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IgM paraproteinemia in a patient with primary lateral sclerosis
Neuromuscular Disorders 9 (1999) 38–40
Case report
IgM paraproteinemia in a patient with primary lateral sclerosis Joy Desai*, Michael Swash Department of Neurology, The Royal London Hospital, Whitechapel, London E1 1BB, UK Received 20 April 1998; received in revised form 30 July 1998; accepted 21 August 1998
Abstract Primary lateral sclerosis is an uncommon, distinct clinical entity. We report a patient with primary lateral sclerosis in whom investigations revealed an IgM monoclonal gammopathy, raised CSF protein and persistently high ESR. A number of reports suggest that lymphoproliferative disorders, paraproteinemia and clinico-pathological syndromes mimicking motor neuron diseases may be associated. We discuss the clinical features noted in our patient in relation to these reports, and the possible pathogenetic mechanisms. 1999 Elsevier Science B.V. All rights reserved Keywords: Primary lateral sclerosis; IgM paraproteinemia; Lymphoproliferative disorders; Motor neuron diseases; Pyramidal tract involvement
1. Introduction Two reports have delineated the clinical features, neuropathology and neuroimaging characteristics of primary lateral sclerosis [1,2]. The rare clinical association of lympho-proliferative disorders with motor neuron diseases has been reported [3,4]. We encountered a patient with clinical and laboratory features of primary lateral sclerosis, in whom investigations revealed an IgM monoclonal gammopathy, persistently raised ESR, and an elevated CSF protein.
2. Case report In May 1990, a 69 year old man, previously well, noted gradually progressive difficulty in walking and stiffness in both legs. He stumbled frequently. By early 1992 he noticed weakness and stiffness in both arms and hands with resultant difficulty in buttoning his clothes and performing routine manual tasks. In 1993 there was a change in his speech. He developed progressive difficulty in swallowing liquids with frequent bouts of coughing when attempting to swal* Corresponding author. Tel.: +44-171-3777472; fax: +44-171-3777008/ 3777318; e-mails: [email protected] or [email protected]
0960-8966/99/$ - see front matter PII: S09 60-8966(98)000 89-3
low quickly. He had no sensory symptoms, no change in his mental abilities or twitching of muscles. There was no neck pain or stiffness. His bladder and bowel functions were preserved. His weight and appetite were normal. There was no family history of neurological disorder. He continued to deteriorate, and by 1995 he required assistance for most activities of daily living. No new symptom suggestive of involvement of other parts of the neuraxis developed. A paraproteinemia of the IgM type was detected during investigation, and he was treated with a course of prednisolone and chlorambucil for a period of 6 months. There were no changes in his neurological disorder though the paraprotein levels dropped to normal values. The treatment was discontinued. By 1997, he was wheelchair bound with severe spasticity and could only communicate with great difficulty due to progressive dysarthria. He could not swallow solids but could manage semi-solids and liquids with some difficulty. Examination in mid-1993, revealed that he was an asthenic, afebrile individual without skin rash, lymphadenopathy or organomegaly. His vital signs were normal. Cardiorespiratory and gastrointestinal assessments were normal. On a Mini Mental Status Examination, his score was 29/ 29. There was a spastic dysarthria. The jaw-jerk was brisk and tongue movements were slow. Palatal movements were
1999 Elsevier Science B.V. All rights reserved
J. Desai, M. Swash / Neuromuscular Disorders 9 (1999) 38–40
symmetrically diminished and the gag reflex was exaggerated. No fasciculations were seen in the tongue or in other muscles. He was weak and spastic in all four limbs with the lower limbs more severely affected. His gait was spastic and laborious. There was no muscle wasting. Muscle strength was 3/5 in the proximal muscles and 3/5 to 4/5 in the distal muscles on the MRC scale. All the deep tendon reflexes were brisk and a few beats of clonus were elicited at both ankles. Both plantar responses were extensor. Sensory examination was normal and there were no cerebellar signs or nystagmus. Skull, spine, and peripheral nerve examination were normal. During the following 4 years his disability progressed and he became confined to a wheel-chair. Strength declined to 2/ 5 on the MRC scale in most muscles. Spasticity increased with progressively severe involvement of upper limb and oropharyngeal muscles. His mental state remained normal. There was no bladder or bowel dysfunction. He did not develop pressure sores. Normal tests included urinary analysis, hepato-renal biochemistry, vitamin B-12 levels, Lyme serology, serologic tests for syphilis, thyroid function tests, anti-dsDNA, ANA, RA and cryoglobulins. Haematological evaluation revealed an elevated ESR at 100–120 mm/h on serial assessments, with normal cellular counts and morphology on smear. Serum protein immuno-electrophoresis revealed an elevated monoclonal band of IgM (kappa light chains) in the range of 12–14 g/l. Chest X-ray, skull and spine X-rays, abdominal ultrasonography and CT of the chest and abdomen were all normal. A skeletal survey was normal. MRI of the brain and spine were normal. These radiological investigations were performed in 1995 and in 1997. Bone marrow biopsy performed in 1995 was normal. The patient refused a second marrow examination at follow-up in 1997. CSF examination revealed an elevated protein level at 65 and 90 g/l on two different occasions, with normal cellular counts and an absence of oligoclonal bands. Anti-MAG, anti-GM1 and anti-Hu antibodies were not detectable. Anti-SGPG antibodies titres could not be assessed. After a course of plasmapheresis at 40 ml/kg per day for 5 days followed by oral prednisolone and chlorambucil daily for 6 months, the IgM levels dropped to 2–4 g/l, without change in the neurological features. Nerve conduction and EMG studies were performed in all four limbs. Motor and sensory nerve conductions, F-wave responses, and H-reflex were normal. EMG examination of the proximal and distal muscles did not reveal any evidence of denervation. These neurophysiological findings did not change on follow-up 4 years later.
3. Discussion Our patient fulfils the clinical and laboratory criteria for primary lateral sclerosis proposed by Pringle et al. [2] in 1992. Laboratory investigations revealed an IgM (kappa
39
light chain) monoclonal gammopathy, persistently raised ESR, and elevated CSF protein. The usual neurological presentation of IgM paraproteinemia is that of a chronic, slowly progressive, sensory-motor, symmetrical polyneuropathy [5]. Occasionally, a fasciculatory postural tremor of the outstretched hands is observed. Neurophysiological assessment in these patients often reveals a demyelinating type of sensory-motor neuropathy. A proportion of these patients have an anti-MAG antibody in their sera which binds to the myelin sheaths of peripheral nerves. It is believed that this may lead to demyelinating neuropathy [5]. A raised ESR, an elevated CSF protein level and a characteristic M-band on immunoelectrophoresis are the major diagnostic features. Rare neurological manifestations of IgM paraproteinemia include the syndrome of continuous muscle fibre activity [6] and, possibly, amyotrophic lateral sclerosis [7]. Younger et al. [8,9] kindled interest in the clinical association between lymphoma, paraproteinemia, motor neuron diseases and amyotrophic lateral sclerosis. Gordon et al. [3] reported 26 patients with motor neuron disease in whom investigations revealed associated lymphoproliferative disease and reviewed 30 cases from other centres. They suggested that an elevated CSF protein may signal the presence of underlying lymphoproliferative disease in patients with MND with monoclonal gammopathy and a raised ESR [3,8]. They also noted that 56% of the 16 post-mortems performed in their patients revealed pathology in the pyramidal tracts. Clinically, all these patients had definite upper motor neuron signs. Our patient with the characteristic upper motor neuron features of primary lateral sclerosis had a persistently raised ESR and an elevated CSF protein level, raising a clinical suspicion of an underlying lymphoproliferative disorder. However, bone marrow biopsy and skeletal survey with imaging of the chest and abdomen failed to reveal an overt lymphoproliferative disorder or plasma cell dyscrasia. In one of the patients with clinical features of ALS reported by Gordon et al. [3], diffuse asymptomatic Hodgkin’s disease was detected only at autopsy despite extensive investigations performed during life. It is possible that our patient’s clinical syndrome has a similar basis. Leone and Phillips reported a patient with an anterior horn cell disorder and prominent upper motor neuron signs mimicking ALS, in whom investigations revealed an IgG paraproteinemia and marrow biopsy an asymptomatic, chronic lymphocytic leukaemia [4]. We considered a diagnosis of Bing–Neel syndrome in our patient but the marrow biopsy was normal and we did not detect hyperviscosity, a characteristic feature of this disorder. Our patient refused a second bone marrow biopsy, as his clinical symptoms had failed to respond to immunosuppressive therapy. The basis for the persistence of the neurological features after treatment of the gammopathy is unknown. It could be argued that our patient represents the mere chance association of primary lateral sclerosis and benign monoclonal gammopathy. Primary lateral sclerosis is so rare
40
J. Desai, M. Swash / Neuromuscular Disorders 9 (1999) 38–40
that the two largest series describing the disorder consist of a total of only 16 patients [1,2]. The incidence of benign monoclonal gammopathy increases with age reaching 3% in the eighth decade and 10% in the ninth decade [10]. Approximately 15–20% of M proteins are of the IgM type. We feel, as suggested by Gordon et al. [3] that the finding of an elevated CSF protein in our patient suggests a causative relation between the primary lateral sclerosis and the gammopathy. Primary lateral sclerosis has been reported previously in a patient with multiple myeloma [11]. We report the second description of paraproteinemia in a patient with primary lateral sclerosis, adding to the increasing suspicion of an association between motor neuron diseases and aberrant function of plasma/lymphoid cells [9]. The pathogenesis of neurological complications in lymphoproliferative disease is unknown, except in POEMS syndrome in which, endoneurial deposits of M protein have been detected by indirect immunolabelling techniques in nerve biopsy specimens [12]. Activation of the alternative pathway of complement and the ‘membrane attack complex’ by immuno-globulins could contribute to such damage [13]. We suspect that such mechanisms may have contributed to our patient’s clinical syndrome which was restricted to involvement of the upper motor neuron.
References [1] Younger DS, Chou S, Hays AP. Primary lateral sclerosis: a clinical diagnosis re-emerges. Arch Neurol 1988;45:1304–1307.
[2] Pringle CE, Hudson AJ, Munoz DG, Kiernan JA, Brown WF, Ebers GC. Primary lateral sclerosis: clinical features, neuropathology and diagnostic criteria. Brain 1992;115:495–520. [3] Gordon PH, Rowland LP, Younger DS, et al. Lymphoproliferative disorders and motor neuron disease: an update. Neurology 1997; 48:1671–1678. [4] Leone KV, Phillips LH. Lymphoproliferative disorders and motor neuron disease. To the editor. Neurology 1998;50:576. [5] Kelly JJ. Polyneuropathies associated with plasma cell dyscrasias. Semin Neurol 1987;7:30. [6] Zifko U, Drlicek M, Machacek E, Jellinger K, Grisold W. Syndrome of continuous muscle fibre activity and plasmacytoma with IgM paraproteinemia. Neurology 1994;44:560–561. [7] Rowland LP, Sherman WL, Hays AP, et al. Autopsy-proven amyotrophic lateral sclerosis, Waldenstrom’s macroglobulinemia and antibodies to sulphated glucuronic acid paragloboside. Neurology 1995;45:827–829. [8] Younger DS, Rowland LP, Latov N, et al. Motor neuron disease and amyotrophic lateral sclerosis: relation of high CSF protein content to paraproteinemia and clinical syndromes. Neurology 1990;40:595– 599. [9] Younger DS, Rowland LP, Latov N, et al. Lymphoma, motor neuron diseases, and amyotrophic lateral sclerosis. Ann Neurol 1991;29:78– 86. [10] Axelsson U, Bachmann R, Hallen J. Frequency of pathological proteins (M-components) in 6,995 sera from an adult population. Acta Med Scand 1966;179:235–247. [11] Brownell B, Trevor-Hughes J. Central nervous system in motor neuron disease. J Neurol Neurosurg Psychiatry 1970;33:338–357. [12] Adams D, Said G. Ultrastructural characterisation of the M protein in nerve biopsy of patients with POEMS syndrome. J Neurol Neurosurg Psychiatry 1998;64:809–812. [13] Hiemstra PS, Biewenga J, Corter A, et al. Activation of complement by human serum IgA, secretory IgA, and IgA1 fragments. Mol Immunol 1988;25:527–533.
Case report
IgM paraproteinemia in a patient with primary lateral sclerosis Joy Desai*, Michael Swash Department of Neurology, The Royal London Hospital, Whitechapel, London E1 1BB, UK Received 20 April 1998; received in revised form 30 July 1998; accepted 21 August 1998
Abstract Primary lateral sclerosis is an uncommon, distinct clinical entity. We report a patient with primary lateral sclerosis in whom investigations revealed an IgM monoclonal gammopathy, raised CSF protein and persistently high ESR. A number of reports suggest that lymphoproliferative disorders, paraproteinemia and clinico-pathological syndromes mimicking motor neuron diseases may be associated. We discuss the clinical features noted in our patient in relation to these reports, and the possible pathogenetic mechanisms. 1999 Elsevier Science B.V. All rights reserved Keywords: Primary lateral sclerosis; IgM paraproteinemia; Lymphoproliferative disorders; Motor neuron diseases; Pyramidal tract involvement
1. Introduction Two reports have delineated the clinical features, neuropathology and neuroimaging characteristics of primary lateral sclerosis [1,2]. The rare clinical association of lympho-proliferative disorders with motor neuron diseases has been reported [3,4]. We encountered a patient with clinical and laboratory features of primary lateral sclerosis, in whom investigations revealed an IgM monoclonal gammopathy, persistently raised ESR, and an elevated CSF protein.
2. Case report In May 1990, a 69 year old man, previously well, noted gradually progressive difficulty in walking and stiffness in both legs. He stumbled frequently. By early 1992 he noticed weakness and stiffness in both arms and hands with resultant difficulty in buttoning his clothes and performing routine manual tasks. In 1993 there was a change in his speech. He developed progressive difficulty in swallowing liquids with frequent bouts of coughing when attempting to swal* Corresponding author. Tel.: +44-171-3777472; fax: +44-171-3777008/ 3777318; e-mails: [email protected] or [email protected]
0960-8966/99/$ - see front matter PII: S09 60-8966(98)000 89-3
low quickly. He had no sensory symptoms, no change in his mental abilities or twitching of muscles. There was no neck pain or stiffness. His bladder and bowel functions were preserved. His weight and appetite were normal. There was no family history of neurological disorder. He continued to deteriorate, and by 1995 he required assistance for most activities of daily living. No new symptom suggestive of involvement of other parts of the neuraxis developed. A paraproteinemia of the IgM type was detected during investigation, and he was treated with a course of prednisolone and chlorambucil for a period of 6 months. There were no changes in his neurological disorder though the paraprotein levels dropped to normal values. The treatment was discontinued. By 1997, he was wheelchair bound with severe spasticity and could only communicate with great difficulty due to progressive dysarthria. He could not swallow solids but could manage semi-solids and liquids with some difficulty. Examination in mid-1993, revealed that he was an asthenic, afebrile individual without skin rash, lymphadenopathy or organomegaly. His vital signs were normal. Cardiorespiratory and gastrointestinal assessments were normal. On a Mini Mental Status Examination, his score was 29/ 29. There was a spastic dysarthria. The jaw-jerk was brisk and tongue movements were slow. Palatal movements were
1999 Elsevier Science B.V. All rights reserved
J. Desai, M. Swash / Neuromuscular Disorders 9 (1999) 38–40
symmetrically diminished and the gag reflex was exaggerated. No fasciculations were seen in the tongue or in other muscles. He was weak and spastic in all four limbs with the lower limbs more severely affected. His gait was spastic and laborious. There was no muscle wasting. Muscle strength was 3/5 in the proximal muscles and 3/5 to 4/5 in the distal muscles on the MRC scale. All the deep tendon reflexes were brisk and a few beats of clonus were elicited at both ankles. Both plantar responses were extensor. Sensory examination was normal and there were no cerebellar signs or nystagmus. Skull, spine, and peripheral nerve examination were normal. During the following 4 years his disability progressed and he became confined to a wheel-chair. Strength declined to 2/ 5 on the MRC scale in most muscles. Spasticity increased with progressively severe involvement of upper limb and oropharyngeal muscles. His mental state remained normal. There was no bladder or bowel dysfunction. He did not develop pressure sores. Normal tests included urinary analysis, hepato-renal biochemistry, vitamin B-12 levels, Lyme serology, serologic tests for syphilis, thyroid function tests, anti-dsDNA, ANA, RA and cryoglobulins. Haematological evaluation revealed an elevated ESR at 100–120 mm/h on serial assessments, with normal cellular counts and morphology on smear. Serum protein immuno-electrophoresis revealed an elevated monoclonal band of IgM (kappa light chains) in the range of 12–14 g/l. Chest X-ray, skull and spine X-rays, abdominal ultrasonography and CT of the chest and abdomen were all normal. A skeletal survey was normal. MRI of the brain and spine were normal. These radiological investigations were performed in 1995 and in 1997. Bone marrow biopsy performed in 1995 was normal. The patient refused a second marrow examination at follow-up in 1997. CSF examination revealed an elevated protein level at 65 and 90 g/l on two different occasions, with normal cellular counts and an absence of oligoclonal bands. Anti-MAG, anti-GM1 and anti-Hu antibodies were not detectable. Anti-SGPG antibodies titres could not be assessed. After a course of plasmapheresis at 40 ml/kg per day for 5 days followed by oral prednisolone and chlorambucil daily for 6 months, the IgM levels dropped to 2–4 g/l, without change in the neurological features. Nerve conduction and EMG studies were performed in all four limbs. Motor and sensory nerve conductions, F-wave responses, and H-reflex were normal. EMG examination of the proximal and distal muscles did not reveal any evidence of denervation. These neurophysiological findings did not change on follow-up 4 years later.
3. Discussion Our patient fulfils the clinical and laboratory criteria for primary lateral sclerosis proposed by Pringle et al. [2] in 1992. Laboratory investigations revealed an IgM (kappa
39
light chain) monoclonal gammopathy, persistently raised ESR, and elevated CSF protein. The usual neurological presentation of IgM paraproteinemia is that of a chronic, slowly progressive, sensory-motor, symmetrical polyneuropathy [5]. Occasionally, a fasciculatory postural tremor of the outstretched hands is observed. Neurophysiological assessment in these patients often reveals a demyelinating type of sensory-motor neuropathy. A proportion of these patients have an anti-MAG antibody in their sera which binds to the myelin sheaths of peripheral nerves. It is believed that this may lead to demyelinating neuropathy [5]. A raised ESR, an elevated CSF protein level and a characteristic M-band on immunoelectrophoresis are the major diagnostic features. Rare neurological manifestations of IgM paraproteinemia include the syndrome of continuous muscle fibre activity [6] and, possibly, amyotrophic lateral sclerosis [7]. Younger et al. [8,9] kindled interest in the clinical association between lymphoma, paraproteinemia, motor neuron diseases and amyotrophic lateral sclerosis. Gordon et al. [3] reported 26 patients with motor neuron disease in whom investigations revealed associated lymphoproliferative disease and reviewed 30 cases from other centres. They suggested that an elevated CSF protein may signal the presence of underlying lymphoproliferative disease in patients with MND with monoclonal gammopathy and a raised ESR [3,8]. They also noted that 56% of the 16 post-mortems performed in their patients revealed pathology in the pyramidal tracts. Clinically, all these patients had definite upper motor neuron signs. Our patient with the characteristic upper motor neuron features of primary lateral sclerosis had a persistently raised ESR and an elevated CSF protein level, raising a clinical suspicion of an underlying lymphoproliferative disorder. However, bone marrow biopsy and skeletal survey with imaging of the chest and abdomen failed to reveal an overt lymphoproliferative disorder or plasma cell dyscrasia. In one of the patients with clinical features of ALS reported by Gordon et al. [3], diffuse asymptomatic Hodgkin’s disease was detected only at autopsy despite extensive investigations performed during life. It is possible that our patient’s clinical syndrome has a similar basis. Leone and Phillips reported a patient with an anterior horn cell disorder and prominent upper motor neuron signs mimicking ALS, in whom investigations revealed an IgG paraproteinemia and marrow biopsy an asymptomatic, chronic lymphocytic leukaemia [4]. We considered a diagnosis of Bing–Neel syndrome in our patient but the marrow biopsy was normal and we did not detect hyperviscosity, a characteristic feature of this disorder. Our patient refused a second bone marrow biopsy, as his clinical symptoms had failed to respond to immunosuppressive therapy. The basis for the persistence of the neurological features after treatment of the gammopathy is unknown. It could be argued that our patient represents the mere chance association of primary lateral sclerosis and benign monoclonal gammopathy. Primary lateral sclerosis is so rare
40
J. Desai, M. Swash / Neuromuscular Disorders 9 (1999) 38–40
that the two largest series describing the disorder consist of a total of only 16 patients [1,2]. The incidence of benign monoclonal gammopathy increases with age reaching 3% in the eighth decade and 10% in the ninth decade [10]. Approximately 15–20% of M proteins are of the IgM type. We feel, as suggested by Gordon et al. [3] that the finding of an elevated CSF protein in our patient suggests a causative relation between the primary lateral sclerosis and the gammopathy. Primary lateral sclerosis has been reported previously in a patient with multiple myeloma [11]. We report the second description of paraproteinemia in a patient with primary lateral sclerosis, adding to the increasing suspicion of an association between motor neuron diseases and aberrant function of plasma/lymphoid cells [9]. The pathogenesis of neurological complications in lymphoproliferative disease is unknown, except in POEMS syndrome in which, endoneurial deposits of M protein have been detected by indirect immunolabelling techniques in nerve biopsy specimens [12]. Activation of the alternative pathway of complement and the ‘membrane attack complex’ by immuno-globulins could contribute to such damage [13]. We suspect that such mechanisms may have contributed to our patient’s clinical syndrome which was restricted to involvement of the upper motor neuron.
References [1] Younger DS, Chou S, Hays AP. Primary lateral sclerosis: a clinical diagnosis re-emerges. Arch Neurol 1988;45:1304–1307.
[2] Pringle CE, Hudson AJ, Munoz DG, Kiernan JA, Brown WF, Ebers GC. Primary lateral sclerosis: clinical features, neuropathology and diagnostic criteria. Brain 1992;115:495–520. [3] Gordon PH, Rowland LP, Younger DS, et al. Lymphoproliferative disorders and motor neuron disease: an update. Neurology 1997; 48:1671–1678. [4] Leone KV, Phillips LH. Lymphoproliferative disorders and motor neuron disease. To the editor. Neurology 1998;50:576. [5] Kelly JJ. Polyneuropathies associated with plasma cell dyscrasias. Semin Neurol 1987;7:30. [6] Zifko U, Drlicek M, Machacek E, Jellinger K, Grisold W. Syndrome of continuous muscle fibre activity and plasmacytoma with IgM paraproteinemia. Neurology 1994;44:560–561. [7] Rowland LP, Sherman WL, Hays AP, et al. Autopsy-proven amyotrophic lateral sclerosis, Waldenstrom’s macroglobulinemia and antibodies to sulphated glucuronic acid paragloboside. Neurology 1995;45:827–829. [8] Younger DS, Rowland LP, Latov N, et al. Motor neuron disease and amyotrophic lateral sclerosis: relation of high CSF protein content to paraproteinemia and clinical syndromes. Neurology 1990;40:595– 599. [9] Younger DS, Rowland LP, Latov N, et al. Lymphoma, motor neuron diseases, and amyotrophic lateral sclerosis. Ann Neurol 1991;29:78– 86. [10] Axelsson U, Bachmann R, Hallen J. Frequency of pathological proteins (M-components) in 6,995 sera from an adult population. Acta Med Scand 1966;179:235–247. [11] Brownell B, Trevor-Hughes J. Central nervous system in motor neuron disease. J Neurol Neurosurg Psychiatry 1970;33:338–357. [12] Adams D, Said G. Ultrastructural characterisation of the M protein in nerve biopsy of patients with POEMS syndrome. J Neurol Neurosurg Psychiatry 1998;64:809–812. [13] Hiemstra PS, Biewenga J, Corter A, et al. Activation of complement by human serum IgA, secretory IgA, and IgA1 fragments. Mol Immunol 1988;25:527–533.