Stuart D. Cook, MD, and Abdul Rahman Alchaki

Dr. Cook is the Ruth Dunietz Kushner and Michael Jay Serwitz Professor of Neurology/Neurosciences at Rutgers, the State University of New Jersey, Newark. Dr. Alchaki is a resident in the Deptartment of Neurology/Neurosciences at Rutgers, the State University of New Jersey, Newark.

Disclosure: Stuart Cook has received honoraria for lectures from Bayer HealthCare and Merck Serono. He has served as a consultant for Merck Serono, Bayer HealthCare, Teva, Novartis, Sanofi-Aventis, Biogen Idec, and Actinobac Biomed. He has served on steering committees for the BEYOND and CLARITY Studies and as a member of Advisory Boards for Merck Serono, Bayer HealthCare, Teva, Biogen Idec, Sanofi Aventis, and Actinobac Biomed.

The Initial Years (1838 to 1930s)

The earliest recognition of MS clinical features and pathology was attributed to Jean-Martin Charcot, Robert Carswell, and Jean Cruveilhier in Europe from 1838 to 1868. Beyond those early descriptions, relatively few MS breakthroughs occurred until the 1930s, when Thomas Rivers discovered experimental autoimmune encephalomyelitis (EAE), a demyelinating disease, in animals. His insightful concepts were widely cited and ultimately contributed to undestanding of the immune mechanisms of MS and acute disseminated encephalomyelitis (ADEM).

Advances in Diagnosis (1965 to 1992)

In 1965, Schumacher et al provided the essential clinical criteria for MS diagnosis. Poser et al refined these criteria in 1983. In 2001, McDonald et al added neuroimaging, CSF analysis, and evoked potentials to further complement MS clinical diagnosis. For the first time, the disease could generally be recognized.

Early Treatments

Various treatments for MS were tried over the years, without great success. However, in 1953, a small descriptive trial by Miller and Gibbons reported clinical benefits in patients using intramuscular (IM) adrenocorticotropic hormone (ACTH) for MS and disseminated encephalomyelitis. This was followed in 1970 by a Cooperative Study of IM ACTH versus placebo by Rose et al, which resulted in ACTH, and subsequently oral corticosteroids, being widely used to treat MS, particularly for acute exacerbations of the disease. However, robust evidence of long-term steroids remain limited, even to the present.

High-Dose Steroids

By 1980, the initial descriptive treatment of high-dose intravenous (IV) steroids for demyelinating diseases, including MS and transverse myelitis, by Dowling et al resulted in rapid clinical improvement in some patients. This result was ultimately confirmed by others. High-dose IV steroids became the gold standard for acute attacks, particularly those aggressive in nature. In the mid 1980s, work by Troiano et al, as well as others, showed that the rapid use of high-dose IV as well as oral steroids showed similar effects, with reduction or elimination of CT contrast-enhancing lesions within as few as eight hours, while lower doses or alternative-day treatments were less effective. In addition, descriptive studies of immune modulatory and immunosuppressive drugs, as well as small randomized studies, were published. These agents did not receive FDA approval.

The Golden Age of Therapy (1993 to 2018)

A remarkable era in MS prognosis and treatment began with immunomodulation injections of Betaseron (INFβ-1b), Avonex (INFβ-1a), and Copaxone (glatiramer acetate). This can be attributed, at least in part, to advances in molecular biology, genetics, and neuroimaging, and support by corporate, private, and public funding. Since the initial FDA approval of INFβ-1b, 15 MS therapies have become clinically available, including eight injectables, three orals, and four infusion treatments (see Table 1). In addition, two other drugs have been FDA approved for uses other than MS: rituximab (approved for lymphoma) and cladribine (for hairy cell leukemia), with the latter now approved by the European Medicines Agency for MS. Table 1 depicts characteristics of these therapies approved by US or European agencies (or for other disorders increasingly used off label for MS) in an attempt to compare annual relapse rates (ARR) and decreases in the percent of gadolinium-enhancing MS lesions versus placebo. This information was chosen because ARR has been uniformly selected and defined for such trials, while percent decrease of gadolinium-enhancing lesions on MRI has been the most sensitive barometer available for assessing acute clinical activity. As a result, risk-benefit considerations have been critical in evaluating these drug treatments, with efficacy improving greatly over time, whereas risks have been more variable.

Disease Categories

In 1996, Lublin and Reingold provided a new classification, not specifically for the diagnosis of MS, but rather for the clinical course of the disease. Initially, there were four categories—relapsing-remitting MS, secondary progressive MS, primary progressive MS, and progressive-relapsing MS—that were universally identified. These were thought to be relatively distinct clinical categories, but over time it became clear that the classification did not fully distinguish MS disease activity within these categories. For that reason, it was subsequently recommended, by Lincoln et al in 2009 and Cook et al in 2012, to include MRI, a vastly more sensitive modality, as well as clinical data in assessing disease activity.

On another note, MS and neuromyelitis optica (NMO), although having similar features, were clearly identified as different diseases by Lennon et al in 2004. Differences in pathology, clinical characteristics, immunology, and therapy separate the two disorders.

MRI in MS

Work by Young et al in 1981 established the central role of MRI brain imaging in MS diagnosis and therapeutic considerations. Since then it has become ubiquitous.

An example of a sensitive and highly productive MRI protocol is the BECOME study of MS and clinically isolated syndrome by Cadavid et al from 2009 to 2017. In this study, IFNβ-1b was compared with glatiramer acetate treatment. Cadavid et al used a 3T scanner with triple-dose gadolinium, performed monthly for as long as 24 consecutive months. This unique study brought about a virtual gold mine of valuable research and clinical information. This included proof that gadolinium-enhancing lesions persisted for six months or more, evidence of a 30:1 ratio of new MRI brain lesions to clinical activity, and documentation that 96% of T2 lesions and black holes derive from prior gadolinium-enhancing lesions. It was further noted that 80% to 90% of acute black holes disappeared with treatment and 75% to 80% of patients taking IFNβ-1b or glatiramer acetate had new MRI lesions despite continuing treatment. Perhaps most interestingly, monthly MRIs could predict relapse and disability in a relatively small number of patients, depending upon the frequency and activity of MRI lesions. In 2017, Brown et al documented that magnetization transfer ratio recovery in MS brain lesions occurred more significantly with glatiramer acetate than with IFNβ-1b, whereas more chronic black hole lesions were found with glatiramer acetate. Also in 2017, Maranzano et al found evidence of acute inflammatory leukocortical lesions, which were not as well recognized previously.

In summary, it has become increasingly clear that MRI is the most sensitive available barometer for evaluating activity, pathology, and prognosis in most aspects of MS.

The Future of MS

While it is not yet a curable disease, there is growing evidence that MS prognosis has improved and will continue to improve. This is based on incremental decreases in acute MS exacerbations, progressive disability, and MRI lesion activity, as well as a combination of the three—no evidence of disease activity (NEDA).

Not only are drug therapies becoming more effective, but patients and physicians now have many more treatment options to carefully consider with regard to efficacy, side effect profiles, treatment frequency, route of administration, cost, and quality of life. Newer drugs with different mechanisms of action such as cladribine, now approved in Europe, fulfill most of these beneficial criteria (see Giovannoni et al, 2010). More promising MS treatments, including long-acting induction therapies, are still being evaluated. As with other complex diseases, multiple therapies are likely to be used as well.

In summary, compared with the time before 1993, MS will be much less likely to be a progressive disease, and quality of life will be much improved. In my opinion, patients will be less fearful about their prognosis than ever before, and with appropriate evaluations and treatments, we may realize that disabling MS will be far less common.

Suggested Reading

Brown JW, Pardini M, Brownlee WJ, et al. An abnormal periventricular magnetization transfer ratio gradient occurs early in multiple sclerosis. Brain. 2017;140(2):387-398.

Cadavid D, Wolansky LJ, Skurnick J, et al. Efficacy of treatment of MS with IFNbeta-1b or glatiramer acetate by monthly brain MRI in the BECOME study. Neurology. 2009;72(23):1976-1983.

Cook SD, Dhib-Jalbut S, Dowling P, et al. Use of magnetic resonance imaging as well as clinical disease activity in the clinical classification of multiple sclerosis and assessment of its course: a report from an international CMSC consensus conference, March 5-7, 2010. Int J MS Care. 2012;14(3):105-114.

Dowling PC, Bosch VV, Cook SD. Possible beneficial effect of high-dose intravenous steroid therapy in acute demyelinating disease and transverse myelitis. Neurology. 1980;30(7 Pt 2):33-36.

Giovannoni G, Comi G, Cook S, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):416-426.

Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004;364(9451):2106-2112.

Lincoln JA, Cadavid D, Pollard J, et al. We should use magnetic resonance imaging to classify and monitor the course of multiple sclerosis. Arch Neurol. 2009;66(3):412-414.

Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 1996;46(4):907-911.

Maranzano J, Rudko DA, Nakamura K, et al. MRI evidence of acute inflammation in leukocortical lesions of patients with early multiple sclerosis. Neurology. 2017;89(7):714-721.

McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol. 2001;50(1):121-127.

Miller HG, Gibbons JL. Acute disseminated encephalomyelitis and acute disseminated sclerosis; results of treatment with A.C.T.H. Br Med J. 1953;2(4850):1345-1348.

Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1983;13(3):227-231.

Rose AS, Kuzma JW, Kurtzke JF, et al. Cooperative study in the evaluation of therapy in multiple sclerosis. ACTH vs. placebo--final report. Neurology. 1970;20(5):1-59.

Troiano R, Hafstein M, Ruderman M, et al. Effect of high-dose intravenous steroid administration on contrast-enhancing computed tomographic scan lesions in multiple sclerosis. Ann Neurol. 1984;15(3):257-263.

Troiano RA, Hafstein MP, Zito G, et al. The effect of oral corticosteroid dosage on CT enhancing multiple sclerosis plaques. J Neurol Sci. 1985;70(1):67-72.

Young IR, Hall AS, Pallis A, et al. Nuclear magnetic resonance imaging of the brain in multiple sclerosis. Lancet. 1981;2(8255):1063-1066.

Stuart D. Cook, MD, and Abdul Rahman Alchaki

Dr. Cook is the Ruth Dunietz Kushner and Michael Jay Serwitz Professor of Neurology/Neurosciences at Rutgers, the State University of New Jersey, Newark. Dr. Alchaki is a resident in the Deptartment of Neurology/Neurosciences at Rutgers, the State University of New Jersey, Newark.

Disclosure: Stuart Cook has received honoraria for lectures from Bayer HealthCare and Merck Serono. He has served as a consultant for Merck Serono, Bayer HealthCare, Teva, Novartis, Sanofi-Aventis, Biogen Idec, and Actinobac Biomed. He has served on steering committees for the BEYOND and CLARITY Studies and as a member of Advisory Boards for Merck Serono, Bayer HealthCare, Teva, Biogen Idec, Sanofi Aventis, and Actinobac Biomed.

The Initial Years (1838 to 1930s)

The earliest recognition of MS clinical features and pathology was attributed to Jean-Martin Charcot, Robert Carswell, and Jean Cruveilhier in Europe from 1838 to 1868. Beyond those early descriptions, relatively few MS breakthroughs occurred until the 1930s, when Thomas Rivers discovered experimental autoimmune encephalomyelitis (EAE), a demyelinating disease, in animals. His insightful concepts were widely cited and ultimately contributed to undestanding of the immune mechanisms of MS and acute disseminated encephalomyelitis (ADEM).

Advances in Diagnosis (1965 to 1992)

In 1965, Schumacher et al provided the essential clinical criteria for MS diagnosis. Poser et al refined these criteria in 1983. In 2001, McDonald et al added neuroimaging, CSF analysis, and evoked potentials to further complement MS clinical diagnosis. For the first time, the disease could generally be recognized.

Early Treatments

Various treatments for MS were tried over the years, without great success. However, in 1953, a small descriptive trial by Miller and Gibbons reported clinical benefits in patients using intramuscular (IM) adrenocorticotropic hormone (ACTH) for MS and disseminated encephalomyelitis. This was followed in 1970 by a Cooperative Study of IM ACTH versus placebo by Rose et al, which resulted in ACTH, and subsequently oral corticosteroids, being widely used to treat MS, particularly for acute exacerbations of the disease. However, robust evidence of long-term steroids remain limited, even to the present.

High-Dose Steroids

By 1980, the initial descriptive treatment of high-dose intravenous (IV) steroids for demyelinating diseases, including MS and transverse myelitis, by Dowling et al resulted in rapid clinical improvement in some patients. This result was ultimately confirmed by others. High-dose IV steroids became the gold standard for acute attacks, particularly those aggressive in nature. In the mid 1980s, work by Troiano et al, as well as others, showed that the rapid use of high-dose IV as well as oral steroids showed similar effects, with reduction or elimination of CT contrast-enhancing lesions within as few as eight hours, while lower doses or alternative-day treatments were less effective. In addition, descriptive studies of immune modulatory and immunosuppressive drugs, as well as small randomized studies, were published. These agents did not receive FDA approval.

The Golden Age of Therapy (1993 to 2018)

A remarkable era in MS prognosis and treatment began with immunomodulation injections of Betaseron (INFβ-1b), Avonex (INFβ-1a), and Copaxone (glatiramer acetate). This can be attributed, at least in part, to advances in molecular biology, genetics, and neuroimaging, and support by corporate, private, and public funding. Since the initial FDA approval of INFβ-1b, 15 MS therapies have become clinically available, including eight injectables, three orals, and four infusion treatments (see Table 1). In addition, two other drugs have been FDA approved for uses other than MS: rituximab (approved for lymphoma) and cladribine (for hairy cell leukemia), with the latter now approved by the European Medicines Agency for MS. Table 1 depicts characteristics of these therapies approved by US or European agencies (or for other disorders increasingly used off label for MS) in an attempt to compare annual relapse rates (ARR) and decreases in the percent of gadolinium-enhancing MS lesions versus placebo. This information was chosen because ARR has been uniformly selected and defined for such trials, while percent decrease of gadolinium-enhancing lesions on MRI has been the most sensitive barometer available for assessing acute clinical activity. As a result, risk-benefit considerations have been critical in evaluating these drug treatments, with efficacy improving greatly over time, whereas risks have been more variable.

Disease Categories

In 1996, Lublin and Reingold provided a new classification, not specifically for the diagnosis of MS, but rather for the clinical course of the disease. Initially, there were four categories—relapsing-remitting MS, secondary progressive MS, primary progressive MS, and progressive-relapsing MS—that were universally identified. These were thought to be relatively distinct clinical categories, but over time it became clear that the classification did not fully distinguish MS disease activity within these categories. For that reason, it was subsequently recommended, by Lincoln et al in 2009 and Cook et al in 2012, to include MRI, a vastly more sensitive modality, as well as clinical data in assessing disease activity.

On another note, MS and neuromyelitis optica (NMO), although having similar features, were clearly identified as different diseases by Lennon et al in 2004. Differences in pathology, clinical characteristics, immunology, and therapy separate the two disorders.

MRI in MS

Work by Young et al in 1981 established the central role of MRI brain imaging in MS diagnosis and therapeutic considerations. Since then it has become ubiquitous.

An example of a sensitive and highly productive MRI protocol is the BECOME study of MS and clinically isolated syndrome by Cadavid et al from 2009 to 2017. In this study, IFNβ-1b was compared with glatiramer acetate treatment. Cadavid et al used a 3T scanner with triple-dose gadolinium, performed monthly for as long as 24 consecutive months. This unique study brought about a virtual gold mine of valuable research and clinical information. This included proof that gadolinium-enhancing lesions persisted for six months or more, evidence of a 30:1 ratio of new MRI brain lesions to clinical activity, and documentation that 96% of T2 lesions and black holes derive from prior gadolinium-enhancing lesions. It was further noted that 80% to 90% of acute black holes disappeared with treatment and 75% to 80% of patients taking IFNβ-1b or glatiramer acetate had new MRI lesions despite continuing treatment. Perhaps most interestingly, monthly MRIs could predict relapse and disability in a relatively small number of patients, depending upon the frequency and activity of MRI lesions. In 2017, Brown et al documented that magnetization transfer ratio recovery in MS brain lesions occurred more significantly with glatiramer acetate than with IFNβ-1b, whereas more chronic black hole lesions were found with glatiramer acetate. Also in 2017, Maranzano et al found evidence of acute inflammatory leukocortical lesions, which were not as well recognized previously.

In summary, it has become increasingly clear that MRI is the most sensitive available barometer for evaluating activity, pathology, and prognosis in most aspects of MS.

The Future of MS

While it is not yet a curable disease, there is growing evidence that MS prognosis has improved and will continue to improve. This is based on incremental decreases in acute MS exacerbations, progressive disability, and MRI lesion activity, as well as a combination of the three—no evidence of disease activity (NEDA).

Not only are drug therapies becoming more effective, but patients and physicians now have many more treatment options to carefully consider with regard to efficacy, side effect profiles, treatment frequency, route of administration, cost, and quality of life. Newer drugs with different mechanisms of action such as cladribine, now approved in Europe, fulfill most of these beneficial criteria (see Giovannoni et al, 2010). More promising MS treatments, including long-acting induction therapies, are still being evaluated. As with other complex diseases, multiple therapies are likely to be used as well.

In summary, compared with the time before 1993, MS will be much less likely to be a progressive disease, and quality of life will be much improved. In my opinion, patients will be less fearful about their prognosis than ever before, and with appropriate evaluations and treatments, we may realize that disabling MS will be far less common.

Suggested Reading

Brown JW, Pardini M, Brownlee WJ, et al. An abnormal periventricular magnetization transfer ratio gradient occurs early in multiple sclerosis. Brain. 2017;140(2):387-398.

Cadavid D, Wolansky LJ, Skurnick J, et al. Efficacy of treatment of MS with IFNbeta-1b or glatiramer acetate by monthly brain MRI in the BECOME study. Neurology. 2009;72(23):1976-1983.

Cook SD, Dhib-Jalbut S, Dowling P, et al. Use of magnetic resonance imaging as well as clinical disease activity in the clinical classification of multiple sclerosis and assessment of its course: a report from an international CMSC consensus conference, March 5-7, 2010. Int J MS Care. 2012;14(3):105-114.

Dowling PC, Bosch VV, Cook SD. Possible beneficial effect of high-dose intravenous steroid therapy in acute demyelinating disease and transverse myelitis. Neurology. 1980;30(7 Pt 2):33-36.

Giovannoni G, Comi G, Cook S, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):416-426.

Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004;364(9451):2106-2112.

Lincoln JA, Cadavid D, Pollard J, et al. We should use magnetic resonance imaging to classify and monitor the course of multiple sclerosis. Arch Neurol. 2009;66(3):412-414.

Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 1996;46(4):907-911.

Maranzano J, Rudko DA, Nakamura K, et al. MRI evidence of acute inflammation in leukocortical lesions of patients with early multiple sclerosis. Neurology. 2017;89(7):714-721.

McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol. 2001;50(1):121-127.

Miller HG, Gibbons JL. Acute disseminated encephalomyelitis and acute disseminated sclerosis; results of treatment with A.C.T.H. Br Med J. 1953;2(4850):1345-1348.

Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1983;13(3):227-231.

Rose AS, Kuzma JW, Kurtzke JF, et al. Cooperative study in the evaluation of therapy in multiple sclerosis. ACTH vs. placebo--final report. Neurology. 1970;20(5):1-59.

Troiano R, Hafstein M, Ruderman M, et al. Effect of high-dose intravenous steroid administration on contrast-enhancing computed tomographic scan lesions in multiple sclerosis. Ann Neurol. 1984;15(3):257-263.

Troiano RA, Hafstein MP, Zito G, et al. The effect of oral corticosteroid dosage on CT enhancing multiple sclerosis plaques. J Neurol Sci. 1985;70(1):67-72.

Young IR, Hall AS, Pallis A, et al. Nuclear magnetic resonance imaging of the brain in multiple sclerosis. Lancet. 1981;2(8255):1063-1066.

Stuart D. Cook, MD, and Abdul Rahman Alchaki

Dr. Cook is the Ruth Dunietz Kushner and Michael Jay Serwitz Professor of Neurology/Neurosciences at Rutgers, the State University of New Jersey, Newark. Dr. Alchaki is a resident in the Deptartment of Neurology/Neurosciences at Rutgers, the State University of New Jersey, Newark.

Disclosure: Stuart Cook has received honoraria for lectures from Bayer HealthCare and Merck Serono. He has served as a consultant for Merck Serono, Bayer HealthCare, Teva, Novartis, Sanofi-Aventis, Biogen Idec, and Actinobac Biomed. He has served on steering committees for the BEYOND and CLARITY Studies and as a member of Advisory Boards for Merck Serono, Bayer HealthCare, Teva, Biogen Idec, Sanofi Aventis, and Actinobac Biomed.

The Initial Years (1838 to 1930s)

The earliest recognition of MS clinical features and pathology was attributed to Jean-Martin Charcot, Robert Carswell, and Jean Cruveilhier in Europe from 1838 to 1868. Beyond those early descriptions, relatively few MS breakthroughs occurred until the 1930s, when Thomas Rivers discovered experimental autoimmune encephalomyelitis (EAE), a demyelinating disease, in animals. His insightful concepts were widely cited and ultimately contributed to undestanding of the immune mechanisms of MS and acute disseminated encephalomyelitis (ADEM).

Advances in Diagnosis (1965 to 1992)

In 1965, Schumacher et al provided the essential clinical criteria for MS diagnosis. Poser et al refined these criteria in 1983. In 2001, McDonald et al added neuroimaging, CSF analysis, and evoked potentials to further complement MS clinical diagnosis. For the first time, the disease could generally be recognized.

Early Treatments

Various treatments for MS were tried over the years, without great success. However, in 1953, a small descriptive trial by Miller and Gibbons reported clinical benefits in patients using intramuscular (IM) adrenocorticotropic hormone (ACTH) for MS and disseminated encephalomyelitis. This was followed in 1970 by a Cooperative Study of IM ACTH versus placebo by Rose et al, which resulted in ACTH, and subsequently oral corticosteroids, being widely used to treat MS, particularly for acute exacerbations of the disease. However, robust evidence of long-term steroids remain limited, even to the present.

High-Dose Steroids

By 1980, the initial descriptive treatment of high-dose intravenous (IV) steroids for demyelinating diseases, including MS and transverse myelitis, by Dowling et al resulted in rapid clinical improvement in some patients. This result was ultimately confirmed by others. High-dose IV steroids became the gold standard for acute attacks, particularly those aggressive in nature. In the mid 1980s, work by Troiano et al, as well as others, showed that the rapid use of high-dose IV as well as oral steroids showed similar effects, with reduction or elimination of CT contrast-enhancing lesions within as few as eight hours, while lower doses or alternative-day treatments were less effective. In addition, descriptive studies of immune modulatory and immunosuppressive drugs, as well as small randomized studies, were published. These agents did not receive FDA approval.

The Golden Age of Therapy (1993 to 2018)

A remarkable era in MS prognosis and treatment began with immunomodulation injections of Betaseron (INFβ-1b), Avonex (INFβ-1a), and Copaxone (glatiramer acetate). This can be attributed, at least in part, to advances in molecular biology, genetics, and neuroimaging, and support by corporate, private, and public funding. Since the initial FDA approval of INFβ-1b, 15 MS therapies have become clinically available, including eight injectables, three orals, and four infusion treatments (see Table 1). In addition, two other drugs have been FDA approved for uses other than MS: rituximab (approved for lymphoma) and cladribine (for hairy cell leukemia), with the latter now approved by the European Medicines Agency for MS. Table 1 depicts characteristics of these therapies approved by US or European agencies (or for other disorders increasingly used off label for MS) in an attempt to compare annual relapse rates (ARR) and decreases in the percent of gadolinium-enhancing MS lesions versus placebo. This information was chosen because ARR has been uniformly selected and defined for such trials, while percent decrease of gadolinium-enhancing lesions on MRI has been the most sensitive barometer available for assessing acute clinical activity. As a result, risk-benefit considerations have been critical in evaluating these drug treatments, with efficacy improving greatly over time, whereas risks have been more variable.

Disease Categories

In 1996, Lublin and Reingold provided a new classification, not specifically for the diagnosis of MS, but rather for the clinical course of the disease. Initially, there were four categories—relapsing-remitting MS, secondary progressive MS, primary progressive MS, and progressive-relapsing MS—that were universally identified. These were thought to be relatively distinct clinical categories, but over time it became clear that the classification did not fully distinguish MS disease activity within these categories. For that reason, it was subsequently recommended, by Lincoln et al in 2009 and Cook et al in 2012, to include MRI, a vastly more sensitive modality, as well as clinical data in assessing disease activity.

On another note, MS and neuromyelitis optica (NMO), although having similar features, were clearly identified as different diseases by Lennon et al in 2004. Differences in pathology, clinical characteristics, immunology, and therapy separate the two disorders.

MRI in MS

Work by Young et al in 1981 established the central role of MRI brain imaging in MS diagnosis and therapeutic considerations. Since then it has become ubiquitous.

An example of a sensitive and highly productive MRI protocol is the BECOME study of MS and clinically isolated syndrome by Cadavid et al from 2009 to 2017. In this study, IFNβ-1b was compared with glatiramer acetate treatment. Cadavid et al used a 3T scanner with triple-dose gadolinium, performed monthly for as long as 24 consecutive months. This unique study brought about a virtual gold mine of valuable research and clinical information. This included proof that gadolinium-enhancing lesions persisted for six months or more, evidence of a 30:1 ratio of new MRI brain lesions to clinical activity, and documentation that 96% of T2 lesions and black holes derive from prior gadolinium-enhancing lesions. It was further noted that 80% to 90% of acute black holes disappeared with treatment and 75% to 80% of patients taking IFNβ-1b or glatiramer acetate had new MRI lesions despite continuing treatment. Perhaps most interestingly, monthly MRIs could predict relapse and disability in a relatively small number of patients, depending upon the frequency and activity of MRI lesions. In 2017, Brown et al documented that magnetization transfer ratio recovery in MS brain lesions occurred more significantly with glatiramer acetate than with IFNβ-1b, whereas more chronic black hole lesions were found with glatiramer acetate. Also in 2017, Maranzano et al found evidence of acute inflammatory leukocortical lesions, which were not as well recognized previously.

In summary, it has become increasingly clear that MRI is the most sensitive available barometer for evaluating activity, pathology, and prognosis in most aspects of MS.

The Future of MS

While it is not yet a curable disease, there is growing evidence that MS prognosis has improved and will continue to improve. This is based on incremental decreases in acute MS exacerbations, progressive disability, and MRI lesion activity, as well as a combination of the three—no evidence of disease activity (NEDA).

Not only are drug therapies becoming more effective, but patients and physicians now have many more treatment options to carefully consider with regard to efficacy, side effect profiles, treatment frequency, route of administration, cost, and quality of life. Newer drugs with different mechanisms of action such as cladribine, now approved in Europe, fulfill most of these beneficial criteria (see Giovannoni et al, 2010). More promising MS treatments, including long-acting induction therapies, are still being evaluated. As with other complex diseases, multiple therapies are likely to be used as well.

In summary, compared with the time before 1993, MS will be much less likely to be a progressive disease, and quality of life will be much improved. In my opinion, patients will be less fearful about their prognosis than ever before, and with appropriate evaluations and treatments, we may realize that disabling MS will be far less common.

Suggested Reading

Brown JW, Pardini M, Brownlee WJ, et al. An abnormal periventricular magnetization transfer ratio gradient occurs early in multiple sclerosis. Brain. 2017;140(2):387-398.

Cadavid D, Wolansky LJ, Skurnick J, et al. Efficacy of treatment of MS with IFNbeta-1b or glatiramer acetate by monthly brain MRI in the BECOME study. Neurology. 2009;72(23):1976-1983.

Cook SD, Dhib-Jalbut S, Dowling P, et al. Use of magnetic resonance imaging as well as clinical disease activity in the clinical classification of multiple sclerosis and assessment of its course: a report from an international CMSC consensus conference, March 5-7, 2010. Int J MS Care. 2012;14(3):105-114.

Dowling PC, Bosch VV, Cook SD. Possible beneficial effect of high-dose intravenous steroid therapy in acute demyelinating disease and transverse myelitis. Neurology. 1980;30(7 Pt 2):33-36.

Giovannoni G, Comi G, Cook S, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):416-426.

Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004;364(9451):2106-2112.

Lincoln JA, Cadavid D, Pollard J, et al. We should use magnetic resonance imaging to classify and monitor the course of multiple sclerosis. Arch Neurol. 2009;66(3):412-414.

Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 1996;46(4):907-911.

Maranzano J, Rudko DA, Nakamura K, et al. MRI evidence of acute inflammation in leukocortical lesions of patients with early multiple sclerosis. Neurology. 2017;89(7):714-721.

McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol. 2001;50(1):121-127.

Miller HG, Gibbons JL. Acute disseminated encephalomyelitis and acute disseminated sclerosis; results of treatment with A.C.T.H. Br Med J. 1953;2(4850):1345-1348.

Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1983;13(3):227-231.

Rose AS, Kuzma JW, Kurtzke JF, et al. Cooperative study in the evaluation of therapy in multiple sclerosis. ACTH vs. placebo--final report. Neurology. 1970;20(5):1-59.

Troiano R, Hafstein M, Ruderman M, et al. Effect of high-dose intravenous steroid administration on contrast-enhancing computed tomographic scan lesions in multiple sclerosis. Ann Neurol. 1984;15(3):257-263.

Troiano RA, Hafstein MP, Zito G, et al. The effect of oral corticosteroid dosage on CT enhancing multiple sclerosis plaques. J Neurol Sci. 1985;70(1):67-72.

Young IR, Hall AS, Pallis A, et al. Nuclear magnetic resonance imaging of the brain in multiple sclerosis. Lancet. 1981;2(8255):1063-1066.

WASHINGTON, DC—Alcohol is a major seizure precipitant in the context of hazardous drinking and withdrawal, according to a study presented at the 71st Annual Meeting of the American Epilepsy Society. Occasional social drinking, however, is an uncommon cause of seizure breakthrough in predominantly focal epilepsy, said the researchers.

The seizure-inducing effect of alcohol withdrawal in chronic alcohol abuse is apparent, but the effect of binge drinking and modest social drinking among patients with epilepsy is less clear. Christian Samsonsen, MD, a neurologist at St. Olav’s University Hospital in Trondheim, Norway, and colleagues conducted a prospective, observational cross-over study to examine the relationship between alcohol and seizure disorders in acutely hospitalized patients. They also examined the clinical characteristics of patients with alcohol-related seizures and their drinking patterns.

Evaluating Drinking Patterns

The study included 134 consecutive patients with seizures. Ninety-two patients had epilepsy, and 42 patients had isolated seizures not diagnosed as epilepsy. At hospital admission, researchers conducted a semistructured interview and applied the Alcohol Use Disorders Identification Test (AUDIT).

Investigators defined withdrawal seizure as having an AUDIT score of 8 or greater and alcohol intake within the last two days. They defined binge drinking as drinking more than four units in one session for females and more than five units in one session for males. They defined social drinking as having an AUDIT score of less than 8 and not drinking more than 12 units in one day.

The researchers recorded daily alcohol consumption during the five days prior to the seizure, as well as sleep time during the prior three days. Researchers then performed a follow-up telephone interview on a seizure-free day at least four weeks later.

Seizures Were More Common on Sunday and Monday

In all, 28% of patients had an AUDIT score of 8 or greater (ie, hazardous drinking), including 22% of patients with epilepsy and 43% of patients with isolated seizures. Alcohol consumption and nonfocal seizures were increased in isolated seizures, suggesting withdrawal.

One in five patients with epilepsy had been binge drinking, and 59 (64%) patients with epilepsy had been socially drinking. Among the patients who had been socially drinking, alcohol intake was not different prior to seizure, compared with follow-up, downgrading the role of modest social drinking as a seizure precipitant, said the researchers. Among the 19 patients with idiopathic generalized epilepsy, however, “even social drinking two days prior to seizure was associated with seizures,” the researchers said. Patients with epilepsy were more likely to have had their seizures on a Sunday (21%) or Monday (23%)than on other days. Patients with single seizures were more likely to have had their seizures on a Monday (29%) than on other days. Seizures associated with binge drinking were more common on Sunday.

Overall, binge drinking was associated with loss of seizure control in people with epilepsy; however, “alcohol alone should not always be blamed,” said the researchers. “In people with epilepsy, alcohol intake is often combined with other seizure precipitants,” such as sleep loss, they concluded.

—Erica Tricarico

Suggested Reading

Samsonsen C, Sand T, Brathen G, et al. The impact of sleep loss on the facilitation of seizures: A prospective case-crossover study. Epilepsy Res. 2016;127:260-266.

WASHINGTON, DC—Alcohol is a major seizure precipitant in the context of hazardous drinking and withdrawal, according to a study presented at the 71st Annual Meeting of the American Epilepsy Society. Occasional social drinking, however, is an uncommon cause of seizure breakthrough in predominantly focal epilepsy, said the researchers.

The seizure-inducing effect of alcohol withdrawal in chronic alcohol abuse is apparent, but the effect of binge drinking and modest social drinking among patients with epilepsy is less clear. Christian Samsonsen, MD, a neurologist at St. Olav’s University Hospital in Trondheim, Norway, and colleagues conducted a prospective, observational cross-over study to examine the relationship between alcohol and seizure disorders in acutely hospitalized patients. They also examined the clinical characteristics of patients with alcohol-related seizures and their drinking patterns.

Evaluating Drinking Patterns

The study included 134 consecutive patients with seizures. Ninety-two patients had epilepsy, and 42 patients had isolated seizures not diagnosed as epilepsy. At hospital admission, researchers conducted a semistructured interview and applied the Alcohol Use Disorders Identification Test (AUDIT).

Investigators defined withdrawal seizure as having an AUDIT score of 8 or greater and alcohol intake within the last two days. They defined binge drinking as drinking more than four units in one session for females and more than five units in one session for males. They defined social drinking as having an AUDIT score of less than 8 and not drinking more than 12 units in one day.

The researchers recorded daily alcohol consumption during the five days prior to the seizure, as well as sleep time during the prior three days. Researchers then performed a follow-up telephone interview on a seizure-free day at least four weeks later.

Seizures Were More Common on Sunday and Monday

In all, 28% of patients had an AUDIT score of 8 or greater (ie, hazardous drinking), including 22% of patients with epilepsy and 43% of patients with isolated seizures. Alcohol consumption and nonfocal seizures were increased in isolated seizures, suggesting withdrawal.

One in five patients with epilepsy had been binge drinking, and 59 (64%) patients with epilepsy had been socially drinking. Among the patients who had been socially drinking, alcohol intake was not different prior to seizure, compared with follow-up, downgrading the role of modest social drinking as a seizure precipitant, said the researchers. Among the 19 patients with idiopathic generalized epilepsy, however, “even social drinking two days prior to seizure was associated with seizures,” the researchers said. Patients with epilepsy were more likely to have had their seizures on a Sunday (21%) or Monday (23%)than on other days. Patients with single seizures were more likely to have had their seizures on a Monday (29%) than on other days. Seizures associated with binge drinking were more common on Sunday.

Overall, binge drinking was associated with loss of seizure control in people with epilepsy; however, “alcohol alone should not always be blamed,” said the researchers. “In people with epilepsy, alcohol intake is often combined with other seizure precipitants,” such as sleep loss, they concluded.

—Erica Tricarico

Suggested Reading

Samsonsen C, Sand T, Brathen G, et al. The impact of sleep loss on the facilitation of seizures: A prospective case-crossover study. Epilepsy Res. 2016;127:260-266.

WASHINGTON, DC—Alcohol is a major seizure precipitant in the context of hazardous drinking and withdrawal, according to a study presented at the 71st Annual Meeting of the American Epilepsy Society. Occasional social drinking, however, is an uncommon cause of seizure breakthrough in predominantly focal epilepsy, said the researchers.

The seizure-inducing effect of alcohol withdrawal in chronic alcohol abuse is apparent, but the effect of binge drinking and modest social drinking among patients with epilepsy is less clear. Christian Samsonsen, MD, a neurologist at St. Olav’s University Hospital in Trondheim, Norway, and colleagues conducted a prospective, observational cross-over study to examine the relationship between alcohol and seizure disorders in acutely hospitalized patients. They also examined the clinical characteristics of patients with alcohol-related seizures and their drinking patterns.

Evaluating Drinking Patterns

The study included 134 consecutive patients with seizures. Ninety-two patients had epilepsy, and 42 patients had isolated seizures not diagnosed as epilepsy. At hospital admission, researchers conducted a semistructured interview and applied the Alcohol Use Disorders Identification Test (AUDIT).

Investigators defined withdrawal seizure as having an AUDIT score of 8 or greater and alcohol intake within the last two days. They defined binge drinking as drinking more than four units in one session for females and more than five units in one session for males. They defined social drinking as having an AUDIT score of less than 8 and not drinking more than 12 units in one day.

The researchers recorded daily alcohol consumption during the five days prior to the seizure, as well as sleep time during the prior three days. Researchers then performed a follow-up telephone interview on a seizure-free day at least four weeks later.

Seizures Were More Common on Sunday and Monday

In all, 28% of patients had an AUDIT score of 8 or greater (ie, hazardous drinking), including 22% of patients with epilepsy and 43% of patients with isolated seizures. Alcohol consumption and nonfocal seizures were increased in isolated seizures, suggesting withdrawal.

One in five patients with epilepsy had been binge drinking, and 59 (64%) patients with epilepsy had been socially drinking. Among the patients who had been socially drinking, alcohol intake was not different prior to seizure, compared with follow-up, downgrading the role of modest social drinking as a seizure precipitant, said the researchers. Among the 19 patients with idiopathic generalized epilepsy, however, “even social drinking two days prior to seizure was associated with seizures,” the researchers said. Patients with epilepsy were more likely to have had their seizures on a Sunday (21%) or Monday (23%)than on other days. Patients with single seizures were more likely to have had their seizures on a Monday (29%) than on other days. Seizures associated with binge drinking were more common on Sunday.

Overall, binge drinking was associated with loss of seizure control in people with epilepsy; however, “alcohol alone should not always be blamed,” said the researchers. “In people with epilepsy, alcohol intake is often combined with other seizure precipitants,” such as sleep loss, they concluded.

—Erica Tricarico

Suggested Reading

Samsonsen C, Sand T, Brathen G, et al. The impact of sleep loss on the facilitation of seizures: A prospective case-crossover study. Epilepsy Res. 2016;127:260-266.

“BLACK PATIENTS PRESENT WITH MORE SEVERE VASCULAR DISEASE AND A GREATER BURDEN OF RISK FACTORS THAN WHITE PATIENTS AT TIME OF MAJOR VASCULAR INTERVENTION.” Journal of Vascular Surgery, February 2018.

African Americans come into the vascular operating room with significant co-morbidities that may explain their more severe level of disease and higher risk factors, report researchers who reviewed 76,000 vascular cases for their report in the February edition of the Journal of Vascular Surgery.

This study drills deeper into the severity of vascular disease in African Americans, adding more fuel to the discussion of health disparities between racial and ethnic groups explored by the American Medical Association, which found that minorities are less likely to receive routine medical care and face higher rates of morbidity and mortality than non-minorities.

Invited commentator Dr. William R. Flinn found the study so profound he stated, “It should be read by every vascular surgeon, in fact, by every physician.”

Researchers have observed similar outcomes in vascular surgical procedures, but determining the cause of these disparities is difficult, since databases do not provide detail on disease severity.

For this report, a multi-institutional team of vascular surgeons led by vascular surgeon Dr. Marc Schermerhorn from Beth Israel Deaconess Medical Center took direct aim at this problem. Using de-identified data from the Vascular Quality Initiative gathered between 2009 and 2014, they found that compared to white patients, black patients were:

• Younger
• More likely to smoke
• More often diagnosed with insulin-dependent diabetes, hypertension, congestive heart failure and end-stage renal disease
• Less often medicated with statins
• Less often insured

Black patients also were sicker at the time of surgery. Compared with whites, black patients had more severe:

• Carotid disease (36% versus 31% symptomatic lesions)
• AAA (27% versus 16% symptoms/rupture, and more iliac aneurysm)
• PAD (73% versus 62% critical limb ischemia)

Furthermore, black patients were less likely to be discharged on aspirin and statin therapy after treatment for AAA and PAD than whites.

The authors note that their study is limited by factors common to all database studies including missing data, variability in definitions, and no way to adjust for socio-economic factors, compliance, family support, hospital type and timing of referral.

“Even in hospitals invested in quality improvement – as evidenced by participation in the VQI – black patients present with more advanced disease and more comorbidities compared with whites, despite presenting at a younger age,” states first author Dr. Peter Soden.  “And these disparities were uniform across the spectrum of vascular disease, including carotids, AAA and PAD.” 

The increase in presenting risk factors, along with disparity in medical management, offers clues as to the well-reported worse outcomes for black patients after major vascular procedures.

“The majority of the disparities highlighted in this manuscript are not from biologic differences, but instead from social, economic and health care delivery factors,” noted Dr. Flinn. “What this most clearly suggests is that there are untold numbers of black [patients] throughout the country with undiagnosed and untreated carotid disease, abdominal aortic aneurysm and PAD (and hypertension, and diabetes, and chronic kidney disease) because they do not have equitable access to health care in the United States in the 21^st century.

“The vascular community has a unique opportunity to contribute to the health care debate in this country,” he added. “I hope we have both the scientific rigor and the political courage to pursue it aggressively.”

To download the complete article (freely available Jan.  22 - March 31), click: vsweb.org/JVS-Severe.

“BLACK PATIENTS PRESENT WITH MORE SEVERE VASCULAR DISEASE AND A GREATER BURDEN OF RISK FACTORS THAN WHITE PATIENTS AT TIME OF MAJOR VASCULAR INTERVENTION.” Journal of Vascular Surgery, February 2018.

African Americans come into the vascular operating room with significant co-morbidities that may explain their more severe level of disease and higher risk factors, report researchers who reviewed 76,000 vascular cases for their report in the February edition of the Journal of Vascular Surgery.

This study drills deeper into the severity of vascular disease in African Americans, adding more fuel to the discussion of health disparities between racial and ethnic groups explored by the American Medical Association, which found that minorities are less likely to receive routine medical care and face higher rates of morbidity and mortality than non-minorities.

Invited commentator Dr. William R. Flinn found the study so profound he stated, “It should be read by every vascular surgeon, in fact, by every physician.”

Researchers have observed similar outcomes in vascular surgical procedures, but determining the cause of these disparities is difficult, since databases do not provide detail on disease severity.

For this report, a multi-institutional team of vascular surgeons led by vascular surgeon Dr. Marc Schermerhorn from Beth Israel Deaconess Medical Center took direct aim at this problem. Using de-identified data from the Vascular Quality Initiative gathered between 2009 and 2014, they found that compared to white patients, black patients were:

• Younger
• More likely to smoke
• More often diagnosed with insulin-dependent diabetes, hypertension, congestive heart failure and end-stage renal disease
• Less often medicated with statins
• Less often insured

Black patients also were sicker at the time of surgery. Compared with whites, black patients had more severe:

• Carotid disease (36% versus 31% symptomatic lesions)
• AAA (27% versus 16% symptoms/rupture, and more iliac aneurysm)
• PAD (73% versus 62% critical limb ischemia)

Furthermore, black patients were less likely to be discharged on aspirin and statin therapy after treatment for AAA and PAD than whites.

The authors note that their study is limited by factors common to all database studies including missing data, variability in definitions, and no way to adjust for socio-economic factors, compliance, family support, hospital type and timing of referral.

“Even in hospitals invested in quality improvement – as evidenced by participation in the VQI – black patients present with more advanced disease and more comorbidities compared with whites, despite presenting at a younger age,” states first author Dr. Peter Soden.  “And these disparities were uniform across the spectrum of vascular disease, including carotids, AAA and PAD.” 

The increase in presenting risk factors, along with disparity in medical management, offers clues as to the well-reported worse outcomes for black patients after major vascular procedures.

“The majority of the disparities highlighted in this manuscript are not from biologic differences, but instead from social, economic and health care delivery factors,” noted Dr. Flinn. “What this most clearly suggests is that there are untold numbers of black [patients] throughout the country with undiagnosed and untreated carotid disease, abdominal aortic aneurysm and PAD (and hypertension, and diabetes, and chronic kidney disease) because they do not have equitable access to health care in the United States in the 21^st century.

“The vascular community has a unique opportunity to contribute to the health care debate in this country,” he added. “I hope we have both the scientific rigor and the political courage to pursue it aggressively.”

To download the complete article (freely available Jan.  22 - March 31), click: vsweb.org/JVS-Severe.

“BLACK PATIENTS PRESENT WITH MORE SEVERE VASCULAR DISEASE AND A GREATER BURDEN OF RISK FACTORS THAN WHITE PATIENTS AT TIME OF MAJOR VASCULAR INTERVENTION.” Journal of Vascular Surgery, February 2018.

African Americans come into the vascular operating room with significant co-morbidities that may explain their more severe level of disease and higher risk factors, report researchers who reviewed 76,000 vascular cases for their report in the February edition of the Journal of Vascular Surgery.

This study drills deeper into the severity of vascular disease in African Americans, adding more fuel to the discussion of health disparities between racial and ethnic groups explored by the American Medical Association, which found that minorities are less likely to receive routine medical care and face higher rates of morbidity and mortality than non-minorities.

Invited commentator Dr. William R. Flinn found the study so profound he stated, “It should be read by every vascular surgeon, in fact, by every physician.”

Researchers have observed similar outcomes in vascular surgical procedures, but determining the cause of these disparities is difficult, since databases do not provide detail on disease severity.

For this report, a multi-institutional team of vascular surgeons led by vascular surgeon Dr. Marc Schermerhorn from Beth Israel Deaconess Medical Center took direct aim at this problem. Using de-identified data from the Vascular Quality Initiative gathered between 2009 and 2014, they found that compared to white patients, black patients were:

• Younger
• More likely to smoke
• More often diagnosed with insulin-dependent diabetes, hypertension, congestive heart failure and end-stage renal disease
• Less often medicated with statins
• Less often insured

Black patients also were sicker at the time of surgery. Compared with whites, black patients had more severe:

• Carotid disease (36% versus 31% symptomatic lesions)
• AAA (27% versus 16% symptoms/rupture, and more iliac aneurysm)
• PAD (73% versus 62% critical limb ischemia)

Furthermore, black patients were less likely to be discharged on aspirin and statin therapy after treatment for AAA and PAD than whites.

The authors note that their study is limited by factors common to all database studies including missing data, variability in definitions, and no way to adjust for socio-economic factors, compliance, family support, hospital type and timing of referral.

“Even in hospitals invested in quality improvement – as evidenced by participation in the VQI – black patients present with more advanced disease and more comorbidities compared with whites, despite presenting at a younger age,” states first author Dr. Peter Soden.  “And these disparities were uniform across the spectrum of vascular disease, including carotids, AAA and PAD.” 

The increase in presenting risk factors, along with disparity in medical management, offers clues as to the well-reported worse outcomes for black patients after major vascular procedures.

“The majority of the disparities highlighted in this manuscript are not from biologic differences, but instead from social, economic and health care delivery factors,” noted Dr. Flinn. “What this most clearly suggests is that there are untold numbers of black [patients] throughout the country with undiagnosed and untreated carotid disease, abdominal aortic aneurysm and PAD (and hypertension, and diabetes, and chronic kidney disease) because they do not have equitable access to health care in the United States in the 21^st century.

“The vascular community has a unique opportunity to contribute to the health care debate in this country,” he added. “I hope we have both the scientific rigor and the political courage to pursue it aggressively.”

To download the complete article (freely available Jan.  22 - March 31), click: vsweb.org/JVS-Severe.

Applications are due March 2 for the Wylie Scholar Award, co-sponsored by the SVS Foundation and Vascular Cures. The three-year, $150,000 grant is awarded to a promising vascular surgeon-scientist in North America and is designed to support outstanding surgeon-scientists conducting innovative academic research in the early stages of their careers.

Applications are due March 2 for the Wylie Scholar Award, co-sponsored by the SVS Foundation and Vascular Cures. The three-year, $150,000 grant is awarded to a promising vascular surgeon-scientist in North America and is designed to support outstanding surgeon-scientists conducting innovative academic research in the early stages of their careers.

Applications are due March 2 for the Wylie Scholar Award, co-sponsored by the SVS Foundation and Vascular Cures. The three-year, $150,000 grant is awarded to a promising vascular surgeon-scientist in North America and is designed to support outstanding surgeon-scientists conducting innovative academic research in the early stages of their careers.

SVS members, please remind any vascular PAs with whom you work to consider submitting an abstract for the inaugural PA programming or be a speaker during our 2018 Vascular Annual Meeting. More information is here -- please forward to your PAs!

SVS members, please remind any vascular PAs with whom you work to consider submitting an abstract for the inaugural PA programming or be a speaker during our 2018 Vascular Annual Meeting. More information is here -- please forward to your PAs!

SVS members, please remind any vascular PAs with whom you work to consider submitting an abstract for the inaugural PA programming or be a speaker during our 2018 Vascular Annual Meeting. More information is here -- please forward to your PAs!

Postpartum psychosis is a psychiatric emergency that can endanger the life of the mother and the newborn child if untreated. About 1 to 2 mothers in 1,000 experiences postpartum psychosis after delivery.¹ This rate is much higher among women with an established diagnosis of bipolar disorder before pregnancy.¹

Expedient recognition, diagnosis, and referral to a high-level psychiatric facility (usually a locked inpatient unit) are critical for ensuring the safety of mother and infant. A diligent medical workup followed by thorough education for the patient and family are important steps in caring for patients with postpartum psychosis. Close mental health follow-up, pharmacologic interventions, informed decision making regarding breastfeeding, and preserving the sleep-wake cycle are critical for stabilization.²

The authors present the case of a patient admitted to VA Central California Health Care System (VACCHCS) with postpartum psychosis and a discussion on existing research on the prevalence of postpartum psychosis, relevant risk factors, the association with bipolar disorder, and treatment strategies.

Case Presentation

A 31-year-old active-duty female with no history of mental illness was admitted to the psychiatric unit because new-onset disorganized behavior was preventing her from functioning at her workplace. Two weeks after giving birth to her second child, the patient began exhibiting an uncharacteristic, debilitating labile mood and disorganized behavior. Her supervisors required her to present for medical attention about 3 months after the birth of her child. She was transferred to VACCHCS for higher level medical care on military orders. The patient’s husband initially attributed these psychiatric symptoms to vocational stress and taking care of 2 young children. He observed the patient exhibiting tearfulness about her job, which quickly alternated with euphoric episodes of singing and dancing at inappropriate times, such as when the children had quieted down and were being prepared to go to bed.

At the initial psychiatric evaluation after transfer to VACCHCS, the patient appeared well-kept and slightly overweight. In general her appearance was unremarkable. Throughout the examination she sang both subtly and loudly and at times was confrontational and irritable.

She related oddly and often was guarded and difficult to engage; she sang and played with her blanket in a childlike way. She smiled and laughed inappropriately, mumbled incoherently to herself, scanned the room suspiciously, and often made intense eye contact. Her affect was labile, both tearful and euphoric at several points in the examination. Her thought process was tangential, illogical, grandiose, difficult to redirect, and with loose associations. Her thought content consisted of delusions (“I’ve got the devil on my back”) and grandiosity (“I am everyone, I am you…the president, the mayor”), and she often stated that she planned to become a singer or performer.

The patient claimed she was neither suicidal nor had thoughts of infanticide. She reported having no visual and auditory hallucinations but often seemed to be responding to internal stimuli: She mumbled to herself and looked intensely at parts of the room. Cognitively, the patient was fully intact to recent and remote events but displayed a poor attention span. She did not exhibit any motor abnormalities, such as tremor, rigidity, weakness, sensory loss, or abnormal gait.

The patient’s workup included full chemistry, complete blood count, thyroid-stimulating hormone, antithyroid antibodies, calcium, rapid plasma reagin to rule out syphilis, toxicology, folate, vitamin B₁₂, and vitamin D. All laboratory results were negative or within normal limits, although the urine drug screen was positive for cannabis. The patient’s husband noted that his wife never used cannabis except the weekend before her admission, when she impulsively went dancing, which was out of character for her. Her psychotic symptoms had been present weeks before the cannabis use; therefore, the her symptoms could not be attributed to a substance-induced psychotic disorder. A test for synthetic cannabis derivatives was negative. Newer synthetic compounds can cause more severe substance-induced psychotic symptoms than those of cannabis.³

The patient was diagnosed with postpartum psychosis and was started on the oral antipsychotic olanzapine 10 mg at bedtime. Additional doses were administered to control ongoing symptoms, which included a disorganized thought process; loose associations; euphoria; grandiosity; delusional content, such as “You are just a tool in place to help me;” reports of feeling as though she were in “outer space, outside in the galaxy;” decreased need for sleep; and irritability. The patient spent an entire interview with her eyes closed, stating that she could “hear” better because she was overstimulated if her eyes were open. She also described olfactory hallucinations of “strong perfume,” which the 2 providers present could not detect.

Olanzapine was not well tolerated because of sedation and was discontinued in favor of risperidone, 2 mg twice daily. Risperidone was more effective and better tolerated. Lithium was initiated the next day with target dosing at 300 mg in the morning and 600 mg at night. The patient became capable of linear, organized discussion and planning but remained euphoric with high energy; she exhibited grandiosity with frequent singing and dancing throughout her hospital stay. She often described her mood as “good, excellent, exuberant, exciting,” perseverating on the way words sounded and giggling in a childlike manner. She continued to have intrusive dreams of “hell and the devil” and that she was killed by gunshot.

The patient was continued on lithium and risperidone and transferred to a larger military hospital for further inpatient management, respecting military orders. Before discharge, a family conference was held with the patient and her husband to educate them on the importance of continued treatment, close follow-up, regular sleep patterns, and not breastfeeding while taking the prescribed medications. Although she was not back to her baseline at the time of transfer, the patient had stabilized significantly and gained sufficient insight into her condition.

Discussion

Postpartum psychosis can present with a prodromal phase consisting of fatigue, insomnia, restlessness, tearfulness, and emotional lability, making early identification difficult. Later, florid psychotic symptoms can include suspiciousness, confusion, incoherence, irrational statements, obsessive concern about the infant’s health, and delusions, including a belief that the baby is dead or defective. Some women might deny that the birth occurred or feel that they are unmarried, virginal, or persecuted.¹ More concerning symptoms include auditory hallucinations commanding the mother to harm or kill the infant and/or herself. Symptoms often begin within days to weeks of birth, usually 2 to 3 weeks after delivery but can occur as long as 8 weeks postpartum.¹ Several cases of infanticide and suicide have been documented.¹ The risk of experiencing another psychotic episode in subsequent pregnancies can be as high as 50%.^4-6 Regardless of symptom severity at onset, postpartum psychosis is a psychiatric emergency and must be treated as such.

Bipolar Disorder and Postpartum Psychosis

A close relationship exists between postpartum psychosis and development of bipolar disorder. A postpartum psychotic episode often is the harbinger of bipolar illness.⁷ About two-thirds of women who have an episode of postpartum psychosis will experience an underlying affective disorder within a year of childbirth.^1,8 It is unclear what triggers the psychotic episode, but it has been theorized that major systemic shifts in hormone levelsor trauma of delivery could instigate development of symptoms.^1,9

Risk factors include obstetric complications; perinatal infant mortality; previous episodes of bipolar disorder, psychosis, or postpartum psychosis; family history of bipolar disorder or postpartum psychosis; sleep deprivation; increased environmental stress; and lack of partner support.¹⁰ The strongest risk factor for developing postpartum psychosis is a personal or family history of bipolar disorder or a related psychotic disorder.¹¹ This risk factor is identified in about 40% to 50% cases of postpartum psychosis.¹¹

Treatment

Standard treatment for postpartum psychosis includes an antipsychotic and often lithium and benzodiazepines.^1,7,10,11 This treatment approach differs slightly from treating a patient with a nonpostpartum psychotic illness, who generally would not receive mood stabilizers, such as lithium. Including a mood stabilizer for postpartum psychosis is warranted because of the association between postpartum psychosis and bipolar disorder, which is treated with a mood stabilizer.

Prevalence

Postpartum psychosis is identified in 1 to 2 per 1,000 childbirths. In women who have had an earlier episode of postpartum psychosis or have a diagnosis of bipolar disorder, the rate is up to 100 times higher.¹ Kendell and colleagues found that psychiatric admissions occurred at a rate 7 times higher in the 30 days after birth than in the prepregnancy period, suggesting that metabolic factors might be involved in triggering postpartum psychotic symptoms.¹² An abrupt hormonal loss occurs at childbirth; hormones peak 200-fold during gestation and decline rapidly within a day after birth.⁹ Despite the severity of symptoms in postpartum psychosis, these patients tend to have a better prognosis than that of women with psychotic episodes not related to pregnancy.⁴

Patients with bipolar disorder have the highest risk of psychotic episodes during the postpartum period, with a study reporting 260 episodes of psychosis per deliveries among women with bipolar disorder.¹³ Studies such as this suggest that episodes of postpartum psychosis might be a variant or atypical presentation of an underlying bipolar disorder or a predisposition to developing the disorder.¹⁴ In a study that compared 58 patients with postpartum psychosis with to 52 individuals with nonchildbearing-related psychosis, manic symptoms were more common among the postpartum group.¹⁵ Family studies have shown that the risk of psychiatric illness among first-degree relatives of women with postpartum psychosis is 10% to 50%, which is higher than in the general population.¹⁴

Brockington and colleagues found that patients with postpartum psychosis had more mood lability, distractibility, and confusion than those with psychosis unrelated to pregnancy.¹⁵ Patients with postpartum psychosis were more likely to have impaired sensorium, bizarre quality of delusions, and memory loss. Psychosis with onset after childbirth included high levels of thought disorganization, delusions of reference, delusions of persecution, and greater levels of homicidal ideation and behavior.¹⁶ This study also reported symptoms such as visual, tactile, and olfactory hallucinations and a presentation similar to that of delirium.

Chandra and colleagues found that 53% of women with postpartum psychosis had delusions about the infant, including beliefs that someone would harm or kill the baby or that the baby would be harmed by their breast milk.¹⁷ Compared with women with bipolar disorder, Oostheuizen and colleagues found that women with postpartum psychosis had delusions of control, such as feeling under the influence of an overpowering force that controlled their actions.¹⁸ Infanticidal thoughts are common among patients with postpartum psychosis, and about 4% of women committed infanticide.¹

Rapid stabilization and treatment are important because postpartum psychosis is considered a psychiatric emergency.⁷ Potential consequences of delayed diagnosis and treatment include harm or death of the infant by infanticide and death of the mother by suicide. A thorough physical examination is important to rule out metabolic or neuroendocrine causes of psychosis other than postpartum hormonal shifts. These could include causes of altered mental status: stroke, pulmonary embolism, amniotic fluid emboli, Sheehan syndrome, thyroid disorders, electrolyte abnormalities, acute hemorrhage, sepsis, and substance toxicity or withdrawal.¹⁰ A complete blood count, full chemistry, thyroid function tests, antithyroid antibody tests, calcium, vitamin B₁₂, and folate should be measured.^7,10

Initial treatment should include antipsychotics and often mood stabilizers such as lithium. Managing insomnia aggressively is also necessary for initial stabilization and to prevent a repeat manic episode if the patient develops bipolar disorder.² Many experts argue that sleep loss in combination with other risk factors might be the final common pathway for development of postpartum psychosis in women predisposed to this disorder.^19,20

Treating insomnia in an outpatient setting includes teaching sleep hygiene practices and relaxation techniques. Although these methods to regulate sleep could be encouraged during the emergent inpatient stabilization of a patient with postpartum psychosis, pharmacologic approaches are necessary for acute mania and psychosis. Concern about possible dependence on benzodiazepines and other sedating sleep aids are valid; however, the benefit of acute stabilization of psychotic symptoms outweighs the potential risk of dependence.

Typically, first-line treatment is an antipsychotic, and second-generation antipsychotics generally are preferred over first-generation antipsychotics because of their more benign adverse effect profile.^21,22 There are no controlled trials that compare antipsychotics with placebo or other interventions for postpartum psychosis. Therefore, use of atypical antipsychotics is based on randomized trials demonstrating efficacy in reducing psychosis in bipolar disorder, depression with psychotic features, and schizoaffective disorder.^23,24 Once the patient is treated with an antipsychotic, further use of psychotropic medications, such as lithium or other mood stabilizers, should be based on the patient’s clinical presentation. For example, the patient in this case study primarily had manic symptoms consistent with bipolar disorder, making lithium or another mood stabilizer an appropriate choice.

Bergink and colleagues demonstrated positive outcomes with a treatment algorithm involving sequential use of benzodiazepines to improve sleep, an antipsychotic to decrease acute manic symptoms, lithium to stabilize mood based on symptoms, and electroconvulsive therapy if other treatments were not successful.²⁵ Case studies document that administering estrogen led to recovery from postpartum psychosis, although patients often relapsed when estrogen was stopped.²⁶ Electroconvulsive therapy has shown promising results, especially in patients who do not respond to antipsychotic medications or lithium.^27,28

Antipsychotic and Other Psychotropic Medications

Choice of an antipsychotic and other psychotropic medications to treat postpartum psychosis is based on the patient’s breastfeeding status. The benefits of treatment should be weighed against the risks of a breastfeeding infant’s exposure to the medication. Because postpartum psychosis is a psychiatric emergency, the benefits of the medication are considered to outweigh any potential adverse effect to the breastfeeding infant exposed to the medication. Risks of untreated postpartum psychosis to the infant include rejection of the infant, poor parental relationships, suicide, infanticide, long-term failure to bond with the child, delayed infant development, and failure to thrive.²⁹ Also, many mothers—including the patient in this presentation—decide that the benefits of treatment outweigh those of breastfeeding and choose to feed their infant with formula. Even if the patient chooses to bottle-feed her infant, consider administering medications that are considered safer for breastfeeding because the patient may need to continue the psychotropic during later pregnancies to prevent future psychotic episodes.³⁰ All psychotropic medications pass into breast milk.²⁹ Studies on the long-term effect of these medications on the infant are limited, but experts tend to recommend olanzapine, quetiapine, and risperidone over aripiprazole and ziprasidone.^21,31-33

Lithium often is used to treat postpartum psychosis. Studies examining risk to the infant after long-term exposure to lithium through breast milk have not been conducted, but the American Academy of Pediatrics discourages its use during breastfeeding because of concerns about toxicity in the infant.^34-36

Sleep regulation is important to treat bipolar disorder and to prevent future episodes.^2,20,21 To ensure safety of the infant and mother before discharge, family education is imperative to establish close follow-up, adequate sleep, and reduction of stressors.^7,10 Separation from the infant might be necessary after discharge, and someone should monitor the infant at all times until the outpatient mental health provider confirms that all psychotic symptoms have resolved.^7,10 Successful treatment of postpartum psychosis requires close communication among the mental health provider, the pediatrician, and the obstetrician or women’s health provider.¹⁰ Because a close-knit team approach after discharge from the acute psychiatric unit is necessary, the care of such a patient and her child provides an educational opportunity for individuals working in integrated care clinics.

Conclusion

Postpartum psychosis is a psychiatric emergency requiring immediate treatment to prevent dire outcomes such as suicide or infanticide. Treatment considerations include the cost-benefit analysis of breastfeeding and the toxicity of psychotropic medications when ingested by the infant via breast milk. A close relationship has been demonstrated between postpartum psychosis and bipolar disorder.

Preferred treatment regimens include lithium and an antipsychotic. Educate the family as a unit about the diagnosis and treatment, the importance of adequate sleep for treatment and prophylaxis, and the decision on whether to discontinue breastfeeding despite its well-known benefits for mother and infant. Stabilization is a multifaceted process and needs to be reinforced with a solid plan for support and follow-up appointments. Because of the higher risk of relapse, educate patients about prophylactic treatment during subsequent pregnancies and monitor for development of bipolar disorder in the future.

Postpartum psychosis is a psychiatric emergency that can endanger the life of the mother and the newborn child if untreated. About 1 to 2 mothers in 1,000 experiences postpartum psychosis after delivery.¹ This rate is much higher among women with an established diagnosis of bipolar disorder before pregnancy.¹

Expedient recognition, diagnosis, and referral to a high-level psychiatric facility (usually a locked inpatient unit) are critical for ensuring the safety of mother and infant. A diligent medical workup followed by thorough education for the patient and family are important steps in caring for patients with postpartum psychosis. Close mental health follow-up, pharmacologic interventions, informed decision making regarding breastfeeding, and preserving the sleep-wake cycle are critical for stabilization.²

The authors present the case of a patient admitted to VA Central California Health Care System (VACCHCS) with postpartum psychosis and a discussion on existing research on the prevalence of postpartum psychosis, relevant risk factors, the association with bipolar disorder, and treatment strategies.

Case Presentation

A 31-year-old active-duty female with no history of mental illness was admitted to the psychiatric unit because new-onset disorganized behavior was preventing her from functioning at her workplace. Two weeks after giving birth to her second child, the patient began exhibiting an uncharacteristic, debilitating labile mood and disorganized behavior. Her supervisors required her to present for medical attention about 3 months after the birth of her child. She was transferred to VACCHCS for higher level medical care on military orders. The patient’s husband initially attributed these psychiatric symptoms to vocational stress and taking care of 2 young children. He observed the patient exhibiting tearfulness about her job, which quickly alternated with euphoric episodes of singing and dancing at inappropriate times, such as when the children had quieted down and were being prepared to go to bed.

At the initial psychiatric evaluation after transfer to VACCHCS, the patient appeared well-kept and slightly overweight. In general her appearance was unremarkable. Throughout the examination she sang both subtly and loudly and at times was confrontational and irritable.

She related oddly and often was guarded and difficult to engage; she sang and played with her blanket in a childlike way. She smiled and laughed inappropriately, mumbled incoherently to herself, scanned the room suspiciously, and often made intense eye contact. Her affect was labile, both tearful and euphoric at several points in the examination. Her thought process was tangential, illogical, grandiose, difficult to redirect, and with loose associations. Her thought content consisted of delusions (“I’ve got the devil on my back”) and grandiosity (“I am everyone, I am you…the president, the mayor”), and she often stated that she planned to become a singer or performer.

The patient claimed she was neither suicidal nor had thoughts of infanticide. She reported having no visual and auditory hallucinations but often seemed to be responding to internal stimuli: She mumbled to herself and looked intensely at parts of the room. Cognitively, the patient was fully intact to recent and remote events but displayed a poor attention span. She did not exhibit any motor abnormalities, such as tremor, rigidity, weakness, sensory loss, or abnormal gait.

The patient’s workup included full chemistry, complete blood count, thyroid-stimulating hormone, antithyroid antibodies, calcium, rapid plasma reagin to rule out syphilis, toxicology, folate, vitamin B₁₂, and vitamin D. All laboratory results were negative or within normal limits, although the urine drug screen was positive for cannabis. The patient’s husband noted that his wife never used cannabis except the weekend before her admission, when she impulsively went dancing, which was out of character for her. Her psychotic symptoms had been present weeks before the cannabis use; therefore, the her symptoms could not be attributed to a substance-induced psychotic disorder. A test for synthetic cannabis derivatives was negative. Newer synthetic compounds can cause more severe substance-induced psychotic symptoms than those of cannabis.³

The patient was diagnosed with postpartum psychosis and was started on the oral antipsychotic olanzapine 10 mg at bedtime. Additional doses were administered to control ongoing symptoms, which included a disorganized thought process; loose associations; euphoria; grandiosity; delusional content, such as “You are just a tool in place to help me;” reports of feeling as though she were in “outer space, outside in the galaxy;” decreased need for sleep; and irritability. The patient spent an entire interview with her eyes closed, stating that she could “hear” better because she was overstimulated if her eyes were open. She also described olfactory hallucinations of “strong perfume,” which the 2 providers present could not detect.

Olanzapine was not well tolerated because of sedation and was discontinued in favor of risperidone, 2 mg twice daily. Risperidone was more effective and better tolerated. Lithium was initiated the next day with target dosing at 300 mg in the morning and 600 mg at night. The patient became capable of linear, organized discussion and planning but remained euphoric with high energy; she exhibited grandiosity with frequent singing and dancing throughout her hospital stay. She often described her mood as “good, excellent, exuberant, exciting,” perseverating on the way words sounded and giggling in a childlike manner. She continued to have intrusive dreams of “hell and the devil” and that she was killed by gunshot.

The patient was continued on lithium and risperidone and transferred to a larger military hospital for further inpatient management, respecting military orders. Before discharge, a family conference was held with the patient and her husband to educate them on the importance of continued treatment, close follow-up, regular sleep patterns, and not breastfeeding while taking the prescribed medications. Although she was not back to her baseline at the time of transfer, the patient had stabilized significantly and gained sufficient insight into her condition.

Discussion

Postpartum psychosis can present with a prodromal phase consisting of fatigue, insomnia, restlessness, tearfulness, and emotional lability, making early identification difficult. Later, florid psychotic symptoms can include suspiciousness, confusion, incoherence, irrational statements, obsessive concern about the infant’s health, and delusions, including a belief that the baby is dead or defective. Some women might deny that the birth occurred or feel that they are unmarried, virginal, or persecuted.¹ More concerning symptoms include auditory hallucinations commanding the mother to harm or kill the infant and/or herself. Symptoms often begin within days to weeks of birth, usually 2 to 3 weeks after delivery but can occur as long as 8 weeks postpartum.¹ Several cases of infanticide and suicide have been documented.¹ The risk of experiencing another psychotic episode in subsequent pregnancies can be as high as 50%.^4-6 Regardless of symptom severity at onset, postpartum psychosis is a psychiatric emergency and must be treated as such.

Bipolar Disorder and Postpartum Psychosis

A close relationship exists between postpartum psychosis and development of bipolar disorder. A postpartum psychotic episode often is the harbinger of bipolar illness.⁷ About two-thirds of women who have an episode of postpartum psychosis will experience an underlying affective disorder within a year of childbirth.^1,8 It is unclear what triggers the psychotic episode, but it has been theorized that major systemic shifts in hormone levelsor trauma of delivery could instigate development of symptoms.^1,9

Risk factors include obstetric complications; perinatal infant mortality; previous episodes of bipolar disorder, psychosis, or postpartum psychosis; family history of bipolar disorder or postpartum psychosis; sleep deprivation; increased environmental stress; and lack of partner support.¹⁰ The strongest risk factor for developing postpartum psychosis is a personal or family history of bipolar disorder or a related psychotic disorder.¹¹ This risk factor is identified in about 40% to 50% cases of postpartum psychosis.¹¹

Treatment

Standard treatment for postpartum psychosis includes an antipsychotic and often lithium and benzodiazepines.^1,7,10,11 This treatment approach differs slightly from treating a patient with a nonpostpartum psychotic illness, who generally would not receive mood stabilizers, such as lithium. Including a mood stabilizer for postpartum psychosis is warranted because of the association between postpartum psychosis and bipolar disorder, which is treated with a mood stabilizer.

Prevalence

Postpartum psychosis is identified in 1 to 2 per 1,000 childbirths. In women who have had an earlier episode of postpartum psychosis or have a diagnosis of bipolar disorder, the rate is up to 100 times higher.¹ Kendell and colleagues found that psychiatric admissions occurred at a rate 7 times higher in the 30 days after birth than in the prepregnancy period, suggesting that metabolic factors might be involved in triggering postpartum psychotic symptoms.¹² An abrupt hormonal loss occurs at childbirth; hormones peak 200-fold during gestation and decline rapidly within a day after birth.⁹ Despite the severity of symptoms in postpartum psychosis, these patients tend to have a better prognosis than that of women with psychotic episodes not related to pregnancy.⁴

Patients with bipolar disorder have the highest risk of psychotic episodes during the postpartum period, with a study reporting 260 episodes of psychosis per deliveries among women with bipolar disorder.¹³ Studies such as this suggest that episodes of postpartum psychosis might be a variant or atypical presentation of an underlying bipolar disorder or a predisposition to developing the disorder.¹⁴ In a study that compared 58 patients with postpartum psychosis with to 52 individuals with nonchildbearing-related psychosis, manic symptoms were more common among the postpartum group.¹⁵ Family studies have shown that the risk of psychiatric illness among first-degree relatives of women with postpartum psychosis is 10% to 50%, which is higher than in the general population.¹⁴

Brockington and colleagues found that patients with postpartum psychosis had more mood lability, distractibility, and confusion than those with psychosis unrelated to pregnancy.¹⁵ Patients with postpartum psychosis were more likely to have impaired sensorium, bizarre quality of delusions, and memory loss. Psychosis with onset after childbirth included high levels of thought disorganization, delusions of reference, delusions of persecution, and greater levels of homicidal ideation and behavior.¹⁶ This study also reported symptoms such as visual, tactile, and olfactory hallucinations and a presentation similar to that of delirium.

Chandra and colleagues found that 53% of women with postpartum psychosis had delusions about the infant, including beliefs that someone would harm or kill the baby or that the baby would be harmed by their breast milk.¹⁷ Compared with women with bipolar disorder, Oostheuizen and colleagues found that women with postpartum psychosis had delusions of control, such as feeling under the influence of an overpowering force that controlled their actions.¹⁸ Infanticidal thoughts are common among patients with postpartum psychosis, and about 4% of women committed infanticide.¹

Rapid stabilization and treatment are important because postpartum psychosis is considered a psychiatric emergency.⁷ Potential consequences of delayed diagnosis and treatment include harm or death of the infant by infanticide and death of the mother by suicide. A thorough physical examination is important to rule out metabolic or neuroendocrine causes of psychosis other than postpartum hormonal shifts. These could include causes of altered mental status: stroke, pulmonary embolism, amniotic fluid emboli, Sheehan syndrome, thyroid disorders, electrolyte abnormalities, acute hemorrhage, sepsis, and substance toxicity or withdrawal.¹⁰ A complete blood count, full chemistry, thyroid function tests, antithyroid antibody tests, calcium, vitamin B₁₂, and folate should be measured.^7,10

Initial treatment should include antipsychotics and often mood stabilizers such as lithium. Managing insomnia aggressively is also necessary for initial stabilization and to prevent a repeat manic episode if the patient develops bipolar disorder.² Many experts argue that sleep loss in combination with other risk factors might be the final common pathway for development of postpartum psychosis in women predisposed to this disorder.^19,20

Treating insomnia in an outpatient setting includes teaching sleep hygiene practices and relaxation techniques. Although these methods to regulate sleep could be encouraged during the emergent inpatient stabilization of a patient with postpartum psychosis, pharmacologic approaches are necessary for acute mania and psychosis. Concern about possible dependence on benzodiazepines and other sedating sleep aids are valid; however, the benefit of acute stabilization of psychotic symptoms outweighs the potential risk of dependence.

Typically, first-line treatment is an antipsychotic, and second-generation antipsychotics generally are preferred over first-generation antipsychotics because of their more benign adverse effect profile.^21,22 There are no controlled trials that compare antipsychotics with placebo or other interventions for postpartum psychosis. Therefore, use of atypical antipsychotics is based on randomized trials demonstrating efficacy in reducing psychosis in bipolar disorder, depression with psychotic features, and schizoaffective disorder.^23,24 Once the patient is treated with an antipsychotic, further use of psychotropic medications, such as lithium or other mood stabilizers, should be based on the patient’s clinical presentation. For example, the patient in this case study primarily had manic symptoms consistent with bipolar disorder, making lithium or another mood stabilizer an appropriate choice.

Bergink and colleagues demonstrated positive outcomes with a treatment algorithm involving sequential use of benzodiazepines to improve sleep, an antipsychotic to decrease acute manic symptoms, lithium to stabilize mood based on symptoms, and electroconvulsive therapy if other treatments were not successful.²⁵ Case studies document that administering estrogen led to recovery from postpartum psychosis, although patients often relapsed when estrogen was stopped.²⁶ Electroconvulsive therapy has shown promising results, especially in patients who do not respond to antipsychotic medications or lithium.^27,28

Antipsychotic and Other Psychotropic Medications

Choice of an antipsychotic and other psychotropic medications to treat postpartum psychosis is based on the patient’s breastfeeding status. The benefits of treatment should be weighed against the risks of a breastfeeding infant’s exposure to the medication. Because postpartum psychosis is a psychiatric emergency, the benefits of the medication are considered to outweigh any potential adverse effect to the breastfeeding infant exposed to the medication. Risks of untreated postpartum psychosis to the infant include rejection of the infant, poor parental relationships, suicide, infanticide, long-term failure to bond with the child, delayed infant development, and failure to thrive.²⁹ Also, many mothers—including the patient in this presentation—decide that the benefits of treatment outweigh those of breastfeeding and choose to feed their infant with formula. Even if the patient chooses to bottle-feed her infant, consider administering medications that are considered safer for breastfeeding because the patient may need to continue the psychotropic during later pregnancies to prevent future psychotic episodes.³⁰ All psychotropic medications pass into breast milk.²⁹ Studies on the long-term effect of these medications on the infant are limited, but experts tend to recommend olanzapine, quetiapine, and risperidone over aripiprazole and ziprasidone.^21,31-33

Lithium often is used to treat postpartum psychosis. Studies examining risk to the infant after long-term exposure to lithium through breast milk have not been conducted, but the American Academy of Pediatrics discourages its use during breastfeeding because of concerns about toxicity in the infant.^34-36

Sleep regulation is important to treat bipolar disorder and to prevent future episodes.^2,20,21 To ensure safety of the infant and mother before discharge, family education is imperative to establish close follow-up, adequate sleep, and reduction of stressors.^7,10 Separation from the infant might be necessary after discharge, and someone should monitor the infant at all times until the outpatient mental health provider confirms that all psychotic symptoms have resolved.^7,10 Successful treatment of postpartum psychosis requires close communication among the mental health provider, the pediatrician, and the obstetrician or women’s health provider.¹⁰ Because a close-knit team approach after discharge from the acute psychiatric unit is necessary, the care of such a patient and her child provides an educational opportunity for individuals working in integrated care clinics.

Conclusion

Postpartum psychosis is a psychiatric emergency requiring immediate treatment to prevent dire outcomes such as suicide or infanticide. Treatment considerations include the cost-benefit analysis of breastfeeding and the toxicity of psychotropic medications when ingested by the infant via breast milk. A close relationship has been demonstrated between postpartum psychosis and bipolar disorder.

Preferred treatment regimens include lithium and an antipsychotic. Educate the family as a unit about the diagnosis and treatment, the importance of adequate sleep for treatment and prophylaxis, and the decision on whether to discontinue breastfeeding despite its well-known benefits for mother and infant. Stabilization is a multifaceted process and needs to be reinforced with a solid plan for support and follow-up appointments. Because of the higher risk of relapse, educate patients about prophylactic treatment during subsequent pregnancies and monitor for development of bipolar disorder in the future.

Postpartum psychosis is a psychiatric emergency that can endanger the life of the mother and the newborn child if untreated. About 1 to 2 mothers in 1,000 experiences postpartum psychosis after delivery.¹ This rate is much higher among women with an established diagnosis of bipolar disorder before pregnancy.¹

Expedient recognition, diagnosis, and referral to a high-level psychiatric facility (usually a locked inpatient unit) are critical for ensuring the safety of mother and infant. A diligent medical workup followed by thorough education for the patient and family are important steps in caring for patients with postpartum psychosis. Close mental health follow-up, pharmacologic interventions, informed decision making regarding breastfeeding, and preserving the sleep-wake cycle are critical for stabilization.²

The authors present the case of a patient admitted to VA Central California Health Care System (VACCHCS) with postpartum psychosis and a discussion on existing research on the prevalence of postpartum psychosis, relevant risk factors, the association with bipolar disorder, and treatment strategies.

Case Presentation

A 31-year-old active-duty female with no history of mental illness was admitted to the psychiatric unit because new-onset disorganized behavior was preventing her from functioning at her workplace. Two weeks after giving birth to her second child, the patient began exhibiting an uncharacteristic, debilitating labile mood and disorganized behavior. Her supervisors required her to present for medical attention about 3 months after the birth of her child. She was transferred to VACCHCS for higher level medical care on military orders. The patient’s husband initially attributed these psychiatric symptoms to vocational stress and taking care of 2 young children. He observed the patient exhibiting tearfulness about her job, which quickly alternated with euphoric episodes of singing and dancing at inappropriate times, such as when the children had quieted down and were being prepared to go to bed.

At the initial psychiatric evaluation after transfer to VACCHCS, the patient appeared well-kept and slightly overweight. In general her appearance was unremarkable. Throughout the examination she sang both subtly and loudly and at times was confrontational and irritable.

She related oddly and often was guarded and difficult to engage; she sang and played with her blanket in a childlike way. She smiled and laughed inappropriately, mumbled incoherently to herself, scanned the room suspiciously, and often made intense eye contact. Her affect was labile, both tearful and euphoric at several points in the examination. Her thought process was tangential, illogical, grandiose, difficult to redirect, and with loose associations. Her thought content consisted of delusions (“I’ve got the devil on my back”) and grandiosity (“I am everyone, I am you…the president, the mayor”), and she often stated that she planned to become a singer or performer.

The patient claimed she was neither suicidal nor had thoughts of infanticide. She reported having no visual and auditory hallucinations but often seemed to be responding to internal stimuli: She mumbled to herself and looked intensely at parts of the room. Cognitively, the patient was fully intact to recent and remote events but displayed a poor attention span. She did not exhibit any motor abnormalities, such as tremor, rigidity, weakness, sensory loss, or abnormal gait.

The patient’s workup included full chemistry, complete blood count, thyroid-stimulating hormone, antithyroid antibodies, calcium, rapid plasma reagin to rule out syphilis, toxicology, folate, vitamin B₁₂, and vitamin D. All laboratory results were negative or within normal limits, although the urine drug screen was positive for cannabis. The patient’s husband noted that his wife never used cannabis except the weekend before her admission, when she impulsively went dancing, which was out of character for her. Her psychotic symptoms had been present weeks before the cannabis use; therefore, the her symptoms could not be attributed to a substance-induced psychotic disorder. A test for synthetic cannabis derivatives was negative. Newer synthetic compounds can cause more severe substance-induced psychotic symptoms than those of cannabis.³

The patient was diagnosed with postpartum psychosis and was started on the oral antipsychotic olanzapine 10 mg at bedtime. Additional doses were administered to control ongoing symptoms, which included a disorganized thought process; loose associations; euphoria; grandiosity; delusional content, such as “You are just a tool in place to help me;” reports of feeling as though she were in “outer space, outside in the galaxy;” decreased need for sleep; and irritability. The patient spent an entire interview with her eyes closed, stating that she could “hear” better because she was overstimulated if her eyes were open. She also described olfactory hallucinations of “strong perfume,” which the 2 providers present could not detect.

Olanzapine was not well tolerated because of sedation and was discontinued in favor of risperidone, 2 mg twice daily. Risperidone was more effective and better tolerated. Lithium was initiated the next day with target dosing at 300 mg in the morning and 600 mg at night. The patient became capable of linear, organized discussion and planning but remained euphoric with high energy; she exhibited grandiosity with frequent singing and dancing throughout her hospital stay. She often described her mood as “good, excellent, exuberant, exciting,” perseverating on the way words sounded and giggling in a childlike manner. She continued to have intrusive dreams of “hell and the devil” and that she was killed by gunshot.

The patient was continued on lithium and risperidone and transferred to a larger military hospital for further inpatient management, respecting military orders. Before discharge, a family conference was held with the patient and her husband to educate them on the importance of continued treatment, close follow-up, regular sleep patterns, and not breastfeeding while taking the prescribed medications. Although she was not back to her baseline at the time of transfer, the patient had stabilized significantly and gained sufficient insight into her condition.

Discussion

Postpartum psychosis can present with a prodromal phase consisting of fatigue, insomnia, restlessness, tearfulness, and emotional lability, making early identification difficult. Later, florid psychotic symptoms can include suspiciousness, confusion, incoherence, irrational statements, obsessive concern about the infant’s health, and delusions, including a belief that the baby is dead or defective. Some women might deny that the birth occurred or feel that they are unmarried, virginal, or persecuted.¹ More concerning symptoms include auditory hallucinations commanding the mother to harm or kill the infant and/or herself. Symptoms often begin within days to weeks of birth, usually 2 to 3 weeks after delivery but can occur as long as 8 weeks postpartum.¹ Several cases of infanticide and suicide have been documented.¹ The risk of experiencing another psychotic episode in subsequent pregnancies can be as high as 50%.^4-6 Regardless of symptom severity at onset, postpartum psychosis is a psychiatric emergency and must be treated as such.

Bipolar Disorder and Postpartum Psychosis

A close relationship exists between postpartum psychosis and development of bipolar disorder. A postpartum psychotic episode often is the harbinger of bipolar illness.⁷ About two-thirds of women who have an episode of postpartum psychosis will experience an underlying affective disorder within a year of childbirth.^1,8 It is unclear what triggers the psychotic episode, but it has been theorized that major systemic shifts in hormone levelsor trauma of delivery could instigate development of symptoms.^1,9

Risk factors include obstetric complications; perinatal infant mortality; previous episodes of bipolar disorder, psychosis, or postpartum psychosis; family history of bipolar disorder or postpartum psychosis; sleep deprivation; increased environmental stress; and lack of partner support.¹⁰ The strongest risk factor for developing postpartum psychosis is a personal or family history of bipolar disorder or a related psychotic disorder.¹¹ This risk factor is identified in about 40% to 50% cases of postpartum psychosis.¹¹

Treatment

Standard treatment for postpartum psychosis includes an antipsychotic and often lithium and benzodiazepines.^1,7,10,11 This treatment approach differs slightly from treating a patient with a nonpostpartum psychotic illness, who generally would not receive mood stabilizers, such as lithium. Including a mood stabilizer for postpartum psychosis is warranted because of the association between postpartum psychosis and bipolar disorder, which is treated with a mood stabilizer.

Prevalence

Postpartum psychosis is identified in 1 to 2 per 1,000 childbirths. In women who have had an earlier episode of postpartum psychosis or have a diagnosis of bipolar disorder, the rate is up to 100 times higher.¹ Kendell and colleagues found that psychiatric admissions occurred at a rate 7 times higher in the 30 days after birth than in the prepregnancy period, suggesting that metabolic factors might be involved in triggering postpartum psychotic symptoms.¹² An abrupt hormonal loss occurs at childbirth; hormones peak 200-fold during gestation and decline rapidly within a day after birth.⁹ Despite the severity of symptoms in postpartum psychosis, these patients tend to have a better prognosis than that of women with psychotic episodes not related to pregnancy.⁴

Patients with bipolar disorder have the highest risk of psychotic episodes during the postpartum period, with a study reporting 260 episodes of psychosis per deliveries among women with bipolar disorder.¹³ Studies such as this suggest that episodes of postpartum psychosis might be a variant or atypical presentation of an underlying bipolar disorder or a predisposition to developing the disorder.¹⁴ In a study that compared 58 patients with postpartum psychosis with to 52 individuals with nonchildbearing-related psychosis, manic symptoms were more common among the postpartum group.¹⁵ Family studies have shown that the risk of psychiatric illness among first-degree relatives of women with postpartum psychosis is 10% to 50%, which is higher than in the general population.¹⁴

Brockington and colleagues found that patients with postpartum psychosis had more mood lability, distractibility, and confusion than those with psychosis unrelated to pregnancy.¹⁵ Patients with postpartum psychosis were more likely to have impaired sensorium, bizarre quality of delusions, and memory loss. Psychosis with onset after childbirth included high levels of thought disorganization, delusions of reference, delusions of persecution, and greater levels of homicidal ideation and behavior.¹⁶ This study also reported symptoms such as visual, tactile, and olfactory hallucinations and a presentation similar to that of delirium.

Chandra and colleagues found that 53% of women with postpartum psychosis had delusions about the infant, including beliefs that someone would harm or kill the baby or that the baby would be harmed by their breast milk.¹⁷ Compared with women with bipolar disorder, Oostheuizen and colleagues found that women with postpartum psychosis had delusions of control, such as feeling under the influence of an overpowering force that controlled their actions.¹⁸ Infanticidal thoughts are common among patients with postpartum psychosis, and about 4% of women committed infanticide.¹

Rapid stabilization and treatment are important because postpartum psychosis is considered a psychiatric emergency.⁷ Potential consequences of delayed diagnosis and treatment include harm or death of the infant by infanticide and death of the mother by suicide. A thorough physical examination is important to rule out metabolic or neuroendocrine causes of psychosis other than postpartum hormonal shifts. These could include causes of altered mental status: stroke, pulmonary embolism, amniotic fluid emboli, Sheehan syndrome, thyroid disorders, electrolyte abnormalities, acute hemorrhage, sepsis, and substance toxicity or withdrawal.¹⁰ A complete blood count, full chemistry, thyroid function tests, antithyroid antibody tests, calcium, vitamin B₁₂, and folate should be measured.^7,10

Initial treatment should include antipsychotics and often mood stabilizers such as lithium. Managing insomnia aggressively is also necessary for initial stabilization and to prevent a repeat manic episode if the patient develops bipolar disorder.² Many experts argue that sleep loss in combination with other risk factors might be the final common pathway for development of postpartum psychosis in women predisposed to this disorder.^19,20

Treating insomnia in an outpatient setting includes teaching sleep hygiene practices and relaxation techniques. Although these methods to regulate sleep could be encouraged during the emergent inpatient stabilization of a patient with postpartum psychosis, pharmacologic approaches are necessary for acute mania and psychosis. Concern about possible dependence on benzodiazepines and other sedating sleep aids are valid; however, the benefit of acute stabilization of psychotic symptoms outweighs the potential risk of dependence.

Typically, first-line treatment is an antipsychotic, and second-generation antipsychotics generally are preferred over first-generation antipsychotics because of their more benign adverse effect profile.^21,22 There are no controlled trials that compare antipsychotics with placebo or other interventions for postpartum psychosis. Therefore, use of atypical antipsychotics is based on randomized trials demonstrating efficacy in reducing psychosis in bipolar disorder, depression with psychotic features, and schizoaffective disorder.^23,24 Once the patient is treated with an antipsychotic, further use of psychotropic medications, such as lithium or other mood stabilizers, should be based on the patient’s clinical presentation. For example, the patient in this case study primarily had manic symptoms consistent with bipolar disorder, making lithium or another mood stabilizer an appropriate choice.

Bergink and colleagues demonstrated positive outcomes with a treatment algorithm involving sequential use of benzodiazepines to improve sleep, an antipsychotic to decrease acute manic symptoms, lithium to stabilize mood based on symptoms, and electroconvulsive therapy if other treatments were not successful.²⁵ Case studies document that administering estrogen led to recovery from postpartum psychosis, although patients often relapsed when estrogen was stopped.²⁶ Electroconvulsive therapy has shown promising results, especially in patients who do not respond to antipsychotic medications or lithium.^27,28

Antipsychotic and Other Psychotropic Medications

Choice of an antipsychotic and other psychotropic medications to treat postpartum psychosis is based on the patient’s breastfeeding status. The benefits of treatment should be weighed against the risks of a breastfeeding infant’s exposure to the medication. Because postpartum psychosis is a psychiatric emergency, the benefits of the medication are considered to outweigh any potential adverse effect to the breastfeeding infant exposed to the medication. Risks of untreated postpartum psychosis to the infant include rejection of the infant, poor parental relationships, suicide, infanticide, long-term failure to bond with the child, delayed infant development, and failure to thrive.²⁹ Also, many mothers—including the patient in this presentation—decide that the benefits of treatment outweigh those of breastfeeding and choose to feed their infant with formula. Even if the patient chooses to bottle-feed her infant, consider administering medications that are considered safer for breastfeeding because the patient may need to continue the psychotropic during later pregnancies to prevent future psychotic episodes.³⁰ All psychotropic medications pass into breast milk.²⁹ Studies on the long-term effect of these medications on the infant are limited, but experts tend to recommend olanzapine, quetiapine, and risperidone over aripiprazole and ziprasidone.^21,31-33

Lithium often is used to treat postpartum psychosis. Studies examining risk to the infant after long-term exposure to lithium through breast milk have not been conducted, but the American Academy of Pediatrics discourages its use during breastfeeding because of concerns about toxicity in the infant.^34-36

Sleep regulation is important to treat bipolar disorder and to prevent future episodes.^2,20,21 To ensure safety of the infant and mother before discharge, family education is imperative to establish close follow-up, adequate sleep, and reduction of stressors.^7,10 Separation from the infant might be necessary after discharge, and someone should monitor the infant at all times until the outpatient mental health provider confirms that all psychotic symptoms have resolved.^7,10 Successful treatment of postpartum psychosis requires close communication among the mental health provider, the pediatrician, and the obstetrician or women’s health provider.¹⁰ Because a close-knit team approach after discharge from the acute psychiatric unit is necessary, the care of such a patient and her child provides an educational opportunity for individuals working in integrated care clinics.

Conclusion

Postpartum psychosis is a psychiatric emergency requiring immediate treatment to prevent dire outcomes such as suicide or infanticide. Treatment considerations include the cost-benefit analysis of breastfeeding and the toxicity of psychotropic medications when ingested by the infant via breast milk. A close relationship has been demonstrated between postpartum psychosis and bipolar disorder.

Preferred treatment regimens include lithium and an antipsychotic. Educate the family as a unit about the diagnosis and treatment, the importance of adequate sleep for treatment and prophylaxis, and the decision on whether to discontinue breastfeeding despite its well-known benefits for mother and infant. Stabilization is a multifaceted process and needs to be reinforced with a solid plan for support and follow-up appointments. Because of the higher risk of relapse, educate patients about prophylactic treatment during subsequent pregnancies and monitor for development of bipolar disorder in the future.

Photo by Larry Young

LA JOLLA, CA—Mogamulizumab is a valuable new therapeutic option for patients with cutaneous T-cell lymphoma (CTCL), according to researchers.

Results of the phase 3 MAVORIC study indicated that mogamulizumab is more effective than vorinostat in previously treated patients with CTCL.

Mogamulizumab produced a better overall response rate (ORR) and prolonged progression-free survival (PFS) in these patients.

Infusion-related reactions and drug eruptions were more common in patients who received mogamulizumab.

Youn H. Kim, MD, of the Stanford Cancer Institute in Palo Alto, California, and her colleagues presented these results in a poster at the 10th Annual T-cell Lymphoma Forum. The study was funded by Kyowa Kirin Pharmaceutical Development, Inc.

MAVORIC enrolled 372 adults with histologically confirmed mycosis fungoides (MF) or Sézary syndrome (SS) who had failed at least 1 systemic therapy. They were randomized to receive mogamulizumab at 1.0 mg/kg (weekly for the first 4-week cycle and then every 2 weeks) or vorinostat at 400 mg daily.

Patients were treated until disease progression or unacceptable toxicity. Those receiving vorinostat could crossover to mogamulizumab if they progressed or experienced intolerable toxicity.

Baseline characteristics were similar between the treatment arms. The median age was 64 (range, 54-73) in the mogamulizumab arm and 65 (range, 56-72) in the vorinostat arm. Ninety-nine percent and 100% of patients, respectively, had an ECOG performance status of 0 to 1.

A little more than half of patients in each arm had MF—57% in the mogamulizumab arm and 53% in the vorinostat arm.

The median number of prior systemic therapies was 3 in both arms (range, 1-18 in the mogamulizumab arm and 0-14 in the vorinostat arm).

Efficacy

The primary endpoint was PFS, and mogamulizumab provided a significant improvement there. The median PFS was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio=0.53, P<0.0001).

The researchers also observed a significant improvement in global ORR with mogamulizumab. It was 28% (52/189) in that arm and 5% (9/186) in the vorinostat arm (P<0.0001).

For patients with MF, the ORR was 21% with mogamulizumab and 7% with vorinostat. For SS patients, the ORR was 37% and 2%, respectively.

Responses by disease compartment were superior with mogamulizumab as well.

“Especially in the blood compartment, mogamulizumab had very striking activity over vorinostat,” Dr Kim said.

The blood ORR was 68% with mogamulizumab and 19% with vorinostat. The skin ORR was 42% and 16%, respectively. The lymph node ORR was 17% and 4%, respectively. The viscera ORR was 0% in both arms.

After crossover, the ORR in the mogamulizumab arm was 30% (41/136).

The median duration of response (DOR) was 14 months in the mogamulizumab arm and 9 months in the vorinostat arm.

For MF patients, the median DOR was 13 months with mogamulizumab and 9 months with vorinostat. For SS patients, the median DOR was 17 months and 7 months, respectively.

Safety

“Side effects [of mogamulizumab] were very well tolerable,” Dr Kim said. “Most significant is rash and infusion reactions, but, in terms of severe adverse events, [they] were very minimal.”

The most common treatment-emergent adverse events (AEs), occurring in at least 20% of patients in either arm (mogamulizumab and vorinostat, respectively), were:

• Infusion-related reactions (33.2% vs 0.5%)
• Drug eruptions (23.9% vs 0.5%)
• Diarrhea (23.4% vs 61.8%)
• Nausea (15.2% vs 42.5%)
• Thrombocytopenia (11.4% vs 30.6%)
• Dysgeusia (3.3% vs 28.0%)
• Increased blood creatinine (3.3% vs 28.0%)
• Decreased appetite (7.6% vs 24.7%).

There were no grade 4 AEs in the mogamulizumab arm and 2 cases of grade 4 thrombocytopenia in the vorinostat arm.

Grade 3 AEs in the mogamulizumab arm included drug eruptions (n=8), infusion-related reactions (n=3), fatigue (n=3), decreased appetite (n=2), nausea (n=1), pyrexia (n=1), and diarrhea (n=1).

Grade 3 AEs in the vorinostat arm included thrombocytopenia (n=11), fatigue (n=11), diarrhea (n=9), nausea (n=3), decreased appetite (n=2), and dysgeusia (n=1).

“So the results are, overall, positive,” Dr Kim said. “The data is submitted to the [US Food and Drug Administration]. We are really hoping that [mogamulizumab] will be approved so that we would have a new, exciting treatment for our patients with mycosis fungoides and Sézary syndrome.”

Photo by Larry Young

LA JOLLA, CA—Mogamulizumab is a valuable new therapeutic option for patients with cutaneous T-cell lymphoma (CTCL), according to researchers.

Results of the phase 3 MAVORIC study indicated that mogamulizumab is more effective than vorinostat in previously treated patients with CTCL.

Mogamulizumab produced a better overall response rate (ORR) and prolonged progression-free survival (PFS) in these patients.

Infusion-related reactions and drug eruptions were more common in patients who received mogamulizumab.

Youn H. Kim, MD, of the Stanford Cancer Institute in Palo Alto, California, and her colleagues presented these results in a poster at the 10th Annual T-cell Lymphoma Forum. The study was funded by Kyowa Kirin Pharmaceutical Development, Inc.

MAVORIC enrolled 372 adults with histologically confirmed mycosis fungoides (MF) or Sézary syndrome (SS) who had failed at least 1 systemic therapy. They were randomized to receive mogamulizumab at 1.0 mg/kg (weekly for the first 4-week cycle and then every 2 weeks) or vorinostat at 400 mg daily.

Patients were treated until disease progression or unacceptable toxicity. Those receiving vorinostat could crossover to mogamulizumab if they progressed or experienced intolerable toxicity.

Baseline characteristics were similar between the treatment arms. The median age was 64 (range, 54-73) in the mogamulizumab arm and 65 (range, 56-72) in the vorinostat arm. Ninety-nine percent and 100% of patients, respectively, had an ECOG performance status of 0 to 1.

A little more than half of patients in each arm had MF—57% in the mogamulizumab arm and 53% in the vorinostat arm.

The median number of prior systemic therapies was 3 in both arms (range, 1-18 in the mogamulizumab arm and 0-14 in the vorinostat arm).

Efficacy

The primary endpoint was PFS, and mogamulizumab provided a significant improvement there. The median PFS was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio=0.53, P<0.0001).

The researchers also observed a significant improvement in global ORR with mogamulizumab. It was 28% (52/189) in that arm and 5% (9/186) in the vorinostat arm (P<0.0001).

For patients with MF, the ORR was 21% with mogamulizumab and 7% with vorinostat. For SS patients, the ORR was 37% and 2%, respectively.

Responses by disease compartment were superior with mogamulizumab as well.

“Especially in the blood compartment, mogamulizumab had very striking activity over vorinostat,” Dr Kim said.

The blood ORR was 68% with mogamulizumab and 19% with vorinostat. The skin ORR was 42% and 16%, respectively. The lymph node ORR was 17% and 4%, respectively. The viscera ORR was 0% in both arms.

After crossover, the ORR in the mogamulizumab arm was 30% (41/136).

The median duration of response (DOR) was 14 months in the mogamulizumab arm and 9 months in the vorinostat arm.

For MF patients, the median DOR was 13 months with mogamulizumab and 9 months with vorinostat. For SS patients, the median DOR was 17 months and 7 months, respectively.

Safety

“Side effects [of mogamulizumab] were very well tolerable,” Dr Kim said. “Most significant is rash and infusion reactions, but, in terms of severe adverse events, [they] were very minimal.”

The most common treatment-emergent adverse events (AEs), occurring in at least 20% of patients in either arm (mogamulizumab and vorinostat, respectively), were:

• Infusion-related reactions (33.2% vs 0.5%)
• Drug eruptions (23.9% vs 0.5%)
• Diarrhea (23.4% vs 61.8%)
• Nausea (15.2% vs 42.5%)
• Thrombocytopenia (11.4% vs 30.6%)
• Dysgeusia (3.3% vs 28.0%)
• Increased blood creatinine (3.3% vs 28.0%)
• Decreased appetite (7.6% vs 24.7%).

There were no grade 4 AEs in the mogamulizumab arm and 2 cases of grade 4 thrombocytopenia in the vorinostat arm.

Grade 3 AEs in the mogamulizumab arm included drug eruptions (n=8), infusion-related reactions (n=3), fatigue (n=3), decreased appetite (n=2), nausea (n=1), pyrexia (n=1), and diarrhea (n=1).

Grade 3 AEs in the vorinostat arm included thrombocytopenia (n=11), fatigue (n=11), diarrhea (n=9), nausea (n=3), decreased appetite (n=2), and dysgeusia (n=1).

“So the results are, overall, positive,” Dr Kim said. “The data is submitted to the [US Food and Drug Administration]. We are really hoping that [mogamulizumab] will be approved so that we would have a new, exciting treatment for our patients with mycosis fungoides and Sézary syndrome.”

Photo by Larry Young

LA JOLLA, CA—Mogamulizumab is a valuable new therapeutic option for patients with cutaneous T-cell lymphoma (CTCL), according to researchers.

Results of the phase 3 MAVORIC study indicated that mogamulizumab is more effective than vorinostat in previously treated patients with CTCL.

Mogamulizumab produced a better overall response rate (ORR) and prolonged progression-free survival (PFS) in these patients.

Infusion-related reactions and drug eruptions were more common in patients who received mogamulizumab.

Youn H. Kim, MD, of the Stanford Cancer Institute in Palo Alto, California, and her colleagues presented these results in a poster at the 10th Annual T-cell Lymphoma Forum. The study was funded by Kyowa Kirin Pharmaceutical Development, Inc.

MAVORIC enrolled 372 adults with histologically confirmed mycosis fungoides (MF) or Sézary syndrome (SS) who had failed at least 1 systemic therapy. They were randomized to receive mogamulizumab at 1.0 mg/kg (weekly for the first 4-week cycle and then every 2 weeks) or vorinostat at 400 mg daily.

Patients were treated until disease progression or unacceptable toxicity. Those receiving vorinostat could crossover to mogamulizumab if they progressed or experienced intolerable toxicity.

Baseline characteristics were similar between the treatment arms. The median age was 64 (range, 54-73) in the mogamulizumab arm and 65 (range, 56-72) in the vorinostat arm. Ninety-nine percent and 100% of patients, respectively, had an ECOG performance status of 0 to 1.

A little more than half of patients in each arm had MF—57% in the mogamulizumab arm and 53% in the vorinostat arm.

The median number of prior systemic therapies was 3 in both arms (range, 1-18 in the mogamulizumab arm and 0-14 in the vorinostat arm).

Efficacy

The primary endpoint was PFS, and mogamulizumab provided a significant improvement there. The median PFS was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio=0.53, P<0.0001).

The researchers also observed a significant improvement in global ORR with mogamulizumab. It was 28% (52/189) in that arm and 5% (9/186) in the vorinostat arm (P<0.0001).

For patients with MF, the ORR was 21% with mogamulizumab and 7% with vorinostat. For SS patients, the ORR was 37% and 2%, respectively.

Responses by disease compartment were superior with mogamulizumab as well.

“Especially in the blood compartment, mogamulizumab had very striking activity over vorinostat,” Dr Kim said.

The blood ORR was 68% with mogamulizumab and 19% with vorinostat. The skin ORR was 42% and 16%, respectively. The lymph node ORR was 17% and 4%, respectively. The viscera ORR was 0% in both arms.

After crossover, the ORR in the mogamulizumab arm was 30% (41/136).

The median duration of response (DOR) was 14 months in the mogamulizumab arm and 9 months in the vorinostat arm.

For MF patients, the median DOR was 13 months with mogamulizumab and 9 months with vorinostat. For SS patients, the median DOR was 17 months and 7 months, respectively.

Safety

“Side effects [of mogamulizumab] were very well tolerable,” Dr Kim said. “Most significant is rash and infusion reactions, but, in terms of severe adverse events, [they] were very minimal.”

The most common treatment-emergent adverse events (AEs), occurring in at least 20% of patients in either arm (mogamulizumab and vorinostat, respectively), were:

• Infusion-related reactions (33.2% vs 0.5%)
• Drug eruptions (23.9% vs 0.5%)
• Diarrhea (23.4% vs 61.8%)
• Nausea (15.2% vs 42.5%)
• Thrombocytopenia (11.4% vs 30.6%)
• Dysgeusia (3.3% vs 28.0%)
• Increased blood creatinine (3.3% vs 28.0%)
• Decreased appetite (7.6% vs 24.7%).

There were no grade 4 AEs in the mogamulizumab arm and 2 cases of grade 4 thrombocytopenia in the vorinostat arm.

Grade 3 AEs in the mogamulizumab arm included drug eruptions (n=8), infusion-related reactions (n=3), fatigue (n=3), decreased appetite (n=2), nausea (n=1), pyrexia (n=1), and diarrhea (n=1).

Grade 3 AEs in the vorinostat arm included thrombocytopenia (n=11), fatigue (n=11), diarrhea (n=9), nausea (n=3), decreased appetite (n=2), and dysgeusia (n=1).

“So the results are, overall, positive,” Dr Kim said. “The data is submitted to the [US Food and Drug Administration]. We are really hoping that [mogamulizumab] will be approved so that we would have a new, exciting treatment for our patients with mycosis fungoides and Sézary syndrome.”

Despite the increased risk for invasive pneumococcal disease, prophylactic antibiotics are underused in children with sickle cell anemia, according to data from more than 2,000 children in six states.

Less than one-fifth (18%) of young children (aged 3 months to 5 years) with sickle cell anemia (SCA) receive at least 300 days of prophylactic antibiotics to reduce their risk of pneumococcal infections, the analysis found.

“Although the effectiveness of daily penicillin prophylaxis has been known for decades, limited evidence indicates low rates of compliance among children,” wrote Sarah L. Reeves, PhD, of the University of Michigan, Ann Arbor, and her colleagues. The report was published in Pediatrics.

The researchers reviewed Medicaid claims for 2,821 children with SCA from the period of 2005-2012 for a total of 5,014 person-years. The data were taken from six states: Florida, Illinois, Louisiana, Michigan, South Carolina, and Texas. Antibiotic prophylaxis was defined as four different treatment protocols: oral penicillin; oral penicillin or erythromycin; oral penicillin, erythromycin, or amoxicillin; or any antibiotic that could protect against Streptococcus pneumoniae.

Overall, the children in the study averaged 1.7 sickle cell disease–related inpatient hospitalizations annually, as well as 13.2 sickle cell disease–related outpatient visits and 3.8 emergency department visits per year.

The proportion of children who received 300 days or more of prophylactic antibiotics varied by state, by year, and by type of treatment. “In this multistate analysis, receipt of antibiotic prophylaxis among children with SCA was persistently low, irrespective of year or state,” the researchers noted.

The odds that a child received 300 days or more of prophylactic antibiotics increased with each outpatient visit, including well child visits and sickle cell disease–related visits (odds ratios 1.08 and 1.01, respectively).

A child in the third quartile of sickle cell disease–related outpatient visits (defined as 17 annual visits) was 15% more likely than was a child in the first quartile (defined as six annual visits) to receive at least 300 days of antibiotics.

The study findings were limited by several factors including potential overestimation of how many children received medication, the researchers said. However, the results suggest the need for practical and effective intervention that targets barriers to treatment adherence, they said.

“Provider-focused strategies to increase adherence could capitalize on the numerous annual outpatient encounters with the health care system that children with SCA are already experiencing,” they wrote.

The study was supported by a grant from the Agency for Healthcare Research and Quality and the Centers for Medicare and Medicaid Services. The researchers reported having no financial disclosures.

SOURCE: Reeves S et al. Pediatrics. 2018;141(3):e20172182. doi: 10.1542/peds.2017-2182.

Despite the increased risk for invasive pneumococcal disease, prophylactic antibiotics are underused in children with sickle cell anemia, according to data from more than 2,000 children in six states.

Less than one-fifth (18%) of young children (aged 3 months to 5 years) with sickle cell anemia (SCA) receive at least 300 days of prophylactic antibiotics to reduce their risk of pneumococcal infections, the analysis found.

“Although the effectiveness of daily penicillin prophylaxis has been known for decades, limited evidence indicates low rates of compliance among children,” wrote Sarah L. Reeves, PhD, of the University of Michigan, Ann Arbor, and her colleagues. The report was published in Pediatrics.

The researchers reviewed Medicaid claims for 2,821 children with SCA from the period of 2005-2012 for a total of 5,014 person-years. The data were taken from six states: Florida, Illinois, Louisiana, Michigan, South Carolina, and Texas. Antibiotic prophylaxis was defined as four different treatment protocols: oral penicillin; oral penicillin or erythromycin; oral penicillin, erythromycin, or amoxicillin; or any antibiotic that could protect against Streptococcus pneumoniae.

Overall, the children in the study averaged 1.7 sickle cell disease–related inpatient hospitalizations annually, as well as 13.2 sickle cell disease–related outpatient visits and 3.8 emergency department visits per year.

The proportion of children who received 300 days or more of prophylactic antibiotics varied by state, by year, and by type of treatment. “In this multistate analysis, receipt of antibiotic prophylaxis among children with SCA was persistently low, irrespective of year or state,” the researchers noted.

The odds that a child received 300 days or more of prophylactic antibiotics increased with each outpatient visit, including well child visits and sickle cell disease–related visits (odds ratios 1.08 and 1.01, respectively).

A child in the third quartile of sickle cell disease–related outpatient visits (defined as 17 annual visits) was 15% more likely than was a child in the first quartile (defined as six annual visits) to receive at least 300 days of antibiotics.

The study findings were limited by several factors including potential overestimation of how many children received medication, the researchers said. However, the results suggest the need for practical and effective intervention that targets barriers to treatment adherence, they said.

“Provider-focused strategies to increase adherence could capitalize on the numerous annual outpatient encounters with the health care system that children with SCA are already experiencing,” they wrote.

The study was supported by a grant from the Agency for Healthcare Research and Quality and the Centers for Medicare and Medicaid Services. The researchers reported having no financial disclosures.

SOURCE: Reeves S et al. Pediatrics. 2018;141(3):e20172182. doi: 10.1542/peds.2017-2182.

Despite the increased risk for invasive pneumococcal disease, prophylactic antibiotics are underused in children with sickle cell anemia, according to data from more than 2,000 children in six states.

Less than one-fifth (18%) of young children (aged 3 months to 5 years) with sickle cell anemia (SCA) receive at least 300 days of prophylactic antibiotics to reduce their risk of pneumococcal infections, the analysis found.

“Although the effectiveness of daily penicillin prophylaxis has been known for decades, limited evidence indicates low rates of compliance among children,” wrote Sarah L. Reeves, PhD, of the University of Michigan, Ann Arbor, and her colleagues. The report was published in Pediatrics.

The researchers reviewed Medicaid claims for 2,821 children with SCA from the period of 2005-2012 for a total of 5,014 person-years. The data were taken from six states: Florida, Illinois, Louisiana, Michigan, South Carolina, and Texas. Antibiotic prophylaxis was defined as four different treatment protocols: oral penicillin; oral penicillin or erythromycin; oral penicillin, erythromycin, or amoxicillin; or any antibiotic that could protect against Streptococcus pneumoniae.

Overall, the children in the study averaged 1.7 sickle cell disease–related inpatient hospitalizations annually, as well as 13.2 sickle cell disease–related outpatient visits and 3.8 emergency department visits per year.

The proportion of children who received 300 days or more of prophylactic antibiotics varied by state, by year, and by type of treatment. “In this multistate analysis, receipt of antibiotic prophylaxis among children with SCA was persistently low, irrespective of year or state,” the researchers noted.

The odds that a child received 300 days or more of prophylactic antibiotics increased with each outpatient visit, including well child visits and sickle cell disease–related visits (odds ratios 1.08 and 1.01, respectively).

A child in the third quartile of sickle cell disease–related outpatient visits (defined as 17 annual visits) was 15% more likely than was a child in the first quartile (defined as six annual visits) to receive at least 300 days of antibiotics.

The study findings were limited by several factors including potential overestimation of how many children received medication, the researchers said. However, the results suggest the need for practical and effective intervention that targets barriers to treatment adherence, they said.

“Provider-focused strategies to increase adherence could capitalize on the numerous annual outpatient encounters with the health care system that children with SCA are already experiencing,” they wrote.

The study was supported by a grant from the Agency for Healthcare Research and Quality and the Centers for Medicare and Medicaid Services. The researchers reported having no financial disclosures.

SOURCE: Reeves S et al. Pediatrics. 2018;141(3):e20172182. doi: 10.1542/peds.2017-2182.

Sexual harassment is one of the most insidious and caustic evils in the US workplace—and it knows no bounds, judging by the rampant allegations throughout 2017 and into 2018. While sexual harassment affects both sexes, the majority of cases target women.

In a recent survey, the New York Times asked 615 men about objectionable behavior toward colleagues, including whether they have made uninvited attempts to stroke, fondle, or kiss a coworker. Twenty-five percent admitted to telling crude jokes or sharing inappropriate videos. Two percent said they had pressured people into sexual acts by offering rewards or threatening retaliation—that means 12 men admitted to this.¹

Sadly, the health care industry is not immune from this corruption. In fact, sexual harassment is a major problem in health care—one that is particularly prevalent in nursing, according to Fiedler and Hamby.² More than 50% of female nurses, physicians, and students report experiencing sexual harassment.³ And even that, I believe, is an underreported percentage.

Sexual harassment in the workplace includes any situation in which there is a demand for sexual favors in exchange for a job benefit or where an unwanted condition on any person’s employment is imposed because of that person’s sex. Since 1964, Title VII of the Civil Rights Act (42 USC Sec.2000e-2[a]) has prohibited discrimination in places of employment based on an individual’s sex.⁴ In 1976, it was acknowledged that this also prohibits sexual harassment as a form of sex discrimination. In 1991, amendments (42 USC Sec.1981 [a][1]) authorized compensatory and punitive damages as well as jury trials.⁵

The Equal Employment Opportunity Commission (EEOC), the federal agency that enforces Title VII, stipulates that

• Harassment can include unwelcome sexual advances, requests for sexual favors, and other verbal or physical harassment—but it does not have to be sexual in nature (eg, making offensive comments about women in general).
• Both women and men can be victims and harassers—and the victim and harasser can be the same sex.
• Harassment is illegal when it is so frequent or severe that it creates a hostile or offensive work environment, or when it results in an adverse employment decision (eg, the victim being fired or demoted).⁶

Although the EEOC guidelines are not law, they do guide the judicial interpretation of what constitutes sexual harassment. Sexual harassment is an increasing source of workplace lawsuits that often result in large judgments against employers. Clinicians can file class-action suits against hospitals and other institutions, and juries may render verdicts on harassment complaints to the tune of millions of dollars.

Unfortunately, it is common for workplace harassment to go unreported. According to the EEOC, standard responses to workplace sexual harassment include avoiding the harasser, denying or downplaying the gravity of the situation, or attempting to ignore, forget, or endure the behavior. The least common response is to take formal action—either by reporting it internally or filing a legal complaint. Further, roughly three of four individuals who experience harassment in the workplace never tell a supervisor, manager, or union representative due to fear of disbelief, inaction, blame, or social or professional retaliation.⁷

How can we, as clinicians, protect ourselves and others from this type of harassment? Establishing a strong zero-tolerance policy on sexual harassment and reporting unacceptable behavior is the only answer. I realize this is no easy issue, but we must be firm in our resolve. Although 2017 was a watershed year with “Silence Breaker” or “#MeToo,” there are still many voices not being heard.⁸

So, here is my request: If you have been directly affected by, or have observed, objectionable behavior that violates your organization’s policy or code of conduct (or your personal sense of decency), document the incident and report it. You may be hesitant; maybe you think the behavior is an isolated act, or maybe the offender is a well-liked colleague who usually acts professionally. But your role is not to decide whether this behavior is acute or chronic—the human resources department will determine that. Maybe you are reluctant to report harassment because you fear reprisal. This is understandable, but remember that intimidation allows the behavior to persist. If the incident was upsetting and objectionable, it needs to be reported—no matter what.

The process of documenting and reporting varies depending on your institution’s policy but typically involves writing a factual description of the incident, including the time, place, and a list of any witnesses (including patients). Make sure your report is objective, and include any effect the behavior has had on patient care. Document any verbal exchanges verbatim, if possible. File the report as soon as possible, and remember to document everything. Nothing is trivial when it comes to building a case against sexual harassment. After you document and report the incident, continue to act professionally.⁹

If you are unable to resolve a harassment-related issue through your employer’s internal procedure, you may need to pursue the matter via the EEOC or your state’s human rights or civil rights enforcement agency.¹⁰ But know that any time and effort you put into reporting this is worthwhile; predatory behavior often crosses the workplace to other social realms. The other people being affected will be grateful that you came forward.

Some of you may be reading this and thinking, “Easy for you to say, Randy. You are not the one being harassed!” I know. This is not an easy topic for anyone. I have been shocked and appalled by the level and prevalence of sexual harassment in the workplace. I was always taught (by my grandmother—thank you!) to respect women. My hope is that by introducing this sensitive topic, we can open the discussion and encourage everyone to speak up. Please share your thoughts, comments, and ideas with me at PAeditor@frontlinemedcom.com—let’s start a conversation.

Sexual harassment is one of the most insidious and caustic evils in the US workplace—and it knows no bounds, judging by the rampant allegations throughout 2017 and into 2018. While sexual harassment affects both sexes, the majority of cases target women.

In a recent survey, the New York Times asked 615 men about objectionable behavior toward colleagues, including whether they have made uninvited attempts to stroke, fondle, or kiss a coworker. Twenty-five percent admitted to telling crude jokes or sharing inappropriate videos. Two percent said they had pressured people into sexual acts by offering rewards or threatening retaliation—that means 12 men admitted to this.¹

Sadly, the health care industry is not immune from this corruption. In fact, sexual harassment is a major problem in health care—one that is particularly prevalent in nursing, according to Fiedler and Hamby.² More than 50% of female nurses, physicians, and students report experiencing sexual harassment.³ And even that, I believe, is an underreported percentage.

Sexual harassment in the workplace includes any situation in which there is a demand for sexual favors in exchange for a job benefit or where an unwanted condition on any person’s employment is imposed because of that person’s sex. Since 1964, Title VII of the Civil Rights Act (42 USC Sec.2000e-2[a]) has prohibited discrimination in places of employment based on an individual’s sex.⁴ In 1976, it was acknowledged that this also prohibits sexual harassment as a form of sex discrimination. In 1991, amendments (42 USC Sec.1981 [a][1]) authorized compensatory and punitive damages as well as jury trials.⁵

The Equal Employment Opportunity Commission (EEOC), the federal agency that enforces Title VII, stipulates that

• Harassment can include unwelcome sexual advances, requests for sexual favors, and other verbal or physical harassment—but it does not have to be sexual in nature (eg, making offensive comments about women in general).
• Both women and men can be victims and harassers—and the victim and harasser can be the same sex.
• Harassment is illegal when it is so frequent or severe that it creates a hostile or offensive work environment, or when it results in an adverse employment decision (eg, the victim being fired or demoted).⁶

Although the EEOC guidelines are not law, they do guide the judicial interpretation of what constitutes sexual harassment. Sexual harassment is an increasing source of workplace lawsuits that often result in large judgments against employers. Clinicians can file class-action suits against hospitals and other institutions, and juries may render verdicts on harassment complaints to the tune of millions of dollars.

Unfortunately, it is common for workplace harassment to go unreported. According to the EEOC, standard responses to workplace sexual harassment include avoiding the harasser, denying or downplaying the gravity of the situation, or attempting to ignore, forget, or endure the behavior. The least common response is to take formal action—either by reporting it internally or filing a legal complaint. Further, roughly three of four individuals who experience harassment in the workplace never tell a supervisor, manager, or union representative due to fear of disbelief, inaction, blame, or social or professional retaliation.⁷

How can we, as clinicians, protect ourselves and others from this type of harassment? Establishing a strong zero-tolerance policy on sexual harassment and reporting unacceptable behavior is the only answer. I realize this is no easy issue, but we must be firm in our resolve. Although 2017 was a watershed year with “Silence Breaker” or “#MeToo,” there are still many voices not being heard.⁸

So, here is my request: If you have been directly affected by, or have observed, objectionable behavior that violates your organization’s policy or code of conduct (or your personal sense of decency), document the incident and report it. You may be hesitant; maybe you think the behavior is an isolated act, or maybe the offender is a well-liked colleague who usually acts professionally. But your role is not to decide whether this behavior is acute or chronic—the human resources department will determine that. Maybe you are reluctant to report harassment because you fear reprisal. This is understandable, but remember that intimidation allows the behavior to persist. If the incident was upsetting and objectionable, it needs to be reported—no matter what.

The process of documenting and reporting varies depending on your institution’s policy but typically involves writing a factual description of the incident, including the time, place, and a list of any witnesses (including patients). Make sure your report is objective, and include any effect the behavior has had on patient care. Document any verbal exchanges verbatim, if possible. File the report as soon as possible, and remember to document everything. Nothing is trivial when it comes to building a case against sexual harassment. After you document and report the incident, continue to act professionally.⁹

If you are unable to resolve a harassment-related issue through your employer’s internal procedure, you may need to pursue the matter via the EEOC or your state’s human rights or civil rights enforcement agency.¹⁰ But know that any time and effort you put into reporting this is worthwhile; predatory behavior often crosses the workplace to other social realms. The other people being affected will be grateful that you came forward.

Some of you may be reading this and thinking, “Easy for you to say, Randy. You are not the one being harassed!” I know. This is not an easy topic for anyone. I have been shocked and appalled by the level and prevalence of sexual harassment in the workplace. I was always taught (by my grandmother—thank you!) to respect women. My hope is that by introducing this sensitive topic, we can open the discussion and encourage everyone to speak up. Please share your thoughts, comments, and ideas with me at PAeditor@frontlinemedcom.com—let’s start a conversation.

Sexual harassment is one of the most insidious and caustic evils in the US workplace—and it knows no bounds, judging by the rampant allegations throughout 2017 and into 2018. While sexual harassment affects both sexes, the majority of cases target women.

In a recent survey, the New York Times asked 615 men about objectionable behavior toward colleagues, including whether they have made uninvited attempts to stroke, fondle, or kiss a coworker. Twenty-five percent admitted to telling crude jokes or sharing inappropriate videos. Two percent said they had pressured people into sexual acts by offering rewards or threatening retaliation—that means 12 men admitted to this.¹

Sadly, the health care industry is not immune from this corruption. In fact, sexual harassment is a major problem in health care—one that is particularly prevalent in nursing, according to Fiedler and Hamby.² More than 50% of female nurses, physicians, and students report experiencing sexual harassment.³ And even that, I believe, is an underreported percentage.

Sexual harassment in the workplace includes any situation in which there is a demand for sexual favors in exchange for a job benefit or where an unwanted condition on any person’s employment is imposed because of that person’s sex. Since 1964, Title VII of the Civil Rights Act (42 USC Sec.2000e-2[a]) has prohibited discrimination in places of employment based on an individual’s sex.⁴ In 1976, it was acknowledged that this also prohibits sexual harassment as a form of sex discrimination. In 1991, amendments (42 USC Sec.1981 [a][1]) authorized compensatory and punitive damages as well as jury trials.⁵

The Equal Employment Opportunity Commission (EEOC), the federal agency that enforces Title VII, stipulates that

• Harassment can include unwelcome sexual advances, requests for sexual favors, and other verbal or physical harassment—but it does not have to be sexual in nature (eg, making offensive comments about women in general).
• Both women and men can be victims and harassers—and the victim and harasser can be the same sex.
• Harassment is illegal when it is so frequent or severe that it creates a hostile or offensive work environment, or when it results in an adverse employment decision (eg, the victim being fired or demoted).⁶

Although the EEOC guidelines are not law, they do guide the judicial interpretation of what constitutes sexual harassment. Sexual harassment is an increasing source of workplace lawsuits that often result in large judgments against employers. Clinicians can file class-action suits against hospitals and other institutions, and juries may render verdicts on harassment complaints to the tune of millions of dollars.

Unfortunately, it is common for workplace harassment to go unreported. According to the EEOC, standard responses to workplace sexual harassment include avoiding the harasser, denying or downplaying the gravity of the situation, or attempting to ignore, forget, or endure the behavior. The least common response is to take formal action—either by reporting it internally or filing a legal complaint. Further, roughly three of four individuals who experience harassment in the workplace never tell a supervisor, manager, or union representative due to fear of disbelief, inaction, blame, or social or professional retaliation.⁷

How can we, as clinicians, protect ourselves and others from this type of harassment? Establishing a strong zero-tolerance policy on sexual harassment and reporting unacceptable behavior is the only answer. I realize this is no easy issue, but we must be firm in our resolve. Although 2017 was a watershed year with “Silence Breaker” or “#MeToo,” there are still many voices not being heard.⁸

So, here is my request: If you have been directly affected by, or have observed, objectionable behavior that violates your organization’s policy or code of conduct (or your personal sense of decency), document the incident and report it. You may be hesitant; maybe you think the behavior is an isolated act, or maybe the offender is a well-liked colleague who usually acts professionally. But your role is not to decide whether this behavior is acute or chronic—the human resources department will determine that. Maybe you are reluctant to report harassment because you fear reprisal. This is understandable, but remember that intimidation allows the behavior to persist. If the incident was upsetting and objectionable, it needs to be reported—no matter what.

The process of documenting and reporting varies depending on your institution’s policy but typically involves writing a factual description of the incident, including the time, place, and a list of any witnesses (including patients). Make sure your report is objective, and include any effect the behavior has had on patient care. Document any verbal exchanges verbatim, if possible. File the report as soon as possible, and remember to document everything. Nothing is trivial when it comes to building a case against sexual harassment. After you document and report the incident, continue to act professionally.⁹

If you are unable to resolve a harassment-related issue through your employer’s internal procedure, you may need to pursue the matter via the EEOC or your state’s human rights or civil rights enforcement agency.¹⁰ But know that any time and effort you put into reporting this is worthwhile; predatory behavior often crosses the workplace to other social realms. The other people being affected will be grateful that you came forward.

Some of you may be reading this and thinking, “Easy for you to say, Randy. You are not the one being harassed!” I know. This is not an easy topic for anyone. I have been shocked and appalled by the level and prevalence of sexual harassment in the workplace. I was always taught (by my grandmother—thank you!) to respect women. My hope is that by introducing this sensitive topic, we can open the discussion and encourage everyone to speak up. Please share your thoughts, comments, and ideas with me at PAeditor@frontlinemedcom.com—let’s start a conversation.

This video was filmed at Metabolic & Endocrine Disease Summit (MEDS). Click here to learn more.

This video was filmed at Metabolic & Endocrine Disease Summit (MEDS). Click here to learn more.

This video was filmed at Metabolic & Endocrine Disease Summit (MEDS). Click here to learn more.