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1 All authors: Department of Radiology, Changhai Hospital, 174 Changhai Rd., Shanghai, China 200433.
Received December 9, 2002;
accepted after revision March 18, 2003.
Address correspondence to P. Wang
(lionred98{at}sohu.com
or
zhangoldcat{at}hotmail.com).
Abstract
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SUBJECTS AND METHODS. The subjects were 45 patients with myasthenia gravis. The diagnosis was determined by the patients' histories, physical findings, neostigmine tests, and morphologic changes. According to the Osserman classification, the 45 patients with myasthenia gravis were classified as stage I (n = 26), stage III (n = 13), and stage IV (n = 6). A 21- or 22-gauge needle was inserted into the thymus under CT guidance, and then ethanol was injected step by step until it was distributed throughout the whole thymoma, the hyperplasia of the thymus, or the normal thymus. The amount of ethanol injected ranged from 2 to 13 mL, with a mean of 7 mL.
RESULTS. CT follow-up at 3-4 weeks showed that the thymus or thymoma was completely or mostly necrotized. CT follow-up at 3 months showed that the vertical, transverse, and anteroposterior dimensions of the thymus in all 45 myasthenia gravis patients decreased by 59.2%, 68.6%, and 73.2%, respectively, compared with those before percutaneous ethanol injection treatment. The therapeutic effect was observable clinically 2 days after treatment in 44 patients, including 36 patients who were able to open their eyes after treatment. A 5-year follow-up study showed that the condition markedly improved in 35 patients, improved in nine patients, and failed to improve in one patient who did not respond to the treatment. After treatment, 37 patients presented with low-grade fever (range, 37.3-37.7°C; mean, 37.5°C), which resolved 3 days later without treatment; all 45 patients complained of mild retrosternal pain after ethanol injection.
CONCLUSION. The therapeutic effect of CT-guided percutaneous ethanol injection into the thymus of patients with myasthenia gravis is definite. This procedure is safe and has low morbidity. CT-guided percutaneous ethanol injection is a minimally invasive alternative treatment for myasthenia gravis.
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Preparations Before Treatment
This project was approved before its initiation by the medical committee of
the hospital. The therapeutic effects and possible complications were fully
disclosed, and informed consent was obtained from every patient. Diazepam (10
mg) was prescribed to patients who were nervous. The clotting time was
recorded for every patient.
Before percutaneous ethanol injection, the operator (a professor or associate professor specializing in CT diagnosis and CT-guided interventional therapy) interpreted the CT images and planned the procedure so as to secure a safe route of needle insertion. It is preferable to select the puncture point beside the sternum and a route that does not transverse the thoracic cavity to avoid pneumothorax and pleuritis. If it is difficult to reach the thymus through the parasternal route, a puncture route through the sternum can be considered.
The Procedure
Patients were supine with the anterior chest exposed. The puncture point
was usually selected at a parasternal site. One puncture site was sufficient
for each patient. First, CT was performed to locate the thymus, and then the
safest and shortest route for inserting the needle was selected on the basis
of the calculated angle and depth. Parasternal puncture was used in 44
patients, and transsternal puncture was used in only one patient to avoid the
risk of causing pneumothorax.
The puncture site was sterilized routinely, draped, and anesthetized locally with 4-5 mL of 2% lidocaine. The needle was incrementally advanced to the target. The needle was inserted into the thymus incrementally according to the preplanned route, angle, and depth. When CT confirmed that the needle tip had reached the center of the thymus or thymoma, biopsy was performed using a 20-gauge core biopsy device. Then a 21- or 22-gauge puncture needle was inserted into the center of the thymus or thymoma as described previously, and ethanol containing 3-5% contrast material (Omnipaque [iohexol], Nycomed, Shanghai, China) was injected slowly into the thymus. The total amount of ethanol was equivalent to the volume of the thymus (the volume of the thymus or thymoma equals the sum of the area of each slice times the thickness; the area of each slice and the volume of the thymus or thymoma can be calculated by a CT workstation). The injection was completed in three or four steps. After each step, CT was performed to observe whether there was any reflux of the ethanol from the thymus. Because the thymus tissue is relatively soft, one injection site is usually enough to disperse the ethanol throughout the thymus. In cases of a large hyperplasia or thymoma, two or three sites can be used by adjusting the needle tip properly to ensure that ethanol is fully distributed throughout the thymus or thymoma. When the ethanol was fully distributed into the hyperplastic or normal thymus or the thymoma and the normal surrounding thymus, the needle was withdrawn. The puncture wound was cleansed and covered with aseptic gauze. One hundred milliliters of normal saline plus cephradine (6 g) was administered IV twice a day for 2 days to prevent infection; 5% glucose and saline 250 mL with 2.0 g of Dicynone ([ethamsylate] OM Pharma, Geneva, Switzerland) was administered IV to prevent hemorrhage.
Temperature and blood pressure were monitored closely for 1 week after treatment as well as patients' complaints and clinical manifestations. If the temperature exceeded 37.6°C, routine blood analysis was performed. Follow-up was conducted at 3-4 weeks; 3 and 6 months; and 1, 2, 3, 4, and 5 years; follow-up included CT evaluation of the thymus (performed by a senior CT radiologist), evaluation of clinical symptoms and signs (muscle tone), compliance with drug use, and evaluation of drug dosage (performed by senior neurologists).
Criteria for Clinical Outcomes
Clinically cured.—The clinical symptoms and signs
disappeared. The patient resumed a routine without using any drug for
myasthenia gravis; and there was no relapse during 3 years of follow-up.
Markedly improved.—The clinical symptoms and signs markedly improved; the patient was able to manage a daily routine and resume light work. The patient's drug dosage for myasthenia gravis was reduced by more than 75%.
Improved.—The clinical symptoms and signs improved. The patient was able to perform part of his or her daily routine, and the drug dosage for myasthenia gravis was reduced by more than 50%.
Failed.—The clinical symptoms and signs showed no improvement or became worse.
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CT Evaluation of Percutaneous Ethanol Injection
CT performed immediately after the treatment of percutaneous ethanol
injection showed that the ethanol-contrast mixture was distributed over the
whole thymus (Figs. 1A and
1B). CT follow-up at 3-4 weeks
showed that the 39 hyperplastic thymuses, one normal thymus, and five thymomas
presented with low density (Fig.
1C), which did not enhance after IV injection of 100 mL of
Omnipaque, indicating that the thymus or thymoma was completely or mostly
necrotized.
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The rate of decrease in vertical, transverse, and anteroposterior dimensions of the thymus and thymoma at different times after treatment is shown in Table 1.
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There was a decrease in vertical, transverse, and anteroposterior dimensions of the thymus or thymomas 3-4 weeks after treatment, and the decrease was more marked 3 months after treatment. The difference was significant compared with the size of the thymus or thymoma before treatment (p < 0.01). After 6 months, shrinkage began to slow down and showed no significant difference compared with the rate at 3 months after treatment (p > 0.05).
Therapeutic Effect of Percutaneous Ethanol Injection on Myasthenia
Gravis
Therapeutic effects were clinically observable 2 days after treatment by
percutaneous ethanol injection in 44 patients, and the treatment failed in one
patient. Thirty-six patients were able to open their eyes after treatment. In
three patients who had the disease for more than 15 years and in whom medical
treatment and radiotherapy had been unsuccessful, the symptoms improved
markedly after percutaneous ethanol injection, and they were able to resume a
daily routine. A 5-year follow-up study showed that, of the 45 patients who
received percutaneous ethanol injection, 35 had marked improvement, nine had
improvement, and one had no improvement.
Complications
Thirty-seven patients presented with low-grade fever (range,
37.3-37.7°C; mean, 37.5°C) after percutaneous ethanol injection that
resolved 3 days later without treatment. No febrile reaction was reported in
the remaining eight patients. All 45 patients complained of mild retrosternal
pain when ethanol was injected into the thymus, which subsided 2 days later
without treatment. No hemorrhage or infection was observed in any patient.
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The thymus is an important central immune organ and plays an important role in the development and progression of myasthenia gravis. According to the literature [6-8], 90% of patients with myasthenia gravis have an abnormality of the thymus, of whom 10-20% have thymoma, 70-80% have hyperplasia of the thymus, and only a few have a normal thymus. The data from the Changhai Hospital reveal that 30% of patients had thymoma and 50% had hyperplasia, and 33-75% of patients with thymoma had myasthenia gravis. In our series, 77.4% of patients with myasthenia gravis had hyperplasia of the thymus, and 16.1% had thymoma; these findings are consistent with what has been reported.
Histologic and immunologic studies have confirmed that acetylcholine receptors exist on the surface of myoid cells in the thymus. When the organism is diseased by infection or other causes, the acetylcholine receptors on the surface of myoid cells may fall off and contact the immune organ, producing an antibody. This secondarily causes a morphologic change of the acetylcholine receptors at the neuromuscular junction, leading to myasthenia gravis. In addition, hyperplasia in the thymus exacerbates the autoimmune reaction, causing significant elevation of autoimmune antibodies in serum [9], such as citric acid extract Ab, which is associated with the development of myasthenia gravis. Therefore, development and progression of myasthenia gravis is closely related to the thymus. Thymectomy and radiotherapy to relieve the symptoms are based on this understanding. The mechanism and basis of treatment with percutaneous ethanol injection lies in the fact that ethanol is capable of dehydrating the thymus and blocking blood vessels, causing coagulative necrosis of the tissue [10].
Comparison with Surgery and Radiotherapy and Indications for
Percutaneous Ethanol Injection
Most researchers believe that thymectomy is indicated for young men and
women who have onset of the disease at 20-30 years old, who present with
systemic myasthenia, and who have a poor response to anticholinesterase
treatment regardless of whether the antiacetylcholine receptor antibody level
is elevated or whether the condition is complicated by thymoma or hyperplasia
[11,
12]. There is controversy over
whether thymectomy is indicated for myasthenia gravis patients younger than 14
years old. It is generally accepted that surgical excision can be considered
for patients less than 14 years old who have systemic myasthenia gravis
[13,
14]. Surgical excision is
usually not considered for patients with the simple ophthalmoplegic type
unless the condition is becoming more severe and the patient has failed to
respond to anticholinesterase agents. The cure rate of thymectomy is between
70% and 90%, depending on the clinical classification, pathologic type,
pathologic grading, and duration of disease. Although the therapeutic outcome
of thymectomy is relatively good, the procedure is traumatic and has a high
risk of complications such as pneumothorax, hemorrhage, and infection. In
addition, thymectomy is not indicated for all patients.
The therapeutic rate of radiotherapy for myasthenia gravis is slightly less than that of thymectomy. The recommended dosage is 40-50 Gy or 60 Gy for thymoma. However, thymus radiotherapy is associated with a series of problems such as adverse reactions, unstable outcomes, and relapse of the clinical symptoms.
Considering the advantages and disadvantages, we believe that seeking a new effective technique with less trauma and lower morbidity is a task for clinical researchers. Comparing the therapeutic outcomes of thymectomy and radiotherapy, we found that CT-guided percutaneous ethanol injection is better, with a curative rate of 99% (44/45). The effects are rapid and durable. One reason may be that most of the patients in our series had Osserman stage I disease.
In our series, 37 of 45 patients presented with low-grade fever (range, 37.3-37.7°C; mean, 37.5°C), and all patients complained of mild retrosternal pain after treatment, but both fever and pain disappeared within 2 or 3 days with no treatment. This finding indicates that this technique is safe and minimally traumatic. One patient in our series failed to respond to the treatment. The reason for this failure is not known, nor is the reason known for failure of thymectomy in another patient.
Because percutaneous ethanol injection is safe and minimally traumatic, it can be used as an alternative treatment for patients with myasthenia gravis and hyperplasia of the thymus, normal thymus, or thymoma, for patients who do not wish to undergo thymectomy, or for those who had a poor response to radiotherapy.
We report the findings of 45 patients with myasthenia gravis who received CT-guided percutaneous ethanol injection of the thymus. A long-term follow-up study with more patients is needed to give a more comprehensive evaluation of the therapeutic outcome, morbidity, and advantages and disadvantages of the technique.
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