Press
M Y A S T H E N I A IN PATIENTS W I T H D E R M A T O M Y O S I T I S Clinical, Electrophysiological and Ultrastructural Studies
C. VASILESCU, G. BUCUR, A. PETROVICI and A. FLORESCU Institute of Neurology and Psychiatry, Bucharest 75622 (Romania)
(Received 22 August, 1977) (Accepted 30 March, 1978)
SUMMARY In 4 patients with clinical signs of dermatomyositis, confirmed by electromyography and muscle biopsy, a form of muscle fatigue was detected which was expressed clinically by predominantly proximal motor deficit, with phonation and deglutition disturbances, slightly influenced by prostigmine. In all patients, stimulation of the ulnar nerve at 3-10 Hz induced a decrement of muscle-evoked potentials in abductor digiti minimi and at 15-50 Hz an increment at the end of the trains (1.2 sec in duration) of repetitive stimulation (preceded in two cases by a decrement in the response to the fifth stimulus in the train). Stimulation at 30 Hz for 10 sec resulted in a transient facilitation, followed (at 3 Hz stimulation) by postactivation exhaustion which disappeared after 5-15 min. The post-tetanic facilitation, the incremental response and the myasthenic symptoms reverted to normal under treatment with corticosteroids, an immunosuppressor agent and guanidine hydrochloride. A mixed, pre- and postsynaptic mechanism is presumed to underlie the muscle fatigue in our patients. Electron microscopy of muscle biopsies disclosed zones of necrosis and, in incipient stages, large agglomerations of glycogen that had disorganized the structure of myofibrils. The end-plates in the biopsies were larger than normal and the cholinesterase reaction was hyperactive. Serum immunoelectrophoretic and electrophoretic d a t a - - increase of IgG and IgM, decrease of IgA and hypergammaglobulinaemia - - point to a possible autoimmune mechanism of the neuromuscular disorders in our patients.
Requests for reprints to: Dr. Constantin Vasilescu, Institute of Neurology and Psychiatry, C.P. 5880, Sos. Berceni 10-12, Bucharest 75622, Romania.
130 INTRODUCTION Cases of myasthenia gravis associated with polymyositis and cases of polymyositis displaying certain symptoms of the myasthenic type have been described, but muscle fatiguability characteristic of myasthenia gravis is not a usual feature of dermatomyositis. In 4 cases in which dermatomyositis was associated with clinical signs of myasthenic type, we performed a detailed clinical, electrophysiological and ultrastructural study in an attempt to obtain a correct interpretation of the symptoms and to determine effective therapy both of the primary disease and of the myasthenic symptoms. Estimation of the severity of the dermatomyositis was according to the classification proposed by Walton and Adams (1958) and by Barwick and Walton (1963) for polymyositis. METHODS
Electrophysiological techniques All the electrophysiological recordings were obtained with a type 14A21 twochannel DISA electromyograph. Stimulation was through surface electrodes, type 13K62, using a square wave of 0.1 msec duration of supramaximal intensity (150~ greater than the intensity inducing maximal electrical response in the muscles investigated) and 1-100 Hz frequency. Successive stimulus trains 1.2 sec in duration were applied at 3 min stimulus-free intervals. Muscle-evoked potentials (MEPs) in the abductor digiti minimi on stimulation of the ulnar nerve at the wrist were recorded from type 13K60 surface electrodes. The surface recordings were made with bellytendon leads under isometric conditions. A ground electrode was placed between the stimulating and recording electrodes. The skin under all electrodes was cleansed with alcohol, and the skin impedance was reduced with electrode paste. As errors may occur in the recording of MEPs if the distance between the surface electrode and the muscle varies during contraction, we fixed the small, thin (6 x 12 x 1.5 ram) plates of the electrode, 15 mm far from each other, on a rigid plastic plate. This was then fastened to the skin on the hypothenar eminence, with an elastic band, in a belly-tendon arrangement. With a view to minimizing hand and finger movements we fixed the forearm, hand and fingers on a stand with a heavy base (similar to that used by Slomid, Rosenfalck and Buchthal 1968). The intramuscular temperature in the abductor digiti minimi and near the stimulating cathode at the ulnar nerve at the wrist was 34.5-35 °C in all muscles investigated. For temperature measurements we used a DISA 14G05 Biological Temperature Unit with 13L10 Concentric Needle Electrode with Temperature Sensor. The MEP recordings were taken (i) under basic conditions, (ii) after a 10-min ischaemia (at 130 mm Hg pressure) of the respective limb, (iii) 30--40 min after i.m. injection of prostigmine and (iv) after treatment with prednisone or an immunosuppressor agent and guanidine hydrochloride. On the 5th stimulation in the trains 1,2
131 sec in duration, a decrement may appear. The degree of neuromuscular (NM) block was indicated by the formula D5 = 1 - - ~ , in which V is the voltage of the MEPs, while the accompanying figure is the ordinal number of the respective potential in the train (1.2 sec in duration) of stimuli at frequencies from 3 to 100 Hz. Hence, V1 is the voltage of the first potential in such a train. The letter D indicates the decrement, D5 being the decrement of the fifth response in the train. When an increment occurs, it is denoted as I. This was considered by Desmedt (1973a) to be a sensitive method of detecting N M block. In the present paper, the values of the peak-to-peak amplitude are given, as a rule, for the first, fifth and last potentials of the train.
Histological techniques For light-microscopic examinations, biopsies were taken from the muscle studied. The tissue was fixed in 10 ~ formalin solution. Longitudinal and transverse sections 5 # m thick, were cut and stained with haematoxylin-eosin (HE). In Case 1, the tissue was also prepared for histochemistry at the time of biopsy. The sections were stained with HE, succinic dehydrogenase (SDH), lactic dehydrogenase (LDH) and nicotinamide adenine dinucleotide dehydrogenase (NADH). Serial frozen sections of the muscles in Case 1 were stained with the method of Koelle and Friedenwald (1949) for determination of cholinesterase activity. Electron microscopy The biopsy fragments for electron microscopy were cut immediately after sampling, into 1-mm a blocks. These were fixed in 2 . 5 ~ buffered glutaraldehyde, postfixed in osmium tetroxide, embedded in Vestopal and cut in very thin sections that were stained with uranyl acetate and lead citrate and examined on a HU-11 H I T A C H I electron microscope. Treatment Treatment of dermatomyositis with prednisone given in the doses suggested by Walton 0971) and by De Vere and Bradley (1975), wasd beneficial. In Case I where prednisone was ineffective, a cytostatic substance (Chlorambucil) was successfully administered. Symptomatic therapy of the muscle fatigue, consisting of a combination of prostigmine and guanidine hydrochloride, was applied. REPORT OF CASES AND RESULTS OF INVESTIGATIONS
Case 1 M. F., a female aged 24 with dermatomyositis and myasthenic symptoms. The disease began 6 months before admission to hospital and worsened progressively.The most significantsigns were marked weakness on walking and in other voluntary movements, increasing in the course of the day and on exertion; induration of limb muscles; phonation and deglutition disturbances (dysphagia with reflux of fluids through the nose). On admission (10.1.1975)the patient exhibited oedematous violaceousplaques localizedperiorbitally and on the external aspect of the hands and forearms. There was marked loss of weight and greatly diminished muscle power, the patient being unable to stand or walk. Dysphonia and dysphagia persisted. Sedimentation rate: 51/h; 89/2h.
132
Serum electrophoresis. Albumin 33~o; globulins ...... 6 7 ~ : (tl ~: 2%, ¢~2 : 1 6 ~ , /~ 19%, 30 ~ (hypoalbuminaemia and hypergammaglobulinaemia). Serumimmunoelectrophoresis. lgG : 2 1 5 1 U ( N ~:- 1 0 0 ± 5 0 1 U ) , I g A 401U(N 100~ 50 IU), IgM -- 228 IU (N 100 ± 50 1U). Electromyogram. In the biceps brachii, gastrocnemius and 1st dorsal interosseous no resting potentials were recorded. On maximal contraction there was a low-voltage interference tracing (600 I~V amplitude) with a 7-msec mean duration of motor unit potentials (MUPs) and increased percentage of polyphasic M UPs. Muscle biopsy was taken from the gastrocnemius. Light microscopy showed multiple perivascular lympho-histiocytic infiltrates, intense proliferation of subsarcolemmal nuclei and, in some of the muscle fibres, central nuclei. Treatment. Administration of prostigmine was followed after 30 min by a slight improvement in muscle power and in swallowing and phonation. Prednisone failed to influence the clinical picture and was withdrawn. Treatment was continued with chlorambucil (0.2 mg/kg b.w.), while for the muscle fatigue we gave guanidine hydrochloride in doses that were gradually increased to 50 mg/kg b.w., and prostigmine. After 3 weeks of such therapy there was progressive improvement leading to recovery of the muscular and cutaneous symptoms. There was gradual disappearance of fatiguability and ofdeglutition and phonation disturbances, complete resolution of skin flush and oedema and the sedimentation rate and electromyogram (EMG) became normal. Further course of disease. In October 1976, i.e. 17 months after discharge from hospital, the patient again developed the symptoms of the disease. As she was unresponsive to corticotherapy, she was again treated with chlorambucil and guanidine hydrochloride. The clinical symptomatology characteristic of dermatomyositis, the muscle fatigue and the biochemical alterations remitted within two weeks of initiation of therapy. The cause of dermatomyositis remained obscure, no malignant tumour being detected. ~:-
7
Case 2 D.G., a 46-year-old male with dermatomyositis and muscle fatigue. The disease had begun 16 months before hospitalization, with cutaneous palmar lesions of the dermatomyositis type, followed in a few weeks by muscle weakness and diffuse muscular pain. After tonsillectomy, proximal weakness of the upper and lower limbs developed and increased with fatigue. Muscle pain was exacerbated by mild trauma. Dysphagia for fluids and solids, dyspnea and dysphonia (hoarse voice, interrupted speech implying great effort) also occurred following tonsillectomy. Oedema was present in the lower limbs and cheeks. Sedimentation rate: 40/h, 70/2h. Serum electrophoresis. Albumin ~ 48 %. Globulins : 52 %: al -- 5 %, as - 13 %, [J = 15 ~ , -
19700.
Electromyogram. In the tibialis anterior, biceps brachii, gastrocnemius and extensor digitorum communis no resting potentials were recorded. On maximal contraction there was a low-voltage interference tracing ('450/tV, mean amplitude) with a 5 msec mean duration of MUPs, and increased percentage of polyphasic MUPs. Muscle biopsy. The biopsy taken from the deltoid muscle showed intense proliferation of su~sarcolemmal nuclei. Some of the fibres contained central nuclei. Course of disease. Under treatment with prednisone and prostigmine there was definite improvement of the clinical, biochemical and electromyographic abnormalities. Case 3 C,N., a female aged 18 with dermatomyositis and muscle fatigue. Onset of disease with muscle weakness occurred 5 months before admission to hospital and was soon followed by diffuse muscle pain, both spontaneous and on palpation. After admission, gait impairment was noted. At the end of the day walking was no longer possible without support. Muscle weakness was most marked in the muscles of the pelvic girdle, but weakness was also present in the shoulder girdle. Swallowing of solids was impaired. Sedimentation rate: 48/h, 80/2h. Serum electrophoresis. Albumin -- 42 %. Globulins : 58 %: al - 7 %, as - 11%, fl - 11%, :, = 2 9 % .
Muscle biopsy taken from the biceps brachii disclosed a diffuse, moderate lymphocytic infiltration (nodulous in certain zones), perivascular infiltrates and degeneration of muscle fibres. Electromyogram. In the tibialis anterior, biceps brachii and deltoid no resting potentials were
133 recorded. On maximal contraction there was an interference tracing of low (500 #V) mean amplitude with 3.5 msec mean duration of MUPs and increased percentage of polyphasic MUPs. Treatment and course of disease. Following administration of prednisone, guanidine hydrochloride and prostigmine, definite improvement of the clinical, biochemical and EMG features occurred. Case 4
V.A., a female aged 42 with dermatomyositis and muscle fatigue. The onset of the disease was with muscle pain and tenderness and transient arthritis in the wrist and finger joints. Predominantly proximal weakness in the upper and lower limbs was enhanced on exertion and fatigue. The gait was impaired. She had dysphagia, especially for solids, and a nasal voice. These symptoms did not remit following anticholinesterase medication. The skin of the forearm and calves showed changes typical of dermatomyositis. Reynaud's phenomenon was present. Sedimentation rate was 13/h and 30/2h. Serum electrophoresis. Albumin : 46 %. Globulins : 54 ~ : cq - 8 %, a2 : 11%, fl = 15 %, ? -- 20%. Serum immunoelectrophoresis. IgG : 200 IU, IgA : 40 IU, IgM - 250 IU. Electromyogram. In tibialis anterior, biceps brachii and deltoid muscles no resting potentials were recorded. On maximal contraction there was an interference pattern of low (800 #V) mean amplitude with a 4 msec duration of MUPs and increased percentage of polyphasic MUPs. Muscle biopsy taken from the biceps brachii showed atrophy of muscle fibres and perivascular histiocytic infiltrates with proliferation of subsarcolemmal nuclei. Treatment and course of disease. Under treatment with large doses (60 mg/day) of prednisone given for a month, continued with maintenance doses (20 mg/day) and guanidine hydrochloride for a further two months, the cutaneous, muscular and biochemical alterations remitted. Glycosuria found after the first month of treatment with prednisone, necessitated reduction of the dose. There was definite improvement of the motor deficit and of the disturbances of phonation and deglutition. RESULTS Electrophysiology
In all 4 cases, tests for d i s o r d e r s o f n e u r o m u s c u l a r t r a n s m i s s i o n showed a d e c r e m e n t o f response to s t i m u l a t i o n at low frequencies (1-10 Hz) a n d an i n c r e m e n t at h i g h e r frequencies (15-50 Hz). In Case 1 t h e change in r e a c t i v i t y o c c u r r e d at 15 H z when the i n c r e m e n t a p p e a r e d . A t 30 H z s t i m u l a t i o n for 10 sec a t r a n s i e n t facilitation (increase by + 4 5 % in M E P voltage as c o m p a r e d to the value before s t i m u l a t i o n ) occurred at the end o f s t i m u l a t i o n , which was followed (at 3 Hz) by a p o s t a c t i v a t i o n e x h a u s t i o n (decrease b y - - 5 0 % in the M E P a m p l i t u d e ) t h a t d i s a p p e a r e d after 5-15 min (Fig. 1). T h e d e c r e m e n t (Ds) increased with increasing s t i m u l a t i o n frequency (Fig. 1). A t 15-50 H z there was a m a r k e d d e c r e m e n t (Ds) with, at the end o f the train, a m i n o r i n c r e m e n t o f p e a k - t o - p e a k voltage o f p o t e n t i a l s (Fig. 2A). U n d e r the influence o f ischaemia there was a fall in the M E P a m p l i t u d e (Fig. 2B). T h r e e weeks after daily a d m i n i s t r a t i o n o f i m m u n o s u p p r e s s o r agent a n d guanidine h y d r o c h l o r i d e the i n c r e m e n t a n d the p o s t - t e t a n i c facilitation were no longer f o u n d at a n y s t i m u l a t i o n frequency, b u t the d e c r e m e n t persisted (Fig. 3). I n Case 2 p r o s t i g m i n e i n d u c e d a decrease in the d u r a t i o n ( f r o m 12 to 8 msec) o f M E P s which b e c a m e synchronized, a n d d i s a p p e a r a n c e o f their p o l y p h a s i c aspect (Fig. 4, F2: transverse ' s p e c i a l ' r e c o r d i n g ) p r e s e n t before injection (Fig. 4, F I : transverse ' s p e c i a l ' recording).
134
Fig. 1. Patient M.F. T h e M E P s in the a b d u c t o r digiti m i n i m i o n s t i m u l a t i o n o f the ulnar nerve at wrist, at various stimulation frequencies, u n d e r basic conditions, a before tetanization (at 3 Hz); b ~ at the e n d o f a tetanization at 30 Hz, 10 sec in duration ; c-1 at various time intervals (10 sec-20 rain) after tetanization.
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Fig. 4. Patient D.G. MEPs in the abductor digiti minimi on stimulation of the ulnar nerve at wrist. A1-F1 ~ under basic conditions. Az-F2 ~ 40 rain after administration of 3 mg prostigmine. CI-Fa = transverse ("special") recording. Calibration: 10 msec/2 mV/Division. C2-F2 = transverse ("special") recording. Calibration : 10 msec/5 mV/Division.
137
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Fig. 5. Patient C.N. MEPs in abductor digiti minimi on stimulation of the ulnar nerve at wrist. A1-E1 = under basic conditions. A2-E~= 40 min afteri.m, injection of 3 mg prostigmine. I: MEPs on application of the first train of repetitive stimulation (25 Hz). II: MEPs on application of the 15thconsecutive train of stimuli at the same frequency. In Case 3, at frequencies above 10 Hz, there was an increment in the fifth potential (15) which persisted up to the end of the trains and increased gradually with increasing stimulation frequency. The voltage of the first potential (V1) was equal to that of the potentials at the end of the last train in a continuous series of 15 trains (25 Hz), each 1.2 sec in duration (Fig. 5, I-II). On using an increased number of successive trains of repetitive stimulation at 25 Hz, the defect of N M transmission disappeared on application of the 15th train. As compared to the initial 1.85 mV (V1) voltage, there was a +31 ~ increment of the 5th response (V5 = 2.42 mV) and a q- 19 ~ increment at the end (V2s ---- 2.2 mV) of the first train of repetitive stimulation. On application of the 15th successive train, V1 exhibited the same values as V5 (2.42 mV), while V2s decreased to 2.2 mV. In Case 4 the decrement increased with increasing stimulation frequency: D5 was - - 1 0 ~ at 3 Hz, --29 ~ at 6 Hz and reached ---44 ~ at 25 Hz, but at this frequency the amplitude of V2s attained the value of the first response (V1). On higher-frequency stimulation (15-50 Hz) a minor increment (not exceeding + 13 ~ ) was noted. At 30 Hz for 10 sec, a transient facilitation occurred. This was followed by a postactivation exhaustion (--40 ~o) which disappeared after 5-15 minutes. In all 4 cases prostigmine injection was followed by an increment in the amplitude of potentials, which varied from one case to another. Thus, for example, the MEP voltage increased by + 185 ~ (from 0.7 to 2 mV) in Case 3 and by +229 ~ (from 1.7 to 5.6 mV) in Case 2. The MEP decrement (Cases 1 and 4) was unaffected by prostigmine. EMG alterations In all 4 cases the E M G alterations were of the myopathic type, and no spontaneous activity was present.
138
Fig. 6. Patient D.G. Biopsy from the deltoid muscle. Muscle fibres sectioned longitudinally. Intense proliferation of subsarcolemmal nuclei, Some of the fibres show central nuclei. HE, : 360.
Histological findings Muscle b i o p s y in all 4 cases showed perivascular a n d interstitial i n f l a m m a t o r y cells with d e s t r u c t i o n o f muscle fibres in Cases 1 a n d 3. In Case 2 there was an intense p r o l i f e r a t i o n o f s u b s a r c o l e m m a l nuclei and, in some muscle fibres, central nuclei (Fig. 6). H i s t o c h e m i c a l e x a m i n a t i o n in Case 1 showed a m o r e intense e n z y m a t i c activity at the p e r i p h e r y o f t y p e I fibre. L D H activity was m o r e m a r k e d in the cells r o u n d the muscle fibres. The e n d - p l a t e s were larger t h a n n o r m a l , displaying a very intense cholinesterase activity (Fig. 7).
Fig. 7. Patient M.F. The end-plates are large with intense cholinesterase activity and a rich network of neurofibrils. Biopsy from the gastrocnemius muscle stained by the method of Koelte and Friedenwald for cholinesterase activity, x 700.
139
Fig. 8. Patient M.F. Focal deposits of glycogen. Some of the deposits are in the vicinity of damaged myofibrils. Widening of the tubules of sarcoplasmic reticutum, x 20,000.
Fig. 9. Patient M.F. Two zones of necrosis surrounded by deposits of glycogen (subsarcolemmic). Diffuse and focal deposits of glycogen, x 20,000.
140
Electron microscopy Examination performed in Case 1 disclosed zones of necrosis surrounded by glycogen deposits while in the earlier stages of disease large agglomerations of glycogen (focal and diffuse) had disorganized the structure of myofibrils (Figs. 8 and 9). DISCUSSION In our patients with dermatomyositis, correlation of clinical symptoms of myasthenia with the EMG, biopsy and MEP data suggests that the underlying mechanism of the myasthenic symptoms has both a pre- and a postsynaptic component. The presence of a decrement above 10 ~ in all the 4 cases at lower-frequency (3-10 Hz) stimulation and the occurrence in Cases 1 and 4 of a 'dip' between the initial decrement and the secondary increment at higher-frequency (15-50 Hz) stimulation and of post-tetanic facilitation followed by a postactivation exhaustion clearly show that muscle weakness, dysphonia and dysphagia constitute a syndrome of myasthenia developing concomitantly with or later in the course of dermatomyositis (within several months). This assumption is in agreement with the data reported by Johns, Crowley, Miller and Campa (1971) who described the syndrome of myasthenia in patients with polymyositis, included by these authors in the group D ('polymyositis with late myasthenia'). The diagnosis of dermatomyositis with concomitant, and particularly with late myasthenic symptoms, was made in our cases on the basis of several elements such as cutaneous alterations characteristic of dermatomyositis with predominantly proximal muscle weakness and deglutition and phonation disturbances, which were slightly responsive to prostigmine. Also contributing to the diagnosis were the myopathic type EMG changes and the MEP alterations (above 10 ~ decrement, post-tetanic facilitation followed by postactivation exhaustion) that have been described by Desmedt (1957, 1973a) as characteristic of myasthenia gravis. We found in our Cases 1 and 4, at the end of the train of higher-frequency (15-50 Hz) stimulation, a minor increment which was preceded at the fifth potential (Ds) by a characteristic 'dip' that increased with the increasing stimulation frequency and became enhanced following application of a number of successive trains. These data are in agreement with those of Struppler (1955), Lambert, Rooke, Eaton and Hodgson (1961), Slomi6 et al. (1968) and Desmedt (1973a) who showed that the 'dip' increased with the rate of stimulation and with the severity of involvement. The characteristic (above 40 ~) increment found in our Cases 2 and 3 at higher-frequency stimulation does not argue against the interpretation that the myasthenic symptoms are here the expression of a syndrome of myasthenia occurring in the course of dermatomyositis, for it is known that in slight involvement (as in our Cases 2 and 3), the decrement is less important and can be swamped by the increment (Desmedt 1973a). One might, therefore, conclude that the different reactivity in our 4 cases was due to the different degrees of involvement - - severe in Case 1, moderate in Case 4 and slight in Cases 2 and 3 - - as revealed by our MEP data. The diagnosis of dermatomyositis in these 4 cases, made on the basis of clinical
141 and MEP data, was confirmed by the presence of biochemical alterations such as the elevated sedimentation rate, serum hypergammaglobulinaemia, increase of IgG and IgM and decrease of IgA. In addition, serum electrophoretic and immunoelectrophoretic data point to a possible autoimmune mechanism of the NM transmission disorders in these patients. In this connection, it should be mentioned that, in experimental studies, Toyka, Drachman, Griffin, Kao and Winkelstein (1977) have shown that 'highly purified' IgG determines a 'myasthenogene' activity. Since myasthenia gravis is regarded as an autoimmune disease, it is of interest that this condition may be associated with concomitant or late polymyositis (K~Srner and Regli 1965; Klein and Lennartz 1966; Namba, Brunner and Grob 1973; Reznik 1974; Hopf and Thorwirth 1977; Huffmann and Leven 1977). Johns et al. (1971) found this association in 15 ~o of their cases, distributed in two groups-- 'myasthenia with late polymyositis' and 'concomitant myasthenia and polymyositis'. Cases of polymyositis displaying in their course a syndrome of myasthenia have also been described (Benedek 1944; Christensen and Levison 1950; Reese and Harman 1954; Bonduelle, Bouygues and Coulon 1955; Garcin, Lapresle, Gruner and Scherrer 1955; Pearson 1964; Barraquer-Bordas, Peres-Serra and Salisachs-Rowe 1965; Jesel, Stoebner, Zenglein and Isch 1969; Walton 1971 ; Namba et al. 1973; Cacquet, Festal, Deslign~res, Pierres, Lapresle and Laroche 1974; De Vere and Bradley 1975; Reuck, Thiery, De Coster and Van der Eecken 1976; Hopf and Thorwirth 1977; Huffmann and Leven 1977). Matthews and Burne (1953) described two cases of chronic polymyositis in which the only signs at the onset and for several months, were abnormal muscle fatigue and bilateral palpebral ptosis. Garcin et al. (1955) held the view that the clinical symptomatology in polymyositis is that of atypical myasthenia manifested by motor deficit involving the proximal segments of the limbs and the pharyngeal and ocular muscles. In our cases with dermatomyositis, prostigmine had a slight effect upon the myasthenic symptoms, varying from one patient to another, and unlike myasthenia gravis, it did not reverse the defect of NM transmission disclosed by the MEP study. The reported effect of prostigmine on the myasthenic symptoms in dermato- or polymyositis are contradictory. While a number of authors reported a good effect (Christensen and Levison 1950; Briickel, Pfeiffer and Krficke 1951; Reese and Harman 1954; Bonduelle et al. 1955; Garcin et al. 1955; Johns et al. 1971), others have shown that the results were doubtful or even absent (Matthews and Burne 1953; Cacquet et al. 1974; Hopf and Thorwirth 1977; Huffmann and Leven 1977). The histological and ultrastructural alterations in our patients suggest an affection of end-plates. Such an affection has been incriminated in myasthenia gravis by CoErs and Desmedt (1959) who found dysplastic elongated end-plates on light microscopy. It seems that the transient disappearance of the polyphasic feature of MUPs and their synchronization, noted in our Case 2 following administration of prostigmine, resulted in a transient restoration of the geometry of synaptic cleft and folds which had been noted by Engel and Santa (1973) in myasthenia gravis. On the other hand, it appears that in our Case 1, the decrement which persisted after 3 weeks of treatment with immunosuppressor agent and guanidine hydrochloride, might be
142 determined by the myositic lesions and by the change in the size (enlargement) and reactivity of end-plates. Failure of prostigmine to influence the decrement might be related to the presence of larger-than-normal end-plates in the biopsy and to the muscle fibre lesions evidenced by our EMG, histological and ultrastructural examinations. This assumption is supported by some data in myasthenia gravis: Engel and Santa (1973) found a change in the geometry of synaptic cleft and folds; Simpson (1969, 1971) showed that acetylcholine (ACh) quanta would produce a smaller postsynaptic depolarization even if both quantum size and end-plate reactivity to ACh were normal; Elmqvist (1973) found that the fall in the amplitude of the compound muscle action potentials is due to reduction in the number of muscle fibres in which action potentials are elicited. In our opinion, the 'dip' occurring in the fifth response to higher-frequency (15-50 Hz) stimulation appears to indicate the severity of the myasthenic defect which persisted after immunosuppressor or prednisone therapy and was uninfluenced by prostigmine. In contrast, the increment which, in our Cases 2 and 3 with less severe dermatomyositis and myasthenic symptoms, was suppressed by treatment with prednisone and guanidine hydrochloride or (in Case 3) by repetitive higher-frequency stimulation, appears to be characteristic of less severe myasthenic symptoms. The increment and post-tetanic facilitation which disappeared after the treatment, would be the effect of a presynaptic mechanism. An increment above 40 ~o has been described not only in myasthenia gravis (0zdemir and Young 1971 ; Desmedt 1973a), but also in the Lambert-Eaton syndrome, experimental magnesium ion poisoning, low calcium ion concentration, neomycin or botulinum toxin (Etmqvist and Lambert 1968; Elmqvist 1973). A reduction in the amount of ACh per vesicle (quantum size) may be incriminated in our Cases 2 and 3. Such a reduction was reported by Elmqvist (1973) and Elmqvist and Lambert (1968) in myasthenia gravis where it produced a proportional reduction of end-plate potential amplitude without change in the decremental pattern. The fact that on application of the last (15th) train (at 25 Hz) we found in Case 3 a rise in the amplitude of V1, might be explicable, as Desmedt (1973b) presumes in myasthenia gravis, by the changes in the number of quanta released per volley, which depend on the availability of readily releasable quanta and on potency of the electro-secretory process in the pre-synaptic membrane. ACKNOWLEDGEMENTS The authors wish to thank Dr. Graziella Marcovici, Dr. Marilena Alexianu and Dr. N. Anghelescu for helpful discussion on the interpretation of the histological data.
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143 Benedek, L. (1944) Pseudomyasthenisches Syndrom bei Polymyositis interstitialis chronica fibrosa, Mschr. Psychiat. Neurol., 109: 93-99. Bonduelle, M., P. Bouygues and J. Coulon (1955) Le syndrome myasth6nique des polymyosites, Rev. neuroL, 92: 546-551. Br~ckel, K. W., E. F. Pfeiffer and W. Kriicke (1951) Das dermatomyositische Syndrom, Hautarzt, 2: 148-156. Cacquet, R., G. Festal, S. Deslign6res, M. Pierres, J. Lapresle and C. Laroche (1974) Polymyosite ~t forme myasth6nique, thymome, d6g6n6rescence musculaire lisse, Nouv. Presse mdd., 3 : 743-746. Christensen, E. and H. Levison (1950) Chronic polymyositis, Acta psychiat. (Kbh.), 25:137-152. CoErs, C. and J. E. Desmedt (1959) Mise en 6vidence d'une malformation caract6ristique de la jonction neuromusculaire dans la myasth6nie - - Correlation histo- et physiopathologique, Acta neurol. belg., 59: 539-561. Desmedt, J. E. (1957) Nature of the defect of neuromuscular transmission in myasthenic patients - "Post-tetanic exhaustion", Nature (Lond.), 179: 156-157. Desmedt, J. E. (1973a) The neuromuscular disorder in myasthenia gravis, Part 1 (Electrical and mechanical response to nerve stimulation in hand muscles). In: J. E. Desmedt (Ed.), New Developments in Electromyography and Clinical Neurophysiology, Vol. 1, Karger, Basel, pp. 241-304. Desmedt, J. E. (1973b) The neuromuscular disorder in myasthenia gravis, Part 2 (Presynaptic cholinergic metabolism, myasthenic-like syndromes and a hypothesis). In: J, E. Desmedt (Ed.), New Developments in Electromyography and Clinical Neurophysiology, 1Iol. 1, Karger, Basel, pp. 305342. DeVere, R. and W. G. Bradley (1975) Polymyositis - - Its presentation, morbidity and mortality, Brain, 98 : 637-666. Elmqvist, D. (1973) Neuromuscular transmission defects. In" J. E. Desmedt (Ed.), New Developments in Electromyography and Clinical Neurophysiology, 1Iol. 1, Karger, Basel, pp. 229-240. Elmqvist, D. and E. H. Lambert (1968) Detailed analysis of neuromuscular transmission in a patient with the myasthenic syndrome sometimes associated with bronchogenic carcinoma, Proc. Mayo Clin., 43 : 689-713. Engel, A. G. and T. Santa (1973) Motor endplate fine structure - - Quantitative analysis in disorders of neuromuscular transmission and prostigmine-induced alterations. In: J. E. Desmedt (Ed.), New Developments in Electromyography and Clinical Neurophysiology, Vol. 1, Karger, Basel, pp. 196228. Garcin, R., J. Lapresle, J. Gruner and J. Scherrer (1955) Les polymyosites, Rev. neurol., 92:465-510. Hopf, H. C. and V. Thorwirth (1977) Myasthenie-Myositis-Myopathie. In: G. Hertel, H. G. Mertens, K. Ricker and K. Schimrigk (Eds.), Myasthenia gravis und andere Sti~rungen der neuromuskuliiren Synapse, Thieme, Stuttgart, pp. 142-147. Huffmann, G. and B. Leven (1977) Myasthenie und Polymyositis. In: G. Hertel, H. G. Mertens, K. Ricker and K. Schimrigk (Eds.), Myasthenia gravis und andere St6rungen der neuromuskuliiren Synapse, Thieme, Stuttgart, pp. 147-150. Jesel, M., P. Stoebner, J. P. Zenglein and F. Isch (1969) Syndrome myasth6niforme et polymyosite - Correlations cliniques, 61ectromyographiques et ultrastructurales dans deux cas, Rev. Oto-neuroophtal., 41 : 173-183. Johns, T. R., W. J. Crowley, J. A. Miller and J. F. Campa (1971) The syndrome of myasthenia and polymyositis with comments on therapy, Ann. N. Y. Acad. Sci., 183: 64-71. Klein, H. O. and K. J. Lennartz (1966) Zur Syntropie von Myasthenia gravis, Polymyositis, Myokarditis und Thymom - - Zugleich ein Beitrag zur Pathogenese, Dtsch. med. Wschr., 91 : 1727-1730. Koelle, G. B. and J. S. Friedenwald (1949) A histochemical method for localizing cholinesterase activity, Proc. Soc. exp. Biol. (N.Y.), 70: 617-622. K/)rner, F. and F. Regli (1965) Zur Syntropie von Myasthenie und Myositis, Dtsch. reed. Wschr., 90: 1950-1954. Lambert, E. H. and D. Elmqvist (1971) Quantal components of end-plate potentials in the myasthenic syndrome, Ann. N. Y. Acad. Sci., 183 : 183-199. Lambert, E. H., E. D. Rooke, L. M. Eaton and C. H. Hodgson (1961) Myasthenic syndrome occasionally associated with bronchial neoplasm - - Neurophysiologic studies. In: H. R. Viers (Ed.), Myasthenia Gravis, Thomas, Springfield, I11., pp. 362-410. Matthews, W. B. and J. C. Burne (1953) The neurological aspect of dermatomyositis, J. Neurol. Neurosurg. Psychiat., 16: 49-55. Namba, T., N. G. Brunner and D. Grob (1973) Association of myasthenia gravis with pemphigus vulgaris, candida albicans infection, polymyositis and myocarditis, J. neurol. Sci., 20: 231-242.
144 Ozdemir, C. and R. R. Young ( 1971 ) Electrical testing in myasthenia gravis, Ann. N. Y. Acad. Sci., I ~3 : 286-302. Pearson, C. M. (1964) Polymyositis and related disorders, ln: J. N. Walton (Ed.), Disorders oJ Voluntary Muscle, Churchill, London, pp. 305-335. Reese, H. and J. W. Harman (1954) A hitherto unclassified muscular disorder, Trans. Amer. neural. Ass., 79 : 82-87. Reuck, J. De, E. Thiery, W. DeCoster and H. Van der Eecken (1976) Myasthenic syndrome in polymyositis, Europ. Neurol., 14:275-284. Reznik, M. (1974) Deux cas de syndrome myasth6nique avec thymome, polymyosite, myocardite et thyroidite, J. neurol. Sci., 22: 341-351. Simpson, J. A. (1969) The defect in myasthenia gravis. In: E. E. Bittar and N. Bittar (Eds.), Biological Basis o f Medicine, Academic Press, London, pp. 345-348. Simpson, J. A. (1971) A morphological explanation of the transmission defect in myasthenia gravis, Ann. N.Y. Acad. Sci., 183: 241-247. Slomi6, A., A. Rosenfalck and F. Buchthal (1968) Electrical and mechanical responses of normal and myasthenic muscle, Brain Res., 10: 1-78. Struppler, A. (1955) Experimentelle Untersuchungen zur Pathogenese der Myasthenie, Z. ges. exp. Med., 125 : 244-273. Toyka, K. V., D. B. Drachman, A. Pestronk, D. E. Griffin, 1. Kao and J. A. Winkelstein (1977) Die pathogenetische Bedeutung yon "myasthenogenen" Immunoglobulinen. In: G. Hertel, H. G. Mertens, K. Ricker and K. Schimrigk (Eds.), Myasthenia gravis und andere St6rungen der neuromuskuliiren Synapse, Thieme, Stuttgart, pp. 19-22. Walton, J. N. (1971) Polymyositis and related disorders, Presse mdd., 79: 435-438. Walton, J. N. and R. D. Adams (1958)Polymyositis, Livingstone, Edinburgh.
