BIOL PSYCHIATRY 1992;31:1151-1156
1151
CASE REPORTS
Depression as a Cerebral Manifestation of Scleroderma: Immunological Findings in Serum and Cerebrospinal Fluid N. MOiler, B. Gizycld-Nienhaus, W. Gtinther, and M. Meurer
Introduction The immunological hallmark of systemic scleroderma is the appearance of various autoantibodies in the serum (Meurer et al 1985; Chorzelski et al 1985; Tan 1988). In contrast to other collagenous vascular diseases, such as systemic lupus erythematodes (LE) and periarteritis nodosa, the nervous system is described as being rarely involved in systemic scleroderma (Gordon and Silverstein 1970). There exists a great amount of information about psychiatric symptoms in systemic LE (Feinglass et al 1976), but in patients with systemic scleroderma psychiatric manifestations have very rarely been noted; only one patient (Wise and Ginzler 1975) has been reported in the literature as suffering from an acute organic brain syndrome, resulting in hallucinations, paranoid delusions, disorientation, and hyperactivity. This case, however, showed positive antinuclear antibodies (ANA) but no cerebrospinal fluid (CSF) abnormalities and the psychiatric symptomatology responded to systemic corticos*,eroid therapy (Wise and Ginzler 1957). Two older case reports described depressive syndromes in patients suffering from systemic scleroderma (Sensemann 1957; Gulledge 1968), but no results of neuropsychiatric organic investigations such as CSF and electroencephalogram (EEG) have been noted. On the other hand, reports in the literature of pathological EEGs (Gottwald and Sturm 198 l) and an involvement of the autonomic nervous system (K|imiuk et al 1988) in scleroderma patients suggest that psychiatric manifestations in scleroderma are more common. In an extensive study, Gordon and Silverstein (1970) found neurological symptoms in about 18% ,~" 130 patients with systemic scleroderma. So far, however, neurological involvement has been mostly observed as cranial nerve lesions, mainly IV (Teasdall et al 1980) and V nerve (Mejias 1986; Berth-Jones et al 1990; Kabadi and Sinkoff 1977; Thompson and Robertson 1973) neuropathy. Until now there are few findings suggesting a direct central nervous system (CNS) involvement in scleroderma, possibly because less attention has been given to it. The case reported here shows scleroderma-typical autoantibodies and inflammatory signs in the CNS, presenting it as a chronic depressive syndrome.
From the Psychiatric Hospital (NM, WG), and the Department of Dermatology (BGN, MM), University of Munich, Muni,:h, Germany. Address reprint requests to Dr. N. Miiller, Psychiatric Hospital, University of Munich, Nussbaumstr. 7, D-8000 M~nchen 2, Germany. Ro-~.,i June 19, 1991; revised February 28, 1992. © 1992 Society of Biological Psychiatry
0006-3223/92/$05.00
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BIOL PSYCHIATRY 1992;31:1151-1156
N. Mtiller et al
Case Report CS, a 63-year-old farmer's wife, living on an isolated farm, observed the first symptoms of Raynaud's syndrome more than 10 years ago. Five years ago, she additionally noted puffy edema of the fingers and difficulties with swallowing. Two years ago, she observed telangiectasias on the bridge of her nose. Without experiencing any former psychiatric disorder, she first developed a depressive syndrome l0 years ago. This syndrome was characterized by feelings of desperation, anxiety, and insufficiency as well as a lack of drive and sleeplessness. Under treatment with antidepressants, she reported total remission of her complaints; this treatment was successfully continued for over 10 years. When she was admitted to a general hospital, her antidepressant medication was discontinued whereupon the depressive symptoms returned. On admission to our hospital, CS was in a depressive mood; she suffered from a lack of drive and interest, from a lack of appetite and from sleeplessness. In addition, her capacity to concentrate, as well as her memory, were considerably impaired. Her thought process was slowed down, she could not stop brooding and she expressed the wish to die. Furthermore, she reported the occasional appearance of slight auditory and visual hallucinations during the night. No family history of psychiatric or neurological disease and no abuse of alcohol or drugs could be evaluated. The dermatological findings included disseminated telangiectasia on the nose, forehead, and palms of the hands, edematous swelling of the fingers on both hands, and thickening of the skin primarily on the face and the fingers. In addition, there was discrete microstoma with radial furrowing and fibrosis of the sublingual frenulum. X-ray examination of the hands showed clumpy soft-tissue calcification of fingers DI left and D2 right, as well as acroosteolysis of DI right. Digital subtraction angiography of the left arm revealed obstructive and destructive vessel changes. By scintigraphy, characteristic esophageal involvement of systemic scleroderma could be demonstrated with dilatation, transport dysfunction, reflux, and esophagitis. No focal neurological signs have been found. The electroencephalogram (EEG) showed slight general changes with groups of bilateral theta waves. In the magnetic resonance imaging (MRI) of the brain, multiple areas of intensified signals which are suggestive of ischemia due to vascular lesions were detected (see Figure 1).
Findings in Serum and CSF Pathological serum findings included a slightly elevated blood sedimentation rate (35/68 Westergreen) and the demonstration of antinucle~r antibodies (ANA) both by indirect immunofluorescence (IIF), using HEp 2 cells and by Westernblot immunoprecipitation using Hela cell extracts as antigen substrate. By ~IF, the ANAs were found to have a very high titer of more than 10, 240 and with a horn ~genous nuclear binding pattern with staining of chromosomal proteins in mitotic cells. By Westernblot immunoprecipitation we tried to further analyze the antigen specificity of the ANAs found in the patient's serum (Figure 2). We found a strong reactivity of the serum with a protein of about 29 kDa molecular weight and a less intense reactivity with many other proteins between 96 and 20 kDa, which are present in the cytoplasmic Hela cell extract. The reactivity of the serum with nuclear Hela cell antigens was even stronger
Depression and Immunology in Scleroderma
BIOL PSYCHIATRY 1992;31:1151-1156
1153
Figure 1. Magnetic Resonance Imaging (Mk, l) of the BIain. Multiple areas of intensified signals, representing vasculitis-like lesions mostly paraventricular and periventricular.
(Figure 2). The band at the 100 kDa position could correspond to anti Scl 70 antibodies that recognize a 100 kJ)a DNA topoisomerase I. This antibody is highly specific for systemic scleroderma (Meurer et al 1985; Tan 1988). The cell count in the CSF was 4.3 cells/mm s, the differentiation showed lymphocytes, monocytes, and lymphoid plasma cells as signs of a slight inflammatory process. The protein content was 44 rag% with a slight increase of CSF immunoglobulin G (IgG) to 4.1 mg% (normal < 4.0), and a local IgG synthesis in the CNS as well as oligoclonal bands. Interestingly, by Westemblot analysis of CSF a distinct ANA reactivity could be demonstrated (Figure 2), using the cytoplasmic Hela cell extract. CSF gave a yield~'d band with a 29 kDa protein ~ d a 20 kDa protein; with the nuclear Hela cell extract, a weak band at the 100 kDa and 20 kDa position could be seen. Most of these bands were also seen when serum was analyzed (see a r r o w s in Figure 2).
1154
BIOL PSYCHIATRY 1992;31:1151-1156
N. Miiller et al
Figure 2. Westernblot of cytoplasmic extract (A) or nuclear extract (B) from Hela cells with serum rospinal fluid (CSF.) The cytoplssmic extract of the CSF and serum shows protein bands with 20 and 29 kJIa proteins, and the nuclear extract shows protein bands with the 100 kDa (anti Scl 70 antibodies, highly specific for scleroderma) and the 20 kDa position in the CSF and serum. Many other proteins between 20 kDa and 96 kDa are present in the serum.
Comments Visual hallucinations, EEG abnormalities, CSF findings of a local IgG synthesis, plasmoid cells, and oligoclonal bands as well as vasculitis-like MRT findings point to an organic, inflammatory cause of the depressive syndrome. The diagnosis of systemic scleroderma was cbllnrmed by the clinical picture, with typical cutaneous and esophageal manifestations and by the demonstration of antinuclear antibodies with specificity for topoisomerase I. In addition to this scleroderma-specific antibody (Wise and Ginzler 1975;Tan 1988),antinuclear antibodies with other specificity,
Depression and Immunology in Scleroderma
BIOLPSYCHIATRY 1992;31:1151-1156
1155
not yet characterized, were found in the serum and in the CSF by Westernblot analysis (Figure 2). The pathogenesis of neurological symptoms in scleroderma is controversial (BerthJones et al 1990). Although some authors (Kabadi and Sinkoff 1977) suggest that thickening of the connective tissue nerve sheath may be responsible, others (Teasdall et al 1980) hypothesized a combination of microangiopathy and fibrosis. Thompson and Robertson (1973) suggest that microvascular lesions that are found in various organs, may also occur in the nervous system. To o~r knowledge, this case report demonstrates for the first time the presence of ANAs in tt,e CSF combined with psychiatric manifestations in a patient with systemic scleroderma. Whether or not the specific topolsomerase I antinuclear antibodies is causing the vascular lesions found in the MRI cannot yet be answered. However, it has not yet been proven that the local ANA production in the CNS is pathogenetically related to the white matter lesions observed in this patient by MRI. On the other hand, it seems improbable that the MRI lesions are not due to the inflammatory process of the CNS accompanied by autoantibody production. In further studies, neurological and psychiatric manifestations in systemic scleroderma should be investigated by neuroimaging methods such as MRI and by immunological methods such as Westernblot for the demonstration of autoantibodies with possible specificity for neural tissue both of serum and CSF.
References Berth-Jones J, Coates PAA, Graham-Brown RAC, Bul~.~D A (1990): Neurological complications of systemic s,~!e~,sis---Areport of t~-ee cases ~ d reviews of the literature. Clin Exp Dermatol 15: 91-94. Chorzelski TP, Jablonska S, Beutner EH, et al (1985): Anticentromere antibody: An immunological marker of a subset of systemic sclerosis. 8r J Dermatol 113: 381-389. Feinglass F.J, Amett FC, Dorsch CA, Zizik TM, Stevens MB (1976): Neuro-psychiatfic manifestations of systemic lupus erythematodes: Diagnosis, clinical spectrum, and relationship to other features of the disease. Medicine 55: 323-339. Gordon RM, Silverstein A (1970): Neumlogic manifestations in progressive systemic sclerosis. Arch Neurol 22: 126-134. Gottwald W, Storm U (1981): EEG-Befunde bei 44 ausgewahlten Patienten mit Sklerodermie. Nervenarzt 55: 219-227. Gulledge AD (1968): Scleroderma. Some psychiatric aspects of progressive systemic sclerosis. Y Cansas Med 5oc 69: 593-596. Kabadi UM, Sinkoff MW (1977): Trigeminal neuralgia in progressive systemic sclerosis. Postgrad Med 61: 176-177. Klimiuk PS, Taylor L, Baker RD, Jayson MIV (1988); Autonomic neuropathy in systemic sclerosis. Ann Rheum Dis 47: 542-545. Mejias E (1986): Superior oblique muscle paralysis in CREST syndrome. PR Health Sci Y 5: 2729. Meurer M, Scharf A, LuderschmidtC, Braun-FalcoO (1985): Zentromerantik6rper und Antik6rper gegen Scl-70-Nucleoprotein bei progressiver systemischerSHerodermie. Dtsch Med Wochenschr 110: 8-14. Sensemann LA (1957): Scleroderma. Associated with neurological and psychogenic symptoms-with four case reports. R/Meal J 40: 684-688. Tan EM (1988): Antinuclear antibodies: Diagnostic markers for autoimmune diseases and probes for cell biology. Adv lmmuno144: 93-151.
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Teasdall RD, Frayha RA, Shulman LE (1980): Cranial nerve involvement in systemic sclerosis (scleroderma). A report of 10 cases. Medicine 59: 149-159. Thompson PD, Robertson GJ (1973): Trigeminal neuropathy heralding scleroderma. J Maine Med Assn 64: 123-124. Wise T, Ginzler EM (1975): Scleroderma cerebritis, an unusual manifestation of progressive systemic sclerosis. Dis Nerv Syst 36: 60-62.
1151
CASE REPORTS
Depression as a Cerebral Manifestation of Scleroderma: Immunological Findings in Serum and Cerebrospinal Fluid N. MOiler, B. Gizycld-Nienhaus, W. Gtinther, and M. Meurer
Introduction The immunological hallmark of systemic scleroderma is the appearance of various autoantibodies in the serum (Meurer et al 1985; Chorzelski et al 1985; Tan 1988). In contrast to other collagenous vascular diseases, such as systemic lupus erythematodes (LE) and periarteritis nodosa, the nervous system is described as being rarely involved in systemic scleroderma (Gordon and Silverstein 1970). There exists a great amount of information about psychiatric symptoms in systemic LE (Feinglass et al 1976), but in patients with systemic scleroderma psychiatric manifestations have very rarely been noted; only one patient (Wise and Ginzler 1975) has been reported in the literature as suffering from an acute organic brain syndrome, resulting in hallucinations, paranoid delusions, disorientation, and hyperactivity. This case, however, showed positive antinuclear antibodies (ANA) but no cerebrospinal fluid (CSF) abnormalities and the psychiatric symptomatology responded to systemic corticos*,eroid therapy (Wise and Ginzler 1957). Two older case reports described depressive syndromes in patients suffering from systemic scleroderma (Sensemann 1957; Gulledge 1968), but no results of neuropsychiatric organic investigations such as CSF and electroencephalogram (EEG) have been noted. On the other hand, reports in the literature of pathological EEGs (Gottwald and Sturm 198 l) and an involvement of the autonomic nervous system (K|imiuk et al 1988) in scleroderma patients suggest that psychiatric manifestations in scleroderma are more common. In an extensive study, Gordon and Silverstein (1970) found neurological symptoms in about 18% ,~" 130 patients with systemic scleroderma. So far, however, neurological involvement has been mostly observed as cranial nerve lesions, mainly IV (Teasdall et al 1980) and V nerve (Mejias 1986; Berth-Jones et al 1990; Kabadi and Sinkoff 1977; Thompson and Robertson 1973) neuropathy. Until now there are few findings suggesting a direct central nervous system (CNS) involvement in scleroderma, possibly because less attention has been given to it. The case reported here shows scleroderma-typical autoantibodies and inflammatory signs in the CNS, presenting it as a chronic depressive syndrome.
From the Psychiatric Hospital (NM, WG), and the Department of Dermatology (BGN, MM), University of Munich, Muni,:h, Germany. Address reprint requests to Dr. N. Miiller, Psychiatric Hospital, University of Munich, Nussbaumstr. 7, D-8000 M~nchen 2, Germany. Ro-~.,i June 19, 1991; revised February 28, 1992. © 1992 Society of Biological Psychiatry
0006-3223/92/$05.00
1152
BIOL PSYCHIATRY 1992;31:1151-1156
N. Mtiller et al
Case Report CS, a 63-year-old farmer's wife, living on an isolated farm, observed the first symptoms of Raynaud's syndrome more than 10 years ago. Five years ago, she additionally noted puffy edema of the fingers and difficulties with swallowing. Two years ago, she observed telangiectasias on the bridge of her nose. Without experiencing any former psychiatric disorder, she first developed a depressive syndrome l0 years ago. This syndrome was characterized by feelings of desperation, anxiety, and insufficiency as well as a lack of drive and sleeplessness. Under treatment with antidepressants, she reported total remission of her complaints; this treatment was successfully continued for over 10 years. When she was admitted to a general hospital, her antidepressant medication was discontinued whereupon the depressive symptoms returned. On admission to our hospital, CS was in a depressive mood; she suffered from a lack of drive and interest, from a lack of appetite and from sleeplessness. In addition, her capacity to concentrate, as well as her memory, were considerably impaired. Her thought process was slowed down, she could not stop brooding and she expressed the wish to die. Furthermore, she reported the occasional appearance of slight auditory and visual hallucinations during the night. No family history of psychiatric or neurological disease and no abuse of alcohol or drugs could be evaluated. The dermatological findings included disseminated telangiectasia on the nose, forehead, and palms of the hands, edematous swelling of the fingers on both hands, and thickening of the skin primarily on the face and the fingers. In addition, there was discrete microstoma with radial furrowing and fibrosis of the sublingual frenulum. X-ray examination of the hands showed clumpy soft-tissue calcification of fingers DI left and D2 right, as well as acroosteolysis of DI right. Digital subtraction angiography of the left arm revealed obstructive and destructive vessel changes. By scintigraphy, characteristic esophageal involvement of systemic scleroderma could be demonstrated with dilatation, transport dysfunction, reflux, and esophagitis. No focal neurological signs have been found. The electroencephalogram (EEG) showed slight general changes with groups of bilateral theta waves. In the magnetic resonance imaging (MRI) of the brain, multiple areas of intensified signals which are suggestive of ischemia due to vascular lesions were detected (see Figure 1).
Findings in Serum and CSF Pathological serum findings included a slightly elevated blood sedimentation rate (35/68 Westergreen) and the demonstration of antinucle~r antibodies (ANA) both by indirect immunofluorescence (IIF), using HEp 2 cells and by Westernblot immunoprecipitation using Hela cell extracts as antigen substrate. By ~IF, the ANAs were found to have a very high titer of more than 10, 240 and with a horn ~genous nuclear binding pattern with staining of chromosomal proteins in mitotic cells. By Westernblot immunoprecipitation we tried to further analyze the antigen specificity of the ANAs found in the patient's serum (Figure 2). We found a strong reactivity of the serum with a protein of about 29 kDa molecular weight and a less intense reactivity with many other proteins between 96 and 20 kDa, which are present in the cytoplasmic Hela cell extract. The reactivity of the serum with nuclear Hela cell antigens was even stronger
Depression and Immunology in Scleroderma
BIOL PSYCHIATRY 1992;31:1151-1156
1153
Figure 1. Magnetic Resonance Imaging (Mk, l) of the BIain. Multiple areas of intensified signals, representing vasculitis-like lesions mostly paraventricular and periventricular.
(Figure 2). The band at the 100 kDa position could correspond to anti Scl 70 antibodies that recognize a 100 kJ)a DNA topoisomerase I. This antibody is highly specific for systemic scleroderma (Meurer et al 1985; Tan 1988). The cell count in the CSF was 4.3 cells/mm s, the differentiation showed lymphocytes, monocytes, and lymphoid plasma cells as signs of a slight inflammatory process. The protein content was 44 rag% with a slight increase of CSF immunoglobulin G (IgG) to 4.1 mg% (normal < 4.0), and a local IgG synthesis in the CNS as well as oligoclonal bands. Interestingly, by Westemblot analysis of CSF a distinct ANA reactivity could be demonstrated (Figure 2), using the cytoplasmic Hela cell extract. CSF gave a yield~'d band with a 29 kDa protein ~ d a 20 kDa protein; with the nuclear Hela cell extract, a weak band at the 100 kDa and 20 kDa position could be seen. Most of these bands were also seen when serum was analyzed (see a r r o w s in Figure 2).
1154
BIOL PSYCHIATRY 1992;31:1151-1156
N. Miiller et al
Figure 2. Westernblot of cytoplasmic extract (A) or nuclear extract (B) from Hela cells with serum rospinal fluid (CSF.) The cytoplssmic extract of the CSF and serum shows protein bands with 20 and 29 kJIa proteins, and the nuclear extract shows protein bands with the 100 kDa (anti Scl 70 antibodies, highly specific for scleroderma) and the 20 kDa position in the CSF and serum. Many other proteins between 20 kDa and 96 kDa are present in the serum.
Comments Visual hallucinations, EEG abnormalities, CSF findings of a local IgG synthesis, plasmoid cells, and oligoclonal bands as well as vasculitis-like MRT findings point to an organic, inflammatory cause of the depressive syndrome. The diagnosis of systemic scleroderma was cbllnrmed by the clinical picture, with typical cutaneous and esophageal manifestations and by the demonstration of antinuclear antibodies with specificity for topoisomerase I. In addition to this scleroderma-specific antibody (Wise and Ginzler 1975;Tan 1988),antinuclear antibodies with other specificity,
Depression and Immunology in Scleroderma
BIOLPSYCHIATRY 1992;31:1151-1156
1155
not yet characterized, were found in the serum and in the CSF by Westernblot analysis (Figure 2). The pathogenesis of neurological symptoms in scleroderma is controversial (BerthJones et al 1990). Although some authors (Kabadi and Sinkoff 1977) suggest that thickening of the connective tissue nerve sheath may be responsible, others (Teasdall et al 1980) hypothesized a combination of microangiopathy and fibrosis. Thompson and Robertson (1973) suggest that microvascular lesions that are found in various organs, may also occur in the nervous system. To o~r knowledge, this case report demonstrates for the first time the presence of ANAs in tt,e CSF combined with psychiatric manifestations in a patient with systemic scleroderma. Whether or not the specific topolsomerase I antinuclear antibodies is causing the vascular lesions found in the MRI cannot yet be answered. However, it has not yet been proven that the local ANA production in the CNS is pathogenetically related to the white matter lesions observed in this patient by MRI. On the other hand, it seems improbable that the MRI lesions are not due to the inflammatory process of the CNS accompanied by autoantibody production. In further studies, neurological and psychiatric manifestations in systemic scleroderma should be investigated by neuroimaging methods such as MRI and by immunological methods such as Westernblot for the demonstration of autoantibodies with possible specificity for neural tissue both of serum and CSF.
References Berth-Jones J, Coates PAA, Graham-Brown RAC, Bul~.~D A (1990): Neurological complications of systemic s,~!e~,sis---Areport of t~-ee cases ~ d reviews of the literature. Clin Exp Dermatol 15: 91-94. Chorzelski TP, Jablonska S, Beutner EH, et al (1985): Anticentromere antibody: An immunological marker of a subset of systemic sclerosis. 8r J Dermatol 113: 381-389. Feinglass F.J, Amett FC, Dorsch CA, Zizik TM, Stevens MB (1976): Neuro-psychiatfic manifestations of systemic lupus erythematodes: Diagnosis, clinical spectrum, and relationship to other features of the disease. Medicine 55: 323-339. Gordon RM, Silverstein A (1970): Neumlogic manifestations in progressive systemic sclerosis. Arch Neurol 22: 126-134. Gottwald W, Storm U (1981): EEG-Befunde bei 44 ausgewahlten Patienten mit Sklerodermie. Nervenarzt 55: 219-227. Gulledge AD (1968): Scleroderma. Some psychiatric aspects of progressive systemic sclerosis. Y Cansas Med 5oc 69: 593-596. Kabadi UM, Sinkoff MW (1977): Trigeminal neuralgia in progressive systemic sclerosis. Postgrad Med 61: 176-177. Klimiuk PS, Taylor L, Baker RD, Jayson MIV (1988); Autonomic neuropathy in systemic sclerosis. Ann Rheum Dis 47: 542-545. Mejias E (1986): Superior oblique muscle paralysis in CREST syndrome. PR Health Sci Y 5: 2729. Meurer M, Scharf A, LuderschmidtC, Braun-FalcoO (1985): Zentromerantik6rper und Antik6rper gegen Scl-70-Nucleoprotein bei progressiver systemischerSHerodermie. Dtsch Med Wochenschr 110: 8-14. Sensemann LA (1957): Scleroderma. Associated with neurological and psychogenic symptoms-with four case reports. R/Meal J 40: 684-688. Tan EM (1988): Antinuclear antibodies: Diagnostic markers for autoimmune diseases and probes for cell biology. Adv lmmuno144: 93-151.
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Teasdall RD, Frayha RA, Shulman LE (1980): Cranial nerve involvement in systemic sclerosis (scleroderma). A report of 10 cases. Medicine 59: 149-159. Thompson PD, Robertson GJ (1973): Trigeminal neuropathy heralding scleroderma. J Maine Med Assn 64: 123-124. Wise T, Ginzler EM (1975): Scleroderma cerebritis, an unusual manifestation of progressive systemic sclerosis. Dis Nerv Syst 36: 60-62.
