72070ournal ofNeurology, Neurosurgery, and Psychiatry 1993;56:720-723

interval of 0-24 second. Pulmonary function does not change the clinical course of PSS. tests revealed a slightly restrictive ventilato- Corticosteroids are considered to aggravate LETTERS TO ry defect; the ratio of FEVl/FVC was 0-96 symptoms of PSS. Some investigators have and the ratio of FVC observed/FVC pre- reported that CyA was effective against THE EDITOR dicted was 0 73. Cold water (10°C) immer- PSS.45 Our first trial of CyA in PSS with sion test on the skin of the hand showed a CNS vasculitis appeared dramatically suc- delay in regaining the initial temperature, cessful. which was compatible with Raynaud's phe- KAZUYUKI ISHIDA Progressive systemic sclerosis with TOMOYUKI KAMATA CNS vasculitis and cyclosporin A nomenon. CSF was normal. Radiograph of HIROSHI TSUKAGOSHI therapy the chest showed fine fibrotic strands in the Department ofNeurology lower portions of both lungs. Barium-meal YOSHIO TANIZAKI Department ofNeurosurgery, Progressive systemic sclerosis is a multi- revealed a dilated oesophagus with Kakeyu Hospital, Nagano, J7apan system disorder characterised by inflam- decreased peristalsis. MRI scan of the head matory, vascular and fibrotic changes of disclosed ischaemic lesions in the right Correspondence to: Dr Ishida, Department of skin and a variety of internal organs. Most occipital region, the right middle cerebellar Neurology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-Ku, Tokyo, reports describing neurological complica- peduncle, and the basilar part of the pons. 1 3, Japan. tions of PSS have focused on damage to the Digital subtraction angiogram (DSA) peripheral nervous system. CNS dysfunc- showed localised severe stenosis and post- tions are rare and are thought to result from stenotic dilation, a "string of beads" appear- 1 Lee JE, Haynes JM. Carotid arteritis and cere- uraemia, hypoxaemia, and severe hyperten- ance, from the distal end of the right bral infarction due to scleroderma. sion. This is the first trial of cyclosporin A vertebral to the proximal portion of the Neurology 1967;17:18-22. 2 Estey E, Lieberman A, Pinto R, Meltzer M, (CyA) in a patient with CNS vasculitis basilar arteries (fig). There was no definite Ransohoff J. Cerebral arteritis in scleroder- secondary to PSS. stenosis in other arteries. Skin biopsy speci- ma. Stroke 1979;10:595-7. A 67 year old woman was admitted with men showed proliferation of thickened col- 3 Pathak R, Gabor AJ. Scleroderma and central nervous system vasculitis. Stroke 1991;22: difficulty in walking and with speech. She lagen fibres in the dermis. 410-3. had been in good health until December Based on these findings, we diagnosed 4 Zachariae H, Halkier-Sorensen L, 1985, when she noted that her hands PSS, following the scleroderma criteria of Heickendroff L, Zachariae E, Hansen HE. turned white in a cold environment. the American Rheumatism Association, and Cyclosporin A treatment of systemic sclero- sis. BrJ Dermnatol. 1990;122:677-81. Subsequently, she developed a nonproduc- we attributed the abnormal angiogram find- 5 Gisslinger H, Burghuber OC, Stacher G, tive cough. In February 1986 she experi- ings to vasculitis. Treatment was started Schwarz W, Punzengruber C, Grainger W, enced occasional dizziness. In July 1990 she with CyA 8 mg/kg a day. Two months later, Luger TA, Wolff K, Smolen JS. Efficacy of cyclosporin A in systemic sclerosis. Clin Exp began to walk with a waddle. urinalysis disclosed an increase in urinary Rheumatol 1991;9:383-90. On admission, her blood pressure, pulse, fl,-microglobulin, a sign of renal damage body temperature, and respiration were caused by CyA. Immediately the dose was normal. The skin of her face was so taut reduced to 6 mg/kg, and during the next that she was unable to open her mouth month it was reduced by 1 mg/kg every Ocular myasthenia: diagnostic value of fully; her lips were thin and shortened. She week, to 3 mg/kg. single fibre EMG in the orbicularis had telangiectasis on the chest. Auscultation Though the abnormal findings of sero- oculi muscle of the chest disclosed fine crackles on the logical tests were not improved, during this lower fields of both lungs. The skin of her period the urinary fi2-microglobulin When myasthenia gravis is restricted to fingers and hands was firm and thickened returned to normal. The patient's nonpro- ocular muscles it can present a difficult and tightly bound to underlying subcuta- ductive cough subsided and Raynaud's phe- diagnosis. Firstly, the response to Tensilon neous tissue. The skin changes spread from nomenon did not occur. The skin iv can be negative or ambiguous; secondly, her hands to the chest. Calcinosis cutis was involvement gradually diminished, and the repetitive nerve stimulation and titration of not found. Raynaud's phenomenon could abnormal ECG findings and pulmonary serum anti-acetylcholine receptor antibodies be induced by cold stimuli. function tests improved: PR interval, 0-20 (anti-AChR abs) often give negative She had dysarthria; left hemiparesis with second; FVC observed/FVC predicted ratio, results.' Chronic progressive external slight rigidity and spasticity; and mild inco- 0-8. The neurological symptoms that result- ophthalmoplegia (CPEO) must be distin- ordination. Deep tendon reflexes were nor- ed from multiple CNS infarction remained guished. Single fibre electromyography mal and pathological reflexes were absent. stable. Cold water immersion test showed a (EMG) has proved the most sensitive diag- The ESR, blood count, and biochemical normal recovery to the initial temperature. nostic test in patients with myasthenia tests, were normal. The C-reactive protein One year after the beginning of CyA gravis.2 However, increased jitter and was negative; rheumatoid factor positive; treatment, the patient takes 150 mg/day (3 impulse blocking can also be found in nerve antinuclear antibody present in a 1:320 mg/kg/day) of CyA, her hands and fingers and muscle diseases34 and abnormal find- dilution; anti-Scl-70 antibody (antisclero- are still slightly firm and thick, but autoanti- ings have been reported in some patients derma antibody) was positive in a 1:16 dilu- bodies, including anti-Scl-70 antibody, with chronic progressive external ophthal- tion. Electrocardiogram showed first-degree have normalised, except for a positive ANA moplegia.56 atrioventricular block with a prolonged PR in a 1:160 dilution. In this study, we verified the diagnostic The classical "string of beads" appear- sensitivity of single fibre EMG of the orbic- ance on the angiogram is characteristic of ularis oculi muscle in patients with ocular vasculitis, but may be present in infection myasthenia gravis and its usefulness in the and arteriosc'erosis. There have been three distinction from chronic progressive exter- reports about PSS with CNS vasculitis.'-' In nal ophthalmoplegia. all the cases the authors diagnosed PSS We studied 14 patients with purely ocu-

w ...... based on angiograms, and in Lee's report, lar myasthenia and 8 patients affected with r : ::: .... d .,. post mortem examination disclosed chronic progressive external ophthalmople- mononuclear cell infiltration into the left gia. There were 7 male and 7 female ,x, .. B -. g -: internal carotid artery.' patients with myasthenia gravis, aged have aiiii ;=T>e >^...X...... Recently, some researchers empha- 13-61, mean (SD) 41-4 (18-3), with dura- JS _ .t. .& $ :: sised the importance of vascular involve- tion of disease ranging from 1-40 years, ment in the pathogenesis of PSS, and have mean (SD) 7 (10-1). The diagnosis of ocu- .g- }.: :. suggested that it was probably the initial lar myasthenia was based on history and :^g:g.:: ::..;. : ::. ..:.: event preceding abnormal fibrosis. Why our clinical signs together with at least one of

_ ffi.-e :,. {.: ^ had CNS vasculitis without _ :e Jr patient systemic these features: unequivocal improvement _E .. r:. s vasculitis is unclear. We assume that there after intravenous edrophonium; presence of _L_ .. j are unknown differences in antigenicity serum antibodies to AChR; decremental between arteries of the CNS and other response to repetitive nerve stimulation. organ systems. Thirteen patients showed fluctuating ptosis Figure Digital subtraction angiogram shows Effective drug therapy in PSS has not and/or diplopia, while in one case, with localised stenosis and post-stenotic dilation. been established. D-penicillamine has been long-standing disease, clear fluctuations *..,}ThereXo-LA:.:iP:t...... was..*...... 0'o..ep no:,°.ffi^.^.sr:--:-.g.4...definite...... ,0..o>B..:.:5E,:d...^m.o.:w.-:stenosis...... :X.-.^R.::.:....::l:...... in:::other arteries. reported to reduce skin thickening, but it were not evident. Twelve patients improved Letters to the Editor 721 considerably on the Tensilon test, six had ocular form of the disease. Single fibre myelin and a pathogenetic role of the M- detectable anti-AChR abs, five showed EMG has proved the most sensitive tech- component has been proposed. However, decremental pattern on RNS performed on nique in detecting the neuromuscular trans- other mechanisms, besides the M-compo- proximal muscles (deltoid and biceps mission defect in ocular myasthenia gravis, nent acting as antibody, may be operating. brachii). In the patient without fluctuations especially when facial muscles are tested. In vitro studies have shown that monoclonal of clinical signs, in whom the Tensilon test The orbicularis oculi muscle shows abnor- antibodies against MAG in a patient with was negative, the diagnosis of myasthenia mal results more often than the frontalis monoclonal gammopathy were subject to gravis was confirmed by the presence of muscle.68 Unfortunately, single fibre EMG T-cell regulation,' but the role of a T-cell serum anti-AChR abs. Muscle biopsy per- abnormalities can also be seen in primary mediated immune response has not been formed in this patient as well in another neuropathic and myopathic disorders as a further investigated. case with no detectable anti-AChR abs, result of abnormal conduction of the Interleukin-2 (IL-2), which is synthesised showed normal findings. All patients had a impulse in degenerating or reinnervating by antigen or mitogen activated T lympho- follow up period of at least two years and nerve terminals and newly formed end- cytes, plays an essential role in triggering alternative diagnoses were excluded. plates.34 In CPEO patients, Krendel and T-lymphocyte proliferation, T-cell differen- Eight patients had chronic progressive Sanders described increased jitter and tiation, and surface expression of IL-2 external ophthalmoplegia, 3 males and 5 blocking in facial (frontalis) and in arm receptors (IL-2R) on T-cells. It also induces females, aged 35-71, mean (SD) 56 (14-9) muscles'6 and a primary defect of neuro- maturation and proliferation of B-lympho- with duration of disease ranging from muscular transmission has been suggested cytes. Surface bound IL-2 has a rapid 1-5-17 years mean (SD) 5-3 (5-1). All in this condition.5 In our study, single fibre turnover. Therefore the measurement of patients had clinical weakness restricted to EMG performed in the orbicularis oculi soluble (s) IL-2R in serum is preferable as a ocular muscles and five complained of mild muscle revealed a neuromuscular transmis- means to evaluate T-cell activation. fluctuations of ptosis. In this group, serum sion defect in 93% of patients with purely Elevated serum levels of sIL-2R have been anti-AChR ab titration and repetitive nerve ocular myasthenia gravis and so demon- demonstrated in several autoimmune dis- stimulation gave negative results, while the strated a diagnostic capacity significantly ease states, for example, multiple sclerosis2, response to the Tensilon test was negative higher than the Tensilon test, repetitive and the Guillain-Barre syndrome.2 in four cases and equivocal (minimal nerve stimulation or anti-AChR ab titration. We analysed sIL-2R levels in serum as a improvement of ptosis) in the other four. Also, in our experience, the sensitivity of measure of T-cell activation in 19 patients The diagnosis of chronic progressive exter- single fibre EMG is higher in facial muscles, (12 men and 7 women, age 43-85 years, nal ophthalmoplegia was confirmed by the particularly in the orbicularis oculi, than in mean age 68) with monoclonal gammopa- presence of typical ragged red fibres on the extensor digitorum communis muscle. thy (15 with MGUS and 4 with muscle biopsy in all cases. M MILONE Waldenstrom's macroglobulinaemia; 17 of Single fibre EMG was performed in the ML MONACO IgM- and 2 of IgG-isotype) and demyelinat- A EVOLI orbicularis oculi muscle during slight volun- S SERVIDEI ing PN. Seventeen of these patients had tary contraction. A single fibre EMG elec- P TONALI anti-MAG and/or anti-peripheral nerve trode (Medelec SF 25) was inserted in the Institute ofNeurology, myelin (PNM) antibodies. Sera from 19 Catholic University, inferior and lateral portion of the muscle Rome, Italy patients (13 men and 6 women, age 43-80 and recordings were made on a Medelec years, mean age 66) with monoclonal gam- Mystro electromyograph. For each muscle Correspondence to: Dr. Milone, Institute of mopathy (15 with MGUS and 4 with mul- tested, 20 action potential pairs were Neurology, Catholic University, Policlinico A. tiple myeloma; 13 of IgG-, 2 of IgM-, 2 of analysed and the overall mean jitter as mean Gemelli, Lgo Gemelli 8, 00168 Rome, Italy IgA-isotype, and 2 with light chain protein- consecutive difference (MCD), the percent- uria) without PN and without antibodies age of potential pairs with prolonged jitter against MAG or PNM, and sera from 15 and the percentage of potential pairs with healthy individuals (9 men and 6 women, blocking were evaluated. In agreement with 1 Evoli A, Tonali P, Bartoccioni E, Lo Monaco age 47-80 years, mean age 66) without M. Ocular myasthenia: diagnostic and thera- other authors,7 we considered a jitter study peutic problems. Acta Neurol Scand 1988; monoclonal gammopathy served as con- pathological when either a value for mean 77:31-5. trols. Antibodies against MAG and PNM MCD was above the 95% upper limit for 2 Sanders DB, Howard JF, Johns TR. Single- were analysed by enzyme linked fiber electromyography in myasthenia gravis. age or a jitter was above the 95% upper Neurology 1979;29:68-76. immunosorbent assays (ELISA) essentially limit for potential pairs in more than 10% 3 Stalberg E, Schwartz MS, Trontelj JV. Single as described previously.34 In 15 patients of pairs. The reference values for these fiber electromyography in various processes with monoclonal gammopathy and PN, 2 parameters, in different age groups, were affecting the anterior horn cell. J Neurol Sci serum or more were obtained dur- 1975;24:403-15. samples derived from literature data.7 4 Stalberg E, Trontelj J. Single fiber electromyo- ing or shortly after tapering off the Single fibre EMG studies were per- graphy. Old Woking, Surrey: Mirvalle Press, immunosuppressive treatment. Serum formed, at least 48 hours after discontinu- 1979. samples were stored at - 70°C, and thawed 5 Krendel DA, Sanders DB, Massey JM. Single ing therapy, on patients with myasthenia. fiber electromyography in chronic external only once. Serum sIL-2R levels were mea- Results of the single fibre EMG in the ophthalmoplegia. Muscle Nerve 1985;8:624. sured using a commercial ELISA kit orbicularis oculi muscle were pathological 6 Sanders DB, Howard J. AAEE minimono- (Cellfree, T Cell Diagnostics, Inc, in 13 of 14 patients (93%) with purely ocu- graph . 25: single fiber electromyography in Cambridge, MA) according to instructions myasthenia gravis. Muscle Nerve 1986;9: lar myasthenia gravis. Eleven patients 809-19. from the manufacturer. Values exceeding showed abnormal mean jitter and more 7 Ad hoc committee of the AAEM special inter- the mean value +2SD (> 919 U/ml) of 50 than 10% potential pairs had prolonged jit- est group on single fiber EMG, Gilchrist blood donors were considered pathological JM, coordinator. Muscle Nerve 1992;15: ter (in 8 patients blocking was recorded); 151-161. (manufacturers information). two patients had mean MCD below the 8 Trontelj JV, Khuraibet A, Mihelin M. The jit- Seven of 19 patients with M-component 95% upper limit and respectively 20% and ter in stimulated orbicularis oculi muscle: associated PN had increased sIL-2R levels 40% potential pairs with prolonged jitter. technique and normal values. J Neurol in the first serum sample, compared with 2 In all patients with chronic progressive Neurosurg Psychiatry 1988;51:814-9. of 19 M-component patients without PN (p external ophthalmoplegia, single fibre EMG = 0-06 according to Fisher's exact test, one- studies showed values within the nornal tail) and 1 of 15 healthy controls (p < 0.05 limits. The mean jitter did not exceed Soluble interleukin-2 Receptor levels in according to Fisher's exact test, one-tail) 25 psec. Only one patient had 5% of poten- serum of patients with demyelinating (fig). At the time of the sample 4 patients tial pairs with prolonged jitter and no block- polyneuropathy associated with mono- with M-component associated PN and 4 ing was recorded. clonal ganmmopathy M-component patients without PN were In patients with ocular myasthenia gravis, receiving immunosuppressive treatment. the positivity rate with single fibre EMG Monoclonal gammopathies, especially One of 4 treated patients with M-compo- was higher than with the Tensilon test monoclonal gammopathy of uncertain sig- nent associated PN had elevated serum sIL- (86%), RNS (36%) or anti-AChR abs nificance (MGUS) with IgM M-compo- 2R levels and 6 of 15 untreated patients had (43%). nents, are associated with demyelinating elevated serum sIL-2R levels. Serum anti-AChR abs, which are present polyneuropathy (PN). In approximately In 15 patients with M-component associ- in more than 90% of patients with gener- 50% of these patients, the IgM M-compo- ated PN, subsequent serum samples were alised myasthenia gravis, are detectable in a nent reacts with myelin associated glycopro- taken during or shortly after tapering off the much lower percentage of patients with the tein (MAG) or other subcomponents of immunosuppressive treatment. Seven of