Reviews

Many cancer patients don't sleep well, for a variety of reasons. It is an important problem: not only does poor sleep worsen quality of life, it may affect prognosis. Moreover, treatment is available.

Yet many physicians caring for cancer patients do not ask about sleep problems, underestimating their impact or focusing on more urgent problems. Also, patients may not want to bring up the topic because they consider poor sleep to be unavoidable and untreatable and because they fear that reporting it may shift the focus of their treatment from trying to cure the cancer to easing its symptoms.

This practical review will help health care professionals avoid the common barriers to diagnosis and treatment of poor sleep in cancer patients. Because there are few data on other sleep disorders such as sleep apnea and restless leg syndrome, we will focus on the most common one in cancer patients—insomnia—and its effects on other symptoms and quality of life.

MORE PATIENTS SURVIVE CANCER NOW

Today, more patients are surviving cancer, but cancer symptoms and the side effects of surgery, chemotherapy, and radiation therapy may persist for years.^1,2 The most common complaints include cancer-related fatigue, leg restlessness, anxiety, insomnia, and excessive sleepiness.³

Sleep disturbances appear to contribute to the other problems and are relatively easier to quantify. Most studies of sleep disorders in cancer patients have looked specifically at insomnia,⁴ although a few have explored the prevalence of other sleep disorders, such as sleep-disordered breathing and limb movements during sleep.⁵

The International Classification of Sleep Disorders, 2nd edition,⁶ defines insomnia as difficulty going to sleep or staying asleep (the latter defined as waking up in the middle of the night, with wakeful episodes lasting more than 30 minutes), early-morning awakenings (waking 30 minutes or more before the intended time), or nonrestorative sleep, causing significant distress or impairment of day-time functioning.

INSOMNIA WORSENS QUALITY OF LIFE

Insomnia significantly worsens quality of life in cancer patients, and if it can be detected and effectively treated, quality of life is likely to improve. Studies in cancer patients have found that those with insomnia:

• Were less able to cope with stress and carry on their activities of daily living³
• Were much less able to function and reported more pain, less energy, and greater difficulty in dealing with emotional problems⁷
• Had poor quality of life, both physically and emotionally.^3,8

PERHAPS MORE THAN HALF OF CANCER PATIENTS HAVE INSOMNIA

Depending on the methods used and populations studied, at least 30% and perhaps more than half of patients with cancer have insomnia (Table 1).^3,4,8–14 It is one of the most commonly reported complaints in this group,^15–17 and it occurs before, during, and after treatment of cancer.

Although the prevalence may differ in various cancers, it is still higher than in the general population. In a study of about 450 patients with cancer or depression and 300 healthy volunteers, 62% of the cancer patients reported moderate to severe sleep disturbance, compared with 52% of the depressed patients and 30% of the healthy volunteers.¹⁸

When Davidson et al³ surveyed nearly 1,000 cancer patients, one-third said they had insomnia. The problem was most prevalent in lung and breast cancer patients.

In a longitudinal study by Savard et al,¹³ the prevalence of insomnia declined over time but remained high even at the end of 18 months. It was more prevalent in patients with gynecologic and breast cancer than in those with prostate cancer.^13,19

SLEEP PROBLEMS ARE UNDERREPORTED

Sleep problems in cancer patients often go unrecognized because patients do not report them. In a survey of 150 patients,²⁰ 44% reported having had sleep problems during the preceding month. However, only one-third of those with sleep problems told their health care providers. This highlights the need for physicians to address sleep complaints in cancer patients at every visit and, if needed, to refer them to a sleep specialist for further evaluation and management.

INSOMNIA IS OFTEN ASSOCIATED WITH OTHER PROBLEMS

Many things can interfere with sleep in cancer patients: the cancer itself (eg, pain due to tumor invasion), medical treatments (eg, narcotics, chemotherapy, neuroleptics, sympathomimetics, steroids, sedative hypnotics), psychosocial disturbances (eg, depression, anxiety, stress), and comorbid medical issues.

In this population, insomnia is often part of a cluster of symptoms that includes pain, fatigue, depression, and anxiety. These act synergistically, worsening quality of life.^21–24

Cancer-related fatigue is a distressing, persistent, subjective sense of tiredness or exhaustion that is related to cancer or cancer treatment, that is not proportional to recent activity and that interferes with usual functioning.²⁵ It has been reported by up to 90% of cancer patients in some studies.^26–28

Cancer-related fatigue worsens quality of life and is one of the most distressing and persistent symptoms experienced before, during, and after cancer treatment.^29,30 Furthermore, it can lead to sleep disturbances and daytime somnolence and further aggravate insomnia.^31,32 The two conditions are often reported as part of a cluster of interrelated symptoms that include pain, depression, and loss of concentration and other cognitive functions, suggesting that they may share a common etiology.^33–35

Åhsberg et al³⁶ examined different aspects of perceived cancer-related fatigue in patients undergoing radiotherapy and found correlations between lack of energy, sleepiness, and cancer-related fatigue.

Current understanding of the possible link between cancer-related fatigue and insomnia suggests that interventions targeting the insomnia and daytime sleepiness could decrease the fatigue as well.³¹

Pain and insomnia in cancer patients

Pain is reported by 60% to 90% of patients with advanced cancer,^37,38 its intensity usually varying with the extent of disease. Too often, it is inadequately controlled.³⁹ Furthermore, it is thought to contribute to insomnia.⁴⁰

In a study of more than 1,600 cancer patients, nearly 60% reported insomnia in addition to pain.⁴¹ The severity of pain directly correlated with the probability of insomnia.

Conversely, research suggests that sleep disturbances, primarily insomnia, can increase cancer patients’ sensitivity to pain.⁴² One hypothesis is that adequate sleep is needed to promote processes relevant to recovery from pain, both physiologic (ie, tissue repair) and psychological (ie, transient cessation of the perception of pain signals).⁴³

Paradoxically, opioids can worsen insomnia

Cancer pain is often treated with opioids, which, paradoxically, can cause or worsen insomnia.

Although opioids induce sleep, they also depress respiration, and at night, they can cause or worsen sleep-disordered breathing (obstructive or central sleep apnea or ataxic breathing), leading to episodes of hypoxia, arousals, and fragmented sleep.⁴⁴ Moreover, opioids can lead to daytime sedation. Further, psychostimulants such as methylphenidate, given to counteract opioid-induced sedation, can cause anxiety and insomnia. Thus, the interaction between cancer-related pain, insomnia, and pain management leads to a vicious cycle. Understanding this process, we can try to break the cycle and help patients with cancer sleep better.

However, how best to treat sleep-disordered breathing in patients taking opioids long-term is not well established.

In general, the primary intervention is to reduce the opioid dose. Practitioners should continually assess the need for these drugs and consider referral to a drug-behavior treatment center to help with discontinuation of opioid use when deemed medically appropriate.⁴⁵ Other strategies include positive airway pressure ventilation including continuous positive airway pressure, bilevel pressure devices with backup rate, or adaptive servoventilators. In some cases oxygen supplementation may be required.

Sleep-disordered breathing, when recognized and diagnosed, should be managed in partnership with a sleep specialist.

Depression and insomnia in cancer patients

By some estimates, up to half of cancer patients suffer from depression at some point in their illness.²⁸ And not without reason: these patients face uncertainty about their life, and this often results in depression or anxiety.⁴⁶

Many cancer patients with depression also have insomnia.²⁸ Indeed, patients with persistent insomnia are at greater risk of developing psychological disorders such as depression and anxiety.⁴⁷

In a survey of cancer patients, insomnia symptoms were more often attributed to thoughts or concerns about health, family, friends, the cancer diagnosis, and finances than to the actual physical effects of cancer.⁴⁸

CANCER TREATMENT AND INSOMNIA

Many cancer patients experience sleep disturbances even before starting treatment.⁴⁹ Liu et al⁵⁰ showed that, in 76 women about to undergo chemotherapy for breast cancer, those who already had sleep disturbances, fatigue, and depression had more problems, and more severe problems, during chemotherapy.

Radiation therapy and chemotherapy have been reported to cause or precipitate insomnia (Table 2).^8,13

Hormonal therapy and biological therapy can also cause or worsen preexisting insomnia.^51,52 For example, androgen deprivation therapy for prostate cancer and hormonal therapy for breast cancer are often associated with sleep problems.^49,50 Possible mechanisms of insomnia include hot flashes, night sweats, and anxiety caused by such treatments. Biological agents such as interferons, interleukins, and tumor necrosis factor (TNF) alpha, which are often used to treat malignant melanoma, can affect the sleep-wake cycle, leading to insomnia.⁵³

Corticosteroids sharply raise serum cortisol levels, which can lead to insomnia. Cancer patients receiving dexamethasone to prevent radiation-induced emesis experienced more insomnia than patients who did not receive dexamethasone.⁵⁴

IMMUNOLOGIC BASIS OF INSOMNIA IN CANCER PATIENTS

Cancer cells produce inflammatory cytokines such as interleukin 1 (IL-1), interleukin 6 (IL-6), and TNF alpha, and inflammation plays a role in tumor progression and possibly tumorigenesis.⁵⁵

Specific cytokines also help regulate the sleep-wake cycle. Levels of IL-6 and TNF alpha peak during sleep, and daytime IL-6 levels are inversely related to the amount of nocturnal sleep.⁵⁶ Vgontzas et al⁵⁷ showed that although mean levels of 24-hour IL-6 and TNF alpha secretion were not significantly different in patients with insomnia vs healthy controls, chronic insomnia was associated with a shift in IL-6 and TNF alpha secretion from nighttime to daytime.⁵⁷

Cancer and its treatment can affect secretion of the cytokines that play a role in the sleep-wake cycle. Thus, the sleep disturbances associated with cancer may also be related to the abnormalities in cytokine levels caused by either cancer or its treatment.

Mills et al⁵⁸ found that inflammatory markers such as vascular endothelial growth factor and soluble intercellular adhesion molecule-1 were significantly elevated during chemotherapy in breast cancer patients, and the elevated vascular endothelial growth factor levels were associated with poorer sleep during treatment.

Further research is warranted to establish causality, to help us understand the mechanisms of insomnia and other cancer symptoms, and to develop new treatments for these complaints.

POOR SLEEP AND CANCER RISK AND OUTCOMES

Sleep disturbances have negative health consequences in cancer. Their impact ranges from plausible carcinogenesis to affecting the course of the disease and cancer survival.

Poor sleep and risk of cancer

Epidemiologic studies have examined a possible link between circadian rhythm disruption and breast cancer risk, using both direct measures such as melatonin levels and indirect measures such as sleep duration and shift work. (Melatonin production is related to sleep duration, and night-shift work leads to disruption of sleep pattern and quality of sleep, thus lowering melatonin levels.⁵⁹)

The findings were mixed. Breast cancer risk was significantly and inversely associated with urinary melatonin levels (6-sulfatoxymelatonin) in the Nurses’ Health Study II,⁶⁰ but not in the Guernsey III study in the United Kingdom.⁶¹ Breast cancer risk was significantly lower with longer sleep duration in Finnish women⁶² and in Chinese women in Singapore,⁶³ but not in American women.^64,65 Results of three cohort studies^66–68 and two case-control studies^69,70 suggested a higher breast cancer risk in women who work evening or overnight shifts. Shorter sleep duration was associated with a higher risk of colorectal adenomas.⁷¹

These studies make a strong case for an association of cancer with circadian rhythm disruption and shorter sleep duration, possibly from an effect on melatonin levels. However, one should be cautious in interpreting epidemiologic studies: although they show sleep disturbances to be associated with cancer risk, they do not establish causality.

Insomnia and cancer outcomes

Evidence is growing that sleep disturbances may affect compliance with treatment, immune function, and outcomes—including survival—in cancer patients.^23,24

In patients newly diagnosed with various types of cancer, Degner and Sloan⁷² showed that those who suffered from insomnia, nausea, poor appetite, and pain had a lower survival rate at 5 years, independent of the cancer stage. However, no separate analyses were performed to examine the specific influence of insomnia on cancer survival.

Thompson and Li⁷³ analyzed data from 101 breast cancer patients with available Oncotype DX recurrence scores (a proprietary genetic test performed on tumor tissue that predicts the likelihood of recurrence). The scores were strongly correlated with average hours of sleep per night before breast cancer diagnosis, with fewer hours of sleep associated with a higher (worse) score.

Since these studies were retrospective and merely suggest associations, prospective studies, using more standardized questionnaires and objective measures, are needed to establish causality and to further our understanding of the mechanisms involved.

HELPING CANCER PATIENTS SLEEP BETTER

Insomnia is generally diagnosed with a thorough history that includes sleep, medical issues, substance use, and psychiatric issues. The sleep history should include specific insomniarelated complaints, presleep conditions and habits, sleep-wake habits, other sleep-related symptoms, and daytime consequences. To obtain the information, one can use questionnaires, sleep logs, psychological screening tests, and bed-partner interviews.⁷⁴

Managing insomnia involves both pharmacologic and nonpharmacologic treatment. It is also important to treat the associated disorders such as depression and anxiety disorders that often accompany insomnia. Long-term management of cancer patients should not be limited to surveillance of cancer but should also involve aggressive treatment of clusters of symptoms such as insomnia, cancer-related fatigue, and pain to yield better long-term quality of life.^75–77

Nonpharmacologic treatment: Cognitive-behavioral therapy

Nonpharmacologic interventions use psychological and behavioral therapies. The American Academy of Sleep Medicine guidelines recommend cognitive behavioral therapy for all patients with insomnia, either alone or in combination with hypnotic medications.

Cognitive-behavioral therapy for insomnia includes various components that help the patient learn coping skills and ways to prevent or mitigate the severity of future episodes (Table  3). Various randomized controlled trials found it to be effective for treating insomnia in the general population.^77–79

Several studies found that cognitive-behavioral therapy for insomnia was effective in cancer patients, not only improving sleep quality but also decreasing psychological distress, resulting in better overall quality of life.^80,81

Savard et al⁸¹ conducted a randomized controlled trial of cognitive-behavioral therapy for insomnia in 57 patients with breast cancer, examining subjective and objective sleep measures, psychological functioning, quality of life, and immunologic responses. They found significant improvements in sleep efficiency, mood, quality of life, depression, anxiety, and need for sleep medications. Improvements in subjective sleep measures persisted on 12-month follow-up.

Berger et al,⁸² in another randomized controlled trial, assessed behavioral therapy using stimulus control, modified sleep restriction, relaxation therapy, and sleep hygiene in breast cancer patients receiving adjuvant chemotherapy. Behavioral therapy improved sleep quality over time, as measured by the Pittsburgh Sleep Quality Index.

Espie et al⁸³ evaluated the effect of cognitive-behavioral therapy on prostate, colorectal, gynecologic, and breast cancer patients, with similar results.⁸³

Cognitive-behavioral therapy is at least as effective as drug therapy for insomnia in the general population. In the limited studies done in cancer patients, it has been shown to be effective irrespective of the type of cancer and is associated with better long-term outcomes. It diminishes the distress associated with early insomnia, can reduce anxiety, and can promote sleep.

A National Institutes of Health conference on insomnia concluded that cognitivebehavioral therapy is at least as effective as medications for brief treatment of chronic insomnia and that its beneficial effects, in contrast to those produced by medications, may last beyond the termination of treatment.⁸⁴

It is important to think about numerous factors when considering options such as cognitive-behavioral therapy, as patients with cancer have different complications that may affect sleep quality, such as cancer-related fatigue, cancer-related depression, psychological reactions to the disease, side effects of treatment, and cancer-related pain. These need to be addressed as well.

If cognitive-behavioral therapy is not available, self-help interventions (eg, written material, videos, television and Internet resources) can be used. These have several advantages over professionally administered interventions, including greater accessibility, less burden for the patient, and lower cost. Research is under way evaluating this approach in cancer patients.⁸⁵

The focus of therapy should be to treat underlying disorders that may be causing or contributing to insomnia. However, a substantial number of patients may need to be assessed for pharmacotherapy for insomnia.

Sleep problems in the general population are commonly treated with drugs, and most of the recommendations in cancer patients are based on experience in the general population. However, sleep medications should be used cautiously in cancer patients, since to our knowledge there have been no studies of these agents in patients with cancer.

Side effects also need to be considered. For example, sleep medications can profoundly worsen cancer-related fatigue.

Hypnotics are often prescribed for cancer patients.^86,87 A study in five major oncology centers showed that about half of the 1,500 patients were prescribed at least one psychotropic drug.⁸⁶ In this study, hypnotics were the most frequently prescribed drugs, accounting for 48% of total prescriptions, and 44% of the psychotropic prescriptions were written for sleep.

Benzodiazepine receptor agonists such as zaleplon, zolpidem, and eszopiclone can be used for problems with falling asleep and staying asleep.^88,89 They are better tolerated than older, long-acting benzodiazepines,⁹⁰ which can cause alterations in sleep-cycle architecture or rebound insomnia. The earlier agents can also cause adverse effects such as tolerance, drowsiness, and cognitive impairment.

A National Institutes of Health conference stated that benzodiazepine receptor agonists are efficacious in the short-term management of insomnia and that their adverse effects are much less frequent and severe than those of the benzodiazepines or other sedating drugs.⁸⁴ It also stated that all antidepressants, antihistamines (H1 receptor antagonists), and anti-psychotics have potentially significant adverse effects that raise concerns about their risk-to-benefit ratio and their suitability as treatment for chronic insomnia.

Benzodiazepines are commonly prescribed for insomnia. They increase sleep efficiency, decrease arousals, and increase stage 2 sleep.

Melatonin receptor agonists have been approved by the US Food and Drug Administration for treating insomnia. A recent meta-analysis of eight studies in healthy patients showed improvements in subjective and objective sleep outcomes with the use of ramelteon.⁹¹ The dosages primarily used were 4 to 32 mg. However, most of the studies used a dosage of 4 to 8 mg.

Antidepressants. Some of the antidepressants are also used for insomnia, but they can cause daytime fatigue.

Mirtazapine was shown to be effective for insomnia and coexistent mood disorder in cancer patients, but larger trials are needed.⁹²

A recent clinical trial with secondary data analyses evaluated the effect of paroxetine on insomnia, depression, and fatigue in patients with cancer. Paroxetine significantly reduced insomnia in both depressed and nondepressed patients after 2 to 3 weeks of treatment.⁹³

Table 4 summarizes classes of drugs used for insomnia and their additional therapeutic properties.

Many cancer patients don't sleep well, for a variety of reasons. It is an important problem: not only does poor sleep worsen quality of life, it may affect prognosis. Moreover, treatment is available.

Yet many physicians caring for cancer patients do not ask about sleep problems, underestimating their impact or focusing on more urgent problems. Also, patients may not want to bring up the topic because they consider poor sleep to be unavoidable and untreatable and because they fear that reporting it may shift the focus of their treatment from trying to cure the cancer to easing its symptoms.

This practical review will help health care professionals avoid the common barriers to diagnosis and treatment of poor sleep in cancer patients. Because there are few data on other sleep disorders such as sleep apnea and restless leg syndrome, we will focus on the most common one in cancer patients—insomnia—and its effects on other symptoms and quality of life.

MORE PATIENTS SURVIVE CANCER NOW

Today, more patients are surviving cancer, but cancer symptoms and the side effects of surgery, chemotherapy, and radiation therapy may persist for years.^1,2 The most common complaints include cancer-related fatigue, leg restlessness, anxiety, insomnia, and excessive sleepiness.³

Sleep disturbances appear to contribute to the other problems and are relatively easier to quantify. Most studies of sleep disorders in cancer patients have looked specifically at insomnia,⁴ although a few have explored the prevalence of other sleep disorders, such as sleep-disordered breathing and limb movements during sleep.⁵

The International Classification of Sleep Disorders, 2nd edition,⁶ defines insomnia as difficulty going to sleep or staying asleep (the latter defined as waking up in the middle of the night, with wakeful episodes lasting more than 30 minutes), early-morning awakenings (waking 30 minutes or more before the intended time), or nonrestorative sleep, causing significant distress or impairment of day-time functioning.

INSOMNIA WORSENS QUALITY OF LIFE

Insomnia significantly worsens quality of life in cancer patients, and if it can be detected and effectively treated, quality of life is likely to improve. Studies in cancer patients have found that those with insomnia:

• Were less able to cope with stress and carry on their activities of daily living³
• Were much less able to function and reported more pain, less energy, and greater difficulty in dealing with emotional problems⁷
• Had poor quality of life, both physically and emotionally.^3,8

PERHAPS MORE THAN HALF OF CANCER PATIENTS HAVE INSOMNIA

Depending on the methods used and populations studied, at least 30% and perhaps more than half of patients with cancer have insomnia (Table 1).^3,4,8–14 It is one of the most commonly reported complaints in this group,^15–17 and it occurs before, during, and after treatment of cancer.

Although the prevalence may differ in various cancers, it is still higher than in the general population. In a study of about 450 patients with cancer or depression and 300 healthy volunteers, 62% of the cancer patients reported moderate to severe sleep disturbance, compared with 52% of the depressed patients and 30% of the healthy volunteers.¹⁸

When Davidson et al³ surveyed nearly 1,000 cancer patients, one-third said they had insomnia. The problem was most prevalent in lung and breast cancer patients.

In a longitudinal study by Savard et al,¹³ the prevalence of insomnia declined over time but remained high even at the end of 18 months. It was more prevalent in patients with gynecologic and breast cancer than in those with prostate cancer.^13,19

SLEEP PROBLEMS ARE UNDERREPORTED

Sleep problems in cancer patients often go unrecognized because patients do not report them. In a survey of 150 patients,²⁰ 44% reported having had sleep problems during the preceding month. However, only one-third of those with sleep problems told their health care providers. This highlights the need for physicians to address sleep complaints in cancer patients at every visit and, if needed, to refer them to a sleep specialist for further evaluation and management.

INSOMNIA IS OFTEN ASSOCIATED WITH OTHER PROBLEMS

Many things can interfere with sleep in cancer patients: the cancer itself (eg, pain due to tumor invasion), medical treatments (eg, narcotics, chemotherapy, neuroleptics, sympathomimetics, steroids, sedative hypnotics), psychosocial disturbances (eg, depression, anxiety, stress), and comorbid medical issues.

In this population, insomnia is often part of a cluster of symptoms that includes pain, fatigue, depression, and anxiety. These act synergistically, worsening quality of life.^21–24

Cancer-related fatigue is a distressing, persistent, subjective sense of tiredness or exhaustion that is related to cancer or cancer treatment, that is not proportional to recent activity and that interferes with usual functioning.²⁵ It has been reported by up to 90% of cancer patients in some studies.^26–28

Cancer-related fatigue worsens quality of life and is one of the most distressing and persistent symptoms experienced before, during, and after cancer treatment.^29,30 Furthermore, it can lead to sleep disturbances and daytime somnolence and further aggravate insomnia.^31,32 The two conditions are often reported as part of a cluster of interrelated symptoms that include pain, depression, and loss of concentration and other cognitive functions, suggesting that they may share a common etiology.^33–35

Åhsberg et al³⁶ examined different aspects of perceived cancer-related fatigue in patients undergoing radiotherapy and found correlations between lack of energy, sleepiness, and cancer-related fatigue.

Current understanding of the possible link between cancer-related fatigue and insomnia suggests that interventions targeting the insomnia and daytime sleepiness could decrease the fatigue as well.³¹

Pain and insomnia in cancer patients

Pain is reported by 60% to 90% of patients with advanced cancer,^37,38 its intensity usually varying with the extent of disease. Too often, it is inadequately controlled.³⁹ Furthermore, it is thought to contribute to insomnia.⁴⁰

In a study of more than 1,600 cancer patients, nearly 60% reported insomnia in addition to pain.⁴¹ The severity of pain directly correlated with the probability of insomnia.

Conversely, research suggests that sleep disturbances, primarily insomnia, can increase cancer patients’ sensitivity to pain.⁴² One hypothesis is that adequate sleep is needed to promote processes relevant to recovery from pain, both physiologic (ie, tissue repair) and psychological (ie, transient cessation of the perception of pain signals).⁴³

Paradoxically, opioids can worsen insomnia

Cancer pain is often treated with opioids, which, paradoxically, can cause or worsen insomnia.

Although opioids induce sleep, they also depress respiration, and at night, they can cause or worsen sleep-disordered breathing (obstructive or central sleep apnea or ataxic breathing), leading to episodes of hypoxia, arousals, and fragmented sleep.⁴⁴ Moreover, opioids can lead to daytime sedation. Further, psychostimulants such as methylphenidate, given to counteract opioid-induced sedation, can cause anxiety and insomnia. Thus, the interaction between cancer-related pain, insomnia, and pain management leads to a vicious cycle. Understanding this process, we can try to break the cycle and help patients with cancer sleep better.

However, how best to treat sleep-disordered breathing in patients taking opioids long-term is not well established.

In general, the primary intervention is to reduce the opioid dose. Practitioners should continually assess the need for these drugs and consider referral to a drug-behavior treatment center to help with discontinuation of opioid use when deemed medically appropriate.⁴⁵ Other strategies include positive airway pressure ventilation including continuous positive airway pressure, bilevel pressure devices with backup rate, or adaptive servoventilators. In some cases oxygen supplementation may be required.

Sleep-disordered breathing, when recognized and diagnosed, should be managed in partnership with a sleep specialist.

Depression and insomnia in cancer patients

By some estimates, up to half of cancer patients suffer from depression at some point in their illness.²⁸ And not without reason: these patients face uncertainty about their life, and this often results in depression or anxiety.⁴⁶

Many cancer patients with depression also have insomnia.²⁸ Indeed, patients with persistent insomnia are at greater risk of developing psychological disorders such as depression and anxiety.⁴⁷

In a survey of cancer patients, insomnia symptoms were more often attributed to thoughts or concerns about health, family, friends, the cancer diagnosis, and finances than to the actual physical effects of cancer.⁴⁸

CANCER TREATMENT AND INSOMNIA

Many cancer patients experience sleep disturbances even before starting treatment.⁴⁹ Liu et al⁵⁰ showed that, in 76 women about to undergo chemotherapy for breast cancer, those who already had sleep disturbances, fatigue, and depression had more problems, and more severe problems, during chemotherapy.

Radiation therapy and chemotherapy have been reported to cause or precipitate insomnia (Table 2).^8,13

Hormonal therapy and biological therapy can also cause or worsen preexisting insomnia.^51,52 For example, androgen deprivation therapy for prostate cancer and hormonal therapy for breast cancer are often associated with sleep problems.^49,50 Possible mechanisms of insomnia include hot flashes, night sweats, and anxiety caused by such treatments. Biological agents such as interferons, interleukins, and tumor necrosis factor (TNF) alpha, which are often used to treat malignant melanoma, can affect the sleep-wake cycle, leading to insomnia.⁵³

Corticosteroids sharply raise serum cortisol levels, which can lead to insomnia. Cancer patients receiving dexamethasone to prevent radiation-induced emesis experienced more insomnia than patients who did not receive dexamethasone.⁵⁴

IMMUNOLOGIC BASIS OF INSOMNIA IN CANCER PATIENTS

Cancer cells produce inflammatory cytokines such as interleukin 1 (IL-1), interleukin 6 (IL-6), and TNF alpha, and inflammation plays a role in tumor progression and possibly tumorigenesis.⁵⁵

Specific cytokines also help regulate the sleep-wake cycle. Levels of IL-6 and TNF alpha peak during sleep, and daytime IL-6 levels are inversely related to the amount of nocturnal sleep.⁵⁶ Vgontzas et al⁵⁷ showed that although mean levels of 24-hour IL-6 and TNF alpha secretion were not significantly different in patients with insomnia vs healthy controls, chronic insomnia was associated with a shift in IL-6 and TNF alpha secretion from nighttime to daytime.⁵⁷

Cancer and its treatment can affect secretion of the cytokines that play a role in the sleep-wake cycle. Thus, the sleep disturbances associated with cancer may also be related to the abnormalities in cytokine levels caused by either cancer or its treatment.

Mills et al⁵⁸ found that inflammatory markers such as vascular endothelial growth factor and soluble intercellular adhesion molecule-1 were significantly elevated during chemotherapy in breast cancer patients, and the elevated vascular endothelial growth factor levels were associated with poorer sleep during treatment.

Further research is warranted to establish causality, to help us understand the mechanisms of insomnia and other cancer symptoms, and to develop new treatments for these complaints.

POOR SLEEP AND CANCER RISK AND OUTCOMES

Sleep disturbances have negative health consequences in cancer. Their impact ranges from plausible carcinogenesis to affecting the course of the disease and cancer survival.

Poor sleep and risk of cancer

Epidemiologic studies have examined a possible link between circadian rhythm disruption and breast cancer risk, using both direct measures such as melatonin levels and indirect measures such as sleep duration and shift work. (Melatonin production is related to sleep duration, and night-shift work leads to disruption of sleep pattern and quality of sleep, thus lowering melatonin levels.⁵⁹)

The findings were mixed. Breast cancer risk was significantly and inversely associated with urinary melatonin levels (6-sulfatoxymelatonin) in the Nurses’ Health Study II,⁶⁰ but not in the Guernsey III study in the United Kingdom.⁶¹ Breast cancer risk was significantly lower with longer sleep duration in Finnish women⁶² and in Chinese women in Singapore,⁶³ but not in American women.^64,65 Results of three cohort studies^66–68 and two case-control studies^69,70 suggested a higher breast cancer risk in women who work evening or overnight shifts. Shorter sleep duration was associated with a higher risk of colorectal adenomas.⁷¹

These studies make a strong case for an association of cancer with circadian rhythm disruption and shorter sleep duration, possibly from an effect on melatonin levels. However, one should be cautious in interpreting epidemiologic studies: although they show sleep disturbances to be associated with cancer risk, they do not establish causality.

Insomnia and cancer outcomes

Evidence is growing that sleep disturbances may affect compliance with treatment, immune function, and outcomes—including survival—in cancer patients.^23,24

In patients newly diagnosed with various types of cancer, Degner and Sloan⁷² showed that those who suffered from insomnia, nausea, poor appetite, and pain had a lower survival rate at 5 years, independent of the cancer stage. However, no separate analyses were performed to examine the specific influence of insomnia on cancer survival.

Thompson and Li⁷³ analyzed data from 101 breast cancer patients with available Oncotype DX recurrence scores (a proprietary genetic test performed on tumor tissue that predicts the likelihood of recurrence). The scores were strongly correlated with average hours of sleep per night before breast cancer diagnosis, with fewer hours of sleep associated with a higher (worse) score.

Since these studies were retrospective and merely suggest associations, prospective studies, using more standardized questionnaires and objective measures, are needed to establish causality and to further our understanding of the mechanisms involved.

HELPING CANCER PATIENTS SLEEP BETTER

Insomnia is generally diagnosed with a thorough history that includes sleep, medical issues, substance use, and psychiatric issues. The sleep history should include specific insomniarelated complaints, presleep conditions and habits, sleep-wake habits, other sleep-related symptoms, and daytime consequences. To obtain the information, one can use questionnaires, sleep logs, psychological screening tests, and bed-partner interviews.⁷⁴

Managing insomnia involves both pharmacologic and nonpharmacologic treatment. It is also important to treat the associated disorders such as depression and anxiety disorders that often accompany insomnia. Long-term management of cancer patients should not be limited to surveillance of cancer but should also involve aggressive treatment of clusters of symptoms such as insomnia, cancer-related fatigue, and pain to yield better long-term quality of life.^75–77

Nonpharmacologic treatment: Cognitive-behavioral therapy

Nonpharmacologic interventions use psychological and behavioral therapies. The American Academy of Sleep Medicine guidelines recommend cognitive behavioral therapy for all patients with insomnia, either alone or in combination with hypnotic medications.

Cognitive-behavioral therapy for insomnia includes various components that help the patient learn coping skills and ways to prevent or mitigate the severity of future episodes (Table  3). Various randomized controlled trials found it to be effective for treating insomnia in the general population.^77–79

Several studies found that cognitive-behavioral therapy for insomnia was effective in cancer patients, not only improving sleep quality but also decreasing psychological distress, resulting in better overall quality of life.^80,81

Savard et al⁸¹ conducted a randomized controlled trial of cognitive-behavioral therapy for insomnia in 57 patients with breast cancer, examining subjective and objective sleep measures, psychological functioning, quality of life, and immunologic responses. They found significant improvements in sleep efficiency, mood, quality of life, depression, anxiety, and need for sleep medications. Improvements in subjective sleep measures persisted on 12-month follow-up.

Berger et al,⁸² in another randomized controlled trial, assessed behavioral therapy using stimulus control, modified sleep restriction, relaxation therapy, and sleep hygiene in breast cancer patients receiving adjuvant chemotherapy. Behavioral therapy improved sleep quality over time, as measured by the Pittsburgh Sleep Quality Index.

Espie et al⁸³ evaluated the effect of cognitive-behavioral therapy on prostate, colorectal, gynecologic, and breast cancer patients, with similar results.⁸³

Cognitive-behavioral therapy is at least as effective as drug therapy for insomnia in the general population. In the limited studies done in cancer patients, it has been shown to be effective irrespective of the type of cancer and is associated with better long-term outcomes. It diminishes the distress associated with early insomnia, can reduce anxiety, and can promote sleep.

A National Institutes of Health conference on insomnia concluded that cognitivebehavioral therapy is at least as effective as medications for brief treatment of chronic insomnia and that its beneficial effects, in contrast to those produced by medications, may last beyond the termination of treatment.⁸⁴

It is important to think about numerous factors when considering options such as cognitive-behavioral therapy, as patients with cancer have different complications that may affect sleep quality, such as cancer-related fatigue, cancer-related depression, psychological reactions to the disease, side effects of treatment, and cancer-related pain. These need to be addressed as well.

If cognitive-behavioral therapy is not available, self-help interventions (eg, written material, videos, television and Internet resources) can be used. These have several advantages over professionally administered interventions, including greater accessibility, less burden for the patient, and lower cost. Research is under way evaluating this approach in cancer patients.⁸⁵

The focus of therapy should be to treat underlying disorders that may be causing or contributing to insomnia. However, a substantial number of patients may need to be assessed for pharmacotherapy for insomnia.

Sleep problems in the general population are commonly treated with drugs, and most of the recommendations in cancer patients are based on experience in the general population. However, sleep medications should be used cautiously in cancer patients, since to our knowledge there have been no studies of these agents in patients with cancer.

Side effects also need to be considered. For example, sleep medications can profoundly worsen cancer-related fatigue.

Hypnotics are often prescribed for cancer patients.^86,87 A study in five major oncology centers showed that about half of the 1,500 patients were prescribed at least one psychotropic drug.⁸⁶ In this study, hypnotics were the most frequently prescribed drugs, accounting for 48% of total prescriptions, and 44% of the psychotropic prescriptions were written for sleep.

Benzodiazepine receptor agonists such as zaleplon, zolpidem, and eszopiclone can be used for problems with falling asleep and staying asleep.^88,89 They are better tolerated than older, long-acting benzodiazepines,⁹⁰ which can cause alterations in sleep-cycle architecture or rebound insomnia. The earlier agents can also cause adverse effects such as tolerance, drowsiness, and cognitive impairment.

A National Institutes of Health conference stated that benzodiazepine receptor agonists are efficacious in the short-term management of insomnia and that their adverse effects are much less frequent and severe than those of the benzodiazepines or other sedating drugs.⁸⁴ It also stated that all antidepressants, antihistamines (H1 receptor antagonists), and anti-psychotics have potentially significant adverse effects that raise concerns about their risk-to-benefit ratio and their suitability as treatment for chronic insomnia.

Benzodiazepines are commonly prescribed for insomnia. They increase sleep efficiency, decrease arousals, and increase stage 2 sleep.

Melatonin receptor agonists have been approved by the US Food and Drug Administration for treating insomnia. A recent meta-analysis of eight studies in healthy patients showed improvements in subjective and objective sleep outcomes with the use of ramelteon.⁹¹ The dosages primarily used were 4 to 32 mg. However, most of the studies used a dosage of 4 to 8 mg.

Antidepressants. Some of the antidepressants are also used for insomnia, but they can cause daytime fatigue.

Mirtazapine was shown to be effective for insomnia and coexistent mood disorder in cancer patients, but larger trials are needed.⁹²

A recent clinical trial with secondary data analyses evaluated the effect of paroxetine on insomnia, depression, and fatigue in patients with cancer. Paroxetine significantly reduced insomnia in both depressed and nondepressed patients after 2 to 3 weeks of treatment.⁹³

Table 4 summarizes classes of drugs used for insomnia and their additional therapeutic properties.

Many cancer patients don't sleep well, for a variety of reasons. It is an important problem: not only does poor sleep worsen quality of life, it may affect prognosis. Moreover, treatment is available.

Yet many physicians caring for cancer patients do not ask about sleep problems, underestimating their impact or focusing on more urgent problems. Also, patients may not want to bring up the topic because they consider poor sleep to be unavoidable and untreatable and because they fear that reporting it may shift the focus of their treatment from trying to cure the cancer to easing its symptoms.

This practical review will help health care professionals avoid the common barriers to diagnosis and treatment of poor sleep in cancer patients. Because there are few data on other sleep disorders such as sleep apnea and restless leg syndrome, we will focus on the most common one in cancer patients—insomnia—and its effects on other symptoms and quality of life.

MORE PATIENTS SURVIVE CANCER NOW

Today, more patients are surviving cancer, but cancer symptoms and the side effects of surgery, chemotherapy, and radiation therapy may persist for years.^1,2 The most common complaints include cancer-related fatigue, leg restlessness, anxiety, insomnia, and excessive sleepiness.³

Sleep disturbances appear to contribute to the other problems and are relatively easier to quantify. Most studies of sleep disorders in cancer patients have looked specifically at insomnia,⁴ although a few have explored the prevalence of other sleep disorders, such as sleep-disordered breathing and limb movements during sleep.⁵

The International Classification of Sleep Disorders, 2nd edition,⁶ defines insomnia as difficulty going to sleep or staying asleep (the latter defined as waking up in the middle of the night, with wakeful episodes lasting more than 30 minutes), early-morning awakenings (waking 30 minutes or more before the intended time), or nonrestorative sleep, causing significant distress or impairment of day-time functioning.

INSOMNIA WORSENS QUALITY OF LIFE

Insomnia significantly worsens quality of life in cancer patients, and if it can be detected and effectively treated, quality of life is likely to improve. Studies in cancer patients have found that those with insomnia:

• Were less able to cope with stress and carry on their activities of daily living³
• Were much less able to function and reported more pain, less energy, and greater difficulty in dealing with emotional problems⁷
• Had poor quality of life, both physically and emotionally.^3,8

PERHAPS MORE THAN HALF OF CANCER PATIENTS HAVE INSOMNIA

Depending on the methods used and populations studied, at least 30% and perhaps more than half of patients with cancer have insomnia (Table 1).^3,4,8–14 It is one of the most commonly reported complaints in this group,^15–17 and it occurs before, during, and after treatment of cancer.

Although the prevalence may differ in various cancers, it is still higher than in the general population. In a study of about 450 patients with cancer or depression and 300 healthy volunteers, 62% of the cancer patients reported moderate to severe sleep disturbance, compared with 52% of the depressed patients and 30% of the healthy volunteers.¹⁸

When Davidson et al³ surveyed nearly 1,000 cancer patients, one-third said they had insomnia. The problem was most prevalent in lung and breast cancer patients.

In a longitudinal study by Savard et al,¹³ the prevalence of insomnia declined over time but remained high even at the end of 18 months. It was more prevalent in patients with gynecologic and breast cancer than in those with prostate cancer.^13,19

SLEEP PROBLEMS ARE UNDERREPORTED

Sleep problems in cancer patients often go unrecognized because patients do not report them. In a survey of 150 patients,²⁰ 44% reported having had sleep problems during the preceding month. However, only one-third of those with sleep problems told their health care providers. This highlights the need for physicians to address sleep complaints in cancer patients at every visit and, if needed, to refer them to a sleep specialist for further evaluation and management.

INSOMNIA IS OFTEN ASSOCIATED WITH OTHER PROBLEMS

Many things can interfere with sleep in cancer patients: the cancer itself (eg, pain due to tumor invasion), medical treatments (eg, narcotics, chemotherapy, neuroleptics, sympathomimetics, steroids, sedative hypnotics), psychosocial disturbances (eg, depression, anxiety, stress), and comorbid medical issues.

In this population, insomnia is often part of a cluster of symptoms that includes pain, fatigue, depression, and anxiety. These act synergistically, worsening quality of life.^21–24

Cancer-related fatigue is a distressing, persistent, subjective sense of tiredness or exhaustion that is related to cancer or cancer treatment, that is not proportional to recent activity and that interferes with usual functioning.²⁵ It has been reported by up to 90% of cancer patients in some studies.^26–28

Cancer-related fatigue worsens quality of life and is one of the most distressing and persistent symptoms experienced before, during, and after cancer treatment.^29,30 Furthermore, it can lead to sleep disturbances and daytime somnolence and further aggravate insomnia.^31,32 The two conditions are often reported as part of a cluster of interrelated symptoms that include pain, depression, and loss of concentration and other cognitive functions, suggesting that they may share a common etiology.^33–35

Åhsberg et al³⁶ examined different aspects of perceived cancer-related fatigue in patients undergoing radiotherapy and found correlations between lack of energy, sleepiness, and cancer-related fatigue.

Current understanding of the possible link between cancer-related fatigue and insomnia suggests that interventions targeting the insomnia and daytime sleepiness could decrease the fatigue as well.³¹

Pain and insomnia in cancer patients

Pain is reported by 60% to 90% of patients with advanced cancer,^37,38 its intensity usually varying with the extent of disease. Too often, it is inadequately controlled.³⁹ Furthermore, it is thought to contribute to insomnia.⁴⁰

In a study of more than 1,600 cancer patients, nearly 60% reported insomnia in addition to pain.⁴¹ The severity of pain directly correlated with the probability of insomnia.

Conversely, research suggests that sleep disturbances, primarily insomnia, can increase cancer patients’ sensitivity to pain.⁴² One hypothesis is that adequate sleep is needed to promote processes relevant to recovery from pain, both physiologic (ie, tissue repair) and psychological (ie, transient cessation of the perception of pain signals).⁴³

Paradoxically, opioids can worsen insomnia

Cancer pain is often treated with opioids, which, paradoxically, can cause or worsen insomnia.

Although opioids induce sleep, they also depress respiration, and at night, they can cause or worsen sleep-disordered breathing (obstructive or central sleep apnea or ataxic breathing), leading to episodes of hypoxia, arousals, and fragmented sleep.⁴⁴ Moreover, opioids can lead to daytime sedation. Further, psychostimulants such as methylphenidate, given to counteract opioid-induced sedation, can cause anxiety and insomnia. Thus, the interaction between cancer-related pain, insomnia, and pain management leads to a vicious cycle. Understanding this process, we can try to break the cycle and help patients with cancer sleep better.

However, how best to treat sleep-disordered breathing in patients taking opioids long-term is not well established.

In general, the primary intervention is to reduce the opioid dose. Practitioners should continually assess the need for these drugs and consider referral to a drug-behavior treatment center to help with discontinuation of opioid use when deemed medically appropriate.⁴⁵ Other strategies include positive airway pressure ventilation including continuous positive airway pressure, bilevel pressure devices with backup rate, or adaptive servoventilators. In some cases oxygen supplementation may be required.

Sleep-disordered breathing, when recognized and diagnosed, should be managed in partnership with a sleep specialist.

Depression and insomnia in cancer patients

By some estimates, up to half of cancer patients suffer from depression at some point in their illness.²⁸ And not without reason: these patients face uncertainty about their life, and this often results in depression or anxiety.⁴⁶

Many cancer patients with depression also have insomnia.²⁸ Indeed, patients with persistent insomnia are at greater risk of developing psychological disorders such as depression and anxiety.⁴⁷

In a survey of cancer patients, insomnia symptoms were more often attributed to thoughts or concerns about health, family, friends, the cancer diagnosis, and finances than to the actual physical effects of cancer.⁴⁸

CANCER TREATMENT AND INSOMNIA

Many cancer patients experience sleep disturbances even before starting treatment.⁴⁹ Liu et al⁵⁰ showed that, in 76 women about to undergo chemotherapy for breast cancer, those who already had sleep disturbances, fatigue, and depression had more problems, and more severe problems, during chemotherapy.

Radiation therapy and chemotherapy have been reported to cause or precipitate insomnia (Table 2).^8,13

Hormonal therapy and biological therapy can also cause or worsen preexisting insomnia.^51,52 For example, androgen deprivation therapy for prostate cancer and hormonal therapy for breast cancer are often associated with sleep problems.^49,50 Possible mechanisms of insomnia include hot flashes, night sweats, and anxiety caused by such treatments. Biological agents such as interferons, interleukins, and tumor necrosis factor (TNF) alpha, which are often used to treat malignant melanoma, can affect the sleep-wake cycle, leading to insomnia.⁵³

Corticosteroids sharply raise serum cortisol levels, which can lead to insomnia. Cancer patients receiving dexamethasone to prevent radiation-induced emesis experienced more insomnia than patients who did not receive dexamethasone.⁵⁴

IMMUNOLOGIC BASIS OF INSOMNIA IN CANCER PATIENTS

Cancer cells produce inflammatory cytokines such as interleukin 1 (IL-1), interleukin 6 (IL-6), and TNF alpha, and inflammation plays a role in tumor progression and possibly tumorigenesis.⁵⁵

Specific cytokines also help regulate the sleep-wake cycle. Levels of IL-6 and TNF alpha peak during sleep, and daytime IL-6 levels are inversely related to the amount of nocturnal sleep.⁵⁶ Vgontzas et al⁵⁷ showed that although mean levels of 24-hour IL-6 and TNF alpha secretion were not significantly different in patients with insomnia vs healthy controls, chronic insomnia was associated with a shift in IL-6 and TNF alpha secretion from nighttime to daytime.⁵⁷

Cancer and its treatment can affect secretion of the cytokines that play a role in the sleep-wake cycle. Thus, the sleep disturbances associated with cancer may also be related to the abnormalities in cytokine levels caused by either cancer or its treatment.

Mills et al⁵⁸ found that inflammatory markers such as vascular endothelial growth factor and soluble intercellular adhesion molecule-1 were significantly elevated during chemotherapy in breast cancer patients, and the elevated vascular endothelial growth factor levels were associated with poorer sleep during treatment.

Further research is warranted to establish causality, to help us understand the mechanisms of insomnia and other cancer symptoms, and to develop new treatments for these complaints.

POOR SLEEP AND CANCER RISK AND OUTCOMES

Sleep disturbances have negative health consequences in cancer. Their impact ranges from plausible carcinogenesis to affecting the course of the disease and cancer survival.

Poor sleep and risk of cancer

Epidemiologic studies have examined a possible link between circadian rhythm disruption and breast cancer risk, using both direct measures such as melatonin levels and indirect measures such as sleep duration and shift work. (Melatonin production is related to sleep duration, and night-shift work leads to disruption of sleep pattern and quality of sleep, thus lowering melatonin levels.⁵⁹)

The findings were mixed. Breast cancer risk was significantly and inversely associated with urinary melatonin levels (6-sulfatoxymelatonin) in the Nurses’ Health Study II,⁶⁰ but not in the Guernsey III study in the United Kingdom.⁶¹ Breast cancer risk was significantly lower with longer sleep duration in Finnish women⁶² and in Chinese women in Singapore,⁶³ but not in American women.^64,65 Results of three cohort studies^66–68 and two case-control studies^69,70 suggested a higher breast cancer risk in women who work evening or overnight shifts. Shorter sleep duration was associated with a higher risk of colorectal adenomas.⁷¹

These studies make a strong case for an association of cancer with circadian rhythm disruption and shorter sleep duration, possibly from an effect on melatonin levels. However, one should be cautious in interpreting epidemiologic studies: although they show sleep disturbances to be associated with cancer risk, they do not establish causality.

Insomnia and cancer outcomes

Evidence is growing that sleep disturbances may affect compliance with treatment, immune function, and outcomes—including survival—in cancer patients.^23,24

In patients newly diagnosed with various types of cancer, Degner and Sloan⁷² showed that those who suffered from insomnia, nausea, poor appetite, and pain had a lower survival rate at 5 years, independent of the cancer stage. However, no separate analyses were performed to examine the specific influence of insomnia on cancer survival.

Thompson and Li⁷³ analyzed data from 101 breast cancer patients with available Oncotype DX recurrence scores (a proprietary genetic test performed on tumor tissue that predicts the likelihood of recurrence). The scores were strongly correlated with average hours of sleep per night before breast cancer diagnosis, with fewer hours of sleep associated with a higher (worse) score.

Since these studies were retrospective and merely suggest associations, prospective studies, using more standardized questionnaires and objective measures, are needed to establish causality and to further our understanding of the mechanisms involved.

HELPING CANCER PATIENTS SLEEP BETTER

Insomnia is generally diagnosed with a thorough history that includes sleep, medical issues, substance use, and psychiatric issues. The sleep history should include specific insomniarelated complaints, presleep conditions and habits, sleep-wake habits, other sleep-related symptoms, and daytime consequences. To obtain the information, one can use questionnaires, sleep logs, psychological screening tests, and bed-partner interviews.⁷⁴

Managing insomnia involves both pharmacologic and nonpharmacologic treatment. It is also important to treat the associated disorders such as depression and anxiety disorders that often accompany insomnia. Long-term management of cancer patients should not be limited to surveillance of cancer but should also involve aggressive treatment of clusters of symptoms such as insomnia, cancer-related fatigue, and pain to yield better long-term quality of life.^75–77

Nonpharmacologic treatment: Cognitive-behavioral therapy

Nonpharmacologic interventions use psychological and behavioral therapies. The American Academy of Sleep Medicine guidelines recommend cognitive behavioral therapy for all patients with insomnia, either alone or in combination with hypnotic medications.

Cognitive-behavioral therapy for insomnia includes various components that help the patient learn coping skills and ways to prevent or mitigate the severity of future episodes (Table  3). Various randomized controlled trials found it to be effective for treating insomnia in the general population.^77–79

Several studies found that cognitive-behavioral therapy for insomnia was effective in cancer patients, not only improving sleep quality but also decreasing psychological distress, resulting in better overall quality of life.^80,81

Savard et al⁸¹ conducted a randomized controlled trial of cognitive-behavioral therapy for insomnia in 57 patients with breast cancer, examining subjective and objective sleep measures, psychological functioning, quality of life, and immunologic responses. They found significant improvements in sleep efficiency, mood, quality of life, depression, anxiety, and need for sleep medications. Improvements in subjective sleep measures persisted on 12-month follow-up.

Berger et al,⁸² in another randomized controlled trial, assessed behavioral therapy using stimulus control, modified sleep restriction, relaxation therapy, and sleep hygiene in breast cancer patients receiving adjuvant chemotherapy. Behavioral therapy improved sleep quality over time, as measured by the Pittsburgh Sleep Quality Index.

Espie et al⁸³ evaluated the effect of cognitive-behavioral therapy on prostate, colorectal, gynecologic, and breast cancer patients, with similar results.⁸³

Cognitive-behavioral therapy is at least as effective as drug therapy for insomnia in the general population. In the limited studies done in cancer patients, it has been shown to be effective irrespective of the type of cancer and is associated with better long-term outcomes. It diminishes the distress associated with early insomnia, can reduce anxiety, and can promote sleep.

A National Institutes of Health conference on insomnia concluded that cognitivebehavioral therapy is at least as effective as medications for brief treatment of chronic insomnia and that its beneficial effects, in contrast to those produced by medications, may last beyond the termination of treatment.⁸⁴

It is important to think about numerous factors when considering options such as cognitive-behavioral therapy, as patients with cancer have different complications that may affect sleep quality, such as cancer-related fatigue, cancer-related depression, psychological reactions to the disease, side effects of treatment, and cancer-related pain. These need to be addressed as well.

If cognitive-behavioral therapy is not available, self-help interventions (eg, written material, videos, television and Internet resources) can be used. These have several advantages over professionally administered interventions, including greater accessibility, less burden for the patient, and lower cost. Research is under way evaluating this approach in cancer patients.⁸⁵

The focus of therapy should be to treat underlying disorders that may be causing or contributing to insomnia. However, a substantial number of patients may need to be assessed for pharmacotherapy for insomnia.

Sleep problems in the general population are commonly treated with drugs, and most of the recommendations in cancer patients are based on experience in the general population. However, sleep medications should be used cautiously in cancer patients, since to our knowledge there have been no studies of these agents in patients with cancer.

Side effects also need to be considered. For example, sleep medications can profoundly worsen cancer-related fatigue.

Hypnotics are often prescribed for cancer patients.^86,87 A study in five major oncology centers showed that about half of the 1,500 patients were prescribed at least one psychotropic drug.⁸⁶ In this study, hypnotics were the most frequently prescribed drugs, accounting for 48% of total prescriptions, and 44% of the psychotropic prescriptions were written for sleep.

Benzodiazepine receptor agonists such as zaleplon, zolpidem, and eszopiclone can be used for problems with falling asleep and staying asleep.^88,89 They are better tolerated than older, long-acting benzodiazepines,⁹⁰ which can cause alterations in sleep-cycle architecture or rebound insomnia. The earlier agents can also cause adverse effects such as tolerance, drowsiness, and cognitive impairment.

A National Institutes of Health conference stated that benzodiazepine receptor agonists are efficacious in the short-term management of insomnia and that their adverse effects are much less frequent and severe than those of the benzodiazepines or other sedating drugs.⁸⁴ It also stated that all antidepressants, antihistamines (H1 receptor antagonists), and anti-psychotics have potentially significant adverse effects that raise concerns about their risk-to-benefit ratio and their suitability as treatment for chronic insomnia.

Benzodiazepines are commonly prescribed for insomnia. They increase sleep efficiency, decrease arousals, and increase stage 2 sleep.

Melatonin receptor agonists have been approved by the US Food and Drug Administration for treating insomnia. A recent meta-analysis of eight studies in healthy patients showed improvements in subjective and objective sleep outcomes with the use of ramelteon.⁹¹ The dosages primarily used were 4 to 32 mg. However, most of the studies used a dosage of 4 to 8 mg.

Antidepressants. Some of the antidepressants are also used for insomnia, but they can cause daytime fatigue.

Mirtazapine was shown to be effective for insomnia and coexistent mood disorder in cancer patients, but larger trials are needed.⁹²

A recent clinical trial with secondary data analyses evaluated the effect of paroxetine on insomnia, depression, and fatigue in patients with cancer. Paroxetine significantly reduced insomnia in both depressed and nondepressed patients after 2 to 3 weeks of treatment.⁹³

Table 4 summarizes classes of drugs used for insomnia and their additional therapeutic properties.

Current therapies for myasthenia gravis can help most patients achieve sustained improvement. The overall prognosis has dramatically improved over the last 4 decades: the mortality rate used to be 75%; now it is 4.5%.¹

Myasthenia gravis is the most common disorder of neuromuscular junction transmission and is also one of the best characterized autoimmune diseases. However, its symptoms—primarily weakness—vary from patient to patient, and in the same patient, by time of day and over longer time periods. The variation in symptoms can be very confusing to undiagnosed patients and puzzling to unsuspecting physicians. Such diagnostic uncertainty can give the patient additional frustration and emotional stress, which in turn exacerbate his or her condition.

In this review, we will give an overview of the pathogenesis, clinical manifestations, diagnosis, and treatment of myasthenia gravis.

TWO PEAKS IN INCIDENCE BY AGE

The annual incidence of myasthenia gravis is approximately 10 to 20 new cases per million, with a prevalence of about 150 to 200 per million.²

The age of onset has a bimodal distribution, with an early incidence peak in the second to third decade with a female predominance and a late peak in the 6th to the 8th decade with a male predominance.²

Myasthenia gravis is commonly associated with several other autoimmune disorders, including hypothyroidism, hyperthyroidism, systemic lupus erythematosus, rheumatoid arthritis, vitiligo, diabetes, and, more recently recognized, neuromyelitis optica.³

ANTIBODIES AGAINST AChR AND MuSK

In most cases of myasthenia gravis the patient has autoimmune antibodies against constituents of the neuromuscular junction, specifically acetylcholine receptor (AChR) and muscle-specific tyrosine kinase (MuSK) (Figure 1).

AChR antibody-positive myasthenia gravis

When antibodies bind to AChR on the postsynaptic membrane, they cross-link neighboring AChR units, which are absorbed into the muscle fiber and are broken up.⁴ In addition, the complement system is activated to mediate further damage on the postsynaptic membrane.

AChR antibodies may come from germinal centers of the thymus, where clustered myoid cells express AChR on the plasma membrane surface.⁵ About 60% of AChR antibody-positive myasthenia gravis patients have an enlarged thymus, and 10% have a thymoma—a tumor of the epithelial cells of this organ. Conversely, about 15% of patients with a thymoma have clinical myasthenia gravis, and an additional 20% possess antibodies against AChR in the serum without myasthenic symptoms.⁵

MuSK antibody-positive myasthenia gravis

Like AChR, MuSK is a transmembrane component of the postsynaptic neuromuscular junction. During formation of the neuromuscular junction, MuSK is activated through the binding of agrin (a nerve-derived proteoglycan) to lipoprotein-related protein 4 (LRP4), after which complicated intracellular signaling promotes the assembly and stabilization of AChR.⁶

Unlike AChR antibodies, antibodies against MuSK do not activate the complement system, and complement fixation is not essential for clinical myasthenic symptoms to appear.⁷ Also, myasthenia gravis with MuSK antibodies is rarely associated with thymoma.⁸

The precise mechanism by which MuSK antibody impairs transmission at the neuromuscular junction has been a mystery until recently. Animal models, including MuSK-mutant mice and mice injected with MuSK protein or with purified immunoglobulin G from patients with this disease, have revealed a significant reduction of AChR clusters and destruction of neuromuscular junction structures.^7,9–12

In addition, MuSK antibodies produce pre-synaptic dysfunction, manifesting as a reduction of acetylcholine content. This information is based on studies in mice and on in vitro electrophysiologic analyses of neuromuscular junctions from a patient with this disease.^7,9–13

Finally, MuSK antibodies may indirectly affect the recycling of acetylcholine. After post-synaptic activation, acetylcholine is normally hydrolized by acetylcholinesterase, which is located in the synaptic cleft but anchored to MuSK on the postsynaptic membrane. MuSK antibodies block the binding of MuSK to acetylcholinesterase, possibly leading to less accumulation of acetylcholinesterase.¹⁴ This process may explain why patients with MuSK antibody-positive myasthenia gravis tend to respond poorly to acetylcholinesterase inhibitors (more about this below).

In a series of 562 consecutive patients with generalized weakness due to myasthenia gravis, 92% were positive for AChR antibody, 3% were positive for MuSK antibody, and 5% were seronegative (possessing neither antibody).¹⁵ In contrast, about 50% of patients with purely ocular myasthenia gravis (ie, with isolated weakness of the levator palpebrae superioris, orbicularis oculi, or oculomotor muscles) are seropositive for AChR antibody. Only a few ocular MuSK antibody-positive cases have been described, leaving the rest seronegative. Rarely, both antibodies can be detected in the same patient.¹⁶

In patients who are negative for AChR antibodies at the time of disease onset, sero-conversion may occur later during the course. Repeating serologic testing 6 to 12 months later may detect AChR antibodies in approximately 15% of patients who were initially seronegative.^15,17

The clinical presentation, electrophysiologic findings, thymic pathologic findings, and treatment responses are similar in AChR antibody-positive and seronegative myasthenia gravis.¹⁷ Muscle biopsy study in seronegative cases demonstrates a loss of AChR as well.¹⁸

Based on these observations, it has been proposed that seronegative patients may have low-affinity antibodies that can bind to tightly clustered AChRs on the postsynaptic membrane but escape detection by routine radioimmunoassays in a solution phase. With a sensitive cell-based immunofluorescence assay, low-affinity antibodies to clustered AChRs were detected in 66% of patients with generalized myasthenia gravis and in 50% of those with ocular myasthenia gravis who were seronegative on standard assays.^19,20 These low-affinity AChR antibodies can also activate complement in vitro, increasing the likelihood that they are pathogenic. However, assays to detect low-affinity AChR antibodies are not yet commercially available.

Within the past year, three research groups independently reported detecting antibodies to LRP4 in 2% to 50% of seronegative myasthenia gravis patients. This wide variation in the prevalence of LRP4 antibodies could be related to patient ethnicity and methods of detection.^21–23 LRP4 is a receptor for agrin and is required for agrin-induced MuSK activation and AChR clustering. LRP antibodies can activate complement; therefore, it is plausible that LRP4 antibody binding leads to AChR loss on the postsynaptic membrane. However, additional study is needed to determine if LRP4 antibodies are truly pathogenic in myasthenia gravis.

A DISORDER OF FATIGABLE WEAKNESS

Myasthenia gravis is a disorder of fatigable weakness producing fluctuating symptoms. Symptoms related to the involvement of specific muscle groups are listed in Table 1. Muscle weakness is often worse later in the day or after exercise.

Ocular myasthenia gravis accounts for about 15% of all cases. Of patients initially presenting with ocular symptoms only, twothirds will ultimately develop generalized symptoms, most within the first 2 years.²⁴ No factor has been identified that predicts conversion from an ocular to a generalized form.

Several clinical phenotypes of MuSK antibody-positive myasthenia gravis have been described. An oculobulbar form presents with diplopia, ptosis, dysarthria, and profound atrophy of the muscles of the tongue and face. A restricted myopathic form presents with prominent neck, shoulder, and respiratory weakness without ocular involvement. A third form is a combination of ocular and proximal limb weakness, indistinguishable from AChR antibody-positive disease.²⁵

MuSK antibody-positive patients do not respond as well to acetylcholinesterase inhibitors as AChR antibody-positive patients do. In one study, nearly 70% of MuSK antibody-positive patients demonstrated no response, poor tolerance, or cholinergic hypersensitivity to these agents.²⁵ Fortunately, most MuSK antibody-positive patients have a favorable response to immunosuppressive therapy—sometimes a dramatic improvement after plasmapheresis.⁸

DIAGNOSIS OF MYASTHENIA GRAVIS

The common differential diagnoses for myasthenia gravis are listed in Table 2.

The essential feature of myasthenia gravis is fluctuating muscle weakness, often with fatigue. Many patients complain of weakness of specific muscle groups after their repeated usage. Pain is generally a less conspicuous symptom, and generalized fatigue without objective weakness is inconsistent with myasthenia gravis.

Signs of muscle weakness may include droopy eyelids, diplopia, inability to hold the head straight, difficulty swallowing or chewing, speech disturbances, difficulty breathing, and difficulty raising the arms or rising from the sitting position. A historical pattern of ptosis alternating from one eye to the other is fairly characteristic of myasthenia gravis.

The weakness of orbicularis oculi is easily identified on examination by prying open the eyes during forced eye closure. Limb weakness is usually more significant in the arms than in the legs. An often-neglected feature of myasthenia gravis is finger extensor weakness with a relative sparing of other distal hand muscles.²

The ice-pack test is performed by placing a small bag of ice over the ptotic eye for 2 to 5 minutes and assessing the degree of ptosis for any noticeable improvement. This test is not very helpful for assessing ocular motor weakness.

The edrophonium (Tensilon) test can be used for patients with ptosis or ophthalmoparesis. Edrophonium, a short-acting acetylcholinesterase inhibitor, is given intravenously while the patient is observed for objective improvement. The patient’s cardiovascular status should be monitored for arrhythmias and hypotension. Atropine should be immediately available in case severe bradycardia develops.

The ice-pack test and the edrophonium test can give false-negative and false-positive results, and the diagnosis of myasthenia gravis must be verified by other diagnostic tests.

Testing for circulating AChR antibodies, MuSK antibodies, or both is the first step in the laboratory confirmation of myasthenia gravis.

There are three AChR antibody subtypes: binding, blocking, and modulating. Binding antibodies are present in 80% to 90% of patients with generalized myasthenia gravis and 50% of those with ocular myasthenia gravis. Testing for blocking and modulating AChR antibodies increases the sensitivity by less than 5% when added to testing for binding antibodies.

AChR antibody titers correlate poorly with disease severity between patients. However, in individual patients, antibody titers tend to go down in parallel with clinical improvement.

MuSK antibody is detected in nearly half of myasthenia gravis patients with generalized weakness who are negative for AChR antibody.

Electrophysiologic tests

Electrophysiologic tests can usually confirm the diagnosis of seronegative myasthenia gravis. They are also helpful in seropositive patients who have unusual clinical features or a poor response to treatment.

Repetitive nerve stimulation studies use a slow rate (2–5 Hz) of repetitive electrical stimulation. The study is positive if the motor response declines by more than 10%. However, a decremental response is not specific for myasthenia gravis, as it may be seen in other neuromuscular disorders such as motor neuron disease or Lambert-Eaton myasthenic syndrome.

This test is technically easier to do in distal muscles than in proximal muscles, but less sensitive. Therefore, proximal muscles such as the trapezius or facial muscles are usually also sampled to maximize the yield. To further maximize the sensitivity, muscles being tested should be warm, and acetylcholinesterase inhibitors should be withheld for 12 hours before.

Repetitive nerve stimulation studies in distal muscles are positive in approximately 75% of patients with generalized myasthenia gravis and in 30% with ocular myasthenia gravis.²⁶

Single-fiber electromyography is more technically demanding than repetitive nerve stimulation and is less widely available. It is usually performed with a special needle electrode that can simultaneously identify action potentials arising from individual muscle fibers innervated by the same axon.

Variability in time of the second action potential relative to the first is called “jitter.” Abnormal jitter is seen in more than 95% of patients with generalized myasthenia gravis and in 85% to 90% of those with ocular myasthenia gravis.^26,27 However, abnormal jitter can also be seen in other neuromuscular diseases such as motor neuron disease or in neuromuscular junctional disorders such as Lambert-Eaton myasthenic syndrome.

Imaging studies

Chest computed tomography or magnetic resonance imaging with contrast should be performed in all myasthenia gravis patients to look for a thymoma.

TREATMENT OF MYASTHENIA GRAVIS

Acetylcholinesterase inhibitors

As a reasonable first therapy in mild cases of myasthenia gravis, acetylcholinesterase inhibitors slow down the degradation of acetylcholine and prolong its effect in the neuromuscular junction, but they are not disease-modifying and their benefits are mild.

Pyridostigmine is the usual choice of acetylcholinesterase inhibitor. Its onset of action is rapid (15 to 30 minutes) and its action lasts for 3 to 4 hours. For most patients, the effective dosage range is 60 mg to 90 mg every 4 to 6 hours. A long-acting form is also available and can be given as a single nighttime dose.

Immunomodulating therapy

Patients who have moderate to severe symptoms require some form of immunomodulating therapy.

Plasmapheresis or intravenous immune globulin is reserved for patients with severe or rapidly worsening disease because their beneficial effects can be seen within the first week of treatment.

Longer-acting immunotherapies (corticosteroids, azathioprine, mycophenolate mofetil and others) have a slower onset of responses but provide sustained benefits. Which drug to use depends on factors such as comorbidity, side effects, and cost.

Drugs to avoid

A number of medications can exacerbate weakness in myasthenia gravis and should be avoided or used with caution. The list is long, but ones that deserve the most attention are penicillamine, interferons, procainamide, quinidine, and antibiotics, including quinolones and aminoglycosides. A more comprehensive list of medications that may exacerbate myasthenia gravis symptoms can be found in a review by Keesey.²

RAPID INDUCTION IMMUNOTHERAPIES : PLASMAPHERESIS, IMMUNE GLOBULIN

Both plasmapheresis and intravenous immune globulin act quickly over days, but in most patients their effects last only a few weeks. Both are used as rescue therapies for myasthenic crises, bridging therapy to slow-acting immunotherapeutic agents, or maintenance treatment for poorly controlled cases.

Several retrospective studies have confirmed the efficacy of plasmapheresis in more than 80% of patients with generalized symptoms.^28,29

In a randomized trial in patients with generalized therapies, intravenous immune globulin improved muscle strength in the group of patients with severe symptoms.³⁰ The effective dosage of intravenous immune globulin varies from 1 to 2 g/kg without observed difference between doses.³¹ Trials comparing the efficacy of intravenous immune globulin and plasmapheresis in acute and severe myasthenia gravis did not reveal a difference in efficacy.^32,33 Intravenous immune globulin at a minimal dose of 0.4 g/kg every 3 months has been successfully used as a long-term maintenance monotherapy, and such a role could be expanded to more patients with further studies.³⁴

The choice between plasmapheresis and intravenous immune globulin is often based on the ability of a patient to tolerate each treatment and on the availability of the plasmapheresis procedure. Intravenous immune globulin is easier to administer, is associated with fewer adverse events related to vascular access, and is therefore more appropriate than plasmapheresis in some centers.

CHRONIC MAINTENANCE IMMUNOMODULATING TREATMENT

Corticosteroids

Prednisone, the most commonly used agent, leads to remission or marked improvement in 70% to 80% of patients with ocular or generalized myasthenia gravis.³⁵ It may also reduce the progression of ocular myasthenia gravis to the generalized form.³⁶

The effective dose of prednisone depends on the severity and distribution of symptoms. Some patients may need up to 1.0 mg/kg/day (usually 50 to 80 mg per day). In patients with mild to moderate symptoms, a lower maximal dosage such as 20 to 40 mg per day can be sufficient.

Within 1 to 2 weeks after starting high-dose prednisone, up to 50% of patients may develop a transient deterioration, including possible precipitation of a myasthenic crisis.³⁷ For this reason, high-dose prednisone is commonly started only in hospitalized patients who are also receiving plasmapheresis or intravenous immune globulin. Otherwise, an outpatient dose-escalation protocol can be used to achieve a target dose over several weeks.

Prednisone tapering can begin after the patient has been on the maximal dose for 1 to 2 months and significant improvement is evident. A monthly tapering of 5 to 10 mg is preferred, then more slowly after the daily dose reaches 30 mg. The usual maintenance dose averages about 5 mg daily.

Common side effects of prednisone include weight gain, cushingoid features, easy bruising, cataracts, glaucoma, hypertension, diabetes, dyslipidemia, and osteoporosis. Patients are advised to take supplemental calcium (1,500 mg per day) and vitamin D (400 to 800 IU per day). For those most at risk of osteoporosis, treatment with a bisphosphonate should be considered.

Other immunotherapeutic agents are often needed, either to replace the corticosteroid or to permit use of lower doses of it. Because of their delayed onset of action, starting such corticosteroid-sparing agents early in the course is often necessary. These agents are often initially combined with high-dose prednisone, with an eventual goal of weaning off prednisone entirely. This strategy offers the advantage of relatively rapid induction while avoiding the long-term adverse effects of corticosteroid treatment.

Azathioprine

Azathioprine doesn’t begin to show a beneficial effect in myasthenia gravis for 6 to 12 months, and it often reaches its maximal efficacy only after 1 to 2 years of treatment.³⁸

In a study of 78 myasthenia gravis patients, 91% improved when treated with azathioprine alone or together with prednisone.³⁹ In another study using azathioprine and prednisolone for generalized myasthenia gravis, nearly two-thirds of patients came off prednisolone while maintaining remission for 3 years.³⁸

A typical maintenance dose is 2 to 3 mg/kg/day. Common side effects are nausea, vomiting, and malaise. Less frequent side effects include hematologic abnormalities, abnormal liver function, and pancreatitis. Monthly monitoring of complete blood cell counts and liver function tests is warranted for the first 6 months, then less often.

One in 300 people in the general population is homozygous for a mutant allele in the thiopurine methyltransferase (TPMT) gene. Patients with this genotype should not receive azathioprine because of the risk of life-threatening bone marrow suppression.⁴⁰ A slightly increased risk of various forms of lymphoma has been documented.⁴¹

A well-tolerated medication with few side effects, mycophenolate mofetil is being used more in myasthenia gravis. The results of two recent randomized trials suggested that it is not effective in improving myasthenia gravis symptoms or sparing prednisone dosage when used for 90 days or 36 weeks.^42,43 However, extensive clinical experience supports its longterm efficacy in myasthenia gravis.

In a retrospective study of 85 patients with generalized myasthenia gravis, mycophenolate at doses of 1 to 3 g daily improved symptoms in 73% and produced remission in 50%. Steroid dosage was reduced in 71% of patients.⁴⁴

Another retrospective study, with 102 patients, verified a slow development of clinical benefit after months of mycophenolate therapy alone or in combination with prednisone. Approximately 50% of patients achieved a minimal manifestation status after 6 to 12 months of mycophenolate treatment. Eventually, at 24 months of treatment, 80% of patients had a desirable outcome of minimal clinical manifestation or better, 55% of patients were able to come off prednisone entirely, and 75% were taking less than 7.5 mg of prednisone per day.⁴⁵

Common side effects of mycophenolate include nausea, diarrhea, and infections such as urinary tract infections and herpes reactivation. The complete blood cell count needs to be monitored frequently during the first 6 months of therapy. Leukopenia can occur but rarely necessitates stopping mycophenolate. Long-term safety data are lacking, but so far there has been no clearly increased risk of malignancy.

Mycophenolate exposure in pregnancy results in a high incidence of major fetal malformations. Therefore, its use in pregnant patients is discouraged, and women of child-bearing age should use effective contraception.⁴⁶

Cyclosporine

A randomized trial in a small number of patients suggested that cyclosporine is fairly effective as monotherapy.⁴⁷ Its onset of action in myasthenia gravis is faster than that of other corticosteroid-sparing agents, and clinical benefit can often be observed as early as 1 to 2 months. A dose of 5 mg/kg/day and a maintenance serum level of 100 to 150 ng/mL are generally recommended. However, renal, hepatic, and hematologic toxicities and interactions with other medications make cyclosporine a less attractive choice.

Methotrexate

A randomized trial evaluated the utility of methotrexate as a steroid-sparing agent compared with azathioprine.⁴⁸ At 24 months, its steroid-sparing effect was similar to that of azathioprine, and the prednisone dosage had been reduced in more than 50% of patients.

Another phase II trial studying the efficacy of methotrexate in myasthenia gravis is under way.⁴⁹

Rituximab

Rituximab is a monoclonal antibody against B-cell membrane marker CD20. A growing number of case series support its efficacy in patients with severe generalized myasthenia gravis refractory to multiple immunosuppressants.^16,50 It seems particularly effective for MuSK antibody-positive disease, reducing MuSK antibody titers and having a treatment effect that lasts for years.

The standard dosage is 375 mg/m² per week for 4 consecutive weeks. Peripheral B cells tend to be depleted within 2 weeks after the first infusion, while T-cell populations remain unchanged.⁵⁰

A minimal infusion reaction such as flushing and chills can be seen with the first infusion. Patients may be more susceptible to certain infections such as reactivation of herpes zoster, but overall rituximab is well tolerated. Rare cases of progressive multifocal leukoencephalopathy have been reported in patients taking it, but none have occurred so far in myasthenia gravis treatment.

Cyclophosphamide

Cyclophosphamide is an alkylating agent that reduces proliferation of both B and T cells. It can be effective in myasthenia gravis, but potentially serious side effects limit its use. It should be reserved for the small percentage of cases that are refractory to other immunotherapies.

Thymectomy

Surgical treatment should be considered for patients with thymoma. If the tumor cannot be surgically resected, chemoradiotherapy can be considered for relief of myasthenic symptoms and for prevention of local invasion.

Thymomas recur in a minority of patients many years after the initial resection, sometimes without myasthenia gravis symptoms. A recurrence of symptoms does not necessarily indicate a recurrence of thymoma. The lack of correlation between myasthenia gravis symptoms and thymoma recurrence highlights the importance of radiologic follow-up in these patients.

For patients without thymoma, many experts believe that thymectomy is beneficial in patients under age 60 who have generalized myasthenia gravis. The likelihood of medication-free remission is about twice as high, and the likelihood of becoming asymptomatic is about one and a half times higher after thymectomy.⁵¹ However, it takes up to several years for the benefits of thymectomy to manifest, and thymectomy does not guarantee protection from developing AChR antibody-positive myasthenia gravis in the future.

The optimal timing of thymectomy is not well established; however, the procedure is usually recommended within the first 3 years of diagnosis.⁵² The response rates from thymectomy are similar for AChR antibody-positive and seronegative patients. In general, thymectomy for MuSK antibody-positive patients has not been effective, and its role in ocular myasthenia gravis is unclear.^2,53

Current therapies for myasthenia gravis can help most patients achieve sustained improvement. The overall prognosis has dramatically improved over the last 4 decades: the mortality rate used to be 75%; now it is 4.5%.¹

Myasthenia gravis is the most common disorder of neuromuscular junction transmission and is also one of the best characterized autoimmune diseases. However, its symptoms—primarily weakness—vary from patient to patient, and in the same patient, by time of day and over longer time periods. The variation in symptoms can be very confusing to undiagnosed patients and puzzling to unsuspecting physicians. Such diagnostic uncertainty can give the patient additional frustration and emotional stress, which in turn exacerbate his or her condition.

In this review, we will give an overview of the pathogenesis, clinical manifestations, diagnosis, and treatment of myasthenia gravis.

TWO PEAKS IN INCIDENCE BY AGE

The annual incidence of myasthenia gravis is approximately 10 to 20 new cases per million, with a prevalence of about 150 to 200 per million.²

The age of onset has a bimodal distribution, with an early incidence peak in the second to third decade with a female predominance and a late peak in the 6th to the 8th decade with a male predominance.²

Myasthenia gravis is commonly associated with several other autoimmune disorders, including hypothyroidism, hyperthyroidism, systemic lupus erythematosus, rheumatoid arthritis, vitiligo, diabetes, and, more recently recognized, neuromyelitis optica.³

ANTIBODIES AGAINST AChR AND MuSK

In most cases of myasthenia gravis the patient has autoimmune antibodies against constituents of the neuromuscular junction, specifically acetylcholine receptor (AChR) and muscle-specific tyrosine kinase (MuSK) (Figure 1).

AChR antibody-positive myasthenia gravis

When antibodies bind to AChR on the postsynaptic membrane, they cross-link neighboring AChR units, which are absorbed into the muscle fiber and are broken up.⁴ In addition, the complement system is activated to mediate further damage on the postsynaptic membrane.

AChR antibodies may come from germinal centers of the thymus, where clustered myoid cells express AChR on the plasma membrane surface.⁵ About 60% of AChR antibody-positive myasthenia gravis patients have an enlarged thymus, and 10% have a thymoma—a tumor of the epithelial cells of this organ. Conversely, about 15% of patients with a thymoma have clinical myasthenia gravis, and an additional 20% possess antibodies against AChR in the serum without myasthenic symptoms.⁵

MuSK antibody-positive myasthenia gravis

Like AChR, MuSK is a transmembrane component of the postsynaptic neuromuscular junction. During formation of the neuromuscular junction, MuSK is activated through the binding of agrin (a nerve-derived proteoglycan) to lipoprotein-related protein 4 (LRP4), after which complicated intracellular signaling promotes the assembly and stabilization of AChR.⁶

Unlike AChR antibodies, antibodies against MuSK do not activate the complement system, and complement fixation is not essential for clinical myasthenic symptoms to appear.⁷ Also, myasthenia gravis with MuSK antibodies is rarely associated with thymoma.⁸

The precise mechanism by which MuSK antibody impairs transmission at the neuromuscular junction has been a mystery until recently. Animal models, including MuSK-mutant mice and mice injected with MuSK protein or with purified immunoglobulin G from patients with this disease, have revealed a significant reduction of AChR clusters and destruction of neuromuscular junction structures.^7,9–12

In addition, MuSK antibodies produce pre-synaptic dysfunction, manifesting as a reduction of acetylcholine content. This information is based on studies in mice and on in vitro electrophysiologic analyses of neuromuscular junctions from a patient with this disease.^7,9–13

Finally, MuSK antibodies may indirectly affect the recycling of acetylcholine. After post-synaptic activation, acetylcholine is normally hydrolized by acetylcholinesterase, which is located in the synaptic cleft but anchored to MuSK on the postsynaptic membrane. MuSK antibodies block the binding of MuSK to acetylcholinesterase, possibly leading to less accumulation of acetylcholinesterase.¹⁴ This process may explain why patients with MuSK antibody-positive myasthenia gravis tend to respond poorly to acetylcholinesterase inhibitors (more about this below).

In a series of 562 consecutive patients with generalized weakness due to myasthenia gravis, 92% were positive for AChR antibody, 3% were positive for MuSK antibody, and 5% were seronegative (possessing neither antibody).¹⁵ In contrast, about 50% of patients with purely ocular myasthenia gravis (ie, with isolated weakness of the levator palpebrae superioris, orbicularis oculi, or oculomotor muscles) are seropositive for AChR antibody. Only a few ocular MuSK antibody-positive cases have been described, leaving the rest seronegative. Rarely, both antibodies can be detected in the same patient.¹⁶

In patients who are negative for AChR antibodies at the time of disease onset, sero-conversion may occur later during the course. Repeating serologic testing 6 to 12 months later may detect AChR antibodies in approximately 15% of patients who were initially seronegative.^15,17

The clinical presentation, electrophysiologic findings, thymic pathologic findings, and treatment responses are similar in AChR antibody-positive and seronegative myasthenia gravis.¹⁷ Muscle biopsy study in seronegative cases demonstrates a loss of AChR as well.¹⁸

Based on these observations, it has been proposed that seronegative patients may have low-affinity antibodies that can bind to tightly clustered AChRs on the postsynaptic membrane but escape detection by routine radioimmunoassays in a solution phase. With a sensitive cell-based immunofluorescence assay, low-affinity antibodies to clustered AChRs were detected in 66% of patients with generalized myasthenia gravis and in 50% of those with ocular myasthenia gravis who were seronegative on standard assays.^19,20 These low-affinity AChR antibodies can also activate complement in vitro, increasing the likelihood that they are pathogenic. However, assays to detect low-affinity AChR antibodies are not yet commercially available.

Within the past year, three research groups independently reported detecting antibodies to LRP4 in 2% to 50% of seronegative myasthenia gravis patients. This wide variation in the prevalence of LRP4 antibodies could be related to patient ethnicity and methods of detection.^21–23 LRP4 is a receptor for agrin and is required for agrin-induced MuSK activation and AChR clustering. LRP antibodies can activate complement; therefore, it is plausible that LRP4 antibody binding leads to AChR loss on the postsynaptic membrane. However, additional study is needed to determine if LRP4 antibodies are truly pathogenic in myasthenia gravis.

A DISORDER OF FATIGABLE WEAKNESS

Myasthenia gravis is a disorder of fatigable weakness producing fluctuating symptoms. Symptoms related to the involvement of specific muscle groups are listed in Table 1. Muscle weakness is often worse later in the day or after exercise.

Ocular myasthenia gravis accounts for about 15% of all cases. Of patients initially presenting with ocular symptoms only, twothirds will ultimately develop generalized symptoms, most within the first 2 years.²⁴ No factor has been identified that predicts conversion from an ocular to a generalized form.

Several clinical phenotypes of MuSK antibody-positive myasthenia gravis have been described. An oculobulbar form presents with diplopia, ptosis, dysarthria, and profound atrophy of the muscles of the tongue and face. A restricted myopathic form presents with prominent neck, shoulder, and respiratory weakness without ocular involvement. A third form is a combination of ocular and proximal limb weakness, indistinguishable from AChR antibody-positive disease.²⁵

MuSK antibody-positive patients do not respond as well to acetylcholinesterase inhibitors as AChR antibody-positive patients do. In one study, nearly 70% of MuSK antibody-positive patients demonstrated no response, poor tolerance, or cholinergic hypersensitivity to these agents.²⁵ Fortunately, most MuSK antibody-positive patients have a favorable response to immunosuppressive therapy—sometimes a dramatic improvement after plasmapheresis.⁸

DIAGNOSIS OF MYASTHENIA GRAVIS

The common differential diagnoses for myasthenia gravis are listed in Table 2.

The essential feature of myasthenia gravis is fluctuating muscle weakness, often with fatigue. Many patients complain of weakness of specific muscle groups after their repeated usage. Pain is generally a less conspicuous symptom, and generalized fatigue without objective weakness is inconsistent with myasthenia gravis.

Signs of muscle weakness may include droopy eyelids, diplopia, inability to hold the head straight, difficulty swallowing or chewing, speech disturbances, difficulty breathing, and difficulty raising the arms or rising from the sitting position. A historical pattern of ptosis alternating from one eye to the other is fairly characteristic of myasthenia gravis.

The weakness of orbicularis oculi is easily identified on examination by prying open the eyes during forced eye closure. Limb weakness is usually more significant in the arms than in the legs. An often-neglected feature of myasthenia gravis is finger extensor weakness with a relative sparing of other distal hand muscles.²

The ice-pack test is performed by placing a small bag of ice over the ptotic eye for 2 to 5 minutes and assessing the degree of ptosis for any noticeable improvement. This test is not very helpful for assessing ocular motor weakness.

The edrophonium (Tensilon) test can be used for patients with ptosis or ophthalmoparesis. Edrophonium, a short-acting acetylcholinesterase inhibitor, is given intravenously while the patient is observed for objective improvement. The patient’s cardiovascular status should be monitored for arrhythmias and hypotension. Atropine should be immediately available in case severe bradycardia develops.

The ice-pack test and the edrophonium test can give false-negative and false-positive results, and the diagnosis of myasthenia gravis must be verified by other diagnostic tests.

Testing for circulating AChR antibodies, MuSK antibodies, or both is the first step in the laboratory confirmation of myasthenia gravis.

There are three AChR antibody subtypes: binding, blocking, and modulating. Binding antibodies are present in 80% to 90% of patients with generalized myasthenia gravis and 50% of those with ocular myasthenia gravis. Testing for blocking and modulating AChR antibodies increases the sensitivity by less than 5% when added to testing for binding antibodies.

AChR antibody titers correlate poorly with disease severity between patients. However, in individual patients, antibody titers tend to go down in parallel with clinical improvement.

MuSK antibody is detected in nearly half of myasthenia gravis patients with generalized weakness who are negative for AChR antibody.

Electrophysiologic tests

Electrophysiologic tests can usually confirm the diagnosis of seronegative myasthenia gravis. They are also helpful in seropositive patients who have unusual clinical features or a poor response to treatment.

Repetitive nerve stimulation studies use a slow rate (2–5 Hz) of repetitive electrical stimulation. The study is positive if the motor response declines by more than 10%. However, a decremental response is not specific for myasthenia gravis, as it may be seen in other neuromuscular disorders such as motor neuron disease or Lambert-Eaton myasthenic syndrome.

This test is technically easier to do in distal muscles than in proximal muscles, but less sensitive. Therefore, proximal muscles such as the trapezius or facial muscles are usually also sampled to maximize the yield. To further maximize the sensitivity, muscles being tested should be warm, and acetylcholinesterase inhibitors should be withheld for 12 hours before.

Repetitive nerve stimulation studies in distal muscles are positive in approximately 75% of patients with generalized myasthenia gravis and in 30% with ocular myasthenia gravis.²⁶

Single-fiber electromyography is more technically demanding than repetitive nerve stimulation and is less widely available. It is usually performed with a special needle electrode that can simultaneously identify action potentials arising from individual muscle fibers innervated by the same axon.

Variability in time of the second action potential relative to the first is called “jitter.” Abnormal jitter is seen in more than 95% of patients with generalized myasthenia gravis and in 85% to 90% of those with ocular myasthenia gravis.^26,27 However, abnormal jitter can also be seen in other neuromuscular diseases such as motor neuron disease or in neuromuscular junctional disorders such as Lambert-Eaton myasthenic syndrome.

Imaging studies

Chest computed tomography or magnetic resonance imaging with contrast should be performed in all myasthenia gravis patients to look for a thymoma.

TREATMENT OF MYASTHENIA GRAVIS

Acetylcholinesterase inhibitors

As a reasonable first therapy in mild cases of myasthenia gravis, acetylcholinesterase inhibitors slow down the degradation of acetylcholine and prolong its effect in the neuromuscular junction, but they are not disease-modifying and their benefits are mild.

Pyridostigmine is the usual choice of acetylcholinesterase inhibitor. Its onset of action is rapid (15 to 30 minutes) and its action lasts for 3 to 4 hours. For most patients, the effective dosage range is 60 mg to 90 mg every 4 to 6 hours. A long-acting form is also available and can be given as a single nighttime dose.

Immunomodulating therapy

Patients who have moderate to severe symptoms require some form of immunomodulating therapy.

Plasmapheresis or intravenous immune globulin is reserved for patients with severe or rapidly worsening disease because their beneficial effects can be seen within the first week of treatment.

Longer-acting immunotherapies (corticosteroids, azathioprine, mycophenolate mofetil and others) have a slower onset of responses but provide sustained benefits. Which drug to use depends on factors such as comorbidity, side effects, and cost.

Drugs to avoid

A number of medications can exacerbate weakness in myasthenia gravis and should be avoided or used with caution. The list is long, but ones that deserve the most attention are penicillamine, interferons, procainamide, quinidine, and antibiotics, including quinolones and aminoglycosides. A more comprehensive list of medications that may exacerbate myasthenia gravis symptoms can be found in a review by Keesey.²

RAPID INDUCTION IMMUNOTHERAPIES : PLASMAPHERESIS, IMMUNE GLOBULIN

Both plasmapheresis and intravenous immune globulin act quickly over days, but in most patients their effects last only a few weeks. Both are used as rescue therapies for myasthenic crises, bridging therapy to slow-acting immunotherapeutic agents, or maintenance treatment for poorly controlled cases.

Several retrospective studies have confirmed the efficacy of plasmapheresis in more than 80% of patients with generalized symptoms.^28,29

In a randomized trial in patients with generalized therapies, intravenous immune globulin improved muscle strength in the group of patients with severe symptoms.³⁰ The effective dosage of intravenous immune globulin varies from 1 to 2 g/kg without observed difference between doses.³¹ Trials comparing the efficacy of intravenous immune globulin and plasmapheresis in acute and severe myasthenia gravis did not reveal a difference in efficacy.^32,33 Intravenous immune globulin at a minimal dose of 0.4 g/kg every 3 months has been successfully used as a long-term maintenance monotherapy, and such a role could be expanded to more patients with further studies.³⁴

The choice between plasmapheresis and intravenous immune globulin is often based on the ability of a patient to tolerate each treatment and on the availability of the plasmapheresis procedure. Intravenous immune globulin is easier to administer, is associated with fewer adverse events related to vascular access, and is therefore more appropriate than plasmapheresis in some centers.

CHRONIC MAINTENANCE IMMUNOMODULATING TREATMENT

Corticosteroids

Prednisone, the most commonly used agent, leads to remission or marked improvement in 70% to 80% of patients with ocular or generalized myasthenia gravis.³⁵ It may also reduce the progression of ocular myasthenia gravis to the generalized form.³⁶

The effective dose of prednisone depends on the severity and distribution of symptoms. Some patients may need up to 1.0 mg/kg/day (usually 50 to 80 mg per day). In patients with mild to moderate symptoms, a lower maximal dosage such as 20 to 40 mg per day can be sufficient.

Within 1 to 2 weeks after starting high-dose prednisone, up to 50% of patients may develop a transient deterioration, including possible precipitation of a myasthenic crisis.³⁷ For this reason, high-dose prednisone is commonly started only in hospitalized patients who are also receiving plasmapheresis or intravenous immune globulin. Otherwise, an outpatient dose-escalation protocol can be used to achieve a target dose over several weeks.

Prednisone tapering can begin after the patient has been on the maximal dose for 1 to 2 months and significant improvement is evident. A monthly tapering of 5 to 10 mg is preferred, then more slowly after the daily dose reaches 30 mg. The usual maintenance dose averages about 5 mg daily.

Common side effects of prednisone include weight gain, cushingoid features, easy bruising, cataracts, glaucoma, hypertension, diabetes, dyslipidemia, and osteoporosis. Patients are advised to take supplemental calcium (1,500 mg per day) and vitamin D (400 to 800 IU per day). For those most at risk of osteoporosis, treatment with a bisphosphonate should be considered.

Other immunotherapeutic agents are often needed, either to replace the corticosteroid or to permit use of lower doses of it. Because of their delayed onset of action, starting such corticosteroid-sparing agents early in the course is often necessary. These agents are often initially combined with high-dose prednisone, with an eventual goal of weaning off prednisone entirely. This strategy offers the advantage of relatively rapid induction while avoiding the long-term adverse effects of corticosteroid treatment.

Azathioprine

Azathioprine doesn’t begin to show a beneficial effect in myasthenia gravis for 6 to 12 months, and it often reaches its maximal efficacy only after 1 to 2 years of treatment.³⁸

In a study of 78 myasthenia gravis patients, 91% improved when treated with azathioprine alone or together with prednisone.³⁹ In another study using azathioprine and prednisolone for generalized myasthenia gravis, nearly two-thirds of patients came off prednisolone while maintaining remission for 3 years.³⁸

A typical maintenance dose is 2 to 3 mg/kg/day. Common side effects are nausea, vomiting, and malaise. Less frequent side effects include hematologic abnormalities, abnormal liver function, and pancreatitis. Monthly monitoring of complete blood cell counts and liver function tests is warranted for the first 6 months, then less often.

One in 300 people in the general population is homozygous for a mutant allele in the thiopurine methyltransferase (TPMT) gene. Patients with this genotype should not receive azathioprine because of the risk of life-threatening bone marrow suppression.⁴⁰ A slightly increased risk of various forms of lymphoma has been documented.⁴¹

A well-tolerated medication with few side effects, mycophenolate mofetil is being used more in myasthenia gravis. The results of two recent randomized trials suggested that it is not effective in improving myasthenia gravis symptoms or sparing prednisone dosage when used for 90 days or 36 weeks.^42,43 However, extensive clinical experience supports its longterm efficacy in myasthenia gravis.

In a retrospective study of 85 patients with generalized myasthenia gravis, mycophenolate at doses of 1 to 3 g daily improved symptoms in 73% and produced remission in 50%. Steroid dosage was reduced in 71% of patients.⁴⁴

Another retrospective study, with 102 patients, verified a slow development of clinical benefit after months of mycophenolate therapy alone or in combination with prednisone. Approximately 50% of patients achieved a minimal manifestation status after 6 to 12 months of mycophenolate treatment. Eventually, at 24 months of treatment, 80% of patients had a desirable outcome of minimal clinical manifestation or better, 55% of patients were able to come off prednisone entirely, and 75% were taking less than 7.5 mg of prednisone per day.⁴⁵

Common side effects of mycophenolate include nausea, diarrhea, and infections such as urinary tract infections and herpes reactivation. The complete blood cell count needs to be monitored frequently during the first 6 months of therapy. Leukopenia can occur but rarely necessitates stopping mycophenolate. Long-term safety data are lacking, but so far there has been no clearly increased risk of malignancy.

Mycophenolate exposure in pregnancy results in a high incidence of major fetal malformations. Therefore, its use in pregnant patients is discouraged, and women of child-bearing age should use effective contraception.⁴⁶

Cyclosporine

A randomized trial in a small number of patients suggested that cyclosporine is fairly effective as monotherapy.⁴⁷ Its onset of action in myasthenia gravis is faster than that of other corticosteroid-sparing agents, and clinical benefit can often be observed as early as 1 to 2 months. A dose of 5 mg/kg/day and a maintenance serum level of 100 to 150 ng/mL are generally recommended. However, renal, hepatic, and hematologic toxicities and interactions with other medications make cyclosporine a less attractive choice.

Methotrexate

A randomized trial evaluated the utility of methotrexate as a steroid-sparing agent compared with azathioprine.⁴⁸ At 24 months, its steroid-sparing effect was similar to that of azathioprine, and the prednisone dosage had been reduced in more than 50% of patients.

Another phase II trial studying the efficacy of methotrexate in myasthenia gravis is under way.⁴⁹

Rituximab

Rituximab is a monoclonal antibody against B-cell membrane marker CD20. A growing number of case series support its efficacy in patients with severe generalized myasthenia gravis refractory to multiple immunosuppressants.^16,50 It seems particularly effective for MuSK antibody-positive disease, reducing MuSK antibody titers and having a treatment effect that lasts for years.

The standard dosage is 375 mg/m² per week for 4 consecutive weeks. Peripheral B cells tend to be depleted within 2 weeks after the first infusion, while T-cell populations remain unchanged.⁵⁰

A minimal infusion reaction such as flushing and chills can be seen with the first infusion. Patients may be more susceptible to certain infections such as reactivation of herpes zoster, but overall rituximab is well tolerated. Rare cases of progressive multifocal leukoencephalopathy have been reported in patients taking it, but none have occurred so far in myasthenia gravis treatment.

Cyclophosphamide

Cyclophosphamide is an alkylating agent that reduces proliferation of both B and T cells. It can be effective in myasthenia gravis, but potentially serious side effects limit its use. It should be reserved for the small percentage of cases that are refractory to other immunotherapies.

Thymectomy

Surgical treatment should be considered for patients with thymoma. If the tumor cannot be surgically resected, chemoradiotherapy can be considered for relief of myasthenic symptoms and for prevention of local invasion.

Thymomas recur in a minority of patients many years after the initial resection, sometimes without myasthenia gravis symptoms. A recurrence of symptoms does not necessarily indicate a recurrence of thymoma. The lack of correlation between myasthenia gravis symptoms and thymoma recurrence highlights the importance of radiologic follow-up in these patients.

For patients without thymoma, many experts believe that thymectomy is beneficial in patients under age 60 who have generalized myasthenia gravis. The likelihood of medication-free remission is about twice as high, and the likelihood of becoming asymptomatic is about one and a half times higher after thymectomy.⁵¹ However, it takes up to several years for the benefits of thymectomy to manifest, and thymectomy does not guarantee protection from developing AChR antibody-positive myasthenia gravis in the future.

The optimal timing of thymectomy is not well established; however, the procedure is usually recommended within the first 3 years of diagnosis.⁵² The response rates from thymectomy are similar for AChR antibody-positive and seronegative patients. In general, thymectomy for MuSK antibody-positive patients has not been effective, and its role in ocular myasthenia gravis is unclear.^2,53

Current therapies for myasthenia gravis can help most patients achieve sustained improvement. The overall prognosis has dramatically improved over the last 4 decades: the mortality rate used to be 75%; now it is 4.5%.¹

Myasthenia gravis is the most common disorder of neuromuscular junction transmission and is also one of the best characterized autoimmune diseases. However, its symptoms—primarily weakness—vary from patient to patient, and in the same patient, by time of day and over longer time periods. The variation in symptoms can be very confusing to undiagnosed patients and puzzling to unsuspecting physicians. Such diagnostic uncertainty can give the patient additional frustration and emotional stress, which in turn exacerbate his or her condition.

In this review, we will give an overview of the pathogenesis, clinical manifestations, diagnosis, and treatment of myasthenia gravis.

TWO PEAKS IN INCIDENCE BY AGE

The annual incidence of myasthenia gravis is approximately 10 to 20 new cases per million, with a prevalence of about 150 to 200 per million.²

The age of onset has a bimodal distribution, with an early incidence peak in the second to third decade with a female predominance and a late peak in the 6th to the 8th decade with a male predominance.²

Myasthenia gravis is commonly associated with several other autoimmune disorders, including hypothyroidism, hyperthyroidism, systemic lupus erythematosus, rheumatoid arthritis, vitiligo, diabetes, and, more recently recognized, neuromyelitis optica.³

ANTIBODIES AGAINST AChR AND MuSK

In most cases of myasthenia gravis the patient has autoimmune antibodies against constituents of the neuromuscular junction, specifically acetylcholine receptor (AChR) and muscle-specific tyrosine kinase (MuSK) (Figure 1).

AChR antibody-positive myasthenia gravis

When antibodies bind to AChR on the postsynaptic membrane, they cross-link neighboring AChR units, which are absorbed into the muscle fiber and are broken up.⁴ In addition, the complement system is activated to mediate further damage on the postsynaptic membrane.

AChR antibodies may come from germinal centers of the thymus, where clustered myoid cells express AChR on the plasma membrane surface.⁵ About 60% of AChR antibody-positive myasthenia gravis patients have an enlarged thymus, and 10% have a thymoma—a tumor of the epithelial cells of this organ. Conversely, about 15% of patients with a thymoma have clinical myasthenia gravis, and an additional 20% possess antibodies against AChR in the serum without myasthenic symptoms.⁵

MuSK antibody-positive myasthenia gravis

Like AChR, MuSK is a transmembrane component of the postsynaptic neuromuscular junction. During formation of the neuromuscular junction, MuSK is activated through the binding of agrin (a nerve-derived proteoglycan) to lipoprotein-related protein 4 (LRP4), after which complicated intracellular signaling promotes the assembly and stabilization of AChR.⁶

Unlike AChR antibodies, antibodies against MuSK do not activate the complement system, and complement fixation is not essential for clinical myasthenic symptoms to appear.⁷ Also, myasthenia gravis with MuSK antibodies is rarely associated with thymoma.⁸

The precise mechanism by which MuSK antibody impairs transmission at the neuromuscular junction has been a mystery until recently. Animal models, including MuSK-mutant mice and mice injected with MuSK protein or with purified immunoglobulin G from patients with this disease, have revealed a significant reduction of AChR clusters and destruction of neuromuscular junction structures.^7,9–12

In addition, MuSK antibodies produce pre-synaptic dysfunction, manifesting as a reduction of acetylcholine content. This information is based on studies in mice and on in vitro electrophysiologic analyses of neuromuscular junctions from a patient with this disease.^7,9–13

Finally, MuSK antibodies may indirectly affect the recycling of acetylcholine. After post-synaptic activation, acetylcholine is normally hydrolized by acetylcholinesterase, which is located in the synaptic cleft but anchored to MuSK on the postsynaptic membrane. MuSK antibodies block the binding of MuSK to acetylcholinesterase, possibly leading to less accumulation of acetylcholinesterase.¹⁴ This process may explain why patients with MuSK antibody-positive myasthenia gravis tend to respond poorly to acetylcholinesterase inhibitors (more about this below).

In a series of 562 consecutive patients with generalized weakness due to myasthenia gravis, 92% were positive for AChR antibody, 3% were positive for MuSK antibody, and 5% were seronegative (possessing neither antibody).¹⁵ In contrast, about 50% of patients with purely ocular myasthenia gravis (ie, with isolated weakness of the levator palpebrae superioris, orbicularis oculi, or oculomotor muscles) are seropositive for AChR antibody. Only a few ocular MuSK antibody-positive cases have been described, leaving the rest seronegative. Rarely, both antibodies can be detected in the same patient.¹⁶

In patients who are negative for AChR antibodies at the time of disease onset, sero-conversion may occur later during the course. Repeating serologic testing 6 to 12 months later may detect AChR antibodies in approximately 15% of patients who were initially seronegative.^15,17

The clinical presentation, electrophysiologic findings, thymic pathologic findings, and treatment responses are similar in AChR antibody-positive and seronegative myasthenia gravis.¹⁷ Muscle biopsy study in seronegative cases demonstrates a loss of AChR as well.¹⁸

Based on these observations, it has been proposed that seronegative patients may have low-affinity antibodies that can bind to tightly clustered AChRs on the postsynaptic membrane but escape detection by routine radioimmunoassays in a solution phase. With a sensitive cell-based immunofluorescence assay, low-affinity antibodies to clustered AChRs were detected in 66% of patients with generalized myasthenia gravis and in 50% of those with ocular myasthenia gravis who were seronegative on standard assays.^19,20 These low-affinity AChR antibodies can also activate complement in vitro, increasing the likelihood that they are pathogenic. However, assays to detect low-affinity AChR antibodies are not yet commercially available.

Within the past year, three research groups independently reported detecting antibodies to LRP4 in 2% to 50% of seronegative myasthenia gravis patients. This wide variation in the prevalence of LRP4 antibodies could be related to patient ethnicity and methods of detection.^21–23 LRP4 is a receptor for agrin and is required for agrin-induced MuSK activation and AChR clustering. LRP antibodies can activate complement; therefore, it is plausible that LRP4 antibody binding leads to AChR loss on the postsynaptic membrane. However, additional study is needed to determine if LRP4 antibodies are truly pathogenic in myasthenia gravis.

A DISORDER OF FATIGABLE WEAKNESS

Myasthenia gravis is a disorder of fatigable weakness producing fluctuating symptoms. Symptoms related to the involvement of specific muscle groups are listed in Table 1. Muscle weakness is often worse later in the day or after exercise.

Ocular myasthenia gravis accounts for about 15% of all cases. Of patients initially presenting with ocular symptoms only, twothirds will ultimately develop generalized symptoms, most within the first 2 years.²⁴ No factor has been identified that predicts conversion from an ocular to a generalized form.

Several clinical phenotypes of MuSK antibody-positive myasthenia gravis have been described. An oculobulbar form presents with diplopia, ptosis, dysarthria, and profound atrophy of the muscles of the tongue and face. A restricted myopathic form presents with prominent neck, shoulder, and respiratory weakness without ocular involvement. A third form is a combination of ocular and proximal limb weakness, indistinguishable from AChR antibody-positive disease.²⁵

MuSK antibody-positive patients do not respond as well to acetylcholinesterase inhibitors as AChR antibody-positive patients do. In one study, nearly 70% of MuSK antibody-positive patients demonstrated no response, poor tolerance, or cholinergic hypersensitivity to these agents.²⁵ Fortunately, most MuSK antibody-positive patients have a favorable response to immunosuppressive therapy—sometimes a dramatic improvement after plasmapheresis.⁸

DIAGNOSIS OF MYASTHENIA GRAVIS

The common differential diagnoses for myasthenia gravis are listed in Table 2.

The essential feature of myasthenia gravis is fluctuating muscle weakness, often with fatigue. Many patients complain of weakness of specific muscle groups after their repeated usage. Pain is generally a less conspicuous symptom, and generalized fatigue without objective weakness is inconsistent with myasthenia gravis.

Signs of muscle weakness may include droopy eyelids, diplopia, inability to hold the head straight, difficulty swallowing or chewing, speech disturbances, difficulty breathing, and difficulty raising the arms or rising from the sitting position. A historical pattern of ptosis alternating from one eye to the other is fairly characteristic of myasthenia gravis.

The weakness of orbicularis oculi is easily identified on examination by prying open the eyes during forced eye closure. Limb weakness is usually more significant in the arms than in the legs. An often-neglected feature of myasthenia gravis is finger extensor weakness with a relative sparing of other distal hand muscles.²

The ice-pack test is performed by placing a small bag of ice over the ptotic eye for 2 to 5 minutes and assessing the degree of ptosis for any noticeable improvement. This test is not very helpful for assessing ocular motor weakness.

The edrophonium (Tensilon) test can be used for patients with ptosis or ophthalmoparesis. Edrophonium, a short-acting acetylcholinesterase inhibitor, is given intravenously while the patient is observed for objective improvement. The patient’s cardiovascular status should be monitored for arrhythmias and hypotension. Atropine should be immediately available in case severe bradycardia develops.

The ice-pack test and the edrophonium test can give false-negative and false-positive results, and the diagnosis of myasthenia gravis must be verified by other diagnostic tests.

Testing for circulating AChR antibodies, MuSK antibodies, or both is the first step in the laboratory confirmation of myasthenia gravis.

There are three AChR antibody subtypes: binding, blocking, and modulating. Binding antibodies are present in 80% to 90% of patients with generalized myasthenia gravis and 50% of those with ocular myasthenia gravis. Testing for blocking and modulating AChR antibodies increases the sensitivity by less than 5% when added to testing for binding antibodies.

AChR antibody titers correlate poorly with disease severity between patients. However, in individual patients, antibody titers tend to go down in parallel with clinical improvement.

MuSK antibody is detected in nearly half of myasthenia gravis patients with generalized weakness who are negative for AChR antibody.

Electrophysiologic tests

Electrophysiologic tests can usually confirm the diagnosis of seronegative myasthenia gravis. They are also helpful in seropositive patients who have unusual clinical features or a poor response to treatment.

Repetitive nerve stimulation studies use a slow rate (2–5 Hz) of repetitive electrical stimulation. The study is positive if the motor response declines by more than 10%. However, a decremental response is not specific for myasthenia gravis, as it may be seen in other neuromuscular disorders such as motor neuron disease or Lambert-Eaton myasthenic syndrome.

This test is technically easier to do in distal muscles than in proximal muscles, but less sensitive. Therefore, proximal muscles such as the trapezius or facial muscles are usually also sampled to maximize the yield. To further maximize the sensitivity, muscles being tested should be warm, and acetylcholinesterase inhibitors should be withheld for 12 hours before.

Repetitive nerve stimulation studies in distal muscles are positive in approximately 75% of patients with generalized myasthenia gravis and in 30% with ocular myasthenia gravis.²⁶

Single-fiber electromyography is more technically demanding than repetitive nerve stimulation and is less widely available. It is usually performed with a special needle electrode that can simultaneously identify action potentials arising from individual muscle fibers innervated by the same axon.

Variability in time of the second action potential relative to the first is called “jitter.” Abnormal jitter is seen in more than 95% of patients with generalized myasthenia gravis and in 85% to 90% of those with ocular myasthenia gravis.^26,27 However, abnormal jitter can also be seen in other neuromuscular diseases such as motor neuron disease or in neuromuscular junctional disorders such as Lambert-Eaton myasthenic syndrome.

Imaging studies

Chest computed tomography or magnetic resonance imaging with contrast should be performed in all myasthenia gravis patients to look for a thymoma.

TREATMENT OF MYASTHENIA GRAVIS

Acetylcholinesterase inhibitors

As a reasonable first therapy in mild cases of myasthenia gravis, acetylcholinesterase inhibitors slow down the degradation of acetylcholine and prolong its effect in the neuromuscular junction, but they are not disease-modifying and their benefits are mild.

Pyridostigmine is the usual choice of acetylcholinesterase inhibitor. Its onset of action is rapid (15 to 30 minutes) and its action lasts for 3 to 4 hours. For most patients, the effective dosage range is 60 mg to 90 mg every 4 to 6 hours. A long-acting form is also available and can be given as a single nighttime dose.

Immunomodulating therapy

Patients who have moderate to severe symptoms require some form of immunomodulating therapy.

Plasmapheresis or intravenous immune globulin is reserved for patients with severe or rapidly worsening disease because their beneficial effects can be seen within the first week of treatment.

Longer-acting immunotherapies (corticosteroids, azathioprine, mycophenolate mofetil and others) have a slower onset of responses but provide sustained benefits. Which drug to use depends on factors such as comorbidity, side effects, and cost.

Drugs to avoid

A number of medications can exacerbate weakness in myasthenia gravis and should be avoided or used with caution. The list is long, but ones that deserve the most attention are penicillamine, interferons, procainamide, quinidine, and antibiotics, including quinolones and aminoglycosides. A more comprehensive list of medications that may exacerbate myasthenia gravis symptoms can be found in a review by Keesey.²

RAPID INDUCTION IMMUNOTHERAPIES : PLASMAPHERESIS, IMMUNE GLOBULIN

Both plasmapheresis and intravenous immune globulin act quickly over days, but in most patients their effects last only a few weeks. Both are used as rescue therapies for myasthenic crises, bridging therapy to slow-acting immunotherapeutic agents, or maintenance treatment for poorly controlled cases.

Several retrospective studies have confirmed the efficacy of plasmapheresis in more than 80% of patients with generalized symptoms.^28,29

In a randomized trial in patients with generalized therapies, intravenous immune globulin improved muscle strength in the group of patients with severe symptoms.³⁰ The effective dosage of intravenous immune globulin varies from 1 to 2 g/kg without observed difference between doses.³¹ Trials comparing the efficacy of intravenous immune globulin and plasmapheresis in acute and severe myasthenia gravis did not reveal a difference in efficacy.^32,33 Intravenous immune globulin at a minimal dose of 0.4 g/kg every 3 months has been successfully used as a long-term maintenance monotherapy, and such a role could be expanded to more patients with further studies.³⁴

The choice between plasmapheresis and intravenous immune globulin is often based on the ability of a patient to tolerate each treatment and on the availability of the plasmapheresis procedure. Intravenous immune globulin is easier to administer, is associated with fewer adverse events related to vascular access, and is therefore more appropriate than plasmapheresis in some centers.

CHRONIC MAINTENANCE IMMUNOMODULATING TREATMENT

Corticosteroids

Prednisone, the most commonly used agent, leads to remission or marked improvement in 70% to 80% of patients with ocular or generalized myasthenia gravis.³⁵ It may also reduce the progression of ocular myasthenia gravis to the generalized form.³⁶

The effective dose of prednisone depends on the severity and distribution of symptoms. Some patients may need up to 1.0 mg/kg/day (usually 50 to 80 mg per day). In patients with mild to moderate symptoms, a lower maximal dosage such as 20 to 40 mg per day can be sufficient.

Within 1 to 2 weeks after starting high-dose prednisone, up to 50% of patients may develop a transient deterioration, including possible precipitation of a myasthenic crisis.³⁷ For this reason, high-dose prednisone is commonly started only in hospitalized patients who are also receiving plasmapheresis or intravenous immune globulin. Otherwise, an outpatient dose-escalation protocol can be used to achieve a target dose over several weeks.

Prednisone tapering can begin after the patient has been on the maximal dose for 1 to 2 months and significant improvement is evident. A monthly tapering of 5 to 10 mg is preferred, then more slowly after the daily dose reaches 30 mg. The usual maintenance dose averages about 5 mg daily.

Common side effects of prednisone include weight gain, cushingoid features, easy bruising, cataracts, glaucoma, hypertension, diabetes, dyslipidemia, and osteoporosis. Patients are advised to take supplemental calcium (1,500 mg per day) and vitamin D (400 to 800 IU per day). For those most at risk of osteoporosis, treatment with a bisphosphonate should be considered.

Other immunotherapeutic agents are often needed, either to replace the corticosteroid or to permit use of lower doses of it. Because of their delayed onset of action, starting such corticosteroid-sparing agents early in the course is often necessary. These agents are often initially combined with high-dose prednisone, with an eventual goal of weaning off prednisone entirely. This strategy offers the advantage of relatively rapid induction while avoiding the long-term adverse effects of corticosteroid treatment.

Azathioprine

Azathioprine doesn’t begin to show a beneficial effect in myasthenia gravis for 6 to 12 months, and it often reaches its maximal efficacy only after 1 to 2 years of treatment.³⁸

In a study of 78 myasthenia gravis patients, 91% improved when treated with azathioprine alone or together with prednisone.³⁹ In another study using azathioprine and prednisolone for generalized myasthenia gravis, nearly two-thirds of patients came off prednisolone while maintaining remission for 3 years.³⁸

A typical maintenance dose is 2 to 3 mg/kg/day. Common side effects are nausea, vomiting, and malaise. Less frequent side effects include hematologic abnormalities, abnormal liver function, and pancreatitis. Monthly monitoring of complete blood cell counts and liver function tests is warranted for the first 6 months, then less often.

One in 300 people in the general population is homozygous for a mutant allele in the thiopurine methyltransferase (TPMT) gene. Patients with this genotype should not receive azathioprine because of the risk of life-threatening bone marrow suppression.⁴⁰ A slightly increased risk of various forms of lymphoma has been documented.⁴¹

A well-tolerated medication with few side effects, mycophenolate mofetil is being used more in myasthenia gravis. The results of two recent randomized trials suggested that it is not effective in improving myasthenia gravis symptoms or sparing prednisone dosage when used for 90 days or 36 weeks.^42,43 However, extensive clinical experience supports its longterm efficacy in myasthenia gravis.

In a retrospective study of 85 patients with generalized myasthenia gravis, mycophenolate at doses of 1 to 3 g daily improved symptoms in 73% and produced remission in 50%. Steroid dosage was reduced in 71% of patients.⁴⁴

Another retrospective study, with 102 patients, verified a slow development of clinical benefit after months of mycophenolate therapy alone or in combination with prednisone. Approximately 50% of patients achieved a minimal manifestation status after 6 to 12 months of mycophenolate treatment. Eventually, at 24 months of treatment, 80% of patients had a desirable outcome of minimal clinical manifestation or better, 55% of patients were able to come off prednisone entirely, and 75% were taking less than 7.5 mg of prednisone per day.⁴⁵

Common side effects of mycophenolate include nausea, diarrhea, and infections such as urinary tract infections and herpes reactivation. The complete blood cell count needs to be monitored frequently during the first 6 months of therapy. Leukopenia can occur but rarely necessitates stopping mycophenolate. Long-term safety data are lacking, but so far there has been no clearly increased risk of malignancy.

Mycophenolate exposure in pregnancy results in a high incidence of major fetal malformations. Therefore, its use in pregnant patients is discouraged, and women of child-bearing age should use effective contraception.⁴⁶

Cyclosporine

A randomized trial in a small number of patients suggested that cyclosporine is fairly effective as monotherapy.⁴⁷ Its onset of action in myasthenia gravis is faster than that of other corticosteroid-sparing agents, and clinical benefit can often be observed as early as 1 to 2 months. A dose of 5 mg/kg/day and a maintenance serum level of 100 to 150 ng/mL are generally recommended. However, renal, hepatic, and hematologic toxicities and interactions with other medications make cyclosporine a less attractive choice.

Methotrexate

A randomized trial evaluated the utility of methotrexate as a steroid-sparing agent compared with azathioprine.⁴⁸ At 24 months, its steroid-sparing effect was similar to that of azathioprine, and the prednisone dosage had been reduced in more than 50% of patients.

Another phase II trial studying the efficacy of methotrexate in myasthenia gravis is under way.⁴⁹

Rituximab

Rituximab is a monoclonal antibody against B-cell membrane marker CD20. A growing number of case series support its efficacy in patients with severe generalized myasthenia gravis refractory to multiple immunosuppressants.^16,50 It seems particularly effective for MuSK antibody-positive disease, reducing MuSK antibody titers and having a treatment effect that lasts for years.

The standard dosage is 375 mg/m² per week for 4 consecutive weeks. Peripheral B cells tend to be depleted within 2 weeks after the first infusion, while T-cell populations remain unchanged.⁵⁰

A minimal infusion reaction such as flushing and chills can be seen with the first infusion. Patients may be more susceptible to certain infections such as reactivation of herpes zoster, but overall rituximab is well tolerated. Rare cases of progressive multifocal leukoencephalopathy have been reported in patients taking it, but none have occurred so far in myasthenia gravis treatment.

Cyclophosphamide

Cyclophosphamide is an alkylating agent that reduces proliferation of both B and T cells. It can be effective in myasthenia gravis, but potentially serious side effects limit its use. It should be reserved for the small percentage of cases that are refractory to other immunotherapies.

Thymectomy

Surgical treatment should be considered for patients with thymoma. If the tumor cannot be surgically resected, chemoradiotherapy can be considered for relief of myasthenic symptoms and for prevention of local invasion.

Thymomas recur in a minority of patients many years after the initial resection, sometimes without myasthenia gravis symptoms. A recurrence of symptoms does not necessarily indicate a recurrence of thymoma. The lack of correlation between myasthenia gravis symptoms and thymoma recurrence highlights the importance of radiologic follow-up in these patients.

For patients without thymoma, many experts believe that thymectomy is beneficial in patients under age 60 who have generalized myasthenia gravis. The likelihood of medication-free remission is about twice as high, and the likelihood of becoming asymptomatic is about one and a half times higher after thymectomy.⁵¹ However, it takes up to several years for the benefits of thymectomy to manifest, and thymectomy does not guarantee protection from developing AChR antibody-positive myasthenia gravis in the future.

The optimal timing of thymectomy is not well established; however, the procedure is usually recommended within the first 3 years of diagnosis.⁵² The response rates from thymectomy are similar for AChR antibody-positive and seronegative patients. In general, thymectomy for MuSK antibody-positive patients has not been effective, and its role in ocular myasthenia gravis is unclear.^2,53

A woman in her 50s underwent hysterectomy performed by a surgeon, who then assigned an ObGyn to her follow-up care. The day after surgery, the patient had severe abdominal pain with decreased blood pressure and increased heart and respiration rates. The ObGyn admitted the patient to the intensive care unit (ICU), and then designated Dr. A, the patient’s family practitioner to continue her care. Dr. A was not available, so his associate, Dr. B, took over. Over the phone, Dr. B requested pulmonary, cardiology, and infectious disease consults. In the ICU the next day, the patient suffered respiratory arrest and was intubated. When her abdomen became rigid and swollen, emergency surgery revealed that a colon perforation had allowed fecal matter to reach the abdominal cavity. The woman died the next day from complications of sepsis, peritonitis, and multiple organ failure.

ESTATE’S CLAIM None of the physicians assigned to her care ever saw the patient in the ICU. Earlier surgery could have prevented her death. The physicians involved in her care failed to communicate with each other properly.

DEFENDANTS’ DEFENSE The case was settled during the trial.

VERDICT A $3.2 million Illinois settlement was reached with the hospital.

BOTH PARENTS HAD PLATELET ANTIBODIES
When a 32-year-old woman became pregnant with her third child, she sought treatment at a clinic. The mother informed the nurse practi-tioner that her two other children had been diagnosed with low platelets at birth, but they were now healthy and had no further problems.

The woman gave birth vaginally to her third child at term. The newborn had Apgar scores of 8 and 8, at 1 and 5 minutes, respectively. However, the child’s platelet level was 26 x 103/µL. The baby was transferred to another hospital the next day, where he was diagnosed with hydrocephalus and neonatal alloimmune thrombocytopenia. He suffered a massive intracranial hemorrhage, which caused severe neurologic injuries and brain damage. A shunt was placed. The child has significant cognitive deficits as well as cerebral palsy with mild developmental delays. Testing showed that each parent had a different genotype for platelet antibodies.

PARENTS’ CLAIM The parents should have been tested for platelet antibodies prior to this birth due to the family’s history. A prenatal diagnosis of neonatal alloimmune thrombocytopenia would have allowed for treatment with gamma globulin, which could have avoided the intracranial hemorrhage.

DEFENDANTS’ DEFENSE The case was settled during the trial.  

VERDICT A $4.8 million California settlement was reached.

CORD PROLAPSE NOT CARED FOR IN AMBULANCE
At 36 weeks’ gestation, a mother called an ambulance when her membranes ruptured and she noticed an umbilical cord prolapse.

The child was in a breech presentation, experienced oxygen deprivation, and sustained severe neurologic damage.

PARENTS’ CLAIM The ambulance service was negligent in its care. The ambulance service dispatcher advised the mother to stand, squat, and push before the ambulance arrived. The ambulance attendants failed to take basic actions to relieve pressure on the prolapsed umbilical cord. The ambulance did not stop at two closer hospitals, which delayed arrival for an additional 20 minutes.

DEFENDANTS’ DEFENSE The case was settled during the trial.

VERDICT A $2.7 million settlement was reached, but before it was submitted to the court for approval, the child died. The defendants then sought to revoke the settlement, but the parents claimed breach of contract. The defendants claimed that the agreement was orally negotiated independent of defense counsel and was unenforceable due to the child’s death and lack of court approval. A Texas judge issued summary judgment on breach of contract and awarded $2.7 million plus $40,000 in attorney fees to the parents.    

SECOND- AND THIRD-DEGREE BURNS TO PERINEUM
A mother received an epidural injection during vaginal delivery. Six hours later, the patient asked a nurse for a warm compress to place on her perineum. The nurse heated the compress in a microwave and then applied it to the perineal area. The compress caused second- and third-degree burns to the patient’s labia and inner left thigh. She underwent surgical repair of the burned area, and, a year later, had plastic surgery.

PATIENT’S CLAIM The nurse was negligent in overheating the compress.

DEFENDANTS’ DEFENSE The hospital agreed that the nurse who heated and applied the compress had been negligent. The hospital paid all medical expenses relating to the burns, including follow-up surgeries. 

VERDICT A $190,000 Utah verdict was returned for noneconomic damages.

DOCUMENTATION MAKES A DIFFERENCE FOR OBGYN AFTER CHILD DIES
A 30-year-old physician was pregnant with her first child. Due to a low amniotic fluid index and lagging fetal growth, she saw a maternal-fetal medicine specialist, who suggested labor induction at 39 weeks.

Labor progressed slowly. After three attempts at vacuum-assisted delivery, the ObGyn recommended cesarean delivery. The parents eventually consented to cesarean delivery after another failed vacuum-assisted attempt. Although the ObGyn had recommended cesarean 2 hours earlier, surgery was not ordered on an emergent basis.

At birth, the baby’s resuscitation took more than 20 minutes. The child lost nearly one-third of her blood volume; she had a subgaleal hemorrhage. Both parties agreed that the vacuum device probably caused the bleeding.

The child had hypoxic ischemic encephalopathy and disseminated intravascular coagulation. She suffered a myocardial infarction at 3 days of age. Without electrical brain activity, life support was removed, and the child died at 5 days of age. An autopsy found possible hypereosinophilic syndrome as the concurrent cause of death.

PARENTS’ CLAIM The mother claimed she was not informed of the risks, benefits, and alternatives to vacuum extraction; she would not have consented had she known the risks. The mother, her husband, and two family members maintained that the ObGyn offered the possibility of cesarean delivery as a question, but did not insist on it. The mother claimed she wanted what was best for the baby, and never refused a cesarean. The resuscitation efforts caused eosinophilic infiltration into several organs.

PHYSICIAN’S DEFENSE The ObGyn charted that the parents were “adamant about having a vaginal delivery,” and said she told the parents what she charted. The obstetric nurse testified that the mother delayed consent because she felt vaginal delivery was imminent. The ObGyn acted properly; eosinophilia caused the baby’s death.  

VERDICT An Illinois defense verdict was returned.

HIGH BP TO BLAME FOR DEATHS OF BOTH MOTHER AND CHILD
A 23-year-old woman’s pregnancy was at high risk because of very high blood pressure (BP). At 34 weeks’ gestation, she went to a county hospital with symptoms of high BP; she was treated and discharged 3 days later. She returned to the hospital to be checked twice more within a month. The day after the third visit, she suffered a seizure and was taken to a university hospital, where emergency cesarean delivery was performed. The mother died from an aortic rupture during delivery.

The child was born with brain injuries and died at age 4 years due to neurologic complications.

ESTATE’S CLAIM The mother was not properly treated at the county hospital, resulting in both deaths; she should not have been discharged. Under monitoring, she would have undergone delivery before the aortic rupture occurred, avoiding the baby’s brain injury.

DEFENDANTS’ DEFENSE The mother was stable when released; aortic rupture is unpredictable and unpreventable, and would have occurred under any circumstances. It is highly unusual that a woman of her age would have an aortic rupture.

VERDICT A $3,062,803 California verdict was returned. The parties then settled for $1,782,000 (with the county assuming the medical lien).

NECROTIZING FASCIITIS FROM PERFORATED COLON
A woman underwent laparoscopic-assisted vaginal hysterectomy performed by her ObGyn, and was discharged after 3 days. The next day, she went to another hospital’s emergency department (ED) with abdominal distention and rigidity, severe abdominal pain, and vomiting. She had a toxic appearance, rapid pulse rate, and hypotension. In emergency surgery, several liters of dark brown, foul-smelling fluid were found in her abdomen, and feculent peritonitis and necrotizing fasciitis were diagnosed due to a perforated sigmoid colon. She required multiple hospitalizations and operations.

PATIENT’S CLAIM Perforation occur­red during hysterectomy. The ObGyn failed to recognize the injury prior to discharge. The hospital staff did not properly assess her or communicate her symptoms to the ObGyn.

DEFENDANTS’ DEFENSE There was no negligence; proper care was given.

VERDICT A $2,922,503 Florida verdict was returned, with the jury finding the ObGyn 30% at fault and the hospital 70% at fault.

FAILURE TO REACT TO FETAL DISTRESS: $15.6M
After delivery at full term, a child suffered convulsions and seizures on her second day of life. A CT scan showed brain injuries. At age 11 years, she has severe learning and developmental delays, and requires 24-hour care.

PARENTS’ CLAIM Severe decelerations with slow return to baseline occurred several times during labor and delivery. The nurse midwife failed to recognize and react to fetal distress. A cesarean delivery should have been performed instead of a vaginal delivery. The delay in delivery caused the child’s injuries.

DEFENDANTS’ DEFENSE A prenatal neurogenetic disorder caused the child’s injuries. 

VERDICT A $15.6 million Maryland verdict was returned. It will not be automatically reduced; the awarded noneconomic damages do not exceed the state cap.

LATE DELIVERY; SEVERE INJURY TO CHILD
At 40 weeks’ gestation, a woman was admitted to the hospital in labor. When the mother’s membranes were ruptured, a small amount of meconium was noted, but the fetal monitor strips were reassuring. Two hours later, the nurse and midwife noted a pattern of decelerations, but they felt the pattern was nonrepetitive and reactive. Thirty minutes later, the nurse and midwife noted decelerations to 90 bpm with pushing, but did not call a physician.

Another midwife arrived to assist the first midwife who was new to practice. The mother was given oxygen, her position was changed, and an IV fluid bolus was administered. Thirty minutes later, the nurses recognized late decelerations and called a Code White twice while the fetal heart rate continued to decelerate. After the attending physician unsuccessfully attempted vacuum extraction, an emergency cesarean delivery was performed.

The child’s Apgar scores were 2, 3, and 3, at 1, 5, and 10 minutes, respectively. The cord blood pH was 6.66, indicating severe metabolic acidosis. She developed seizures within the first few minutes of life. Imaging studies showed global hypoxic ischemic encephalopathy. The child cannot walk, talk, or sit up unsupported at age 8, and requires a G-tube. She is cortically blind and requires antiseizure medication.

PARENTS’ CLAIM The nurse, two midwives, and physician were negligent in their care of the mother and child.

DEFENDANTS’ DEFENSE The case was settled during the trial.  

VERDICT A $5 million Massachusetts settlement was reached.

WHAT CAUSED INFECTION AFTER ABORTION?
A 20-year-old woman underwent a surgical termination of pregnancy performed by an ObGyn. After discharge, the patient developed pain and other complications requiring rehospitalization and additional surgery for a pelvic infection.

PATIENT’S CLAIM Complications were due to a uterine perforation that spontaneously sealed before it could be detected. The ObGyn was negligent in the performance of the elective abortion. The patient has a large scar on her abdomen because of the additional operation.

PHYSICIAN’S DEFENSE Perforation of the uterus is a known complication of the procedure. However, no perforation occurred; it was not found on imaging, and spontaneous sealing of a perforation cannot occur. The patient’s complications were due to a subclinical infection that was activated by the surgery.  

VERDICT A New York defense verdict was returned.

We want to hear from you. Tell us what you think!

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

A woman in her 50s underwent hysterectomy performed by a surgeon, who then assigned an ObGyn to her follow-up care. The day after surgery, the patient had severe abdominal pain with decreased blood pressure and increased heart and respiration rates. The ObGyn admitted the patient to the intensive care unit (ICU), and then designated Dr. A, the patient’s family practitioner to continue her care. Dr. A was not available, so his associate, Dr. B, took over. Over the phone, Dr. B requested pulmonary, cardiology, and infectious disease consults. In the ICU the next day, the patient suffered respiratory arrest and was intubated. When her abdomen became rigid and swollen, emergency surgery revealed that a colon perforation had allowed fecal matter to reach the abdominal cavity. The woman died the next day from complications of sepsis, peritonitis, and multiple organ failure.

ESTATE’S CLAIM None of the physicians assigned to her care ever saw the patient in the ICU. Earlier surgery could have prevented her death. The physicians involved in her care failed to communicate with each other properly.

DEFENDANTS’ DEFENSE The case was settled during the trial.

VERDICT A $3.2 million Illinois settlement was reached with the hospital.

BOTH PARENTS HAD PLATELET ANTIBODIES
When a 32-year-old woman became pregnant with her third child, she sought treatment at a clinic. The mother informed the nurse practi-tioner that her two other children had been diagnosed with low platelets at birth, but they were now healthy and had no further problems.

The woman gave birth vaginally to her third child at term. The newborn had Apgar scores of 8 and 8, at 1 and 5 minutes, respectively. However, the child’s platelet level was 26 x 103/µL. The baby was transferred to another hospital the next day, where he was diagnosed with hydrocephalus and neonatal alloimmune thrombocytopenia. He suffered a massive intracranial hemorrhage, which caused severe neurologic injuries and brain damage. A shunt was placed. The child has significant cognitive deficits as well as cerebral palsy with mild developmental delays. Testing showed that each parent had a different genotype for platelet antibodies.

PARENTS’ CLAIM The parents should have been tested for platelet antibodies prior to this birth due to the family’s history. A prenatal diagnosis of neonatal alloimmune thrombocytopenia would have allowed for treatment with gamma globulin, which could have avoided the intracranial hemorrhage.

DEFENDANTS’ DEFENSE The case was settled during the trial.  

VERDICT A $4.8 million California settlement was reached.

CORD PROLAPSE NOT CARED FOR IN AMBULANCE
At 36 weeks’ gestation, a mother called an ambulance when her membranes ruptured and she noticed an umbilical cord prolapse.

The child was in a breech presentation, experienced oxygen deprivation, and sustained severe neurologic damage.

PARENTS’ CLAIM The ambulance service was negligent in its care. The ambulance service dispatcher advised the mother to stand, squat, and push before the ambulance arrived. The ambulance attendants failed to take basic actions to relieve pressure on the prolapsed umbilical cord. The ambulance did not stop at two closer hospitals, which delayed arrival for an additional 20 minutes.

DEFENDANTS’ DEFENSE The case was settled during the trial.

VERDICT A $2.7 million settlement was reached, but before it was submitted to the court for approval, the child died. The defendants then sought to revoke the settlement, but the parents claimed breach of contract. The defendants claimed that the agreement was orally negotiated independent of defense counsel and was unenforceable due to the child’s death and lack of court approval. A Texas judge issued summary judgment on breach of contract and awarded $2.7 million plus $40,000 in attorney fees to the parents.    

SECOND- AND THIRD-DEGREE BURNS TO PERINEUM
A mother received an epidural injection during vaginal delivery. Six hours later, the patient asked a nurse for a warm compress to place on her perineum. The nurse heated the compress in a microwave and then applied it to the perineal area. The compress caused second- and third-degree burns to the patient’s labia and inner left thigh. She underwent surgical repair of the burned area, and, a year later, had plastic surgery.

PATIENT’S CLAIM The nurse was negligent in overheating the compress.

DEFENDANTS’ DEFENSE The hospital agreed that the nurse who heated and applied the compress had been negligent. The hospital paid all medical expenses relating to the burns, including follow-up surgeries. 

VERDICT A $190,000 Utah verdict was returned for noneconomic damages.

DOCUMENTATION MAKES A DIFFERENCE FOR OBGYN AFTER CHILD DIES
A 30-year-old physician was pregnant with her first child. Due to a low amniotic fluid index and lagging fetal growth, she saw a maternal-fetal medicine specialist, who suggested labor induction at 39 weeks.

Labor progressed slowly. After three attempts at vacuum-assisted delivery, the ObGyn recommended cesarean delivery. The parents eventually consented to cesarean delivery after another failed vacuum-assisted attempt. Although the ObGyn had recommended cesarean 2 hours earlier, surgery was not ordered on an emergent basis.

At birth, the baby’s resuscitation took more than 20 minutes. The child lost nearly one-third of her blood volume; she had a subgaleal hemorrhage. Both parties agreed that the vacuum device probably caused the bleeding.

The child had hypoxic ischemic encephalopathy and disseminated intravascular coagulation. She suffered a myocardial infarction at 3 days of age. Without electrical brain activity, life support was removed, and the child died at 5 days of age. An autopsy found possible hypereosinophilic syndrome as the concurrent cause of death.

PARENTS’ CLAIM The mother claimed she was not informed of the risks, benefits, and alternatives to vacuum extraction; she would not have consented had she known the risks. The mother, her husband, and two family members maintained that the ObGyn offered the possibility of cesarean delivery as a question, but did not insist on it. The mother claimed she wanted what was best for the baby, and never refused a cesarean. The resuscitation efforts caused eosinophilic infiltration into several organs.

PHYSICIAN’S DEFENSE The ObGyn charted that the parents were “adamant about having a vaginal delivery,” and said she told the parents what she charted. The obstetric nurse testified that the mother delayed consent because she felt vaginal delivery was imminent. The ObGyn acted properly; eosinophilia caused the baby’s death.  

VERDICT An Illinois defense verdict was returned.

HIGH BP TO BLAME FOR DEATHS OF BOTH MOTHER AND CHILD
A 23-year-old woman’s pregnancy was at high risk because of very high blood pressure (BP). At 34 weeks’ gestation, she went to a county hospital with symptoms of high BP; she was treated and discharged 3 days later. She returned to the hospital to be checked twice more within a month. The day after the third visit, she suffered a seizure and was taken to a university hospital, where emergency cesarean delivery was performed. The mother died from an aortic rupture during delivery.

The child was born with brain injuries and died at age 4 years due to neurologic complications.

ESTATE’S CLAIM The mother was not properly treated at the county hospital, resulting in both deaths; she should not have been discharged. Under monitoring, she would have undergone delivery before the aortic rupture occurred, avoiding the baby’s brain injury.

DEFENDANTS’ DEFENSE The mother was stable when released; aortic rupture is unpredictable and unpreventable, and would have occurred under any circumstances. It is highly unusual that a woman of her age would have an aortic rupture.

VERDICT A $3,062,803 California verdict was returned. The parties then settled for $1,782,000 (with the county assuming the medical lien).

NECROTIZING FASCIITIS FROM PERFORATED COLON
A woman underwent laparoscopic-assisted vaginal hysterectomy performed by her ObGyn, and was discharged after 3 days. The next day, she went to another hospital’s emergency department (ED) with abdominal distention and rigidity, severe abdominal pain, and vomiting. She had a toxic appearance, rapid pulse rate, and hypotension. In emergency surgery, several liters of dark brown, foul-smelling fluid were found in her abdomen, and feculent peritonitis and necrotizing fasciitis were diagnosed due to a perforated sigmoid colon. She required multiple hospitalizations and operations.

PATIENT’S CLAIM Perforation occur­red during hysterectomy. The ObGyn failed to recognize the injury prior to discharge. The hospital staff did not properly assess her or communicate her symptoms to the ObGyn.

DEFENDANTS’ DEFENSE There was no negligence; proper care was given.

VERDICT A $2,922,503 Florida verdict was returned, with the jury finding the ObGyn 30% at fault and the hospital 70% at fault.

FAILURE TO REACT TO FETAL DISTRESS: $15.6M
After delivery at full term, a child suffered convulsions and seizures on her second day of life. A CT scan showed brain injuries. At age 11 years, she has severe learning and developmental delays, and requires 24-hour care.

PARENTS’ CLAIM Severe decelerations with slow return to baseline occurred several times during labor and delivery. The nurse midwife failed to recognize and react to fetal distress. A cesarean delivery should have been performed instead of a vaginal delivery. The delay in delivery caused the child’s injuries.

DEFENDANTS’ DEFENSE A prenatal neurogenetic disorder caused the child’s injuries. 

VERDICT A $15.6 million Maryland verdict was returned. It will not be automatically reduced; the awarded noneconomic damages do not exceed the state cap.

LATE DELIVERY; SEVERE INJURY TO CHILD
At 40 weeks’ gestation, a woman was admitted to the hospital in labor. When the mother’s membranes were ruptured, a small amount of meconium was noted, but the fetal monitor strips were reassuring. Two hours later, the nurse and midwife noted a pattern of decelerations, but they felt the pattern was nonrepetitive and reactive. Thirty minutes later, the nurse and midwife noted decelerations to 90 bpm with pushing, but did not call a physician.

Another midwife arrived to assist the first midwife who was new to practice. The mother was given oxygen, her position was changed, and an IV fluid bolus was administered. Thirty minutes later, the nurses recognized late decelerations and called a Code White twice while the fetal heart rate continued to decelerate. After the attending physician unsuccessfully attempted vacuum extraction, an emergency cesarean delivery was performed.

The child’s Apgar scores were 2, 3, and 3, at 1, 5, and 10 minutes, respectively. The cord blood pH was 6.66, indicating severe metabolic acidosis. She developed seizures within the first few minutes of life. Imaging studies showed global hypoxic ischemic encephalopathy. The child cannot walk, talk, or sit up unsupported at age 8, and requires a G-tube. She is cortically blind and requires antiseizure medication.

PARENTS’ CLAIM The nurse, two midwives, and physician were negligent in their care of the mother and child.

DEFENDANTS’ DEFENSE The case was settled during the trial.  

VERDICT A $5 million Massachusetts settlement was reached.

WHAT CAUSED INFECTION AFTER ABORTION?
A 20-year-old woman underwent a surgical termination of pregnancy performed by an ObGyn. After discharge, the patient developed pain and other complications requiring rehospitalization and additional surgery for a pelvic infection.

PATIENT’S CLAIM Complications were due to a uterine perforation that spontaneously sealed before it could be detected. The ObGyn was negligent in the performance of the elective abortion. The patient has a large scar on her abdomen because of the additional operation.

PHYSICIAN’S DEFENSE Perforation of the uterus is a known complication of the procedure. However, no perforation occurred; it was not found on imaging, and spontaneous sealing of a perforation cannot occur. The patient’s complications were due to a subclinical infection that was activated by the surgery.  

VERDICT A New York defense verdict was returned.

We want to hear from you. Tell us what you think!

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

A woman in her 50s underwent hysterectomy performed by a surgeon, who then assigned an ObGyn to her follow-up care. The day after surgery, the patient had severe abdominal pain with decreased blood pressure and increased heart and respiration rates. The ObGyn admitted the patient to the intensive care unit (ICU), and then designated Dr. A, the patient’s family practitioner to continue her care. Dr. A was not available, so his associate, Dr. B, took over. Over the phone, Dr. B requested pulmonary, cardiology, and infectious disease consults. In the ICU the next day, the patient suffered respiratory arrest and was intubated. When her abdomen became rigid and swollen, emergency surgery revealed that a colon perforation had allowed fecal matter to reach the abdominal cavity. The woman died the next day from complications of sepsis, peritonitis, and multiple organ failure.

ESTATE’S CLAIM None of the physicians assigned to her care ever saw the patient in the ICU. Earlier surgery could have prevented her death. The physicians involved in her care failed to communicate with each other properly.

DEFENDANTS’ DEFENSE The case was settled during the trial.

VERDICT A $3.2 million Illinois settlement was reached with the hospital.

BOTH PARENTS HAD PLATELET ANTIBODIES
When a 32-year-old woman became pregnant with her third child, she sought treatment at a clinic. The mother informed the nurse practi-tioner that her two other children had been diagnosed with low platelets at birth, but they were now healthy and had no further problems.

The woman gave birth vaginally to her third child at term. The newborn had Apgar scores of 8 and 8, at 1 and 5 minutes, respectively. However, the child’s platelet level was 26 x 103/µL. The baby was transferred to another hospital the next day, where he was diagnosed with hydrocephalus and neonatal alloimmune thrombocytopenia. He suffered a massive intracranial hemorrhage, which caused severe neurologic injuries and brain damage. A shunt was placed. The child has significant cognitive deficits as well as cerebral palsy with mild developmental delays. Testing showed that each parent had a different genotype for platelet antibodies.

PARENTS’ CLAIM The parents should have been tested for platelet antibodies prior to this birth due to the family’s history. A prenatal diagnosis of neonatal alloimmune thrombocytopenia would have allowed for treatment with gamma globulin, which could have avoided the intracranial hemorrhage.

DEFENDANTS’ DEFENSE The case was settled during the trial.  

VERDICT A $4.8 million California settlement was reached.

CORD PROLAPSE NOT CARED FOR IN AMBULANCE
At 36 weeks’ gestation, a mother called an ambulance when her membranes ruptured and she noticed an umbilical cord prolapse.

The child was in a breech presentation, experienced oxygen deprivation, and sustained severe neurologic damage.

PARENTS’ CLAIM The ambulance service was negligent in its care. The ambulance service dispatcher advised the mother to stand, squat, and push before the ambulance arrived. The ambulance attendants failed to take basic actions to relieve pressure on the prolapsed umbilical cord. The ambulance did not stop at two closer hospitals, which delayed arrival for an additional 20 minutes.

DEFENDANTS’ DEFENSE The case was settled during the trial.

VERDICT A $2.7 million settlement was reached, but before it was submitted to the court for approval, the child died. The defendants then sought to revoke the settlement, but the parents claimed breach of contract. The defendants claimed that the agreement was orally negotiated independent of defense counsel and was unenforceable due to the child’s death and lack of court approval. A Texas judge issued summary judgment on breach of contract and awarded $2.7 million plus $40,000 in attorney fees to the parents.    

SECOND- AND THIRD-DEGREE BURNS TO PERINEUM
A mother received an epidural injection during vaginal delivery. Six hours later, the patient asked a nurse for a warm compress to place on her perineum. The nurse heated the compress in a microwave and then applied it to the perineal area. The compress caused second- and third-degree burns to the patient’s labia and inner left thigh. She underwent surgical repair of the burned area, and, a year later, had plastic surgery.

PATIENT’S CLAIM The nurse was negligent in overheating the compress.

DEFENDANTS’ DEFENSE The hospital agreed that the nurse who heated and applied the compress had been negligent. The hospital paid all medical expenses relating to the burns, including follow-up surgeries. 

VERDICT A $190,000 Utah verdict was returned for noneconomic damages.

DOCUMENTATION MAKES A DIFFERENCE FOR OBGYN AFTER CHILD DIES
A 30-year-old physician was pregnant with her first child. Due to a low amniotic fluid index and lagging fetal growth, she saw a maternal-fetal medicine specialist, who suggested labor induction at 39 weeks.

Labor progressed slowly. After three attempts at vacuum-assisted delivery, the ObGyn recommended cesarean delivery. The parents eventually consented to cesarean delivery after another failed vacuum-assisted attempt. Although the ObGyn had recommended cesarean 2 hours earlier, surgery was not ordered on an emergent basis.

At birth, the baby’s resuscitation took more than 20 minutes. The child lost nearly one-third of her blood volume; she had a subgaleal hemorrhage. Both parties agreed that the vacuum device probably caused the bleeding.

The child had hypoxic ischemic encephalopathy and disseminated intravascular coagulation. She suffered a myocardial infarction at 3 days of age. Without electrical brain activity, life support was removed, and the child died at 5 days of age. An autopsy found possible hypereosinophilic syndrome as the concurrent cause of death.

PARENTS’ CLAIM The mother claimed she was not informed of the risks, benefits, and alternatives to vacuum extraction; she would not have consented had she known the risks. The mother, her husband, and two family members maintained that the ObGyn offered the possibility of cesarean delivery as a question, but did not insist on it. The mother claimed she wanted what was best for the baby, and never refused a cesarean. The resuscitation efforts caused eosinophilic infiltration into several organs.

PHYSICIAN’S DEFENSE The ObGyn charted that the parents were “adamant about having a vaginal delivery,” and said she told the parents what she charted. The obstetric nurse testified that the mother delayed consent because she felt vaginal delivery was imminent. The ObGyn acted properly; eosinophilia caused the baby’s death.  

VERDICT An Illinois defense verdict was returned.

HIGH BP TO BLAME FOR DEATHS OF BOTH MOTHER AND CHILD
A 23-year-old woman’s pregnancy was at high risk because of very high blood pressure (BP). At 34 weeks’ gestation, she went to a county hospital with symptoms of high BP; she was treated and discharged 3 days later. She returned to the hospital to be checked twice more within a month. The day after the third visit, she suffered a seizure and was taken to a university hospital, where emergency cesarean delivery was performed. The mother died from an aortic rupture during delivery.

The child was born with brain injuries and died at age 4 years due to neurologic complications.

ESTATE’S CLAIM The mother was not properly treated at the county hospital, resulting in both deaths; she should not have been discharged. Under monitoring, she would have undergone delivery before the aortic rupture occurred, avoiding the baby’s brain injury.

DEFENDANTS’ DEFENSE The mother was stable when released; aortic rupture is unpredictable and unpreventable, and would have occurred under any circumstances. It is highly unusual that a woman of her age would have an aortic rupture.

VERDICT A $3,062,803 California verdict was returned. The parties then settled for $1,782,000 (with the county assuming the medical lien).

NECROTIZING FASCIITIS FROM PERFORATED COLON
A woman underwent laparoscopic-assisted vaginal hysterectomy performed by her ObGyn, and was discharged after 3 days. The next day, she went to another hospital’s emergency department (ED) with abdominal distention and rigidity, severe abdominal pain, and vomiting. She had a toxic appearance, rapid pulse rate, and hypotension. In emergency surgery, several liters of dark brown, foul-smelling fluid were found in her abdomen, and feculent peritonitis and necrotizing fasciitis were diagnosed due to a perforated sigmoid colon. She required multiple hospitalizations and operations.

PATIENT’S CLAIM Perforation occur­red during hysterectomy. The ObGyn failed to recognize the injury prior to discharge. The hospital staff did not properly assess her or communicate her symptoms to the ObGyn.

DEFENDANTS’ DEFENSE There was no negligence; proper care was given.

VERDICT A $2,922,503 Florida verdict was returned, with the jury finding the ObGyn 30% at fault and the hospital 70% at fault.

FAILURE TO REACT TO FETAL DISTRESS: $15.6M
After delivery at full term, a child suffered convulsions and seizures on her second day of life. A CT scan showed brain injuries. At age 11 years, she has severe learning and developmental delays, and requires 24-hour care.

PARENTS’ CLAIM Severe decelerations with slow return to baseline occurred several times during labor and delivery. The nurse midwife failed to recognize and react to fetal distress. A cesarean delivery should have been performed instead of a vaginal delivery. The delay in delivery caused the child’s injuries.

DEFENDANTS’ DEFENSE A prenatal neurogenetic disorder caused the child’s injuries. 

VERDICT A $15.6 million Maryland verdict was returned. It will not be automatically reduced; the awarded noneconomic damages do not exceed the state cap.

LATE DELIVERY; SEVERE INJURY TO CHILD
At 40 weeks’ gestation, a woman was admitted to the hospital in labor. When the mother’s membranes were ruptured, a small amount of meconium was noted, but the fetal monitor strips were reassuring. Two hours later, the nurse and midwife noted a pattern of decelerations, but they felt the pattern was nonrepetitive and reactive. Thirty minutes later, the nurse and midwife noted decelerations to 90 bpm with pushing, but did not call a physician.

Another midwife arrived to assist the first midwife who was new to practice. The mother was given oxygen, her position was changed, and an IV fluid bolus was administered. Thirty minutes later, the nurses recognized late decelerations and called a Code White twice while the fetal heart rate continued to decelerate. After the attending physician unsuccessfully attempted vacuum extraction, an emergency cesarean delivery was performed.

The child’s Apgar scores were 2, 3, and 3, at 1, 5, and 10 minutes, respectively. The cord blood pH was 6.66, indicating severe metabolic acidosis. She developed seizures within the first few minutes of life. Imaging studies showed global hypoxic ischemic encephalopathy. The child cannot walk, talk, or sit up unsupported at age 8, and requires a G-tube. She is cortically blind and requires antiseizure medication.

PARENTS’ CLAIM The nurse, two midwives, and physician were negligent in their care of the mother and child.

DEFENDANTS’ DEFENSE The case was settled during the trial.  

VERDICT A $5 million Massachusetts settlement was reached.

WHAT CAUSED INFECTION AFTER ABORTION?
A 20-year-old woman underwent a surgical termination of pregnancy performed by an ObGyn. After discharge, the patient developed pain and other complications requiring rehospitalization and additional surgery for a pelvic infection.

PATIENT’S CLAIM Complications were due to a uterine perforation that spontaneously sealed before it could be detected. The ObGyn was negligent in the performance of the elective abortion. The patient has a large scar on her abdomen because of the additional operation.

PHYSICIAN’S DEFENSE Perforation of the uterus is a known complication of the procedure. However, no perforation occurred; it was not found on imaging, and spontaneous sealing of a perforation cannot occur. The patient’s complications were due to a subclinical infection that was activated by the surgery.  

VERDICT A New York defense verdict was returned.

We want to hear from you. Tell us what you think!

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.