Clinical Updates
Distally Predominant Myasthenia Gravis
Source: Nations SP, et al. Distal myasthenia gravis. Neurology 1999;52:632-634.
From a retrospective chart review of 236 mg patients, Nations and colleagues noted nine (3%) with more pronounced distal than proximal muscle weakness. Finger extensors were most frequently affected, more so than distal leg or foot muscles. Three patients demonstrated distal weakness at onset, one after one month of ocular MG, and five after 3-45 years of disease. In patients with distally predominant muscle weakness, don’t think of myasthenia until all other diagnoses are excluded.
Plasma Exchange or Immunoglobulin for Myasthenic Crisis
Source: Qureshi AI, et al. Plasma exchange versus intravenous immunoglobulin treatment in myasthenic crisis. Neurology 1999;52:629-632.
Between 1990 and 1997, 54 patients with myasthenic crisis, defined as respiratory insufficiency with a forced vital capacity below one liter, negative inspiratory force below 20 cm H2O, or requiring mechanical ventilation, were identified retrospectively from admission records of four university hospitals. Intravenous immune globulin (IVIG), 400 mg/kg/d for five days, had been administered in 26 cases, and plasma exchange (PE), five or six exchanges of 25-45 cc/kg each, was administered in 28. Cardiac, pulmonary, and hypertensive diseases were similar among the two groups and treatment selection was based on hospital preference.
At two weeks following initiation of treatment, significantly more PE patients were extubated (P = 0.02), and at four weeks, PE outcome was superior to IVIG. Fewer PE patients remained on a ventilator, none remained with a tracheotomy, and more patients had no disability (P = 0.04). PE patients experienced more complications (13 vs 5), comprising infections (n = 6), cardiovascular instability (n = 6), and coagulopathy (n = 1), with longer intensive care and overall hospital stays, but these differences were not statistically significant. PE appears to be preferable to IVIG for the management of myasthenic crisis with respiratory failure.
Pregnancy and Myasthenia Gravis
Source: Batocchi AP, et al. Course and treatment of myasthenia gravis during pregnancy. Neurology 1999;52:447-452.
Sixty-four pregnancies among 47 myasthenia gravis (MG) patients, ages 19-39, were studied over a period extending from 1978-1997. Women were examined before, during, and after pregnancy. Those who were symptomatic received anti-cholinesterase (AChE) agents, prednisone or azathioprine if AChEs were inadequate, and plasmapheresis (PE), or intravenous immunoglobulin (IVIG) for myasthenic crisis. Anti-acetylcholine receptor binding antibodies (anti-AChR) were measured in mother and child, and repetitive nerve stimulation was performed on any child suspected of neonatal myasthenia. Results were analyzed using chi-square and Mann-Whitney U tests.
Forty patients (85%) were anti-AChR antibody positive. Twenty women had mild MG (Osserman 2A), 25 severe MG (Osserman 2B, 3, and 4), and two had purely ocular disease (Osserman 1). Forty-four underwent thymectomy, 42 preconception and two postpartum. Of these, four showed thymoma, 35 had hyperplasia, and five had only normal/involuted thymus tissue.
Among women in remission, four of 23 (17%) developed mild MG during pregnancy and this was brought under control with AChEs alone. Among those with active MG on medication, approximately 40% either improved during pregnancy (n = 12), or remained unchanged (n = 13), while approximately 20% (n = 6) worsened. Four of the latter were mild in degree and were controlled with an increase in AChE dose alone, whereas two went into crisis, requiring high-dose prednisone, azathioprine, repeated PE and IVIG. Considering all completed pregnancies, 18.5% (n = 10) worsened during pregnancy, 60% in the first trimester (n = 6), 10% in the second (n = 1), and 30% in the third (n = 3). Postpartum, approximately 15% improved (n = 7) and 30% worsened (n = 15), the latter occurring immediately (n = 11) or within the puerperium (n = 4). Ten pregnancies aborted, six (induced) for psychosocial reasons, three (4.6%) spontaneously, with one ectopic pregnancy (1.5%). Of the 10 miscarriages, only one MG exacerbation resulted, following an induced abortion.
Four of 54 pregnancies delivered prematurely (7.4%), two each at 32 weeks and 35 weeks. Thirty percent overall were delivered by C-section (n = 16) and, collectively, 55 children were born to 43 MG women, with 9% (n = 5) premature and one, whose mother was on methotrexate up to a few months preconception, with multiple congenital anomalies. Approximately 50% of newborns assayed for anti-AChR antibody were positive but only 9% (5 of 55) demonstrated signs of neonatal MG, its occurrence not correlating with maternal AChR antibody positivity or titer. The course of MG during pregnancy is unpredictable and can change with different pregnancies, its long-term outcome is not worsened by pregnancy, its severity does not correlate with the occurrence of neonatal MG, and MG treatment may be safely administered to pregnant MG women.
COMMENTARY
What role do CD4+ and CD8+ T-cells play in the pathogenesis of MG is a classic unanswered question. Anti-acetylcholine receptor (anti-AChR) antibodies are IgG isotypes whose production is stimulated by helper T cells, but an AChR-specific helper T-cell effect has yet to be demonstrated (Hohlfeld R. Neurology 1999; 52:443-445). A series of elegant experiments by Wang and associates (Wang ZY, et al. Neurology 1999;52:484-497) may now provide some answers. Using severe combined immunodeficiency (SCID) mice, which lack mature T and B cells due to defective DNA-dependent protein kinase activity (Blunt T, et al. Cell 1995;80:813-823), a number of man/mouse models of MG were created by intraperitoneally engrafting the mice with lymphocytes from MG patients. These chimeric models were used to determine the role of CD4+ and CD8+ T-cells in symptomatic MG.
Using blood from the same MG patients, SCID mice were engrafted with one of the following: 1) blood lymphocytes (BL), 2) BL depleted of CD4+ T-cells, 3) BL depleted of CD8+ T-cells, 4) BL depleted of CD4+ T-cells but reconstituted with autologous CD4+ T-cells specific for AChR, or 5) BL depleted of CD4+ T-cells but reconstituted with autologous CD4+ T-cells specific for two unrelated antigens, tetanus and diphtheria toxoids. Myasthenic weakness and human AChR antibodies frequently developed in mice from experiments 1, 3, and 4, all of which included CD4+ T-cells, but not from experiment 2 or 5, which were depleted of CD4+ T-cells but included CD8+ T-cells. Muscle weakness did not always correlate with AChR antibody positivity, nor did antibody positivity predict weakness, but anticholinesterase agents could transiently reverse weakness when present. Presumably, highly pathogenic antibody is formed and binds to the receptor, thereby clearing the serum, resulting in weakness with the (apparent) absence of antibody. Mice engrafted with normal control serum neither developed MG weakness nor AChR antibodies. CD4+ T-cells particularly AChR-specific CD4+ T-cells but not CD8+ T-cells, appear necessary for the pathogenesis of MG weakness.
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