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УДК: 616.831.8-009.17
A-М. Bubuioc1, A. Kudebayeva2, S. Turuspekova3, V. Lisnic1
1Department of Neurology, Nicolae Testemitanu State University of Medicine and Pharmacy Diomid Gherman Institute of Neurology and Neurosurgery Chisinau, the Republic of Moldova 2 Department of Neurology, Kazakh Medical University of Continuing Education 3 Department of Nervous Diseases with course of Neurosurgery Asfendiyarov Kazakh National Medical University Almaty, Kazakhstan
LAMBERT-EATON MYASTHENIC SYNDROME
Resume: Lambert-Eaton myasthenic syndrome (LEMS) is a neuromuscular junction disorder in which antibodies against voltage-gated calcium channels (VGCC) arise as a result of a cross-reaction with an underlying tumor (most frequently small lung cell carcinoma), or as a primary autoimmune process. The clinical criteria are proximal muscle weakness, autonomic symptoms, reduced tendon reflexes, positive VGCC antibodies and repetitive nerve stimulation abnormalities. Once the suspicion of LEMS arises, patients require thorough investigations and diligent monitoring. Keywords: Lambert-Eaton myasthenic syndrome, paraneoplastic, increment
А-М. Бубуёк1, А.Ж. Кудебаева2, С.Т. ТуруспековаЗ, В.С. Лисник1
1 Николае Тестемицану атындагы мемлекетткмедицина жэне фармацияyHueepcumemi Диомид Герман атындагы неврология жэне Нейрохирургия институты Кишинев, Молдова Республикасы 2 Цазац медициналыц узджаз быт беру унuверcuтетi Алматы, Цазацстан 3 С.Ж. Асфендияров атындагы Цазац улттыцмедицинаунuверcuтетi Алматы, Цазацстан
МИАСТЕНИКАЛЬЩ ЛАМБЕРТ-ИТОН СИНДРОМЫ
Tyuiw Миастеникалыц Ламберт-Итон синдромы (МЛИС) - бул ск процеа (кебтесе усац жасушалы екпенщ цатерлi iciгi] немесе бастапцы аутоиммундыц процесс реттде цозгалатын, кернеу енетт кальций каналдарына (КЕКК) антиденелер тузумен сипатталатын жуйке-булшыцет ауруы. Клиникалыц белгыер булшыцеттщ проксимальды элаздт, вегетатuвтi симптомдар, ащр рефлекстертщ темендеу1 КЕКК-ге антиденелердщ болуы, булшыцет белсендыт потенциалыныц амплитудасыныц темендеуi (M-жауап) темен жuiлiктегi цайталанатын ынталандыруга жауап бередг Егер МЛИС кyдiктi болса, науцастар муцият текcерудi жэне бацылауды цажет етедг Tyurndi свздер: Ламберт-Итон миастеникалыц синдром, паранеопластикалыц, инкремент
А-М. Бубуёк1, А.Ж. Кудебаева2, С.Т. ТуруспековаЗ, В.С. Лисник1
1 Государственный университет медицины и фармации имени Николае Тестемицану Институт неврологии и нейрохирургии имени Диомида Германа
Кишинев, Республика Молдова 2 Казахский медицинский университет непрерывного образования Алматы, Казахстан 3 Казахский национальный медицинский университет имени Асфендиярова
Алматы, Казахстан
МИАСТЕНИЧЕСКИЙ СИНДРОМ ЛАМБЕРТА-ИТОНА
Резюме: Миастенический Синдром Ламберта-Итона (МСЛИ) - это нервно-мышечное заболевание, характеризующееся образованием антител к потенциалзависимым кальциевым каналам (ПЗКК), триггером которых является опухолевый процесс (чаще всего мелкоклеточный рак легких) или как первичный аутоиммунный процесс. Характерными клиническими признаками являются проксимальная мышечная слабость, вегетативные симптомы, снижение сухожильных рефлексов, наличие антител к ПЗКК, снижение амплитуды потенциала мышечной активности (М-ответа) в ответ на низкочастотную повторяющуюся стимуляцию. При подозрении на МСЛИ пациентам требуется тщательное обследование и динамическое наблюдение. Ключевые слова: миастенический синдром Ламберта-Итона, паранеопластический, инкремент
Introduction
Lambert-Eaton myasthenic syndrome (LEMS) is a neuromuscular junction (NMJ) disorder similar to myasthenia gravis (MG), which was first described in patients with lung carcinoma in 1956 by Lambert, Eaton
and Rooke [1]. Presently, the condition divides into paraneoplastic LEMS associated mostly with small cell lung carcinoma (SCLC-LEMS) (50-60%) and primary autoimmune LEMS in which no neoplasm is identified (4050%) [2]. Just like MG, LEMS is an autoimmune disease in
which antibodies impair the release of acetylcholine, compromising the transmission of nerve impulses to the muscles leading to muscle weakness. However, unlike MG, the antibodies are directed against voltage gated calcium channels (VGCC) that are located on the presynaptic membrane [3].
The incidence of LEMS is estimated at 0.5 per million person-years and its prevalence is estimated at 2.5 per million [2], making it an extremely rare disease. LEMS is considered 46 times less prevalent than MG [4], a fact most likely explained by the low survival rate of SCLC. However, the incidence and prevalence of both LEMS and MG have been rising lately, probably as a result of an increased awareness of these syndromes and timely treatment [5], [6]. Elder men with a history of smoking seem to be more affected by paraneoplastic LEMS, while the primary autoimmune form affects both men and women of all ages [5]. J. Newsom-Davis and colleagues made the first comprehensive clinical description of LEMS in 1988 [7] associating it with a clinical triad consisting of: proximal weakness (especially of the lower limbs), hyporeflexia/ areflexia and autonomic features. There are still debates concerning which symptoms are considered typical and atypical for LEMS [8]. One of the first symptoms is usually weakness in the proximal muscles of the legs, which leads to gait disturbance / false apraxia. The patient may notice that it is becoming increasingly difficult to rise from a chair or to climb the stairs. The weakness usually spreads from the lower to the upper limbs (caudally to cranially) and from the proximal to the distal muscles [5]. The muscle weakness seems to increase after physical exertion, in a manner similar to myasthenia gravis (which is often the clinician's first suspicion). In some cases, however, there is a short-term increase in muscle strength after a few contractions. This phenomenon can also be noticed regarding the deep tendon reflexes, which may become brisker after exercise.
Ocular symptoms, bulbar and respiratory muscles involvement and cerebellar ataxia may also be present. Almost all patients present at least some form of autonomic dysfunction, notably dry mouth, constipation, erectile dysfunction; but also dry eyes, altered sudomotor function, orthostatic hypotension, micturition difficulties [5], [9].
In the case of paraneoplastic LEMS, the onset of symptoms usually precedes the diagnosis of cancer by several months. The rapid progression and emergence of new symptoms seems to be indicative of SCLC-LEMS, while a slower progression is associated with primary autoimmune LEMS [8]. In the presence of LEMS, the risk of an underlying SCLC is estimated at 62% [7], and it declines considerably after 2 years. Apart from the clinical progression, factors such as age, gender, personal history of smoking, HLA-profile, the presence of SOX (SRY-related HMG-box genes) antibodies and the DELTA-P (Dutch-English LEMS Tumor Association Prediction) score may be used to differentiate between SCLC-LEMS and primary autoimmune LEMS [2], [8], [10].
Pathogenically, LEMS is associated with autoantibodies directed against VGCC on the presynaptic membrane. The
first observations in this regard were made by Fukunaga et al. who discovered a paucity of voltage-sensitive calcium channels on freeze-fractured presynaptic membranes in LEMS [11], followed by a successful animal model [12] and eventually the diagnostic test that is used today [13]. The antibodies most often found in LEMS, whether autoimmune or paraneoplastic, are directed against VGCC type N and P/Q [13]. Their sensitivity is estimated at 90100% [2]. These antibodies are also associated with other autoimmune, paraneoplastic or non-paraneoplastic neurological conditions (e.g. cerebellar degeneration, myasthenia gravis, breast adenocarcinoma, lymphoma) [14], [15] and the results must be interpreted cautiously. The electrophysiological features of LEMS include reduced amplitudes on motor nerve conduction studies, decrement with low-frequency stimulation, increment with high-frequency stimulation or facilitation after maximal voluntary contraction [2], [16]. A higher than 100% increase in compound muscle action potential - CMAP amplitude (increment) is considered pathological [5]. This feature has an approximately 90% sensitivity and is 100% specific for LEMS [5].
All patients in which LEMS is suspected should be thoroughly investigated for an underlying malignancy. Mandatory CT scans of the chest may be followed by a bronchoscopy or PET-CT scan and, if negative, must be repeated every 3-6 months for 2 years.
Case report. In this review, we present a series of clinical cases in which the diagnosis of LEMS was confirmed or suspected. Most of the patients are still under supervision and continue to be monitored meticulously, both concerning the possibility of an underlying tumor and the response to treatment.
Case 1 A 58-year-old male developed proximal muscle weakness followed by gait disturbance (requiring unilateral walking support). He noticed his symptoms for the first time while having difficulties when rising from the chair. The patient also complained of xerostomia and hypohydrosis. The patient had a personal history of smoking up to 60 cigarettes/day (138 pack-years). He also suffered from low back pain, diabetes mellitus, arterial hypertension and obesity (BMI of 39.1). Upon neurological examination muscle strength was decreased in all limbs 4/5 (MRC scale) distally and 3/5 proximally, deep tendon reflexes were decreased and improved after exercise. EMG with slow repetitive nerve stimulation revealed a decrement of 21% at rest, with a compound muscle action potential (CMAP) increase of more than 100% in amplitude after isotonic exercise (figure 1) [17]. The CT scan of the chest (figure 2) [17] and oncological markers assay were not indicative of a neoplastic process. However, both antibodies against type N and PQ VGCC were positive (table 1). The patient received plasmapheresis and initiated treatment with Prednisone and Azathioprine, which slightly improved his condition. The patient also received 3,4-diaminopyridine for two months with a partially positive effect.
following a 30 seconds isotonic exercise in the left ulnar nerve. Lung CT without pathological changes.
Figure 1 - Electrophysiological studies Figure 2 - CT scan at onset
Figure 3 - CT scan after 9 months
Nine months after the onset of symptoms, during a follow-up CT examination of the lungs (figure 3) the result was suggestive of a pulmonary neoplasm. The patient was referred towards specialized oncological care, the diagnosis of SCLC was confirmed and treatment was initiated, but the outcome was unfortunately lethal. Case 2 A 62-year-old female complained of generalized muscle weakness, difficulty in climbing up and down the stairs, occasional dysphagia and dyspnea, dry and itchy skin, joint pain. Upon neurological examination the muscle strength was 4/5 MRC scale in all limbs, deep tendon reflexes were slightly decreased. Myasthenia gravis was suspected clinically, however anti-acetylcholine receptor and anti-MuSK antibodies were negative. The CT scan of the chest showed no pathology. Electrophysiological studies showed decreased CMAP and a 29% decrement. She also suffered from low back pain, coxarthrosis and osteoporosis. The clinical response to acetylcholinesterase inhibitors was not significant. She received
pyridostigmine, oral corticosteroid treatment (the dosage was modified according to her symptoms and has varied from 60 to 8 mg/day of prednisolone) and several sessions of plasma exchange over the course of 7 years. During a follow-up medical examination, serological tests were recommended repeatedly. Anti-acetylcholine receptor and anti-MuSK antibodies were consistently negative, but antibodies against PQ type VGCC were positive (Table 1). Follow-up chest CT showed no abnormalities. The patient was diagnosed with primary autoimmune LEMS and continues to be monitored.
Case 3 A 51-year-old male presented with muscular weakness in the proximal part of his upper and lower limbs, gait disturbance, mild dysphonia, dysarthria, dysphagia, paresthesia in the distal part of his lower limbs, occasional diplopia and xerostomia. His symptoms had progressed slowly over 3 years, with an onset in his lower limbs, followed by weakness of the upper limbs to which dysphonia, dysarthria and dysphagia were eventually
associated. The patient was a construction worker and had a personal history of back pain and one severe physical attack resulting in multiple traumas. On neurological examination, proximal muscle strength was reduced in all limbs. Deep tendon reflexes were slightly diminished and the patient presented mild ataxia. Brain MRI showed no abnormalities. MRI of the cervical spine revealed a compressive C6-C7 disc herniation. The serological test was positive for antibodies against type N VGCC (Table 1). Thoracic CT scan showed no pulmonary abnormalities. A diagnosis of LEMS was suspected, the patient received several sessions of plasma exchange and was started on pyridostigmine and oral corticosteroids, which improved his condition, and he continues to be monitored.
Case 4 A 31-year-old male presented with back pain and weakness in the proximal muscles of his lower limbs as well as reduced deep tendon reflexes and decreased muscle strength. During his extensive work-up, a serological test was recommended and anti-acetylcholine receptor and anti-MuSK antibodies were negative while anti- PQ type VGCC antibodies were positive (Table 1). The lung CT did not point out pathological changes. The patient initiated treatment with Prednisolone 35 mg/day and Methotrexate 15mg weekly with a gradual improvement and he is under surveillance.
Case 5 A 36-years-old female underwent a thoracic X-ray while suffering from pneumonia. Coincidentally, the image showed a mediastinal neoplasm (7x4x13 cm) (figure 3), that was further confirmed through CT.
Figure 3 - Case 5, thoracic X-ray suggestive of thymoma.
The tumor was removed through video-assisted thoracoscopic surgery (VATS). Hystopathological examination revealed a WHO type B2 thymoma. After surgery, the patient suffered from bronchial obstruction, bronchiectasis and was treated by a pulmonologist while remaning physically active.
Two years later she noticed the gradual onset of general muscle weakness and shortness of breath. These symptoms were followed by diplopia, blepharoptosis, mild dysarthria and disphagia associated with sialorrhea in the morning. The symptoms were more prominent in the first half of the day and she also claimed that she noticed a slight short-term relief after physical activities such as running. The neurological exam showed mild ptosis, more prominent on the left, negative Simpson sign, diminished muscular strength in all limbs, normal deep tendon reflexes. A thoracic CT scan and serological tests were recommended. The MRI showed a mediastinal mass which the thoracic surgeon confirmed as scar tissue, not a reccurence of thymoma. Anti-acetylcholine receptor antibodies were positive, anti-MuSK antibodies were negative while anti- type T VGCC antibodies were atypically positive (table 1). The patient was diagnosed with MG and received pyridostigmine, oral corticosteroids, plasmapheresis. These measures offered only slight relief and immunosuppressive drugs were considered. After receiving two doses of cyclophosphamide once a month with a positive result, the patient's state suddenly
worsened as she developed a myasthenic crisis and is slowly recovering.
Case 6 A 80-year-old male developed progressive weakness of the proximal muscles of his lower limbs over a period of 6 months. The patient had a personal history of basal cell carcinoma, diagnosed when he was 71 years old, which was treated successfully. Other malignancies were not found. N type VGCC antibodies were positive. The patient's condition improved on Pyrdostigmine and the patient is under surveillance.
Case 7 A 67-year-old female complained of dysphagia for liquids and weakness in her lower limbs for over 16 years. Initially, she was diagnosed with spondylotic myelopathy associated with flaccid paraparesis and neuropathic pain. At the onset of her symptoms, a diagnosis of myasthenia gravis was suspected, but the electrophysiological exam, serological tests and thoracic CT scan did not confirm the diagnosis. During a follow-up examination, antibodies against N type VGCC were positive. A thorough search for an underlying neoplasm was initiated and the patient continues to be monitored.
Table 1. AchR- Acetylcholine receptor antibodies, MuSK- Muscle-specific tyrosine kinase, "-" - negative / no abnormalities.
Case Gender, age at onset Duration of symptoms Symptoms Anti-VGCC antibodies AchR antibo dies <0,25 nmol/l Anti-MuSK antibodies <0,05 nmol/l Electrophysiological studies CT of the lungs and mediastinum Neo plasm
N-Type <10 (index) PQ-Type <40 pmol/L
1 M, 58 1 year - Proximal muscle weakness; - Autonomic symptoms; 20,9 248,9 - Decrement; - Increment with high-frequency stimulation Pulmonary mass Yes
2 F, 62 7 years - Proximal muscle weakness; - Autonomic symptoms; 77.7 Decrement No
3 M, 48 3 years - Proximal muscle weakness; - Autonomic symptoms; - Bulbar weakness; 13.4 - Facilitation after maximal voluntary contraction; No
4 M, 31 1.5 years - Proximal muscle weakness; 9.7 291.7 - Decrement; - Increment with high-frequency stimulation; No
5 F, 38 3 years - Ocular, bulbar symptoms; Generalized muscle weakness; 14.51 32.1 -Decrement; Thymoma Yes
б M, 80 6 months - Proximal muscle weakness; 23.41 Yes (prior to LEMS)
7 F, 51 16 years Generalized muscle weakness; - Bulbar symptoms; 11.б2 No
Discussion
This series of cases represents a group of patients in whom the diagnosis of LEMS was either confirmed or suspected. In the group with confirmed LEMS, most were elder males, but the age of onset varied from 31 to 80 years old. Three patients presented proximal muscle weakness of the lower limbs, which caused gait disturbances and progressively extended to the upper limbs. Two patients also had bulbar symptoms (dysphagia, dysarthria, dysphonia) and three presented autonomic symptoms (dry mouth, hypohydrosis associated with dry skin). Deep tendon reflexes were diminished in most cases. Only one patient had a history of smoking.
The EMG of three patients revealed increment with high-frequency stimulation or facilitation after maximal voluntary contraction.
One patient was diagnosed with lung carcinoma 9 months after the diagnosis of LEMS was confirmed. One patient has been monitored for 7 years and has not developed a tumor. One patient developed LEMS 9 years after having suffered from basal cell carcinoma.The rest of the patients are under observation.
All of the patients were positive for either anti- type N or type PQ VGCC antibodies with values ranging from 9.7 to 23.41 for type N (index < 10) and 77.7 to 291.7 for PQ type (<40 pmol/L). In spite of being highly specific for LEMS, the presence of these antibodies must be correlated with the clinical findings and should be interpreted carefully. One patient was both positive for anti-acetylcholine receptor and anti-VGCC antibodies, which is a rare co-occurrence
and has raised questions towards the existence of a MG -LEMS overlap syndrome [18], [19]. All of the patients described showed little to no clinical response to pyridostigmine, but improved partially and gradually from plasmapheresis, oral corticosteroids or immunosuppressive drugs.
Treatment options in LEMS are relatively limited. The mainstay is the treatment of the underlying tumor. For symptomatic management, 3,4-diaminopyridine was one of the first drugs studied [20], [21] and is the drug of choice, given at a maximum dose of 100mg per day [22]. It blocks presynaptic potassium channels, increasing the release of acetylcholine [3] and is also known as amifampridine, but is mostly used for research and is not readily available in most countries. One of the patients reported (case 1) received 3,4-diaminopyridine for two months with a partially positive effect. Intravenous immunoglobulin has been tested in one limited trial and showed positive results [23]. Other options include combinations of plasmapheresis, steroids, immunosuppressive agents, guanidine [24], [25]. Some other candidates could be mycophenolate mofetil, anti-CD20 and anti-TNF agents [22].
Conclusions
LEMS is a rare condition that is mostly underdiagnosed. The clinical criteria are: proximal muscle weakness, autonomic symptoms, reduced tendon reflexes, positive VGCC antibodies and repetitive nerve stimulation abnormalities [5]. These findings should be analyzed in a
complex manner. Once the suspicion of LEMS arises, patients require thorough investigations and diligent monitoring. It often takes years until a clinical case such as those presented above is fully resolved.
Authors' Contributions. All authors participated equally
in the writing of this article.
No conflicts of interest have been declared.
This material has not been previously submitted for
publication in other publications and is not under
consideration by other publishers.
There was no third-party funding or medical
representation in the conduct of this work.
Funding - no funding was provided.
Авторлардьщ yneci. Барлык; авторлар осы макаланы
жазуга тен, дэрежеде катысты.
Мудделер цацтьгеысы - мэлiмделген жо;.
Бул материал баска басылымдарда жариялау ушш бурын мэлiмделмеген жэне баска басылымдардын, карауына усынылмаган.
Осы жумысты ЖYргiзу кезiнде сырткы уйымдар мен медициналык екшджтердщ каржыландыруы жасалган жок;.
Царжыландыру жYргiзiлмедi.
Вклад авторов. Все авторы принимали равносильное участие при написании данной статьи. Конфликт интересов - не заявлен. Данный материал не был заявлен ранее, для публикации в других изданиях и не находится на рассмотрении другими издательствами. При проведении данной работы не было финансирования сторонними организациями и медицинскими представительствами. Финансирование - не проводилось.
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Контактные данные
Anna-Maria Bubuioc 8 777 525 60 26 anamaria.bubuioc@gmail.com
