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Skin involvement in amyotrophic lateral sclerosis
Skin involvement in
amyotrophic lateral sclerosis
Gerhard Kolde, Rainer Bachus, Albert C
Ludolph
Summary Background Patients with sporadic amyotrophic lateral sclerosis (ALS) show disorganised collagen and elastin of the dermis. We looked for inflammatory alterations to cutaneous blood vessels.
findings Seven patients with sporadic ALS were investigated; five were confined to bed, but none had bedsores. Light and electron microscopy of skin showed an oedematous dermis with collagen fibrils of irregular diameter. Small blood vessels were characterised by duplicated basement membranes and deposition of &bgr;amyloid protein, the main component of the neuronal and non-neuronal amyloid deposits in Alzheimer’s disease. These skin changes were seen in all degrees of disability, but none was found in age-matched and sex-matched Patients and
controls.
Interpretation The skin in ALS is characterised by a distinctive pattern of alterations of connective tissue and
control purposes, biopsy samples from the same skin region were taken from ten sex-matched and age-matched patients (mean age 59 years; range 48-66 years) who had plastic surgery.
Results of ALS skin showed slightly atrophic epidermis, oedematous dermis with separated collagen fibrils and some mucinous deposits, and thickening of blood-vessel walls, but no inflammatory infiltration. Staining methods for amyloid (Congo red, crystal violet, and thioflavine T)
Histology
were
negative.
Electron microscopy showed a reduced diameter of cross-striated collagen fibrils (figure la). Fibrils were separated by electronlucent spaces which often contained small deposits of fine granular, non-fibrillous material. Blood vessels were characterised by duplicated basement membranes giving them an onion-peel-like appearance (figure lb). Between the closely apposed membrane layers, there were irregularly arranged, mostly single, fine
blood vessels. Examination of skin is an additional and easily accessible investigation which may help elucidate the pathogenesis of ALS. Lancet 1996; 347: 1226-27
Introduction lateral sclerosis (ALS) is a fatal degenerative disease of motor neurons of unknown cause.’ The absence of bedsores in those patients who are bed-ridden is considered characteristic,2,3 but the skin changes and their relationship to the pathogenesis of the disease are unclear. Microscopical and biochemical studies suggested slight changes of collagen and elastin fibres, and of ground substance in the dermis.4 We report a cutaneous vasculopathy with deposits of (3-amyloid protein.
Amyotrophic
Patients and methods We investigated seven randomly selected patients with the sporadic form of ALS (two men, five women; aged 51-63 years). All had overt disease and unequivocal progressive upper-motor and lower-motor neuron disease. Disease severity was estimated according to Norris’ scorer as 60-80 in two patients, less than 60 in
four, and a "locked-in state" in one. Five patients were confined to bed, but none of these had bedsores. On dermatological examination (GK), the skin of all patients felt supple and slightly waxy, and showed decreased elasticity with a delayed-return phenomenon. After informed consent, skin-biopsy samples were taken from the inner aspect of the forearm and processed for light and electron microscopy. For Department of Dermatology (Prof G Kolde MD), Virchow-Clinics, Humboldt-University of Berlin, D-13353 Berlin, Germany, and Department of Neurology (R Bachus MD, A C Ludolph MD), Charité, Humboldt-University of Berlin, D-10117 Berlin, Germany
Correspondence 1226
to: Prof Gerhard Kolde
Figure
1: Electron
microscopy of ALS skin
connective tissue with reduced and irregular diameters of collagen fibres, and fine granular deposits (arrow). (M agnlficatlon x 28 100.) b: blood vessel with onion peel-like arranged duplications of the basement membrane (arrows). ( X8300.) a:
alterations of connective tissue have also been found in
chickling-pea-induced neurolathyrism, an upper motorneuron disease prevalent in India, Bangladesh, and Ethiopia.7 In this disease, cross-linking of collagen and elastin is inhibited by continuous ingestion of the lathyrus toxin (3-amino-propionitrile. However, this toxin is unlikely to be responsible for the neurological disturbances in these patients." Small blood vessels in ALS skin had
Figure 2: Immunohistochemical stainings for (3-amyloid positive staining of blood vessel wall with the monoclonal antibody against (3-amyloid protein (arrows). (Hemalaun; x 100.) b: no staining of blood vessel with the monoclonal antibody against p-amyioid precursor protein 695 (arrows). (Hemalaun; x 100.) a:
amyloid filaments with diameters between 7 and 10 nm. These filaments had no cross striations and were only rarely arranged in helical pairs and bundles. Similar filaments were also found in close apposition to the basement membrane of dermal sweat glands. Immunohistochemical done on staining was and sections the deparaffinised trypsinised histological by indirect immunoperoxidase method. The specificity of labelling was checked by replacing the applied antibodies with equal amounts of non-specific immune sera. In all patients (but not in controls), there was distinct vascular and periadnexal labelling with a polyclonal antibody provided by D J Selkoeand a monoclonal antibody
(DAKOPATTS, Hamburg, Germany) against (3-amyloid protein (figure 2a). No positive reaction was seen when the sections were incubated with a polyclonal antibody (Boehringer Mannheim, Germany) against p-amyloid precursor protein 695 (figure 2b). No specimen showed immunoreactivity for amyloid A and L protein (DAKOPATTS), paired helical filaments (Boehringer Mannheim), or tau protein (Boehringer Mannheim). Discussion Due to the lack of bedsores, cutaneous involvement in ALS was first suggested by Charcot more than 100 years ago.2 The structural changes of cutaneous connective tissue observed in this and other studies are caused by disturbed turnover and cross-linking of collagen and elastin fibres.4 Similar microscopic and biochemical
distinctive noninflammatory vasculopathy, which together with the dermal oedema and alterations of the fibrils may prevent pressure sores from external tissue compression.9 A similar vasculopathy has also been described for muscle blood capillaries in ALS.’° We observed deposits of (3amyloid protein close to blood vessels and epidermal appendages. Vascular deposits of this 39 to 43-aminoacid polypeptide are characteristically found in the brain of several disorders including Alzheimer’s disease and Down’s syndrome. In both diseases, p-amyloid protein has also been detected in the blood vessel walls of the skin.6 Deposition of this plasma membrane-derived peptide is thought to result from abnormal or reduced degradation by intracellular secretases which may explain its neuronal and cutaneous occurrence in some people older than 75 years of age.",’2 Our patients were however younger, and none of the age-matched controls showed vascular p-amyloid protein. Cutaneous examination of patients with ALS is an additional and easily accessible feature of this disease. Further analyses of the complex skin alterations may help to elucidate the basic pathological mechanisms of ALS, and the cutaneous deposition of (3-amyloid protein suggests a closer relationship to other degenerative disorders of the central nervous system than was a
previously thought. References Williams DB, Windebank AY. Motor neuron disease (Amyotrophic lateral sclerosis). Mayo Clin Proc 1991; 66: 54-82. 2 Charcot JM. Lecon sur le maladies du systeme nerveux faites a la Salpetriere. Paris, France, Vol II, 1880. 3 Furukawa T, Toyokura Y. Amytrophic lateral sclerosis and bedsores. Lancet 1976; i: 862. 4 Ono S, Yamauchi M. Elastin cross-linking in the skin from patients with amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 1994; 57: 94-96. 5 Norris FH, Colanchini FR, Fallat RJ, et al. The administration of guanidine in amyotrophic lateral sclerosis. Neurology 1974; 24: 721-28. 6 Joachim CL, Mori H, Selkoe DJ. Amyloid &bgr;-protein deposition in tissues other than brain in Alzheimer’s disease. Nature 1989; 341: 226-30. 7 Roy DN, Spencer PS. Lathyrogens. In: Cheeke PR, ed. Toxicants of plant origin. CRC Press, Boca Raton, Florida, 1990: 170-201. 8 Ludolph AC, Hugon J, Dwivedi MP, et al. Studies on the etiology and pathogenesis of motor neuron disease. I. Lathyrism: clinical findings in established cases. Brain 1987; 110: 149-65. 9 Daniel RK, Priest DL, Wheatley DC. Etiologic factors in pressure sores: an experimental model. Arch Phys Med Rehabil 1981; 62: 492-98. 10 Kniffen JC, Quick DT. Skeletal muscle capillary abnormalities in amyotrophic lateral sclerosis. Neurology 1969; 19: 312. 11 Citron M, Teplow DB, Selkoe DJ. Generation of amyloid beta protein from its precursor is sequence specific. Neuron 1995; 14: 661-70. 12 Naidu A, Quon D, Cordell B. &bgr;-amyloid peptide produced in vitro is degraded by proteinases by cultured cell. J Biol Chem 1995; 270: 1
1369-74.
1227
amyotrophic lateral sclerosis
Gerhard Kolde, Rainer Bachus, Albert C
Ludolph
Summary Background Patients with sporadic amyotrophic lateral sclerosis (ALS) show disorganised collagen and elastin of the dermis. We looked for inflammatory alterations to cutaneous blood vessels.
findings Seven patients with sporadic ALS were investigated; five were confined to bed, but none had bedsores. Light and electron microscopy of skin showed an oedematous dermis with collagen fibrils of irregular diameter. Small blood vessels were characterised by duplicated basement membranes and deposition of &bgr;amyloid protein, the main component of the neuronal and non-neuronal amyloid deposits in Alzheimer’s disease. These skin changes were seen in all degrees of disability, but none was found in age-matched and sex-matched Patients and
controls.
Interpretation The skin in ALS is characterised by a distinctive pattern of alterations of connective tissue and
control purposes, biopsy samples from the same skin region were taken from ten sex-matched and age-matched patients (mean age 59 years; range 48-66 years) who had plastic surgery.
Results of ALS skin showed slightly atrophic epidermis, oedematous dermis with separated collagen fibrils and some mucinous deposits, and thickening of blood-vessel walls, but no inflammatory infiltration. Staining methods for amyloid (Congo red, crystal violet, and thioflavine T)
Histology
were
negative.
Electron microscopy showed a reduced diameter of cross-striated collagen fibrils (figure la). Fibrils were separated by electronlucent spaces which often contained small deposits of fine granular, non-fibrillous material. Blood vessels were characterised by duplicated basement membranes giving them an onion-peel-like appearance (figure lb). Between the closely apposed membrane layers, there were irregularly arranged, mostly single, fine
blood vessels. Examination of skin is an additional and easily accessible investigation which may help elucidate the pathogenesis of ALS. Lancet 1996; 347: 1226-27
Introduction lateral sclerosis (ALS) is a fatal degenerative disease of motor neurons of unknown cause.’ The absence of bedsores in those patients who are bed-ridden is considered characteristic,2,3 but the skin changes and their relationship to the pathogenesis of the disease are unclear. Microscopical and biochemical studies suggested slight changes of collagen and elastin fibres, and of ground substance in the dermis.4 We report a cutaneous vasculopathy with deposits of (3-amyloid protein.
Amyotrophic
Patients and methods We investigated seven randomly selected patients with the sporadic form of ALS (two men, five women; aged 51-63 years). All had overt disease and unequivocal progressive upper-motor and lower-motor neuron disease. Disease severity was estimated according to Norris’ scorer as 60-80 in two patients, less than 60 in
four, and a "locked-in state" in one. Five patients were confined to bed, but none of these had bedsores. On dermatological examination (GK), the skin of all patients felt supple and slightly waxy, and showed decreased elasticity with a delayed-return phenomenon. After informed consent, skin-biopsy samples were taken from the inner aspect of the forearm and processed for light and electron microscopy. For Department of Dermatology (Prof G Kolde MD), Virchow-Clinics, Humboldt-University of Berlin, D-13353 Berlin, Germany, and Department of Neurology (R Bachus MD, A C Ludolph MD), Charité, Humboldt-University of Berlin, D-10117 Berlin, Germany
Correspondence 1226
to: Prof Gerhard Kolde
Figure
1: Electron
microscopy of ALS skin
connective tissue with reduced and irregular diameters of collagen fibres, and fine granular deposits (arrow). (M agnlficatlon x 28 100.) b: blood vessel with onion peel-like arranged duplications of the basement membrane (arrows). ( X8300.) a:
alterations of connective tissue have also been found in
chickling-pea-induced neurolathyrism, an upper motorneuron disease prevalent in India, Bangladesh, and Ethiopia.7 In this disease, cross-linking of collagen and elastin is inhibited by continuous ingestion of the lathyrus toxin (3-amino-propionitrile. However, this toxin is unlikely to be responsible for the neurological disturbances in these patients." Small blood vessels in ALS skin had
Figure 2: Immunohistochemical stainings for (3-amyloid positive staining of blood vessel wall with the monoclonal antibody against (3-amyloid protein (arrows). (Hemalaun; x 100.) b: no staining of blood vessel with the monoclonal antibody against p-amyioid precursor protein 695 (arrows). (Hemalaun; x 100.) a:
amyloid filaments with diameters between 7 and 10 nm. These filaments had no cross striations and were only rarely arranged in helical pairs and bundles. Similar filaments were also found in close apposition to the basement membrane of dermal sweat glands. Immunohistochemical done on staining was and sections the deparaffinised trypsinised histological by indirect immunoperoxidase method. The specificity of labelling was checked by replacing the applied antibodies with equal amounts of non-specific immune sera. In all patients (but not in controls), there was distinct vascular and periadnexal labelling with a polyclonal antibody provided by D J Selkoeand a monoclonal antibody
(DAKOPATTS, Hamburg, Germany) against (3-amyloid protein (figure 2a). No positive reaction was seen when the sections were incubated with a polyclonal antibody (Boehringer Mannheim, Germany) against p-amyloid precursor protein 695 (figure 2b). No specimen showed immunoreactivity for amyloid A and L protein (DAKOPATTS), paired helical filaments (Boehringer Mannheim), or tau protein (Boehringer Mannheim). Discussion Due to the lack of bedsores, cutaneous involvement in ALS was first suggested by Charcot more than 100 years ago.2 The structural changes of cutaneous connective tissue observed in this and other studies are caused by disturbed turnover and cross-linking of collagen and elastin fibres.4 Similar microscopic and biochemical
distinctive noninflammatory vasculopathy, which together with the dermal oedema and alterations of the fibrils may prevent pressure sores from external tissue compression.9 A similar vasculopathy has also been described for muscle blood capillaries in ALS.’° We observed deposits of (3amyloid protein close to blood vessels and epidermal appendages. Vascular deposits of this 39 to 43-aminoacid polypeptide are characteristically found in the brain of several disorders including Alzheimer’s disease and Down’s syndrome. In both diseases, p-amyloid protein has also been detected in the blood vessel walls of the skin.6 Deposition of this plasma membrane-derived peptide is thought to result from abnormal or reduced degradation by intracellular secretases which may explain its neuronal and cutaneous occurrence in some people older than 75 years of age.",’2 Our patients were however younger, and none of the age-matched controls showed vascular p-amyloid protein. Cutaneous examination of patients with ALS is an additional and easily accessible feature of this disease. Further analyses of the complex skin alterations may help to elucidate the basic pathological mechanisms of ALS, and the cutaneous deposition of (3-amyloid protein suggests a closer relationship to other degenerative disorders of the central nervous system than was a
previously thought. References Williams DB, Windebank AY. Motor neuron disease (Amyotrophic lateral sclerosis). Mayo Clin Proc 1991; 66: 54-82. 2 Charcot JM. Lecon sur le maladies du systeme nerveux faites a la Salpetriere. Paris, France, Vol II, 1880. 3 Furukawa T, Toyokura Y. Amytrophic lateral sclerosis and bedsores. Lancet 1976; i: 862. 4 Ono S, Yamauchi M. Elastin cross-linking in the skin from patients with amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 1994; 57: 94-96. 5 Norris FH, Colanchini FR, Fallat RJ, et al. The administration of guanidine in amyotrophic lateral sclerosis. Neurology 1974; 24: 721-28. 6 Joachim CL, Mori H, Selkoe DJ. Amyloid &bgr;-protein deposition in tissues other than brain in Alzheimer’s disease. Nature 1989; 341: 226-30. 7 Roy DN, Spencer PS. Lathyrogens. In: Cheeke PR, ed. Toxicants of plant origin. CRC Press, Boca Raton, Florida, 1990: 170-201. 8 Ludolph AC, Hugon J, Dwivedi MP, et al. Studies on the etiology and pathogenesis of motor neuron disease. I. Lathyrism: clinical findings in established cases. Brain 1987; 110: 149-65. 9 Daniel RK, Priest DL, Wheatley DC. Etiologic factors in pressure sores: an experimental model. Arch Phys Med Rehabil 1981; 62: 492-98. 10 Kniffen JC, Quick DT. Skeletal muscle capillary abnormalities in amyotrophic lateral sclerosis. Neurology 1969; 19: 312. 11 Citron M, Teplow DB, Selkoe DJ. Generation of amyloid beta protein from its precursor is sequence specific. Neuron 1995; 14: 661-70. 12 Naidu A, Quon D, Cordell B. &bgr;-amyloid peptide produced in vitro is degraded by proteinases by cultured cell. J Biol Chem 1995; 270: 1
1369-74.
1227