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Although relapses of multiple sclerosis occur unpredictably and at odd intervals, two factors have been identified that may trigger an exacerbation: viral infections and the puerperium.1 2Viral infections probably act through a release of inflammatory cytokines, such as interferon-γ (INF-γ), that stimulate the immune system and facilitate the entry of activated T lymphocytes into the CNS.1 Relapses during the puerperium are likely to be precipitated by changes in the hormonal milieu after delivery.2 We report on three patients with multiple sclerosis in whom successive exacerbations occurred exclusively during the premenstrual period.
Patient 1, a 21 year old women student sought evaluation for episodes of alternating right and left sided paraesthesias, which existed for about 4 months. She also complained of fatigue. There was a history of infectious mononucleosis 6 years earlier. She did not use an oral contraceptive. Neurological examination showed hyperreflexia and Babinski’s sign in the right leg. Magnetic resonance imaging of the brain showed multiple white matter lesions on T2 weighted sequences, mainly in the left occipital and right parietal lobe. Oligoclonal bands were present in the CSF. One month later she was admitted to hospital because of weakness in the left leg, urge incontinence, and diminished sensation below Th7. Symptoms had started 3 days before her menstruation. She was treated with 1 g/day intravenous methylprednisolone for 5 days with rapid improvement over the next 2 weeks.
One month later she presented with a left hemiparesis and diminished sensation below Th1, which had started 2 days before the menstruation. She was treated with high dose intravenous methylprednisolone. During the next premenstrual period, 1 day before onset of the menstrual bleeding, she developed right sided cerebellar ataxia and diminished vision in the left eye; the expanded disability status scale (EDSS) was 5.0. She received a course of high dose intravenous methylprednisolone. Two months later the EDSS was 2.5, and she was included in an open pilot study with bromocriptine. Her clinical state did not change until 11 months later when she presented with worsening of right sided cerebellar ataxia; the symptoms had started 2 days before the menstruation. The ataxia improved gradually without corticosteroid treatment. After completion of the 1 year period specified in the trial protocol, she continued bromocriptine for another 8 months, and then stopped. She had no relapses on follow up for >3 years. At the last visit her EDSS was 2.0.
Patient 2 gave birth to two boys after uncomplicated pregnancies at the ages of 21 and 26. She used an oral contraceptive between the ages of 28 and 31. At the age of 33, 2 days before her menstruation, she noticed weakness in the right leg. This improved gradually over the next 3 weeks. Six months later, on the day before her menstruation, she developed a right sided hemiparesis. Brain MRI showed widespread white matter lesions of high intensity signals on T2 weighted sequences. Visual evoked responses were delayed. Examination of CSF showed oligoclonal bands. She was treated with high dose intravenous methylprednisolone, which was followed by gradual improvement. Three months later she experienced left sided facial weakness and coordination disturbances, and subsequently with intervals of about 3 months, she had three further relapses. Each relapse occurred during the premenstrual period (1 to 4 days before menstruation), and was treated with a course of high dose intravenous methylprednisolone. During the next 2 years her condition was stable; at the last visit her EDSS was 2.5.
Patient 3 was a 33 year old nulliparous woman in previous good health who experienced numbness in the right side of her body. She did not use an oral contraceptive. On examination there was diminution of touch, pinprick, and proprioceptive sensation over the right side of the body. The tendon reflexes on the right side were brisker, and a right Babinski’s sign was present. Brain MRI showed multiple hyperintense white matter lesions in the periventricular areas, cerebellum, and pons on T2 weighted sequences. Examination of CSF showed oligoclonal bands. In December 1994 she was admitted to hospital because of weakness in the right arm and numbness in the left arm and leg. Symptoms had started 2 days before onset of menstruation. She was treated with high dose intravenous methylprednisolone, resulting in gradual improvement. Between December 1994 and March 1996 she had 5 further relapses, occurring with intervals of 3 months. All relapses started 1–4 days before menstruation, and were treated with a course of high dose intravenous methylprednisolone (figure). After exacerbation in March 1996 she was treated with subcutaneous INF-β-1b and she started a vegetarian diet. There were no further relapses up to her last visit in July 1997.
These 3 women with relapsing-remitting multiple sclerosis had a particular disease course, characterised by exacerbations that occurred exclusively during the premenstrual period. This is probably different from the premenstrual transient worsening of existing symptoms which occurs in many women with relapsing-remitting multiple sclerosis.3 However, we cannot exclude that the underlying mechanism is different and that the patients described here may be at one end of a range. Exacerbations in the premenstrual period are likely to be triggered by dynamic changes in sex hormone concentrations. Before the menstrual bleeding there is a sudden fall in circulating levels of progesterone and oestradiol. Both sex steroids have numerous regulatory effects on the immune system, including an influence on T cell populations, and the production of cytokines.4 5
Inflammatory cytokines, or so called Th1 cytokines, such as INF-γ, tumour necrosis factor-α (TNF-α), and interleukins 1 and 2 (IL-1 and IL-2), seem to play a key part in the generation of exacerbations in multiple sclerosis.6 Pathways through which sex steroids influence the immune system are complex and incompletely understood. Oestrogens may inhibit the release of Th1 cytokines, such as IL-1 and TNF-α, whereas progesterone may enhance the release of Th2 cytokines, which inhibit the production and activity of the Th1 cytokines.7-9 Thus the abrupt withdrawal of progesterone and oestradiol in the premenstrual phase may shift the balance in favour of the production of inflammatory Th1 cytokines. Also, other hormones, such as inhibin, may contribute to this effect. The circulating concentration of inhibin, a hormone which decreases INF-γ production, also sharply declines just before the menstruation.10 Changes in concentrations of circulating sex hormones during the menstrual cycle were also found to influence disease activity in other putative autoimmune disorders, including rheumatoid arthritis, systemic lupus erythematosus, and autoimmune thyroid disease.5 11 12
An important question that needs to be investigated is whether the premenstrual period is an independent risk factor for exacerbations in the whole female multiple sclerosis population. This should be examined by a large prospective study. Unravelling the roles of sex hormones in the immune system and cytokine network that may regulate disease activity in multiple sclerosis may provide clues for the development of new therapeutic strategies.