Clinical and Experimental Dermatology 1990; 15: 91-94.
Neurological complications of systemic sclerosis— a report of three cases and review of the literature J.BERTH-JONES, P.A.A.COATES, R.A.C.GRAHAM-BROWN AND D.A.BURNS Department of Dermatology, Leicester Royal Infirmary, Leicester LE 1 5WW, UK Accepted for publication 8 August 1989
Summary We report three cases of systemic sclerosis demonstrating four different neurological complications: trigeminal neuropathy, peripheral neuropathy, carpal-tunnel syndrome and prolonged response to local anaesthesia. A review of the literature reveals a wide range of neurological abnormalities associated with systemic sclerosis. When they occur, these are often presenting features. In view of the fact that systemic sclerosis has been considered by some to be primarily a disease of the autonomic nervous system,'"^ the neurological features have received surprisingly little attention. This is particularly true of the dermatological literature although systemic sclerosis is often managed by dermatologists. We suspect that neurological complications are not uncommon, and are often overlooked. We therefore report three cases of systemic sclerosis demonstrating four different neurological complications, and review the literature.
Case reports Case 1
A 36-year-old female patient presented to the Department of Neurology at the Leicester Royal Infirmary in 1984. She gave a 4-month history of pain and numbness in both hands; this was particulary severe at night. She was noted to have mild swelling of the hands. There was weakness of abduction of the thumbs. Surgery was performed bilaterally to decompress the carpal tunnels. This relieved the symptoms. Two years later she represented with Raynaud's phenomenon, thickened skin over the forearms, acrosclerosis, symptoms of reflux oesophagitis and mild Correspondence: Dr J.Berth-Jones, Department of Dermatology Leicester Royal Infirmary, Leicester LEI 5WW, UK.
dyspnoea, leading to a clinical diagnosis of systemic sclerosis. A barium swallow revealed decreased motility in the lower third of the oesophagus. Pulmonaryfunction tests were indicative of early pulmonary fibrosis. Normal or negative investigations included routine haematology and biochemistry, rheumatoid factor, antinuclear factor, antibodies to Ro and La, and extractable nuclear antigens. Eighteen months after the diagnosis of systemic sclerosis she developed weakness of the legs and painful dysaesthesia of the feet. Examination revealed weakness and wasting of the distal muscles of the lower limb, with absent ankle jerks. Pain and soft touch sensation were diminished distal to the mid-calf and over the finger-tips. Nerve conduction studies now showed the features of an axonal sensory neuropathy affecting principally the lower limbs. Both sural nerve action potentials showed prolonged latencies and reduced amplitudes but the conduction velocities were within the normal range. Histology of a sural nerve showed a reduction in the number of myelinated fibres of all diameters. There was no evidence of vasculitis or fibrosis affecting the segment of the nerve sampled. Plasma creatine kinase levels were normal. No evidence was found of any common cause of peripheral neuropathy such as diabetes mellitus, alcohol abuse, drug effect or vitamin deficiency. There were no symptoms suggestive of autonomic neuropathy, and variations in heart rate with respiration and with changes of posture were normal. Case 2
This patient, a 45-year-old Asian female, has suffered from Raynaud's phenomenon for 15 years and from asthma since childhood. In September 1986 she presented to the Department of Rheumatology at the Leicester Royal Infirmary with a 4month history of pain, numbness, tingling and weakness of grip in both hands. The pain often extended up to the elbow, it usually occurred after using the hands but also often woke her at night. Examination revealed slight 91
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weakness of grip but no wasting in the hands, and pattern, IgG), anti-RNP and anti-Sm were positive, and sensation appeared normal. Pressure or tapping over the anti-centromere, anti-double-stranded DNA antibodies carpal tunnel at either wrist reproduced her symptoms. and rheumatoid factor were not detectable. Blink reflex latencies evoked by supra-orbital nerve Nerve conduction studies demonstrated mild prolongation of motor terminal latency ofthe median nerves in both stimulation showed no definite Rl and R2 components hands. Bilateral carpal-tunnel decompressions were per- suggesting an afferent nerve defect on the right. A highformed in March 1987 with prompt relief of symptoms. intensity stimulus of 30-40 mA was required to elicit the In January 1987, during an emergency admission for reflex. treatment of asthma, slight swelling of the fingers was first noted, and 6 months later this had progressed to Discussion sclerodactyly. She subsequently developed changes of scleroderma involving all four limbs, face and trunk in a The three patients reported had clinical features which symmetrical pattern. were diagnostic of systemic sclerosis. In Case 3 there were Abnormal investigations included the anti-nuclear serological markers equally compatible with mixedfactor which has consistently been elevated at a titre connective-tissue disease but there were no clinical varying from 1:4000 to 1:256 (IgG, homogeneous findings to support this diagnosis. Both the presenting pattern). Pulmonary function tests demonstrated a features and her subsequent course were typical of reduced diffusing capacity for carbon monoxide suggest- systemic sclerosis. All three also demonstrated neurological problems. ing a degree of pulmonary fibrosis. Electrocardiograms showed right-axis deviation. Normal or negative investi- Case 1 developed carpal-tunnel syndrome as a presenting gations included antihodies to double-stranded DNA and feature of systemic sclerosis, although the latter diagnosis extractable nuclear antigen, rheumatoid factor, immuno- was not confirmed until 2 years later. This patient globulin levels, chest X-ray, barium swallow. X-rays of subsequently developed a sensorimotor peripheral neurothe hands and wrists, plasma viscosity, routine haemato- pathy. Case 2 also developed carpal-tunnel syndrome as a logy and biochemistry, creatinine clearance, urinalysis presenting feature of systemic sclerosis. Case 3 developed and serum creatine kinase levels. Variations in heart rate trigeminal neuropathy and also reported a prolonged response to local anaesthesia as presenting features of this with respiration and changes of posture were normal. disease. Altered sensation, with or without pain, in the distriCase 3 bution of the trigeminal nerve is the most frequently A 39-year-old female patient presented to the Depart- reported neurological manifestation of systemic scleroment of Neurology at the Leicester Royal Infirmary in sis,'''^ and is often a presenting feature.'*'''" There are April 1988 with a 3-year history of Raynaud's phenome- also reports of involvement of the sixth, seventh and non and progressive right-sided facial numbness develop- eighth cranial nerves.'"''^ The pathogenesis is somewhat controversial. Kabadi* ing over the preceding 10 months. Three weeks prior to the onset of this latter symptom, the patient had received suggested that thickening of the connective tissue sheath a local anaesthetic injection to the right upper jaw, the ofthe nerve may he responsible. Teasdall and colleagues'" suggested a combination of microangiopathy and fibrosis, effect of which had persisted for 24 h. Examination showed sclerodactyly, prominence ofthe whereas Thompson' suggested that a vasculitic process proximal nail-fold capillaries, pterygium inversum was most likely because the onset of trigeminal neurounguis, peri-oral furrowing, 'beaking' of the nose and pathy often appeared to be sudden. However, the telangiectasia over the cheeks and nose. In the nervous evolution of trigeminal neuropathy in our third case was system the only demonstrable abnormality was a reduc- clearly slow and progressive over several months. Peripheral neuropathy has now been reported on tion in pain and touch sensation over the second and third numerous occasions occurring in association with sysdivisions of the right trigeminal nerve. The sensory loss temic sclerosis.^'''*"'^ In the majority of cases this was a extended into the mouth but taste sensation was spared. Motor function of the fifth cranial nerve appeared presenting feature.'' '^ Most commonly the neuropathy unaffected, and the corneal reflex was preserved. There was of a mixed motor and sensory type predominantly was no evidence of autonomic neuropathy. Variations in involving the lower limbs, similar to that seen in our first heart rate with respiration and changes of posture were patient. The associated dysaesthesiae often appear to be painful.''•'** normal. In a case-control study, Christopher and Robinson^" Routine haematology, biochemistry, chest X-ray, and a barium swallow were normal. CT head scan showed no examined nerve conduction in 17 patients with systemic abnormality. Plasma viscosity was raised at 1-86 cp (1 5- sclerosis and 22 healthy controls. Ulnar, median-sensory 1-72), ANF was positive at a titre of 1:1000 (speckled and peroneal nerves all showed evidence of decreased
NEUROLOGICAL COMPLICATIONS OF SYSTEMIC SCLEROSIS conduction velocity in the patients. This abnormality was . present in both motor and sensory nerves. Little information is available concerning the aetiology of the neuropathy. In four of these cases, however,'**' ''•" histological examination of peripheral nerves was performed revealing increased collagen deposition in the epineurium and perineurium. Di Trapani" also noted vascular changes including thickening of the intima and adventitial oedema in the vasa nervorum. Carpal-tunnel syndrome'^'^'^^^ has previously heen reported as a feature in eight cases of systemic sclerosis. In seven of these, as in our cases, the diagnosis of carpaltunnel syndrome preceded that of systemic sclerosis. The median nerve compression may he due to oedema, arthritis or tenosynovitis. Meralgia paraesthetica^** has also heen reported. There are three previous reports of local anaesthetics having an abnormally prolonged action in systemic sclerosis.^'"^' Eisele and Reitan,^^ while evaluating sympathetic tone in the arm of a patient who had previously undergone sympathectomy for Raynaud's phenomenon, noticed that the action of a hrachial plexus block was unusually prolonged. Further investigation revealed that this phenomenon could be demonstrated even in clinically uninvolved abdominal skin. They ascribed their findings to impaired blood flow. In addition to the well-recognized overlap syndrome between systemic sclerosis and polymyositis,^** there would appear to be a distinct scleroderma myopathy,^"^ This is present in nearly all cases of systemic sclerosis if sought carefully, but is usually asymptomatic.•"*•'' The most sensitive investigation is electromyography.^''^^ Histologically, the most common change appears to be interstitial and peri-vascularfibrosis.^''Ultrastucture has been reported to show endothelial proliferation leading to narrowing or obliteration of the capillary lumen.^^ Impotence is a well-described association of systemic sclerosis''--''*"^' and may be a prominent complaint at presentation. In all reported cases impotence was due to erectile failure and libido was unaffected. Nowlin and colleagues^^ investigated ten patients with systemic sclerosis under their care and found that six of these suffered from impotence, suggesting that this complication is common but may only be elicited by direct questioning. Nowlin demonstrated reduced penile blood pressure in impotent patients compared to controls, supporting the hypothesis that this complaint was a result of vascular disease. Lally^'* in his description of five cases postulated that both vascular disease and autonomic neuropathy may be causal factors. Fibrosis of the corpora cavernosa was demonstrated in one case.^'' A case demonstrating clinical evidence of autonomic neuropathy has been described recently by Sonnex and colleagues.^^ These authors investigated a patient with systemic sclerosis who complained of diarrhoea, abdomi-
93
nal pain and fainting episodes and found pronounced postural hypotension. This patient also demonstrated a lack of normal variations in heart rate occurring with respiration and change of posture. They proceeded to investigate a further six patients with systemic sclerosis and found evidence of asymptomatic parasympathetic dysfunction in three of these. Perhaps the most unusual neurological complication of systemic sclerosis is subacute combined degeneration of the cord consequent upon gastrointestinal involvement and malabsorption of vitamin B12.^' Isolated reports also exist of systemic sclerosis in association with carotid arteritis and cerebral infarction,"*** myasthenia gravis,^'"*' migrane,**^ transverse myelopathy,'*'' multiple sclerosis,"*^ and steroid-responsive psychosis.**' It is difficult to evaluate the significance of these reports. Convulsions have been reported to occur in systemic sclerosis but the incidence seems unlikely to be higher than in the general population except in cases related to uraemia or hypertension.^•'•*''** A high incidence of nonspecific EEG abnormalities has been observed, but these seem to hold no diagnostic or prognostic value."*' It would appear that neurological complications of systemic sclerosis are not rare. Direct questioning and neurological examination are therefore important in the follow-up of patients with this condition. Since neurological features can develop early in the course of systemic sclerosis, this disease should always be considered in the differential diagnosis of trigeminal neuropathy, carpal-tunnel syndrome, peripheral neuropathy and impotence. In view of the paucity and often conflicting nature of information regarding the aetiology of these complications, every opportunity should be taken to investigate patients fully. This should include electrophysiological studies and histological examination of affected tissue whenever possible. Acknowledgment We wish to thank Dr Paul Millac, consultant in neurology at the Leicester Royal Infirmary for advice and for permission to report his patients. References 1, Rake G, On the pathology and pathogenesis of scleroderma. Bulletin of the Johns Hopkins Hospital 1931; 48: 212-227, 2, Ormea F, Sur la pathogenie neuro-vegetative de la maladie sclerodermique. Archives Beiges de Dermatologie et de Syphiligraphie 1959; 14: 423-432, 3, Lortat-Jacob JL, Giuli R, Estenne B, Duperrat B, Conte-Marti J, Arguments chiruricaux en faveur de I'origine nerveuse de la sclerodermie, Annates de Dermatologie et de Syphiligraphie 1974; 101: 121-134, 4, Beighton P, Gumpel JM, Cornes NGM, Prodromal trigeminal
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sensory neuropathy in progressive systemic sclerosis. Annals ofthe 26, Rheumatic Diseases 1968; 27: 367-369, 5, Gordon RM, Silverstein A, Neurologic manifestations in progres- 27, sive systemic sclerosis. Archives of Neurology 1970; 22: 126-134, 6, Ashworth B, Tait BGW, Trigeminal neuropathy in connective tissue disease. Neurology 1971; 21: 609-614, 7, Thompson PD, Robertson GJ, Trigeminal neuropathy heralding 28, scleroderma. Journal of the Maine Medical Association 1973; 64: 123-124, 8, Kabadi UM, Sinkoff MW, Trigeminal neuralgia in progressive 29, systemic sclerosis. Postgraduate Medicine 1977; 61: 176-177, 9, Burke MJ, Carty JE, Trigeminal neuropathy as the presenting symptom of systemic sclerosis. Postgraduate Medical Journal 30, 1979; 55: 423-42S, 10, Teasdall RD, Frayha RA, Shulman LE, Cranial nerve involvement in systemic sclerosis (scleroderma): a report often cases. 31, Medicine 1980; 59: 149-159, 11, Farrell DA, Medsger TA, Trigeminal neuropathy in progressive 32, systemic sclerosis, American Journal of Medicine 1982; 73: 57-62, 12, Lecky BRF, Hughes RAC, Murray NMF, Trigeminal sensory 33, neuropathy—a study of 22 cases. Brain 1987; 110: 1463-1485, 13, Rush JA, Isolated superior oblique paralysis in progressive systemic sclerosis. Annals of Ophthalmology 1981; 13: IXl-llQ. 14, Richter RB, Peripheral neuropathy and connective disease. 34, Journal of Neuropathology and Experimental Neurology 1954; 13: 35, 168-180, 15, Kibler RF, Clifford Rose F, Peripheral neuropathy in the "collagen diseases" a case of scleroderma neuropathy, British 36, Medical Journal 1960; 1: 1781-1784, 16, Hagberg B, Leonhardt T, Skogh M. Familial occurrence of collagen diseases, 1, Progressive systemic sclerosis and systemic 37, lupus erythematosus, Acta Medica Scandinavica 1961; 169: 727734. 17, Di Trapani G, TuUi A, La Cara A, Laurienzo P, Mazza S, David 38, P, Peripheral neuropathy in course of progressive systemic sclerosis, Acta Neuropathologica 1986; 72: 103-110, 18, RuDusky BM, Neurologic manifestations of collagen disease: a 39, report of four cases, Pennsylvania Medical Journal 1964; 67: 40, 30-34, 19, Sukenik S, Abarbanel JM, Buskila D, Potashnik G, Horowitz J. Impotence, carpal tunnel syndrome and peripheral neuropathy as 41, presenting symptoms in progressive systemic sclerosis, _7oHrnfl/ of Rheumatology 1987; 14: 641-643, 20, Christopher RP, Robinson H, Studies of nerve conduction in 42, patients with scleroderma. Southern Medical Journal 1972; 65: 668-672, 21, Quinones CA, Perry HO, Rushton JG, Carpal tunnel syndrome in 43, dermatomyositis and scleroderma. Archives of Dermatology 1966; 44, 94: 20-25, 22, Lee P, Bruni J, Sukenik S, Neurological manifestations in systemic sclerosis (scleroderma). Journal of Rheumatology 1984; 11:480-483, 45, 23, Barr WG, Blair SJ, Carpal tunnel syndrome as the initial manifestation of scleroderma,_7o«''«fl/o///a«'^'5'M''g^^O' 1988; 13A; 378-380, 46, 24, Kaufmann J, Canoso JJ, Progressive systemic sclerosis and meralgia paraesthetica. Annals of Internal Medicine 1986; 105: 47, 973, 25, Eisele JH, Reitan JA, Scleroderma, Raynaud's phenomenon and local anesthetics, Anesthesiology 1971; 34: 386-387,
Lewis GBH, Prolonged regional analgesia in scleroderma, Canadian Anaesthetists Society Journal 1974; 21: 495-497, Neill RS, Progressive systemic sclerosis: prolonged sensory blockade following regional anaesthesia in association with a reduced response to systemic analgesics, British Journal of Anaesthesia 1980; 52: 623-625, Bohan A, Peter JB, Bowman RL, Pearson CM, A computer assisted analysis of 153 patients with polymyositis and dermatomyositis. Medicine 1977; 56: 255-286, Medsger TA, Rodnan GP, Moossy J, Vester JW. Skeletal muscle involvement in progressive systemic sclerosis (scleroderma). Arthritis and Rheumatism 1968; 11: 554-568, Clements PJ, Furst DE, Campion DS et al. Muscle disease in progressive systemic sclerosis. Diagnostic and therapeutic considerations. Arthritis and Rheumatism 1978; 21: bl-lX. Hausmanowa-Petrusewicz I, Kozminska A, Electromyographic findings in scleroderma. Archives of Neurology 1961; 4: 281-287, Hausmanowa-Petrusewicz I, Jablonska S, Blaszczyk M, Matz B. Electromyographic findings in various forms of progressive systemic sclerosis. Arthritis and Rheumatism 1982; 25: 61-65, Michalowski R, Kudejko J, Electron microscopic observations on skeletal muscle in diffuse scleroderma, British Journal ofDermatology 1966; 78: 24-28, Lally EV, Jimenez SA, Impotence in progressive systemic sclerosis. Annals of Internal Medicine 1981; 95: 150-153, Klein LE, Posner MS, Progressive systemic sclerosis and impotence. Annals of Internal Medicine 1981; 95: 658-659, Nowlin NS, Brick JE, Weaver DJ, Wilson DA, Judd HL, Lu JKH, Carlson HE, Impotence in scleroderma. Annals of Internal Medicine 1986; 104: 794-798, Sukenik S, Horowitz J, Buskila D, Abarbanel JM, Lismer L, Avinoach 1, Impotence in systemic sclerosis. Annals of Internal Medicine 1987; 106:910-911. Sonnex C, Paice E, White AG, Autonomic neuropathy in systemic sclerosis: a case report and evaluation of six patients. Annals of the Rheumatic Diseases 1986; 45: 957-960, Bierregaard B, Hojgaard K, Neurological symptoms in scleroderma. Archives of Dermatology 1976; 112: 1030-1031, Lee JE, Haynes JM, Carotid arteritis and cerebral infarction due to scleroderma. Neurology 1967; 17: 18-22, Mitchell GW, Lichtenfeld PJ, McDonald CJ, Myasthenia gravis and scleroderma. Journal of the American Medical Association 1975; 233: 531, Goldberg NC, Duncan SC, Winkelmann RK, Migraine and systemic scleroderma. Archives of Dermatology 1978; 114: 550— 551, Brown JJ, Murphy MJ, Transverse myelopathy in progressive systemic sclerosis. Annals of Neurology 1985; 17: 615-617, Trostle DC, Helfrich D, Medsger TA, Systemic sclerosis (scleroderma) and multiple sclerosis. Arthritis and Rheumatism 1986; 29: 124-127, Wise TN, Ginzler EM, Scleroderma cerebritis, an unusual manifestation of progressive systemic sclerosis. Diseases of the Nervous System 1975; 36: 60-62, Tuffanelli DL, Winkelmann RK, Systemic scleroderma: a clinical study oilll cases. Archives of Dermatology 1961; 84: 359-371, Sfava Z, Stein J, Electro-encephalography in scleroderma, Dermatologica 1961; 123: 375-390,
Neurological complications of systemic sclerosis— a report of three cases and review of the literature J.BERTH-JONES, P.A.A.COATES, R.A.C.GRAHAM-BROWN AND D.A.BURNS Department of Dermatology, Leicester Royal Infirmary, Leicester LE 1 5WW, UK Accepted for publication 8 August 1989
Summary We report three cases of systemic sclerosis demonstrating four different neurological complications: trigeminal neuropathy, peripheral neuropathy, carpal-tunnel syndrome and prolonged response to local anaesthesia. A review of the literature reveals a wide range of neurological abnormalities associated with systemic sclerosis. When they occur, these are often presenting features. In view of the fact that systemic sclerosis has been considered by some to be primarily a disease of the autonomic nervous system,'"^ the neurological features have received surprisingly little attention. This is particularly true of the dermatological literature although systemic sclerosis is often managed by dermatologists. We suspect that neurological complications are not uncommon, and are often overlooked. We therefore report three cases of systemic sclerosis demonstrating four different neurological complications, and review the literature.
Case reports Case 1
A 36-year-old female patient presented to the Department of Neurology at the Leicester Royal Infirmary in 1984. She gave a 4-month history of pain and numbness in both hands; this was particulary severe at night. She was noted to have mild swelling of the hands. There was weakness of abduction of the thumbs. Surgery was performed bilaterally to decompress the carpal tunnels. This relieved the symptoms. Two years later she represented with Raynaud's phenomenon, thickened skin over the forearms, acrosclerosis, symptoms of reflux oesophagitis and mild Correspondence: Dr J.Berth-Jones, Department of Dermatology Leicester Royal Infirmary, Leicester LEI 5WW, UK.
dyspnoea, leading to a clinical diagnosis of systemic sclerosis. A barium swallow revealed decreased motility in the lower third of the oesophagus. Pulmonaryfunction tests were indicative of early pulmonary fibrosis. Normal or negative investigations included routine haematology and biochemistry, rheumatoid factor, antinuclear factor, antibodies to Ro and La, and extractable nuclear antigens. Eighteen months after the diagnosis of systemic sclerosis she developed weakness of the legs and painful dysaesthesia of the feet. Examination revealed weakness and wasting of the distal muscles of the lower limb, with absent ankle jerks. Pain and soft touch sensation were diminished distal to the mid-calf and over the finger-tips. Nerve conduction studies now showed the features of an axonal sensory neuropathy affecting principally the lower limbs. Both sural nerve action potentials showed prolonged latencies and reduced amplitudes but the conduction velocities were within the normal range. Histology of a sural nerve showed a reduction in the number of myelinated fibres of all diameters. There was no evidence of vasculitis or fibrosis affecting the segment of the nerve sampled. Plasma creatine kinase levels were normal. No evidence was found of any common cause of peripheral neuropathy such as diabetes mellitus, alcohol abuse, drug effect or vitamin deficiency. There were no symptoms suggestive of autonomic neuropathy, and variations in heart rate with respiration and with changes of posture were normal. Case 2
This patient, a 45-year-old Asian female, has suffered from Raynaud's phenomenon for 15 years and from asthma since childhood. In September 1986 she presented to the Department of Rheumatology at the Leicester Royal Infirmary with a 4month history of pain, numbness, tingling and weakness of grip in both hands. The pain often extended up to the elbow, it usually occurred after using the hands but also often woke her at night. Examination revealed slight 91
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weakness of grip but no wasting in the hands, and pattern, IgG), anti-RNP and anti-Sm were positive, and sensation appeared normal. Pressure or tapping over the anti-centromere, anti-double-stranded DNA antibodies carpal tunnel at either wrist reproduced her symptoms. and rheumatoid factor were not detectable. Blink reflex latencies evoked by supra-orbital nerve Nerve conduction studies demonstrated mild prolongation of motor terminal latency ofthe median nerves in both stimulation showed no definite Rl and R2 components hands. Bilateral carpal-tunnel decompressions were per- suggesting an afferent nerve defect on the right. A highformed in March 1987 with prompt relief of symptoms. intensity stimulus of 30-40 mA was required to elicit the In January 1987, during an emergency admission for reflex. treatment of asthma, slight swelling of the fingers was first noted, and 6 months later this had progressed to Discussion sclerodactyly. She subsequently developed changes of scleroderma involving all four limbs, face and trunk in a The three patients reported had clinical features which symmetrical pattern. were diagnostic of systemic sclerosis. In Case 3 there were Abnormal investigations included the anti-nuclear serological markers equally compatible with mixedfactor which has consistently been elevated at a titre connective-tissue disease but there were no clinical varying from 1:4000 to 1:256 (IgG, homogeneous findings to support this diagnosis. Both the presenting pattern). Pulmonary function tests demonstrated a features and her subsequent course were typical of reduced diffusing capacity for carbon monoxide suggest- systemic sclerosis. All three also demonstrated neurological problems. ing a degree of pulmonary fibrosis. Electrocardiograms showed right-axis deviation. Normal or negative investi- Case 1 developed carpal-tunnel syndrome as a presenting gations included antihodies to double-stranded DNA and feature of systemic sclerosis, although the latter diagnosis extractable nuclear antigen, rheumatoid factor, immuno- was not confirmed until 2 years later. This patient globulin levels, chest X-ray, barium swallow. X-rays of subsequently developed a sensorimotor peripheral neurothe hands and wrists, plasma viscosity, routine haemato- pathy. Case 2 also developed carpal-tunnel syndrome as a logy and biochemistry, creatinine clearance, urinalysis presenting feature of systemic sclerosis. Case 3 developed and serum creatine kinase levels. Variations in heart rate trigeminal neuropathy and also reported a prolonged response to local anaesthesia as presenting features of this with respiration and changes of posture were normal. disease. Altered sensation, with or without pain, in the distriCase 3 bution of the trigeminal nerve is the most frequently A 39-year-old female patient presented to the Depart- reported neurological manifestation of systemic scleroment of Neurology at the Leicester Royal Infirmary in sis,'''^ and is often a presenting feature.'*'''" There are April 1988 with a 3-year history of Raynaud's phenome- also reports of involvement of the sixth, seventh and non and progressive right-sided facial numbness develop- eighth cranial nerves.'"''^ The pathogenesis is somewhat controversial. Kabadi* ing over the preceding 10 months. Three weeks prior to the onset of this latter symptom, the patient had received suggested that thickening of the connective tissue sheath a local anaesthetic injection to the right upper jaw, the ofthe nerve may he responsible. Teasdall and colleagues'" suggested a combination of microangiopathy and fibrosis, effect of which had persisted for 24 h. Examination showed sclerodactyly, prominence ofthe whereas Thompson' suggested that a vasculitic process proximal nail-fold capillaries, pterygium inversum was most likely because the onset of trigeminal neurounguis, peri-oral furrowing, 'beaking' of the nose and pathy often appeared to be sudden. However, the telangiectasia over the cheeks and nose. In the nervous evolution of trigeminal neuropathy in our third case was system the only demonstrable abnormality was a reduc- clearly slow and progressive over several months. Peripheral neuropathy has now been reported on tion in pain and touch sensation over the second and third numerous occasions occurring in association with sysdivisions of the right trigeminal nerve. The sensory loss temic sclerosis.^'''*"'^ In the majority of cases this was a extended into the mouth but taste sensation was spared. Motor function of the fifth cranial nerve appeared presenting feature.'' '^ Most commonly the neuropathy unaffected, and the corneal reflex was preserved. There was of a mixed motor and sensory type predominantly was no evidence of autonomic neuropathy. Variations in involving the lower limbs, similar to that seen in our first heart rate with respiration and changes of posture were patient. The associated dysaesthesiae often appear to be painful.''•'** normal. In a case-control study, Christopher and Robinson^" Routine haematology, biochemistry, chest X-ray, and a barium swallow were normal. CT head scan showed no examined nerve conduction in 17 patients with systemic abnormality. Plasma viscosity was raised at 1-86 cp (1 5- sclerosis and 22 healthy controls. Ulnar, median-sensory 1-72), ANF was positive at a titre of 1:1000 (speckled and peroneal nerves all showed evidence of decreased
NEUROLOGICAL COMPLICATIONS OF SYSTEMIC SCLEROSIS conduction velocity in the patients. This abnormality was . present in both motor and sensory nerves. Little information is available concerning the aetiology of the neuropathy. In four of these cases, however,'**' ''•" histological examination of peripheral nerves was performed revealing increased collagen deposition in the epineurium and perineurium. Di Trapani" also noted vascular changes including thickening of the intima and adventitial oedema in the vasa nervorum. Carpal-tunnel syndrome'^'^'^^^ has previously heen reported as a feature in eight cases of systemic sclerosis. In seven of these, as in our cases, the diagnosis of carpaltunnel syndrome preceded that of systemic sclerosis. The median nerve compression may he due to oedema, arthritis or tenosynovitis. Meralgia paraesthetica^** has also heen reported. There are three previous reports of local anaesthetics having an abnormally prolonged action in systemic sclerosis.^'"^' Eisele and Reitan,^^ while evaluating sympathetic tone in the arm of a patient who had previously undergone sympathectomy for Raynaud's phenomenon, noticed that the action of a hrachial plexus block was unusually prolonged. Further investigation revealed that this phenomenon could be demonstrated even in clinically uninvolved abdominal skin. They ascribed their findings to impaired blood flow. In addition to the well-recognized overlap syndrome between systemic sclerosis and polymyositis,^** there would appear to be a distinct scleroderma myopathy,^"^ This is present in nearly all cases of systemic sclerosis if sought carefully, but is usually asymptomatic.•"*•'' The most sensitive investigation is electromyography.^''^^ Histologically, the most common change appears to be interstitial and peri-vascularfibrosis.^''Ultrastucture has been reported to show endothelial proliferation leading to narrowing or obliteration of the capillary lumen.^^ Impotence is a well-described association of systemic sclerosis''--''*"^' and may be a prominent complaint at presentation. In all reported cases impotence was due to erectile failure and libido was unaffected. Nowlin and colleagues^^ investigated ten patients with systemic sclerosis under their care and found that six of these suffered from impotence, suggesting that this complication is common but may only be elicited by direct questioning. Nowlin demonstrated reduced penile blood pressure in impotent patients compared to controls, supporting the hypothesis that this complaint was a result of vascular disease. Lally^'* in his description of five cases postulated that both vascular disease and autonomic neuropathy may be causal factors. Fibrosis of the corpora cavernosa was demonstrated in one case.^'' A case demonstrating clinical evidence of autonomic neuropathy has been described recently by Sonnex and colleagues.^^ These authors investigated a patient with systemic sclerosis who complained of diarrhoea, abdomi-
93
nal pain and fainting episodes and found pronounced postural hypotension. This patient also demonstrated a lack of normal variations in heart rate occurring with respiration and change of posture. They proceeded to investigate a further six patients with systemic sclerosis and found evidence of asymptomatic parasympathetic dysfunction in three of these. Perhaps the most unusual neurological complication of systemic sclerosis is subacute combined degeneration of the cord consequent upon gastrointestinal involvement and malabsorption of vitamin B12.^' Isolated reports also exist of systemic sclerosis in association with carotid arteritis and cerebral infarction,"*** myasthenia gravis,^'"*' migrane,**^ transverse myelopathy,'*'' multiple sclerosis,"*^ and steroid-responsive psychosis.**' It is difficult to evaluate the significance of these reports. Convulsions have been reported to occur in systemic sclerosis but the incidence seems unlikely to be higher than in the general population except in cases related to uraemia or hypertension.^•'•*''** A high incidence of nonspecific EEG abnormalities has been observed, but these seem to hold no diagnostic or prognostic value."*' It would appear that neurological complications of systemic sclerosis are not rare. Direct questioning and neurological examination are therefore important in the follow-up of patients with this condition. Since neurological features can develop early in the course of systemic sclerosis, this disease should always be considered in the differential diagnosis of trigeminal neuropathy, carpal-tunnel syndrome, peripheral neuropathy and impotence. In view of the paucity and often conflicting nature of information regarding the aetiology of these complications, every opportunity should be taken to investigate patients fully. This should include electrophysiological studies and histological examination of affected tissue whenever possible. Acknowledgment We wish to thank Dr Paul Millac, consultant in neurology at the Leicester Royal Infirmary for advice and for permission to report his patients. References 1, Rake G, On the pathology and pathogenesis of scleroderma. Bulletin of the Johns Hopkins Hospital 1931; 48: 212-227, 2, Ormea F, Sur la pathogenie neuro-vegetative de la maladie sclerodermique. Archives Beiges de Dermatologie et de Syphiligraphie 1959; 14: 423-432, 3, Lortat-Jacob JL, Giuli R, Estenne B, Duperrat B, Conte-Marti J, Arguments chiruricaux en faveur de I'origine nerveuse de la sclerodermie, Annates de Dermatologie et de Syphiligraphie 1974; 101: 121-134, 4, Beighton P, Gumpel JM, Cornes NGM, Prodromal trigeminal
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