Multifocal, metaphyseal osteonecrosis of knee due to pulse steroid treatment after cessation of fingolimod treatment in a 19-week-pregnant patient

Summary

In MS, discontinuation of some therapies may result in increased disease activity. Fingolimod is one such agent, and severe attacks that may advance the expanded disability status scale (EDSS) may occur after the cessation of Fingolimod. Such effects may not respond to classical pulse steroid treatment [1]. High-dose pulse steroid treatments may cause osteonecrosis.

We hereby present a case of multifocal, metaphyseal osteonecrosis of the knee due to pulse steroid treatment after cessation of fingolimod treatment, which had developed in a patient who was 19 weeks pregnant.

CASE

We present the case of a 32-year-old woman who was in the 19th gestational week of pregnancy at admission. She had been diagnosed with relapsing-remitting multiple sclerosis (MS) in 2017, and was receiving Fingolimod therapy since an attack that had occurred a year prior to the admission directly related with this study. Medical history showed that she was free from any attacks and drug-related adverse effects within this year. Her expanded disability status scale (EDSS) assessment while on Fingolimod therapy was as follows: Pyramidal functions: minimal disability (2 points), sensory functions: mild loss of vibration sensation in both lower extremities (1 point), mental functions: minor functional loss (2 points). Thus, the patient was attending follow-up in our clinic with an expanded disability status scale (EDSS) score of 2.5. Fingolimod treatment was discontinued on the 5th week of pregnancy. Glatiramer acetate (3 times a week) was recommended. However, the patient refused treatment. Although the patient was given detailed information that the pregnancy period would interfere with the treatment, the patient did not want to terminate her pregnancy and continued to refuse treatment. After about 14 weeks of well-being, she applied to our neurology outpatient clinic with weakness in the right extremities (relative to the left) and difficulty in maintaining balance (at the 19th gestational week). Neurological examination findings were as follows: motor (muscle) strength was 4-/5 in the right upper extremity, 4+/5 in the right lower extremity. Deep tendon reflexes (DTR) were +++ on the right, ++ on the left. Babinski reflexes were positive on the right and unresponsive on the left. The patient was found to have mild hemiparesis on the right.

Her EDSS assessment without Fingolimod therapy was as follows: right-sided mild hemiparesis (3 points), sensory functions: moderate loss of vibration sensation in both lower extremities (2 points), mental functions: minor functional loss (2 points) with an overall EDSS of 3.5 points. Observation of gait revealed that the patient was walking cautiously due to right-sided mild hemiparesis accompanied by sensorial ataxia. The patient had never smoked or consumed alcohol. The patient had no other systemic disease history. Laboratory findings were as follows: C-reactive protein: 6.0 (mg/dL), erythrocyte sedimentation rate: 68 (mm/h), hemoglobin: 10.6 (g/dL), hematocrit: 31.3%, leukocyte count: 7300/mm3, lymphocyte count: 1600/mm3, rheumatoid factor: negative, Brucella test: negative. Thyroid function test values and vitamin B12 levels were within reference ranges. The development of the fetus was normal. Compared to the contrast MRI findings taken a year before(Figure 1),non-contrast cranial and cervical magnetic resonance imaging (MRI) findings obtained during pregnancy are presented in Figure 2.( between the Mrg images, there have been cross-sectional deviations of mm depending on the technical shooting).

The presenting symptoms that had lasted for more than 24 hours and the 1 point increase in the EDSS score (from 2.5 points while on Fingolimod treatment to 3.5 points 14 weeks after termination of treatment) were identified as disease activity, and therefore, we planned an initial 5-day pulse steroid treatment for the patient. Before the administration of steroid treatment, we consulted with the attending gynecologist to assess fetal development and plan therapy. They did not have any additional suggestions. The 5-day pulse steroid treatment did not yield any clinical improvement and the treatment was extended to 7 days; however, again, no improvement was observed. As a result, plasmapheresis was planned. However, on the 7th day of MP application, the patient reapplied to our clinic describing increasing pain with movement in the right knee. MRI findings of the right knee, ordered with a preliminary diagnosis of cortisone-induced osteonecrosis, are presented in Figure 3 [2]. According to the radiographic classification of knee osteonecrosis by Aglietti et al., she was determined to have stage 2 osteonecrosis, and the patient received a conclusive diagnosis of steroid-induced multifocal metaphyseal osteonecrosis. Rest was recommended because weight gain could not be controlled due to ongoing pregnancy, and the patient was scheduled for appropriate follow-up studies. Orthopedic surgery was not considered in the patient during follow-up. Conservative treatment and rest were the recommended treatments throughout her pregnancy. The birth took place by cesarean section, after which the mother did not experience relapse. On physical examination, there was partial limitation in the knees and her rehabilitation continued in the physical therapy unit. Neurological examination remained stable (EDSS: 3.5). In the baby, no congenital malformation due to fingolimod treatment (the first 5 weeks of pregnancy) was detected, but the baby had low birth weight (2450 g). Glatiramer acetate was recommended in the postpartum period.

DISCUSSION

We report a case of multifocal, metaphyseal osteonecrosis of the knee due to pulse steroid treatment after cessation of fingolimod treatment, which had developed in a patient who was 19 weeks pregnant.

Even though pregnancy is classically associated with a significant reduction in clinical recurrence rate, there are several reports of dramatic worsening of disease during pregnancy following discontinuation of fingolimod [3]. Therefore, many women may face an elevated risk of relapse during the period between disease modifying treatment (DMT) discontinuation and the potentially protective effects of pregnancy (in MS). For pregnant women with severe or highly active MS, if such treatment is necessary, clinicians may consider switching to a different drug such as glatiramer acetate which is classified as a pregnancy Category B drug by the U.S. Food and Drug Administration (Appendix 1, http:// links.lww.com/AOG/A570) [4].

As such, the treatment of women with demyelinating diseases can be continued with glatiramer acetate before and during pregnancy; however, some therapies commonly used in MS are relatively contraindicated during pregnancy [5]. These therapies include fingolimod, dimethyl fumarate and teriflunomide, which are small molecules that could cross the placenta and potentially cause birth defects [6].

No safety concerns have been identified with platform injectable DMTs. [1]. In the case study presented by Canibano et al. rituximab (1 gr/day with 15-day intervals) treatment, which is a form of DMT infusion therapy administered during pregnancy after fingolimod withdrawal, was suggested to be effective in preventing disability development in a pregnant woman [7]. The use of DMTs during pregnancy is ultimately guided by patient decisions. It is acceptable to use glatiramer acetate during pregnancy[8]. Once a woman with MS is pregnant, prevention of relapses can be planned either with the use of monthly intravenous immunoglobulin (IVIG) treatment or monthly steroids after the first trimester, but safety data are limited [4]. It is well-established that corticosteroid use should be limited during pregnancy. Even so, safe use of corticosteroids is possible during pregnancy and administration approach is dependent on the type of steroid, dose, treatment duration and gestational age. Several previous studies have reported that the risk of cleft lip and palate increases with corticosteroid use in the first trimester. Prednisone, prednisolone and methylprednisolone are accepted to be safe for use during the second and third trimesters, since they cross the placenta minimally. Less than 10% of the maternal dose of prednisone, prednisolone, and methylprednisolone reaches the fetus by metabolism to inactive forms through the placenta; Unfortunately, the potential teratogenic effects of these inactive forms remain unclear [8]. At relapse, intravenous methylprednisolone treatment (1 gr/day for 3–5 days) is recommended [9]. In a case report by Canniboan and colleagues, a female who discontinued fingolimod therapy in the first month of pregnancy was administered 5 days of 1 gr/day methylprednisolone treatment (twice, with a 1-week interval) after developing new active lesions in the infratentorial and cervical regions, which had increased EDSS from 3.0 to 7.0 points. However, response to treatment was mild, and rituximab therapy was initiated at the 22nd week of gestation; resulting in a decrease of EDSS score from 7.0 to 4.5 points[7]. The literature on this topic demonstrates the use of high-dose corticosteroids after ceasing fingolimod therapy due to pregnancy; nonetheless, patients who are resistant to these treatments have also been reported. For instance, Lindsey Dalka et al, have reported a 25-year-old, morbidly obese, quadriplegic, pregnant patient who was resistant to a 6-day high-dose steroid treatment which had been applied due to MS-related transverse myelitis. The authors suggested that rebound demyelinization had been triggered by termination of fingolimod treatment, that these attacks were resistant to high-dose steroids, and emphasized that plasmapheresis had been beneficial in their case [10]. Considering that our patient was in the second trimester and had suffered from disease progression that increased EDSS score by 1 point, we decided to utilize a 5-day 1 gr/day pulse steroid treatment; however, the patient was unresponsive to therapy. Taking into account prior literature and case reports on this topic, our case supports the suggestion that pregnant patients may be resistant to high-dose steroid treatment and that active disease may progress in these patients who cease to use fingolimod therapy. Such data is evidently valuable for clinicians, especially with respect to the treatment planning and management of pregnant patients. Our case was resistant to high-dose corticosteroid therapy, and we could not apply the planned plasmapheresis treatment due to avascular bone necrosis occurring in the knee. MS is not an independent risk factor for avascular bone necrosis, and, although the risk of osteonecrosis is known to be elevated with long-term high-dose steroid treatment, this risk may also increase with short-term high-dose steroid therapies [11], as demonstrated by our case.

CONCLUSION

In pregnant patients with rebound effects due to fingolimod withdrawal, severe clinical manifestations are often identified. In this situation, the first treatment option is typically high-dose intravenous corticosteroids however these attacks were resistant to high-dose steroids. High-dose pulse steroid treatments may cause osteonecrosis, particularly in the femur, shoulder, knee and wrist. Although MS disease itself is not an independent risk factor for AVN, there appears to be an increased risk of AVN resulting from the administration of short-term high-dose intravenous corticosteroid treatment.

Asst. Prof. Ayfer Ertekin, MD

Department of Neurology

Private Siirt Hayat Hospital

Ozel Siirt Hayat Hastanesi

Noroloji Bolumu, Bahcelievler

Kurtalan Yolu Caddesi D:No:20

56000 Siirt Merkez/Siirt

Turkey

ayfertekin1976@gmail.com

Accepted for review: 28. 9. 2020

Accepted for print: 11. 5. 2021