Clinical experience with repository corticotropin injection in patients with multiple sclerosis experiencing mood changes with intravenous methylprednisolone: a case series

Abstract

The elevated prevalence of neuropsychiatric symptoms and disorders among patients with multiple sclerosis (MS) is well recognized, as are potential neuropsychiatric side effects of treatment with corticosteroids. Both methylprednisolone (MP) and repository corticotropin injection (HP Acthar^® gel) have demonstrated efficacy in reducing short-term disability after exacerbations of MS. Although historical data are limited, repository corticotropin injection has not generally been associated with detrimental neuropsychiatric effects. We describe six cases of patients with relapsing-remitting MS who had previously experienced detrimental mood changes with MP treatment. Some of these patients had previous histories of mood disorders or other neuropsychiatric symptoms prior to MS diagnosis. All six patients were subsequently treated with repository corticotropin injection for MS exacerbations and each demonstrated improvements in MS symptoms. This clinical experience suggests that repository corticotropin injection should be considered as an alternative for patients who do not tolerate corticosteroids or have difficulties associated with intravenous medication. Furthermore, the rate of neuropsychiatric side effects observed in these patients was low. These observations support repository corticotropin injection as a viable alternative for the treatment of acute exacerbations of MS, particularly in patients who have a history of neuropsychiatric disorders or symptoms either independently or in response to MP treatment. In reviewing both the published data and our own clinical experience regarding potential neuropsychiatric adverse events with treatment for MS exacerbations, we hope to stimulate further research into the potential efficacy and safety of repository corticotropin injection among patients with some form of neuropsychiatric complications that must be considered when establishing a treatment plan for MS.

Introduction

Neuropsychiatric symptoms and comorbidities are highly prevalent among patients with multiple sclerosis (MS) [Diaz-Olavarrieta et al. 1999; Marrie et al. 2009; Paparrigopoulos et al. 2010]. Compared with healthy controls, neuropsychiatric symptoms are significantly higher in patients with MS. The neuropsychiatric symptoms of MS include abnormalities in cognition, mood, affect, and behavior. The most common comorbidity is depression, which affects as much as 80% of patients, followed by anxiety (16.5%, and as high as 37% in one cohort), and bipolar disorder (2.4%) [Diaz-Olavarrieta et al. 1999; Marrie et al. 2009; Paparrigopoulos et al. 2010]. However, the presence of neuropsychiatric conditions among patients with MS may be neglected, as mental health comorbidities are often underdiagnosed and undertreated [Marrie et al. 2009; Paparrigopoulos et al. 2010].

Potential reasons for the elevated rates of neuropsychiatric disorders and symptoms in patients with MS include the physiological changes inherent in the disease, side effects of MS treatments, and psychological responses to their diagnosis or symptoms [Iacovides and Andreoulakis, 2011; Paparrigopoulos et al. 2010]. Regardless of the potential causes, patients with MS should be evaluated for mood disorders and neuropsychiatric symptoms and the findings should be taken into account when determining treatment [Lienert et al. 2013; Marrie et al. 2009; Paparrigopoulos et al. 2010]. When possible, therapeutic options for MS exacerbations should be chosen for each patient with the goals of minimizing the risks of neuropsychiatric side effects or exacerbation of pre-existing conditions.

Treatment for exacerbations of MS has generally consisted of intravenous (IV) corticosteroids, usually methylprednisolone (MP), oral steroids, or repository corticotropin injection (HP Acthar^® gel, Mallinckrodt ARD Inc., Hazelwood, MO, USA) [Filippini et al. 2000; Tsang and Macdonell, 2011]. Both MP and corticotropin (adrenocorticotrophic hormone [ACTH]) have demonstrated efficacy in reducing short-term disability after exacerbations of MS [Filippini et al. 2000; Iacovides and Andreoulakis, 2011; Lienert et al. 2013; Martinelli et al. 2009; Paparrigopoulos et al. 2010; Tsang and Macdonell, 2011].

Discussion of adverse events (AEs) with either MP or ACTH treatment is limited by the fact that many study reports have not included sufficient information on the observed presence or absence of AEs [Filippini et al. 2000]. The available data support an association between corticosteroid treatment and mood disorders as well as other neuropsychiatric disorders such as sleep disturbances, cognitive impairment, and psychosis in some patients [Iacovides and Andreoulakis, 2011; Klein, 1992; Lewis and Smith, 1983; Lienert et al. 2013; Martinelli et al. 2009; Paparrigopoulos et al. 2010; Sellebjerg et al. 1998; Sorensen et al. 2009; Tsang and Macdonell 2011; Warrington and Bostwick, 2006]. Commonly occurring nonpsychiatric AEs for corticotropin injection are similar to those of corticosteroids, as related to stimulation of cortisol release, and include fluid retention and edema, possible change in glucose tolerance, elevated blood pressure, and increased appetite and weight gain. Neuropsychiatric symptoms of corticotropin injection have not been commonly reported. However, they may be similar in type (although not in frequency) to patients with Cushing’s syndrome, based on their levels of circulating cortisol and ACTH [Filippini et al. 2000; Starkman et al. 1981].

Clinical experience generally includes a wider range of patients than those included in clinical trials. As such, it can provide a wealth of information on the treatment of patients with complex medical and treatment histories or comorbidities that are usually grounds for exclusion from formal trials. Herein, we present six clinical cases of patients with relapsing-remitting MS who had experienced mood changes with previous IV MP treatment and were therefore treated with repository corticotropin injection for subsequent acute exacerbations.

Case 1

A 40-year-old female patient with a history of bipolar disorder was diagnosed with MS consistent with McDonald criteria in 2007. The treatments she received for bipolar disorder included lithium. After receiving the MS diagnosis, she began treatment with glatiramer acetate, but discontinued due to intolerable injection-site reactions. The patient was first seen at our center in 2008. Follow-up magnetic resonance imaging (MRI) showed new brain lesions and she reported episodes of full-body weakness and facial numbness. She was treated with a 3-day course of IV MP but showed no improvement in her MS and reported some anxiety and possible manic symptoms. She then began treatment with interferon-β (IFNβ)-1a intramuscular (IM) injection. At her next visit, she reported suicidal ideation, for which she was hospitalized.

The patient subsequently became pregnant, stopped IFNβ-1a IM during the pregnancy, and was not seen during this time. At her next visit in January 2011, she reported that she had been hospitalized for two episodes of MS exacerbation while pregnant. IFNβ-1a IM was restarted in January 2011, with a follow-up visit in March 2011. The patient was advised to stop IFNβ-1a IM due to her previous psychiatric issues and she began treatment with fingolimod. She completed her first dose observation in May 2011, and at her June follow-up appointment, she reported improvement in symptoms including less fatigue and reduced numbness, and said she was happy to remain on fingolimod.

In September 2011, she reported an MS exacerbation that manifested with blurred vision and weakness and stated that she had stopped fingolimod because it was making her feel worse. It was recommended that she try repository corticotropin injection for her acute exacerbation due to concerns about previous mood changes after treatment with IV MP and her history of bipolar disorder. She consented to treatment with repository corticotropin injection and reported improvement in relapse symptoms with no psychiatric side effects. She also requested a restart of IFNβ-1a IM at half dose, but subsequently reported headaches and feeling ‘off-balance’ in February 2012, and was administered 3 days of repository corticotropin injection 80 IU/day subcutaneously (SC), which she reported had a ‘good’ effect on symptoms with no side effects. She restarted disease-modifying therapy (DMT) with natalizumab in April 2012. At follow up in June 2012, she reported that she was ‘doing well’, with the exception of chronic migraines, for which she was being treated with onabotulinumtoxinA therapy. To date, the patient remains on natalizumab and her MS symptoms and MRIs have remained stable overall.

Case 2

A 61-year-old male patient was diagnosed with MS consistent with Poser criteria in 1991 by another neurologist. At that time, he reported some leg numbness and tingling, but decided not to begin treatment with DMT. He had a history of neurogenic bladder, benign prostatic hypertrophy, hydronephrosis, osteopenia, and anxiety and depression, for which he had been treated with fluoxetine.

He was first seen in September 2009, at which time he reported an increase in leg numbness and some weakness and dizziness occurring over the previous year. Before coming to our center, he had been asked to consider pulsed therapy with IV MP. He declined treatment with glatiramer acetate or IFNβ. In January 2010, he complained of worsening left-extremity weakness and numbness and was again urged to start DMT.

Over the next 5 years, he was treated with multiple agents, including duloxetine, gabapentin, and nortriptyline for neuropathic pain as well as baclofen and onabotulinumtoxinA for spasticity. He agreed to begin treatment with glatiramer acetate in March 2010, but stopped treatment in 2011 due to injection-site reactions.

He presented in March 2012 with complaints of weakness, burning sensation, numbness, and generalized fatigue. He was offered IV MP but declined because he indicated that a previous course of IV MP to treat MS had caused irritability and depression, and said that he was not able to comply with infusion appointments.

He was subsequently treated with repository corticotropin injection 80 IU/day SC for 3 days consecutively in early March. During his follow-up visit in May 2012, he reported that treatment with repository corticotropin injection was ‘very effective’ and that the treatment did not adversely affect his mood in the manner that he had experienced previously when treated with MP. He declined DMT, but over the next five visits received treatment with dalfampridine to improve his walking speed. He has reported no acute relapses during this time. Currently, he is not receiving DMT and his MRI and symptoms are generally stable, but he does report intermittent episodes of left-extremity tightness, numbness, and weakness.

Case 3

A 25-year-old female patient had a history of orthopedic fractures from a car accident in February 2011. She also experienced anxiety, for which she was being treated with citalopram. Her history revealed numbness in her left thigh that progressed to her lower leg. MRI revealed central lesions and three possible cord lesions consistent with MS.

In April 2012, a diagnosis of MS was confirmed by MRI consistent with McDonald criteria, by another neurologist. At that time she was symptomatic with left-eye visual disturbance and loss of balance. The patient began treatment with IFNβ-1a SC and subsequently reported minor flu-like symptoms. She was off medication for 2 weeks at the end of August/early September 2012 while on vacation, but did restart medication afterward. During that time she reported new symptoms of right-sided numbness of the upper extremity and face. On 26 November 2012, she called with complaints of blurred vision, extreme fatigue, and numbness of the left upper extremity.

IFNβ-1 SC was discontinued after tests showed elevated aspartate aminotransferase above 200 U/L and alanine aminotransferase above 400 U/L. An MRI scan at the end of October showed three new enhancing lesions, but no new cervical lesions. After 5 days of treatment with IV MP, her numbness had improved, but her vision had not. She developed severe acne and generally felt that the steroid treatment was not completely effective.

In January 2013, she agreed to start treatment with fingolimod because she still had complaints of blurred vision. In March 2013, the patient called with complaints of complete numbness from the waist down and was scheduled for fingolimod first-dose observation on 7 March 2013. On 23 March 2013, she was seen at a local hospital emergency department for complaints of severe dizziness and vomiting. She was given IV fluids and discharged. Upon follow-up visit on 10 April, 2013, she complained of eye pain and feeling off-balance. MRIs showed multiple new white-matter lesions with enhancing MRI revealing a large tumefactive lesion in her right temporal lobe, and possible mild mass effect. She was treated with 5 days of IV MP, but her symptoms did not completely resolve and she reported negative mood changes, particularly depression. The self-reported depression was considered attributable to IV MP as it was a change that had occurred during the treatment.

On 26 April 2013, she was treated with repository corticotropin injection 80 IU/day SC for 6 days for the acute exacerbation and was prescribed natalizumab as disease-modifying therapy. Upon follow up on 3 May 2013, she reported overall improvement in symptoms and no side effects from repository corticotropin injection. She began her first natalizumab infusion on 14 June 2013. She later reported that she was feeling ‘great’ and that it was the best she had felt in 2 years.

The patient remains ‘very satisfied’ and at a follow-up appointment in May 2014, reported that she was doing ‘great’ and had been symptom-free since the previous August. Her MRIs remained stable over that time.

Case 4

A 66-year-old female patient had a history of degenerative disc disease and spinal stenosis, autoimmune hepatitis and fatty liver disease, syncope, and complaints of depression. She indicated that she had possibly had MS symptoms since she was a teenager; primarily experiencing symptoms of fatigue.

In 1987, she reported symptoms of numbness on her left side and left arm after awakening one morning. She was referred to a gynecologist possibly related to complaints of numbness around the pelvic area, which subsequently resolved spontaneously. Two months later, she experienced numbness and tingling predominantly of the left arm and was diagnosed with MS by a neurologist, based on Poser criteria. Her history revealed that she had been treated with IFNβ-1b over a period of 4 years for difficulty in balance and walking, but stopped treatment due to flu-like symptoms. She was then treated with glatiramer acetate for 5–6 months after it was approved, but stopped due to injection-site reactions.

The patient came to our center in 2011. She was encouraged to begin treatment with fingolimod or natalizumab, but was reluctant to start fingolimod due to concerns of possible side effects. She was found to be JC virus (JCV)-positive and accordingly declined natalizumab. In the past, she recalled having been treated with IV MP, but the date and dosage could not be determined. However, she reported having become psychotic during one course of IV MP and was subsequently hospitalized for psychiatric care with a diagnosis of steroid-induced psychosis.

On 16 November 2012, she reported more difficulty with balance and walking and was treated with repository corticotropin injection 80 IU/day SC for 3 days for acute exacerbation of mobility difficulties. At an office follow-up visit on 19 December 2012, she reported that symptoms were ‘significantly’ better and stated that she had not experienced any side effects and her mood was stable. At a visit on 17 April 2013, she reported ‘feeling worse over the last few weeks’ and had some generalized weakness, muscle spasms in the legs, and fatigue. She was treated at this visit with repository corticotropin injection 80 IU/day SC for 5 days for acute relapse. She stated that it ‘helped all of my MS symptoms’, noting improvement in hand control, no muscle spasms, improved balance, and no negative mood changes. She then began monthly pulse dosing of repository corticotropin injection 80 IU/day SC on 2 consecutive days per month for 6 months.

At a visit on 15 October 2013, she reported doing ‘very well’ on repository corticotropin injection administered by monthly pulse at 80 IU/day SC on 2 consecutive days per month for 6 months, and was stable in terms of symptoms, MRIs, and examination findings. On 14 January 2014, she was encouraged to consider DMT. At a follow-up visit in April 2014, she had gastrointestinal complaints and said she was seeing a specialist. She stated that her MS was stable and repository corticotropin injection pulsed therapy was stopped. As of July 2014, she was feeling stable in terms of her MS symptoms and her MRIs remained stable as well.

Case 5

A 48-year-old female patient with a history of strabismus reported that she experienced tingling in her right leg in 1996 that resolved spontaneously. A month later, she developed numbness in both legs and consulted a neurologist and was diagnosed with MS consistent with Poser criteria. She received treatment with IV MP, of unknown dose or duration, and showed improvement until 6 months later when she developed numbness and tingling of the right hand.

She was treated with glatiramer acetate and reported doing well for several years, but then started having recurrent relapses. Around 2004, she went back to work and had two exacerbations, both occurring within 6–8 weeks. She began IFNβ-1a SC around 2005, with no evident side effects to treatment. At the end of October 2010, an MRI showed new lesions in the cervical spine; no clinical presentation was reported. She came to our center on 17 February 2011.

She received 3 days of IV MP and in December 2010 reported increased fatigue and weakness. Her main issues upon coming to our center were bilateral hand tingling, occasional clumsiness and fatigue, primarily of the right leg, but sometimes both legs, and also some difficulty with cognition, memory, and processing speed. At her follow-up visit in December 2011, serial MRI showed no new lesions since an examination in September 2011 and she remained on IFNβ-1a SC.

She called on 24 May 2012, complaining of worsening leg weakness and a ‘tight’ sensation around her abdomen and torso. A course of MP was recommended for acute relapse, but she indicated that she had experienced side effects to prior steroid therapy, including severe insomnia and negative mood changes, primarily irritability. She was administered repository corticotropin injection 80 IU/day SC for 3 days. She called on 7 June 2012, complaining of continued symptoms and was treated again with repository corticotropin injection for an additional 3 days.

At her follow-up visit on 22 June 2012, she reported feeling ‘80% improved’, with some mild residual tightness in the mid-back, but stated she tolerated repository corticotropin injection well and had no mood changes, specifically no irritability. She was encouraged to change her DMT from IFNβ-1a SC to natalizumab and began treatment with 300 mg/15 mL concentrate every 4 weeks in July 2012. She reported feeling ‘very good’ on natalizumab with no new symptoms and showed no change in MRI.

The last natalizumab infusion was administered in January 2013. She was JCV-positive and wanted to discontinue treatment and an alternate DMT was recommended. She was treated with repository corticotropin injection 80 IU/day SC for 5 days in early March 2013 for acute MS relapse symptoms. She reported that it had a ‘good effect’, specifically commenting about improved energy and no side effects. She agreed to start treatment with teriflunomide.

At follow up on 28 May 2013, she reported some mild nausea and diarrhea after starting teriflunomide, but said that she had improved. At her August 2013 visit, she reported dizziness and fatigue, and MRI revealed a new enhancing lesion in the left aspect of the pons and a new white-matter lesion in the cerebral cortex and enlargement of a right temporal horn lesion. She was not taking teriflunomide at this time. Repository corticotropin injection 80 IU/day SC was administered for 5 days in early September and she reported some improvement regarding her fatigue and dizziness. She was encouraged to consider an alternate DMT and started fingolimod, with first-dose observation in October 2013. She reported feeling well on fingolimod at her follow-up visit on 2 February 2014. An MRI in February 2014 showed two new right temporal white-matter lesions and one left pericallosal lesion compared with September 2013 imaging; no enhancement was noted. The new lesions were thought to have possibly developed during the transition from teriflunomide to fingolimod. To date, she is tolerating treatment well and remains on fingolimod.

Case 6

A 45-year-old, right-handed female patient with relapsing-remitting MS presented to us in 2007. She had first been diagnosed at age 12 years and had a lifelong history of agitation when treated with IV MP for her MS exacerbations. At presentation, she was taking glatiramer acetate and had subsequently suffered exacerbations of her MS, requiring treatment. She was treated with IV MP for left hemiparesis in March 2008, August 2008, and December 2008, but suffered severe agitation, psychosis, and insomnia despite the use of quetiapine 25 mg every 6 h and decreasing her MP dose from 1000 mg daily for 3 days to 500 mg daily for 2 days. In addition, the decrease in IV steroid dose and duration had diminished the treatment’s overall efficacy. In order to minimize agitation, oral prednisone (1 mg/kg/day for 5 days, followed by 5-day taper) had also previously been used to treat exacerbations. Although she tolerated the oral prednisone, her relapse symptoms persisted.

In December 2010, she experienced an acute MS exacerbation with diplopia from right cranial nerve VI (abducens nerve) palsy with right lateral rectus weakness, dizziness, and gait imbalance. On examination, she had right-eye lateral abduction limited to only 20 degrees and an ataxic gait due to the diplopia. She was then treated with repository corticotropin injection 80 IU/day SC for 5 days.

On the second day of the 5-day repository corticotropin injection treatment course, the patient called to report that her dizziness and gait ataxia had resolved and that her double vision had improved enough to drive again. She was encouraged to return for re-evaluation. She returned for evaluation on the fourth day of the 5-day course of treatment and the cranial nerve VI abducens gaze palsy of the right eye had improved to 40 degrees of lateral abduction. Of note, she later reported no agitation or psychosis and stated that she had tolerated the repository corticotropin injection for 5 days without any of the side effects she had experienced with IV MP. Moreover, she had not used any of the eszopiclone samples that she had been provided with in case of insomnia.

Discussion

The potential neuropsychiatric AEs of corticosteroid treatments are well known [Warrington and Bostwick, 2006]. Among affected patients, euphoria or hypomania is associated with shorter-term treatment while depression is more closely associated with long-term corticosteroid treatment [Bolanos et al. 2004]. Psychosis, which may manifest as hallucinations, delusions, or disorganized thinking, is much less common, but is estimated to occur in up to a sixth of patients [Warrington and Bostwick, 2006]. These data did not determine if pre-existing psychiatric issues are a risk factor for steroid-related psychiatric disturbances. One survey of the literature related to steroid treatment, which included clinical trials, controlled studies on the side effects of steroid therapy, and case reports, concluded that pre-existing psychiatric illness does not seem to increase the likelihood of a reaction to steroid therapy [Ling et al. 1981]. Another survey of the literature concluded that it was not possible to determine from the data if past psychiatric illness or premorbid personality disturbances are risk factors for the development of a steroid-induced psychiatric syndrome in the absence of control data [Lewis and Smith, 1983]. Corticotropin injection may also be associated with central nervous system effects ranging from euphoria and mood swings (possibly associated with release of cortisol), irritability (particularly in infants treated for infantile spasms), psychotic manifestations, personality changes, trouble sleeping, and depression [Mallinckrodt ARD, 2015].

Both MP and ACTH have been examined for the treatment of acute exacerbations of MS. A systematic review examining the safety and efficacy of MP and ACTH in the treatment of patients with acute exacerbations of MS identified six trials that were appropriate for review [Filippini et al. 2000]. Overall, the four trials of MP (total n = 140) and two trials of ACTH (total n = 237) supported similar benefits of MP and ACTH in acute MS exacerbations [Durelli et al. 1985; Filipovic et al. 1997; Miller et al. 1961; Milligan et al. 1987; Rose et al. 1970; Sellebjerg et al. 1998]. In this review, insomnia was included in the category of psychiatric disturbances. Overall, psychiatric disturbances were more common among participants given MP compared with controls, while no such effect was reported among participants given ACTH compared with controls [Filippini et al. 2000; Sellebjerg et al. 1998].

Historical data related to mood changes with ACTH are limited. Of four trials that examined short-term treatment of patients with MS with an ACTH analogue compared with either placebo [Rose et al. 1970] or IV MP [Abbruzzese et al. 1983; Barnes et al. 1985; Thompson et al. 1989], few provided data pertinent to mood changes. A large study of 197 MS patients (n = 103, ACTH; n = 94, placebo) reported some evidence, albeit limited, of improvement in mood, but without further details about the types of mood changes [Rose et al. 1970]. Depression and anxiety were reported in one patient each who received ACTH, although there was no clarification as to the functional status of these patients [Rose et al. 1970]. One study specified that of the three patients on MP and two on ACTH who failed to complete the study, one patient on ACTH ‘became agitated and paranoid’ on day 13 of treatment and was withdrawn from the study, though no other details were provided [Thompson et al. 1989]. Finally, two of the studies of patients receiving either ACTH or MP did not provide information regarding mood changes in either group [Abbruzzese et al. 1983; Barnes et al. 1985].

Our observations from this case series are consistent with a recent retrospective study that also found positive clinical outcomes with repository corticotropin injection in patients who had failed to respond to MP (1 g/day IV for 3–5 days or 1 g/day orally for 7–10 days) based on safety (n = 2), AEs (n = 6), both safety and AEs (n = 9), or safety and lack of efficacy (n = 1) [Berkovich and Agius, 2014]. A total of 18 cases were examined in which the patient had presented with at least one acute exacerbation of MS between 2008 and 2011; three patients had a history of a psychiatric condition. All patients were subsequently treated with repository corticotropin injection, 80 IU/day IM or SC for 5–7 days. Psychiatric complaints reported after treatment with MP included insomnia (n = 4), anxiety (n = 3), psychosis (n = 1), and worsening of other psychiatric conditions (n = 1); these complaints were not reported after treatment with repository corticotropin injection.

Equivalency of IV MP and repository corticotropic dosage has been studied recently [Lal et al. 2015]. An open-label, randomized, crossover study compared the pharmacodynamics of IV MP (1000 mg) and repository corticotropin gel 80 U SC administered daily for 5 days in 18 healthy adult subjects, as they are the most commonly used dosages in the treatment of acute MS exacerbations. Comparison of treatment was based on cortisol-equivalent exposure and on circulating immune cells. Repository corticotropin gel administration resulted in significantly lower overall serum cortisol-equivalent exposure than IV MP, and 80 U of repository corticotropin gel equated to approximately 30 mg of IV MP. This difference supports a hypothesis that efficacy of repository corticotropin gel in immune-mediated disease may not be solely due to its effects on endogenous steroid production, as treatment of MS exacerbation requires doses of IV MP significantly higher than 30 mg daily. In these healthy volunteers, the percentage change in lymphocytes from baseline was significantly lower after 5 days of repository corticotropin gel than after 5 days of IV MP (-19.13%, IV MP versus -2.77%, ACTH; p < 0.0001), suggesting less systemic immunosuppression with repository corticotropin gel. However, extrapolation and relevance of these results to clinical outcomes need further investigation.

Conclusion

The prevalence of neuropsychiatric symptoms and disorders among patients with MS is well recognized, as are the potential neuropsychiatric side effects of treatment with corticosteroids. Both MP and ACTH have demonstrated efficacy in reducing short-term disability after exacerbations of MS, but ACTH has not generally been associated with neuropsychiatric effects. In our retrospective case series, all six patients who had experienced neuropsychiatric side effects with MP treatment were subsequently treated with repository corticotropin injection for MS exacerbations and each benefitted from improvements in MS symptoms. This clinical experience suggests to us that repository corticotropin injection should be considered for the treatment of acute exacerbations of MS as a viable alternative to IV MP in patients who do not tolerate corticosteroids or have difficulties associated with IV medication, particularly in patients who have a history of neuropsychiatric symptoms.