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Effectiveness of Therapeutic Plasma Exchange in Myasthenia Gravis
Original Article
EFFECTIVENESS OF THERAPEUTIC PLASMA EXCHANGE IN MYASTHENIA GRAVIS R N Makroo*, V Raina**, A Kohli***, V Suri*** and P Kumar+ *Director, **Senior Consultant, Department of Transfusion Medicine, ***Senior Consultant, Department of Neurology, +Registrar, Department of Transfusion Medicine, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India. Correspondence to: Dr. R N Makroo, Director, Department of Transfusion Medicine, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India. Background: Myasthenia gravis is the most common primary disorder of neuromuscular transmission, caused by an acquired immunological abnormality. The patients have a weakness of muscles which can sometimes be life threatening. Treatment modalities include administration of anti- cholinesterase drugs, corticosteroids, immunosuppression drugs, thymectomy, therapeutic plasma exchange and intra venous immunoglobulin (IVIg) and permutation and combination of all these therapies. Aim & Objective: We conducted a retrospective study in Myasthenia gravis patients to find and compare the effectiveness of IVIg treatment vis-à-vis therapeutic plasma exchange, at our hospital. Material & Methods: A total of 60 patients (35 males and 25 females) with a diagnosis of Myasthenia gravis, admitted between 1st January2000 to 31st December 2006 were retrospectively analyzed. Nineteen patients were treated by doing Therapeutic Plasma Exchange (TPE) of approximately 1-1.5 times the patient’s plasma volume on Haemonetics cell separator (MCS / MCS 3p) using FFP 80% & Normal Saline 20% as replacement fluid. All the patients had central line in place for doing the procedure. The case files of all these patients were scrutinized and the treatment modalities were compared. The duration of illness, clinical features, need for assisted / mechanical ventilation, hospital stay, number of therapeutic plasma exchanges performed were analyzed. Results: Twenty four of the 60 Myasthenic patients (40%) improved clinically on anti-cholinesterase drugs alone. The other 36 patients (60%) underwent thymectomy followed by medications (anti-cholinesterase & cortico-steroids). Twelve of these patients improved their muscle power, recovered clinically and were discharged. Six of the remaining 24 patients (average age 45.6 yrs.) were readmitted with myasthenic crisis or impending myasthenic crisis & were put on TPE as next treatment modality and all 6 responded to treatment. Eighteen patients were given IVIg therapy after they showed non-responsiveness to steroids & or immuno-suppressant drugs. Five of these were of younger age group (average age of 23.6 yrs) & recovered completely with IVIg treatment. Thirteen patients did not show substantial improvement & had to be supplemented with TPE. Ten of these patients responded to treatment (average age of 46.1 yrs) while 3 succumbed to the disease process. Conclusion: TPE is a better option as the next line of treatment modality in older patients not responsive to thymectomy & medications. IVIg is the preferred line of treatment in the younger myasthenic patients unresponsive to thymectomy and medications. TPE resulted in less hospital stay and thus decrease in overall expense in treatment. Key words: Myasthenia gravis (MG), Immunoglobulins(IVIg)
Therapeutic
INTRODUCTION MYASTHENIA Gravis (MG) is the most common primary disorder of neuromuscular transmission. What was once a relatively obscure condition of interest primarily to neurologists is the best characterized and understood autoimmune disease. A wide range of potentially effective treatments are available, many of which have implication for the treatment of other autoimmune disorders [1]. It is an acquired autoimmune disease with antibodies against the nicotinic acetylcholine receptor (AChR) at the neuromuscular junction [2]. The hallmark of myasthenia gravis is muscle weakness that increases during periods of activity and improves after periods of rest. Certain muscles such as those that control eye and eyelid movement, facial Apollo Medicine, Vol. 5, No. 2, June 2008
118
Plasma
Exchange(TPE),
Intravenous
expression, chewing, talking, and swallowing are often, but not always, involved. The muscles that control breathing and neck and limb movements may also be affected. Treatment modalities include administration of anti-cholinesterase drugs, corticosteroids, immunosuppression drugs, thymectomy, therapeutic plasma exchange and intra venous immunoglobulin (IVIg) and permutation and combination of all these therapies. MATERIAL AND METHODS A total of 60 patients (35 males & 25 females) were admitted with a diagnosis of myasthenia gravis at Indraprastha Apollo Hospitals between 1st January 2000 to 31st December 2006.We retrospectively analyzed the case
Original Article
records of all these patients. Nineteen patients were treated by doing TPE of approximately 1-1.5 times the patient’s plasma volume on Haemonetics cell separator (MCS + / MCS 3p) using FFP 80% & Normal Saline 20% as replacement fluid. All the patients had central line in place for doing the procedure. The case files of all these patients were scrutinized and the treatment modalities were compared. The duration of illness, clinical features, need for assisted / mechanical ventilation, hospital stay, number of therapeutic plasma exchange performed were analyzed. The patients were categorized as per the Myasthenia Gravis foundation of America (MGFA) classification into various classes (as at the time of admission). Twenty four patients falling in MGFA class IV and class V (severe myasthenia and myasthenia crisis), received either IVIg or plasma exchange or a combination of both. RESULT Twenty four of the 60 patients (40%) had improved clinically on anti-cholinesterase drugs alone and did not require IVIg or therapeutic plasma exchange. The other 36 patients (60%) underwent thymectomy followed by medications (anti-cholinesterase & cortico-steroids). Twelve of these patients had significant improvement in their muscle weakness & improved their power after thymectomy and medications. No significant improvement occurred in the other 24 patients. Six of the remaining 24 patients (average age 45.6 yrs.) were readmitted with myasthenic crisis or impending myasthenic crisis & were put on TPE as next treatment modality and all 6 responded to treatment. The average age of these 6 patients was 45.6 years (youngest 22 yrs to oldest 60 yrs) & the earliest remission was noticed within 5 days of starting TPE. These improved clinically and their average hospital stay was 7.1 days after starting TPE. Eighteen patients were given IVIg therapy after they showed non-responsiveness to steroids & or immuno-suppressant drugs. Five of these 18 patients responded well to treatment. Their average age was 23.6 yrs (youngest 7 yrs to oldest 49 yrs) & average hospital stay was 12.6 days of starting IVIg. Thirteen patients who initially received intravenous immunoglobulin (IVIg) following failure of response to medication and thymectomy had to be augmented with TPE as IVIg therapy alone was not effective in them. Three of these patients still did not improve in spite of extensive TPE and IVIg. The average hospital stay of these 3 patients was 147.33 days. These patients died during their hospital stay. The hospital stay of these three patients was 77 days, 137days, and 228 days. Ten patients who had partial and or minimal benefits on IVIg once supplemented with TPE did show response. The average number of days for achieving a significant improvement in power in these patients was 19.7 days. The average age of these ten patients who required both IVIg
and TPE was 46.1 years (32 yrs to 65 yrs) (Fig. 1). DISCUSSION The present study was conducted with the objective to analyze the treatment based distribution of cases of myasthenia gravis, encountered in our hospital from 2000 to 2006 with reference to age, sex, IVIg, TPE, Thymectomy, and average hospital stay. Very few studies on the various treatment modalities have been carried out both in India and abroad. The mean age of myasthenia patients in our study was 40 yrs (7 yrs to 68 yrs). Therapeutic Plasma Exchange was effective in all age groups. Patients of younger age group responded more to IVIg. As age advances, the probability of supplementing IVIg with TPE increased. The time to achieve clinical improvement with TPE was 7.1 days as compared to IVIg, which was 12.6 days. In patients whom IVIg was not effective, the hospital stay as well as the cost of treatment went up. In contrast Murthy & colleagues found that in patients with myasthenic crisis, both therapeutic options, TPE and IVIg, are equally effective in disease stabilization[3]. Skeie et al 2006 recommended anticholinesterase drugs to be the first line to be given in the management of MG. PE is recommended as a short term treatment in MG specially in severe cases to induce remission and in preparation for surgery. IVIg and PE are equally effective for the treatment of myasthenia gravis exacerbations [4]. Yeh et al in 1999 found daily plasmapheresis to be more effective in the treatment of patients with advanced Myasthenia gravis [5]. Howard recommended that IVIg appears to have a role as an acute treatment intervention in rapidly progressive weakness or as a chronic maintenance therapy when all other treatment modalities have failed. Its response is similar to but slower than the response of TPE [6]. CONCLUSION TPE is a better option as the next line of treatment modality in older patients not responsive to thymectomy & medications. IVIg is the preferred line of treatment in the younger myasthenic patients unresponsive to thymectomy and medications. TPE resulted in less hospital stay and decrease in overall expense in treatment. REFERENCE
119
1. James F Howard. Myasthenia gravis foundation of America, Myasthenia gravis-A Summary.11 Nov1997. 2. Kalb B, Matell G, Pirskanen R. Epidemiology of Myasthenia Gravis: A Population Based Study in Stockholm Sweden, Neuroepidemiology 2002; 21(5): 221-225. Apollo Medicine, Vol. 5, No. 2, June 2008
Original Article
60 Hospitalized Myasthenia Gravis / Crisis Patients Anti-cholinesterase drugs
24 patients improved clinically
36 patients did not improve Thymectomy + medications
24 patients did not improve 6 patients received only TPE (Impending myasthenic crisis)
12 patients showed clinical improvement & discharged
18 patients instituted IVIg therapy (After non-responsiveness to steroids/immuno-suppressants)
All 6 patients recovered
5 patients recovered with only IVIg therapy
13 patients did not show substantial improvement 13 patients given TPE in addition to IVIg
10 patients recovered
3 patients had a fatal prognosis
Fig.1. An analysis of various treatment modalities received with their prognosis Myasthenia gravis patients.
3. Murthy JM, Meena AK Chowdary GV, Naryanan JT. Myasthenia crisis: Clinical features, complications and mortality. Neurology India. 2005; 53(1): 37-40. 4. Skeie GO, Apostolski S, Evoli A, Gilhus NE, Hart IK, Harms L, et al. Guidelines for treatment of autoimmune neuromuscular transmission disorders. Europ. J. Neurology. 2006; 13(7): 691-699.
Apollo Medicine, Vol. 5, No. 2, June 2008
120
5. Yeh J-H. Compare the efficacy of different protocols of plasmapheresis in the treatment of myasthenia gravis. Acta Neurologica Scandinavica1999; 3 (3): 147151. 6. Howard Jr JF. Intravenous immunoglobulins for the treatment of acquired myasthenia gravis. Neurology. 51. (6) S30-S36.
EFFECTIVENESS OF THERAPEUTIC PLASMA EXCHANGE IN MYASTHENIA GRAVIS R N Makroo*, V Raina**, A Kohli***, V Suri*** and P Kumar+ *Director, **Senior Consultant, Department of Transfusion Medicine, ***Senior Consultant, Department of Neurology, +Registrar, Department of Transfusion Medicine, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India. Correspondence to: Dr. R N Makroo, Director, Department of Transfusion Medicine, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India. Background: Myasthenia gravis is the most common primary disorder of neuromuscular transmission, caused by an acquired immunological abnormality. The patients have a weakness of muscles which can sometimes be life threatening. Treatment modalities include administration of anti- cholinesterase drugs, corticosteroids, immunosuppression drugs, thymectomy, therapeutic plasma exchange and intra venous immunoglobulin (IVIg) and permutation and combination of all these therapies. Aim & Objective: We conducted a retrospective study in Myasthenia gravis patients to find and compare the effectiveness of IVIg treatment vis-à-vis therapeutic plasma exchange, at our hospital. Material & Methods: A total of 60 patients (35 males and 25 females) with a diagnosis of Myasthenia gravis, admitted between 1st January2000 to 31st December 2006 were retrospectively analyzed. Nineteen patients were treated by doing Therapeutic Plasma Exchange (TPE) of approximately 1-1.5 times the patient’s plasma volume on Haemonetics cell separator (MCS / MCS 3p) using FFP 80% & Normal Saline 20% as replacement fluid. All the patients had central line in place for doing the procedure. The case files of all these patients were scrutinized and the treatment modalities were compared. The duration of illness, clinical features, need for assisted / mechanical ventilation, hospital stay, number of therapeutic plasma exchanges performed were analyzed. Results: Twenty four of the 60 Myasthenic patients (40%) improved clinically on anti-cholinesterase drugs alone. The other 36 patients (60%) underwent thymectomy followed by medications (anti-cholinesterase & cortico-steroids). Twelve of these patients improved their muscle power, recovered clinically and were discharged. Six of the remaining 24 patients (average age 45.6 yrs.) were readmitted with myasthenic crisis or impending myasthenic crisis & were put on TPE as next treatment modality and all 6 responded to treatment. Eighteen patients were given IVIg therapy after they showed non-responsiveness to steroids & or immuno-suppressant drugs. Five of these were of younger age group (average age of 23.6 yrs) & recovered completely with IVIg treatment. Thirteen patients did not show substantial improvement & had to be supplemented with TPE. Ten of these patients responded to treatment (average age of 46.1 yrs) while 3 succumbed to the disease process. Conclusion: TPE is a better option as the next line of treatment modality in older patients not responsive to thymectomy & medications. IVIg is the preferred line of treatment in the younger myasthenic patients unresponsive to thymectomy and medications. TPE resulted in less hospital stay and thus decrease in overall expense in treatment. Key words: Myasthenia gravis (MG), Immunoglobulins(IVIg)
Therapeutic
INTRODUCTION MYASTHENIA Gravis (MG) is the most common primary disorder of neuromuscular transmission. What was once a relatively obscure condition of interest primarily to neurologists is the best characterized and understood autoimmune disease. A wide range of potentially effective treatments are available, many of which have implication for the treatment of other autoimmune disorders [1]. It is an acquired autoimmune disease with antibodies against the nicotinic acetylcholine receptor (AChR) at the neuromuscular junction [2]. The hallmark of myasthenia gravis is muscle weakness that increases during periods of activity and improves after periods of rest. Certain muscles such as those that control eye and eyelid movement, facial Apollo Medicine, Vol. 5, No. 2, June 2008
118
Plasma
Exchange(TPE),
Intravenous
expression, chewing, talking, and swallowing are often, but not always, involved. The muscles that control breathing and neck and limb movements may also be affected. Treatment modalities include administration of anti-cholinesterase drugs, corticosteroids, immunosuppression drugs, thymectomy, therapeutic plasma exchange and intra venous immunoglobulin (IVIg) and permutation and combination of all these therapies. MATERIAL AND METHODS A total of 60 patients (35 males & 25 females) were admitted with a diagnosis of myasthenia gravis at Indraprastha Apollo Hospitals between 1st January 2000 to 31st December 2006.We retrospectively analyzed the case
Original Article
records of all these patients. Nineteen patients were treated by doing TPE of approximately 1-1.5 times the patient’s plasma volume on Haemonetics cell separator (MCS + / MCS 3p) using FFP 80% & Normal Saline 20% as replacement fluid. All the patients had central line in place for doing the procedure. The case files of all these patients were scrutinized and the treatment modalities were compared. The duration of illness, clinical features, need for assisted / mechanical ventilation, hospital stay, number of therapeutic plasma exchange performed were analyzed. The patients were categorized as per the Myasthenia Gravis foundation of America (MGFA) classification into various classes (as at the time of admission). Twenty four patients falling in MGFA class IV and class V (severe myasthenia and myasthenia crisis), received either IVIg or plasma exchange or a combination of both. RESULT Twenty four of the 60 patients (40%) had improved clinically on anti-cholinesterase drugs alone and did not require IVIg or therapeutic plasma exchange. The other 36 patients (60%) underwent thymectomy followed by medications (anti-cholinesterase & cortico-steroids). Twelve of these patients had significant improvement in their muscle weakness & improved their power after thymectomy and medications. No significant improvement occurred in the other 24 patients. Six of the remaining 24 patients (average age 45.6 yrs.) were readmitted with myasthenic crisis or impending myasthenic crisis & were put on TPE as next treatment modality and all 6 responded to treatment. The average age of these 6 patients was 45.6 years (youngest 22 yrs to oldest 60 yrs) & the earliest remission was noticed within 5 days of starting TPE. These improved clinically and their average hospital stay was 7.1 days after starting TPE. Eighteen patients were given IVIg therapy after they showed non-responsiveness to steroids & or immuno-suppressant drugs. Five of these 18 patients responded well to treatment. Their average age was 23.6 yrs (youngest 7 yrs to oldest 49 yrs) & average hospital stay was 12.6 days of starting IVIg. Thirteen patients who initially received intravenous immunoglobulin (IVIg) following failure of response to medication and thymectomy had to be augmented with TPE as IVIg therapy alone was not effective in them. Three of these patients still did not improve in spite of extensive TPE and IVIg. The average hospital stay of these 3 patients was 147.33 days. These patients died during their hospital stay. The hospital stay of these three patients was 77 days, 137days, and 228 days. Ten patients who had partial and or minimal benefits on IVIg once supplemented with TPE did show response. The average number of days for achieving a significant improvement in power in these patients was 19.7 days. The average age of these ten patients who required both IVIg
and TPE was 46.1 years (32 yrs to 65 yrs) (Fig. 1). DISCUSSION The present study was conducted with the objective to analyze the treatment based distribution of cases of myasthenia gravis, encountered in our hospital from 2000 to 2006 with reference to age, sex, IVIg, TPE, Thymectomy, and average hospital stay. Very few studies on the various treatment modalities have been carried out both in India and abroad. The mean age of myasthenia patients in our study was 40 yrs (7 yrs to 68 yrs). Therapeutic Plasma Exchange was effective in all age groups. Patients of younger age group responded more to IVIg. As age advances, the probability of supplementing IVIg with TPE increased. The time to achieve clinical improvement with TPE was 7.1 days as compared to IVIg, which was 12.6 days. In patients whom IVIg was not effective, the hospital stay as well as the cost of treatment went up. In contrast Murthy & colleagues found that in patients with myasthenic crisis, both therapeutic options, TPE and IVIg, are equally effective in disease stabilization[3]. Skeie et al 2006 recommended anticholinesterase drugs to be the first line to be given in the management of MG. PE is recommended as a short term treatment in MG specially in severe cases to induce remission and in preparation for surgery. IVIg and PE are equally effective for the treatment of myasthenia gravis exacerbations [4]. Yeh et al in 1999 found daily plasmapheresis to be more effective in the treatment of patients with advanced Myasthenia gravis [5]. Howard recommended that IVIg appears to have a role as an acute treatment intervention in rapidly progressive weakness or as a chronic maintenance therapy when all other treatment modalities have failed. Its response is similar to but slower than the response of TPE [6]. CONCLUSION TPE is a better option as the next line of treatment modality in older patients not responsive to thymectomy & medications. IVIg is the preferred line of treatment in the younger myasthenic patients unresponsive to thymectomy and medications. TPE resulted in less hospital stay and decrease in overall expense in treatment. REFERENCE
119
1. James F Howard. Myasthenia gravis foundation of America, Myasthenia gravis-A Summary.11 Nov1997. 2. Kalb B, Matell G, Pirskanen R. Epidemiology of Myasthenia Gravis: A Population Based Study in Stockholm Sweden, Neuroepidemiology 2002; 21(5): 221-225. Apollo Medicine, Vol. 5, No. 2, June 2008
Original Article
60 Hospitalized Myasthenia Gravis / Crisis Patients Anti-cholinesterase drugs
24 patients improved clinically
36 patients did not improve Thymectomy + medications
24 patients did not improve 6 patients received only TPE (Impending myasthenic crisis)
12 patients showed clinical improvement & discharged
18 patients instituted IVIg therapy (After non-responsiveness to steroids/immuno-suppressants)
All 6 patients recovered
5 patients recovered with only IVIg therapy
13 patients did not show substantial improvement 13 patients given TPE in addition to IVIg
10 patients recovered
3 patients had a fatal prognosis
Fig.1. An analysis of various treatment modalities received with their prognosis Myasthenia gravis patients.
3. Murthy JM, Meena AK Chowdary GV, Naryanan JT. Myasthenia crisis: Clinical features, complications and mortality. Neurology India. 2005; 53(1): 37-40. 4. Skeie GO, Apostolski S, Evoli A, Gilhus NE, Hart IK, Harms L, et al. Guidelines for treatment of autoimmune neuromuscular transmission disorders. Europ. J. Neurology. 2006; 13(7): 691-699.
Apollo Medicine, Vol. 5, No. 2, June 2008
120
5. Yeh J-H. Compare the efficacy of different protocols of plasmapheresis in the treatment of myasthenia gravis. Acta Neurologica Scandinavica1999; 3 (3): 147151. 6. Howard Jr JF. Intravenous immunoglobulins for the treatment of acquired myasthenia gravis. Neurology. 51. (6) S30-S36.