Neurologic Manifestations of Progressive Systemic Sclerosis Lea
Averbuch-Heller, MD; Israel Steiner, MD; Oded Abramsky, MD, PhD
Neurologic involvement in progressive systemic sclerosis is considered uncommon. We retrospectively examined the prevalence and nature of neurologic complications in 50 patients with progressive systemic sclerosis. In 20 (40%), neurologic abnormalities were detected, with a total of 28 neurologic manifestations. All levels of the central and peripheral nervous system were affected: muscle (22%), peripheral nerve (18%), spinal cord (8%), and brain (6%). Of note were the presence of myelopathy in four patients and inclusion-body myositis in two. In 10 patients (20%), no definable cause of the neurologic dysfunction could be identified, apart from progressive systemic sclerosis. Thus, neurologic presentations of progressive systemic sclerosis are much more common than previously reported and may be due to direct involvement of the nervous system by a primary pathologic process in a significant number of \s=b\
patients. (Arch Neurol. 1992;49:1292-1295)
ported by impaired results of pulmonary function tests, esophageal motility studies, renal function tests, skin biopsy specimens, and serologie tests, eg, antinuclear and antinucleolar antibodies.
The patients consisted of 40 females and 10 males with a mean age of 45.3 years (range, 9 to 75 years). Their charts were reviewed for the presence of neurologic manifestations. In all patients, the diagnosis of PSS preceded any neurologic symptoms, and no pa¬ tient was referred to our institution for neurologic evaluation. The following patients were not included: (1) three patients with neu¬ rologic complaints who did not undergo complete neurologic ex¬
by a neurologist; (2) one patient with posttraumatic epilepsy; (3) one patient with diabetic neuropathy; and (4) five patients with possible iatrogenic complications (three with my¬ opathy during corticosteroid and colchicine therapy and two with peripheral neuropathy during colchicine therapy). amination
REPORT OF CASES
report following two illustrative cases with unusual neurologic complications of PSS. Case 1.—A 38-year-old white woman was referred to a neurologist for evaluation of a 1-year history of progressive band sensations in her trunk and legs and instability of gait. At the age of 17 years, she had begun to suffer from acrosclerosis; at the age of 26 years, CREST (calcinosis, Raynaud's phenomenon, esophageal hypomotility, sclerodactyly, and telangiectasia) syndrome had been diagnosed. Nine years later, she had developed intes¬ tinal pseudo-obstruction. During the course of the disease, she had been treated for a short period with colchicine and azathio¬ prine, and for the last 4 years she had been treated with corticos¬ teroids, nifedipine, and nonsteroidal anti-inflammatory agents. Neurologic examination revealed general hyperreflexia with bilateral extensor plantar response and a severe loss of vibration and proprioception sense in the lower extremities. The gait was atactic, with a positive Romberg's sign. A complete laboratory workup, including measurement of cyanocobalamin, transcobalamins, and vitamin E, thyroid function tests, lumbar puncture, computed tomographic scans and mag¬ netic resonance images of cervical and thoracic spine, and visual evoked responses did not identify any abnormality. The patient was diagnosed as having posterolateral myelopathy of undeter¬ mined origin. Case 2.—A 22-year-old man of Iranian-Jewish origin was hos¬ pitalized for evaluation of a progressive muscular weakness of 3 years' duration. At the age of 12 years, he had started to suffer from sclerodactyly; 5 years later, diffuse scleroderma had been diagnosed. He had not received any specific treatment for at least We
sclerosis (PSS) is generalized Progressi ve systemicdisease, connective-tissue involving predominantly Un¬ and a
skin, gastrointestinal tract, lungs, heart, kidneys.1 like other collagen disorders, neurologic manifestations in
PSS are considered uncommon, occurring in only 0.8% to 5.6% of patients2,3 and consisting mainly of muscle chang¬ es4,5 and peripheral neuropathy.3 Central nervous system involvement is rare, with few case reports of cerebral arteritis.6 The neurologic abnormalities of PSS were sup¬ posed to be either coincidental, iatrogenic, or secondary to other organ involvement.7 The purpose of this communi¬ cation is to report the higher frequency of neurologic pre¬ sentations in our patients with PSS and to discuss the pos¬ sible relationship between the systemic disease and its
neurologic complications.
PATIENTS AND METHODS Between 1980 and 1990, PSS was diagnosed in 50 patients in the Hadassah University Hospital, Jerusalem, Israel. The diagnosis
based on the combination of clinical and laboratory criteria,1 including acrosclerosis, widespread skin changes, telangiectasias, was
Accepted for publication June 25, 1992. From the Department of Neurology, Hadassah University Hospital and Hebrew University-Hadassah Medical School, Jerusalem, Israel. Reprint requests to Department of Neurology, Hadassah University Hospital, PO Box 12000, IL-91120, Jerusalem, Israel (Dr Averbuch\x=req-\ Heller).
calcinosis, Raynaud's phenomenon, visceral involvement sup¬
the
7 years before his admission. On examination, he had painless proximal asymmetric muscle atrophy and weakness (3/5 on the Medical Research Council
Downloaded From: http://archneur.jamanetwork.com/ by a University of California - San Diego User on 06/08/2015
Table
1.—Neurologie Manifestations With PSS*
Neurologie Manifestation
in 50 Patients
No. (%) of Patients
Myopathy Myasthenia gravis Peripheral neuropathy Myelopathy
11 (22) 1 (2) 9 (18) 4 (8)
Cerebrovascular disease
3 (6)
*PSS indicates progressive systemic sclerosis. Seven than one neurologic system involved.
patients had more
scale); his quadriceps muscle was markedly involved, thus ruling
clinically the diagnosis of quadriceps-sparing myopathy, which affects Iranian Jews.8 Routine laboratory studies were normal except for mildly ele¬ vated level of serum creatine kinase (CK). Electromyography (EMG) showed a mixed myopathic-neurogenic pattern, with spontaneous activity, reduced recruitment, and polyphasic motor unit potentials. A quadriceps muscle biopsy specimen demon¬ strated numerous rimmed vacuoles, fiber necrosis, and lympho¬ cytic infiltrate. On electron microscopy, filamentous intranuclear material was seen. Inclusion-body myositis (IBM) was diagnosed. out
RESULTS
Twenty (40%) of 50 patients with PSS developed symp¬
toms
and signs of neurologic dysfunction at some time in
of their disease. Seven of them had more than neurologic system involved, with a total of 28 neuro¬ logic manifestations. The mean duration of PSS before the appearance of neurologic symptoms was 7.5 years (range, 0.6 to 34 years). No correlation between PSS duration or severity and any of the neurologic complications was found. Five (10%) of the 50 patients with PSS had concomitant Sjögren's syndrome. An identical ratio (two of 20) was found in the subgroup with neurologic manifestations. One of them had polymyositis, and another had peripheral neuropathy in the context of renal failure. None had sys¬ the
course
ticosteroids with or without a cytotoxic agent. One patient died of sepsis and respiratory failure. (3) Inclusion body in two patients. In one of them, the myositis was myopathie process ran a chronic course (case 2); in the second patient, weakness evolved during several months, in a subacute fashion. In both, there were mild elevations of CK level, mixed myopathic-neurogenic pattern on the EMG, and a characteristic picture of IBM on muscle biopsy. The second patient was given high-dose corticosteroids (60 mg/d of prednisone), with rapid laboratory and clinical
diagnosed
improvement.
Peripheral Neuropathy There were nine patients with peripheral neuropathy as defined by the presence of distal weakness, diminished or absent deep tendon reflexes, and sensory disturbances; these findings were supported by neuropathic changes on electrodiagnostic studies. This group could be subdivided into two subgroups: sensorimotor polyneuropathy (seven patients) and mononeuropathy (three patients [trigeminal in one each]). in two and ulnar and carpal tunnel Some of the patients with polyneuropathy had additional risk factors; one patient had renal involvement with ure¬ mia and Sjögren's syndrome, and in five patients there was evidence of gastrointestinal tract involvement, but the re¬ sults of metabolic workup were within normal limits. Three patients with mononeuropathy did not have any as¬ sociated risk factors.
syndrome
one
lupus erythematosus. According to the site involved, the manifestations could be divided into five categories (Table 1): muscle disease, myasthenia gravis, peripheral neuropathy, myelopathy, temic
Myelopathy Four patients in our series had myelopathy (Table 2); in three of them it took the form of posterolateral myelopa¬ thy. Three patients had gastrointestinal tract involvement, but no metabolic deficit could be identified. The complete metabolic (including measurement of cyanocobalamin, transcobalamins, and vitamin E) and radiologie workup for a possible cause of myelopathy in these patients was unremarkable. Cerebrospinal fluid was obtained in all pa¬ tients and was normal, except for minimal elevation of protein level (0.686 g/L [normal, up to 0.650 g/L]) in one of them. The patient described in case 1 (patient 3 in Table 2) illustrates this unusual presentation.
Cerebrovascular Disease
and cerebrovascular disease.
Myopathy There were 11 patients with muscle involvement, de¬ fined by the presence of muscle weakness, supported by elevation of serum CK or aldolase levels, myopathie electromyographic pattern (polyphasic motor units of low amplitude and short duration, increased insertional activ¬ ity), and/or muscle biopsy. Three different entities could be delineated within this group. (1) Simple myopathy, identified in four patients, was characterized by slight re¬ duction in muscle strength, mild elevations of CK or aldo¬ lase level, and myopathie EMG pattern, showing polypha¬ sic motor unit potentials of normal duration and amplitude. None of the four patients received any specific therapy for their myopathy, and in all of them the course of muscle disease was relatively stable. (2) Polymyositis complicated the course of PSS in five patients. The disease was associated with marked elevations of CK level, spon¬ taneous activity on EMG, and signs of inflammation on muscle biopsy specimens. Muscle strength was reduced in all of the patients. All but one responded to high-dose cor-
were three instances of cerebrovascular disease (Table 3). All of these patients were relatively young women, aged 50 to 56 years, who presented with transient ischemie attacks or minor strokes. None of them had any definable risk factor for cerebrovascular disease, including negative antiphospholipid antibodies, but one patient (pa¬ tient 3 in Table 3) had renal involvement of PSS without hypertension. In all three, Doppler examination of carotid arteries failed to reveal any significant abnormality.
There
COMMENT manifestations other than muscle disease in Neurologic PSS are regarded as uncommon.2,3,5,9,10 The peripheral ner¬ vous system was involved in the majority of cases reported and carpal tun¬ (up to 5.6%), with trigeminal nel syndrome being the most frequent (about 3% each).3,9,10 The evidence for involvement of other neurologic systems in PSS can be reduced to anecdotal case reports.6,7,11,12 Our study indicates a much higher prevalence of neuro¬ logic manifestations in PSS than has been recognized pre¬ viously. In our review of 50 patients, at least 20 (40%) had
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neuropathy
Table
Patient/Age, y/Sex
2.—Myelopathy
in Patients With PSS*
Clinical Features
PSS
1/22/M 2/43/F 3/37/F 4/33/M
*PSS
Quadriparesis, EPR, vibration loss Paresthesias, quadriparesis, EPR, vibration loss Band sensations, hyperreflexia, EPR, vibration loss Quadriparesis, EPR, impotence indicates progressive systemic sclerosis; GI, gastrointestinal; and EPR, bilateral
Duration,
y
Cl Tract Involvement
10 -
2
+
20
+
1 extensor
plantar
+
response;
plus sign,
yes; minus
sign,
no.
Table 3.—Cerebrovascular Disease in Patients With PSS*
Patient/Age, y/Sex 1/50/F 2/56/F 3/52/F
*PSS
Clinical Features Recurrent L
hemiparesis
Brain CT Normal
R parietal infarct weakness, hemianopia L R frontal infarct hand weakness Dysphasia, Indicates progressive systemic sclerosis; CT, computed tomography. L hand
neurologic dysfunction, seven of them in more than system, with a total of 28 instances of neurologic problems. All levels of the nervous system were affected: muscle, neuromuscular junction, peripheral nerves, spinal cord, and brain. The increased prevalence included cere¬ brovascular disease (6%) and peripheral neuropathy (18%). Myelopathy, identified in four (8%) of our patients, some one
has not been described before in patients with PSS, to our knowledge, except for a single case report.13 Of note are patients with PSS who have IBM (4%), since the association between these two conditions was already pointed out.14,15 Typically, IBM is steroid resistant. How¬ ever, several examples of beneficial response to steroid were recorded recently.16,17 Muscle involvement was present in 22% of our patients with PSS, which is a somewhat lower prevalence than generally accepted.2,5 This could be attributed to the fact that we did not include patients with clinical presentation of constipation up to intestinal pseudo-obstruction, which might be due to myopathy of intestinal smooth muscle in
treatment
some cases.
Neurologic manifestations in PSS fall into three major categories: (1) coincidental problems, such as posttrau¬ matic epilepsy or diabetic neuropathy, (2) iatrogenic dis¬ ease induced by PSS therapy, such as steroid myopathy, colchicine neuropathy or myopathy, and penicillamineassociated myasthenia gravis, and (3) complications of PSS
itself. The last can be subdivided into two groups: (a) neu¬ rologic involvement secondary to other organ involvement in PSS, such as renal involvement with hypertensive or uremie encephalopathy or neuropathy, gastrointestinal tract involvement with malabsorption and subsequent myelopathy, and peripheral neuropathy or convulsions due to vitamin E, cyanocobalamin, or calciferol deficiency, respectively; and (b) neurologic dysfunction as a result of some primary pathologic process in the nervous system. We have restricted our study to the third category of patients, those whose complications seemed to be related to PSS. In 18 (36%) of our patients, no definable cause, co¬ incidental, iatrogenic, or systemic, for their neurologic dysfunction could be identified. Among them, eight had evidence of gastrointestinal tract involvement, with two instances of simple myopathy, one of polymyositis, three of polyneuropathy, three of myelopathy, and one of tran¬ sient ischemie attacks. In all of them, an extensive workup did not disclose any metabolic abnormality. Even if one
Doppler
PSS
Duration, y
Normal
24
Normal
34
Normal
1
chooses to postulate an indefinable metabolic deficiency and to consider these cases to be secondary to gastrointes¬ tinal tract involvement (which seems unlikely in the cases of myositis and transient ischemie attacks), there still remain 10 patients (20%), with two instances of simple myopathy, four of polymyositis, two of IBM, three of mononeuropathy, two of polyneuropathy, one of myelop¬ athy, and one of minor stroke, in whom the only possible risk factor was PSS itself. We therefore suggest direct ner¬ vous system involvement in a considerable number of pa¬ tients with PSS. The initial event in the pathogenesis of PSS is incom¬ pletely understood. Three pathways are proposed to take place in early stages of PSS1: (1) vascular abnormalities with changes in endothelial cells and basal lamina, (2) dysimmune reactions with both cell-mediated activity and autoantibody production, and (3) alterations of collagen metabolism with proliferation of specific fibroblast subpopulations, leading to fibroblast invasion into tissues and activation of collagen synthesis. The final step of all these is tissue fibrosis. Similarly, the damage to the nervous system in PSS could be the outcome of each of these mechanisms. (1) Ac¬ cording to the vascular mechanism, endothelial changes with subsequent microangiopathy of vasa nervorum may increase a tendency to platelet aggregation and cause tis¬ sue ischemia, accounting for peripheral neuropathy or cerebrovascular disease. (2) Although no clear evidence of a primary pathogenetic role of dysimmune alterations in PSS exists, there is indirect evidence in support of it. The concurrence of PSS with immune-mediated conditions, such as myasthenia gravis, polymyositis, insulindependent diabetes mellitus, and thyroiditis in our and other series,7 is suggestive of dysimmune mechanism, as are the histologie findings in our and other cases of inflammatory myositis, with perimysial and perivascular infiltrate of cells and macrophages.5,16 (3) By the entrap¬ ment mechanism, a fibrotic process may involve perineurium and epineurium, and thus produce pressure on pe¬ ripheral nerves, with resultant mononeuropathy. Moreover, there is at least one case report of symmetric sensorimotor polyneuropathy caused by entrapment of spinal nerve roots and peripheral nerves in fibrotic pro¬ cess, proved by postmortem examination.18 While most of our patients with polyneuropathy and myelopathy had evidence of gastrointestinal tract involvement, none of the
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three patients with mononeuropathy had any. Although no metabolic deficit was found, it gives rise to a question about some unidentifiable metabolic factor, the deficiency of which, caused by gastrointestinal tract involvement, is responsible for polyneuropathy and myelopathy, but not for mononeuropathy. For the latter, a different pathoge¬ netic mechanism is suggested, such as entrapment or
microangiopathy. The apparent rarity of central nervous system abnormal¬ ities in PSS may be attributed to its paucity of connective
tissue and to the lack of an external elastic lamina and sparseness of media and adventitia in cerebral arteries. Therefore, the fibrosis and entrapment mechanism can hardly be responsible for cerebral disease in PSS. Neverthe¬ less, vascular and dysimmune mechanisms may still pro¬ duce cerebral disease in the absence of systemic atheroscle¬ rosis or any vascular risk factors other than PSS itself. In conclusion, neurologic manifestations of PSS are much more frequent than have been previously considered and may involve all levels of the neuraxis. Direct involve¬ ment of the nervous system by a primary pathogenetic process may account for the neurologic presentations in a substantial number of patients.
study was supported in part by the Lena P. Harvey Endow¬ Neurological Research and in part by the Fannie R. Steinpress Research Endowment Fund in Neurology. This
ment Fund for
References 1.
Krieg T,
Meurer M.
Systemic scleroderma: clinical and pathophysio-
logic aspects. J Am Acad Dermatol. 1988;18:457-481.
2. Tuffanelli D, Winkelmann RK. Systemic scleroderma: of 727 cases. Arch Dermatol. 1961;84:359-371.
a
clinical
study
3. Lee P, Bruni J, Sukenik S. Neurological manifestations in systemic sclerosis (scleroderma). J Rheumatol. 1984;11:480-483. 4. Isenberg D. Myositis in other connective tissue disorders. Clin Rheum Dis. 1984;10:151-174. 5. Clements PJ, Furst
DE, Campion DS, et al. Muscle disease in progressystemic sclerosis. Arthritis Rheum. 1978;21:62-71. Lieberman 6. Estey E, A, Pinto R, Meltzer M, Ransohoff J. Cerebral arteritis in scleroderma. Stroke. 1979;10:595-597. 7. Gordon RM, Silverstein A. Neurologic manifestations in progressive systemic sclerosis. Arch Neurol. 1970;22:126-134. 8. Argov Z, Yarom R. 'Rimmed vacuole myopathy'sparing the quadriceps. sive
J Neurol Sci. 1984;64:33-43. 9. Sigal LH. The neurologic presentation of vasculitic and rheumatologic syndromes: a review. Medicine. 1987;66:157-179. 10. Dierckx RA, Aichner F, Gerstenbrand F, Fritsch P. Progressive systemic sclerosis and nervous system involvement: a review of 14 cases. Eur Neurol. 1987;26:134-140. 11. Luer W, Jockel D, Henze T, Schipper HI. Progressive inflammatory lesions of the brain parenchyma in localized scleroderma of the head. J Neurol. 1990;237:379-381. 12. Nishida A, Kaiya H, Uematsu M, Maeda M, Mori S, Wakabayashi S.
global amnesia and Raynaud's phenomenon in scleroderma. Acta Neurol Scand. 1990;81:550-552. 13. Brown JJ, Murphy MJ. Transverse myelopathy in progressive systemic sclerosis. Ann Neurol. 1985;17:615-617. 14. Salama J, Tome FM, Lebon P, Marie L, Delaporte P, Fardeau M. Inclusion body myositis: clinical, morphological and virological study of a new case associated with scleroderma and Klinefelter's syndrome. Rev Neurol. 1980;136:863-878. 15. Helm TN, Valenzuela R, Bergfeld WF, Guitart J, Poolos CJ. In vivo complement C3 binding to the intracellular substance and cytoplasm of epidermal basal cells in a patient with scleroderma and inclusion body myositis. JAm Acad Dermatol. 1990;23:753-754. 16. Lotz BP, Engel AG, Nishino H, Stevens JC, Litchy WJ. Inclusion body myositis: observations in 40 patients. Brain. 1989;112:727-747. 17. Cohen MR, Sulaiman AR, Garancis JC, Wortmann RL. Clinical heterogeneity and treatment response in inclusion body myositis. Arthritis Rheum. Transient
1989;32:734-740.
18. Richter RB. Peripheral neuropathy and Neuropathol Exp Neurol. 1954;13:168-180.
Downloaded From: http://archneur.jamanetwork.com/ by a University of California - San Diego User on 06/08/2015
connective tissue disease. J
Averbuch-Heller, MD; Israel Steiner, MD; Oded Abramsky, MD, PhD
Neurologic involvement in progressive systemic sclerosis is considered uncommon. We retrospectively examined the prevalence and nature of neurologic complications in 50 patients with progressive systemic sclerosis. In 20 (40%), neurologic abnormalities were detected, with a total of 28 neurologic manifestations. All levels of the central and peripheral nervous system were affected: muscle (22%), peripheral nerve (18%), spinal cord (8%), and brain (6%). Of note were the presence of myelopathy in four patients and inclusion-body myositis in two. In 10 patients (20%), no definable cause of the neurologic dysfunction could be identified, apart from progressive systemic sclerosis. Thus, neurologic presentations of progressive systemic sclerosis are much more common than previously reported and may be due to direct involvement of the nervous system by a primary pathologic process in a significant number of \s=b\
patients. (Arch Neurol. 1992;49:1292-1295)
ported by impaired results of pulmonary function tests, esophageal motility studies, renal function tests, skin biopsy specimens, and serologie tests, eg, antinuclear and antinucleolar antibodies.
The patients consisted of 40 females and 10 males with a mean age of 45.3 years (range, 9 to 75 years). Their charts were reviewed for the presence of neurologic manifestations. In all patients, the diagnosis of PSS preceded any neurologic symptoms, and no pa¬ tient was referred to our institution for neurologic evaluation. The following patients were not included: (1) three patients with neu¬ rologic complaints who did not undergo complete neurologic ex¬
by a neurologist; (2) one patient with posttraumatic epilepsy; (3) one patient with diabetic neuropathy; and (4) five patients with possible iatrogenic complications (three with my¬ opathy during corticosteroid and colchicine therapy and two with peripheral neuropathy during colchicine therapy). amination
REPORT OF CASES
report following two illustrative cases with unusual neurologic complications of PSS. Case 1.—A 38-year-old white woman was referred to a neurologist for evaluation of a 1-year history of progressive band sensations in her trunk and legs and instability of gait. At the age of 17 years, she had begun to suffer from acrosclerosis; at the age of 26 years, CREST (calcinosis, Raynaud's phenomenon, esophageal hypomotility, sclerodactyly, and telangiectasia) syndrome had been diagnosed. Nine years later, she had developed intes¬ tinal pseudo-obstruction. During the course of the disease, she had been treated for a short period with colchicine and azathio¬ prine, and for the last 4 years she had been treated with corticos¬ teroids, nifedipine, and nonsteroidal anti-inflammatory agents. Neurologic examination revealed general hyperreflexia with bilateral extensor plantar response and a severe loss of vibration and proprioception sense in the lower extremities. The gait was atactic, with a positive Romberg's sign. A complete laboratory workup, including measurement of cyanocobalamin, transcobalamins, and vitamin E, thyroid function tests, lumbar puncture, computed tomographic scans and mag¬ netic resonance images of cervical and thoracic spine, and visual evoked responses did not identify any abnormality. The patient was diagnosed as having posterolateral myelopathy of undeter¬ mined origin. Case 2.—A 22-year-old man of Iranian-Jewish origin was hos¬ pitalized for evaluation of a progressive muscular weakness of 3 years' duration. At the age of 12 years, he had started to suffer from sclerodactyly; 5 years later, diffuse scleroderma had been diagnosed. He had not received any specific treatment for at least We
sclerosis (PSS) is generalized Progressi ve systemicdisease, connective-tissue involving predominantly Un¬ and a
skin, gastrointestinal tract, lungs, heart, kidneys.1 like other collagen disorders, neurologic manifestations in
PSS are considered uncommon, occurring in only 0.8% to 5.6% of patients2,3 and consisting mainly of muscle chang¬ es4,5 and peripheral neuropathy.3 Central nervous system involvement is rare, with few case reports of cerebral arteritis.6 The neurologic abnormalities of PSS were sup¬ posed to be either coincidental, iatrogenic, or secondary to other organ involvement.7 The purpose of this communi¬ cation is to report the higher frequency of neurologic pre¬ sentations in our patients with PSS and to discuss the pos¬ sible relationship between the systemic disease and its
neurologic complications.
PATIENTS AND METHODS Between 1980 and 1990, PSS was diagnosed in 50 patients in the Hadassah University Hospital, Jerusalem, Israel. The diagnosis
based on the combination of clinical and laboratory criteria,1 including acrosclerosis, widespread skin changes, telangiectasias, was
Accepted for publication June 25, 1992. From the Department of Neurology, Hadassah University Hospital and Hebrew University-Hadassah Medical School, Jerusalem, Israel. Reprint requests to Department of Neurology, Hadassah University Hospital, PO Box 12000, IL-91120, Jerusalem, Israel (Dr Averbuch\x=req-\ Heller).
calcinosis, Raynaud's phenomenon, visceral involvement sup¬
the
7 years before his admission. On examination, he had painless proximal asymmetric muscle atrophy and weakness (3/5 on the Medical Research Council
Downloaded From: http://archneur.jamanetwork.com/ by a University of California - San Diego User on 06/08/2015
Table
1.—Neurologie Manifestations With PSS*
Neurologie Manifestation
in 50 Patients
No. (%) of Patients
Myopathy Myasthenia gravis Peripheral neuropathy Myelopathy
11 (22) 1 (2) 9 (18) 4 (8)
Cerebrovascular disease
3 (6)
*PSS indicates progressive systemic sclerosis. Seven than one neurologic system involved.
patients had more
scale); his quadriceps muscle was markedly involved, thus ruling
clinically the diagnosis of quadriceps-sparing myopathy, which affects Iranian Jews.8 Routine laboratory studies were normal except for mildly ele¬ vated level of serum creatine kinase (CK). Electromyography (EMG) showed a mixed myopathic-neurogenic pattern, with spontaneous activity, reduced recruitment, and polyphasic motor unit potentials. A quadriceps muscle biopsy specimen demon¬ strated numerous rimmed vacuoles, fiber necrosis, and lympho¬ cytic infiltrate. On electron microscopy, filamentous intranuclear material was seen. Inclusion-body myositis (IBM) was diagnosed. out
RESULTS
Twenty (40%) of 50 patients with PSS developed symp¬
toms
and signs of neurologic dysfunction at some time in
of their disease. Seven of them had more than neurologic system involved, with a total of 28 neuro¬ logic manifestations. The mean duration of PSS before the appearance of neurologic symptoms was 7.5 years (range, 0.6 to 34 years). No correlation between PSS duration or severity and any of the neurologic complications was found. Five (10%) of the 50 patients with PSS had concomitant Sjögren's syndrome. An identical ratio (two of 20) was found in the subgroup with neurologic manifestations. One of them had polymyositis, and another had peripheral neuropathy in the context of renal failure. None had sys¬ the
course
ticosteroids with or without a cytotoxic agent. One patient died of sepsis and respiratory failure. (3) Inclusion body in two patients. In one of them, the myositis was myopathie process ran a chronic course (case 2); in the second patient, weakness evolved during several months, in a subacute fashion. In both, there were mild elevations of CK level, mixed myopathic-neurogenic pattern on the EMG, and a characteristic picture of IBM on muscle biopsy. The second patient was given high-dose corticosteroids (60 mg/d of prednisone), with rapid laboratory and clinical
diagnosed
improvement.
Peripheral Neuropathy There were nine patients with peripheral neuropathy as defined by the presence of distal weakness, diminished or absent deep tendon reflexes, and sensory disturbances; these findings were supported by neuropathic changes on electrodiagnostic studies. This group could be subdivided into two subgroups: sensorimotor polyneuropathy (seven patients) and mononeuropathy (three patients [trigeminal in one each]). in two and ulnar and carpal tunnel Some of the patients with polyneuropathy had additional risk factors; one patient had renal involvement with ure¬ mia and Sjögren's syndrome, and in five patients there was evidence of gastrointestinal tract involvement, but the re¬ sults of metabolic workup were within normal limits. Three patients with mononeuropathy did not have any as¬ sociated risk factors.
syndrome
one
lupus erythematosus. According to the site involved, the manifestations could be divided into five categories (Table 1): muscle disease, myasthenia gravis, peripheral neuropathy, myelopathy, temic
Myelopathy Four patients in our series had myelopathy (Table 2); in three of them it took the form of posterolateral myelopa¬ thy. Three patients had gastrointestinal tract involvement, but no metabolic deficit could be identified. The complete metabolic (including measurement of cyanocobalamin, transcobalamins, and vitamin E) and radiologie workup for a possible cause of myelopathy in these patients was unremarkable. Cerebrospinal fluid was obtained in all pa¬ tients and was normal, except for minimal elevation of protein level (0.686 g/L [normal, up to 0.650 g/L]) in one of them. The patient described in case 1 (patient 3 in Table 2) illustrates this unusual presentation.
Cerebrovascular Disease
and cerebrovascular disease.
Myopathy There were 11 patients with muscle involvement, de¬ fined by the presence of muscle weakness, supported by elevation of serum CK or aldolase levels, myopathie electromyographic pattern (polyphasic motor units of low amplitude and short duration, increased insertional activ¬ ity), and/or muscle biopsy. Three different entities could be delineated within this group. (1) Simple myopathy, identified in four patients, was characterized by slight re¬ duction in muscle strength, mild elevations of CK or aldo¬ lase level, and myopathie EMG pattern, showing polypha¬ sic motor unit potentials of normal duration and amplitude. None of the four patients received any specific therapy for their myopathy, and in all of them the course of muscle disease was relatively stable. (2) Polymyositis complicated the course of PSS in five patients. The disease was associated with marked elevations of CK level, spon¬ taneous activity on EMG, and signs of inflammation on muscle biopsy specimens. Muscle strength was reduced in all of the patients. All but one responded to high-dose cor-
were three instances of cerebrovascular disease (Table 3). All of these patients were relatively young women, aged 50 to 56 years, who presented with transient ischemie attacks or minor strokes. None of them had any definable risk factor for cerebrovascular disease, including negative antiphospholipid antibodies, but one patient (pa¬ tient 3 in Table 3) had renal involvement of PSS without hypertension. In all three, Doppler examination of carotid arteries failed to reveal any significant abnormality.
There
COMMENT manifestations other than muscle disease in Neurologic PSS are regarded as uncommon.2,3,5,9,10 The peripheral ner¬ vous system was involved in the majority of cases reported and carpal tun¬ (up to 5.6%), with trigeminal nel syndrome being the most frequent (about 3% each).3,9,10 The evidence for involvement of other neurologic systems in PSS can be reduced to anecdotal case reports.6,7,11,12 Our study indicates a much higher prevalence of neuro¬ logic manifestations in PSS than has been recognized pre¬ viously. In our review of 50 patients, at least 20 (40%) had
Downloaded From: http://archneur.jamanetwork.com/ by a University of California - San Diego User on 06/08/2015
neuropathy
Table
Patient/Age, y/Sex
2.—Myelopathy
in Patients With PSS*
Clinical Features
PSS
1/22/M 2/43/F 3/37/F 4/33/M
*PSS
Quadriparesis, EPR, vibration loss Paresthesias, quadriparesis, EPR, vibration loss Band sensations, hyperreflexia, EPR, vibration loss Quadriparesis, EPR, impotence indicates progressive systemic sclerosis; GI, gastrointestinal; and EPR, bilateral
Duration,
y
Cl Tract Involvement
10 -
2
+
20
+
1 extensor
plantar
+
response;
plus sign,
yes; minus
sign,
no.
Table 3.—Cerebrovascular Disease in Patients With PSS*
Patient/Age, y/Sex 1/50/F 2/56/F 3/52/F
*PSS
Clinical Features Recurrent L
hemiparesis
Brain CT Normal
R parietal infarct weakness, hemianopia L R frontal infarct hand weakness Dysphasia, Indicates progressive systemic sclerosis; CT, computed tomography. L hand
neurologic dysfunction, seven of them in more than system, with a total of 28 instances of neurologic problems. All levels of the nervous system were affected: muscle, neuromuscular junction, peripheral nerves, spinal cord, and brain. The increased prevalence included cere¬ brovascular disease (6%) and peripheral neuropathy (18%). Myelopathy, identified in four (8%) of our patients, some one
has not been described before in patients with PSS, to our knowledge, except for a single case report.13 Of note are patients with PSS who have IBM (4%), since the association between these two conditions was already pointed out.14,15 Typically, IBM is steroid resistant. How¬ ever, several examples of beneficial response to steroid were recorded recently.16,17 Muscle involvement was present in 22% of our patients with PSS, which is a somewhat lower prevalence than generally accepted.2,5 This could be attributed to the fact that we did not include patients with clinical presentation of constipation up to intestinal pseudo-obstruction, which might be due to myopathy of intestinal smooth muscle in
treatment
some cases.
Neurologic manifestations in PSS fall into three major categories: (1) coincidental problems, such as posttrau¬ matic epilepsy or diabetic neuropathy, (2) iatrogenic dis¬ ease induced by PSS therapy, such as steroid myopathy, colchicine neuropathy or myopathy, and penicillamineassociated myasthenia gravis, and (3) complications of PSS
itself. The last can be subdivided into two groups: (a) neu¬ rologic involvement secondary to other organ involvement in PSS, such as renal involvement with hypertensive or uremie encephalopathy or neuropathy, gastrointestinal tract involvement with malabsorption and subsequent myelopathy, and peripheral neuropathy or convulsions due to vitamin E, cyanocobalamin, or calciferol deficiency, respectively; and (b) neurologic dysfunction as a result of some primary pathologic process in the nervous system. We have restricted our study to the third category of patients, those whose complications seemed to be related to PSS. In 18 (36%) of our patients, no definable cause, co¬ incidental, iatrogenic, or systemic, for their neurologic dysfunction could be identified. Among them, eight had evidence of gastrointestinal tract involvement, with two instances of simple myopathy, one of polymyositis, three of polyneuropathy, three of myelopathy, and one of tran¬ sient ischemie attacks. In all of them, an extensive workup did not disclose any metabolic abnormality. Even if one
Doppler
PSS
Duration, y
Normal
24
Normal
34
Normal
1
chooses to postulate an indefinable metabolic deficiency and to consider these cases to be secondary to gastrointes¬ tinal tract involvement (which seems unlikely in the cases of myositis and transient ischemie attacks), there still remain 10 patients (20%), with two instances of simple myopathy, four of polymyositis, two of IBM, three of mononeuropathy, two of polyneuropathy, one of myelop¬ athy, and one of minor stroke, in whom the only possible risk factor was PSS itself. We therefore suggest direct ner¬ vous system involvement in a considerable number of pa¬ tients with PSS. The initial event in the pathogenesis of PSS is incom¬ pletely understood. Three pathways are proposed to take place in early stages of PSS1: (1) vascular abnormalities with changes in endothelial cells and basal lamina, (2) dysimmune reactions with both cell-mediated activity and autoantibody production, and (3) alterations of collagen metabolism with proliferation of specific fibroblast subpopulations, leading to fibroblast invasion into tissues and activation of collagen synthesis. The final step of all these is tissue fibrosis. Similarly, the damage to the nervous system in PSS could be the outcome of each of these mechanisms. (1) Ac¬ cording to the vascular mechanism, endothelial changes with subsequent microangiopathy of vasa nervorum may increase a tendency to platelet aggregation and cause tis¬ sue ischemia, accounting for peripheral neuropathy or cerebrovascular disease. (2) Although no clear evidence of a primary pathogenetic role of dysimmune alterations in PSS exists, there is indirect evidence in support of it. The concurrence of PSS with immune-mediated conditions, such as myasthenia gravis, polymyositis, insulindependent diabetes mellitus, and thyroiditis in our and other series,7 is suggestive of dysimmune mechanism, as are the histologie findings in our and other cases of inflammatory myositis, with perimysial and perivascular infiltrate of cells and macrophages.5,16 (3) By the entrap¬ ment mechanism, a fibrotic process may involve perineurium and epineurium, and thus produce pressure on pe¬ ripheral nerves, with resultant mononeuropathy. Moreover, there is at least one case report of symmetric sensorimotor polyneuropathy caused by entrapment of spinal nerve roots and peripheral nerves in fibrotic pro¬ cess, proved by postmortem examination.18 While most of our patients with polyneuropathy and myelopathy had evidence of gastrointestinal tract involvement, none of the
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three patients with mononeuropathy had any. Although no metabolic deficit was found, it gives rise to a question about some unidentifiable metabolic factor, the deficiency of which, caused by gastrointestinal tract involvement, is responsible for polyneuropathy and myelopathy, but not for mononeuropathy. For the latter, a different pathoge¬ netic mechanism is suggested, such as entrapment or
microangiopathy. The apparent rarity of central nervous system abnormal¬ ities in PSS may be attributed to its paucity of connective
tissue and to the lack of an external elastic lamina and sparseness of media and adventitia in cerebral arteries. Therefore, the fibrosis and entrapment mechanism can hardly be responsible for cerebral disease in PSS. Neverthe¬ less, vascular and dysimmune mechanisms may still pro¬ duce cerebral disease in the absence of systemic atheroscle¬ rosis or any vascular risk factors other than PSS itself. In conclusion, neurologic manifestations of PSS are much more frequent than have been previously considered and may involve all levels of the neuraxis. Direct involve¬ ment of the nervous system by a primary pathogenetic process may account for the neurologic presentations in a substantial number of patients.
study was supported in part by the Lena P. Harvey Endow¬ Neurological Research and in part by the Fannie R. Steinpress Research Endowment Fund in Neurology. This
ment Fund for
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