Immunosuppressive treatment of patients with amyotrophic lateral sclerosis Werdelin L, Boysen G , Jensen TS, Mogensen P. Immunosuppressive treatment of patients with amyotrophic lateral sclerosis. Acta Neurol Scand 1990: 82: 132-134. Documented treatment for amyotrophic lateral sclerosis (ALS) is not available. Several studies have suggested an immunological etiology and an effect on the course of disease, when ALS-patients were treated with immunosuppressants. The aim of the present study was to evaluate the effect of immunosuppressive therapy in ALS-patients comparing the course of disease in treated patients and in historic controls with ALS; 21 patients were included in the study, 17 men and 4 women. Median age at admission was 54 years for men and 61 years for women. 5 had progressive bulbar palsy, 7 both upper and lower motor neuron affections and 9 progressive muscular atrophy. Patients were treated with prednisolone and azathioprine for 1 year and examined regularly; 12 were treated and followed for more than a year. No definite difference between survival in treated patients and their controls was found.
Motor neuron disease or amyotrophic lateral sclerosis (ALS) is not an uncommon disease. The average annual incidence rate has been estimated to 1.4 per 100.000 in a Danish population sample, and the prevalence is low reflecting the short duration of disease (1). Although the cause of ALS is unknown, research activity has been greatly stimulated in the past decade. Toxic, immunologic and viral hypotheses are among the many possible etiologies that has been considered (2). Antibodies against motor horn-cells (3) and myelin (4)have been proved in single studies, as well as immunocomplexes found in renal glomeruli (5). Inhibition of axonal sprouting have been reported (6), as well as decreased activity of nerve-growth factor (7). Several studies suggest that auto-immunity plays a role in the pathogenesis of ALS (8), and several trials of immunosuppression in ALS have been reported but has so far not been able to alter the disease progress (9, 10). However, Ronnevi and Conradi reported in 1986 (1l),that a combined treatment of prednisone and azathioprine seemed to alter the clinical course of the disease. Therefore we found it indicated to try immunosuppression in this group of patients. Material and methods Inclusion
Patients between 25 and 75 years, who fulfilled the following diagnostic criteria: Bilateral progressive 132
L. Werdelin, G. Boysen, T.S. Jensen, P. Mogensen Departments of Neurology Rigshospitalet and Hvidovre Hospital, Copenhagen
Key words: ALS; immunosuppressant therapy; survival; clinical evaluation; scoring-system Lene Werdelin, Department of Neurology, Rigshospitalet, 9 Blegdamsvej, DK-2 100 Copenhagen, Denmark Accepted for publication March 21, 1990
bulbar palsy e.g. paresis and atrophy of the tongue with fasciculations often with cortico-spinal deficits. Upper and lower motor neuron involvement in more than one limb with fasciculations and hyperreflexia. Progressive muscular weakness and atrophy with diminished reflexes (progressive muscular atrophy). Typical changes at electromyography indicating diffuse motor neuron involvement in the presence of normal motor and sensory conduction studies. Exclusion
Exclusion criteria were evidence of compressive myelopathy, systemic disorders such as liver- or kidney-failure, advanced congestive heart-failure, endocrinopathy or autoimmune diseases, tuberculosis, lead-intoxication or monoclonal gammopathies, history or presence of malignancy, borreliosis. Before entering the study a control for each patient was selected from the diagnostic file, matching in sex, age, clinical type of ALS and age at onset, and who was admitted between 1970 and 84. Treatment
The patients were treated according to the schedule shown in Table 1, starting with an intravenous infusion of 1 g methylprednisolone, followed by oral prednisolone medication combined with azathioprine 2 mg/kg daily. Hematologic and hepatologic parameters as well as plasma-glucose were followed as also seen in Table 1. Clinical examination with rating of the patients
Immunosuppression in ALS Table 1. Treatment and control of ALS-patients within the study-period (12 months) Ca and Mg in plasma Hematology and hepatology parameters
1
1
every 3. month
1
1
every month
1
1
1
every 2. month
1 month
2 months
3 months
1 mg methylprednisolone i.v. in 3 days
prednisolone 100 mg every 2. day
75 mg every 2. day
Azathioprine 2 mg/kg daily
-+
1
1
1
1
Clinical control
status was performed using 1) a specially designed quantitated scoring-system assessing mainly upper and motor neuron function and 2) a clinical evaluation of muscle-function assessed by manual strength testing. Muscle assessment were performed in a standard position and included evaluation of the following paired muscle-groups : neck-flexion and extension, shoulder-abduction and adduction, elbow-flexion and extension, wrist-flexion and extension, thumb-abduction, adduction, opposition, finger-abduction, hip-flexion, extension and abduction, knee-flexion and extension, foot-dorsiflexion and plantarextension. Ratings were performed by the same examiner in individual patients every month the first 3 months followed by examination every second month. Results
Since 1986, 21 patients have been included in the study, 17 men and 4 women. Median age of registration was 54 years for men and 61 years for women and with an age of onset of 53 years and 59 years respectively. Five had progressive bulbar palsy, 7 both upper and lower motor neuron affections and 9 progressive muscular atrophy (Table 2). Treatment was withdrawn from 6 patients within the first year due to side-effects or personal reasons. One patient developed serologic affection of the liver, which
Table 2. Patients included in the study Clinical subtypes at onset
Males Females
Bulbar paralysis
ALS
PMA
Total
Age
Age at onset
4 1
6 1
7
2
17 4
54137-68) 61 149-69)
53(37-68) 59(49-691
Study group and control group were identical.
1
4 months 50 mg every 2 day
Table 3. Results Patients followed through more than one year Patients withdrawn from the study Patients, dead within the first year of observation Deceased within total observation period (1986-89) Median survival for patients Median survival for untreated controls
12 6 3 21
6 3 years 2.5 years
normalized following reduction of dose of azathioprine. Thus 12 patients were followed and treated for more than a year, while 3 patients died within the first year of treatment, 2 after more than 6 months treatment. Median survival of these patients was 3 years compared to 2'12 years for corresponding historic controls (Table 3). There was a steady progression of symptoms and signs in the treatment-period for all patients except in 1 patient with PMA, who has been stable for 3 years. Discussion
Immunosuppressive treatment with azathioprine and prednisone did not result in any definite differences between survival and clinical progression in treated patients and historic controls. However, the material is small and thorough statistical evaluation has not been possible. For the historic controls it was not possible to evaluate the course of disease thoroughly, and valid comparison could not be made. The little difference in survival could be due to symptomatic treatment especially in the terminal phase for the treated patients admitted within the last years, where new and better treatment principles have been used. Furthermore, there could very well be a slight effect on the clinical course due to frequent clinical controls. 133
Werdelin et a]. It is obvious that a placebo-controlled trial is superior to the present design, but difficult to set up for both ethical and compliance reasons. Natural history controls have been used in other studies (muscular dystrophy), but before this the natural history of Duchenne were documented through 8years by serial evaluations (12). To this end a thorough and serial evaluation of the natural history of ALS would be of value. One difsculty in clinical trials of ALS is evaluation of disease progression. We tried to quantitate strength and bulbar function as well as ADL and our patients were seen by the same physician at each visit causing a high intraexaminer reliability. Conradi and Ronnevi (13) have found stable symptoms or unusually slow progression in a small group of their immunosuppressed ALS-patients as judged from clinical observations through more than 2 years. In addition they found that the clinical effect was correlated to reduced cytotoxic activity in plasma from ALS-patients (14). Immunosuppression have been tried in other studies. Treatment with high-dose intravenous cyclophosphamide (9) as well as plasmafereses in combination with azathioprine (10) could not alter the progression of the disease, but recently has Appel et al. reported a double-blind study where cyclosporine diminished the progression rate in men who entered the study within 18months after onset of symptoms (15). While the present study has not been able to show a definite effect of immunosuppression,the studies of Conradi and Ronnevi (13, 14) and Appel et al. (15) suggest that immunosuppression has a slight effect. Thus further studies are necessary. The question remains if the immunologic abnormalities which has been described is an associated phenomenon or are due to the course of disease. References 1. HBJER-PEDERSEN E, CHRISTENSEN PB, JENSEN NB. Incidence and prevalence of motor neuron disease in 2 Danish counties. Neuroepidemiology 1989: 8: 151-159.
34
3. ~ I L N S ATL, T FINISON L, ANDRESP. Treatment of ALS: Critic of current ones and what the future holds. Abstract ALS Workshop 1986. 3. WOLFGRAMF, MYERSL. Amyotrophic lateral sclerosis effect of serum on anterior horn-cells in tissue culture. Science 1973: 179: 579-580. 4. LISAKRP, AWIMANB, NORMANM. Antimyelin antibodies in neurologic diseases. Archives of Neurology 1975: 32: 163-167. 5. OLDSTONE MBA, WILSONCG, PARRINLH et al. Evidence for immunecomplex formation in patients with amyotrophic lateral sclerosis. Lancet ii: 1976: 169. ME, BELTONAC, CASHMAN N et al. Inhibition of 6. GURNEY terminal axonal sprouting by serum from patients with amyotrophic lateral sclerosis. N Engl J Med 1984: 311: 933-939. 7. HENDERSON CE, HAUSERSL, HUCHETM, DESSIF et al. Extracts of muscle biopsies from patients with spinal muscular atrophies inhibit neurite outgrowth from spinal neurons. Neurology 1987: 37: 1361-1364. 8. PARRYGJ, HOLTZ SJ, BEN-ZEEVD etal. Gammopathy with proximal motor axonopathy simulating motor neuron disease. Neurology 1986: 36: 273-276. 9. BROWNRH, HAUSERSL, HARRINGTON H et al. Failure of immunosuppression with a 10-14 day course of high-dose intravenous cyclophosphamide to alter the progression of amyotrophic lateral sclerosis. Arch Neurol 1986: 43: 383-384. 10. KELEMEN J, HEDLUNDW, ORLINJB et al. Plasmapheresis with immunosuppression in amyotrophic lateral sclerosis. Arch Neurol 1988: 40: 752-753. 11. RONNEVILO, CONRADIS. A preliminary report on immunosuppressive treatment in a controlled study. Abstract ALS Workshop 1986. 12. MENDELLJR, PROVINCEMA, MOXLEYRT et al. Clinical investigation of Duchenne muscular dystrophy. A methodology for therapeutic trials based on natural history controls. Arch Neurol 1987: 44: 808-811. 13. CONRADI S, RONNEVILO. Effect of immunosuppression on cytotoxic activity in amyotrophic lateral sclerosis. Clinical Neuropharmacology 1987: 10: 280-286. 14. RONNEVILO, CONRADIS. Cytotoxic activity in ALSpatients. TSUBAKI T and YASEY, eds. Amyotrophic lateral sclerosis. Recent advances in research and treatment. Excerpta Medica, Elsevier Science Publishers 1988: 149-154. 15. APPEL SH, STEWARTS S , APPELW et al. A double-blind study of the effectiveness of cyclosporine in amyotrophic lateral sclerosis. Arch Neurol 1988: 45: 381-386.
Motor neuron disease or amyotrophic lateral sclerosis (ALS) is not an uncommon disease. The average annual incidence rate has been estimated to 1.4 per 100.000 in a Danish population sample, and the prevalence is low reflecting the short duration of disease (1). Although the cause of ALS is unknown, research activity has been greatly stimulated in the past decade. Toxic, immunologic and viral hypotheses are among the many possible etiologies that has been considered (2). Antibodies against motor horn-cells (3) and myelin (4)have been proved in single studies, as well as immunocomplexes found in renal glomeruli (5). Inhibition of axonal sprouting have been reported (6), as well as decreased activity of nerve-growth factor (7). Several studies suggest that auto-immunity plays a role in the pathogenesis of ALS (8), and several trials of immunosuppression in ALS have been reported but has so far not been able to alter the disease progress (9, 10). However, Ronnevi and Conradi reported in 1986 (1l),that a combined treatment of prednisone and azathioprine seemed to alter the clinical course of the disease. Therefore we found it indicated to try immunosuppression in this group of patients. Material and methods Inclusion
Patients between 25 and 75 years, who fulfilled the following diagnostic criteria: Bilateral progressive 132
L. Werdelin, G. Boysen, T.S. Jensen, P. Mogensen Departments of Neurology Rigshospitalet and Hvidovre Hospital, Copenhagen
Key words: ALS; immunosuppressant therapy; survival; clinical evaluation; scoring-system Lene Werdelin, Department of Neurology, Rigshospitalet, 9 Blegdamsvej, DK-2 100 Copenhagen, Denmark Accepted for publication March 21, 1990
bulbar palsy e.g. paresis and atrophy of the tongue with fasciculations often with cortico-spinal deficits. Upper and lower motor neuron involvement in more than one limb with fasciculations and hyperreflexia. Progressive muscular weakness and atrophy with diminished reflexes (progressive muscular atrophy). Typical changes at electromyography indicating diffuse motor neuron involvement in the presence of normal motor and sensory conduction studies. Exclusion
Exclusion criteria were evidence of compressive myelopathy, systemic disorders such as liver- or kidney-failure, advanced congestive heart-failure, endocrinopathy or autoimmune diseases, tuberculosis, lead-intoxication or monoclonal gammopathies, history or presence of malignancy, borreliosis. Before entering the study a control for each patient was selected from the diagnostic file, matching in sex, age, clinical type of ALS and age at onset, and who was admitted between 1970 and 84. Treatment
The patients were treated according to the schedule shown in Table 1, starting with an intravenous infusion of 1 g methylprednisolone, followed by oral prednisolone medication combined with azathioprine 2 mg/kg daily. Hematologic and hepatologic parameters as well as plasma-glucose were followed as also seen in Table 1. Clinical examination with rating of the patients
Immunosuppression in ALS Table 1. Treatment and control of ALS-patients within the study-period (12 months) Ca and Mg in plasma Hematology and hepatology parameters
1
1
every 3. month
1
1
every month
1
1
1
every 2. month
1 month
2 months
3 months
1 mg methylprednisolone i.v. in 3 days
prednisolone 100 mg every 2. day
75 mg every 2. day
Azathioprine 2 mg/kg daily
-+
1
1
1
1
Clinical control
status was performed using 1) a specially designed quantitated scoring-system assessing mainly upper and motor neuron function and 2) a clinical evaluation of muscle-function assessed by manual strength testing. Muscle assessment were performed in a standard position and included evaluation of the following paired muscle-groups : neck-flexion and extension, shoulder-abduction and adduction, elbow-flexion and extension, wrist-flexion and extension, thumb-abduction, adduction, opposition, finger-abduction, hip-flexion, extension and abduction, knee-flexion and extension, foot-dorsiflexion and plantarextension. Ratings were performed by the same examiner in individual patients every month the first 3 months followed by examination every second month. Results
Since 1986, 21 patients have been included in the study, 17 men and 4 women. Median age of registration was 54 years for men and 61 years for women and with an age of onset of 53 years and 59 years respectively. Five had progressive bulbar palsy, 7 both upper and lower motor neuron affections and 9 progressive muscular atrophy (Table 2). Treatment was withdrawn from 6 patients within the first year due to side-effects or personal reasons. One patient developed serologic affection of the liver, which
Table 2. Patients included in the study Clinical subtypes at onset
Males Females
Bulbar paralysis
ALS
PMA
Total
Age
Age at onset
4 1
6 1
7
2
17 4
54137-68) 61 149-69)
53(37-68) 59(49-691
Study group and control group were identical.
1
4 months 50 mg every 2 day
Table 3. Results Patients followed through more than one year Patients withdrawn from the study Patients, dead within the first year of observation Deceased within total observation period (1986-89) Median survival for patients Median survival for untreated controls
12 6 3 21
6 3 years 2.5 years
normalized following reduction of dose of azathioprine. Thus 12 patients were followed and treated for more than a year, while 3 patients died within the first year of treatment, 2 after more than 6 months treatment. Median survival of these patients was 3 years compared to 2'12 years for corresponding historic controls (Table 3). There was a steady progression of symptoms and signs in the treatment-period for all patients except in 1 patient with PMA, who has been stable for 3 years. Discussion
Immunosuppressive treatment with azathioprine and prednisone did not result in any definite differences between survival and clinical progression in treated patients and historic controls. However, the material is small and thorough statistical evaluation has not been possible. For the historic controls it was not possible to evaluate the course of disease thoroughly, and valid comparison could not be made. The little difference in survival could be due to symptomatic treatment especially in the terminal phase for the treated patients admitted within the last years, where new and better treatment principles have been used. Furthermore, there could very well be a slight effect on the clinical course due to frequent clinical controls. 133
Werdelin et a]. It is obvious that a placebo-controlled trial is superior to the present design, but difficult to set up for both ethical and compliance reasons. Natural history controls have been used in other studies (muscular dystrophy), but before this the natural history of Duchenne were documented through 8years by serial evaluations (12). To this end a thorough and serial evaluation of the natural history of ALS would be of value. One difsculty in clinical trials of ALS is evaluation of disease progression. We tried to quantitate strength and bulbar function as well as ADL and our patients were seen by the same physician at each visit causing a high intraexaminer reliability. Conradi and Ronnevi (13) have found stable symptoms or unusually slow progression in a small group of their immunosuppressed ALS-patients as judged from clinical observations through more than 2 years. In addition they found that the clinical effect was correlated to reduced cytotoxic activity in plasma from ALS-patients (14). Immunosuppression have been tried in other studies. Treatment with high-dose intravenous cyclophosphamide (9) as well as plasmafereses in combination with azathioprine (10) could not alter the progression of the disease, but recently has Appel et al. reported a double-blind study where cyclosporine diminished the progression rate in men who entered the study within 18months after onset of symptoms (15). While the present study has not been able to show a definite effect of immunosuppression,the studies of Conradi and Ronnevi (13, 14) and Appel et al. (15) suggest that immunosuppression has a slight effect. Thus further studies are necessary. The question remains if the immunologic abnormalities which has been described is an associated phenomenon or are due to the course of disease. References 1. HBJER-PEDERSEN E, CHRISTENSEN PB, JENSEN NB. Incidence and prevalence of motor neuron disease in 2 Danish counties. Neuroepidemiology 1989: 8: 151-159.
34
3. ~ I L N S ATL, T FINISON L, ANDRESP. Treatment of ALS: Critic of current ones and what the future holds. Abstract ALS Workshop 1986. 3. WOLFGRAMF, MYERSL. Amyotrophic lateral sclerosis effect of serum on anterior horn-cells in tissue culture. Science 1973: 179: 579-580. 4. LISAKRP, AWIMANB, NORMANM. Antimyelin antibodies in neurologic diseases. Archives of Neurology 1975: 32: 163-167. 5. OLDSTONE MBA, WILSONCG, PARRINLH et al. Evidence for immunecomplex formation in patients with amyotrophic lateral sclerosis. Lancet ii: 1976: 169. ME, BELTONAC, CASHMAN N et al. Inhibition of 6. GURNEY terminal axonal sprouting by serum from patients with amyotrophic lateral sclerosis. N Engl J Med 1984: 311: 933-939. 7. HENDERSON CE, HAUSERSL, HUCHETM, DESSIF et al. Extracts of muscle biopsies from patients with spinal muscular atrophies inhibit neurite outgrowth from spinal neurons. Neurology 1987: 37: 1361-1364. 8. PARRYGJ, HOLTZ SJ, BEN-ZEEVD etal. Gammopathy with proximal motor axonopathy simulating motor neuron disease. Neurology 1986: 36: 273-276. 9. BROWNRH, HAUSERSL, HARRINGTON H et al. Failure of immunosuppression with a 10-14 day course of high-dose intravenous cyclophosphamide to alter the progression of amyotrophic lateral sclerosis. Arch Neurol 1986: 43: 383-384. 10. KELEMEN J, HEDLUNDW, ORLINJB et al. Plasmapheresis with immunosuppression in amyotrophic lateral sclerosis. Arch Neurol 1988: 40: 752-753. 11. RONNEVILO, CONRADIS. A preliminary report on immunosuppressive treatment in a controlled study. Abstract ALS Workshop 1986. 12. MENDELLJR, PROVINCEMA, MOXLEYRT et al. Clinical investigation of Duchenne muscular dystrophy. A methodology for therapeutic trials based on natural history controls. Arch Neurol 1987: 44: 808-811. 13. CONRADI S, RONNEVILO. Effect of immunosuppression on cytotoxic activity in amyotrophic lateral sclerosis. Clinical Neuropharmacology 1987: 10: 280-286. 14. RONNEVILO, CONRADIS. Cytotoxic activity in ALSpatients. TSUBAKI T and YASEY, eds. Amyotrophic lateral sclerosis. Recent advances in research and treatment. Excerpta Medica, Elsevier Science Publishers 1988: 149-154. 15. APPEL SH, STEWARTS S , APPELW et al. A double-blind study of the effectiveness of cyclosporine in amyotrophic lateral sclerosis. Arch Neurol 1988: 45: 381-386.
