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Primary Sjögren's syndrome presenting as autonomic neuropathy
Netherlands Journal of Medicine 53 Ž1998. 196–200
Brief report
Primary Sjogren’s syndrome presenting as autonomic neuropathy ¨ Case report P.J. Barendregt a
a,)
, H.M. Markusse a , A.J. Man In ’t Veld
b
Department of Rheumatology, Zuiderziekenhuis, Groene Hilledijk 315, 3075 AE Rotterdam, The Netherlands b Department of Internal Medicine I, UniÕersity Hospital Rotterdam–Dijkzigt, Rotterdam, The Netherlands Received 9 February 1998; revised 26 May 1998; accepted 2 June 1998
Abstract Abnormalities of the autonomic nervous system have been described in several connective tissue diseases, but the relation with primary Sjogren’s syndrome is unclear. This report describes a patient with primary Sjogren’s syndrome who presented ¨ ¨ with severe autonomic failure. The present knowledge on dysfunction of the autonomic nervous system in primary Sjogren’s ¨ syndrome and other connective tissue diseases is shortly reviewed. q 1998 Elsevier Science B.V. All rights reserved. Keywords: Sjogren’s syndrome; Autonomic nervous system; Neuropathy ¨
1. Introduction Subclinical autonomic dysfunction has been described in association with a number of connective tissue diseases, including rheumatoid arthritis ŽRA., systemic lupus erythematosus ŽSLE. and systemic sclerosis. However, symptomatic autonomic failure in these diseases is rare w1–5x. The occurrence of central and peripheral neurological disease in priŽSS. syndrome is well known w6–8x. mary Sjogren’s ¨ Abnormalities of the autonomic nervous system in primary SS have rarely been reported and are mostly concerning case reports w9–11x. Recently, a study of 19 patients with primary SS showed evidence for parasympathetic dysfunction w12x. We present a pa-
)
Corresponding author. Tel.: q31-10-2903000.
tient with severe autonomic failure as the first manifestation of the primary SS. This finding highlights the need to further investigate the autonomic nervous system in primary SS.
2. Case report In 1974 a 34-year old woman presented for the first time with complaints of headache, fatigue, palpitations, dizziness, collapse, nausea and vomiting. When visiting the outpatients clinic at that time, a variable arterial blood pressure was found, reaching a value of 170r120 mmHg in horizontal position and a value of 100r60 mmHg after a rest period of 15 min. At neurological examination, a fixed dilatation of the left pupil with an absent response to light was found, on which the diagnosis Adie’s pupil was made. At this first examination laboratory parameters
0300-2977r98r$ - see front matter q 1998 Elsevier Science B.V. All rights reserved. PII: S 0 3 0 0 - 2 9 7 7 Ž 9 8 . 0 0 0 8 0 - 1
P.J. Barendregt et al.r Netherlands Journal of Medicine 53 (1998) 196–200
revealed an ESR of 65 mm in the first hour and a hypergammaglobulinemia of 47 grl Žnormal 8–18 grl.. Since 1982 she also complained of severe fatigue and intermittent joint en muscle pains. Physical examination of joints and muscle was unremarkable. In 1983 positive rheumatoid factors were found. At this time an ESR of 94 mmrh and a gammaglobulin of 50 grl were measured. Radiological examination of hands and feet was normal. Treatment with nonsteroidal-anti-inflammatory-drugs was started. In 1986 the patient started to complain about oral and ocular dryness. An abnormal Schirmer test was found Ž- 10 mm wetting of a paper strip, 5 min after placement in the lower eyelids.. Antinuclear antibodies ŽANA., as well as SS-A ŽSjogren’s Syndrome A. ¨ and SS-B ŽSjogren’s Syndrome B. antibodies were ¨ detected in the serum and in a salivary gland biopsy from the lower lip more than 2 foci of more than 50 lymphocytesr4 mm2 gland tissue were found, which is compatible with the diagnosis primary Sjogren’s ¨ syndrome. At this time, the diagnosis primary SS was made and tear and saliva substitution were successfully prescribed. Because of severe general malaise and arthralgias the patient was treated with 10 mg prednisone daily. In 1989 the patient was hospitalized because of severe, watery diarrhoea with a weight loss of 5 kg and dizzyness. Orthostatic challenge tests were used to evaluate the autonomic nervous system. In horizontal position a low blood pressure of 99r53 mmHg was found Žmean arterial pressure 70 mmHg, heart rate 63 bpm., which dropped to 65r35 mmHg Žmean arterial pressure 46 mmHg, heart rate 76 bpm. 10 min after tilt. In supine position a low value of noradrenaline was found Ž73 pgrml Žnormal 159 " 109.., but values of adrenaline and dopamine were in the normal range. Examination by a neurologist showed signs of a sensory neuropathy Žabsent knee and achilles tendon jerks and diminished sensibility of the lower legs. and an Adie’s pupil of the left eye. Rontgenography, stool examination, duodenoscopy ¨ and coloscopy with histological examination of the gastrointestinal tract did not show any abnormalities and both the diarrhoea and the dizzyness were ascribed to autonomic failure. The diarrhoea was successfully treated with loperamide Ž2 mg twice a day..
197
Symptomatic treatment of the orthostasis was also adequate Žoral salt and elastic stockings.. For the next five years the patient was followed on the outpatients clinic. At this time a stable situation was reached and there was no need to prescribe specific medication. In 1995 a complete physical, neurological and cardiovascular examination was performed. At the time of examination the patient complained about dry eyes, a dry mouth, myalgia, Raynaud’s phenomenon, arthralgia and fatigue. She also complained about headaches, palpitations, postural dizziness and diarrhoea. Physical examination revealed no signs of arthritis, but we found a skin rash on the lower legs, therefore suggesting vasculitis. Neurological and electromyographic examination showed evidence for a sensory neuropathy. Specific cardiovascular function tests were also performed. The patient showed an abnormal heart rate response on both the Valsalva manoeuvre and during deep breathing, suggesting parasympathetic dysfunction. For the Valsalva manoeuvre, the patient was asked to blow into a mouthpiece attached to an aneroid pressure gauge at a pressure of 40 mmHg for 15 sec. The ratio of the longest interbeat interval shortly after ending the manoeuvre to the shortest interbeat interval during the manoeuvre was mea-
Table 1 Results of the orthostatic challenge test
R1 R2 M1 T1 T2 M2 R3 R4
BP Žsys.
BP Ždias.
BP Žmean.
heartrate
97 96 131 102 118 117 128 125
47 46 75 58 71 68 75 70
64 62 94 73 87 84 93 88
65 64 67 71 75 71 79 73
BP in mmHg. heartrate in beatsrmin. R1s first period of 5 min supine rest. R2 s second period of 5 min supine rest. M1s fixed respiration frequency during supine rest. T1s first period of 5 min of 60 degree tilt. T2 s second period of 5 min of 60 degree tilt. M2 s fixed respiration frequency during 60 degree tilt. R3s third period of 5 min supine rest. R4 s fourth period of 5 min supine rest.
198
P.J. Barendregt et al.r Netherlands Journal of Medicine 53 (1998) 196–200
sured and expressed as the Valsalva ratio: 1.13 Žnormal value G 1.21, according to Ewing w13x.. For the deep breathing test, we asked the patient to breathe deeply and evenly at six breaths per min Ž5 sec in and 5 sec out.. The maximum and minimum heartrate during each 10-sec breathing cycle were measured and the mean of the differences during three successive breathing cycles was calculated as the ‘maximum-minimum heartrate’: 4.7 beatsrmin Žnormal value according to Ewing: G 15 beatsrmin.. The results of the orthostatic challenge test Žas a measure of sympathetic function. are listed in Table 1. This test was performed by means of a tilt table on which the patient was lying. Blood pressure and heartrate were measured during supine position and during 608 tilt. Orthostatic hypotension can be defined as a fall in systolic blood pressure of 20 mmHg or more, as we see during the first five minutes of tilt. During this orthostatic tests, blood samples were taken during supine rest and tilt for the determination of plasma catecholamines. The results of the catecholamines are shown in Table 2. During supine rest, a low value of noradrenaline was found. However, a normal increase of all catecholamines was found in response to tilt. In 1997 the patient complained about progressive dizziness, sometimes attended with collapses, especially after rising from the bed in the morning or during long periods in the standing position. At this time a severe orthostasis was found: blood pressure in supine position 200r120 mmHg and during standing up 150r110 mmHg. The orthostatic symptoms disappeared after she was treated with oral salt and fludrocortisone and there was no intervention with the co-existing hypertension Žafter treatment blood pressure in supine position 160r115, during standing up 155r105.. Table 2 Results of plasma catecholamines during orthostatic challenge testing
Noradrenaline Žpgrml. Adrenaline Žpgrml. Dopamine Žpgrml.
Supine rest Žnl.value.
Tilt
159 Ž261"109. 43 Ž25"2. 7 Ž13"8.
285 73 8
Normal values during supine rest were obtained from a normotensive, matched population Žstored in a database..
3. Discussion The patient described suffered from a severe autonomic failure, characterized by dizzyness due to orthostatic hypotension, fatigue, diarrhoea and low concentrations of plasma catecholamines as well as a sensory neuropathy and an Adie’s pupil on the left side. She also suffered from primary SS characterized by oral and ocular dryness, decreased tear production, focal sialadenitis of the lower lip Žabnormal salivary gland biopsy. and laboratory abnormalities including strongly positive serum tests of antinuclear antibodies, rheumatoid factor as well as SS-A and SS-B antibodies. Acquired autonomic neuropathy is most commonly found in diabetes mellitus, renal failure, amyloid, thiamine deficiency and neoplastic disease w14x. In this patient none of these causes were identified, but the criteria used for the classification of primary SS, including the recently developed European criteria, were fulfilled w15,16x. The long delay before the diagnosis primary SS was made illustrates that the diagnosis primary SS may be easily overlooked. Since oral and ocular dryness are common complaints of patients with autonomic failure, it may be hypothesized that especially in patients with symptomatic autonomic failure the diagnosis of concurrent primary SS is also easily missed. Recently a similar case of orthostatic hypotension and parasympathetic failure in a patient with primary SS was reported w9x. Another case of autonomic failure Žoral and ocular dryness, decreased gastrointestinal motility, atony of the bladder and taste and sweating disturbances. in a patient with a possible primary SS has been described w10x. Mc Combe et al. w17x described a patient with possibly primary SS and autonomic neuropathy in whom high doses of corticosteroids were temporarily beneficial which suggests an inflammatory cause. The occurrence of Adie’s pupils in primary SS with or without orthostatic hypotension has also been described w18,19x. We found one abstract comprising five patients with primary SS in which the following autonomic dysfunctions were described: orthostatic hypotension and Adie’s pupils in two, pupillary abnormalities in three, cardiac parasympathetic abnormalities in four and patchy anhidrosis in five w11x.
P.J. Barendregt et al.r Netherlands Journal of Medicine 53 (1998) 196–200
Recently, a systematic study on the autonomic nervous system in primary SS was done w12x. In this study, performed on 19 patients, the autonomic nervous system was evaluated by doing tilt- and deepbreathing tests. The investigators did find evidence for parasympathetic disturbances in this patient group. There is documentation of autonomic dysfunction in several other connective tissue diseases, mostly concerning subclinical parasympathetic disturbances in all these conditions. In RA abnormal cardiovascular reflexes were found in 33–60% of the patients w1,2,20x, but obvious clinical signs Žorthostatic hypotensionrabnormal sweat secretion. were only mentioned in four out of nine RA patients with cardiovascular abnormalities w20x. In SLE at least one abnormal cardiovascular reflex test was found in 15 out of 17 patients tested, and severe orthostatis was found in only one w3x. Recently in systemic sclerosis autonomic neuropathy was found to be extremely common. Cardiovascular reflex tests and plasma catecholamine measurements pointed at parasympathetic impairment w4,5x. The pathogenesis of autonomic neuropathy in connective tissue diseases has not been elucidated, but an immunological mechanism may be responsible. Experimental allergic neuritis has been given as a model of both polyneuropathy and autonomic dysfunction. In diabetes mellitus, auto-antibodies to sympathetic and parasympathetic tissue have been detected w21–23x. Lymphocytic infiltration and neural destruction of dorsal ganglia may be important in the etiology of this neuropathy w22,23x. Furthermore the beneficial effects of immunosuppressive treatment early in the course of autonomic dysfunction in patients with connective tissue disorders also suggest the presence of an autoimmune inflammatory reaction in these patients w17,24x. Primary SS may present with many different features. Considering the occurrence of autonomic neuropathy in other connective tissue diseases, the few reports on abnormalities of the autonomic nervous system in patients with Žpossible. primary SS, as well as the patient described here, we believe autonomic dysfunction should be added to the list of extra-glandular manifestations of primary SS. A study in a larger patient group could be useful to investigate the clinical importance of autonomic nervous
199
system dysfunction in primary SS and to explore a possible relationship with oral and ocular dryness.
References w1x Leden I, Eriksson A, Lilja B, Sturfelt G, Sundkvist G. Autonomic nerve function in rheumatoid arthritis of varying severity. Scand J Rheumatol 1983;12:166–170. w2x Toussirot E, Serratrice G, Valentin P. Autonomic nervous system involvement in rheumatoid arthritis. 50 cases. J Rheumatol 1993;20:1508–1514. w3x Liote´ F, Osterland CK. Autonomic neuropathy in systemic lupus erythematosus: cardiovascular autonomic function assessment. Ann Rheum Dis 1994;53:671–674. w4x Dessein PH, Joffe BI, Metz RM, Millar DL, Lawson M, Stanwix AE. Autonomic dysfunction in systemic sclerosis: sympathetic overactivity and instability. Am J Med 1992;93:143–150. w5x Hermosillo AG, Ortiz R, Dabague J, Casanova JM, Martinez Lavin M. Autonomic dysfunction in diffuse scleroderma vs crest: an assessment by computerized heart rate variability. J Rheumatol 1994;21Ž10.:1849–1854. w6x Alexander GE, Provost TT, Stevens MB, Alexander EL. Sjogren’s syndrome: Central nervous system manifestations. ¨ Neurology 1981;31:1391–1396. w7x Andonopoulos AP, Lagos G, Drosos AA, Moutsopoulos HM. The spectrum of neurological involvement in Sjogren’s syn¨ drome. Br J Rheumatol 1990;29:21–23. w8x Mellgren SI, Conn DL, Stevens JC, Dyck PJ. Peripheral neuropathy in primary Sjogren’s syndrome. Neurology ¨ 1989;39:390–394. w9x Andonopoulos AP, Ballas C. Autonomic cardiovascular neuropathy in primary Sjogren’s syndrome. Rheumatol Int ¨ 1995;15:127–129. w10x Takayama H, Kazahaya Y, Kashihara N, et al. A case of postganglionic cholinergic dysautonomia. J Neurol Neurosurg Psych 1987;50:915–918. w11x Low PA, Mertz LE, Auger RG, et al. The autonomic neuropathies in Sjogren’s syndrome. Neurol 1988;38Žsuppl 1.:26. ¨ w12x Mandl T, Jacobsson L, Sundkvist G, Manthorpe R. Disturbances of autonomic nervous system in primary Sjogren’s ¨ syndrome. Scand J Rheumatol 1997;26:253–258. w13x Ewing DJ, Clarke BF. Autonomic neuropathy: its diagnosis and prognosis. Clin Endocr Metab 1986;15Ž4.:855–888. w14x Low PA In: Clinical autonomic disorders. Evaluation and Management. First Edition. Little, Brown and Company, Boston, Toronto, London, 396. w15x Prause JU, Manthorpe R, Oxholm P, Schmidt M. Definition and criteria for Sjogren’s syndrome used by the contributors ¨ to the First International Seminar on Sjogren’s syndrome. ¨ Scand J Rheumatol 1986;61Žsuppl..:17–18. w16x Vitali C, Bombardieri S, Moutsopoulos HM, et al. Preliminary criteria for the classification of Sjogren’s syndrome. ¨ Arthritis Rheum 1993;36:340–347.
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w17x Mc Combe PA, Sheehan GL, Mc Laughlin DB, Pender MP. Vestibular and ventilatory dysfunction in sensory and autonomic neuropathy associated with primary Sjogren’s syn¨ drome. J Neurol Neurosurg Psych 1992;55Ž12.:1211–1212. w18x Kennett RP, Harding AE. Peripheral neuropathy associated with the sicca syndrome. J Neurol Neurosurg Psychiatry 1986;49:90–92. w19x Gemignary F, Manganelli P, Pavesi G, Marbini A. Polyneuropathy in Sjogren’s syndrome. A case of prevalently auto¨ nomic neuropathy with tonic pupil and hypohidrosis. Funct Neurol 1988;3:337–348. w20x Edmonds ME, Jones TC, Saunders WA, Sturrock RD. Autonomic neuropathy in rheumatoid arthritis. BMJ 1979;2:173– 175.
w21x Appenzeller O, Arnason BG, Adams RD. Experimental autonomic neuropathy: an immunological induced disorder of reflex vasomotor function. J Neurol Neurosurg Psychiatry 1965;28:510–515. w22x Rabinowe SL, Brown FM, Watts BS, Smits AM. Complement-fixing antibodies to sympathetic and parasympathetic tissues in IDDM. Diab Care 1990;13Ž10.:1084–1088. w23x Rabinowe SL, Brown FM, Watts BS, Kadrofske MM, Vinik AI. Anti-sympathetic ganglia antibodies and postural blood pressure in IDDM subjects of varying duration and patients at high risk of developing IDDM. Diab Care 1989;12Ž1.:1–6. w24x Hoyle C, Ewing DJ, Parker AC. Acute autonomic neuropathy in association with systemic lupus erythematosus. Ann Rheum Dis 1985;44:420–424.
Brief report
Primary Sjogren’s syndrome presenting as autonomic neuropathy ¨ Case report P.J. Barendregt a
a,)
, H.M. Markusse a , A.J. Man In ’t Veld
b
Department of Rheumatology, Zuiderziekenhuis, Groene Hilledijk 315, 3075 AE Rotterdam, The Netherlands b Department of Internal Medicine I, UniÕersity Hospital Rotterdam–Dijkzigt, Rotterdam, The Netherlands Received 9 February 1998; revised 26 May 1998; accepted 2 June 1998
Abstract Abnormalities of the autonomic nervous system have been described in several connective tissue diseases, but the relation with primary Sjogren’s syndrome is unclear. This report describes a patient with primary Sjogren’s syndrome who presented ¨ ¨ with severe autonomic failure. The present knowledge on dysfunction of the autonomic nervous system in primary Sjogren’s ¨ syndrome and other connective tissue diseases is shortly reviewed. q 1998 Elsevier Science B.V. All rights reserved. Keywords: Sjogren’s syndrome; Autonomic nervous system; Neuropathy ¨
1. Introduction Subclinical autonomic dysfunction has been described in association with a number of connective tissue diseases, including rheumatoid arthritis ŽRA., systemic lupus erythematosus ŽSLE. and systemic sclerosis. However, symptomatic autonomic failure in these diseases is rare w1–5x. The occurrence of central and peripheral neurological disease in priŽSS. syndrome is well known w6–8x. mary Sjogren’s ¨ Abnormalities of the autonomic nervous system in primary SS have rarely been reported and are mostly concerning case reports w9–11x. Recently, a study of 19 patients with primary SS showed evidence for parasympathetic dysfunction w12x. We present a pa-
)
Corresponding author. Tel.: q31-10-2903000.
tient with severe autonomic failure as the first manifestation of the primary SS. This finding highlights the need to further investigate the autonomic nervous system in primary SS.
2. Case report In 1974 a 34-year old woman presented for the first time with complaints of headache, fatigue, palpitations, dizziness, collapse, nausea and vomiting. When visiting the outpatients clinic at that time, a variable arterial blood pressure was found, reaching a value of 170r120 mmHg in horizontal position and a value of 100r60 mmHg after a rest period of 15 min. At neurological examination, a fixed dilatation of the left pupil with an absent response to light was found, on which the diagnosis Adie’s pupil was made. At this first examination laboratory parameters
0300-2977r98r$ - see front matter q 1998 Elsevier Science B.V. All rights reserved. PII: S 0 3 0 0 - 2 9 7 7 Ž 9 8 . 0 0 0 8 0 - 1
P.J. Barendregt et al.r Netherlands Journal of Medicine 53 (1998) 196–200
revealed an ESR of 65 mm in the first hour and a hypergammaglobulinemia of 47 grl Žnormal 8–18 grl.. Since 1982 she also complained of severe fatigue and intermittent joint en muscle pains. Physical examination of joints and muscle was unremarkable. In 1983 positive rheumatoid factors were found. At this time an ESR of 94 mmrh and a gammaglobulin of 50 grl were measured. Radiological examination of hands and feet was normal. Treatment with nonsteroidal-anti-inflammatory-drugs was started. In 1986 the patient started to complain about oral and ocular dryness. An abnormal Schirmer test was found Ž- 10 mm wetting of a paper strip, 5 min after placement in the lower eyelids.. Antinuclear antibodies ŽANA., as well as SS-A ŽSjogren’s Syndrome A. ¨ and SS-B ŽSjogren’s Syndrome B. antibodies were ¨ detected in the serum and in a salivary gland biopsy from the lower lip more than 2 foci of more than 50 lymphocytesr4 mm2 gland tissue were found, which is compatible with the diagnosis primary Sjogren’s ¨ syndrome. At this time, the diagnosis primary SS was made and tear and saliva substitution were successfully prescribed. Because of severe general malaise and arthralgias the patient was treated with 10 mg prednisone daily. In 1989 the patient was hospitalized because of severe, watery diarrhoea with a weight loss of 5 kg and dizzyness. Orthostatic challenge tests were used to evaluate the autonomic nervous system. In horizontal position a low blood pressure of 99r53 mmHg was found Žmean arterial pressure 70 mmHg, heart rate 63 bpm., which dropped to 65r35 mmHg Žmean arterial pressure 46 mmHg, heart rate 76 bpm. 10 min after tilt. In supine position a low value of noradrenaline was found Ž73 pgrml Žnormal 159 " 109.., but values of adrenaline and dopamine were in the normal range. Examination by a neurologist showed signs of a sensory neuropathy Žabsent knee and achilles tendon jerks and diminished sensibility of the lower legs. and an Adie’s pupil of the left eye. Rontgenography, stool examination, duodenoscopy ¨ and coloscopy with histological examination of the gastrointestinal tract did not show any abnormalities and both the diarrhoea and the dizzyness were ascribed to autonomic failure. The diarrhoea was successfully treated with loperamide Ž2 mg twice a day..
197
Symptomatic treatment of the orthostasis was also adequate Žoral salt and elastic stockings.. For the next five years the patient was followed on the outpatients clinic. At this time a stable situation was reached and there was no need to prescribe specific medication. In 1995 a complete physical, neurological and cardiovascular examination was performed. At the time of examination the patient complained about dry eyes, a dry mouth, myalgia, Raynaud’s phenomenon, arthralgia and fatigue. She also complained about headaches, palpitations, postural dizziness and diarrhoea. Physical examination revealed no signs of arthritis, but we found a skin rash on the lower legs, therefore suggesting vasculitis. Neurological and electromyographic examination showed evidence for a sensory neuropathy. Specific cardiovascular function tests were also performed. The patient showed an abnormal heart rate response on both the Valsalva manoeuvre and during deep breathing, suggesting parasympathetic dysfunction. For the Valsalva manoeuvre, the patient was asked to blow into a mouthpiece attached to an aneroid pressure gauge at a pressure of 40 mmHg for 15 sec. The ratio of the longest interbeat interval shortly after ending the manoeuvre to the shortest interbeat interval during the manoeuvre was mea-
Table 1 Results of the orthostatic challenge test
R1 R2 M1 T1 T2 M2 R3 R4
BP Žsys.
BP Ždias.
BP Žmean.
heartrate
97 96 131 102 118 117 128 125
47 46 75 58 71 68 75 70
64 62 94 73 87 84 93 88
65 64 67 71 75 71 79 73
BP in mmHg. heartrate in beatsrmin. R1s first period of 5 min supine rest. R2 s second period of 5 min supine rest. M1s fixed respiration frequency during supine rest. T1s first period of 5 min of 60 degree tilt. T2 s second period of 5 min of 60 degree tilt. M2 s fixed respiration frequency during 60 degree tilt. R3s third period of 5 min supine rest. R4 s fourth period of 5 min supine rest.
198
P.J. Barendregt et al.r Netherlands Journal of Medicine 53 (1998) 196–200
sured and expressed as the Valsalva ratio: 1.13 Žnormal value G 1.21, according to Ewing w13x.. For the deep breathing test, we asked the patient to breathe deeply and evenly at six breaths per min Ž5 sec in and 5 sec out.. The maximum and minimum heartrate during each 10-sec breathing cycle were measured and the mean of the differences during three successive breathing cycles was calculated as the ‘maximum-minimum heartrate’: 4.7 beatsrmin Žnormal value according to Ewing: G 15 beatsrmin.. The results of the orthostatic challenge test Žas a measure of sympathetic function. are listed in Table 1. This test was performed by means of a tilt table on which the patient was lying. Blood pressure and heartrate were measured during supine position and during 608 tilt. Orthostatic hypotension can be defined as a fall in systolic blood pressure of 20 mmHg or more, as we see during the first five minutes of tilt. During this orthostatic tests, blood samples were taken during supine rest and tilt for the determination of plasma catecholamines. The results of the catecholamines are shown in Table 2. During supine rest, a low value of noradrenaline was found. However, a normal increase of all catecholamines was found in response to tilt. In 1997 the patient complained about progressive dizziness, sometimes attended with collapses, especially after rising from the bed in the morning or during long periods in the standing position. At this time a severe orthostasis was found: blood pressure in supine position 200r120 mmHg and during standing up 150r110 mmHg. The orthostatic symptoms disappeared after she was treated with oral salt and fludrocortisone and there was no intervention with the co-existing hypertension Žafter treatment blood pressure in supine position 160r115, during standing up 155r105.. Table 2 Results of plasma catecholamines during orthostatic challenge testing
Noradrenaline Žpgrml. Adrenaline Žpgrml. Dopamine Žpgrml.
Supine rest Žnl.value.
Tilt
159 Ž261"109. 43 Ž25"2. 7 Ž13"8.
285 73 8
Normal values during supine rest were obtained from a normotensive, matched population Žstored in a database..
3. Discussion The patient described suffered from a severe autonomic failure, characterized by dizzyness due to orthostatic hypotension, fatigue, diarrhoea and low concentrations of plasma catecholamines as well as a sensory neuropathy and an Adie’s pupil on the left side. She also suffered from primary SS characterized by oral and ocular dryness, decreased tear production, focal sialadenitis of the lower lip Žabnormal salivary gland biopsy. and laboratory abnormalities including strongly positive serum tests of antinuclear antibodies, rheumatoid factor as well as SS-A and SS-B antibodies. Acquired autonomic neuropathy is most commonly found in diabetes mellitus, renal failure, amyloid, thiamine deficiency and neoplastic disease w14x. In this patient none of these causes were identified, but the criteria used for the classification of primary SS, including the recently developed European criteria, were fulfilled w15,16x. The long delay before the diagnosis primary SS was made illustrates that the diagnosis primary SS may be easily overlooked. Since oral and ocular dryness are common complaints of patients with autonomic failure, it may be hypothesized that especially in patients with symptomatic autonomic failure the diagnosis of concurrent primary SS is also easily missed. Recently a similar case of orthostatic hypotension and parasympathetic failure in a patient with primary SS was reported w9x. Another case of autonomic failure Žoral and ocular dryness, decreased gastrointestinal motility, atony of the bladder and taste and sweating disturbances. in a patient with a possible primary SS has been described w10x. Mc Combe et al. w17x described a patient with possibly primary SS and autonomic neuropathy in whom high doses of corticosteroids were temporarily beneficial which suggests an inflammatory cause. The occurrence of Adie’s pupils in primary SS with or without orthostatic hypotension has also been described w18,19x. We found one abstract comprising five patients with primary SS in which the following autonomic dysfunctions were described: orthostatic hypotension and Adie’s pupils in two, pupillary abnormalities in three, cardiac parasympathetic abnormalities in four and patchy anhidrosis in five w11x.
P.J. Barendregt et al.r Netherlands Journal of Medicine 53 (1998) 196–200
Recently, a systematic study on the autonomic nervous system in primary SS was done w12x. In this study, performed on 19 patients, the autonomic nervous system was evaluated by doing tilt- and deepbreathing tests. The investigators did find evidence for parasympathetic disturbances in this patient group. There is documentation of autonomic dysfunction in several other connective tissue diseases, mostly concerning subclinical parasympathetic disturbances in all these conditions. In RA abnormal cardiovascular reflexes were found in 33–60% of the patients w1,2,20x, but obvious clinical signs Žorthostatic hypotensionrabnormal sweat secretion. were only mentioned in four out of nine RA patients with cardiovascular abnormalities w20x. In SLE at least one abnormal cardiovascular reflex test was found in 15 out of 17 patients tested, and severe orthostatis was found in only one w3x. Recently in systemic sclerosis autonomic neuropathy was found to be extremely common. Cardiovascular reflex tests and plasma catecholamine measurements pointed at parasympathetic impairment w4,5x. The pathogenesis of autonomic neuropathy in connective tissue diseases has not been elucidated, but an immunological mechanism may be responsible. Experimental allergic neuritis has been given as a model of both polyneuropathy and autonomic dysfunction. In diabetes mellitus, auto-antibodies to sympathetic and parasympathetic tissue have been detected w21–23x. Lymphocytic infiltration and neural destruction of dorsal ganglia may be important in the etiology of this neuropathy w22,23x. Furthermore the beneficial effects of immunosuppressive treatment early in the course of autonomic dysfunction in patients with connective tissue disorders also suggest the presence of an autoimmune inflammatory reaction in these patients w17,24x. Primary SS may present with many different features. Considering the occurrence of autonomic neuropathy in other connective tissue diseases, the few reports on abnormalities of the autonomic nervous system in patients with Žpossible. primary SS, as well as the patient described here, we believe autonomic dysfunction should be added to the list of extra-glandular manifestations of primary SS. A study in a larger patient group could be useful to investigate the clinical importance of autonomic nervous
199
system dysfunction in primary SS and to explore a possible relationship with oral and ocular dryness.
References w1x Leden I, Eriksson A, Lilja B, Sturfelt G, Sundkvist G. Autonomic nerve function in rheumatoid arthritis of varying severity. Scand J Rheumatol 1983;12:166–170. w2x Toussirot E, Serratrice G, Valentin P. Autonomic nervous system involvement in rheumatoid arthritis. 50 cases. J Rheumatol 1993;20:1508–1514. w3x Liote´ F, Osterland CK. Autonomic neuropathy in systemic lupus erythematosus: cardiovascular autonomic function assessment. Ann Rheum Dis 1994;53:671–674. w4x Dessein PH, Joffe BI, Metz RM, Millar DL, Lawson M, Stanwix AE. Autonomic dysfunction in systemic sclerosis: sympathetic overactivity and instability. Am J Med 1992;93:143–150. w5x Hermosillo AG, Ortiz R, Dabague J, Casanova JM, Martinez Lavin M. Autonomic dysfunction in diffuse scleroderma vs crest: an assessment by computerized heart rate variability. J Rheumatol 1994;21Ž10.:1849–1854. w6x Alexander GE, Provost TT, Stevens MB, Alexander EL. Sjogren’s syndrome: Central nervous system manifestations. ¨ Neurology 1981;31:1391–1396. w7x Andonopoulos AP, Lagos G, Drosos AA, Moutsopoulos HM. The spectrum of neurological involvement in Sjogren’s syn¨ drome. Br J Rheumatol 1990;29:21–23. w8x Mellgren SI, Conn DL, Stevens JC, Dyck PJ. Peripheral neuropathy in primary Sjogren’s syndrome. Neurology ¨ 1989;39:390–394. w9x Andonopoulos AP, Ballas C. Autonomic cardiovascular neuropathy in primary Sjogren’s syndrome. Rheumatol Int ¨ 1995;15:127–129. w10x Takayama H, Kazahaya Y, Kashihara N, et al. A case of postganglionic cholinergic dysautonomia. J Neurol Neurosurg Psych 1987;50:915–918. w11x Low PA, Mertz LE, Auger RG, et al. The autonomic neuropathies in Sjogren’s syndrome. Neurol 1988;38Žsuppl 1.:26. ¨ w12x Mandl T, Jacobsson L, Sundkvist G, Manthorpe R. Disturbances of autonomic nervous system in primary Sjogren’s ¨ syndrome. Scand J Rheumatol 1997;26:253–258. w13x Ewing DJ, Clarke BF. Autonomic neuropathy: its diagnosis and prognosis. Clin Endocr Metab 1986;15Ž4.:855–888. w14x Low PA In: Clinical autonomic disorders. Evaluation and Management. First Edition. Little, Brown and Company, Boston, Toronto, London, 396. w15x Prause JU, Manthorpe R, Oxholm P, Schmidt M. Definition and criteria for Sjogren’s syndrome used by the contributors ¨ to the First International Seminar on Sjogren’s syndrome. ¨ Scand J Rheumatol 1986;61Žsuppl..:17–18. w16x Vitali C, Bombardieri S, Moutsopoulos HM, et al. Preliminary criteria for the classification of Sjogren’s syndrome. ¨ Arthritis Rheum 1993;36:340–347.
200
P.J. Barendregt et al.r Netherlands Journal of Medicine 53 (1998) 196–200
w17x Mc Combe PA, Sheehan GL, Mc Laughlin DB, Pender MP. Vestibular and ventilatory dysfunction in sensory and autonomic neuropathy associated with primary Sjogren’s syn¨ drome. J Neurol Neurosurg Psych 1992;55Ž12.:1211–1212. w18x Kennett RP, Harding AE. Peripheral neuropathy associated with the sicca syndrome. J Neurol Neurosurg Psychiatry 1986;49:90–92. w19x Gemignary F, Manganelli P, Pavesi G, Marbini A. Polyneuropathy in Sjogren’s syndrome. A case of prevalently auto¨ nomic neuropathy with tonic pupil and hypohidrosis. Funct Neurol 1988;3:337–348. w20x Edmonds ME, Jones TC, Saunders WA, Sturrock RD. Autonomic neuropathy in rheumatoid arthritis. BMJ 1979;2:173– 175.
w21x Appenzeller O, Arnason BG, Adams RD. Experimental autonomic neuropathy: an immunological induced disorder of reflex vasomotor function. J Neurol Neurosurg Psychiatry 1965;28:510–515. w22x Rabinowe SL, Brown FM, Watts BS, Smits AM. Complement-fixing antibodies to sympathetic and parasympathetic tissues in IDDM. Diab Care 1990;13Ž10.:1084–1088. w23x Rabinowe SL, Brown FM, Watts BS, Kadrofske MM, Vinik AI. Anti-sympathetic ganglia antibodies and postural blood pressure in IDDM subjects of varying duration and patients at high risk of developing IDDM. Diab Care 1989;12Ž1.:1–6. w24x Hoyle C, Ewing DJ, Parker AC. Acute autonomic neuropathy in association with systemic lupus erythematosus. Ann Rheum Dis 1985;44:420–424.