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Original Article
Once myasthenic, always myasthenic? Observations on the behavior and prognosis of myasthenia gravis in a cohort of 100 patients Satish V. Khadilkar, Chetan R. Chaudhari, Tukaram R. Patil, Ninad D. Desai, Kamlesh A. Jagiasi, Ashish G. Bhutada Department of Neurology, Grant Government Medical College and Sir Jamshedjee Jeejeebhoy Group of Hospitals, Byculla, Mumbai, Maharashtra, India
Abstract
Address for correspondence: Dr. Satish V Khadilkar, 110, New Wing, First Floor, Bombay Hospital, 12, New Marine Lines, Mumbai ‑ 400 020, Maharashtra, India. E‑mail: [email protected] Received : 18‑07‑2014 Review completed : 25‑08‑2014 Accepted : 03‑10‑2014
Background: The natural history of myasthenia gravis [MG] is unpredictable: In the first few years the disease course is worst with subsequent gradual disease stabilization. However, some patients tend to have continued disease activity or resurgence of the disease many years into the illness. The factors correlating with disease course need further evaluation. Aims: To study the patterns of remissions, worsening and exacerbations in patients with MG and correlate various factors affecting them. Settings and Design: Retrospective, Institute Review Board (IRB) approved study in tertiary referral neurology center. Materials and Methods: Hundred patients with acquired MG confirming the inclusion criteria were studied. Pharmacological remissions, complete stable remissions, exacerbations, worsening episodes were analyzed with respect to age of onset, disease extent, disease severity at onset and worst of illness, acetyl choline receptor antibody positivity, thymectomy status, period of disease, pharmacotherapy and crisis episodes. Results and Conclusions: In this cohort the percentage of new remission rates per year steadily declined after the first year. Ocular myasthenia had lesser clinical worsening episodes and high chance of complete stable remission. Generalized disease had less chance drug free remission. The risk of episodes of worsening persisted at a steady rate over a period of time, being maximum in the first year. The risk of exacerbations was unpredictable and could occur after prolonged clinical quiescence, often was related to reduction of immunosuppression. The disease course did not differ significantly in the juvenile and adult age-groups. There was a strong case for permanent immunomodulation in MG. Key words: Exacerbation, myasthenia gravis, remission, worsening
Introduction Patients with myasthenia gravis (MG) experience Access this article online Quick Response Code:
Website: www.neurologyindia.com PMID: *** DOI: 10.4103/0028-3886.144438
492
fluctuations in disease activity and have periods of worsening, exacerbation, improvement and remission. Maximum worsening and severity of symptoms are often observed in the first few years and this is followed by clinical improvement.[1‑3] However, it is not uncommon for the patients with MG to have delayed recurrence after many years of onset or a initial stormy course. Some studies have studied the factors associated with remission.[1,4,5] However, the factors associated with deterioration have received little attention.[1,3] Thus there is a need to determine the patterns of remission, worsening and exacerbations in patients with MG. Such Neurology India | Sep-Oct 2014 | Vol 62 | Issue 5
[Downloaded free from http://www.neurologyindia.com on Thursday, November 13, 2014, IP: 202.177.173.189] || Click here to download free Android application fo journal Khadilkar, et al.: Behavior of mysathenia gravis
an analysis would have a bearing on the duration of pharmacological treatment and predicting the chance of disease remission. This study was undertaken to analyze the factors affecting pharmacological remission (PR) and remission off the drugs (complete stable remission, CSR), as well as worsening and exacerbation patterns in 100 patients with MG.
Materials and Methods This is a retrospective study, approved by the institutional review board. The study period was of 6 years, from January 2008 to December 2013. Inclusion criteria included [6] : Patient should have clinical evidence of fatigability in affected muscles, presence of acetylcholine receptor antibody or decremental response on repetitive nerve stimulation (RNS) testing. Exclusion criteria included [6]: Patients with congenital, neonatal, drug‑induced MG and Lambert Eaton Myasthenic syndrome (LEMS). Patients with inadequate records and history were also excluded. Patients with onset of disease before 18 years of age were grouped under juvenile MG.[7] Definitions of outcome parameters [8]: (1) Complete stable remission (CSR) is defined as patient not having symptoms of MG for at least 1 year and had not received any therapy for MG during this period. There should not be detectable weakness of any muscle on examination. Isolated weakness of eyelid closure is accepted; (2) pharmacological remission (PR): The definition criteria are similar to CSR except that the patient continues to take some form of disease‑modifying therapy other than exclusive anti‑cholinesterase medication; (3) minimal manifestations (MM), these patients otherwise fulfill the criteria for CSR or PR but have some weakness detectable on examination; (4) worsening is defined as substantial increase in clinical manifestations or need for more medication to control symptoms; (5) exacerbation is defined as the disease status meeting the criteria for CSR, PR or MM but subsequently developing disease symptoms in excess of those permitted by these criteria: (6) Improved (I) is defined as substantial improvement in the pretreatment clinical manifestations, or sustained and substantial reduction in MG medications as defined by protocol; (7) unchanged (U) is defined as no substantial decrease in pretreatment clinical manifestations or reduction in MG medications; and (8) crisis is defined as motor weakness severe enough to require intubation. Data was collected under following heads: (1) Patient characteristics including age, gender, family history, history of intake of drugs which may cause myasthenia; age at disease onset and the time to generalization; (2) myasthenia gravis foundation of America (MGFA) class[8] at onset, peak and last follow‑up; Neurology India | Sep-Oct 2014 | Vol 62 | Issue 5
timing of remissions, worsening episodes and disease exacerbations and the contributory factors; (3) details of myasthenic crisis episodes; (4) treatment details including dosages and duration of pyridostigmine, prednisolone, immunosuppressant, plasmapheresis and IVIG; and (5) details of thymectomy. I n v e s t i g a t i o n s i n c l u d e d [9]: C o m p l e t e b l o o d picture, thyroid, liver and kidney function tests; anti‑ Acetylcholine receptor (AChR) antibody levels; repetitive nerve stimulation, high‑resolution computerized tomogram (HRCT) scan of the chest, imaging brain as required. Acetyl choline receptor antibody (AChRab): Radioimmunoassay method was used for testing the antibody; values > 0.4 nmol/L were considered positive, values < 0.25 nmol/L were considered negative and values between 0.25 and 0.4 nmol/L were considered borderline.[10] Repetitive nerve stimulation (RNS) test[11]: RNS test was performed at skin temperatures between 34-37oC. Low‑frequency RNS testing was done at 2-3 Hz. Patients were off cholinesterase inhibitor medication for more than 24 hours before the testing. Abductor digitiminimi, extensor indicis, deltoid, trapezius, nasalis, orbicularis oculi and masseter muscles were examined. Decrement of greater than 10% in the baseline to peak amplitudes between first and fourth or fifth response was considered significant. When no decrement was observed with testing the muscles at rest, RNS was repeated after one‑minute voluntary exercise. Concentric needle electromyography and nerve conduction studies were done to rule out primary muscle disease, neuropathies, radiculopathies and anterior horn cell disorders. Therapy protocol included [9,12] : Initial treatment with acetyl cholinesterase inhibitors along with oral corticosteroids and plasmapheresis and immunoglobulin were used as rescue therapies. After a period of disease stabilization oral steroids were gradually tapered to the lowest effective dose along with addition of steroid sparing immunosuppressant. Statistics: Primer biostat software was used. Chi‑Square test and Fischer exact test were used for statistical testing. P
Original Article
Once myasthenic, always myasthenic? Observations on the behavior and prognosis of myasthenia gravis in a cohort of 100 patients Satish V. Khadilkar, Chetan R. Chaudhari, Tukaram R. Patil, Ninad D. Desai, Kamlesh A. Jagiasi, Ashish G. Bhutada Department of Neurology, Grant Government Medical College and Sir Jamshedjee Jeejeebhoy Group of Hospitals, Byculla, Mumbai, Maharashtra, India
Abstract
Address for correspondence: Dr. Satish V Khadilkar, 110, New Wing, First Floor, Bombay Hospital, 12, New Marine Lines, Mumbai ‑ 400 020, Maharashtra, India. E‑mail: [email protected] Received : 18‑07‑2014 Review completed : 25‑08‑2014 Accepted : 03‑10‑2014
Background: The natural history of myasthenia gravis [MG] is unpredictable: In the first few years the disease course is worst with subsequent gradual disease stabilization. However, some patients tend to have continued disease activity or resurgence of the disease many years into the illness. The factors correlating with disease course need further evaluation. Aims: To study the patterns of remissions, worsening and exacerbations in patients with MG and correlate various factors affecting them. Settings and Design: Retrospective, Institute Review Board (IRB) approved study in tertiary referral neurology center. Materials and Methods: Hundred patients with acquired MG confirming the inclusion criteria were studied. Pharmacological remissions, complete stable remissions, exacerbations, worsening episodes were analyzed with respect to age of onset, disease extent, disease severity at onset and worst of illness, acetyl choline receptor antibody positivity, thymectomy status, period of disease, pharmacotherapy and crisis episodes. Results and Conclusions: In this cohort the percentage of new remission rates per year steadily declined after the first year. Ocular myasthenia had lesser clinical worsening episodes and high chance of complete stable remission. Generalized disease had less chance drug free remission. The risk of episodes of worsening persisted at a steady rate over a period of time, being maximum in the first year. The risk of exacerbations was unpredictable and could occur after prolonged clinical quiescence, often was related to reduction of immunosuppression. The disease course did not differ significantly in the juvenile and adult age-groups. There was a strong case for permanent immunomodulation in MG. Key words: Exacerbation, myasthenia gravis, remission, worsening
Introduction Patients with myasthenia gravis (MG) experience Access this article online Quick Response Code:
Website: www.neurologyindia.com PMID: *** DOI: 10.4103/0028-3886.144438
492
fluctuations in disease activity and have periods of worsening, exacerbation, improvement and remission. Maximum worsening and severity of symptoms are often observed in the first few years and this is followed by clinical improvement.[1‑3] However, it is not uncommon for the patients with MG to have delayed recurrence after many years of onset or a initial stormy course. Some studies have studied the factors associated with remission.[1,4,5] However, the factors associated with deterioration have received little attention.[1,3] Thus there is a need to determine the patterns of remission, worsening and exacerbations in patients with MG. Such Neurology India | Sep-Oct 2014 | Vol 62 | Issue 5
[Downloaded free from http://www.neurologyindia.com on Thursday, November 13, 2014, IP: 202.177.173.189] || Click here to download free Android application fo journal Khadilkar, et al.: Behavior of mysathenia gravis
an analysis would have a bearing on the duration of pharmacological treatment and predicting the chance of disease remission. This study was undertaken to analyze the factors affecting pharmacological remission (PR) and remission off the drugs (complete stable remission, CSR), as well as worsening and exacerbation patterns in 100 patients with MG.
Materials and Methods This is a retrospective study, approved by the institutional review board. The study period was of 6 years, from January 2008 to December 2013. Inclusion criteria included [6] : Patient should have clinical evidence of fatigability in affected muscles, presence of acetylcholine receptor antibody or decremental response on repetitive nerve stimulation (RNS) testing. Exclusion criteria included [6]: Patients with congenital, neonatal, drug‑induced MG and Lambert Eaton Myasthenic syndrome (LEMS). Patients with inadequate records and history were also excluded. Patients with onset of disease before 18 years of age were grouped under juvenile MG.[7] Definitions of outcome parameters [8]: (1) Complete stable remission (CSR) is defined as patient not having symptoms of MG for at least 1 year and had not received any therapy for MG during this period. There should not be detectable weakness of any muscle on examination. Isolated weakness of eyelid closure is accepted; (2) pharmacological remission (PR): The definition criteria are similar to CSR except that the patient continues to take some form of disease‑modifying therapy other than exclusive anti‑cholinesterase medication; (3) minimal manifestations (MM), these patients otherwise fulfill the criteria for CSR or PR but have some weakness detectable on examination; (4) worsening is defined as substantial increase in clinical manifestations or need for more medication to control symptoms; (5) exacerbation is defined as the disease status meeting the criteria for CSR, PR or MM but subsequently developing disease symptoms in excess of those permitted by these criteria: (6) Improved (I) is defined as substantial improvement in the pretreatment clinical manifestations, or sustained and substantial reduction in MG medications as defined by protocol; (7) unchanged (U) is defined as no substantial decrease in pretreatment clinical manifestations or reduction in MG medications; and (8) crisis is defined as motor weakness severe enough to require intubation. Data was collected under following heads: (1) Patient characteristics including age, gender, family history, history of intake of drugs which may cause myasthenia; age at disease onset and the time to generalization; (2) myasthenia gravis foundation of America (MGFA) class[8] at onset, peak and last follow‑up; Neurology India | Sep-Oct 2014 | Vol 62 | Issue 5
timing of remissions, worsening episodes and disease exacerbations and the contributory factors; (3) details of myasthenic crisis episodes; (4) treatment details including dosages and duration of pyridostigmine, prednisolone, immunosuppressant, plasmapheresis and IVIG; and (5) details of thymectomy. I n v e s t i g a t i o n s i n c l u d e d [9]: C o m p l e t e b l o o d picture, thyroid, liver and kidney function tests; anti‑ Acetylcholine receptor (AChR) antibody levels; repetitive nerve stimulation, high‑resolution computerized tomogram (HRCT) scan of the chest, imaging brain as required. Acetyl choline receptor antibody (AChRab): Radioimmunoassay method was used for testing the antibody; values > 0.4 nmol/L were considered positive, values < 0.25 nmol/L were considered negative and values between 0.25 and 0.4 nmol/L were considered borderline.[10] Repetitive nerve stimulation (RNS) test[11]: RNS test was performed at skin temperatures between 34-37oC. Low‑frequency RNS testing was done at 2-3 Hz. Patients were off cholinesterase inhibitor medication for more than 24 hours before the testing. Abductor digitiminimi, extensor indicis, deltoid, trapezius, nasalis, orbicularis oculi and masseter muscles were examined. Decrement of greater than 10% in the baseline to peak amplitudes between first and fourth or fifth response was considered significant. When no decrement was observed with testing the muscles at rest, RNS was repeated after one‑minute voluntary exercise. Concentric needle electromyography and nerve conduction studies were done to rule out primary muscle disease, neuropathies, radiculopathies and anterior horn cell disorders. Therapy protocol included [9,12] : Initial treatment with acetyl cholinesterase inhibitors along with oral corticosteroids and plasmapheresis and immunoglobulin were used as rescue therapies. After a period of disease stabilization oral steroids were gradually tapered to the lowest effective dose along with addition of steroid sparing immunosuppressant. Statistics: Primer biostat software was used. Chi‑Square test and Fischer exact test were used for statistical testing. P
