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 » Introduction
 »  Materials and Me...
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ORIGINAL ARTICLE
Year : 2014  |  Volume : 62  |  Issue : 5  |  Page : 492-497

Once myasthenic, always myasthenic? Observations on the behavior and prognosis of myasthenia gravis in a cohort of 100 patients


Department of Neurology, Grant Government Medical College and Sir Jamshedjee Jeejeebhoy Group of Hospitals, Byculla, Mumbai, Maharashtra, India

Date of Submission18-Jul-2014
Date of Decision25-Aug-2014
Date of Acceptance03-Oct-2014
Date of Web Publication12-Nov-2014

Correspondence Address:
Satish V Khadilkar
110, New Wing, First Floor, Bombay Hospital, 12, New Marine Lines, Mumbai - 400 020, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.144438

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 » Abstract 

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.


Keywords: Exacerbation, myasthenia gravis, remission, worsening


How to cite this article:
Khadilkar SV, Chaudhari CR, Patil TR, Desai ND, Jagiasi KA, Bhutada AG. Once myasthenic, always myasthenic? Observations on the behavior and prognosis of myasthenia gravis in a cohort of 100 patients. Neurol India 2014;62:492-7

How to cite this URL:
Khadilkar SV, Chaudhari CR, Patil TR, Desai ND, Jagiasi KA, Bhutada AG. Once myasthenic, always myasthenic? Observations on the behavior and prognosis of myasthenia gravis in a cohort of 100 patients. Neurol India [serial online] 2014 [cited 2019 Nov 17];62:492-7. Available from: http://www.neurologyindia.com/text.asp?2014/62/5/492/144438



 » Introduction Top


Patients with myasthenia gravis (MG) experience 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],[2],[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 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 Top


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; 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.

Investigations included [9] : Complete blood 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 34-37 o C. 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 < 0.05 was considered to be statistically significant.


 » Results Top


The analysis included 100 (65 males and 35 females) patients. Mean age at onset was 42.87 years (range 7-75 years) Mean age at onset for males was 45.67 years (seventh decade) and for females it was 37.65 years (peak fifth decade). Average duration of illness was 4.7 years (range 1-30 years).

At presentation of the 100 patients, the disease was restricted to ocular muscles in 61 (61%) patients [Table 1]. Of these 61 patients, 45 (75%) patients developed generalized disease during the course of the illness. Average period for generalization was 26.6 months, in 28 (62%) patients generalized occurred in the first year of illness. In 16 (16%) patients, the disease remained confined to ocular muscles, mean follow-up period of 4.5 years. Patients with generalized disease had a mean follow up of 4.9 years. Maximum severity of disease was observed in 75 patients in the first year of illness and 13 patients experienced crisis episodes during the study period.
Table 1: Outcomes in patients with ocular onset (N=61)

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PR was achieved in 39 (27 males, 12 females) patients and 6 (5 males, 1 female) of them obtained CSR during the entire course of illness. Sixteen patients went on to remission in the first year of illness, percentage of patients attaining PR declined steadily with increasing duration of illness [Figure 1] whereas cumulative proportion of patients in remission increased with increasing duration of illness [Figure 1]. At last follow-up, 37 patients were in PR, six patients had continued to be CSR, 28 patients improved, 20 worsened and 15 remained unchanged as compared to initial presentation.
Figure 1: Trend of new and cumulative remissions. Line with diamond mark shows the percentage of new remissions achieved in the given year [numerator: Patients beginning remission in the given year; denominator: Total number of non-remitted patients in that given year]. Line with square mark shows the cumulative percentage of remissions achieved from the onset [Numerator: Total number of patients in continued remission; Denominator: Total number of patient followed-up in that year]

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Sixty-three patients (male 39, female 24) experienced a total of 139 episodes of worsening. A total of 17 exacerbation episodes were seen in 14 (male 13, female 1) patients; of these five patients had PR and nine patients had MM. Year-to-year percentage of patients with worsening and exacerbation are shown in [Figure 2] and [Figure 3]. Patients with CSR had fewer numbers of worsening episodes (P = 0.02) and patients with PR experienced 21 episodes of worsening (P = 0.143). Of the 139 events of worsening, no apparent cause was found in 90 events and in the remaining the causes included: Reduction in the treatment in 14, stopping treatment in 13 and infections in 22. Amongst those who experienced episodes of exacerbation, stopping treatment was the cause in 10, reduction in therapy in four, and no apparent cause in three patients. Period of remission or MM before exacerbations was variable 1-17 years (1 year-6; 2 years-2; 3 years-2; 7 years-1; 9 years-1; 12 years-1; 17 years-1 patient).
Figure 2: Trend of worsening in time frame. Worsening is seen to continue with a steady rate every year after the peak in first year. [Numerator: Number of patients having worsening episode in given year; denominator: Total number of patients followed-up in that year]

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Figure 3: Trend of exacerbations in time frame. [Numerator: Number of patients having exacerbation episode in given year; denominator: Total number of patients with remission and minimal manifestations followed-up in that year]. [Stopping of disease modifying treatment was the most frequent cause, attributed in '10' exacerbation episodes amongst 17]

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CSRs were observed in a significant proportion of patients with disease limited to ocular muscles (31.25%) as compared to generalized disease (1.19%) (P < 0.001). Such relation was not observed with PR (P = 0.163). Patients with disease limited ocular muscles also had fewer number of worsening episodes (37.5%) as compared to those with generalized disease (67.85%) (P = 0.027). Significant correlation was not observed with exacerbation episodes (P = 1).

MGFA severity score at onset did not correlate significantly with PR (P = 0.917), CSR (P = 0.541) or worsening episodes (P = 0.119) [Figure 4] whereas exacerbation episodes were consistently observed only in patients with MGFA class I at onset (P = 0.001). MGFA severity score at worst was correlated inversely with PR (P = 0.019) and CSR (P < 0.001). MGFA score at worst did not show correlation with worsening (P = 0.05) [Figure 5] and exacerbation episodes (P = 0.417).
Figure 4: Correlation of 'MGFA at onset, with remission, worsening and exacerbations'. Line with diamond marks shows percentage patients with pharmacological remission; line with square mark shows percentage of patients with worsening; line with triangles shows percentage of patients with exacerbations episodes. Exacerbations seen to have occurred only in patients with class I MGFA at onset [Common denominator: Total number of patients in individual class of 'MGFA at onset']

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Figure 5: Correlation of 'peak MGFA, with remission, worsening and exacerbations'. Line with diamond marks shows percentage patients with pharmacological remission; line with square marks shows percentage of patients with worsening; line with triangles shows percentage of patients with exacerbations episodes. Pharmacological remission seen to be decreasing whereas worsening seen to be increasing with increasing MGFA class [Common denominator: Total number of patients in individual class of 'peak MGFA']

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Patients with disease onset in fifth and sixth decades had the most favorable prognosis in terms of PR (57.5%; P = 0.021), whereas patients with disease onset beyond the sixth decade had the worst outcome in terms of exacerbation episodes (29.1%, P = 0.007). No significant correlations were found between the decade of the disease onset and CSR (0.339) or worsening episodes (P = 0.077). AChRabs were positive in 85/97 patients. AChRab positivity did not have the effect on PR (P = 0.961), CSR (P = 0.756), worsening (P = 0.527) and exacerbations (P = 0.661). Seventeen episodes of myasthenic crisis were observed in 13 patients, none achieved CSR and no significant correlation was observed with PR (P = 0.241) either. High-resolution computed tomography (HRCT) chest showed thymic abnormalities in 29 patients, thymoma in 18 patients and thymic hyperplasia in 11 patients.

Disease-modifying therapy was given to 96 patients; four patients with only ocular manifestations received only pyridostigmine. At the time of last interview 16 patients were receiving steroids alone, 64 steroids and immunosuppressant, 14 azathioprine alone, and two mycophenolate mofetil alone. Adverse effects of medications were noticed in 23 patients; no correlation was observed with use of any category of drugs with PR (P = 0.689) or CSR (P = 0.881). Thymectomy was performed in 20 patients of whom 18 had thymoma. Thymectomy status did not correlate with PR (P = 0.8), CSR (P = 0.59) or exacerbations (P = 0.29) but those who underwent thymectomy had more number of worsening episodes (P = 0.003) than those who did not. Numbers of worsening episodes were more or less same before (30) and after (29) thymectomy in these patients.

Patients with juvenile onset MG (N = 8) were analyzed and compared with the adult onset group. Mean follow-up period was 8.5 years (range 2-19 years). At presentation, disease was limited to ocular muscles in five and it subsequently generalized in four of them. AChRab was positive in seven patients. As compared to adults, CSR was not seen in any patient (P = 1.0), PR was achieved in 2 (25%) patients (P = 0.477). A total of 10 episodes of worsening were observed in four (50%) patients (P = 0.463) and exacerbations were seen in two patients (P = 0.311), in eighth and fourteenth year of their illness respectively. There was no statistical difference in the studied parameters between the juvenile and adult groups.


 » Discussion Top


This study confirms the facts that true remissions are very few (6%) and with medicines satisfactory control of symptoms is achieved only in a proportion (39%) of MG patients. [1],[2],[3],[13],[14],[15]

This study probably for the first time documented that year to year remission rates decrease with time, maximum in the first year. Earlier studies suggested that remission rates increase with the duration of illness and spontaneous clinical remissions are likely from second year onwards. [1],[2],[3],[16],[17],[18] These studies have probably calculated cumulative remission rates. In this study also, cumulative remission rates increased with the duration of follow-up. Rates of occurrence of episodes of worsening were constant after first year of illness, maximal in the first year. Similarly, exacerbation episodes occurred consistently irrespective of duration of illness. However, earlier studies observed that after first 2 years the disease behavior is favorable. [1],[2],[3] The decline in the remission rates over years, the steady rate of deteriorations and unpredictable exacerbations in patients with stable disease are important as they highlight the long-term risk of recurrence of myasthenic symptoms and also argue for long-term treatment options.

The disease severity score at 1 year seemed more important than that at the onset. This study did not find significant difference in remission as well as worsening outcome with severity of disease at onset. Patients in whom the score was favorable and symptoms were restricted to ocular muscles at one year had a better outcome in terms of few worsening episodes and chance of achieving CSR. Only one previous study has documented the association of disease severity at one year in predicting CSR. [19]

The extent of disease at one year was also very important in predicting subsequent disease course. This study suggests that the outcomes in patients with ocular involvement could be (1) disease remaining restricted to ocular muscles at 1 year, achieving remission and even maintaining remission without drugs and (2) disease progressing to generalization and worsening. Some the patients in the second group may have remissions on pharmacotherapy and have chances of exacerbations were high in this group. The status of the disease at the end of first year clearly differentiates the two. In this study only one patient out of 84 with generalized disease had CSR while a third had PR. A proportion of this group of patients have chance of attaining CSR with a mean follow up of 4.9 years. [2],[3] However, in present study, occurrence of CSR was exceptional in the generalized disease group, making a case for prolonged drug therapy.

In this study outcomes in juvenile-onset MG were no different than the adult-onset MG at a mean follow-up of 8.5 years. CSR was not achieved in any of the juvenile patient, only two had PR and occurrences of worsening and exacerbations were noted irrespective of the duration of illness. All the eight patients required continued medications. Some studies suggest that Juvenile MG to have a favorable outcomes, [7],[13] while other studies suggest variable outcomes. Have. [20] The disease course in peri- and post-pubertal patients is similar to that of adults. [21] In this study juvenile MG group largely consisted of post-pubertal patients and the group behaved similar to the adult MG.

In this cohort, drug-free remissions were very few, mainly limited to ocular disease and it is difficult to say whether this group require long-term drug treatment. On the other hand, in the PR and MM group 20% had episodes of exacerbation. Stopping or reducing drug treatment was the commonest reason for these exacerbations. Four patients had their exacerbation episodes after 7 years of stable disease (PR or MM). The remaining patients in this study required long-term medication and still did not have adequate control at some stage of their disease. The optimal duration of therapy in MG is often case based and clinicians take a chance of reducing and eventually stopping therapy after an unspecified symptom free period. This is similar to the situation in other immunological disorders. [22],[23],[24] In some of these diseases, disease markers also come to be negative before the medicines are stopped. In MG however, AChRab can be positive in clinically quiet disease with or without drugs. [4] The declining remission rates over years, the steady rate of deteriorations over a prolonged disease period, unpredictability of exacerbations in controlled disease and propensity of deterioration after reducing immunosuppression in stable disease make a strong case for very long term immunosuppression in patients of MG.


 » Acknowledgement Top


Authors would like to thank Dr. Rakhil Yadav for his help and advice during preparation of the manuscript.

 
 » References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
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